WO2000009489A1 - New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists - Google Patents

New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists Download PDF

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Publication number
WO2000009489A1
WO2000009489A1 PCT/EP1999/005728 EP9905728W WO0009489A1 WO 2000009489 A1 WO2000009489 A1 WO 2000009489A1 EP 9905728 W EP9905728 W EP 9905728W WO 0009489 A1 WO0009489 A1 WO 0009489A1
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alkyl
phenyl
formula
compounds
carboxylic acid
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PCT/EP1999/005728
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German (de)
French (fr)
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Wilhelm Amberg
Rolf Jansen
Georg Kettschau
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Basf Aktiengesellschaft
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Priority to BR9912889-6A priority Critical patent/BR9912889A/en
Priority to CA002340167A priority patent/CA2340167A1/en
Priority to PL99345998A priority patent/PL345998A1/en
Priority to EP99939457A priority patent/EP1104410A1/en
Priority to AU53741/99A priority patent/AU5374199A/en
Priority to JP2000564942A priority patent/JP2002522531A/en
Priority to SK83-2001A priority patent/SK832001A3/en
Priority to IL14091599A priority patent/IL140915A0/en
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to KR1020017001731A priority patent/KR20010072378A/en
Publication of WO2000009489A1 publication Critical patent/WO2000009489A1/en
Priority to NO20010622A priority patent/NO20010622D0/en
Priority to BG105236A priority patent/BG105236A/en
Priority to HR20010164A priority patent/HRP20010164A2/en
Priority to HK02103679.0A priority patent/HK1042086A1/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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • 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, 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 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, 211, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322. 205 (1989), N. Engl. J. Med. 223., 1732 (1993), Nephron 66/373 (1994) , Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996)).
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to the two receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • Mixed endothelin receptor antagonists are compounds that bind to the ET A and the ET B receptor with approximately the same affinity. There is approximately the same affinity for the receptors if the quotient of the affinities is greater than 0.05 (preferably 0.1) and less than 20 (preferably 10).
  • Mixed ET A / ET B receptor antagonists have been described in patent application DE 19636046.3.
  • the spacer Q (see formula XX), which corresponds in length to a CC 4 alkyl chain, is important for these compounds.
  • the task was to identify compounds which bind to the ET A and the ET B receptor with approximately the same affinity and which have more advantageous properties than the already known mixed endothelin receptor antagonists.
  • the invention relates to carboxylic acid derivatives of the formula I.
  • 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;
  • 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 ⁇ -C 4 -haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy, mercapto, C ⁇ -C 4 alkylthio, amino, NH (C ⁇ -C alkyl), N (C ⁇ -C4 alkyl) 2;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two C 1 -C 4 -alkoxy groups ,
  • Halogen nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, C1.-C4 -Alkylth.io, mercapto, amino, NH (C ⁇ -C 4 - Alkyl), N (-CC alkyl) 2 .
  • R 2 is hydrogen, hydroxyl, NH 2 , NH (C ⁇ -C-alkyl), N (-C-C 4 alkyl) 2 , halogen, -C-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C -Alkynyl, -CC 4 -hydroxyalkyl, -CC 4 -haloalkyl, -C ⁇ C -alkoxy, -C-C 4 -haloalkoxy or -C-C 4 alkylthio, or CR 2 is with CR 12 as indicated under Z to one 5- or 6-membered ring linked,
  • C ⁇ -C4-haloalkyl or C ⁇ -C 4 alkyl, or CR 12 forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring, by one or two C ⁇ -C 4 alkyl groups can be substituted and in which one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC 4 -alkyl), at least one of the ring members X, Y or Z being nitrogen.
  • R 3 is hydrogen, hydroxy, NH 2, NH (C ⁇ * -C 4 alkyl), N (C ⁇ -C4 alkyl) 2, halogen, C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, C] .- C 4 -haloalkyl, -C-C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C 1 -C 4 -hydroxyalkyl, C ⁇ -C-alkylthio, or CR 3 is with CR 12th linked as in Z to form a 5- or 6-membered ring.
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl, C -C 4 alkynyl, C ⁇ - C 4 -Halogenalkyi, -C-C 4 alkoxy, phenoxy, carboxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, amino, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 alkyl) ) 2 or phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, * -C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy or -C-C
  • R 6 is C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C; L -C-Alkylthio, C 1 -C 4 -haloalkoxy, -C-C-alkylcarbonyl, C ⁇ -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, carboxamide, NH (C ⁇ -C 4 -alkyl), N (-C 4 alkyl) 2 , or phenyl, which can be substituted one or more times, for example one to three times by halogen,
  • Phenyl or naphthyl which in each case by a plurality of the following radicals may be substituted or halogen, R 15, nitro, mercapto, carboxyl, cyano, hydroxy, amino, C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, C 3 -C e alkenyloxy, dC 4 haloalkyl, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, carboxamide, C x - C 4 -alkoxy, -C-C-haloalkoxy, phenoxy, -C-C 4 -alkylthio, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , dioxomethylene, dioxoethylene or phenyl , which may be mono- or polysub
  • R 7 and R 8 (which may be the same or different):
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • C 1 -C 4 haloalkyl can be linear or branched: such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, tric lormethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2nd -Chlor-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl, *
  • C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 -alkyl can be linear or branched, such as methyl,
  • C 4 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
  • CC 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C ⁇ ⁇ C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • C 3 -C 3 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 1 -C 4 -Alkylthio can be linear or branched such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropyithio or 1, 1-dimethylethylthio;
  • C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
  • C 1 -C 4 -alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl, *
  • C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl
  • Ci-Cs-alkyl can be linear or branched, e.g. C] _- C 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 I and also the intermediates for their preparation, e.g. II, III, IV, V and VI, can have one or more asymmetrically substituted carbon atoms.
  • Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
  • the use of an enantiomerically pure compound as the active ingredient is preferred.
  • the invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
  • the compounds according to the invention are suitable as mixed antagonists as defined at the outset.
  • the compounds of the general formula IV in which W is sulfur or oxygen can be prepared as described in WO 96/11914. In this reaction, the later keto group is protected as a cyclic acetal; however, other protective groups are also conceivable, such as, for example, direthylacetal.
  • enantiomeric compounds of the formula IV can be obtained by carrying out a classic resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV.
  • bases are e.g. 4-chlorophenylethylamine and bases as mentioned in WO 96/11914.
  • Carboxylic acid derivatives of the general formula IV can then be reacted with compounds of the general formula V, substances of type VI being obtained.
  • at least one of the ring members X or Y or Z is nitrogen.
  • the reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
  • 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, dirnethylformamide, dimethylacetamide and N-methylpyrrolidone
  • sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
  • an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide or lithium amide.
  • the compounds according to the invention in which the substituents have the meaning given under the general formula I can finally be prepared by splitting off the keto protective group in the compounds of the formula VI.
  • this can be done by acid hydrolysis.
  • Type I compounds can furthermore be synthesized via compounds having the formula VII.
  • Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolid transferred and then reacted with a corresponding hydroxyl compound H ⁇ R 9 .
  • This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible.
  • These two steps can also be simplified, for example, by adding the carboxylic acid to
  • 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 is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation.
  • R 1 represents a group COOM
  • M is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation.
  • R 9 -A where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and Methylsulfonyl or other equivalent leaving group.
  • the preparation of the compounds I according to the invention requires the use of generally known protective group techniques.
  • the hydroxyl group can first be protected as a benzylet, 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, N (-CC 4 -alkyl) 2 , -C * -C 4 -alkyl, -C-C 4 -alkoxy, -C-C 4 -alkylthio, C ⁇ -C-haloalkyl, C ⁇ -C -haloalkoxy, hydroxymethyl or CR 2 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
  • R 3 is hydrogen, N (C ⁇ -C4 alkyl) 2, C ⁇ -C4-alkyl, C ⁇ -C -alkoxy, C ⁇ -C 4 alkylthio, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 haloalkoxy, hydroxymethyl or CR 3 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which can be mono- to trisubstituted by halogen, cyano, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, phenoxy, CC 4 alkylthio, NH (C ⁇ -C 4- alkyl) or N (C ⁇ -C 4 -alkyl) 2 or phenyl, which can be mono- to trisubstituted by halogen, cyano, C ⁇ -C 4 -alkyl, C ⁇ -C -haloalkyl, C ⁇ -C 4 -alkoxy , C ⁇ -C 4 haloalkoxy or C ⁇ -C 4 alkylchio; or
  • Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-alkyl group;
  • R 6 C 3 -C 8 cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -alkylthio, C ⁇ -C 4 -Haloalkoxy,
  • C ⁇ -C 4 -alkoxycarbonyl or phenyl which can be mono- to trisubstituted by halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C-alkoxy, C ⁇ -C-haloalkoxy or C ⁇ - C 4 alkylthio;
  • Phenyl or naphthyl each of which can be mono- to trisubstituted by halogen, R 15 , cyano, hydroxy, C ⁇ -C-alkyl, C ⁇ -C-haloalkyl, C ⁇ -C 4 -alkylcarbonyl, C ⁇ -C-alkoxycarbonyl, C ⁇ - C 4 -alkoxy, C ⁇ -C-haloalkoxy, phenoxy, C ⁇ -C 4 -alkylthio, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, the one can be substituted up to three times by halogen, cyano, C ⁇ -C-alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C-alkoxy, C ⁇ -C-haloalkoxy or C ⁇ -C 4 -alkylthi ⁇ ;
  • a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one or two halogen atoms and / or one or two of the following radicals: C ⁇ -C 4 -alkyl, C ⁇ -C 4 - Alkoxy, trifluoromethoxy, C ⁇ -C 4 alkylthio, phenyl or phenoxy, the phenyl radicals in turn one to five
  • R 15 is methyl, ethyl, methoxy or ⁇ thoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C-alkyl) 2 , carboxamide or CON (C ⁇ -C 4- alkyl) 2 , -
  • R 2 trifluoromethyl, C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, C ⁇ -C alkylthio, or CR 2 is linked with CR 12 as uncer Z to a 5- or 6-membered ring;
  • At least one of the ring members X, Y or Z is nitrogen
  • R3 trifluoromethyl, C ⁇ -C 4 -alkyl, C ⁇ -C-alkoxy, C ⁇ -C-alkylthio or CR 3 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
  • R 4 and R 5 (which may be the same or different):
  • Phenyl or naphthyl which can be mono- to trisubstituted by halogen, C Halogen-C-alkyl, C ⁇ -C 4 alkoxy, phenoxy or phenyl, which can be mono- to trisubstituted by halogen, C ⁇ -C 4 alkyl or C ⁇ -C 4 alkoxy; or
  • Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group or an S0 group;
  • Phenyl or naphthyl which can each be mono- to trisubstituted by halogen, R 15 , C ⁇ -C-alkyl, C ⁇ -C 4 -haloalkyl, acetyl, C ⁇ -C-alkoxycarbonyl, C ⁇ -C-alkoxy, phenoxy, C ⁇ - C 4 alkylthio, dioxomethylene, dioxoethylene or phenyl, which can be mono- to trisubstituted by halogen, C ⁇ -C-alkyl, CC-alkoxy, or C ⁇ -C 4 -alkylthio;
  • R 7 and R 8 (which may be the same or different):
  • R 15 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, carboxamide or CON (C ⁇ -C 4 -alkyl) 2 , *
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pank , gastrointestinal ulcers.
  • the invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors.
  • 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 endotheliai growth factor).
  • VEGF vascular endotheliai growth factor
  • substances which block the action of VEGF are, for example, antibodies directed against VEGF or specific binding proteins or also low-molecular substances which can specifically inhibit VEGF release or receptor binding.
  • the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
  • the form of application can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally.
  • Another object of the invention is a structural fragment of the formula
  • Such structural fragments are suitable as structural components of endothelin receptor antagonists, in particular of mixed endothelin receptor antagonists.
  • Another object of the invention are endothelin receptor antagonists consisting of a structural fragment of the formula
  • radicals R 1 , R 2 , R 3 , R 4 , R 5 , R, R 8 , W, X, Y and Z have the abovementioned meaning, covalently linked to a group which preferably has a molecular weight of at least 40 has at least 77. 5
  • the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml 20 streptomycin (Gibco, Sigma No. P-0781) increased. After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 cells / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl,
  • test animals were given the test compounds i.v. 30 min before the ETI administration. injected (1 mg / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
  • mice Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for blood pressure measurement) and the jugular vein (application of big endoteline / endothelin 1) are catheterized.
  • big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient is between ecwa 0.5 and 50 mg / kg body weight with oral administration and between approximately 0.1 and 10 mg / kg body weight with parenteral administration.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.

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Abstract

The invention relates to new carboxylic acid derivatives of the formula (I), where the substituents have the meaning given in the description, their production and their use as endothelin-receptor antagonists.

Description

Neue Carbonsäurederivate, die Ketoseitenketten tragen, ihre Herstellung und Verwendung als Endothelin-RezeptorantagonistenNew carboxylic acid derivatives bearing keto side chains, their production and use as endothelin receptor antagonists
Beschreibungdescription
Die vorliegende Erfindung betrifft neue Carbonsäurederivate, deren Herstellung und Verwendung.The present invention relates to new carboxylic acid derivatives, their preparation and use.
Endothelin ist ein aus 21 Aminosäuren aufgebautes Peptid, das von vaskulärem Endothel synthetisiert und freigesetzt wird. Endothelin existiert in drei Isoformen, ET-1, ET-2 und ET-3. Im Folgenden bezeichnet "Endothelin" oder "ET" eine oder alle Isoformen von Endothelin. Endothelin ist ein potenter Vaso- konstriktor und hat einen starken Effekt auf den Gefäßtonus. Es ist bekannt, daß diese Vasokonstriktion von der Bindung von Endothelin an seinen Rezeptor verursacht wird (Nature, 332 , 411-415, 1988; FEBS Letters, 211, 440-444, 1988 und Biochem. Biophys. Res. Commun. , 154, 868-875, 1988).Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. Hereinafter, "endothelin" or "ET" means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 211, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Erhöhte oder abnormale Freisetzung von Endothelin verursacht eine anhaltende Gefäßkontraktion in peripheren, renalen und zerebralen Blutgefäßen, die zu Krankheiten führen kann. Wie in der Literatur berichtet, ist Endothelin in einer Reihe von Krankheiten invol- viert. Dazu zählen: Hypertonie, akuter Myokardinfarkt, pulmonäre Hypertonie, Raynaud-Syndrom, zerebrale Vasospasmen, Schlaganfall, benigne Prostatahypertrophie, Atherosklerose und Asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl . J. Med. 322. 205 (1989), N. Engl. J. Med. 223., 1732 (1993), Nephron 66/ 373 (1994), Stroke 25., 904 (1994), Nature 365., 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56., 663 (1996)).Increased or abnormal release of endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322. 205 (1989), N. Engl. J. Med. 223., 1732 (1993), Nephron 66/373 (1994) , Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996)).
Mindestens zwei Endothelinrezeptorsubtypen, ETA- und ETB-Rezeptor, werden zur Zeit in der Literatur beschrieben (Nature 348, 730 (1990), Nature 348, 732 (1990)). Demnach sollten Substanzen, die die Bindung von Endothelin an die beiden Rezeptoren inhibieren, physiologische Effekte von Endothelin antagonisieren und daher wertvolle Pharmaka darstellen.At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to the two receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
Gemischte Endothelinrezeptorantagonisten sind solche Verbindungen, die mit ungefähr gleicher Affinität an den ETA und den ETB Rezeptor binden. Ungefähr gleiche Affinität zu den Rezeptoren besteht, wenn der Quotient der Affinitäten größer 0,05 (bevorzugt 0,1) und kleiner 20 (bevorzugt 10) ist. In der Patentanmeldung DE 19636046.3 wurden gemischte ETA/ETB- Rezeptorantagonisten beschrieben. Wichtig für diese Verbindungen ist der Spacer Q (siehe Formel XX) , der in seiner Länge einer C-C4-Alkylkette entspricht.Mixed endothelin receptor antagonists are compounds that bind to the ET A and the ET B receptor with approximately the same affinity. There is approximately the same affinity for the receptors if the quotient of the affinities is greater than 0.05 (preferably 0.1) and less than 20 (preferably 10). Mixed ET A / ET B receptor antagonists have been described in patent application DE 19636046.3. The spacer Q (see formula XX), which corresponds in length to a CC 4 alkyl chain, is important for these compounds.
Figure imgf000004_0001
Figure imgf000004_0001
Mit dem Spacer Q = COCR7R8 (siehe Formel I) werden ebenfalls in der Regel gemischte Rezeptorantagonisten erhalten.Mixed receptor antagonists are also generally obtained with the spacer Q = COCR 7 R 8 (see formula I).
15 Es bestand die Aufgabe, Verbindungen zu identifizieren, die mit ungefähr gleicher Affinität an den ETA und den ETB Rezeptor binden und gegenüber den bereits bekannten gemischten Endothelin- Rezeptorantagonisten vorteilhaftere Eigenschaf en besitzen.15 The task was to identify compounds which bind to the ET A and the ET B receptor with approximately the same affinity and which have more advantageous properties than the already known mixed endothelin receptor antagonists.
20 Gegenstand der Erfindung sind Carbonsäurederivate der Formel IThe invention relates to carboxylic acid derivatives of the formula I.
Figure imgf000004_0002
Figure imgf000004_0002
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
30 R1 Tetrazol oder eine Gruppe30 R 1 tetrazole or a group
OO
II C—RII C — R
35 R35 R
a) ein Rest OR9, worin R9 bedeutet:a) a radical OR 9 , in which R 9 denotes:
Wasserstoff, das Kation eines Alkalimetalls, das Kation eines 40 Erdalkalimetalls, ein physiologisch verträgliches organisches Ammoniumion wie tertiäres Cι-C-Alkylammonium oder das Ammoniumion;Hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;
C3-C8-Cycloalkyl, Cι-C8-Alkyl, CH2-Phenyl, die durch einen 45 oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Cι~C-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, Mercapto, Cι-C.4-Alkylthio, Amino, NH (Cι-C4-Alkyl ) , N (C1-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 1 -C 4 -alkyl, C 1 -C 4 - Haloalkyl, Hydroxy, -CC 4 alkoxy, mercapto, -C-C. 4- alkylthio, amino, NH (-CC 4 alkyl), N (C 1 -C 4 alkyl) 2 ;
eine C3-Cg-Alkenyl - oder eine C3-C6-Alkinylgruppe, wobei diese Gruppen ihrerseits ein bis fünf Halogenatome tragen können;a C 3 -Cg alkenyl or a C 3 -C 6 alkynyl group, these groups in turn being able to carry one to five halogen atoms;
ein Phenylrest, welcher ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen kann: Nitro, Cyano, Cι-C4-Alkyl, Cχ-C4-Halogenalkyl , Hydroxy, Cχ-C4-Alkoxy, Mercapto, Cι-C4-Alkylthio, Amino, NH (Cι-C -Alkyl) , N(Cι-C4-Alkyl)2;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, Cχ-C 4 -haloalkyl, hydroxy, Cχ-C 4 -alkoxy, mercapto, Cι -C 4 alkylthio, amino, NH (Cι-C alkyl), N (Cι-C4 alkyl) 2;
b) ein über ein Stickstoffatom verknüpfter 5-gliedriger Hetero- aromat wie Pyrrolyl, Pyrazolyl, Imidazolyl und Triazolyl, welcher ein bis zwei Halogenatome, oder ein bis zwei Cι~C4-Alkyl oder ein bis zwei Ci-C4-Alkoxygruppen tragen kann,b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C 1 -C 4 -alkyl or one or two C 1 -C 4 -alkoxy groups ,
c) eine Gruppec) a group
Figure imgf000005_0001
Figure imgf000005_0001
in der k die Werte 0, 1 und 2, p die Werte 1, 2, 3 und 4 annehmen und R10 fürwhere k is 0, 1 and 2, p is 1, 2, 3 and 4 and R 10 is
Cι-C4-Alkyl, C3-C8-Cycloalkyl, C3-C6-Alkenyi, C3-C6-Alkinyl oder Phenyl steht, das durch einen oder mehrere, z.B. einen bis drei der folgenden Reste substituiert sein kann:C 1 -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-C4-Halogenalkyl, Hydroxy, Cι-C4-Alkoxy, C1.-C4-Alkylth.io, Mercapto, Amino, NH(Cι-C4-Alkyl) , N(Cι-C-Alkyl) 2.Halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, Cι-C 4 alkoxy, C1.-C4 -Alkylth.io, mercapto, amino, NH (Cι-C 4 - Alkyl), N (-CC alkyl) 2 .
d) ein Restd) a rest
OO
11 11 -N—S—R H II O worin R11 bedeutet: 11 11 -N — S — RH II O where R 11 means:
Cι-C4-Alkyl, C!-C4-Halogenalkyl C3-C6-Alkenyl, C3-C6-Alkinyl , C3-C8-Cycloalkyl, wobei diese Reste einen Cι-C4-Alkoxy-, Cι-C4-Alkylthio- und/oder einen Phenylrest wie unter c) genannt tragen können; Phenyl, das durch einen bis drei der folgenden Reste substituiert sein kann: Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogenalkyl, Hydroxy, Cι-C4~Alkoxy, Cι-C4~Alkylthio, Mercapto, Amino, NH(Cι-C -Alkyl) , N(Cι-C -Alkyl ) 2.C 1 -C 4 alkyl, C ! -C 4 haloalkyl C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 -cycloalkyl, these radicals being a Cι-C4 alkoxy, Cι-C4-alkylthio and / or can carry a phenyl radical as mentioned under c); Phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, Cι-C ~ 4 alkoxy, Cι-C4 ~ alkylthio, Mercapto, amino, NH (-CC alkyl), N (-C-alkyl) 2nd
R2 Wasserstoff, Hydroxy, NH2, NH (Cχ-C -Alkyi ) , N(Cι-C4-Alkyl) 2 , Halogen, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, Cι-C4-Hydroxyalkyl, Cι-C4-Halogenalkyl , Cι~C -Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthio, oder CR2 ist mit CR12 wie unter Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft,R 2 is hydrogen, hydroxyl, NH 2 , NH (Cχ-C-alkyl), N (-C-C 4 alkyl) 2 , halogen, -C-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C -Alkynyl, -CC 4 -hydroxyalkyl, -CC 4 -haloalkyl, -C ~ C -alkoxy, -C-C 4 -haloalkoxy or -C-C 4 alkylthio, or CR 2 is with CR 12 as indicated under Z to one 5- or 6-membered ring linked,
X Stickstoff oder Methin,X nitrogen or methine,
Y Stickstoff oder Methin,Y nitrogen or methine,
Z Stickstoff oder CR12, worin R12 Wasserstoff, HalogenZ nitrogen or CR 12 , wherein R 12 is hydrogen, halogen
Cι-C4-Halogenalkyl oder Cι-C4-Alkyl bedeutet, oder CR12 bildet zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring, der durch eine oder zwei Cι-C4-Alkyl- gruppen substituiert sein kann und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder N(Cι-C4-Alkyl) ersetzt sein können, wobei mindestens eines der Ringglieder X, Y oder Z Stickstoff bedeutet. Cι-C4-haloalkyl or Cι-C 4 alkyl, or CR 12 forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring, by one or two Cι-C 4 alkyl groups can be substituted and in which one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC 4 -alkyl), at least one of the ring members X, Y or Z being nitrogen.
R3 Wasserstoff, Hydroxy, NH2, NH (Cι*-C4-Alkyl ) , N(Cι-C4-Alkyl) 2 , Halogen, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, C].-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy, C1-C4-Hydroxyalkyl , Cι-C-Alkylthio, oder CR3 ist mit CR12 wie unter Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft.R 3 is hydrogen, hydroxy, NH 2, NH (Cι * -C 4 alkyl), N (Cι-C4 alkyl) 2, halogen, Cι-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, C] .- C 4 -haloalkyl, -C-C 4 -alkoxy, Cι-C 4 -haloalkoxy, C 1 -C 4 -hydroxyalkyl, Cι-C-alkylthio, or CR 3 is with CR 12th linked as in Z to form a 5- or 6-membered ring.
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, die durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, Nitro, Cyano, Hydroxy, Mercapto, Cι-C4-Alkyl, C2-C4-Alkenyl, C -C4-Alkinyl, Cι-C4-Halogenalkyi , Cι-C4-Alkoxy, Phenoxy, Carboxy, Cι-C4-Halogenalkoxy, Cχ-C4-Alkylthio, Amino, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2 oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι*-C4-Alkyl, Cι-C4-Halogenalkyl , C1-C4~Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthio,* Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-AI yl-Gruppe miteinander verbunden sind;Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, Cι-C 4 alkyl, C 2 -C 4 alkenyl, C -C 4 alkynyl, Cι- C 4 -Halogenalkyi, -C-C 4 alkoxy, phenoxy, carboxy, Cι-C 4 -haloalkoxy, Cχ-C 4 -alkylthio, amino, NH (Cι-C 4 -alkyl), N (Cι-C 4 alkyl) ) 2 or phenyl which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, * -C 4 -alkyl, C 4 haloalkyl, C 1 -C 4 -alkoxy, Cι -C 4 -haloalkoxy or -C-C 4 alkylthio, * Phenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-Al yl group;
C3-C8-Cycloalkyl .C 3 -C 8 cycloalkyl.
R6 C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- oder mehrfach substituiert sein können durch: Halogen, Hydroxy, Mercapto, Carboxy, Nitro, Cyano, Cι-C4-Alkoxy, Cι-C-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, C3-C6-Alkenyloxy, C3-C6-Alkinyl- oxy, C;L-C-Alkylthio, C1-C4-Halogenalkoxy, Cι-C-Alkyl- carbonyl, Cι-C4-Alkoxycarbonyl , C3-C8-Alkylcarbonylalkyl, Carboxamid, NH(Cι-C4-Alkyl) , N(Cι-C4-Alkyl) 2, oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cι-C4-Halogenalkoxy oder Cι-C4-Alkylthio;R 6 is C 3 -C 8 cycloalkyl, where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C; L -C-Alkylthio, C 1 -C 4 -haloalkoxy, -C-C-alkylcarbonyl, Cι-C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, carboxamide, NH (Cι-C 4 -alkyl), N (-C 4 alkyl) 2 , or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 -alkoxy, C 4 -haloalkoxy or Cι-C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils durch einen oder mehrere der folgenden Reste substituiert sein können: Halogen, R15, Nitro, Mercapto, Carboxy, Cyano, Hydroxy, Amino, Cι-C4-Alkyl, C2-C4-Alkenyl, C2-C-Alkinyl, C3-Ce-Alkenyloxy, d-C4-Halogen- alkyl, C3-C6-Alkinyloxy, Cι-C-Alkylcarbonyl , C1-C4-Alkoxy- carbonyl , Carboxamid, Cx-C4-Alkoxy, Cι-C-Halogenalkoxy, Phen- oxy, Cι-C4-Alkylthio, NH (Cχ-C4-Alkyl ) , N(Cι-C4-Alkyl ) 2, Dioxo- methylen, Dioxoethylen oder Phenyl, das ein- oder mehrfach substituiert sein kann, z.B. ein- bis dreifach durch Halogen, Nitro, Cyano, Cι-C4-Alkyl, Cι-C4-Halogen-aikyl , Cι-C4-Alkoxy, C1-C4-Halogenalkoxy oder Cj.-C4-Alkylthio;Phenyl or naphthyl, which in each case by a plurality of the following radicals may be substituted or halogen, R 15, nitro, mercapto, carboxyl, cyano, hydroxy, amino, Cι-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C alkynyl, C 3 -C e alkenyloxy, dC 4 haloalkyl, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, carboxamide, C x - C 4 -alkoxy, -C-C-haloalkoxy, phenoxy, -C-C 4 -alkylthio, NH (Cχ-C 4 -alkyl), N (Cι-C 4 -alkyl) 2 , dioxomethylene, dioxoethylene or phenyl , which may be mono- or polysubstituted, for example mono- to trisubstituted by halogen, nitro, cyano, C 4 -alkyl, C 4 -halogen--alkyl, Cι-C 4 alkoxy, C 1 -C 4 -Halogenalkoxy or Cj . -C 4 alkylthio;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein bis vier Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cι-C4-Alkyl,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 4 -alkyl,
C2-C4-Alkenyl, Cι-C4-Halogenalkyl, Cι-C-Alkoxy, Cι~C4-Halogen- alkoxy, Cι-C-Alkylthio, Phenyl oder Phenoxy, wobei die Phenylreste ihrerseits ein bis fünf Halogenatome und/oder einen bis drei der folgenden Reste tragen können: C1-C4-Alkyl, Cι-C4-Halogenalkyl, Cι-C4-Alkoxy, Cχ-C4-Halogenalkoxy und/oder Cχ-C-Alkylthio ;C 2 -C 4 alkenyl, Cι-C4 haloalkyl, Cι-C alkoxy, halo-Cι ~ C4 alkoxy, Cι-C-alkylthio, phenyl or phenoxy, where the phenyl radicals in turn one to five halogen atoms and / or may carry one to three of the following radicals: C 1 -C 4 -alkyl, C 4 haloalkyl, Cι-C4-alkoxy, Cχ-C 4 -haloalkoxy and / or Cχ-C -alkylthio;
R7 und R8 (die gleich oder verschieden sein können) :R 7 and R 8 (which may be the same or different):
Wasserstoff, Cι-C -Alkyl . Ris d-C-Alkyl, Cι-C4-Alkylthio, Cι-C4-Aikoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH(Cχ-C4-Alkyl) , N(C1-C4-Alkyl) 2 , Carboxamid oder CON(Cι-C4-Alkyl)2;Hydrogen, -CC alkyl. Ris dC-alkyl, -CC 4 -alkylthio, -C-C 4 -alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (Cχ-C 4 -alkyl), N (C 1 -C 4 - Alkyl) 2 , carboxamide or CON (-CC 4 -alkyl) 2 ;
W Schwefel oder Sauerstoff.W sulfur or oxygen.
Hierbei und im weiteren gelten folgende Definitionen:The following definitions apply here and below:
Ein Alkalimetall ist z.B. Lithium, Natrium, Kalium;An alkali metal is e.g. Lithium, sodium, potassium;
Ein Erdalkalimetall ist z.B. Calcium, Magnesium, Barium;An alkaline earth metal is e.g. Calcium, magnesium, barium;
C3-C8-Cycloalkyl ist z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl oder Cyclooctyl;C 3 -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
Cι-C4-Halogenalkyi kann linear oder verzweigt: sein wie z.B. Fluormethyl, Difluormethyl, Trifluormethyl, Chlordifluormethyl, Dichlorfluormethyl, Tric lormethyl, 1-Fluorethyl, 2-Fluorethyl, 2, 2-Difluorethyl, 2 , 2 , 2-Trifluorethyl, 2-Chlor-2 , 2-difluorethyl, 2, 2-Dichlor-2-fluorethyl, 2 , 2 , 2-Trichlorethyl oder Pentafluorethyl ,*C 1 -C 4 haloalkyl can be linear or branched: such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, tric lormethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2nd -Chlor-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl, *
Cι-C4-Halogenalkoxy kann linear oder verzweigt sein wie z.B. Difluormethoxy, Trifluormethoxy, Chlordifluormethoxy, 1-Fluor- ethoxy, 2 , 2-Difluorethoxy, 1, 1, 2 , 2-Tetrafluorethoxy, 2,2,2-Tri- fluorethoxy, 2-Chlor-l, 1, 2-trifluorethoxy, 2-Fluorethoxy oder Pentafluorethoxy;C 1 -C 4 -Halogenalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy , 2-chloro-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
Cι-C4-Alkyl kann linear oder verzweigt sein wie z.B. Methyl,C 1 -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;
C -C4-Alkenyl kann linear oder verzweigt sein wie z.B. Ethenyl, l-Propen-3-yl, l-Propen-2-yl , 1-Propen-l-yl, 2-Methyl-l-propenyl, 1-Butenyl oder 2-Butenyl;C 4 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
C-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 ;CC 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
Cι~C4-Alkoxy kann linear oder verzweigt sein wie z.B. Methoxy, Ethoxy, Propoxy, 1-Methylethoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy oder 1, 1-Dimethylethoxy;Cι ~ C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
C3-C3-Alkenyloxy kann linear oder verzweigt sein wie z.B. Allyl- oxy, 2-Buten-l-yloxy oder 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 3 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;
Cι-C4-Alkylthio kann linear oder verzweigt sein wie z.B. Methyl- thio, Ethylthio, Propylthio, 1-Methylethylthio, Butylthio, 1-Methylpropylthio, 2-Methylpropyithio oder 1, 1-Dimethylethyl- thio;C 1 -C 4 -Alkylthio can be linear or branched such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropyithio or 1, 1-dimethylethylthio;
Cι-C4-Alkylcarbonyl kann linear oder verzweigt sein wie z.B. Acetyl, Ethylcarbonyl oder 2-Propylcarbonyl;C 1 -C 4 -alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
Cι-C4-Alkoxycarbonyl kann linear oder verzweigt sein wie z.B. Methoxycarbonyl , Ethoxycarbonyl , n-Propoxycarbonyl, i-Propoxy- carbonyl oder n-Butoxycarbonyl ,*C 1 -C 4 -alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl, *
C3-C8-Alkylcarbonylalkyl kann linear oder verzweigt sein, z.B. 2-Oxo-prop-l-yl, 3-Oxo-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-oxo-but-1-yl or 3-oxo-but-2-yl
Ci-Cs-Alkyl kann linear oder verzweigt sein wie z.B. C]_-C -Alkyl, Pentyl, Hexyl, Heptyl oder Octyl ;Ci-Cs-alkyl can be linear or branched, e.g. C] _- C 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 Körper- kompartimenten, 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 I und auch die Zwischenprodukte zu ihrer Herstellung, wie z.B. II, III, IV, V und VI, können ein oder mehrere asymmetrisch substituierte Kohlenstoffatome besitzen. Solche Verbindungen können als reine Enantiomere bzw. reine Diastereo- mere oder als deren Mischung vorliegen. Bevorzugt ist die Verwendung einer enantiomerenreinen Verbindung als Wirkstoff.The compounds I and also the intermediates for their preparation, e.g. II, III, IV, V and VI, can have one or more asymmetrically substituted carbon atoms. Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active ingredient is preferred.
Gegenstand der Erfindung ist weiter die Verwendung der oben genannten Carbonsäurederivate zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Hemmstoffen für ETA und ETB Rezeptoren. Die erfindungsgemäßen Verbindungen eignen sich als gemischte Antagonisten, wie sie eingangs definiert wurden. Die Herstellung der Verbindungen mit der allgemeinen Formel IV, in denen W Schwefel oder Sauerstoff ist, kann wie in WO 96/11914 beschrieben, erfolgen. Bei dieser Reaktion ist die spätere Ketogruppe als cyclisches Acetal geschützt; es sind jedoch auch andere Schutzgruppen denkbar, wie z.B. Dirnethylacetal.The invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors. The compounds according to the invention are suitable as mixed antagonists as defined at the outset. The compounds of the general formula IV in which W is sulfur or oxygen can be prepared as described in WO 96/11914. In this reaction, the later keto group is protected as a cyclic acetal; however, other protective groups are also conceivable, such as, for example, direthylacetal.
* •OH
Figure imgf000010_0001
* • OH
Figure imgf000010_0001
II III IVII III IV
Verbindungen der Formel IV können in enantionmerenreiner Form erhalten werden, indem man von enantiomerenreinen Verbindungen der Formel II ausgeht und sie wie in WO 96/11914 beschrieben mit Verbindungen der Formel III umsetzt.Compounds of the formula IV can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula II and reacting them with compounds of the formula III as described in WO 96/11914.
Weiterhin kann man enantiomere Verbindungen der Formel IV erhalten, indem man mit racemischen bzw. diastereomeren Verbindungen der Formel IV eine klassische Racematspaltung mit geeigneten enantiomerenreinen Basen durchführt. Als solche Basen eigenen sich z.B. 4-Chlorphenylethylamin und Basen, wie sie in WO 96/11914 genannt werden.Furthermore, enantiomeric compounds of the formula IV can be obtained by carrying out a classic resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV. As such bases are e.g. 4-chlorophenylethylamine and bases as mentioned in WO 96/11914.
Die Herstellung von Verbindungen der allgemeinen Formel II wurde in WO 96/11914 beschrieben, während Verbindungen der allgemeinen Formel III entweder bekannt sind oder durch allgemein bekannte Methoden synthetisiert werden können wie z.B:The preparation of compounds of the general formula II was described in WO 96/11914, while compounds of the general formula III are either known or can be synthesized by generally known methods, for example:
MβO , w- —H N
Figure imgf000010_0002
IIIMβO, w- —HN
Figure imgf000010_0002
III
Carbonsäurederivate der allgemeinen Formel IV können dann mit Verbindungen der allgemeinen Formel V zur Reaktion gebracht werden, wobei Substanzen vom Typ VI erhalten werden.Carboxylic acid derivatives of the general formula IV can then be reacted with compounds of the general formula V, substances of type VI being obtained.
Figure imgf000010_0003
In Formel V bedeutet Rlδ Halogen oder R17-S0-, wobei R17 Cι-C4-Alkyl, Cι-C4~Halogenalkyl oder Phenyl sein kann. Ferner ist mindestens eines der Ringgiieder X oder Y oder Z Stickstoff. Die Reaktion findet bevorzugt in einem inerten Lösungs- oder Verdün- nungsmittel unter Zusatz einer geeigneten Base, d.h. einer Base, die eine Deprotonierung des Zwischenproduktes IV bewirkt, in einem Temperaturbereich von Raumtemperatur bis zum Siedepunkt des Lösungsmittels statt.
Figure imgf000010_0003
In formula V R lδ halogen or R 17 -S0-, wherein R 17 Cι-C 4 -alkyl, C 4 may be ~ haloalkyl or phenyl. Furthermore, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie a base which brings about a deprotonation of the intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.
Verbindungen des Typs VI mit R1 = COOH lassen sich sich auf diese Weise 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 VI with R 1 = COOH can 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 Ko len- Wasserstoffe, die jeweils gegebenenfalls chloriert sein können, wie zum Beispiel Hexan, Cyclohexan, Petrolether, Ligroin, Benzol, Toluol, Xylol, Methylenchlorid, Chloroform, Kohlenstofftetra- chlorid, Ethylchlorid und Trichlorethylen, Ether, wie zum Beispiel Diisopropylether, Dibutylether, Methyl-tert . -Butylether, Propylenoxid, Dioxan und Tetrahydrofuran, Nitrile, wie zum Beispiel Acetonitril und Propionitril, Säureamide, wie zum Beispiel Dirnethylformamid, Dimethylacetamid und N-Methylpyrrolidon, Sulfoxide und Sulfone, wie zum Beispiel Dimethylsulfoxid 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, dirnethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.
Verbindungen der Formel V sind bekannt, teilweise käuflich oder können nach allgemein bekannter Weise hergestellt werden.Compounds of the formula V are known, some are commercially available or can be prepared in a generally known manner.
Als Base kann ein Alkali- oder Erdalkalimetallhydrid wie Natrium- hydrid, Kaliumhydrid oder Calciumhydrid, ein Carbonat wie Alkali- metallcarbonat, z.B. Natrium- oder Kaliumcarbonat, ein Alkalioder Erdalkalimetallhydroxid wie Natrium- oder Kaiiumhydroxid, eine metallorganische Verbindung wie Butyllithium oder ein Alkali- amid wie Lithiumdiisopropylamid oder Lithiumamid dienen.As the base, an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide or lithium amide.
Die erfindungsgemäßen Verbindungen, in denen die Substituenten die unter der allgemeinen Formel I angegebenen Bedeutung haben, können schließlich hergestellt werden, indem in den Verbindungen der Formel VI die Ketoschutzgruppe abgespalten wird. Im Falle des Ethylenglykolacetals kann dies durch saure Hydrolyse geschehen.
Figure imgf000012_0001
The compounds according to the invention in which the substituents have the meaning given under the general formula I can finally be prepared by splitting off the keto protective group in the compounds of the formula VI. In the case of ethylene glycol acetal, this can be done by acid hydrolysis.
Figure imgf000012_0001
Verbindungen vom Typ I können weiterhin über Verbindungen mit der Formel VII synthetisiert werden.Type I compounds can furthermore be synthesized via compounds having the formula VII.
O R8 OR 8
Figure imgf000012_0002
Figure imgf000012_0002
Die Verbindungen mit der allgemeinen Formel VII können dann mit Grignard-Reagenzien zu den Verbindungen der Formel I umgesetzt werden .The compounds with the general formula VII can then be reacted with Grignard reagents to give the compounds of the formula I.
Figure imgf000012_0003
Figure imgf000012_0003
Verbindungen der Formel I können auch dadurch hergestellt werden, indem man von den entsprechenden Carbonsäuren, d.h. Verbindungen der Formel I, in denen R1 COOH bedeutet, ausgeht und diese zunächst auf übliche Weise in eine aktivierte Form wie ein Säure- halogenid, ein Anhydrid oder Imidazolid überführt und dieses dann mit einer entsprechenden HydroxylVerbindung HÖR9 umsetzt. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen und erfordert oft die Zugabe einer Base, wobei die oben genannten in Betracht kommen. Diese beiden Schritte lassen sich beispiels- weise auch dadurch vereinfachen, daß man die Carbonsäure inCompounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R 1 is COOH, and converting them first in the usual manner into an activated form such as an acid halide, an anhydride or Imidazolid transferred and then reacted with a corresponding hydroxyl compound HÖR 9 . This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible. These two steps can also be simplified, for example, by adding the carboxylic acid to
Gegenwart eines wasserabspaltenden Mittels wie eines Carbodiimids auf die HydroxylVerbindung einwirken läßt.Presence of a water releasing agent such as a carbodiimide on the hydroxyl compound.
Außerdem können Verbindungen der Formel I auch hergestellt werden, indem 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 Equivalent eines Erdalkalimetallkations sein kann. Diese Salze lassen sich mit vielen Verbindungen der Formel R9-A zur Reaktion bringen, wobei A eine übliche nucleofuge Abgangsgruppe bedeutet, beispielsweise Halogen wie Chlor, Brom, Iod oder gegebenenfalls durch Halogen, Alkyl oder Halogenalkyl substituiertes Aryl- oder Alkylsulfonyl wie z.B. Toluolsulfonyl und Methylsulfonyl oder eine andere äquivalente Abgangsgruppe . Verbindungen der Formel R9-A mit einem reaktionsfähigen Substituenten A sind bekannt oder mit dem allgemeinen Fachwissen leicht zu erhalten. Diese Umsetzung läßt sich in den üblichen Lösungsmitteln durchführen und wird vorteilhaft unter Zugabe einer Base, wobei die oben genannten in Betracht kommen, vorgenommen.In addition, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 represents a group COOM, where M is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R 9 -A, where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and Methylsulfonyl or other equivalent leaving group. Compounds of the formula R 9 -A with a reactive substituent A are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, the above-mentioned being suitable.
In einigen Fällen ist zur Herstellung der erfindungsgemäßen Verbindungen I die Anwendung allgemein bekannter Schutzgruppentechniken erforderlich. Soll beispielsweise Rβ = 4-Hydroxyphenyl bedeuten, so kann die Hydroxygruppe zunächst als Benzylet er geschützt sein, der dann auf einer geeigneten Stufe in der Reaktionssequenz gespalten wird.In some cases, the preparation of the compounds I according to the invention requires the use of generally known protective group techniques. For example, if R is β = 4-hydroxyphenyl, the hydroxyl group can first be protected as a benzylet, 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, N(Cι-C4-Alkyl)2, Cι*-C4-Alkyl, Cι-C4-Alkoxy, Cι-C4-Alkylthio, Cχ-C-Halogenalkyl, Cχ-C -Halogenalkoxy, Hydroxymethyl oder CR2 ist mit CR12 wie unter Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 is hydrogen, N (-CC 4 -alkyl) 2 , -C * -C 4 -alkyl, -C-C 4 -alkoxy, -C-C 4 -alkylthio, Cχ-C-haloalkyl, Cχ-C -haloalkoxy, hydroxymethyl or CR 2 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR12 , worin R12 Wasserstoff, Fluor, Trifluormethyl oder Methyl bedeutet oder CR12 bildet zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylen- ring, der durch eine oder zwei Methylgruppen substituiert sein kann, und worin jeweils eine Methylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann wie -CH-CH2-0-, -CH2-CH2-CH2-0-, -CH=CH-0-, -CH=CH-CH20- , -CH (CH3 ) -CH (CH3 ) -0- , -CH=C (CH3 ) -0- , -C (CH3 ) =C (CH3 ) -O-oder -C (CH3 ) =C ( CH3 ) -S ;Z nitrogen or CR 12 , in which R 12 is hydrogen, fluorine, trifluoromethyl or methyl or CR 12 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in which one methylene group can be replaced by oxygen or sulfur such as -CH-CH 2 -0-, -CH 2 -CH 2 -CH 2 -0-, -CH = CH-0-, -CH = CH- CH 2 0-, -CH (CH 3 ) -CH (CH 3 ) -0-, -CH = C (CH 3 ) -0-, -C (CH 3 ) = C (CH 3 ) -O-or - C (CH 3 ) = C (CH 3 ) -S;
mindestens eines der Ringglieder X, Y oder Z ist Stickstoff; R3 Wasserstoff, N(Cχ-C4-Alkyl) 2, Cχ-C4-Alkyl, Cχ-C -Alkoxy, Cχ-C4-Alkylthio, Cχ-C4-Halogenalkyl , Cχ-C4-Halogenalkoxy, Hydroxymethyl oder CR3 ist mit CR12 wie unter Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;at least one of the ring members X, Y or Z is nitrogen; R 3 is hydrogen, N (Cχ-C4 alkyl) 2, Cχ-C4-alkyl, Cχ-C -alkoxy, Cχ-C 4 alkylthio, Cχ-C 4 haloalkyl, Cχ-C 4 haloalkoxy, hydroxymethyl or CR 3 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
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 ein- bis dreifach substituiert sein können durch Halogen, Cyano, Cχ-C4-Alkyl, Cχ-C4-Halogenalkyl, Cχ-C4-Alkoxy, Phenoxy, C-C4-Alkylthio, NH (Cχ-C4-Alkyl) oder N(Cχ-C4-Alkyl) 2 oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cyano, Cχ-C4-Alkyl, Cχ-C -Halogenalkyl, Cχ-C4-Alkoxy, Cχ-C4-Halogenalkoxy oder Cχ-C4-Alkylchio; oderPhenyl or naphthyl, which can be mono- to trisubstituted by halogen, cyano, Cχ-C 4 alkyl, Cχ-C 4 haloalkyl, Cχ-C 4 alkoxy, phenoxy, CC 4 alkylthio, NH (Cχ-C 4- alkyl) or N (Cχ-C 4 -alkyl) 2 or phenyl, which can be mono- to trisubstituted by halogen, cyano, Cχ-C 4 -alkyl, Cχ-C -haloalkyl, Cχ-C 4 -alkoxy , Cχ-C 4 haloalkoxy or Cχ-C 4 alkylchio; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe, ein Sauerstoff- oder Schwefelatom oder eine S02-, NH- oder N-Alkyl-Gruppe miteinander verbunden sind;Phenyl or naphthyl, which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-alkyl group;
C5-C6-Cycloalkyl ;C 5 -C 6 cycloalkyl;
R6 C3-C8-Cycloalkyl, wobei diese Reste jeweils ein- bis dreifach substituiert sein können durch: Halogen, Cχ-C4-Alkoxy, Cχ-C4-Alkyl, Cχ-C4-Alkylthio, Cχ-C4-Halogenalkoxy,R 6 C 3 -C 8 cycloalkyl, where these radicals can each be mono- to trisubstituted by: halogen, Cχ-C 4 -alkoxy, Cχ-C 4 -alkyl, Cχ-C 4 -alkylthio, Cχ-C 4 -Haloalkoxy,
Cχ-C4-Alkoxycarbonyl oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cχ-C4-Alkyl, Cχ-C4-Halogen- alkyl, Cχ-C-Alkoxy, Cχ-C-Halogenalkoxy oder Cχ-C4-Alkylthio;Cχ-C 4 -alkoxycarbonyl or phenyl, which can be mono- to trisubstituted by halogen, Cχ-C 4 -alkyl, Cχ-C 4 -haloalkyl, Cχ-C-alkoxy, Cχ-C-haloalkoxy or Cχ- C 4 alkylthio;
Phenyl oder Naphthyl, die jeweils ein- bis dreifach substituiert sein können durch Halogen, R15, Cyano, Hydroxy, Cχ-C-Alkyl, Cχ-C-Halogenalkyl, Cχ-C4-Alkylcarbonyl , Cχ-C-Alkoxycarbonyl , Cχ-C4-Alkoxy, Cχ-C-Halogenalkoxy, Phenoxy, Cχ-C4-Alkylthio, NH(Cχ-C4-Alkyl) , N(Cχ-C4-Alkyl) 2, Dioxomethylen, Dioxoethylen oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cyano, Cχ-C-Alkyl, Cχ-C4-Halogenalkyl, Cχ-C-Alkoxy, Cχ-C-Halogenalkoxy oder Cχ-C4-Alkylthiθ;Phenyl or naphthyl, each of which can be mono- to trisubstituted by halogen, R 15 , cyano, hydroxy, Cχ-C-alkyl, Cχ-C-haloalkyl, Cχ-C 4 -alkylcarbonyl, Cχ-C-alkoxycarbonyl, Cχ- C 4 -alkoxy, Cχ-C-haloalkoxy, phenoxy, Cχ-C 4 -alkylthio, NH (Cχ-C 4 -alkyl), N (Cχ-C 4 -alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, the one can be substituted up to three times by halogen, cyano, Cχ-C-alkyl, Cχ-C 4 -haloalkyl, Cχ-C-alkoxy, Cχ-C-haloalkoxy or Cχ-C 4 -alkylthiθ;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, welcher ein oder zwei Halogenatome und/oder einen bis zwei der folgenden Reste tragen kann: Cχ-C4-Alkyl, Cχ-C4-Alkoxy, Trifluormethoxy, Cχ-C4-Alkylthio, Phenyl oder Phenoxy, wobei die Phenylreste ihrerseits ein bis fünfa five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which can carry one or two halogen atoms and / or one or two of the following radicals: Cχ-C 4 -alkyl, Cχ-C 4 - Alkoxy, trifluoromethoxy, Cχ-C 4 alkylthio, phenyl or phenoxy, the phenyl radicals in turn one to five
Halogenatome und/oder einen bis drei der folgenden Reste tragen können: Cχ-C-Alkyl, Cχ-C4-Alkoxy und/oder Cχ-C4-Alkylthio; R7 und R8 (die gleich oder verschieden sein können) :Halogen atoms and / or can carry one to three of the following radicals: Cχ-C-alkyl, Cχ-C 4 alkoxy and / or Cχ-C 4 alkylthio; R 7 and R 8 (which may be the same or different):
Wasserstoff, Cχ-C4-Alkyl .Hydrogen, Cχ-C 4 alkyl.
R15 Methyl, Ethyl, Methoxy oder Ξthoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Amino, NH (Cχ-C4-Alkyl) , N(Cχ-C-Alkyl)2, Carboxamid oder CON(Cχ-C4-Alkyl ) 2 ,-R 15 is methyl, ethyl, methoxy or Ξthoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (Cχ-C 4 -alkyl), N (Cχ-C-alkyl) 2 , carboxamide or CON (Cχ-C 4- alkyl) 2 , -
W Schwefel oder Sauerstoff;W sulfur or oxygen;
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 Trifluormethyl, Cχ-C4-Alkyl, Cχ-C -Alkoxy, Cχ-C -Alkylthio, oder CR2 ist mit CR12 wie uncer Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R 2 trifluoromethyl, Cχ-C 4 alkyl, Cχ-C alkoxy, Cχ-C alkylthio, or CR 2 is linked with CR 12 as uncer Z to a 5- or 6-membered ring;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR12 , worin R12 Wasserstoff, Fluor oder Methyl bedeuten oder CR12 bildet zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring, worin jeweils eine Methylengruppe durch Sauerstoff oder Schwefel ersetzt sein kann wie -CH2-CH2-S-, -CH=CH-0-, -CH2-CH2-S-;Z is nitrogen or CR 12 , in which R 12 is hydrogen, fluorine or methyl, or CR 12 forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring, in each of which one methylene group can be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -S-, -CH = CH-0-, -CH 2 -CH 2 -S-;
mindestens eines der Ringglieder X, Y oder Z ist Stickstoff;at least one of the ring members X, Y or Z is nitrogen;
R3 Trifluormethyl, Cχ-C4-Alkyl, Cχ-C-Alkoxy, Cχ-C -Alkylthio oder CR3 ist mit CR12 wie unter Z angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;R3 trifluoromethyl, Cχ-C 4 -alkyl, Cχ-C-alkoxy, Cχ-C-alkylthio or CR 3 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
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 ein- bis dreifach substituiert sein können durch Halogen, Cχ-C-Alkyl, Cχ-C4-Alkoxy, Phenoxy oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cχ-C4-Alkyl oder Cχ-C4-Alkoxy; oderPhenyl or naphthyl, which can be mono- to trisubstituted by halogen, C Halogen-C-alkyl, Cχ-C 4 alkoxy, phenoxy or phenyl, which can be mono- to trisubstituted by halogen, Cχ-C 4 alkyl or Cχ-C 4 alkoxy; or
Phenyl oder Naphthyl, die orthoständig über eine direkte Bindung, eine Methylen-, Ethylen- oder Ethenylengruppe oder eine S0-Gruppe miteinander verbunden sind;Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group or an S0 group;
Cyclohexyl; s Cyclohexyl, das ein- bis dreifach substituiert sein kann durch Cχ-C-Alkoxy, Cχ-C4-Alkyl , Halogen oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cχ-C4-Alkyl, Cχ-C4-Alkoxy;Cyclohexyl; s cyclohexyl, which can be mono- to trisubstituted by Cχ-C-alkoxy, Cχ-C 4 -alkyl, halogen or phenyl, which can be mono- to trisubstituted by halogen, Cχ-C 4 -alkyl, Cχ-C 4 alkoxy;
Phenyl oder Naphthyl, die jeweils ein- bis dreifach substituiert sein können durch Halogen, R15, Cχ-C-Alkyl, Cχ-C4-Halogenalkyl, Acetyl, Cχ-C-Alkoxycarbonyl, Cχ-C-Alkoxy, Phenoxy, Cχ-C4-Alkylthio, Dioxomethylen, Dioxoethylen oder Phenyl, das ein- bis dreifach substituiert sein kann durch Halogen, Cχ-C-Alkyl, C-C-Alkoxy, oder Cχ-C4-Alkylthio;Phenyl or naphthyl, which can each be mono- to trisubstituted by halogen, R 15 , Cχ-C-alkyl, Cχ-C 4 -haloalkyl, acetyl, Cχ-C-alkoxycarbonyl, Cχ-C-alkoxy, phenoxy, Cχ- C 4 alkylthio, dioxomethylene, dioxoethylene or phenyl, which can be mono- to trisubstituted by halogen, Cχ-C-alkyl, CC-alkoxy, or Cχ-C 4 -alkylthio;
R7 und R8 (die gleich oder verschieden sein können) :R 7 and R 8 (which may be the same or different):
Wasserstoff, Cχ-C4-Alkyl.Hydrogen, Cχ-C 4 alkyl.
R15 Methoxy oder Ethoxy, die einen der folgenden Reste tragen: Hydroxy, Carboxy, Carboxamid oder CON(Cχ-C4-Alkyl) 2 ,*R 15 methoxy or ethoxy, which carry one of the following radicals: hydroxy, carboxy, carboxamide or CON (Cχ-C 4 -alkyl) 2 , *
W Schwefel oder Sauerstoff.W sulfur or oxygen.
Die Verbindungen der vorliegenden Erfindung bieten ein neues therapeutisches Potential für die Behandlung von Hypertonie, pulmonalem Hochdruck, Myokardinfarkc, Angina Pectoris, Arrhythmie, akutem/chronischem Nierenversagen, chronischer Herzinsuffizienz, Niereninsuffizienz, zerebralen Vasospasmen, zerebraler Ischämie, Subarachnoidalblutungen, Migräne, Asthma, Atherosklerose, endotoxischem Schock, Endotoxin-in uziertem Organversagen, intravaskulärer Koagulation, Restenose nach Angio- plastie und by-pass Operationen, benigne Prostata-Hyperplasie, ischämisches und durch Intoxikation verursachtes Nierenversagen bzw. Hypertonie, Metastasierung und Wachstum mesenchymaler Tumoren, Kontrastmittel-induziertes Nierenversagen, Pankreatitis, gastrointestinale Ulcera.The compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, asthma endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pank , gastrointestinal ulcers.
Ein weiterer Gegenstand der Erfindung sind Kombinationen aus Endothelinrezeptorantagonisten der Formel I und Inhibitoren des Renin-Angiotensin Systems. Inhibitoren des Renin-Angiotensin- Systems sind Reninhemmer, Angiotensin-II-Antagonisten und Angiotensin-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. 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 beta-blockers. 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 endotheliai growth factor) blockieren. Solche Substanzen sind beispielsweise gegen VEGF gerichtete Antikörper oder spezifische Bindeproteine oder auch niedermolekulare Substanzen, die VEGF Freisetzung oder Rezeptor- bindung spezifisch hemmen können.The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endotheliai growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or also low-molecular substances which can specifically inhibit VEGF release or receptor binding.
Die vorstehend genannten Kombinationen können gleichzeitig oder nacheinander zeitlich abgestuft verabreicht werden. Sie können sowohl in einer einzigen galenischen Formulierung oder auch in getrennten Formulierungen eingesetzt werden. Die Applikations- form kann auch unterschiedlich sein, beispielsweise können die Endothelinrezeptorantagonisten oral und VEGF-Hemmer parenteral verabreicht 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 application 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.
Ein weiterer Gegenstand der Erfindung ist ein strukturelles Fragment der FormelAnother object of the invention is a structural fragment of the formula
Figure imgf000017_0001
Figure imgf000017_0001
worin die Reste R1, R4, R5, R5, R7, R8 und W die oben genannte Bedeutung haben.wherein the radicals R 1 , R 4 , R 5 , R 5 , R 7 , R 8 and W have the meaning given above.
Solche strukturellen Fragmente eignen sich als strukturelle Bestandteile von Endothelin-Rezeptorantagonisten, insbesondere von gemischten Endothelin-Rezeptorantagonisten.Such structural fragments are suitable as structural components of endothelin receptor antagonists, in particular of mixed endothelin receptor antagonists.
Ein weiterer Gegenstand der Erfindung sind Endothelin-Rezeptor- antagonisten, bestehend aus einem strukturellen Fragment der FormelAnother object of the invention are endothelin receptor antagonists consisting of a structural fragment of the formula
Figure imgf000017_0002
worin die Reste R1, R2, R3, R4, R5, R , R8, W, X, Y und Z die oben genannte Bedeutung haben, kovalent verknüpft mit einer Gruppe, die ein Molekulargewicht von mindestens 40, bevorzugt mindestens 77, aufweist. 5
Figure imgf000017_0002
wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R, R 8 , W, X, Y and Z have the abovementioned meaning, covalently linked to a group which preferably has a molecular weight of at least 40 has at least 77. 5
Die gute Wirkung der Verbindungen läßt sich in folgenden Versuchen zeigen:The good effects of the compounds can be shown in the following experiments:
Rezeptorbindungsstudien 0Receptor binding studies 0
Für Bindungsstudien wurden klonierte humane ETA- oder ETB-Rezeptorexprimierende CHO-Zellen eingesetzt.Cloned human ET A or ET B receptor-expressing CHO cells were used for binding studies.
Membranpräpara ion 5Membrane preparation 5
Die ETA- oder ETB-Rezeptorexprimierenden CHO-Zellen wurden in DMEM NUT MIX F12-Medium (Gibco, Nr. 21331-020) mit 10 % fötalem Kälberserum (PAA Laboratories GmbH, Linz, Nr. A15-022), 1 mM Glutamin (Gibco Nr. 25030-024), 100 E/ml Penicillin und 100 μg/ml 20 Streptomycin (Gibco, Sigma Nr P-0781) vermehrt. Nach 48 Stunden wurden die Zellen mit PBS gewaschen und mit 0,05 % trypsin- haltiger PBS 5 Minuten bei 37°C inkubiert. Danach wurde mit Medium neutralisiert und die Zellen durch Zentrifugation bei 300 x g gesammelt.The ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 μg / ml 20 streptomycin (Gibco, Sigma No. P-0781) increased. After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 × g.
2525
Für die Membranpräpara ion wurden die Zellen auf eine Konzentration von 108 Zellen/ml Puffer (50 mM Tris-HCL Puffer, pH 7.4) eingestellt und danach durch Ultraschall desintegriert (Branson Sonifier 250, 40-70 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).
3030
BindungstestsBinding tests
Für den ETA- und ETB-Rezeptorbindungstest wurden die Membranen in Inkubationspuffer (50 mM Tris-HCl, pH 7,4 mit 5 mM MnCl ,For the ET A and ET B receptor binding test, the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl,
35 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]-ET (ETA-Rezeptortest) oder 25 pM [125J]-ET3 (ETB-Rezeptor- test) in Anwesenheit und Abwesenheit von Test-substanz inkubiert. Die unspezifische Bindung wurde mit 10~7 M ET bestimmt. Nach35 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] -ET (ET A receptor test) or 25 pM [125J] -ET 3 (ET B receptor test) incubated in the presence and absence of the test substance. The non-specific binding was determined with 10 ~ 7 M ET. To
40 30 min wurde der freie und der gebundene Radioligand durchThe free and bound radioligand were passed through for 30 min
Filtration über GF/B Glasfaserfilter (Whatman, England) an einem Skatron-Zellsammler (Skatron, Lier, Norwegen) getrennt und die Filter mit eiskaltem Tris-HCl-Puffer, pH 7 , 4 mit 0,2 % BSA gewaschen. Die auf den Filtern gesammelte Radioaktivität wurdeFiltration through GF / B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) separated and the filters washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was
45 mit einem Packard 2200 CA Flüssigkeitszintillationszähler quantifiziert . Testung der ET-Antagonisten in vivo:45 quantified with a Packard 2200 CA liquid scintillation counter. 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 ETl zu einem deutlichen Blutdruckanstieg, der über einen längeren Zeit- r um anhält.In control animals, intravenous administration of 1 μg / kg ETl leads to a significant rise in blood pressure, which persists over a longer period.
Den Testtieren wurde 30 min vor der ETl Gabe die Testverbindungen i.v. injiziert (1 mg/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 mg / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
p.o. - Testung der gemischten ETA- und ETB-Antagonisten:po - testing of mixed ET A and ET B antagonists:
Männliche 250-350g schwere normotone Ratten (Sprague Dawley, Janvier) werden mit den Testsubstanzen oral vorbehandelt. 80 Minuten später werden die Tiere mit Urethan narkotisiert und die A. carotis (für Blutdruckmessung) sowie die V. jugularis (Applikation von big-Endot elin/Endothelin 1) katheterisiert .Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for blood pressure measurement) and the jugular vein (application of big endoteline / endothelin 1) are catheterized.
Nach einer Stabilisierungsphase wird big-Endothelin (20 μg/kg, Appl. Vol. 0,5 ml/kg) bzw. ETl (0,3 μg/kg, Appl. Vol. 0,5 ml/kg) intravenös gegeben. Blutdruck und Herzfrequenz werden kontinuierlich über 30 Minuten registriert. Die deutlichen und langanhaltenden Blutdruckänderungen werden als Fläche unter der Kurve (AUC) berechnet. Zur Bestimmung der antagonistischen Wirkung der Testsubstanzen wird die AUC der substanzbehandelten Tiere mit der AUC der Kontrolltiere verglichen.After a stabilization phase, big endothelin (20 μg / kg, Appl. Vol. 0.5 ml / kg) or ETI (0.3 μg / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (subkutan, intravenös, intramuskulär, intraperi- toneal) verabfolgt werden. Die Applikation kann auch mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It can also be applied with vapors or sprays through the nasopharynx.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägliche Wirkstoffdosis zwischen ecwa 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 ecwa 0.5 and 50 mg / kg body weight with oral administration and between approximately 0.1 and 10 mg / kg body weight with parenteral administration.
Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließ- reguliermitteln, 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 in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
SynthesebeispieleSynthesis examples
Beispiel 1example 1
2-Hydroxy-3 , 3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) - propionsäuremethylescer2-Hydroxy-3,3-diphenyl-3- (2-phenyl- [1,3] dioxolan-2-ylmethoxy) propionic acid methyl ester
Zu einer Lösung von 2-Phenyl- [1, 3] -dioxolan-2-ylmethanol (1,98 g, 11,0 mmol) und 3 , 3-Diphenyl-2 , 3-epoxypropionsäure-methylester (4,71 g, 13,2 mmol; Reinheit lt. HPLC: 71 %) in wasserfreiem Dichlormethan (100 ml) wurde unter Eiskühlung p-Toluolsulfonsäure (0,50 g, 0,27 mmol) gegeben und 15 Minuten bei 0°C gerührt. Die resultierende Lösung wurde mit Natriumhydrogencarbonat-Lösung gewaschen; die organische Phase wurde abgetrennt und überTo a solution of 2-phenyl- [1,3] -dioxolan-2-ylmethanol (1.98 g, 11.0 mmol) and 3,3-diphenyl-2,3-epoxypropionic acid methyl ester (4.71 g, 13.2 mmol; purity according to HPLC: 71%) in anhydrous dichloromethane (100 ml) was added with p-toluenesulfonic acid (0.50 g, 0.27 mmol) while cooling with ice and the mixture was stirred at 0 ° C. for 15 minutes. The resulting solution was washed with sodium hydrogen carbonate solution; the organic phase was separated off and over
Magnesiumsulfat getrocknet. Nach dem Abfiltrieren vom Trockenmittel wurde das Lösungsmittel abdestilliert; das zurückbleibende rohe Öl (4,70 g) wurde ohne weitere Reinigung weiter umgesetzt.Magnesium sulfate dried. After filtering off the drying agent, the solvent was distilled off; the remaining crude oil (4.70 g) was reacted further without further purification.
Beispiel 2Example 2
2-Hydroxy-3 , 3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) - propionsäure2-Hydroxy-3,3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) propionic acid
2-Hydroxy-3- (2-phenyl)- [1, 3] -dioxolan-2-yl-methoxy)-3 , 3-diphenyl- propionsäuremethylester (4,60 g, roh), wurde in Dioxan/Wasser 2:1 (45 mL) gelöst und mit Natriumhydroxid (300 mg, 7,50 mmol) versetzt. Der Ansatz wurde auf 40°C erwärmt und eine Stunde gerührt. Zur Aufarbeitung wurde mit Wasser (150 ml) verdünnt und zweimal mit Ethylacetat extrahiert. Die wäßrige Phase wurde mit Zitronensäure angesäuert und zweimal mit Ethylacetat extrahiert. Die aus dem Sauren erhaltenen Extrakte wurden über Magnesiumsulfat getrocknet und das Lösungsmittel wurde abdestilliert. Es fielen 4,00 g eines rohen Öls an, die ohne weitere Reinigung weiter umgesetzt wurden. Beispiel 32-Hydroxy-3- (2-phenyl) - [1, 3] -dioxolan-2-yl-methoxy) -3, 3-diphenyl-propionic acid methyl ester (4.60 g, crude) was dissolved in dioxane / water 2: 1 (45 mL) dissolved and sodium hydroxide (300 mg, 7.50 mmol) was added. The mixture was heated to 40 ° C. and stirred for one hour. For working up, the mixture was diluted with water (150 ml) and extracted twice with ethyl acetate. The aqueous phase was acidified with citric acid and extracted twice with ethyl acetate. The extracts obtained from the acid were dried over magnesium sulfate and the solvent was distilled off. 4.00 g of a crude oil were obtained, which were reacted further without further purification. Example 3
2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3 , 3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy)-propionsäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3, 3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) propionic acid
Zu einer Lösung von 2-Hydroxy-3- (2-phenyl- [1, 3] -dioxolan-2-yl- methoxy) -3 , 3-diphenylpropionsäure (1,00 g, 1,62 mmol bei 68 % Reinheit lt. HPLC) in wasserfreiem DMF (15 ml) wurde 50 %iges Natriumhydrid (240 mg, 5,00 mmol) in 3 Portionen innerhalb von 3 Minuten zugegeben. Man ließ 5 Minuten nachrühren und trug dann 2-Methansulfonyl-4, 6-dimethylpyrimidin (421 mg, 2,00 mmol) portionsweise ein. Es wurde 16 Stunden bei Zimmertemperatur gerührt. Zur Aufarbeitung wurde der Kolbeninhalt auf Eiswasser gegossen, danach wurde mit Zitronensäure angesäuert und zweimal mit Ether extrahiert. Die organischen Extrakte wurden überTo a solution of 2-hydroxy-3- (2-phenyl- [1, 3] -dioxolan-2-yl-methoxy) -3, 3-diphenylpropionic acid (1.00 g, 1.62 mmol at 68% purity according to HPLC) in anhydrous DMF (15 ml), 50% sodium hydride (240 mg, 5.00 mmol) was added in 3 portions within 3 minutes. The mixture was stirred for 5 minutes and then 2-methanesulfonyl-4, 6-dimethylpyrimidine (421 mg, 2.00 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. For working up, the contents of the flask were poured onto ice water, then acidified with citric acid and extracted twice with ether. The organic extracts were over
Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Es blieben 1,75 g eines Öls zurück, das durch Flash-Chromatographie und nachfolgende Kristallisation aus Ether/n-Hexan weiter gereinigt wurde. Die Titeiverbindung fiel als farbloser Feststoff an (750 mg, 85 % Ausbeute) .Dried magnesium sulfate and the solvent was distilled off. 1.75 g of an oil remained, which was further purified by flash chromatography and subsequent crystallization from ether / n-hexane. The titite compound was obtained as a colorless solid (750 mg, 85% yield).
-LH-NMR (200 MHz, CDC13) : 7.5 - 7.7 ppm (2 H, m) , 7.2 - 7.4 (13 H, m) , 6.3 (1 H, s), 6.2 (1 H, s) , 4.2 - 4.4 (2 H, m) , 4.1 (1 H, d) , 3.9 (3 H, s), 3.8 - 4.0 (2 H, m) , 3.6 (1 H, d) , 2.4 (3 H,s).- L H-NMR (200 MHz, CDC1 3 ): 7.5 - 7.7 ppm (2 H, m), 7.2 - 7.4 (13 H, m), 6.3 (1 H, s), 6.2 (1 H, s), 4.2 - 4.4 (2 H, m), 4.1 (1 H, d), 3.9 (3 H, s), 3.8 - 4.0 (2 H, m), 3.6 (1 H, d), 2.4 (3 H, s ).
Beispiel 4Example 4
2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2-oxo-2-phenyl- ethoxy) -3 , 3-diphenylpropionsäure2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2-oxo-2-phenylethoxy) -3, 3-diphenylpropionic acid
Zu einer Lösung von 2- (4-Methoxy-6-methyi-pyrimidin-2-yl- oxy) -3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) -3 , 3-diphenyl- propionsäure (600 mg, 1,11 mmol) in Dioxan/Wasser 1:1 (20 ml) wurde p-Toluolsulfonsäure gegeben (50 mg) und die resultierende Mischung wurde zwei Stunden bei 80°C gerührt. Nach dem Abkühlen verdünnte man mit Wasser, und es wurde zweimal mit Ether extrahiert. Die vereinigten organischen Phasen wurden über Magnesiumsulfat getrocknet und das Lösungsmittel abdestilliert. Der verbleibende Rückstand (550 mg) wurde durch Kristallisation aus Ether/n-Hexan, nachfolgende Flash-Chromatographie und nochmalige Kristallisation aus Ether/n-Hexan gereinigt. Die Titelverbindung fiel als kristalliner Feststoff an (163 mg, 30 % Ausbeute).To a solution of 2- (4-methoxy-6-methyl-pyrimidin-2-yl-oxy) -3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) -3, 3-diphenyl- Propionic acid (600 mg, 1.11 mmol) in dioxane / water 1: 1 (20 ml) was added p-toluenesulfonic acid (50 mg) and the resulting mixture was stirred at 80 ° C for two hours. After cooling, the mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. The remaining residue (550 mg) was purified by crystallization from ether / n-hexane, subsequent flash chromatography and further crystallization from ether / n-hexane. The title compound was obtained as a crystalline solid (163 mg, 30% yield).
-LH-NMR (200 MHz, CDC13): 7.2 - 7.9 ppm (15 H, m) , 6.2 (2 H, s br) 5.1 (2 H, m) , 3.7 (3 H, s), 2.2 (3 H, s) .- L H-NMR (200 MHz, CDC1 3 ): 7.2 - 7.9 ppm (15 H, m), 6.2 (2 H, s br) 5.1 (2 H, m), 3.7 (3 H, s), 2.2 ( 3 H, s).
ESI-MS : M+ = 498 Analog wurden folgende Verbindungen dargestellt:ESI-MS: M + = 498 The following connections were shown analogously:
Beispiel 5Example 5
2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2-oxo-2-phenyl-ethoxy) - 3 , 3-diphenylpropionsäure2- (4, 6-Dimethyl-pyrimidin-2-yloxy) -3- (2-oxo-2-phenyl-ethoxy) -3, 3-diphenylpropionic acid
•LH-N R (200 MHz, CDC13): 7.8 ppm (2 H, d) , 7.2 - 7.7 (13 H, ) , 6.7 (1 H, s), 6.3 (1 H, s), 5.2 (1 H, d) , 4.9 (1 H, d) , 2.3 (6 H, s) .• L HN R (200 MHz, CDC1 3 ): 7.8 ppm (2 H, d), 7.2 - 7.7 (13 H,), 6.7 (1 H, s), 6.3 (1 H, s), 5.2 (1 H , d), 4.9 (1 H, d), 2.3 (6 H, s).
ESI-MS: M+ = 482ESI-MS: M + = 482
Beispiel 6Example 6
3- [2- ( 4-Bromo-phenyl ) -2-oxo-ethoxy] -2- (4 , 6-dimethyl-pyrimidin- 2-yioxy) -3 , 3-diphenylpropionsäurex 3- [2- (4-Bromo-phenyl) -2-oxo-ethoxy] -2- (4, 6-dimethyl-pyrimidin-2-yioxy) -3, 3-diphenylpropionic acid x
-LH-NMR (200 MHz, CDCI3) : 7.7 ppm (2 H, d) , 7.6 (2 H, d) , 7.2 - 7.5 (10 H, m) , 6.7 (1 H, s), 6.2 (1 H, s) , 5.1 (1 H, d) , 4.9 (1 H, d) , 2.3 (6 H, s) .- L H-NMR (200 MHz, CDCI 3 ): 7.7 ppm (2 H, d), 7.6 (2 H, d), 7.2 - 7.5 (10 H, m), 6.7 (1 H, s), 6.2 ( 1 H, s), 5.1 (1 H, d), 4.9 (1 H, d), 2.3 (6 H, s).
ESI-MS: M+ = 560ESI-MS: M + = 560
Beispiel 7Example 7
3- [2- ( 4-Bromo-phenyl ) -2-oxo-ethoxy] -2- (4-methoxy-6-methyi- pyrimidin-2-yloxy) -3 , 3-diphenylpropionsäure*: 3- [2- (4-Bromo-phenyl) -2-oxo-ethoxy] -2- (4-methoxy-6-methyipyrimidin-2-yloxy) -3, 3-diphenylpropionic acid * :
iH- MR (200 MHz, CDCI3): 7.7 ppm (2 H, d) , 7.6 (2 H, d) , 7.2 - 7.5 (10 H, m) , 6.2 (1 H, s), 6.0 (1 H, s), 5.2 (1 H, d) , 4.9 (1 H, d) , 3.7 (3 H, s), 2.2 (3 H, s) . i H-MR (200 MHz, CDCI 3 ): 7.7 ppm (2 H, d), 7.6 (2 H, d), 7.2 - 7.5 (10 H, m), 6.2 (1 H, s), 6.0 (1 H, s), 5.2 (1 H, d), 4.9 (1 H, d), 3.7 (3 H, s), 2.2 (3 H, s).
ESI-MS: M+ = 576ESI-MS: M + = 576
* Bei der Synthese der 4-Bromophenyl-substituierten Derivate wurde zur abschließenden Acetalspaltung Bortrifluorid-Etherat anstelle von p-Toluolsulfonsäure verwendet.* In the synthesis of the 4-bromophenyl-substituted derivatives, boron trifluoride etherate was used instead of p-toluenesulfonic acid for the final acetal cleavage.
Beispiel 8Example 8
2-Hydroxy-3- [ (methoxy-methyl-carbamoyl ) -methoxy] -3 , 3-diphenyl- propionsäurebenzylester2-Hydroxy-3- [(methoxy-methyl-carbamoyl) methoxy] -3, 3-diphenyl-propionic acid benzyl ester
Zu einer auf -78°C gekühlten Lösung von 2-Hydroxy-iV-methoxy- N- methyl-acetamid (1,19 g, 10,0 mmol) und 3 , 3-Diphenyl-2 , 3-epoxy- propionsäurebenzylester (3,88 g, 11,0 mmol; Reinheit lt. HPLC: 94 %) in wasserfreiem Dichlormethan (100 ml) wurde langsam Bortrifluorid-Etherat (0,10 ml) gegeben. Man ließ zwei Stunden rühren, der Ansatz erwärmte sich in dieser Zeit allmählich auf -20°C, und es wurde durch vorsichtige Zugabe wäßriger Natrium- hydrogencarbonat-Lösung abgebrochen. Die organische Phase wurde mit Natriumhydrogencarbonat-Lösung gewaschen und über Magnesiumsulfat getrocknet. Nach dem Abfiltrieren vom Trockenmittel wurde das Lösungsmittel abdestilliert; das zurückbleibende rohe Öl (5,50 g) wurde ohne weitere Reinigung weiter umgesetzt.To a solution of 2-hydroxy-IV-methoxy-N-methyl-acetamide (1.19 g, 10.0 mmol) and 3,3-diphenyl-2,3-epoxy-propionic acid benzyl ester (3 , 88 g, 11.0 mmol; purity according to HPLC: 94%) in anhydrous dichloromethane (100 ml), boron trifluoride etherate (0.10 ml) was slowly added. The mixture was allowed to stir for two hours, during which time the batch gradually warmed to -20 ° C. and the mixture was stopped by carefully adding aqueous sodium hydrogen carbonate solution. The organic phase was washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off; the remaining crude oil (5.50 g) was reacted further without further purification.
Beispiel 9Example 9
3- [ (Methoxy-methyl-carbamoyl) -methoxy] -2- (4-methoxy-6-methyl- pyrimidin-2-yloxy) -3 , 3-diphenylpropionsäurebenzylester3- [(Methoxy-methyl-carbamoyl) methoxy] -2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3, 3-diphenylpropionic acid benzyl ester
Eine Lösung von 2-Hydroxy-3- [ (methoxy-methyl-carbamoyl) - methoxy] -3 , 3-diphenylpropionsäure-benzylester (1,35 g, roh) wurde unter Eiskühlung mit Kaliumcarbonat (365 mg, 2,64 mmol) und nach 10 Minuten mit 2-Methansulfonyl-4-methoxy-6-methyl- pyrimidin (320 mg, 1,45 mmol) versetzt. Nachfolgend wurde 30 Minuten bei 0°C und dann 16 Stunden bei Zimmertemperatur gerührt. Der Ansatz wurde mit Wasser verdünnt, mit Zitronensäure angesäuert und zweimal mit Ether extrahiert. Die vereinigten organischen Phasen wurde mit Wasser gegengewaschen und über Magnesiumsulfat getrocknet. Nach dem Abdestiliieren des Lösungsmittels blieb ein Schaum zurück (1,60 g) , der durch Flash- Chromatographie und nachfolgende Kristallisation aus Ether/n- Hexan gereinigt wurde; man erhielt 650 mg der Titelverbindung.A solution of 2-hydroxy-3- [(methoxy-methyl-carbamoyl) methoxy] -3, 3-diphenylpropionic acid benzyl ester (1.35 g, crude) was cooled with potassium carbonate (365 mg, 2.64 mmol) while cooling with ice. and after 10 minutes 2-methanesulfonyl-4-methoxy-6-methylpyrimidine (320 mg, 1.45 mmol) was added. The mixture was then stirred at 0 ° C. for 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water, acidified with citric acid and extracted twice with ether. The combined organic phases were washed back with water and dried over magnesium sulfate. After the solvent had been distilled off, a foam remained (1.60 g), which was purified by flash chromatography and subsequent crystallization from ether / n-hexane; 650 mg of the title compound were obtained.
Beispiel 10Example 10
3- [2- (3 , 4-Dimethoxy-phenyl) -2-oxo-ethoxy] -2- (4-methoxy-6-methyl- pyrimidin-2-yloxy) -3 , 3-diphenylpropionsäurebenzylester3- [2- (3,4-Dimethoxy-phenyl) -2-oxo-ethoxy] -2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3, 3-diphenylpropionic acid benzyl ester
Zu einer Lösung von 3- [ (Methoxy-methyl-carbamoyl) -methoxy] - 2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3 , 3-diphenylpropion- säurebenzylester (250 mg, 0,38 mmol, Reinheit lt. HPLC: 86 %) in wasserfreiem Tetrahydrofuran (25 ml) gab man bei Zimmertemperatur eine 1-molare Lösung von 3 , 4-Dimethoxyphenylmagnesiumbromid in Tetrahydrofuran (0,60 mL) . Nach 10 Minuten Rühren wurde nur teilweiser Umsatz beobachtet, daher wurde nochmals 1-molare Lösung von 3 , 4-Dimethoxyphenylmagnesiumbromid in Tetrahydrofuran (0,60 ml) zugetropft. Es wurde nochmals 10 Minuten gerührt, danach wurde das Solvens abgedampft. Der Rückstand wurde in Ethyl- acetat/Ξther 1:2 aufgenommen. Nach Abfiltrieren vom Ungelösten wurde das Lösungsmittel abdestilliert, und der ölige Rückstand (400 mg) wurde durch Flash-Chromatographie gereinigt. Man erhielt die TitelVerbindung als Schaum (125 mg, 49 % Ausbeute bei 95 % Reinheit it. HPLC) .To a solution of 3- [(methoxy-methyl-carbamoyl) methoxy] - 2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3, 3-diphenylpropionic acid benzyl ester (250 mg, 0.38 mmol, purity according to HPLC: 86%) in anhydrous tetrahydrofuran (25 ml), a 1-molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 ml) was added at room temperature. After 10 minutes of stirring, only partial conversion was observed, so another 1-molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 ml) was added dropwise. The mixture was stirred for another 10 minutes, after which the solvent was evaporated off. The residue was taken up in ethyl acetate / ether 1: 2. After the undissolved matter was filtered off, the solvent was distilled off and the oily residue (400 mg) was purified by flash chromatography. You got the title compound as a foam (125 mg, 49% yield with 95% purity according to HPLC).
iH-NMR (400 MHz, CDC13): 7.5 - 7.7 ppm (4 H, m) , 7.4 (2 H, d) , 7.2 - 7.3 (9 H, m) , 6.9 (2 H, d) , 6.8 (1 H, d) , 6.3 (1 H, s), 6.2iH-NMR (400 MHz, CDC1 3 ): 7.5 - 7.7 ppm (4 H, m), 7.4 (2 H, d), 7.2 - 7.3 (9 H, m), 6.9 (2 H, d), 6.8 ( 1 H, d), 6.3 (1 H, s), 6.2
(1 H, s), 5.4 (1 H, d) , 5.0 (2 H, m) , 4.7 (1 H, d) , 3.9 (6 H, s), 3.7 (3 H, s) , 2.3 (3 H, s) .(1 H, s), 5.4 (1 H, d), 5.0 (2 H, m), 4.7 (1 H, d), 3.9 (6 H, s), 3.7 (3 H, s), 2.3 (3 H, s).
Analog oder wie im allgemeinen Teil beschrieben lassen sich die Verbindungen in der Tabelle I herstellen.The compounds in Table I can be prepared analogously or as described in the general part.
Beispiel 11Example 11
Gemäß dem oben beschriebenen Bindungstest wurden für die nach- folgend aufgeführten Verbindungen Rezeptorbindungsdaten gemessen.According to the binding test described above, receptor binding data were measured for the compounds listed below.
Die Ergebnisse sind in Tabelle 2 dargestellt.The results are shown in Table 2.
Tabelle 2Table 2
Rezeptorbindungsdaten (Kχ-Werte)Receptor binding data (Kχ values)
Figure imgf000024_0001
Figure imgf000024_0001
0)
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
0)
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
to into in
Figure imgf000027_0001
Figure imgf000027_0001
toto
Figure imgf000028_0001
Figure imgf000028_0001
toto
Figure imgf000029_0001
Figure imgf000029_0001
Figure imgf000030_0001
to
Figure imgf000030_0001
to
00 00

Claims

Patentansprüche claims
1. Carbonsäurederivate der Formel I1. Carboxylic acid derivatives of the formula I.
Figure imgf000031_0002
g besitzen:
Figure imgf000031_0002
own g:
etalls, das Kation iologisch verträg
Figure imgf000031_0001
etalls, the cation iologically compatible
Figure imgf000031_0001
lkenyl, C3-C6-Alkinyl, nenfalls substi¬lkenyl, C 3 -C 6 alkynyl, if necessary substi¬
ter 5-gliedriger
Figure imgf000031_0003
c) eine Gruppe the 5-membered
Figure imgf000031_0003
c) a group
d) ein Restd) a rest
O —N—S—RO —N — S — R
H II ° worin R11 bedeutet:H II ° in which R 11 means:
Cχ-C4-Alkyl, C3-C6-Alkenyl, C3-C6-Alkinyl, C3-Cg-Cycloalkyl, wobei diese Reste einen Cχ-C4-Alkoxy-, Cχ-C4-Alkylthio- und/oder einen Phenylrest tragen können;Cχ-C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -Cg cycloalkyl, these radicals being a Cχ-C 4 alkoxy, Cχ-C 4 alkylthio and / or can carry a phenyl radical;
Phenyl, gegebenenfalls substituiert.Phenyl, optionally substituted.
R2 Wasserstoff, Hydroxy, NH2, NH (Cχ_C -Alkyl ) , N(Cχ-C-Alkyl)2, Halogen, C-C4-Alkyl, C2-C4-Alkenyl,R 2 is hydrogen, hydroxyl, NH 2 , NH (Cχ_C-alkyl), N (Cχ-C-alkyl) 2 , halogen, CC 4 alkyl, C 2 -C 4 alkenyl,
C2-C4-Alkinyl , Cχ-C4-Halogenalkyl , Cχ-C4-Alkoxy, Cχ-C-Halogenalkoxy oder Cχ-C-Alkylthio, oder CR2 ist mit CR12 wie unten angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;C 2 -C 4 alkynyl, Cχ-C 4 haloalkyl, Cχ-C 4 alkoxy, Cχ-C-haloalkoxy or Cχ-C-alkylthio, or CR 2 is with CR 12 to a 5- or 6 as indicated below -linked ring linked;
X Stickstoff oder Methin;X nitrogen or methine;
Y Stickstoff oder Methin;Y nitrogen or methine;
Z Stickstoff oder CR12, worin R12 Wasserstoff oderZ is nitrogen or CR 12 , wherein R 12 is hydrogen or
Cχ-C-Alkyl bedeutet oder CR12 zusammen mit CR2 oder CR3 einen 5- oder 6-gliedrigen Alkylen- oder Alkenylenring bildet, der gegebenenfalls substituiert sein kann, und worin jeweils eine oder mehrere Methylengruppen durch Sauerstoff, Schwefel, -NH oder -N(Cχ-C -Alkyl) , ersetzt sein können,*Cχ-C-alkyl means or CR 12 together with CR 2 or CR 3 forms a 5- or 6-membered alkylene or alkenylene ring, which may optionally be substituted, and in which in each case one or more methylene groups by oxygen, sulfur, -NH or -N (Cχ-C alkyl), can be replaced, *
R3 Wasserstoff, Hydroxy, NH2, NH (C-C4-Alkyl ) ,R 3 is hydrogen, hydroxy, NH 2 , NH (CC 4 alkyl),
N(Cχ-C-Alkyl)2, Halogen, C-C4_Alkyl , C2_C4_Alkenyl, C2-C-Alkinyl, Cχ-C-Halogenalkyl, Cχ-C-Alkoxy,N (Cχ-C-alkyl) 2 , halogen, CC 4 _alkyl, C 2 _C 4 _alkenyl, C 2 -C alkynyl, Cχ-C-haloalkyl, Cχ-C-alkoxy,
Cχ-C4-Halogenalkoxy, Cχ-C-Alkylthio; oder CR3 ist mit CR12 wie oben angegeben zu einem 5- oder 6-gliedrigen Ring verknüpft;Cχ-C 4 haloalkoxy, Cχ-C-alkylthio; or CR 3 is linked to CR 12 to give a 5- or 6-membered ring as indicated above;
R4 und R5 (die gleich oder verschieden sein können) :R 4 and R 5 (which may be the same or different):
Phenyl oder Naphthyl, gegebenenfalls substituiert,Phenyl or naphthyl, optionally substituted,
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, C3-C8-Cycloalkyl gegebenenfalls substituiert;Phenyl or naphthyl, which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO, NH or N-alkyl group, C 3 -C 8 cycloalkyl optionally substituted;
R6 gegebenenfalls substituiertes C3-C8-Cycloalkyl;R 6 optionally substituted C 3 -C 8 cycloalkyl;
Phenyl oder Naphthyl, gegebenenfalls substituiert;Phenyl or naphthyl, optionally substituted;
ein fünf- oder sechsgliedriger Heteroaromat, enthaltend ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, und welcher gegebenenfalls substituiert sein kann;a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, and which may be substituted;
R7 und R8 (die gleich oder verschieden sein können) :R 7 and R 8 (which may be the same or different):
Wasserstoff oder Cχ-C4-Alkyl;Hydrogen or Cχ-C 4 alkyl;
W Schwefel oder Sauerstoff.W sulfur or oxygen.
2. Arzneimittelzubereitungen, enthaltend mindestens ein Carbonsäurederivat I gemäß Anspruch 1.2. Pharmaceutical preparations containing at least one carboxylic acid derivative I according to claim 1.
3. Verwendung der Carbonsäurederivate gemäß Anspruch 1 zur Behandlung von Krankheiten.3. Use of the carboxylic acid derivatives according to claim 1 for the treatment of diseases.
4. Verwendung der Verbindungen I gemäß Anspruch 1 als Endothe- lin-Rezeptorantagonisten.4. Use of the compounds I according to claim 1 as endothelin receptor antagonists.
5. Verwendung der Carbonsäurederivate I gemäß Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, bei denen erhöhte Endothelinspiegel auftreten.5. 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.
6. Verwendung gemäß Anspruch 5 zur Behandlung von chronischer Herzinsuffizienz, Restenose, Bluthochdruck, pulmonalem Hochdruck, akutem/chronischen Nierenversagen, zerebraler Ischämie, benigne Prostatahyperplasie und Prostatakrebs.6. Use according to claim 5 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer.
7. Pharmazeutisches Kombinationspräparat, enthaltend ein Carbonsäurederivat gemäß Anspruch 1 und einen Inhibitor des Renin- Angiotensin Systems oder einen gemischten ACE/Neutrale Endo- peptidase (NEP) -Hemmer oder einen ß-Blocker. 7. A pharmaceutical combination preparation containing a carboxylic acid derivative according to claim 1 and an inhibitor of the renin-angiotensin system or a mixed ACE / neutral endopeptidase (NEP) inhibitor or a β-blocker.
. Verwendung von Verbindungen der Formel IV. Use of compounds of the formula IV
Figure imgf000034_0001
worin die Reste R1, R4, R5, R6, R7, R8 und W die in Anspruch 1 angegebene Bedeutung haben, als Zwischenprodukt zur Synthese von Endothelin-Rezeptorantagonisten .
Figure imgf000034_0001
wherein the radicals R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and W have the meaning given in claim 1, as an intermediate for the synthesis of endothelin receptor antagonists.
Verwendung eines strukturellen Fragments der FormelUsing a structural fragment of the formula
Figure imgf000034_0002
worin die Reste R1, R4, R5, R6, R7, R8 und W die in Anspruch 1 angegebene Bedeutung haben, als strukturellen Bestandteil eines Endothelin-Rezeptorantagonisten.
Figure imgf000034_0002
wherein the radicals R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and W have the meaning given in claim 1, as a structural component of an endothelin receptor antagonist.
10. Verwendung eines strukturellen Fragments der Formel10. Use of a structural fragment of the formula
Figure imgf000034_0003
worin die Reste R1, R2, R3, R4, R5, R7, R8, W, X, Y und Z die in Anspruch 1 angegebene Bedeutung haben, als strukturellen Bestandteil in einem Endothelin-Rezeptorantagonisten.
Figure imgf000034_0003
wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , W, X, Y and Z have the meaning given in claim 1, as a structural component in an endothelin receptor antagonist.
11. Verbindungen der Formel Via11. Compounds of the formula Via
Figure imgf000034_0004
worin die Reste R1, R2, R3, R4, R5, R6, R7, R8, W, X, Y und Z die in Anspruch 1 angegebene und R18 sowie R19 die folgende Bedeutung haben:
Figure imgf000034_0004
wherein the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, X, Y and Z have the meaning given in Claim 1 and R 18 and R 19 have the following meaning:
R18 und R19 (die gleich oder verschieden sein können) : Cχ-C-Alkyl oder R18 bildet zusammen mit R19 eine Ethylen oder Propylenbrücke, die gegebenenfalls mit einer bis vier Methylgruppen substituiert sein kann. R 18 and R 19 (which may be the same or different): Cχ-C-alkyl or R 18 together with R 19 forms an ethylene or propylene bridge, which can optionally be substituted with one to four methyl groups.
PCT/EP1999/005728 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists WO2000009489A1 (en)

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SK83-2001A SK832001A3 (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
PL99345998A PL345998A1 (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
EP99939457A EP1104410A1 (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
AU53741/99A AU5374199A (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
JP2000564942A JP2002522531A (en) 1998-08-10 1999-08-07 Novel carboxylic acid derivatives having keto side chains, their preparation and their use as endothelin receptor antagonists
BR9912889-6A BR9912889A (en) 1998-08-10 1999-08-07 Carboxylic acid derivative, pharmaceutical preparation, use of carboxylic acid derivatives, use of compounds, preparation of pharmaceutical combination, use of a structural fragment, and, compound
IL14091599A IL140915A0 (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
CA002340167A CA2340167A1 (en) 1998-08-10 1999-08-07 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
KR1020017001731A KR20010072378A (en) 1998-08-10 1999-08-07 New Carboxylic Acid Derivatives Carrying Keto Side-Chains, Their Production and Their Use as Endothelin-Receptor Antagonists
NO20010622A NO20010622D0 (en) 1998-08-10 2001-02-06 Novel carboxylic acid derivatives bearing keto side chains, their preparation and their use as endothelin receptor antagonists
BG105236A BG105236A (en) 1998-08-10 2001-02-09 New carboxylic acid derivatives carrying keto side-chains, their production and use as endothelin-receptor antagonists
HR20010164A HRP20010164A2 (en) 1998-08-10 2001-03-08 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
HK02103679.0A HK1042086A1 (en) 1998-08-10 2002-05-15 New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists

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