WO1999042453A1 - 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists - Google Patents

5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists Download PDF

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Publication number
WO1999042453A1
WO1999042453A1 PCT/EP1999/000776 EP9900776W WO9942453A1 WO 1999042453 A1 WO1999042453 A1 WO 1999042453A1 EP 9900776 W EP9900776 W EP 9900776W WO 9942453 A1 WO9942453 A1 WO 9942453A1
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alkyl
phenyl
ome
alkoxy
halogen
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PCT/EP1999/000776
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German (de)
French (fr)
Inventor
Wilhelm Amberg
Rolf Jansen
Andreas Kling
Dagmar Klinge
Hartmut Riechers
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Basf Aktiengesellschaft
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Priority to HU0100957A priority Critical patent/HUP0100957A3/en
Priority to AU30271/99A priority patent/AU3027199A/en
Priority to JP2000532405A priority patent/JP2002503726A/en
Priority to BR9907911-9A priority patent/BR9907911A/en
Priority to PL99342311A priority patent/PL342311A1/en
Priority to CA002321182A priority patent/CA2321182A1/en
Priority to SK1151-2000A priority patent/SK11512000A3/en
Priority to IL13703899A priority patent/IL137038A0/en
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to KR1020007008925A priority patent/KR20010086247A/en
Priority to EP99911657A priority patent/EP1066268A1/en
Publication of WO1999042453A1 publication Critical patent/WO1999042453A1/en
Priority to BG104577A priority patent/BG104577A/en
Priority to NO20004075A priority patent/NO20004075D0/en
Priority to HR20000602A priority patent/HRP20000602A2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new carboxylic acid derivatives with 5-substituted pyrimidine ring, their preparation and use.
  • Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3.
  • endothelin or "ET” means one or all isoforms of endothelin.
  • Endothelin is a potent vasoconstrictor and 5 has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2., 207 (1990), J. Am. Med. As- sociation 2FJ .. 2868 (1990) Nature ll !, 114 (1990) N. Engl. J. Med 0. 122nd, 205 (1989) N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 3_4f 732 (1990)). Therefore substances that inhibit the binding of endothelin to one or both receptors should antagonize physiological effects of endothelin 0 and should therefore be valuable pharmaceuticals.
  • WO 95/26716, WO 96/11914, WO 97/9294, WO 97/12878, WO 97/38980, WO 97/38981 describe carboxylic acid derivatives and their use as endothelin antaganists. These compounds carry an N atom or a group at the 5 position of the heterocycle ⁇
  • the compounds according to the invention have a grouping at this position
  • the compounds according to the invention are distinguished, for example, by more favorable metabolism in the body.
  • the invention relates to carboxylic acid derivatives of the formula I.
  • R 1 stands for tetrazole or for a group
  • Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;
  • R 7 may furthermore be a phenyl radical which an / or from one to five halogen atoms, and carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxyl, Ci-Cj-alkoxy , Mercapto, -CC 4 alkylthio, amino, 5th
  • a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, wel ⁇
  • 10 cher can carry one to two halogen atoms, or one to two C 1 -C 4 alkyl or one to two C ⁇ ⁇ C alkoxy groups.
  • R 9 means:
  • Phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C 4 alkyl, C ⁇ -45 C 4 haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy, C 4 alkylthio , Mercapto, amino, NH (-C 4 alkyl), N (-C 4 alkyl) 2nd 4
  • R 2 is hydrogen, hydroxy, NH 2 , NH (C ⁇ -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 , halogen, C ⁇ -C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 -alkynyl, C ! -C 4 -hydroxyalkyl, C ⁇ -C 4 -haloalkyl, -C-C 4 alkoxy, C ⁇ -C 4 -haloalkoxy or C ⁇ -C 4 alkylthio, morpholine;
  • R 3 is hydrogen, hydroxy, NH 2 , NH (dC -alkyl), N (-C-C-alkyl) 2 , halogen, C ⁇ ⁇ C 4 -alkyl, C 2 -C-alkenyl, C 2 -C 4 -alkynyl, C ⁇ -C 4 hydroxyalkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 logenalkoxy -Ha-, -NH-0-C ⁇ -C 4 -alkyl, C 4 alkylthio;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C ⁇ -C4 ⁇ alkyl, C ⁇ -C4 haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 - Haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C ! -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (-C 4 -C 4 alkyl) 2 ; or
  • Phenyl or naphthyl which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group; or
  • 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 1 -C 4 -alkyl, C 1 -C 4 - Haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ - C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals themselves can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C4 ⁇ alkyl, C ⁇ -C4-haloalkyl, C ⁇ -C 4 -alkoxy, C 4 -haloalkoxy and / or C 1 -C 4 -alkylthio;
  • R 6 is hydrogen
  • C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 8 cycloalkyl it being possible for these radicals to be substituted one or more times by: hydroxy, Mercapto, carboxy, halo 5 gen, nitro, cyano, C ⁇ -C4-alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C ⁇ -C 4 -alkylthio, C--C 4 -haloalkoxy, C ⁇ -C 4 - Alkylcarbonyl, -CC 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino, NH (-C-C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , phenoxy or phenyl, where the said aryl radicals may be mono- or polysubsti
  • Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl,
  • 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 ⁇ -C 4 ⁇ haloalkoxy, C ⁇ -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, -C-C4 alkoxy, C ⁇ -C 4 haloalkoxy and / or C ⁇ ⁇ C 4 alkylthio;
  • R 6 can only be hydrogen if Z is not a single bond
  • R 12 C 1 -C 4 alkyl, -C-C 4 alkylthio, -C ⁇ C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C ⁇ C 4 alkyl), N (-C 1 -C 4 alkyl) 2 , carboxamide or CON (-C 1 -C 4 alkyl) 2 ;
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • An alkaline earth metal is, for example, calcium, magnesium, barium; 6
  • Organic ammonium ions are protonated amines such as e.g. Ethanol laminate, diethanolamine, ethylene diamine, diethylamine or piperazine;
  • C 3 -C 7 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl or cycloheptyl;
  • C 1 -C 4 -Halogenalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 10 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro 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, for example, di- ⁇ fluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, lfluorethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloro-l, 1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • “-C 4 alkyl can be linear or branched such as methyl
  • C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 25 ip r ⁇ pen-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-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C ⁇ -C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • CC 6 -alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C 3 -C 6 ⁇ alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
  • C ⁇ ⁇ C 4 alkylthio can be linear or branched such as methyl thio, ethyl thio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
  • C 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, for example, metoxycarbonyl, 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
  • C ⁇ -C 8 alkyl can be linear or branched such as C 1 -C 4 alkyl, pentyl, hexyl, heptyl or octyl;
  • Halogen is e.g. Fluorine, chlorine, bromine, iodine.
  • the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs).
  • 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, e.g. II and IV, can have one or more asymmetric substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
  • the use of an enantiomerically pure compound as the active ingredient is preferred.
  • 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 endothelin receptors.
  • Compounds of general formula III are either known or can e.g. can be synthesized by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
  • enantiomerically pure compounds of the formula IVa can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IVa.
  • bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
  • R 10 is halogen or R -S0 2 -, where R 11 can be Cx-Cj-alkyl, -CC 4 -haloalkyl or phenyl.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature 9 range from room temperature to the boiling point of the solvent.
  • solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and Trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and Trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert.
  • nitriles such as, for example, acetonitrile and propionitrile
  • acid amides such as, for example, dimethylformamide, dirnethylacetamide 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 an alkali metal such as lithium diisopropylamide
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 represents a group COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
  • Salts can be reacted with many compounds of the formula R 7 -A, where A is a conventional 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 methylsulfo - nyl or another equivalent leaving group.
  • A is a conventional 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 methylsulfo - nyl or another equivalent leaving group.
  • Compounds of the formula R 7 -A with a reactive substituent A are known or can be easily obtained with the general specialist knowledge. This reaction can be carried
  • the use of generally known protective group techniques is necessary to prepare the compounds I according to the invention.
  • the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
  • carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
  • R 2 is hydrogen, hydroxy, N (-CC 4 alkyl) 2 , -C 4 -alkyl, -C-C-haloalkyl-, -C-C4-alkoxy-, -C-C 4 -haloalkoxy-, C 1 -C 4 -Alkylthio, halogen;
  • R 3 is hydrogen, hydroxy, N (-CC alkyl) 2 , -C-alkyl, -C-C-haloalkyl, -C-C4 ⁇ alkoxy-, -C-C 4 -haloalkoxy-, C 1 - C 4 -alkyl thio, halogen;
  • R 4 and R 5 is phenyl or naphthyl which may be substituted by one or more, for example one to three of the following radicals: halogen, cyano, hydroxy, mercapto, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl, -C-alkoxy, C ! -C 4 haloalkoxy, 11
  • Phenyl or naphthyl which are ortho-linked via a direct binding, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (-C 1 -C 4 -alkyl) group
  • a five-membered heteroaromatic containing one or two nitrogen atoms and / or a sulfur or oxygen atom which can carry one to two halogen atoms and / or one to two of the following radicals: C ⁇ -C 4 alkyl, C 1 -C 4 alkoxy, phenyl , which in turn can carry one to three halogen atoms and / or one to three of the following radicals: -C 4 alkyl, C 4 alkoxy or C 4 alkylthio;
  • Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C ⁇ ⁇ C 4 -alkyl, C 4 haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 -haloalkoxy, phenoxy, -CC 4 alkylthio, NH (-C ⁇ C 4 alkyl) 2 , N (C 1 -C 4 alkyl) 2 ;
  • 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 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4-alkoxy, C ⁇ ⁇ C4-haloalkoxy and / or C ⁇ -C-alkylthio; 12
  • R 4 and R 5 are phenyl (same or different), which by one or more, for example, can be substituted one to three of the following radicals: halogen, hydroxy, C ⁇ -C4 ⁇ alkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 alkylthio or
  • R 4 and R 5 are phenyl groups which are in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH- or N (-CC 4 -alkyl) - Group are connected; or
  • Thiazole, oxazole, thiophene or furan where the heteroaromatics mentioned can be mono- to disubstituted by: halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy;
  • R 4 and R 5 are cyclohexyl
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C 1 -C 4 -alkyl, Cr ⁇ -haloalkyl, C 1 -C 8 -alkoxy, 13
  • a five- or six-membered heteroaromatic containing a nitrogen atom and / or a sulfur or oxygen atom and which to four halogen atoms and / or can carry one to two of the following radicals a: C ⁇ ⁇ C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C ⁇ -C 4 -alkyl, C ⁇ ⁇ C 4 haloalkyl, C ⁇ -C 4 alkoxy and / or C ⁇ -C 4 alkylthi ⁇ ;
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic kidney failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of esenchymal tumors , Contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers, erectile dysfunction.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor).
  • VEGF vascular endothelial growth factor
  • substances which block the action of VEGF are, for example, antibodies directed against VEGF or specific binding proteins or else low molecular weight 14
  • the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
  • the form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally.
  • the ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX F ⁇ 2 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 at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds / constant / output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 ⁇ g Protein per test batch and suspended at 25 ° C with 25 pM [125J] ETi (ET A receptor test) or 25 pM [125J] ET 3 (ET B receptor test) 15
  • incubation buffer 50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA
  • Potential endothelin antagonists are administered to other preparations in the same vessel 15 minutes before the endothelin dose-response curve begins. The effects of endothelin are calculated in% of the K + contracture. Effective endothelin antagonists shift the endothelin dose-response curve to the right.
  • test animals were given the test compounds i.v. 30 min before the ETI administration. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, 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 approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.

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Abstract

The invention relates to carboxylic acid derivatives of formula (I), wherein the substituents have the following meanings; R1= tetrazole or a group (1); R = a radical OR7(2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R2, R3 = hydrogen, hydroxy, NH¿2?, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-halogen alkyl, C1-C4-alkoxy, C1-C4-halogen alkoxy or C1-C4-alkythio; X = halogen, C1-C4-halogen alkyl, hydroxy; R?4 and R5¿ = phenyl or naphthyl, C¿3?-C7-cycloalkyl, phenyl or naphthyl which are bonded in ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2-NH or an N-alkyl group or a 5-membered or 6-membered heteroaromatic; R?6¿ = hydrogen, phenyl or naphthyl, a five or six-membered heteroaromatic, C¿1?-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-C8-cycloalkyl, whereby said radicals can be substituted once or many times, with the proviso that R?6¿ can only stand for hydrogen if Z does not represent a single bond; Z = sulfur, oxygen or a single bond, in addition to the physiologically compatible salts and the enantiomeric-pure and diastereomeric-pure forms. The novel compounds are suitable for combating diseases, especially as endothelin antagonists.

Description

5-SUBSTITUIERTE PYRIMIDIN-2-YLOXY-CARBONSÄUREDERIVATE, DEREN HERSTELLUNG UND DEREN VERWENDUNG ALS ENDOTHELIN-ANTAGONISTEN 5-SUBSTITUTED PYRIMIDIN-2-YLOXY CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND THE USE THEREOF AS ENDOTHELINE ANTAGONISTS
5 Beschreibung5 Description
Die vorliegende Erfindung betrifft neue Carbonsäuredrivate mit 5-substituiertem Pyrimidinring, deren Herstellung und Verwendung.The present invention relates to new carboxylic acid derivatives with 5-substituted pyrimidine ring, their preparation and use.
0 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 Vasokonstriktor und 5 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). 00 Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. Hereinafter, "endothelin" or "ET" means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and 5 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). 0
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- 5 viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonäre Hypertonie, Raynaud Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostatahypertrophie, Atherosklerose, Asthma und Prostatakrebs (J. Vascular Med. Biology 2., 207 (1990), J. Am. Med. As- sociation 2fJ.. 2868 (1990), Nature ll!, 114 (1990), N. Engl . J. 0 Med. 122., 205 (1989), N. Engl. J. Med. 3_2j3, 1732 (1993), Nephron . 373 (1994), Stroke 15, 904 (1994), Nature 3j55, 759 (1993), J. Mol. Cell. Cardiol. 27., -A234 (1995); Cancer Research .56., 663 (1996), Nature Medicine 1, 944,(1995)).Increased or abnormal release of endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2., 207 (1990), J. Am. Med. As- sociation 2FJ .. 2868 (1990) Nature ll !, 114 (1990) N. Engl. J. Med 0. 122nd, 205 (1989) N. Engl. J. Med. 3_2j3, 1732 (1993) Nephron. 373 (1994), Stroke 15, 904 (1994), Nature 3j55, 759 (1993), J. Mol. Cell. Cardiol. 27., -A234 (1995); Cancer Research .56., 663 (1996) , Nature Medicine 1, 944, (1995)).
5 Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB Rezeptor, werden zur Zeit in der Literatur beschrieben (Nature 348, 730 (1990), Nature 3_4f 732 (1990)). Daher sollten Substanzen, die die Bindung von Endothelin an einen oder an beide Rezeptoren inhibieren, physiologische Effekte von Endothelin antagonisieren 0 und daher wertvolle Pharmaka darstellen.5 At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 3_4f 732 (1990)). Therefore substances that inhibit the binding of endothelin to one or both receptors should antagonize physiological effects of endothelin 0 and should therefore be valuable pharmaceuticals.
In WO 95/26716, WO 96/11914, WO 97/9294, WO 97/12878, WO 97/38980, WO 97/38981 werden Carbonsäurederivate und deren Verwendung als Endothelinantaganisten beschrieben. Diese Verbin- 5 düngen tragen an der 5-Position des Heterozyklus ein N-Atom oder eine Gruppe \WO 95/26716, WO 96/11914, WO 97/9294, WO 97/12878, WO 97/38980, WO 97/38981 describe carboxylic acid derivatives and their use as endothelin antaganists. These compounds carry an N atom or a group at the 5 position of the heterocycle \
^ c- • H ^ c- • H
Die erfindungsgemäßen Verbindungen besitzen demgegenüber an die- ser Position eine GruppierungIn contrast, the compounds according to the invention have a grouping at this position
\\
C—XC-X
mit X in der Bedeutung Halogen, Hydroxy und Cj.-C4-Halogenalkyl . Die erfindungsgemäßen Verbindungen zeichnen sich gegenüber den bekannten Endothelinantagonisten beispielsweise durch eine günstigere Metabolisierung im Körper aus.with X meaning halogen, hydroxy and Cj . -C 4 haloalkyl. Compared to the known endothelin antagonists, the compounds according to the invention are distinguished, for example, by more favorable metabolism in the body.
Gegenstand der Erfindung sind Carbonsäurederivate der Formel IThe invention relates to carboxylic acid derivatives of the formula I.
I HI H
-z—c- !-o-T t N =-z — c-! -o-T t N =
I R3 IR 3
wobei R1 steht für Tetrazol oder für eine Gruppewhere R 1 stands for tetrazole or for a group
OO
I I C—RI I C — R
in der R folgende Bedeutung hat:in which R has the following meaning:
a) ein Rest OR7, worin R7 bedeutet:a) a radical OR 7 , in which R 7 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion wie tertiäres Cι-C4-Alkylammonium oder das Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;
C3-Cg-Cycloalkyl, Cι-C8-Alkyl, CH2-Phenyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cx^-Halogenalkyl , Hydroxy, Cι-C4-Alkoxy, Mercapto, C-ι-C4-Alkylthio, Amino,C 3 -Cg-Cycloalkyl, -C-C 8 alkyl, CH 2 -phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, -C-C 4 alkyl, Cx ^ -haloalkyl, hydroxy C 1 -C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, amino,
NH(Cι-C4-Alkyl) , N (C1-C4-Alkyl ) 2;NH (-CC 4 alkyl), N (C 1 -C 4 alkyl) 2 ;
Eine C3-Ce-Alkenyl- oder eine C3-C6-Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können; 3A C 3 -Ce alkenyl or a C 3 -C 6 alkynyl group, these groups in turn being able to carry one to five halogen atoms; 3
R7 kann weiterhin ein Phenylrest sein, welcher ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Ci-C-j-Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino, 5R 7 may furthermore be a phenyl radical which an / or from one to five halogen atoms, and carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxyl, Ci-Cj-alkoxy , Mercapto, -CC 4 alkylthio, amino, 5th
NH(Cι-C4-Alkyl) , N (C1-C4-Alkyl )2;NH (-CC 4 alkyl), N (C 1 -C 4 alkyl) 2 ;
b) ein über ein Stickstoffatom verknüpfter 5-gliedriger Heteroaromat wie Pyrrolyl, Pyrazolyl, Imidazolyl und Triazolyl, wel¬b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, wel¬
10 cher ein bis zwei Halogenatome, oder eins bis zwei C1-C4-Alkyl oder eins bis zwei Cι~C -Alkoxygruppen tragen kann.10 cher can carry one to two halogen atoms, or one to two C 1 -C 4 alkyl or one to two Cι ~ C alkoxy groups.
c) eine Gruppec) a group
1i5ς (0„)k* 0— (CH2)p— S —R1i5ς (0 „ ) k * 0— (CH 2 ) p - S —R
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen und R8 fürwhere k is 0, 1 and 2, p is 1, 2, 3 and 4 and R 8 is
2020th
Cι-C4-Alkyl, C3-C8-Cycloalkyl, C3-C6-Alkenyl, C3-C6-Alkinyl oder Phenyl steht, das durch einen oder mehrere, z.B. ein bis drei der folgenden Reste substituiert sein kann:-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl, which can be substituted by one or more, for example one to three of the following radicals :
25 Halogen, Nitro, Cyano, Cι-C -Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Mercapto, Amino,25 halogen, nitro, cyano, C -alkyl, C 4 haloalkyl, hydroxy, Cι-C 4 -alkoxy, C 4 alkylthio, mercapto, amino,
NH (C1-C4-Alkyl ) , N(C1-C4-Alkyl)2.NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 .
30 d) ein Rest30 d) a rest
N- S-R'N-S-R '
3535
worin R9 bedeutet :where R 9 means:
Cι-C4-Alkyl, C3-C6-Alkenyl , C3-C6-Alkinyl , C3-C8-Cycloalkyl, 40 wobei diese Reste einen Cι-C4-Alkoxy , Cι-C4-Alkylthio- und/ oder einen Phenylrest wie unter c) genannt tragen können;Cι-C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, where these radicals 40 a Cι-C 4 -alkoxy, C 4 alkylthio and / or can carry a phenyl radical as mentioned under c);
Phenyl, das durch ein bis drei der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C4-Alkyl, 45 Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Mercapto, Amino, NH (Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2 4Phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C 4 alkyl, Cι-45 C 4 haloalkyl, hydroxy, Cι-C 4 -alkoxy, C 4 alkylthio , Mercapto, amino, NH (-C 4 alkyl), N (-C 4 alkyl) 2nd 4
Die übrigen Substituenten haben die folgende Bedeutung:The other substituents have the following meaning:
R2 Wasserstoff, Hydroxy, NH2, NH (Cχ-C4-Alkyl) , N(Cι-C4-Alkyl)2, Halogen, Cι-C4-Alkyl, C2-C-Alkenyl , C2-C4-Alkinyl, C!-C4-Hydroxyalkyl, Cχ-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Ha- logenalkoxy oder Cι-C4-Alkylthio, Morpholin;R 2 is hydrogen, hydroxy, NH 2 , NH (Cχ-C 4 alkyl), N (Cι-C 4 alkyl) 2 , halogen, Cι-C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 -alkynyl, C ! -C 4 -hydroxyalkyl, Cχ-C 4 -haloalkyl, -C-C 4 alkoxy, Cι-C 4 -haloalkoxy or Cι-C 4 alkylthio, morpholine;
X Halogen, Cι-C4-Halogenalkyl, Hydroxy;X halogen, -CC 4 haloalkyl, hydroxy;
R3 Wasserstoff, Hydroxy, NH2, NH (d-C -Alkyl ) , N(Cι-C-Alkyl)2, Halogen, Cι~C4-Alkyl, C2-C-Alkenyl , C2-C4-Alkinyl, Cι-C4-Hydroxyalkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Ha- logenalkoxy, -NH-0-Cι-C4-Alkyl, Cι-C4-Alkylthio;R 3 is hydrogen, hydroxy, NH 2 , NH (dC -alkyl), N (-C-C-alkyl) 2 , halogen, Cι ~ C 4 -alkyl, C 2 -C-alkenyl, C 2 -C 4 -alkynyl, Cι-C 4 hydroxyalkyl, Cι-C 4 haloalkyl, Cι-C 4 -alkoxy, C 4 logenalkoxy -Ha-, -NH-0-Cι-C 4 -alkyl, C 4 alkylthio;
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, Cι-C4~Alkyl, Cι-C4-Halogenalkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Mercapto, Alkylcarbonyl, Alkoxy- carbonyl, C!-C4-Alkylthio, Amino, NH (C1-C4-Alkyl ) , N(Cι-C4-Alkyl)2; oderPhenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, Cι-C4 ~ alkyl, Cι-C4 haloalkyl, Cι ~ C 4 -alkoxy, C 4 - Haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C ! -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (-C 4 -C 4 alkyl) 2 ; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bin- düng, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl- Gruppe miteinander verbunden sind; oderPhenyl or naphthyl, which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group; or
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-Αlkyl, Cι-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cχ--C4-Halogenalkoxy, 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 C1-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: C 1 -C 4 -alkyl, C 1 -C 4 - Haloalkyl, Cχ-C 4 -alkoxy, Cχ - C 4 -haloalkoxy, Cι-C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals themselves can carry one to five halogen atoms and / or one to three of the following radicals: Cι-C4 ~ alkyl, Cι-C4-haloalkyl, Cι-C 4 -alkoxy, C 4 -haloalkoxy and / or C 1 -C 4 -alkylthio;
oder C3-C-Cycloalkyl;or C 3 -C cycloalkyl;
R6 Wasserstoff,R 6 is hydrogen,
C-ι-C8-Alkyl , C3-C6-Alkenyl , C3-C6-Alkinyl oder C3-C8-Cycloal- kyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Hydroxy, Mercapto, Carboxy, Halo- 5 gen, Nitro, Cyano, Cχ-C4-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alki- nyloxy, Cι-C4-Alkylthio, Cχ-C4-Halogenalkoxy, Cι-C4-Alkylcar- bonyl, Cι-C4-Alkoxycarbonyl , C3-C8-Alkylcarbonylalkyl, Amino, NH(Cι-C4-Alkyl) , N(C1-C4-Alkyl ) 2, Phenoxy oder Phenyl, wobei die genannten Arylreste ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4~Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenal- koxy, Mercapto, Carboxy, Hydroxy, Amino, R12, Cι-C4~Alkoxy- carbonyl, NH (C1-C4-Alkyl ) , N(Cι-C4-Alkyl)2, Dioxomethylen, Dioxoethylen, Cι-C4-Alkylthio substituiertes Phenyl oder Phenoxy;C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 8 cycloalkyl, it being possible for these radicals to be substituted one or more times by: hydroxy, Mercapto, carboxy, halo 5 gen, nitro, cyano, Cχ-C4-alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, Cι-C 4 -alkylthio, C--C 4 -haloalkoxy, Cι-C 4 - Alkylcarbonyl, -CC 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino, NH (-C-C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 , phenoxy or phenyl, where the said aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C ~ 4 alkyl, Cι-C4-haloalkyl, Cι-C 4 -alkoxy, C 4 -Halogenal- koxy , Mercapto, carboxy, hydroxy, amino, R 12 , -C-C 4 ~ alkoxy-carbonyl, NH (C 1 -C 4 alkyl), N (-C-C 4 alkyl) 2 , dioxomethylene, dioxoethylene, Cι-C 4 alkylthio substituted phenyl or phenoxy;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Cχ-C4-Alkyl, Cι-C4-Halogenalkyl,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, Cι-C 4 -haloalkyl,
Cι-C4~Alkoxy, C-C4~Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, , NH(Cι-C-Alkyl) , N(Cι-C-Alkyl ) 2 oder Dioxomethylen oder Dioxoethylen;-C 4 ~ alkoxy, CC 4 ~ haloalkoxy, phenoxy, -C 4 alkyl thio,, NH (-C -C alkyl), N (-C -C alkyl) 2 or 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: Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cχ-C4-Alkoxy, Cι-C4~Halogenalkoxy, 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, Cχ-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy und/oder Cι~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: -CC 4 alkyl, -C-C 4 - Haloalkyl, Cχ-C 4 alkoxy, Cι-C 4 ~ haloalkoxy, Cι-C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: Cι -C 4 alkyl, Cχ-C 4 haloalkyl, -C-C4 alkoxy, Cι-C 4 haloalkoxy and / or Cι ~ C 4 alkylthio;
mit der Maßgabe, daß R6 nur dann Wasserstoff bedeuten kann, wenn Z keine Einfachbindung darstellt;with the proviso that R 6 can only be hydrogen if Z is not a single bond;
R12 C1-C4-Alkyl, Cι-C4-Alkylthio, Cι~C4-Alkoxy, die einen der fol- genden Reste tragen: Hydroxy, Carboxy, Amino, NH(Cι~C4-Alkyl) , N(Cι-C -Alkyl)2, Carboxamid oder CON(Cι-C4-Alkyl)2;R 12 C 1 -C 4 alkyl, -C-C 4 alkylthio, -C ~ C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (-C ~ C 4 alkyl), N (-C 1 -C 4 alkyl) 2 , carboxamide or CON (-C 1 -C 4 alkyl) 2 ;
Z Schwefel, Sauerstoff oder eine Einfachbindung.Z sulfur, oxygen or a single bond.
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; 6An alkaline earth metal is, for example, calcium, magnesium, barium; 6
Organische Amoniumionen sind protonierte Amine wie z.B. Ethano- lamin, Diethanolamin, Ethylendiamin, Diethylamin oder Piperazin;Organic ammonium ions are protonated amines such as e.g. Ethanol laminate, diethanolamine, ethylene diamine, diethylamine or piperazine;
C3-C7-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, 5 Cyclohexyl oder Cycloheptyl ;C 3 -C 7 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl or cycloheptyl;
Cι-C4-Halogenalkyl kann linear oder verzweigt sein wie z.B. Fluormethyl, Difluormethyl , Trifluormethyl, Chlordifluormethyl, Dich- lorfluormethyl, Trichlormethyl, 1-Fluorethyl , 2-Fluorethyl, 10 2, 2-Difluorethyl, 2 , 2 , 2-Trifluorethyl, 2 -Chlor 2, 2 -difluorethyl, 2, 2-Dichlor-2-fluorethyl, 2 , 2 , 2-Trichlorethyl oder Pentafluore- thyl ;C 1 -C 4 -Halogenalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 10 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro 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. Di- ^ fluormethoxy, Trifluormethoxy, Chlordifluormethoxy, lFluorethoxy, 2, 2-Difluorethoxy, 1, 1, 2 , 2-Tetrafluorethoxy, 2, 2, 2-Trifluor- ethoxy, 2-Chlor-l, 1 , 2-trifluorethoxy, 2-Fluorethoxy oder Penta- fluorethoxy;C 1 -C 4 -Halogenalkoxy can be linear or branched such as, for example, di- ^ fluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, lfluorethoxy, 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,"-C 4 alkyl can be linear or branched such as methyl,
Ethyl, 1-Propyl, 2-Propyl, 2-Methyl-2-propyl, 2-Methyl-l-propyl, 1-Butyl oder 2-Butyl;Ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
C2-C4-Alkenyl kann linear oder verzweigt sein wie z.B. Ethenyl , 25 i-prθpen-3-yl, l-Propen-2-yl, 1-Propen-l-yl, 2-Methyl-1-propenyl, 1-Butenyl oder 2-Butenyl;C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 25 ip rθ pen-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-Propin-l-yl, l-Propin-3-yl, l-Butin-4-yl oder 2-Butin-4-yl;C 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
3030
Cχ-C4-Alkoxy kann linear oder verzweigt sein wie z.B. Methoxy, Ethoxy, Propoxy, 1-Methylethoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy oder 1, 1-Dimethylethoxy;Cχ-C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
35 C-C6-Alkenyloxy kann linear oder verzweigt sein wie z.B. Allyl- oxy, 2-Buten-l-yloxy oder 3-Buten-2-yloxy;CC 6 -alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6~Alkinyloxy kann linear oder verzweigt sein wie z.B. 2-Propin-l-yloxy, 2-Butin-l-yloxy oder 3-Butin-2-yloxy;C 3 -C 6 ~ alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
4040
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;Cι ~ C 4 alkylthio can be linear or branched such as methyl thio, ethyl thio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
45 745 7
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. Metoxycarbonyl, Ethoxycarbonyl , n-Propoxycarbonyl, i-Propoxycar- bonyl oder n-Butoxycarbonyl ;C 1 -C 4 alkoxycarbonyl can be linear or branched, such as, for example, metoxycarbonyl, 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
Cχ-C8-Alkyl kann linear oder verzweigt sein wie z.B. C1-C4-Alkyl, Pentyl , Hexyl , Heptyl oder Octyl ;Cχ-C 8 alkyl can be linear or branched such as C 1 -C 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 und IV, können ein oder mehrere asymmetrische substituierte Kohlenstoffatome besitzen. Solche Verbindungen können als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung vorliegen. Bevorzugt ist die Verwendung einer enantiome- renreinen Verbindung als Wirkstoff.The compounds and also the intermediates for their preparation, e.g. II and IV, can have one or more asymmetric substituted carbon atoms. Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active ingredient is preferred.
Gegenstand der Erfindung ist weiter die Verwendung der oben genannten Carbonsäurederivate zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Hemmstoffen für Endothelinrezep- toren.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 endothelin receptors.
Die Herstellung der Verbindungen mit der allgemeinen Formel IV, in denen Z Schwefel oder Sauerstoff ist (IVa), kann wie in WO 96/11914 beschrieben, erfolgen.The compounds of the general formula IV in which Z is sulfur or oxygen (IVa) can be prepared as described in WO 96/11914.
0 =ι R4 yR H 0 = ι R 4 y R H
R P R6 — Z - Δ7- C^ OH
Figure imgf000009_0001
Figure imgf000009_0002
I ι5 i1 RPR 6 - Z - Δ7- C ^ OH
Figure imgf000009_0001
Figure imgf000009_0002
I ι 5 i 1
II III IVa 8II III IVa 8th
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.
Verbindungen der Formel IVa kann man in enantionmerenreiner Form über eine sauer katalysierte Umetherung erhalten, wie dies in DE 19636046.3 beschrieben wurde.Compounds of the formula IVa can be obtained in enantiomerically pure form via an acid-catalyzed transetherification, as described in DE 19636046.3.
Weiterhin kann man enantiomerenreine Verbindungen der Formel IVa erhalten, indem man mit racemischen bzw. diastereomeren Verbindu- gnen der Formel IVa eine klassische Racematspaltung mit geeigneten enantiomerenreinen Basen durchführt. Als solche Basen eigenen sich z.B. 4-Chlorphenylethylamin und die Basen, die in WO 96/11914 genannt werden.Furthermore, enantiomerically pure compounds of the formula IVa can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IVa. As such bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
Die Herstellung der Verbindungen mit der allgemeinen Formel IV, in denen Z eine Einfachbindung ist (IVb), kann sowohl racemisch als auch in enantiomerenreiner Form wie in WO 97/38981 beschrie- ben, erfolgen.The compounds with the general formula IV in which Z is a single bond (IVb) can be prepared both racemically and in enantiomerically pure form, as described in WO 97/38981.
H c: c- OHH c: c-OH
H I.HI.
IVbIVb
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.
2 r /2 r /
IV .10IV .10
X: X :
In Formel V bedeutet R10 Halogen oder R -S02-, wobei R11 Cx-Cj-Alkyl, Cι-C4-Halogenalkyl oder Phenyl sein kann. Die Reaktion findet bevorzugt in einem inerten Lösungs- oder Verdünnungsmittel unter Zusatz einer geeigneten Base, d.h. einer Base, die eine De- protonierung des Zwischenproduktes IV bewirkt, in einem Tempera- 9 turbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels statt.In formula V, R 10 is halogen or R -S0 2 -, where R 11 can be Cx-Cj-alkyl, -CC 4 -haloalkyl or phenyl. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature 9 range from room temperature to the boiling point of the solvent.
Verbindungen des Typs I mit R1 = COOH lassen sich weiterhin direkt erhalten, wenn man das Zwischenprodukt IV, in dem R1 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 1 = COOH can furthermore be obtained directly if the intermediate IV, in which R 1 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, To- luol, Xylol, Methylenchlorid, Chloroform, Kohlenstofftetrachlo- rid, Ethylchlorid und Trichlorethylen, Ether, wie zum Beispiel Diisopropylether, Dibutylether, Methyl-tert. -Butylether, Propyle- noxid, Dioxan und Tetrahydrofuran, Nitrile, wie zum Beispiel Ace- tonitril und Propionitril, Säureamide, wie zum Beispiel Dimethyl- formamid, Dirnethylacetamid 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, ethers such as diisopropyl ether, dibutyl ether, methyl tert. -Butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dirnethylacetamide 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 Alkalimetallcarbonat, z.B. Natrium- oder Kaiiumcarbonat, ein Alkali- oder Erdalkalimetallhydroxid wie Natrium- oder Kaliumhydroxid, eine metallorganische Verbindung wie Butyllithium oder ein Alka- liamid wie Lithiumdiisopropylamid dienen.As a base there can be an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal such as lithium diisopropylamide 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 Säureha- logenid, 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, wie z. B. Triethylamin, Pyridin, Imidazol oder Diazabicycloundecan in Betracht kommen. Diese beiden Schritte lassen sich beispielsweise auch dadurch vereinfachen, daß man die Carbonsäure in Gegenwart eines wasse- rabspaltenden Mittels wie eines Carbodiimids auf die Hydroxylver- bindung einwirken läßt . 10Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and first converting them 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 usual solvents and often requires the addition of a base, such as. B. triethylamine, pyridine, imidazole or diazabicycloundecane. 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. 10
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 COOM stehen, wobei M ein Alkalimetallkation oder das Äquivalent eines Erdalkalimetallkations sein kann. DieseIn 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 represents a group COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. This
Salze lassen sich mit vielen Verbindungen der Formel R7-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 Methylsulfo- nyl oder eine andere äquivalente Abgangsgruppe. Verbindungen der Formel R7-A mit einem reaktionsfähigen Substituenten A sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durch- führen und wird vorteilhaft unter Zugabe einer Base, wobei die oben genannten in Betracht kommen, vorgenommen.Salts can be reacted with many compounds of the formula R 7 -A, where A is a conventional 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 methylsulfo - nyl or another equivalent leaving group. Compounds of the formula R 7 -A with a reactive substituent A are known or can be easily obtained 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.
In einigen Fällen ist zur Herstellung der erfindungsgemäßen Verbindungen I die Anwendung allgemein bekannter Schutzgruppentech- niken erforderlich. Soll beispielsweise R6 = 4 Hydroxyphenyl bedeuten, so kann die Hydroxygruppe zunächst als Benzylether geschützt sein, der dann auf einer geeigneten Stufe in der Reaktionssequenz gespalten wird.In some cases, the use of generally known protective group techniques is necessary to prepare the compounds I according to the invention. For example, if R 6 = 4 is hydroxyphenyl, the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Verbindungen der Formel I, in denen R1 Tetrazol bedeutet, können wie in WO 96/11914 beschrieben, hergestellt werden.Compounds of the formula I in which R 1 is tetrazole can be prepared as described in WO 96/11914.
Im Hinblick auf die biologische Wirkung sind Carbonsäurederivate der allgemeinen Formel I - sowohl als reine Enantiomere bzw. reine Diastereomere oder als deren Mischung - bevorzugt, in denen die Substituenten folgende Bedeutung haben:With regard to the biological action, carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
R2 Wasserstoff, Hydroxy, N(Cι-C4-Alkyl)2, Cι-C4-Alkyl-, Cι-C-Ha- logenalkyl-, Cι-C4-Alkoxy- , Cι-C4-Halogenalkoxy-, C1-C4-AI- kylthio, Halogen;R 2 is hydrogen, hydroxy, N (-CC 4 alkyl) 2 , -C 4 -alkyl, -C-C-haloalkyl-, -C-C4-alkoxy-, -C-C 4 -haloalkoxy-, C 1 -C 4 -Alkylthio, halogen;
X Halogen, Trifluormethyl;X halogen, trifluoromethyl;
R3 Wasserstoff, Hydroxy, N(Cι-C-Alkyl)2, Cι-C-Alkyl-, Cι-C-Ha- logenalkyl-, Cι-C4~Alkoxy- , Cι-C4-Halogenalkoxy-, C1-C4-AI- kylthio, Halogen;R 3 is hydrogen, hydroxy, N (-CC alkyl) 2 , -C-alkyl, -C-C-haloalkyl, -C-C4 ~ alkoxy-, -C-C 4 -haloalkoxy-, C 1 - C 4 -alkyl thio, halogen;
R4 und R5 Phenyl oder Naphthyl, die durch einen oder mehrere, z.B. einen bis drei der folgenden Reste substituiert sein können: Halogen, Cyano, Hydroxy, Mercapto, Amino, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C-Alkoxy, C!-C4-Halogenalkoxy, 11R 4 and R 5 is phenyl or naphthyl which may be substituted by one or more, for example one to three of the following radicals: halogen, cyano, hydroxy, mercapto, amino, Cι-C 4 -alkyl, C 4 haloalkyl, -C-alkoxy, C ! -C 4 haloalkoxy, 11
Cι-C-Alkylthio, NH (Cι-C4-Alkyl) 2 , N(Cι-C4-Alkyl) 2, C1-C4-AI- kylcarbonyl , Cι~C4-Alkoxycarbonyl ;Cι-C-alkylthio, NH (Cι-C4 alkyl) 2, N (Cι-C4 alkyl) 2, C 1 -C 4 -AI- kylcarbonyl, Cι ~ C 4 alkoxycarbonyl;
Phenyl oder Naphthyl, die orthoständig über eine direkte Bin- düng, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N(Cι~C4-Alkyl) -Gruppe miteinander verbunden sindPhenyl or naphthyl, which are ortho-linked via a direct binding, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 , NH or N (-C 1 -C 4 -alkyl) group
ein fünfgliedriger Heteroaromat, enthaltend ein oder zwei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis zwei Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cχ-C4-Alkyl, Cι-C4-Alkoxy, Phenyl, das seinerseits ein bis drei Halogenatome und/oder einen bis drei der folgenden Reste tragen kann: Cι-C4-Alkyl, Cι-C4-Alkoxy oder Cι-C4-Alkylthio;a five-membered heteroaromatic, containing one or two nitrogen atoms and / or a sulfur or oxygen atom which can carry one to two halogen atoms and / or one to two of the following radicals: Cχ-C 4 alkyl, C 1 -C 4 alkoxy, phenyl , which in turn can carry one to three halogen atoms and / or one to three of the following radicals: -C 4 alkyl, C 4 alkoxy or C 4 alkylthio;
oder C-C7-Cycloalkyl;or CC 7 cycloalkyl;
Cι-C8-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl oder C3-C8-Cycloalkyl wobei diese Reste jeweils ein-oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Cyano, Cι-C4-Alkoxy, C3-C6-Al- kenyloxy, C3-C6-Alkinyloxy, Cι-C4-Alkylthio, Cι-C4~Halogenal- koxy, Cι-C4-Alkylcarbonyl, Hydroxycarbonyl , Cι-C4-Alkoxycarbo- nyl, NH(Cι-C4-Alkyl)2, N(Cι-C4-Alkyl) 2, Phenoxy oder Phenyl, wobei die genannten Arylreste ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Halogen, C1-C4-AI- kyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι~C4-Halogenalkoxy, R12, Ci C4 Alkoxycarbonyl , Dioxomethylen, Dioxoethylen, Cι~C4-Alkylthio Phenyl oder Phenoxy;C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, cyano, Cι -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylthio, -C-C 4 ~ haloalkoxy, -C-C 4 -alkylcarbonyl, hydroxycarbonyl, Cι -C 4 alkoxycarbonyl, NH (-C 4 alkyl) 2 , N (-C 4 alkyl) 2 , phenoxy or phenyl, where the aryl radicals mentioned can be substituted one or more times, for example one to three times by halogen, C 1 -C 4 -AI- alkyl, Cι-C4-haloalkyl, Cι-C4-alkoxy, Cι ~ C4 haloalkoxy, R 12, C C 4 alkoxycarbonyl, dioxomethylene, Dioxoethylen, Cι ~ C 4- alkylthio phenyl or phenoxy;
Phenyl oder Naphthyl, das durch einen oder mehreren der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Hydroxy, Amino, Cι~C4-Alkyl, Cι-C4-Halogenalkyl, Cι~C4-Alkoxy, Cι-C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, NH(Cι~C4-Al- kyl)2, N(C1-C4-Alkyl)2;Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, Cι ~ C 4 -alkyl, C 4 haloalkyl, Cι ~ C 4 -alkoxy, C 4 -haloalkoxy, phenoxy, -CC 4 alkylthio, NH (-C ~ C 4 alkyl) 2 , N (C 1 -C 4 alkyl) 2 ;
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, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, Cι-C-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, Cχ-C4-Alkoxy, Cι~C4-Halogenalkoxy und/oder Cι-C-Alkylthio; 12a 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, Cι-C 4 - Haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C 4 -alkyl, C 4 haloalkyl, Cχ-C4-alkoxy, Cι ~ C4-haloalkoxy and / or Cι-C-alkylthio; 12
R12 Cι-C4-Alkyl, Cι~C4-Alkoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxamid oder CON(Cι-C4-Alkyl) ;R 12 -C 4 alkyl, -C ~ C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxamide or CON (-C 4 alkyl);
Z Schwefel, Sauerstoff oder eine Einfachbindung;Z sulfur, oxygen or a single bond;
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:
R2 Cι-C-Alkyl, Cι-C-Alkoxy, insbesondere Methyl, Ethyl, Me- thoxy, Ethoxy, Difluormethoxy, Trifluormethoxy;R 2 -CC alkyl, -CC alkoxy, especially methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
X Fluor, Trifluormethyl;X fluorine, trifluoromethyl;
R3 Cι-C4-Alkyl-, Cι-C4-Alkoxy, Cι-C4-Alkylthio, insbesondere Methyl, Ethyl, Methoxy, Ethoxy, Difluormethoxy, Trifluormethoxy;R 3 -C 4 alkyl-, -C 4 alkoxy, -C 4 -alkylthio, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;
R4 und R5 Phenyl (gleich oder verschieden), die durch einen oder mehrere, z.B. einen bis drei der folgenden Reste substituiert sein können: Halogen, Hydroxy, Cι-C4~Alkyl, Cι~C4-Alkoxy, Cι-C4-Alkylthio oderR 4 and R 5 are phenyl (same or different), which by one or more, for example, can be substituted one to three of the following radicals: halogen, hydroxy, Cι-C4 ~ alkyl, Cι ~ C 4 -alkoxy, C 4 alkylthio or
R4 und R5 sind Phenylgruppen, die orthoständig über eine di- rekte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N(Cι-C4-Alkyl) -Gruppe miteinander verbunden sind; oderR 4 and R 5 are phenyl groups which are in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH- or N (-CC 4 -alkyl) - Group are connected; or
Thiazol, Oxazol, Thiophen oder Furan, wobei die genannten Heteroaromaten ein- bis zweifach substituiert sein können durch: Halogen, Cχ-C4-Alkyl, Cι-C4-Alkoxy;Thiazole, oxazole, thiophene or furan, where the heteroaromatics mentioned can be mono- to disubstituted by: halogen, Cχ-C 4 alkyl, Cι-C 4 alkoxy;
R4 und R5 sind Cyclohexyl;R 4 and R 5 are cyclohexyl;
R6 Cι-C8-Alkyl, C3-C6-Alkenyl oder C3-C8-Cycloalkyl, wobei diese Reste jeweils ein-oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Cyano, Cχ-C4-Alkoxy, C3-C6-Alkeny- loxy, Cι-C4-Alkylthio, Phenoxy oder Phenyl, wobei die genannten Arylreste ein- oder mehrfach substituiert sein können, z.B. ein- bis dreifach durch Cι-C4-Alkyl, Cι~C4-Alkoxy, Dioxomethylen, Dioxoethylen, Cχ-C4-Alkylthio;R 6 -C 8 alkyl, C 3 -C 6 alkenyl or C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, cyano, Cχ-C 4 alkoxy , C 3 -C 6 -alkenyloxy, -CC 4 -alkylthio, phenoxy or phenyl, where the aryl radicals mentioned can be mono- or polysubstituted, for example one to three times by -C 4 -alkyl, -C ~ C 4 -alkoxy, dioxomethylene, dioxoethylene, Cχ-C 4 -alkylthio;
Phenyl oder Naphthyl, das durch einen oder mehreren der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Hydroxy, Amino, Cι-C-Alkyl, Cr^-Halogenalkyl, Cι-C-Alkoxy, 13Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C 1 -C 4 -alkyl, Cr ^ -haloalkyl, C 1 -C 8 -alkoxy, 13
Cι-C4-Halogenalkoxy, Phenoxy, Cι-C4~Alkylthio, Cι~C4-Akylamino oder Cι-C-Dialkylamino;Cι-C 4 -haloalkoxy, phenoxy, Cι-C ~ 4 alkylthio, Cι ~ C 4 -Akylamino or Cι-C-dialkylamino;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein Stickstoffatom 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-Alkylthio, Phenyl, Phenoxy oder Phenylcar- bonyl, wobei die Phenylreste ihrerseits ein bis fünf Haloge- natome und/oder einen bis drei der folgenden Reste tragen können: Cχ-C4-Alkyl, Cι~C4-Halogenalkyl, Cχ-C4-Alkoxy und/oder Cχ-C4-Alkylthiθ;a five- or six-membered heteroaromatic, containing a nitrogen atom and / or a sulfur or oxygen atom and which to four halogen atoms and / or can carry one to two of the following radicals a: Cι ~ C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: Cχ-C 4 -alkyl, Cι ~ C 4 haloalkyl, Cχ-C 4 alkoxy and / or Cχ-C 4 alkylthiθ;
Y Schwefel, Sauerstoff oder eine Einfachbindung;Y sulfur, oxygen or a single bond;
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pulmo- nalem Hochdruck, Myokardinfarkt , Angina Pectoris, Arrhythmie, akutem/chronischem Nierenversagen, chronischer Herzinsuffizienz, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endoto- xischem Schock, Endotoxin-induziertem Organversagen, intravasku- lärer Koagulation, Restenose nach Angioplastie und by-pass Operationen, benigne Prostata-Hyperplasie, ischämisches und durch In- toxikation verursachtes Nierenversagen bzw. Hypertonie, Metasta- sierung und Wachstum esenchymaler Tumoren, Kontrastmittel-indu- ziertes Nierenversagen, Pankreatitis, gastrointestinale Ulcera, Erektionsstörungen.The compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic kidney failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of esenchymal tumors , Contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers, erectile dysfunction.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus En- dothelinrezeptorantagonisten der Formel I und Inhibitoren des Re- nin-Angiotensin Systems. Inhibitoren des Renin-Angiotensin-Sy- stems sind Reninhemmer, Angiotensin-II-Antagonisten und Angioten- sin-Converting-Enzyme (ACE) -Hemmer. Bevorzugt sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und ACE-Hemmern.The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Beta-Blockern.The invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Diuretika.The invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Substanzen, die die Wirkung von VEGF (vascular endothelial growth factor) blockieren, solche Substanzen sind Beispielsweise gegen VEGF gerichtete Antikörper oder spezifische Bindeproteine oder auch niedermolekulare 14The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or else low molecular weight 14
Substanzen, die VEGF Freisetzung oder Rezeptorbindung spezifisch Hemmen können.Substances that can specifically inhibit VEGF release or receptor binding.
Die vorstehend genannten Kombinationen können gleichzeitig oder nacheinander zeitlich abgestuft verabreicht werden. Sie können sowohl in einer einzigen galenischen Formulierung oder auch in getrennten Formulierungen eingesetzt werden. Die Applikationsform kann auch unterschiedlich sein, beispielsweise können die Endothelinrezeptorantagonisten oral und VEGF- Hemmer parenteral ver- abreicht werden.The combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations. The form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally.
Diese Kombinationspräparate eignen sich vor allem zur Behandlung und Verhütung von Hypertension und deren Folgeerkrankungen, sowie zur Behandlung von Herzinsuffizienz.These combination products are particularly suitable for the treatment and prevention of hypertension and its complications, as well as for the treatment of heart failure.
Die gute Wirkung der Verbindungen läßt sich in folgenden Versuchen zeigen:The good effects of the compounds can be shown in the following experiments:
RezeptorbindungsstudienReceptor binding studies
Für Bindungsstudien wurden klonierte humane ETA- oder ETB-Rezep- tor-exprimierende CHO-Zellen eingesetzt.Cloned human ET A or ET B receptor-expressing CHO cells were used for binding studies.
Me branpräparationMe branch preparation
Die ETA- oder ETB-Rezeptor-exprimierenden CHO-Zellen wurden in DMEM NUT MIX Fι2-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-halti- ger PBS 5 Minuten bei 37°C inkubiert. Danach wurde mit Medium neutralisiert und die Zellen durch Zentrifugation bei 300 x g gesammelt.The ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX Fι 2 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 at 37 ° C for 5 minutes. 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 Soni- fier 250, 40-70 Sekunden/constant/output 20).For the membrane preparation, the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 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 mM MnCl2, 40 mg/ml Bacitracin und 0,2 % BSA) in einer Konzentration von 50 μg Protein pro Testansatz suspendiert und bei 25°C mit 25 pM [125J] ETi (ETA-Rezeptortest) oder 25 pM [125J]-ET3 (ETB Rezeptortest) in 15For the ET A and ET B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 μg Protein per test batch and suspended at 25 ° C with 25 pM [125J] ETi (ET A receptor test) or 25 pM [125J] ET 3 (ET B receptor test) 15
Anwesenheit und Abwesenheit von Test-substanz inkubiert. Die unspezifische Bindung wurde mit 10~7 M E i bestimmt. Nach 30 min wurde der freie und der gebundene Radioligand durch Filtration über GF/B GlasfaserfilterPresence and absence of test substance incubated. The non-specific binding was determined to be 10 ~ 7 ME i. After 30 minutes, the free and bound radioligand were removed by filtration through GF / B glass fiber filters
(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-zin- tillationszähler quantifiziert.(Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid counting counter.
Funktioneller Gefäßtest für Endothelin-RezeptorantagonistenFunctional vascular test for endothelin receptor antagonists
An Aortensegmenten des Kaninchens wird nach einer Vorspannung von 2 g und einer Relaxationszeit von 1 h in Krebs-Henseleitlösung bei 37oC und einem pH-Wert zwischen 7,3 und 7,4 zunächst eine K+-Kontraktur ausgelöst. Nach Auswaschen wird eine Endothelin-Do- siswirkungskurve bis zum Maximum erstellt.After a preload of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37oC and a pH value between 7.3 and 7.4, a K + contracture is first triggered on aortic segments of the rabbit. After washing out, an endothelin dose effect curve is drawn up to the maximum.
Potentielle Endothelin-Antagonisten werden an anderen Präparaten des gleichen Gefäßes 15 min vor Beginn der Endothelin-Dosiswir- kungskurve appliziert. Die Effekte des Endothelins werden in % der K+-Kontraktur berechnet. Bei wirksamen Endothelin-Antagonisten kommt es zur Rechtsverschiebung der Endothelin-Dosiswirkungs- kurve.Potential endothelin antagonists are administered to other preparations in the same vessel 15 minutes before the endothelin dose-response curve begins. The effects of endothelin are calculated in% of the K + contracture. Effective endothelin antagonists shift the endothelin dose-response curve to the right.
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 ETI zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeitraum anhält.In control animals, intravenous administration of 1 μg / kg ETI leads to a significant increase in blood pressure that persists over a longer period.
Den Testtieren wurde 30 min vor der ETI Gabe die Testverbindungen i.v. injiziert (1 ml/kg) . Zur Bestimmung der ET-antagonistischen Eigenschaften wurden die Blutdruckänderungen in den Testtieren mit denen in den Kontrolltieren verglichen.The test animals were given the test compounds i.v. 30 min before the ETI administration. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
p.o. - Testung der gemischten 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. caro- 16 tis (für Blutdruckmessung) sowie die V. jugularis (Applikation von big Endothelin/Endothelin 1) katheterisiert .Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the A. caro- 16 tis (for blood pressure measurement) and the jugular vein (application of big endothelin / endothelin 1) catheterized.
Nach einer Stabilisierungsphase wird big Endothelin (20 μg/kg, Appl. Vol. 0.5 ml/kg) bzw. ETI (0.3 μg/kg, Appl. Vol. 0.5 ml/kg) intravenös gegeben. Blutdruck und Herzfrequenz werden kontinuierlich über 30 Minuten registriert. Die deutlichen und langanhaltenden Blutdruckänderungen werden als Fläche unter der Kurve (AUC) berechnet. Zur Bestimmung der antagonistischen Wirkung der Testsubstanzen wird die AUC der Substanzbehandelten Tiere mit der AUC der Kontrolltiere verglichen.After a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 μg / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, 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 tägli- ehe Wirkstoffdosis zwischen etwa 0,5 und 50 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,1 und 10 mg/kg Körpergewicht bei parenteraler Gabe.The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active ingredient is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füll- Stoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991) . Die so erhaltenen Applikationsformen enthalten den Wirkstoff normalerweise in einer Menge von 0,1 bis 90 Gew.-%.The new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
SynthesebeispieleSynthesis examples
Beispiel 1:Example 1:
2- (4, 6-Dimethoxy-5-fluor-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphe- nylpropionsäuremethylesterMethyl 2- (4, 6-dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionate
Zu einer Suspension von 0.18g NaH (4,2 mmol, 55% in Weißöl) in 10 ml DMF wurden 1.0 g (3,5 mmol) 2-Hydroxy-3-methoxy-3 , 3-diphe- nyl-propionsäuremethylester, in DMF gelöst, zugetropft. Nach 30 171.0 g (3.5 mmol) of methyl 2-hydroxy-3-methoxy-3, 3-diphenyl-propionate was added to a suspension of 0.18 g NaH (4.2 mmol, 55% in white oil) in 10 ml DMF DMF dissolved, added dropwise. After 30 17
Minuten Rühren bei Raumtemperatur wurde das Gemisch mit 830mg (4.8 mmol) 4, 6-Dimethoxy-5-fluor-2-methylsulfonylpyrimidin in 10 ml DMF versetzt und 2 Stunden bei Raumtemperatur gerührt. Der Ansatz wurde auf Eiswasser gegossen dreimal mit Diethylether extra- j hiert. Die Etherphasen wurden mit Magnesiumsulfat getrocknet anschließend filtriert und das Lösungsmittel im Vakuum abgezogen. Der braune Rückstand (1.7g) wurden über MPLC gereinigt, wobei 1,3g des gewünschten Produkts isoliert werden konnten, das direkt weiter umgesetzt wurde.Minutes of stirring at room temperature, 830 mg (4.8 mmol) of 4, 6-dimethoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 ml of DMF were added and the mixture was stirred at room temperature for 2 hours. The mixture was poured onto ice water and extracted three times with diethyl ether. The ether phases were dried with magnesium sulfate, then filtered and the solvent removed in vacuo. The brown residue (1.7 g) was purified by MPLC, whereby 1.3 g of the desired product could be isolated, which was immediately implemented.
Beispiel 2:Example 2:
2- (4, 6-Dimethoxy-5-fluor-pyrimidin-2-yloxy) -3-methoxy-3 , 3-diphe- nylpropionsäure (A) und2- (4, 6-Dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid (A) and
2- (4-Methoxy-5-fluor-6-hydroxy-pyrimidin-2-yloxy)-3-me- thoxy-3 , 3-diphenylpropionsäure (B)2- (4-methoxy-5-fluoro-6-hydroxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid (B)
In 10 ml Dioxan wurden 1,3 g (2,9 mmol) 2- (4, 6-Dimethoxy-5-fluor- pyrimidin-2-yloxy) -3-methoxy-3 , 3-diphenylpropionsäuremethylester gelöst und mit 5,9 ml I N KOH-Lösung versetzt. Das Gemisch wurde vier Stunden unter Rückfluß gerührt. Zu dem Ansatz wurde Wasser gegeben und die wässrige Phase mit Ether zweimal extrahiert. Die wässrige Phase wurde mit 1 N wässsriger HC1 angesäuert, mit Ether extrahiert, die organische Phase über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Der Rückstand wurde in Ether aufgenommen wobei 100 mg vom Produkt B auskristallisierte. Die Mutterlauge wurde mit n-Hexan versetzt, wobei 400 mg vom Produkt A als Feststoff anfielen.1.3 g (2.9 mmol) of 2- (4, 6-dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid methyl ester were dissolved in 10 ml of dioxane, and 5.9 ml IN KOH solution added. The mixture was stirred under reflux for four hours. Water was added to the mixture and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1N aqueous HC1, extracted with ether, the organic phase dried over magnesium sulfate and the solvent was distilled off. The residue was taken up in ether, 100 mg of product B crystallizing out. The mother liquor was mixed with n-hexane, 400 mg of product A being obtained as a solid.
A: 1H-NMR (CDC13, 500MHz): 7,2-7,45 (m, 10H) ; 6,05 (s, 1H) ; 3,95 (s, 6H) ; 3,3 (s, 3H)A: 1 H NMR (CDC1 3 , 500 MHz): 7.2-7.45 (m, 10H); 6.05 (s, 1H); 3.95 (s, 6H); 3.3 (s, 3H)
Smp.: 168-170°CM.p .: 168-170 ° C
B: iH-NMR (DMSO, 250MHz): 7,1-7,4 (m, 10H) ; 6,05 (s, 1H) ; 3,9 (s, 3H); 3,3 (s, 3H)B: i H-NMR (DMSO, 250 MHz): 7.1-7.4 (m, 10H); 6.05 (s, 1H); 3.9 (s. 3H); 3.3 (s, 3H)
Smp. : 115-117°C 18M.p .: 115-117 ° C 18th
Beispiel 3 :Example 3:
2- (4-Morpholino-5-fluor-pyrimidin-2-yloxy) -3-methoxy-3 , 3-diphe- nylpropionsäurebenzylester2- (4-Morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid benzyl ester
Zu einer Suspension von 9,96 g KC03 (72 mmol) in 40 ml DMF wurden 3,3 g (9 mmol) 2-Hydroxy-3-methoxy-3 , 3-diphenyl-propionsäureben- zylester und 4-Morpholino-5-fluor-2-chlorpyrimidin, in DMF gelöst, zugetropft. Dann wurde zunächst 3 Stunden bei 90°C und an- schließend 3 Stunden bei 130°C gerührt. Der Ansatz wurde auf Eiswasser gegossen und dreimal mit Essigester extrahiert. Die Essigesterphasen wurden mit Magnesiumsulfat getrocknet anschließend filtriert und das Lösungsmittel im Vakuum abgezogen. Der braune Rückstand (5,72 g) wurde über MPLC gereinigt und direkt weiter umgesetzt.3.3 g (9 mmol) of 2-hydroxy-3-methoxy-3, 3-diphenyl-propionic acid benzyl ester and 4-morpholino-5 were added to a suspension of 9.96 g of KCO 3 (72 mmol) in 40 ml of DMF -fluoro-2-chloropyrimidine, dissolved in DMF, added dropwise. Then the mixture was first stirred at 90 ° C. for 3 hours and then at 130 ° C. for 3 hours. The mixture was poured onto ice water and extracted three times with ethyl acetate. The ethyl acetate phases were dried with magnesium sulfate and then filtered and the solvent was removed in vacuo. The brown residue (5.72 g) was purified via MPLC and directly reacted further.
Beispiel 4:Example 4:
2- (4-Morpholino-5-fluor-pyrimidin-2-yloxy)-3-methoxy-3,3-diphe- nylpropionsäure2- (4-Morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid
Eine Lösung von 0,9 g 2- (4-Morpholino-5-fluor-pyrimi- din-2-yloxy)-3-methoxy-3,3-diphenylpropionsäurebenzylester in 30 ml Essigester wurde unter Verwendung von 300 mg Palladium auf Ak- tivkohle (10%) mit Wasserstoff unter Normaldruck bei Raumtemperatur über 3 Stunden hydriert. Der Ansatz wurde filtriert, eingeengt und der Rückstand (900 mg) über die MPLC gereinigt.A solution of 0.9 g of benzyl 2- (4-morpholino-5-fluoro-pyrimidine-2-yloxy) -3-methoxy-3,3-diphenylpropionate in 30 ml of ethyl acetate was prepared on Ak- using 300 mg of palladium. Carbon (10%) is hydrogenated with hydrogen under normal pressure at room temperature for 3 hours. The mixture was filtered, concentrated and the residue (900 mg) was purified by MPLC.
1H-NMR (CDC13, 500MHz): 8,95 (d, 1H) ; 7,2-7,5 (m, 10H) ; 6,05 (s, 1H); 3,8 (s, 8H) ; 3,3 (s, 3H)1H-NMR (CDC1 3 , 500MHz): 8.95 (d, 1H); 7.2-7.5 (m, 10H); 6.05 (s, 1H); 3.8 (s, 8H); 3.3 (s, 3H)
Smp.: 174-175°CM.p .: 174-175 ° C
Analog lassen sich die in Tabelle 1 aufgeführten Verbindungen herstellen. The compounds listed in Table 1 can be prepared analogously.
Tabelle I ;oTable I; o
HH
R— Z— C c- y > R— Z— C c- y >
Nr. R1 R4, R5 R6 R2 R3 X ZNo. R 1 R 4 , R 5 R 6 R 2 R 3 XZ
1-1 COOCH3 Phenyl Methyl OMe OMe F 01-1 COOCH 3 phenyl methyl OMe OMe F 0
1-2 COOH Phenyl Methyl OMe OMe F 01-2 COOH phenyl methyl OMe OMe F 0
1-3 COOH Phenyl CH3-S-CH2-CH2- OMe OMe F 0 vo1-3 COOH phenyl CH 3 -S-CH 2 -CH 2 - OMe OMe F 0 vo
1-4 COOH Phenyl Methyl OMe OMe F -1-4 COOH Phenyl Methyl OMe OMe F -
1-5 COOH Phenyl Ethyl OMe OMe F 01-5 COOH Phenyl Ethyl OMe OMe F 0
1-6 COOH Phenyl iso-Propyl OMe OMe F O1-6 COOH phenyl isopropyl OMe OMe F O
1-7 COONa Phenyl Phenyl OMe Me F s1-7 COONa Phenyl Phenyl OMe Me F p
1-8 COOH Phenyl 3,-Φ-Di-OMe-Phenyl-CH2-CH2- OMe OMe F 01-8 COOH phenyl 3, -Φ-di-OMe-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-9 COOH Phenyl (CH3)2-CH-S02-CH2- CH2- OMe OMe F 01-9 COOH phenyl (CH 3 ) 2 -CH-S0 2 -CH 2 - CH 2 - OMe OMe F 0
1-10 COOH Phenyl CH3-S-CH2-CH2- OMe Me F 01-10 COOH phenyl CH 3 -S-CH 2 -CH 2 - OMe Me F 0
1-11 COOH Phenyl -4-OMe-Phenyl-CH2-CH2- OMe OMe F O1-11 COOH phenyl -4-OMe-phenyl-CH 2 -CH 2 - OMe OMe FO
1-12 COOH Phenyl Methyl Me OMe F -1-12 COOH Phenyl Methyl Me OMe F -
1-13 COOH Phenyl (CH3)2-CH-S02-CH2- CH2- OMe NH-OMe F 01-13 COOH phenyl (CH 3 ) 2 -CH-S0 2 -CH 2 - CH 2 - OMe NH-OMe F 0
1-14 COOH Phenyl n-Propyl OMe OMe F 0 π1-14 COOH phenyl n-propyl OMe OMe F 0π
H
Figure imgf000021_0001
1-15 COOCH3 Phenyl n-Propyl OMe OMe CF3 0 o o o H
Figure imgf000021_0001
1-15 COOCH 3 phenyl n-propyl OMe OMe CF 3 0oo
Nr. R1 R4, R5 R6 R2 R3 X ZNo. R 1 R 4 , R 5 R 6 R 2 R 3 XZ
1-16 COOH Phenyl Methyl OMe OMe F s SO1-16 COOH phenyl methyl OMe OMe F s SO
*-* -
1-17 COOH Phenyl n-Propyl OMe OEt F 0 * tΛ-.1-17 COOH phenyl n-propyl OMe OEt F 0 * tΛ-.
1-18 COOH Phenyl n-Butyl OMe OMe F 01-18 COOH phenyl n-butyl OMe OMe F 0
1-19 COOH Phenyl iso-Butyl OMe OMe F 01-19 COOH phenyl isobutyl OMe OMe F 0
1-20 COOH Phenyl iso-Butyl Me Me F 01-20 COOH phenyl isobutyl Me Me F 0
1-21 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CH2- Me Me F 01-21 COOH phenyl 3,4-di-OMe-phenyl-CH 2 -CH 2 - Me Me F 0
1-22 COOH Phenyl tert.-Butyl OMe Me F 01-22 COOH phenyl tert-butyl OMe Me F 0
1-23 COOH Phenyl Cyclopropyl-CH2- Me OMe F 01-23 COOH phenyl cyclopropyl CH 2 - Me OMe F 0
1-24 COOH Phenyl Methyl OMe CF3 F -1-24 COOH phenyl methyl OMe CF 3 F -
1-25 COOH Phenyl Cyclopentyl OMe OMe F 01-25 COOH phenyl cyclopentyl OMe OMe F 0
1-26 COOH Phenyl Cyclohexyl Me Me F 01-26 COOH Phenyl Cyclohexyl Me Me F 0
1-27 COOH Phenyl (CH3)3C-CH2-CH2- OEt OEt F O1-27 COOH phenyl (CH 3 ) 3 C-CH 2 -CH 2 - OEt OEt FO
1-28 COOH Phenyl 3,-4-Dioxomethylen-Ben2yl OMe OMe F s K-t o1-28 COOH phenyl 3, -4-dioxomethylene-Ben2yl OMe OMe F s K-t o
1-29 COOH Phenyl (CH3)2CH-CH2-CH2-€H2- OMe OMe F 01-29 COOH phenyl (CH 3 ) 2 CH-CH 2 -CH 2 - € H 2 - OMe OMe F 0
1-30 COOH Phenyl HO-CH -CH - OEt OMe F 01-30 COOH phenyl HO-CH -CH - OEt OMe F 0
1-31 COOH Phenyl H0 C-(CH2)2- Et Et F O1-31 COOH Phenyl H0 C- (CH 2 ) 2 - Et Et FO
1-32 COOH Phenyl Cyclopropylmethylen OMe OMe F 01-32 COOH phenyl cyclopropylmethylene OMe OMe F 0
1-33 COOH Phenyl H Me Me F 01-33 COOH Phenyl H Me Me F 0
1-34 COOH Phenyl Phenyl OMe OMe F 01-34 COOH Phenyl Phenyl OMe OMe F 0
1-35 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CH2- OMe Me F 01-35 COOH phenyl 3,4-di-OMe-phenyl-CH 2 -CH 2 - OMe Me F 0
1-36 COOH Phenyl Methyl CH3 CH3 F -1-36 COOH phenyl methyl CH 3 CH 3 F -
1-37 COOCH3 Phenyl Phenyl Me Mc F O1-37 COOCH 3 Phenyl Phenyl Me Mc FO
1-38 COOH Phenyl •4-Isopropyl-Phenyl OMe Me F O1-38 COOH phenyl • 4-isopropylphenyl OMe Me F O
1-39 COOH Phenyl 4-SMe-Phenyl OMe OMe F 0 o1-39 COOH phenyl 4-SMe-phenyl OMe OMe F 0 o
1-40 COOH Phenyl 4-OMe-Phenyl Me Me F 0
Figure imgf000022_0001
1-41 COOH Phenyl 3-Et-Phenyl CF3 CF3 F O o o1-40 COOH phenyl 4-OMe-phenyl Me Me F 0
Figure imgf000022_0001
1-41 COOH phenyl 3-Et-phenyl CF 3 CF 3 FO oo
OS OS
Nr. R1 R4, R5 R6 R2 R3 X ZNo. R 1 R 4 , R 5 R 6 R 2 R 3 XZ
SOSO
1-42 COOH Phenyl 2-Me-Phenyl OMe OMe F O SO1-42 COOH Phenyl 2-Me-Phenyl OMe OMe F O SO
1^3 COOH Phenyl 2-Cl-Phenyl OMe OMe F 01 ^ 3 COOH phenyl 2-Cl-phenyl OMe OMe F 0
1^4 COOH 2-Me-Phenyl Methyl OMe OMe F s1 ^ 4 COOH 2-Me-Phenyl Methyl OMe OMe F s
1^5 COOH Phenyl 3-Br-Phenyl OMe OMe F 01 ^ 5 COOH phenyl 3-Br-phenyl OMe OMe F 0
1-46 COOH Phenyl •4-F-Phenyl OMe OMe F 01-46 COOH phenyl • 4-F-phenyl OMe OMe F 0
1-47 COOH Phenyl -4-F-Phenyl Me Me F 01-47 COOH phenyl -4-F-phenyl Me Me F 0
1-48 COOH Phenyl Methyl Et Me F -1-48 COOH Phenyl Methyl Et Me F -
1^9 COOH Phenyl •4-Me-Phenyl OMe OMe F 01 ^ 9 COOH phenyl • 4-Me-phenyl OMe OMe F 0
1-50 COOH Phenyl 3-N02-Phenyl Me OMe F O1-50 COOH phenyl 3-NO 2 -phenyl Me OMe FO
1-51 COOH Phenyl 2-HO-Phenyl OMe OMe F O1-51 COOH phenyl 2-HO-phenyl OMe OMe F O
1-52 COOH Phenyl 3,-4-Di-OMe-Phenyl OMe OMe F 01-52 COOH phenyl 3, -4-di-OMe-phenyl OMe OMe F 0
1-53 COOH Phenyl 3,4-Dioxomethylen-Phenyl Me Me F 01-53 COOH phenyl 3,4-dioxomethylene-phenyl Me Me F 0
1-54 COOH Phenyl Methyl Et Et F s1-54 COOH Phenyl Methyl Et Et F s
1-55 COOH Phenyl 3,4,5-Tri-OMe4-Phenyl OMe OMe F 01-55 COOH phenyl 3,4,5-tri-OMe4-phenyl OMe OMe F 0
1-56 COOH Phenyl Benzyl OMe OMe F 01-56 COOH Phenyl Benzyl OMe OMe F 0
1-57 COOH Phenyl 2-Cl-Benzyl OMe Me F 01-57 COOH Phenyl 2-Cl-Benzyl OMe Me F 0
1-58 COOH Phenyl 3-Br-Benzyl OMe CF3 F 01-58 COOH Phenyl 3-Br-Benzyl OMe CF 3 F 0
1-59 COOH Phenyl •4-F-Benzyl OMe OMe Cl 01-59 COOH phenyl • 4-F-benzyl OMe OMe Cl 0
1-60 COOH Phenyl 2-Me-Benzyl CF3 OMe F 01-60 COOH Phenyl 2-Me-Benzyl CF 3 OMe F 0
1-61 COOH Phenyl Methyl Et Et F -1-61 COOH Phenyl Methyl Et Et F -
1-62 COOH Phenyl 2-Me-Benzyl Me OMe F 01-62 COOH Phenyl 2-Me-Benzyl Me OMe F 0
1-63 COOH Phenyl 3,-4-Di-Me-Phenyl-CH2-CH2- OMe H F o1-63 COOH phenyl 3, -4-di-Me-phenyl-CH 2 -CH 2 - OMe HF o
1-64 COOH Phenyl 3-Et-Benzyl OMe OMe F 01-64 COOH Phenyl 3-Et-Benzyl OMe OMe F 0
I- 35 ■0I- 35 ■ 0
COOH Phenyl •4-iso-Propyl-Benzyl Me Mc F 0 oCOOH phenyl • 4-iso-propyl-benzyl Me Mc F 0 o
HH
1-66 COOH Phenyl 4~OMe-3-Prυpyl-Benzyl OMe OMe F 0
Figure imgf000023_0001
1-67 COOH Phenyl 2-Me-5-Propyl-Benzyl Me OMe F 0 SO so o1-66 COOH Phenyl 4 ~ OMe-3-Propyl-Benzyl OMe OMe F 0
Figure imgf000023_0001
1-67 COOH phenyl 2-Me-5-propyl-benzyl Me OMe F 0 SO so o
OS OS
Nr. R1 R4, R5 R6 R2 R3 X ZNo. R 1 R 4 , R 5 R 6 R 2 R 3 XZ
SOSO
1-68 COOH Phenyl 2-Me-5-Propyl-Benzyl Et Et F 0 so1-68 COOH phenyl 2-Me-5-propyl-benzyl Et Et F 0 so
1-69 COOH Phenyl •4-Me-2-Propyl-Benzyl OMe OMe F 0 *>.1-69 COOH Phenyl • 4-Me-2-Propyl-Benzyl OMe OMe F 0 *>.
1-70 COOH 4-F-Phenyl Methyl OMe OMe F 01-70 COOH 4-F-phenyl methyl OMe OMe F 0
1-71 COOCH3 4-F-Phenyl Methyl Et Et F 01-71 COOCH 3 4-F-Phenyl Methyl Et Et F 0
1-72 COOH 4-Cl-Phenyl Methyl OMe OMe F 01-72 COOH 4-Cl-Phenyl Methyl OMe OMe F 0
1-73 COOH Phenyl Methyl OMe OMe F -1-73 COOH Phenyl Methyl OMe OMe F -
1-74 COOH •4-Me-Phenyl Methyl OMe OMe F 01-74 COOH • 4-Me-Phenyl Methyl OMe OMe F 0
1-75 COOH •4-OMe-Phenyl Ethyl OMe OMe F 01-75 COOH • 4-OMe-Phenyl Ethyl OMe OMe F 0
1-76 COOH 4-Me-Phenyl Methyl Me Me F 01-76 COOH 4-Me-Phenyl Methyl Me Me F 0
1-77 COOH Phenyl 3,.- -Di-OMe-Phenyl-CH2-CH2- Et Et F o1-77 COOH Phenyl 3, - -Di-OMe-Phenyl-CH 2 -CH 2 - Et Et F o
1-78 COOH 3-CF3-Phenyl n-Propyl OMe OMe F 01-78 COOH 3-CF 3 -phenyl n-propyl OMe OMe F 0
1-79 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CH2- Et Me F 01-79 COOH phenyl 3,4-di-OMe-phenyl-CH 2 -CH 2 - Et Me F 0
1-80 COOH 4-F-Phenyl Ethyl OMe OMe F 01-80 COOH 4-F-Phenyl Ethyl OMe OMe F 0
1-81 COOH Phenyl 3-OMe-Phenyl-CH2-CH2- Et Me F 01-81 COOH phenyl 3-OMe-phenyl-CH 2 -CH 2 - Et Me F 0
1-82 COOCH3 Phenyl Methyl OMe OMe F s1-82 COOCH 3 phenyl methyl OMe OMe F p
1-83 COOH 3-Cl-Phenyl Ethyl OMe OMe F 01-83 COOH 3-Cl-Phenyl Ethyl OMe OMe F 0
1-84 COOH 2-F-Phenyl Methyl OMe OMe F 01-84 COOH 2-F-phenyl methyl OMe OMe F 0
1-85 COOH 2-F-Phenyl Methyl OMe OMe F 01-85 COOH 2-F-phenyl methyl OMe OMe F 0
1-86 COOH 2-Me-Phenyl Methyl OMe OMe F 01-86 COOH 2-Me-Phenyl Methyl OMe OMe F 0
1-87 COOH Phenyl 3,4-Di-CI-Phenyl-CH2-CH2- Et Me F o1-87 COOH phenyl 3,4-di-CI-phenyl-CH 2 -CH 2 - Et Me F o
1-88 COOH Phenyl 3,4-Di-Cl-Phenyl-CH2-CH2- OMe OMe F 01-88 COOH phenyl 3,4-di-Cl-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-89 COOH -4-CF3-Phenyl Methyl OMe OMe F 01-89 COOH -4-CF 3 -phenyl methyl OMe OMe F 0
1-90 COOH Phenyl Ethyl Me Me F -1-90 COOH Phenyl Ethyl Me Me F -
1-91 COOH Phenyl Methyl OMe OEt F 0 O1-91 COOH phenyl methyl OMe OEt F 0 O
HH
1-92 COOCH3 Phenyl Methyl OMe OEt F 0
Figure imgf000024_0001
1-93 COOH Phenyl Ethyl OMe NH-OMe F 01-92 COOCH 3 phenyl methyl OMe OEt F 0
Figure imgf000024_0001
1-93 COOH Phenyl Ethyl OMe NH-OMe F 0
© o© o
-4-4
Os Os
Nr. R> R , R5 R6 R2 R3 X Z soNo. R> R, R 5 R 6 R 2 R 3 XZ see above
1-94 COOH 4-OCF3-Phenyl n-Propyl OMe OCF3 F O SO1-94 COOH 4-OCF 3 -phenyl n-propyl OMe OCF 3 FO SO
•≥:• ≥:
1-95 COOH Phenyl Propyl OMe OCF3 F s -u.1-95 COOH phenyl propyl OMe OCF 3 F s -u.
1-96 COOH Phenyl Propyl Me Me F -1-96 COOH Phenyl Propyl Me Me F -
1-97 COOH Phenyl Methyl OMe CF3 F O1-97 COOH phenyl methyl OMe CF 3 FO
1-98 COOH •4-F-Phenyl Benzyl Me Me F 01-98 COOH • 4-F-Phenyl Benzyl Me Me F 0
1-99 COOH Phenyl 3-Cl-Phenyl-CH2-CH2- Et Me F 01-99 COOH phenyl 3-Cl-phenyl-CH 2 -CH 2 - Et Me F 0
1-100 COOH Phenyl 4-Cl-Phenyl-CH2-CH2- OMe OMe F 01-100 COOH phenyl 4-Cl-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-101 COOH -4-Phenyl 3,4-Di-Cl-Phenyl-CH2-CH2- Et Me F 01-101 COOH -4-phenyl 3,4-di-Cl-phenyl-CH 2 -CH 2 - Et Me F 0
1-102 COOH -4-Phenyl 3,4-Di-Cl-Phenyl-CH2-CH2- OMe OMe F 01-102 COOH -4-phenyl 3,4-di-Cl-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-103 COOH Phenyl 3,5-Di-Cl-Phenyl-€H2-CH2- Et Me F 01-103 COOH phenyl 3,5-di-Cl-phenyl- € H 2 -CH 2 - Et Me F 0
1-104 COOH Phenyl 3,5-Di-OMe-Phenyl-CH2-CH2- OMe OMe F o1-104 COOH phenyl 3,5-di-OMe-phenyl-CH 2 -CH 2 - OMe OMe F o
1-105 COOH Phenyl Phenyl OMe OMe F s1-105 COOH phenyl phenyl OMe OMe F p
1-106 COOH Phenyl 3,4-Di-Cl-Phenyl-CH2-CH2- Et Me F s t1-106 COOH phenyl 3,4-di-Cl-phenyl-CH 2 -CH 2 - Et Me F st
1-107 COOH Phenyl 3,4-Di-OMe-Phenyl-CH2-CH2- OMe OMe F 01-107 COOH phenyl 3,4-di-OMe-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-108 COOH Phenyl 3,4-Di-Me-Phenyl-CH2-CH2- Et Me F 01-108 COOH Phenyl 3,4-Di-Me-Phenyl-CH 2 -CH 2 - Et Me F 0
1-109 COOH Phenyl 3,4-Di-Et-Phenyl-CH2-CH2- OMe OMe F 01-109 COOH phenyl 3,4-di-Et-phenyl-CH 2 -CH 2 - OMe OMe F 0
I— 110 COOH 4-F-Phenyl H OMe Me F 0I- 110 COOH 4-F-phenyl H OMe Me F 0
I— 111 COOH Phenyl 3,4-Di-Me-Phenyl-CH2-CH2- Et Me F sI- 111 COOH phenyl 3,4-di-Me-phenyl-CH 2 -CH 2 - Et Me F s
1-112 COOH Phenyl 4-Isopropyl-Phenyl-CH2-CH2- OMe OMe F 01-112 COOH phenyl 4-isopropyl-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-113 COOH -4—F-Phenyl 3,4-Di-Me-Phenyl-CH2-CH2- Et Me F 01-113 COOH -4-F-Phenyl 3,4-Di-Me-Phenyl-CH 2 -CH 2 - Et Me F 0
1-114 COOH Phenyl 4-Et-Phenyl-CH2-CH2- OMe OMe F o1-114 COOH phenyl 4-Et-phenyl-CH 2 -CH 2 - OMe OMe F o
1-115 COOH Phenyl Methyl Me Me F 01-115 COOH Phenyl Methyl Me Me F 0
1-116 COOH Phenyl Methyl Et Et F 01-116 COOH Phenyl Methyl Et Et F 0
1-117 COOH Phenyl Methyl Me "01-117 COOH Phenyl Methyl Me "0
Me CF3 0 oMe CF 3 0 o
HH
1-118 CONHS02Phenyl Phenyl Ethyl OMe CF3 F -
Figure imgf000025_0001
1-119 COOH Phenyl Methyl OMe Me F 0 so so1-118 CONHS0 2 Phenyl Phenyl Ethyl OMe CF 3 F -
Figure imgf000025_0001
1-119 COOH Phenyl Methyl OMe Me F 0 so so
© o© o
-4 ^1-4 ^ 1
O O
Nr. R1 R4, R5 R6 R2 R3 X ZNo. R 1 R 4 , R 5 R 6 R 2 R 3 XZ
SOSO
1-120 COOH Cyclohexyl Methyl OMe OMe F 0 SO1-120 COOH cyclohexyl methyl OMe OMe F 0 SO
1-121 COOH Phenyl Methyl OMe OH F 0 J1-121 COOH phenyl methyl OMe OH F 0 J
1-122 COOCH3 2-F-Phenyl Methyl OMe OMe F 01-122 COOCH 3 2-F-phenylmethyl OMe OMe F 0
1-123 COOC2H5 3-Cl-Phenyl Methyl OMe OMe F 01-123 COOC 2 H 5 3-Cl-Phenyl Methyl OMe OMe F 0
1-124 COOH Phenyl Phenyl OMe Me F s1-124 COOH Phenyl Phenyl OMe Me F s
1-125 COOCH3 Phenyl iso-Propyl OMe Me F 01-125 COOCH 3 phenyl isopropyl OMe Me F 0
1-126 COOC2H5 Phenyl s-Butyl OMe Cl F 01-126 COOC 2 H 5 phenyl s-butyl OMe Cl F 0
1-127 CONHS02Phenyl 3-CF3-Phenyl Methyl OMe Cl F o1-127 CONHS0 2 phenyl 3-CF 3 -phenyl methyl OMe Cl F o
1-128 CONHS02Phenyl Phenyl Ethyl OMe OMe F -1-128 CONHS0 2 Phenyl Phenyl Ethyl OMe OMe F -
1-129 COOH Phenyl 2,3-Di-Cl-Phenyl-CH2-CH2- Et Me F 01-129 COOH phenyl 2,3-di-Cl-phenyl-CH 2 -CH 2 - Et Me F 0
1-130 COOH Phenyl 2,3-Di-OMe-Phenyl-CH2-CH2- OMe OMe F o1-130 COOH phenyl 2,3-di-OMe-phenyl-CH 2 -CH 2 - OMe OMe F o
1-131 COOH 4-Cl-Phenyl 3,-4-Di-Me-Phenyl-CH2-CH2- OMe Me F 01-131 COOH 4-Cl-Phenyl 3, -4-Di-Me-Phenyl-CH 2 -CH 2 - OMe Me F 0
1-132 COOH Phenyl 3,4-Di-Et-Phenyl-CH2-CH2- OMe Me F 0 t1-132 COOH phenyl 3,4-di-Et-phenyl-CH 2 -CH 2 - OMe Me F 0 t
1-133 COOH Phenyl 2,6-Di-Cl-Phenyl-CH2-CH2- Et Me F s1-133 COOH phenyl 2,6-di-Cl-phenyl-CH 2 -CH 2 - Et Me F s
1-134 COOH Phenyl 2,6-Di-OMe-Phenyl-CH2-CH2- OMe OMe F 01-134 COOH phenyl 2,6-di-OMe-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-135 COOH Phenyl 2,6-Di-Me-Phenyl-CH2-CH2- Et Me F 01-135 COOH Phenyl 2,6-Di-Me-Phenyl-CH 2 -CH 2 - Et Me F 0
1-136 COOH Phenyl 2,5-Di-Cl-Phenyl-CH2-CH2- OMe OMe F 01-136 COOH phenyl 2,5-di-Cl-phenyl-CH 2 -CH 2 - OMe OMe F 0
1-137 COOC2H5 Phenyl Trifluorethyl Me Me F 01-137 COOC 2 H 5 phenyl trifluoroethyl Me Me F 0
1-138 COOH Phenyl n-Propyl Et Me F -1-138 COOH phenyl n-propyl Et Me F -
1-139 COOH Phenyl HO-CH2-<HO-CH)-CH2- Me Me F 01-139 COOH phenyl HO-CH 2 - <HO-CH) -CH 2 - Me Me F 0
1-140 COOH Phenyl HO-CH2-<HO-CH)-CH2- OMe OMe F 01-140 COOH phenyl HO-CH 2 - <HO-CH) -CH 2 - OMe OMe F 0
1-141 COOH •4-Cl-Phenyl HO-CH2-<HO-CH)-CH2- OMe Me F o1-141 COOH • 4-Cl-phenyl HO-CH 2 - <HO-CH) -CH 2 - OMe Me F o
1-142 COOH Phenyl HO-CH2-CH2-CH2- OMe Me F 01-142 COOH phenyl HO-CH 2 -CH 2 -CH 2 - OMe Me F 0
1-143 COOH Phenyl H0-CH2-CH2-CH2- Et Me F s o1-143 COOH Phenyl H0-CH 2 -CH 2 -CH 2 - Et Me F so
1-144 COOH Phenyl HO-CH2-CH2-CH2- OMe OMe F 0
Figure imgf000026_0001
1-145 COOH Phenyl HO-CH2-CH2-CH2- Et Me F 0 so o1-144 COOH phenyl HO-CH 2 -CH 2 -CH 2 - OMe OMe F 0
Figure imgf000026_0001
1-145 COOH phenyl HO-CH 2 -CH 2 -CH 2 - Et Me F 0 so o
©©
© ©
1-146 COOH Phenyl 3-Cl-Phenyl OMe Me F S1-146 COOH phenyl 3-Cl-phenyl OMe Me F S
1-147 COOH Phenyl HO-CHr-CH - OMe OMe F 0 SO1-147 COOH phenyl HO-CHr-CH - OMe OMe F 0 SO
SOSO
1-148 COOH Phenyl Phenyl Me Me F 01-148 COOH Phenyl Phenyl Me Me F 0
-ü.-ü.
1-149 COOH Phenyl Phenyl Me OMe F o in1-149 COOH Phenyl Phenyl Me OMe F o in
1-150 COOH Phenyl Phenyl CF3 CF3 F 01-150 COOH phenyl phenyl CF 3 CF 3 F 0
1-151 COOH Phenyl Phenyl Et OMe F 01-151 COOH Phenyl Phenyl Et OMe F 0
1-152 COOH Phenyl Phenyl Et Et F 01-152 COOH Phenyl Phenyl Et Et F 0
1-153 COOH Phenyl 2-Thiazolyl OMe OMe F 01-153 COOH phenyl 2-thiazolyl OMe OMe F 0
1-154 COOCH3 2-F-Phenyl Phenyl OMe OMe F 01-154 COOCH 3 2-F-Phenyl Phenyl OMe OMe F 0
1-155 COOC2H5 3-Cl-Phenyl Phenyl OMe OMe F 01-155 COOC 2 H 5 3-Cl-Phenyl Phenyl OMe OMe F 0
1-156 COOCH3 Phenyl •4-Br-Phenyl OMe Me F 01-156 COOCH 3 phenyl • 4-Br-phenyl OMe Me F 0
1-157 COOC2H5 Phenyl •4-Thiazolyl OMe Cl F 01-157 COOC 2 H 5 phenyl • 4-thiazolyl OMe Cl F 0
1-158 COOH Phenyl Ethyl OMe OMe F -1-158 COOH Phenyl Ethyl OMe OMe F -
1-159 COOH •4-F-Phenyl Methyl Ethyl OMe F 0 to1-159 COOH • 4-F-phenyl methyl ethyl OMe F 0 to
1-160 CONHS02Phenyl 4-F-Phenyl Phenyl OMe OMe F 01-160 CONHS0 2 phenyl 4-F-phenyl phenyl OMe OMe F 0
1-161 COOC2H5 Phenyl 4-Imidazolyl OMe CF3 F 01-161 COOC 2 H 5 phenyl 4-imidazolyl OMe CF 3 F 0
1-162 CONHS02Phenyl •4-CF3-Phenyl Phenyl OMe Cl F 01-162 CONHS0 2 phenyl • 4-CF 3 -phenyl phenyl OMe Cl F 0
1-163 COOCH3 Phenyl 4-F-Phenyl Me OCF3 F o1-163 COOCH 3 phenyl 4-F-phenyl Me OCF 3 F o
1-164 COOC2H5 Phenyl 2-Dimethylaminophenyl Me Me F 01-164 COOC 2 H 5 phenyl 2-dimethylaminophenyl Me Me F 0
1-165 COOH Phenyl Propyl Me OMe F -1-165 COOH Phenyl Propyl Me OMe F -
1-166 COOH Phenyl n-Pentyl Me Me F o1-166 COOH phenyl n-pentyl Me Me F o
1-167 COOH Cyclohexyl Methyl OMe OMe F 01-167 COOH cyclohexyl methyl OMe OMe F 0
1-168 COOH Phenyl Methyl Morpholin H F 01-168 COOH phenyl methyl morpholine H F 0
1-169 COOH Phenyl Phenyl CF3 CF3 F s1-169 COOH phenyl phenyl CF 3 CF 3 F s
1-170 COOH 3-F-Phenyl Methyl OMe OMe F 0 131-170 COOH 3-F-phenyl methyl OMe OMe F 0 13
OO
1-171 COOH 3-OMe-Phenyl Methyl Me OMe F 0 H
Figure imgf000027_0001
1-172 COOH Phenyl Methyl Et CF3 F 0 o so ©1-171 COOH 3-OMe-Phenyl Methyl Me OMe F 0 H
Figure imgf000027_0001
1-172 COOH Phenyl Methyl Et CF 3 F 0 o so ©
©©
O O
1-173 COOH 3-F-Phenyl Methyl OMe Me F 01-173 COOH 3-F-Phenyl Methyl OMe Me F 0
SOSO
1-174 COOH Phenyl Propyl OMe CF3 F - SO1-174 COOH phenyl propyl OMe CF 3 F - SO
**
1-175 CONHS02Phenyl Phenyl Methyl Me Me F 01-175 CONHS0 2 phenyl phenyl methyl Me Me F 0
1-176 CONHS02CH3 Phenyl Methyl Me Me F 01-176 CONHS0 2 CH 3 Phenyl Methyl Me Me F 0
1-177 COONa Phenyl Methyl Et Me F 01-177 COONa Phenyl Methyl Et Me F 0
1-178 CONHS02CH3 Phenyl Methyl Et Me F 01-178 CONHS0 2 CH 3 phenyl methyl Et Me F 0
1-179 Tetrazol Phenyl Methyl OMe OMe F 01-179 Tetrazole Phenyl Methyl OMe OMe F 0
1-180 COOH Phenyl Propyl Et Et F -1-180 COOH Phenyl Propyl Et Et F -
1-181 COOH Phenyl Propyl OMe OMe F -1-181 COOH Phenyl Propyl OMe OMe F -
1-182 COOH 3-Me-Phenyl Methyl OMe OMe F 0
Figure imgf000028_0001
1-183 COOH -4-F-Phenyl Methyl OMe Me F 01-182 COOH 3-Me-Phenyl Methyl OMe OMe F 0
Figure imgf000028_0001
1-183 COOH -4-F-Phenyl Methyl OMe Me F 0
t σ-t σ-
n H eän H eä
"0 so"0 so
SOSO
© o© o
OS OS
Tabelle II l-JTable II 1-J
Figure imgf000029_0001
Figure imgf000029_0001
Nr. R1 A R6 R2 R3 X Z tNo. R 1 AR 6 R 2 R 3 XZ t
-J-J
II— 1 COOH Bindung Methyl OMe OMe F 0II— 1 COOH bond methyl OMe OMe F 0
II-2 COOH CH2 Methyl OMe OMe F 0II-2 COOH CH 2 methyl OMe OMe F 0
II— 3 COOH CH2-CH2 Methyl OMe OMe F 0II- 3 COOH CH 2 -CH 2 methyl OMe OMe F 0
II-4 COOH CH=CH Methyl OMe OMe F 0 π-5 COOH 0 Methyl OMe OMe F 0 π-6 COOH S Methyl OMe OMe F o π-7 COOH NH(CH3) Methyl OMe OMe F 0 π-8 COOH Bindung Isopropyl OMe OMe F 0 π-9 COOH Bindung p-Isopropylphenyl OMe OMe F 0II-4 COOH CH = CH Methyl OMe OMe F 0 π-5 COOH 0 Methyl OMe OMe F 0 π-6 COOH S Methyl OMe OMe F o π-7 COOH NH (CH 3 ) Methyl OMe OMe F 0 π-8 COOH Binding isopropyl OMe OMe F 0 π-9 COOH binding p-isopropylphenyl OMe OMe F 0
11-10 COOH Bindung Benzyl OMe OMe F 011-10 COOH bond benzyl OMe OMe F 0
11—11 COOH CH=CH Ethyl OMe OMe F 0 "0 π11-11 COOH CH = CH ethyl OMe OMe F 0 "0 π
11-12 COOH CH=CH (CH3)2-CH2-CH2- OMe OMe F 0
Figure imgf000029_0002
π-13 COOH CH=CH Cyclopropyl-CH2- OMe OMe F 0 so -•o11-12 COOH CH = CH (CH 3 ) 2 -CH 2 -CH 2 - OMe OMe F 0
Figure imgf000029_0002
π-13 COOH CH = CH cyclopropyl-CH 2 - OMe OMe F 0 so - • o
©©
© ©
2828
Beispi el 5Example 5
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 3 dargestellt.The results are shown in Table 3.
Tabelle 3Table 3
Rezeptorbindungsdaten (Ki-Werte)Receptor binding data (Ki values)
Verbindung ETA [nM] ETB [nM]Connection ET A [nM] ET B [nM]
1-2 7,4 12001-2 7.4 1200
1-121 61 > 10000
Figure imgf000030_0001
1-168 4000 > 7000 1-121 61> 10000
Figure imgf000030_0001
1-168 4000> 7000

Claims

29Patentansprüche : 29 patent claims:
1. Carbonsäurederivate der Formel I R2 1. Carboxylic acid derivatives of the formula IR 2
HH
C c- \\ ll N: C c- \\ ll N :
R3 R 3
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
R1 Tetrazol oder eine Gruppe OR 1 tetrazole or a group O
I II I
C—RC — R
RR
ein Rest OR7, worin R7 bedeutet:a radical OR 7 , in which R 7 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion oder Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically acceptable organic ammonium ion or ammonium ion;
C3-C8-Cycloalkyl, Cι-C8-Alkyl, CH2-Phenyl, das durch einen oder mehrere der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι~C4-Alkoxy, Mercapto, Cι-C-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2;C 3 -C 8 cycloalkyl, -CC 8 alkyl, CH 2 -phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, -C-alkyl, -C-C 4 haloalkyl , Hydroxy, -C ~ C 4 alkoxy, mercapto, -C -C alkylthio, amino, NH (-C -C 4 alkyl), N (-C 4 alkyl) 2 ;
Eine C3-C6-Alkenyl- oder eine C3-C6~Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können;A C 3 -C 6 alkenyl or a C 3 -C 6 ~ alkynyl group, these groups in turn being able to carry one to five halogen atoms;
R7 kann weiterhin ein Phenylrest sein, welcher ein bis fünf Halogenatome und/oder ein bis drei der folgenden Reste tragen kann: Nitro, Cyano, Cι~C4-Alkyl, Cχ-C-Halogen- alkyl, Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino,R 7 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 -Alkoxy, mercapto, -CC 4 -alkylthio, amino,
NH(Cι-C -Alkyl) , N(C1-C4-Alkyl) 2;NH (-CC alkyl), N (C 1 -C 4 alkyl) 2 ;
b) ein über ein Stickstoffatom verknüpfter 5 gliedriger Heteroaromat wie Pyrrolyl, Pyrazolyl, Imidazolyl und Tria- zolyl, welcher ein bis zwei Halogenatome, oder eins bis 30 zwei Cι-C4-Alkyl oder eins bis zwei Cι-C4-Alkoxygruppen tragen kann.b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which has one or two halogen atoms or one to 30 can carry two C 1 -C 4 alkyl or one to two C 1 -C 4 alkoxy groups.
c) eine Gruppe (°Kc) a group ( ° K
—0-(CH2)p-S —R8 -0- (CH 2 ) p -S -R 8
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen und R8 fürwhere k is 0, 1 and 2, p is 1, 2, 3 and 4 and R 8 is
Cι-C4-Alkyl, C3-C8-Cycloalkyl , C3-C6-Alkenyl, C3-C6-Alkinyl oder Phenyl steht, das durch einen oder mehrere, z.B. ein bis drei der folgenden Reste substituiert sein kann:-C-C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or phenyl, which can be substituted by one or more, for example one to three of the following radicals :
Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Cι-C-Alkylthio, Mercapto, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2.Halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mercapto, amino, NH (C 1 -C 4 alkyl), N ( C 1 -C 4 alkyl) 2 .
d) ein Restd) a rest
N S—R9 NS — R 9
HH
worin R9 bedeute :where R 9 means:
Cι-C-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl, C3-C8-Cyclo- alkyl, wobei diese Reste einen Cχ-C4-Alkoxy, Cι~C4-Alkyl- thio- und/oder einen Phenylrest wie unter c) genannt tragen können;C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, these radicals being a Cχ-C 4 -alkoxy, Cι ~ C 4 -alkyl- can carry thio and / or a phenyl radical as mentioned under c);
Phenyl, das durch ein bis drei der folgenden Reste sub- stituiert sein kann: Halogen, Nitro, Cyano, Cx-Cj-Alkyl, Cχ-C-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Cι-C-Alkyl- thio, Mercapto, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl)2 Phenyl, which can be substituted by one to three of the following radicals: halogen, nitro, cyano, Cx-Cj-alkyl, Cχ-C-haloalkyl, hydroxy, Cι-C 4 alkoxy, Cι-C-alkylthio , Mercapto, amino, NH (-C 4 alkyl), N (-C 4 alkyl) 2
R2 Wasserstoff, Hydroxy, NH2, NH(Cι-C-Alkyl) , N(Cι-C4-Al- kyl)2, Halogen, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Cι-C-Hydroxyalkyl, Cι-C-Halogenalkyl, Cι-C4-Alkoxy, C!-C4-Halogenalkoxy oder Cι-C4-Alkylthio, Morpholin;R 2 is hydrogen, hydroxyl, NH 2 , NH (-CC alkyl), N (-C 4 alkyl) 2 , halogen, -C alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, -C-C-hydroxyalkyl, Cι-C-haloalkyl, Cι-C 4 alkoxy, C ! -C 4 -haloalkoxy or -C-C 4 alkylthio, morpholine;
X Halogen, Cι-C4-Halogenalkyl, Hydroxy; 31X halogen, -CC 4 haloalkyl, hydroxy; 31
R3 Wasserstoff, Hydroxy, NH , NH(Cχ-C4-Alkyl) , N(Cι-C4-Al- kyl)2, Halogen, Cι~C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Cι-C-Hydroxyalkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, -NH-0-Cι-C4-Alkyl, Cι-C4-Alkylthio;R 3 is hydrogen, hydroxy, NH, NH (Cχ-C 4 -alkyl), N (-C-C 4 -alkyl) 2 , halogen, Cι ~ C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, -C-C-hydroxyalkyl, Cι-C 4 -haloalkyl, Cι-C 4 -alkoxy, Cι-C 4 -haloalkoxy, -NH-0-Cι-C 4 -alkyl, Cι-C 4 - Alkylthio;
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, Cι-C4-Alkyl, Cι-C4-Halogenalkyl,Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, Cι-C 4 -alkyl, C 4 haloalkyl,
Cι-C4-Alkoxy, Cχ-C4-Halogenalkoxy, Phenoxy, Mercapto, Alkylcarbonyl, Alkoxycarbonyl, Cι-C4-Alkylthio, Amino, NH(Cχ-C4- lkyl) , N(Cι-C-Alkyl) 2 ; oder Cι-C4-alkoxy, Cχ-C 4 haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, Cι-C4 alkylthio, amino, NH (Cχ-C 4 - lkyl), N (Cι-C alkyl) 2 ; 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 sind; oderPhenyl 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; or
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, 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~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: -CC 4 alkyl, -C-C 4 - Haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 4 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals in turn being able to carry one to five halogen atoms and / or one to three of the following radicals: Cι -C 4 -alkyl, -C-C 4 -haloalkyl, -C-C 4 -alkoxy, Cι-C 4 ~ haloalkoxy and / or -C-C 4 ~ alkyl thio;
oder C3-C7-Cycloalkyl ;or C 3 -C 7 cycloalkyl;
R6 Wasserstoff ,R 6 is hydrogen,
Cι-C8-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl oder C3-C8-Cy- cloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Hydroxy, Mercapto, Carboxy, Halogen, Nitro, Cyano, Cι-C4~Alkoxy, C3-C6~Alkeny- loxy, C3-C6-Alkinyloxy, Cι-C4-Alkylthio, Cι~C4-Halogenal- koxy, Cι-C4-Alkylcarbonyl, Cι-C4-Alkoxycarbonyl , C3-Cs-Al- kylcarbonylalkyl, Amino, NH (C1--C4-Alkyl ) , N(C!-C4-Alkyl) 2, Phenyl ein- oder mehrfach substituiert, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι~C4-Halogenalkoxy oder Cχ-C4-Alkylthio substituiertes Phenyl oder Phenoxy; 32C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, where these radicals can each be mono- or polysubstituted by: hydroxy, mercapto, Carboxy, halogen, nitro, cyano, C 1 -C 4 ~ alkoxy, C 3 -C 6 ~ alkenyloxy, C 3 -C 6 alkynyloxy, C -C 4 alkylthio, C ~ C 4 haloalkoxy, Cι -C 4 -alkylcarbonyl, -C-C 4 -alkoxycarbonyl, C 3 -Cs-alkylcarbonylalkyl, amino, NH (C 1 --C 4 -alkyl), N (C ! -C 4 -alkyl) 2 , phenyl - or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, Cι-C4-alkoxy, Cι ~ C4 haloalkoxy or Cχ-C 4 - Alkylthio substituted phenyl or phenoxy; 32
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Amino, Cι-C- l yl, Cι-C4-Ha- logenalkyl, Cι-C4-Alkoxy, Cι~C4-Halogenalkoxy, Phenoxy, Cι-C4-Alkylthio, , NH (Cι-C-Alkyl) , N(Cι-C4-Alkyl) oderPhenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C 1 -C 1 yl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 ~ C 4 haloalkoxy, phenoxy, -C 4 alkylthio,, NH (-C -C alkyl), N (-C 4 alkyl) or
Dioxomethylen oder Dioxoethylen;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: Cι-C-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halo- genalkoxy, Cι-C4~Alkylthio, Phenyl, Phenoxy oder Phenyl- carbonyl, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: C1-C4-Alkyl, Cι-C4-Halogenalkyl, C1-C4-AI- koxy, Cχ-C4-Halogenalkoxy und/oder Cι~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: -CC alkyl, -C-C 4 haloalkyl C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 4 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals in turn carrying one to five halogen atoms and / or one to three of the following radicals can: C 1 -C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy -AI-, Cχ-C 4 -haloalkoxy and / or Cι ~ C 4 alkylthio;
mit der Maßgabe, daß R6 nur dann Wasserstoff bedeuten kann, wenn Z keine Einfachbindung darstellt;with the proviso that R 6 can only be hydrogen if Z is not a single bond;
Z Schwefel, Sauerstoff oder eine Einfachbindung,Z sulfur, oxygen or a single bond,
sowie die physiologisch verträglichen Salze, und die enantio- merenreinen sowie diastereomerenreinen Formen.as well as the physiologically tolerated salts, and the enantiomerically pure and diastereomerically pure forms.
2. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Behandlung von Krankheiten.2. Use of the carboxylic acid derivatives I according to claim 1 for the treatment of diseases.
3. Verwendung der Verbindungen I gemäß Anspruch 1 als Endothe- lin-Rezeptorantagonisten .3. Use of the compounds I according to claim 1 as endothelin receptor antagonists.
4. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, bei denen erhöhte Endothelinspiegel auftreten.4. Use of the carboxylic acid derivatives I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which increased endothelin levels occur.
5. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, bei denen Endothelin zur Entstehung und/oder Progression bei- trägt.5. Use of the carboxylic acid derivatives I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which endothelin contributes to the development and / or progression.
6. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Behandlung von chronischer Herzinsuffizienz, Restenose, Bluthochdruck, pulmonalem Hochdruck, akutem/chronischen Nieren- versagen, zerebraler Ischämie, Astma, benigne Prostatahyper- plasie und Prostatakrebs. 336. Use of the carboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. 33
7. Kombinationen aus Carbonsäurederivaten der Formel I gemäß Anspruch 1 und einem oder mehreren Wirkstoffen, ausgewählt aus Inhibitoren des Renin-Angiotensin Systems wie Reninhemmer, Angiotensin-II-Antagonisten, Angiotensin-Converting-Enzyme (ACE) -Hemmer, gemischten ACE/Neutrale Endopeptidase7. Combinations of carboxylic acid derivatives of the formula I according to claim 1 and one or more active substances, selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE / neutral endopeptidase
(NEP) -Hemmern, ß-Blockern, Diuretika, Calciumantagonisten und VEGF-blockierenden Substanzen.(NEP) inhibitors, β-blockers, diuretics, calcium channel blockers and VEGF-blocking substances.
8. Arzneimittelzubereitungen zur peroralen, parenteralen und in- traperenteralen Anwendung, enthaltend pro Einzeldosis, neben den üblichen Arzneimittelhilfsstoffen, mindestens ein Carbonsäurederivat I gemäß Anspruch 1. 8. Pharmaceutical preparations for oral, parenteral and intraperenteral use, containing per single dose, in addition to the usual pharmaceutical excipients, at least one carboxylic acid derivative I according to claim 1.
PCT/EP1999/000776 1998-02-17 1999-02-05 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists WO1999042453A1 (en)

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