Classifications

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  • 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
  • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
• • 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
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—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
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/60—Three or more oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 15. , 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 3_4_4, 114 (1990), N. Engl. J. Med. 122., 205 (1989), N. Engl. J. Med. 3_2 £, 1732 (1993), Nephron ££, 373
• 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.
• the low plasma separation is mentioned as an advantage of these compounds.
• ET A (ET B ) -specific antagonists we refer to those antagonists whose affinity for the ET A (ET B ) receptor is at least ten times higher than their affinity for the ET B (ET A ) receptor.
• Preferred compounds are those whose affinity difference to the two receptors is at least twenty.
• the invention relates to carboxylic acid derivatives of the formula I.
• R 1 stands for tetrazole or for a group
• Hydrogen the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically compatible organic ammonium ion such as tertiary C 1 -C 4 -alkylammonium or the ammonium ion;
• R 9 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 6 -haloalkyl, hydroxy, C 1 -C 8 -alkoxy, mercapto , -CC alkylthio, amino, NH (C1-C4 alkyl), N (C 1 -C 4 alkyl) 2 ;
• a 5-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C ⁇ -C-alkyl or one or two C ⁇ -C-alkoxy groups.
• a group such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or two C ⁇ -C-alkyl or one or two C ⁇ -C-alkoxy groups.
• Halogen nitro, cyano, C 1 -C 4 alkyl, C ! -C 4 haloalkyl, hydroxy, -C 4 alkoxy, C 4 -C 4 alkylthio, mercapto, amino, NH (-C 4 alkyl), N (-C 4 alkyl) 2 .
• R 11 means:
• Phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy, C 4 alkylthio , Mercapto, amino, NH (C 1 -C 4 alkyl), N (-C -C alkyl) 2nd
• R 2 is hydrogen, hydroxyl, NH 2 , NH (Ci ⁇ alkyl), N (-C - C 4 alkyl) 2 , halogen, -C - C 4 alkyl, C 2 -C alkenyl, C 2 -C 4 -Alkynyl, -C-C 4 -hydroxyalkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy or C ⁇ -C-alkylthio, or CR 2 is with CR 10 as specified under Z to one 5- or 6-membered ring linked. X nitrogen or methine.
• Z is nitrogen or CR 12 , wherein R 12 is hydrogen, halogen or
• C 1 -C 4 alkyl, or CR 12 forms together with CR 2 or CR 3 a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two -C 4 alkyl groups and in each of which one or more methylene groups can be replaced by oxygen, sulfur, -NH or N (-CC alkyl).
• At least one of the ring members X, Y or Z is nitrogen.
• R 3 is hydrogen, hydroxyl, NH 2 , NH (C 1 -C 4 alkyl), N (-C 1 -C 4 alkyl) 2 , halogen, -C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C ⁇ -C4 haloalkyl, C ⁇ ⁇ C alkoxy, C ⁇ -C4-haloalkoxy, C ⁇ -C hydroxyalkyl, C ⁇ -C 4 -alkylthio, or CR 3 is as indicated under Z CR 12 to a 5- or 6-membered ring linked.
• R 4 and R 5 (which may be the same or different):
• Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C 3 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C- alkynyl, C ⁇ -C4 haloalkyl, C ⁇ -C4-alkoxy, phenoxy, carboxyl, q i.
• -C-haloalkoxy -CC 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (-C-C 4 alkyl) or phenyl, which can be substituted one or more times, for example a - up to three times by halogen,
• Phenyl or naphthyl which are linked to one another via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group;
• R 14 (which may be the same or different):
• radicals may each be mono- or can be substituted in many ways: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, C ⁇ -C 4 -alkoxy, C 4 alkylthio, C ⁇ -C4-halo-alkoxy;
• Phenyl or naphthyl each of which may be substituted by one or more of the following radicals: halogen, nitro, carboxamide, mercapto, carboxyl, cyano, hydroxy, amino, R 15, C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl , C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 1 -C 4 haloalkyl, C 3 -C 6 alkynyloxy, C ⁇ -C alkyl-carbonyl, C ⁇ -C 4 alkoxycarbonyl, C ⁇ -C 4 -Alkoxy, -C-C 4 -haloalkoxy, phenoxy, -C-C-alkylthio, NH (C 1 -C 4 alkyl), N (-C-C 4 alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, the one - C ⁇ -C C ⁇ C ⁇ -C
• R 13 and R 14 together form a ring to a closed-sene C 3 -C-alkylene chain which may be mono- or polysubstituted with C ⁇ -C 4 alkyl, C 1 -C 4 alkylthio, C ⁇ -C 4 ⁇ alkoxy, C ⁇ -C 4 haloalkyl, C ⁇ -C4-haloalkoxy, and be an alkylene group interrupted by oxygen, sulfur, nitrogen or N (C ⁇ -C4 alkyl), replaced, as - (CH> 4 - , - (CH 2 ) s-, - (CH 2 ) 6 -, - (CH 2 ) 7 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, - (CH 2 ) -S- ( CH 2 ) 2 -, - (CH 2 ) 2 -NH- (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2 ) 2 -N (
• R 7 and R 8 (which may be the same or different):
• R 15 C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio, C 4 -C 4 -alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C ⁇ -C 4 -alkyl), N (C ⁇ - C 4 alkyl) 2 , carboxamide or CON (-C-alkyl) 2 .
• R 18 is hydrogen
• C 1 -C 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl where these radicals can be substituted one or more times by: halogen, carboxy, cyano, C 1 -C 4 -alkoxy , C 1 -C 4 -Alkylthio, -C-C-haloalkoxy, -C-C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxycarbonyl, C 3 -C 8 -cycloalkyl, amino, NH (-C-C 4 -alkyl), N (-CC alkyl) 2 , phenoxy or phenyl, wherein the aryl radicals mentioned can in turn be substituted one or more times, for example one to three times by halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkyl , C ⁇ -C 4 ⁇ haloalky
• Phenyl or naphthyl which in each case by a plurality of the following radicals or may be substituted halogen, nitro, mercapto, carboxyl, cyano, hydroxy, amino, R 15, C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -C-C 4 -haloalkyl, CC 4 -alkylcarbonyl, C ⁇ -C-alkoxycarbonyl, C ⁇ -C-alkoxy, C ⁇ -C 4 -haloalkoxy, phenoxy, C ⁇ -C 4 -alkylthio , NH (C ⁇ -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C ⁇ -C-alkyl, CC 4
• Phenylcarbonyl or naphthylcarbonyl each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxy, cyano, hydroxy, amino, R 15 , C ⁇ -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C ⁇ -C 4 haloalkyl, C 3 -C 6 alkynyloxy, C ⁇ -C 4 alkylcarbonyl,
• CC 4 -alkoxycarbonyl C ⁇ -C 4 -alkoxy, C ⁇ -C-haloalkoxy, phenoxy, C ⁇ -C-alkylthio, NH (C 1 -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , dioxo- methylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ - C 4 haloalkoxy or C ⁇ -C 4 alkylthio;
• Phenylsulfonyl or naphthylsulfonyl each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, amino, R 15 , C ⁇ -C 4 alkyl,
• R 20 is hydrogen;
• C ⁇ -C 4 alkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, .amino, C ⁇ -C 4 alkoxy, C ⁇ -C 4 alkylthio, C ⁇ -C 4 ⁇ Haloalkoxy, C ⁇ -C 4 -alkoxycarbonyl, CC 8 -cycloalkyl, NH (C 1 -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , indolyl, phenoxy or phenyl, the aryl radicals mentioned in turn - or can be substituted several times, for example one to three times by halogen, hydroxy, mercapto, carboxy, C 1 -C 4 alkyl,
• C ⁇ -C 4 -haloalkyl C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, amino, NH (C ⁇ -C 4 -alkyl), N (CC-alkyl) 2 or C--C 4 -alkylthio.
• R 21 is hydrogen, C ⁇ -C 4 alkyl.
• 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 ⁇ -C 4 haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chlorine -2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
• C ⁇ -C-haloalkoxy can be linear or branched, e.g. Difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
• C ⁇ -C 4 alkyl can be linear or branched such as methyl
• C 2 -C -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 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
• C ⁇ -C-Alkoxy can be linear or branched, e.g. Methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
• C 3 -C 6 ⁇ alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
• C-Cg-Alkynyloxy can be linear or branched, e.g. 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
• C ⁇ -C 4 alkylthio can be linear or branched such as methyl thio, ethyl thio, propyl thio, 1-methyl ethyl thio, butyl thio,
• C ⁇ -C 4 alkylcarbonyl can be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl, 1-propylcarbonyl, 1-butylcarbonyl;
• C ⁇ -C-Alkoxycarbonyl can be linear or branched, e.g. Metoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
• C 3 -C 8 -alkylcarbonylalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-0xo-but-1-yl or 3-oxo-but-2-yl
• C ⁇ -C 8 alkyl can be linear or branched such as C ⁇ -C 4 alkyl, pentyl, hexyl, heptyl or octyl;
• C ⁇ -C 8 alkylcarbonyl can be linear or branched such as C ⁇ -C 4 alkylcarbonyl, 1-pentylcarbonyl, 1-hexylcarbonyl, 1-heptylcarbonyl or 1-octylcarbonyl;
• C 2 -C 8 alkenylcarbonyl can be linear or branched, such as, for example, ethenylcarbonyl, l-propen-3-ylcarbonyl, l-propen-2-ylcarbonyl, 1-propen-l-ylcarbonyl, 2-methyl-1-propenylcarbonyl, 1- Butene-l-ylcarbonyl, 1-penten-l-ylcarbonyl, 1-octene-l-ylcarbonyl;
• C 2 -C 8 alkynylcarbonyl can be linear or branched, such as, for example, ethynylcarbonyl, l-propyn-3-ylcarbonyl, 1-propyn-l-ylcarbonyl, 1-butyn-l-ylcarbonyl, 1-pentyn-l-ylcarbonyl, 1- Octin-l-yl carbonyl; C 3 -C 8 cycloalkylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-methylcyclohex-l-ylcarbonyl cycloheptylcarbonyl or cyclooctylcarbonyl;
• C ⁇ -C 4 alkylsulfonyl can be linear or branched such as methylsulfonyl, ethylsulfonyl or 2-propylsulfonyl, 1-propylsulfonyl, 2-methyl-l-propylsulfonyl, 1-butylsulfonyl;
• C ⁇ -C 8 alkylsulfonyl can be linear or branched such as C ⁇ -C-alkylsulfonyl, 1-pentylsulfonyl, 1-hexylsulfonyl, 1-heptylsulfonyl or 1-octylsulfonyl;
• C 3 -C 8 alkenylsulfonyl can be linear or branched such as l-propen-3-ylsulfonyl, l-propen-2-ylsulfonyl, 1-propen-l-ylsulfonyl, 2-methyl-l-propen-l- ylsulfonyl, 1-butene-l-ylsulfonyl, 1-pentene-l-ylsulfonyl, 1-octene-l-ylsulfonyl
• C 3 -C 8 alkynylsulfonyl can be linear or branched, such as, for example, l-propyn-3-ylsulfonyl, 1-propyn-l-ylsulfonyl, 1-butyn-l-ylsulfonyl, 1-pentyn-l-ylsulfonyl, 1- Octin-l-ylsulfonyl
• C 3 -C 8 cycloalkylsulfonyl is, for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, 4-methylcyclohex-1-ylsulfonyl, cycloheptylsulfonyl or cyclooctylsulfonyl;
• 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, blood circulation, liver, foresee.
• the compounds I and also the intermediates for their preparation, e.g. III, IV and V, 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 furthermore relates to the use of the above-mentioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and ET B receptors.
• the compounds of the invention are suitable as selective and as mixed antagonists as defined at the beginning.
• enantiomeric compounds of the formula V can be obtained by carrying out a classic racemate cleavage with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula V.
• bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
• enantiomerically pure compounds of the formula V can be obtained via an acid-catalyzed transetherification, as described in DE 19636046.3.
• R 16 is halogen or R 17 -S0 2 -, where R 17 can be C ⁇ -C-alkyl, C ⁇ -C 4 -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 intermediate V, 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 can optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon-etra-chloride, ethyl chloride and trichlorethylene, ethers, such as, for example, diisopropyl ether, dibutyl ether, methyl tert.
• chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon-etra-chloride, ethyl chloride and trichlorethylene
• ethers such as, for example, diisopropyl ether, dibutyl
• nitriles such as, for example, acetonitrile and propionitrile
• acid amides such as, for example, dimethylformamide, dirnethylacetamide and N-methylpyrrolidone
• sulfoxides and sulfones such as, for example, dimethyl sulfoxide and sulfolane.
• an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. Sodium or potassium carbonate, an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide such as lithium diisopropylamide or lithium amide.
• 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 Hydroxy1 connection 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
• Carboxylic acids emanate from compounds of the formula I in which R 1 represents a group COOM, where M can be an alkali metal cation or the E-equivalent of an alkaline earth metal cation.
• R 1 represents a group COOM
• M can be an alkali metal cation or the E-equivalent of an alkaline earth metal cation.
• A denotes 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 another equivalent leaving group.
• Compounds of the formula RA with a reactive substituent A are known or are easy to obtain with the general specialist knowledge. This reaction can be carried out in the usual solvents. lead and is advantageously carried out with the addition of a base, the above mentioned being
• the preparation of the compounds I according to the invention requires the use of generally known protective group techniques.
• R 13 4-hydroxyphenyl
• the hydroxy group can first be protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
• carboxylic acid derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
• R 2 is hydrogen, hydroxy, halogen, N (C ⁇ -C 4 -alkyl) 2 , C ⁇ -C 4 -alkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -alkylthio, C ⁇ -C 4 -haloalkyl,
• C ⁇ -C-haloalkoxy, C ⁇ -C-hydroxyalkyl, or CR 2 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
• At least one of the ring members X, Y or Z is nitrogen.
• R 3 is hydrogen, hydroxy, halogen, N (-CC 4 -alkyl) 2 , C ⁇ -C 4 -alkyl, CC 4 -alkoxy, C ⁇ -C-alkylthio, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -hydroxyalkyl , C ⁇ -C-haloalkoxy, or CR 3 is linked with CR 10 as indicated under Z to a 5- or 6-membered ring;
• R 4 and R 5 (which may be the same or different) Phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, amino, C ⁇ -C-alkyl, C ⁇ -C 4 haloalkyl, C -C 4 alkoxy, C ⁇ -C 4 -Halogenalkoxy, phenoxy, C ⁇ -C-alkylthio, NH (C ⁇ -C-alkyl) or N (C ⁇ -C-alkyl) 2 or phenyl, which can be substituted one or more times, for example one to three times by halogen, cyano , C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C alkoxy, C ⁇ -C 4 haloalkoxy or C ⁇ -C 4 alkylthio; or
• Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 2 -, NH or N-alkyl group
• R 6 is a group
• the molecular weight of groups R 13 and R 14 taken together must be at least 60.
• R 13 and R 14 (which may be the same or different):
• C 3 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxy, cyano, C ⁇ -C-alkyl, C ⁇ -C 4 ⁇ alkoxy, C ⁇ -C 4 alkylthio , C 1 -C 4 -Haiogenalkoxy; Phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen,
• R 13 and R 14 together form a C 3 -C 7 alkylene chain which is closed to form a ring and which can be mono- or polysubstituted by C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, and in which an alkylene group is formed Oxygen or sulfur, can be replaced, such as - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 -, - (CH 2 ) 7 -, - (CH 2 ) 2 -0- (CH 2 ) 2 -, - (CH 2 ) 2 -S- (CH 2 ) 2 -;
• R 13 and R 14 together form a C 3 -C 7 alkylene chain or C 4 -C 7 alkenylene chain, to which a phenyl ring is fused, such as 7-aza-bicyclo [4.2.0] - octa-l, 3, 5-triene, 2, 3-dihydroindole, indole, 1, 3-dihydroisoindole, 1,2,3, 4-tetrahydroquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, the phenyl ring in each case can be substituted three times by halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C-haloalkyl, C ⁇ -C 4 -haloalkoxy, hydroxy, carboxy.
• a phenyl ring in each case can be substituted three times by halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C-
• the molecular weight of groups R 13 and R 14 taken together must be at least 46.
• R 7 and R 8 (which may be the same or different):
• R 15 C 1 -C 4 alkyl, C ⁇ -C-alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (CC 4 -alkyl), N (-C-C 4 alkyl) 2 , carboxamide or C0N (CC 4 alkyl) 2 .
• R 18 is hydrogen
• C ⁇ -C 4 alkyl, C 3 -C 4 alkenyl or C 3 -C 4 alkynyl where these radicals can each be substituted one or more times by: halogen, C ⁇ -C-alkoxy, C ⁇ -C 4 -alkylthio , C ⁇ -C 4 haloalkoxy, C 3 -C 8 cycloalkyl, phenoxy or phenyl, where the aryl radicals mentioned can in turn be mono- or polysubstituted, for example one to three times by halogen, hydroxy, -C-C 4 alkyl, C ⁇ -C 4 haloalkyl, C -C 4 alkoxy or C ⁇ -C 4 alkyl thio;
• Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, hydroxyl, R 15 , CC 4 -alkyl, C ⁇ -C-alkoxycarbonyl, CC-alkoxy, C ⁇ -C 4 -alkylthio, dioxomethylene, dioxoethylene or Phenyl which can be mono- or polysubstituted, for example mono- to trisubstituted by halogen, C ⁇ -C-alkyl, C ⁇ -C-haloalkyl, C--C 4 alkoxy;
• Phenylcarbonyl or naphthylcarbonyl each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, R 15 , C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C 4 -alkoxy, phenoxy, C ⁇ -C 4 -alkylthio, dioxomethylene, dioxoethylene or phenyl, which can be substituted one or more times, for example one to three times by halogen, C ⁇ -C 4 - Alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, or C ⁇ -C 4 alkylthio;
• C ⁇ -C 4 -alkylsulfonyl where these radicals can each be mono- or polysubstituted by: halogen, C ⁇ -C-alkoxy, phenyl, it being possible for the said ajryl radical in turn to be mono- to trisubstituted by halogen, C ⁇ -C 4 -Alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 ⁇ alkoxy or C ⁇ -C 4 alkylthio;
• Phenylsulfonyl or naphthylsulfonyl each of which can be substituted by one or more of the following radicals: halogen, cyano, R 15 , C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, dioxomethylene, dioxoethylene or phenyl, which is mono- to trisubstituted can be by halogen, C ⁇ -C 4 alkyl, -C-C-haloalkyl, C ⁇ -C 4 alkoxy or C ⁇ -C-alkylthio;
• R 20 is hydrogen
• C ⁇ -C 4 alkyl where these radicals can each be monosubstituted by: hydroxy, mercapto, carboxy, amino, C 3 -Cs-cycloalkyl, indolyl, phenoxy or phenyl, where the aryl radicals mentioned can in turn be mono- to trisubstituted by halogen, hydroxy, mercapto, carboxy, C ⁇ -C 4 alkyl, C -C alkoxy, amino or C ⁇ -C alkylthio.
• R 21 is hydrogen, C ⁇ -C-alkyl.
• R 2 trifluoromethyl, C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, C ⁇ -C 4 alkylthio,
• CR 2 Hydroxymethyl, or CR 2 is linked to CR 12 as stated under Z to form a 5- or 6-membered ring;
• Z is nitrogen or CR 12 , wherein R 12 is hydrogen, fluorine or
• At least one of the ring members X, Y or Z is nitrogen
• R 3 trifluoromethyl, CC 4 alkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 alkylthio,
• CR 3 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 substituted by one or more of the following radicals: halogen, hydroxy,
• Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0, NH or N-alkyl group
• R 6 is a group
• the molecular weight of groups R 13 and R 14 taken together must be at least 60.
• R 13 and R 14 (which may be the same or different):
• Phenyl which can be mono- to trisubstituted by: halogen, carboxy, hydroxy, amino, R 15 , C ⁇ -C 4 -alkyl, CC-alkoxy, CC 4 -alkylthio, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -Alkyl- carbonyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C-haloalkoxy, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, the one to three times can be substituted by halogen, C ⁇ -C 4 alkyl, C ⁇ -C-alkoxy or C ⁇ -C-alkylthio; or R 13 and R 14 together form a C 3 -C alkylene chain which is closed to a ring and which can be mono- or polysubstituted with C ⁇ -C 4
• R 13 and R 14 together form a closed C 3 -C 7 alkylene chain to which the phenyl ring is fused, such as 2, 3-dihydroindole, indole, 1, 3-dihydroisoindole, 1, 2, 3, 4-tetra- hydroquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, where the phenyl ring can in each case be substituted one to three times by halogen, C ⁇ -C 4 ⁇ alkyl, C ⁇ -C 4 ⁇ alkoxy, C ⁇ -C4-haloalkoxy, hydroxy, carboxy.
• the groups R 13 and R 14 taken together must contain at least 5 carbon atoms.
• R 7 and R 8 (which may be the same or different)
• R 15 C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, which carry one of the following radicals: hydroxy, NH (C ⁇ -C 4 alkyl), N (C ⁇ -C 4 alkyl) 2 , carboxamide or CON ( C ⁇ -C-alkyl) 2 .
• R 18 is hydrogen
• Phenyl which can be monosubstituted to trisubstituted by: halogen, hydroxy, R 15 , C 4 -C 4 -alkyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C-alkoxy, dioxomethylene, dioxoethylene or phenyl, which is mono- to triple can be substituted by: halogen, C ⁇ -C-alkyl, trifluoromethyl, C ⁇ -C 4 -alkoxy;
• R 19 C ⁇ -C-alkylcarbonyl, where these radicals can each be substituted one to three times by: halogen, C ⁇ -C 4 alkoxy, C 3 -C 8 cycloalkyl, phenyl, which in turn can be substituted one to three times can by: halogen, C ⁇ -C 4 alkyl or C ⁇ -C 4 -Alk ⁇ xy;
• C 3 -C 8 cycloalkylcarbonyl Phenylcarbonyl or naphthylcarbonyl, each of which can be substituted by one or more of the following radicals: halogen, R 15 , C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, phenoxy, dioxomethylene, dioxoethylene or phenyl, the one to three times substi - Can be tuiert by: halogen, CC 4 alkyl or C ⁇ -C 4 alkoxy;
• C ⁇ -C 4 -alkylsulfonyl where these radicals can be substituted one to three times by: halogen, C ⁇ -C 4 -alkoxy, phenyl, which in turn can be substituted one to three times by: halogen, C ⁇ -C 4 -alkyl , C ⁇ -C 4 alkoxy or C ⁇ -C-alkylthio;
• R 20 is hydrogen; C ⁇ -C-alkyl.
• R 21 is hydrogen, C -C alkyl.
• the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic kidney failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agents -induced kidney failure, pancreatitis, gastrointestinal ulcers
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
• Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors.
• Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor).
• VEGF vascular endothelial growth factor
• substances which block the action of VEGF are, for example, antibodies directed against VEGF or specific binding proteins or also low molecular weight substances which can specifically inhibit VEGF release or receptor binding.
• the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
• the form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors 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.
• 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 7 , R 8 , W, X, Y and Z have the meaning given above, covalently linked to a group which has a molecular weight of at least 30, preferably 40.
• Another object of the invention are to provide a first object of the invention.
• Endothelin receptor antagonists consisting of a structural fragment of the formula
• radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 20 , R 21 , W, X, Y and Z have the meaning given in Claim 1, via an N-- Atom covalently linked to a group that has a molecular weight of at least 58.
• Another object of the invention are compounds of
• the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours the cells were washed with PBS and with 0.05% trypsin-containing ger PBS incubated 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).
• Incubation buffer 50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA suspended in a concentration of 50 ⁇ g protein per test batch and at 25 ° C. with 25 pM
• test animals were given the test compounds i.V. 30 min before the ETI administration. injected (1 ml / kg). To determine the ET antagonistic properties, the blood pressure changes in the test animals were compared with those in the control animals.
• big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ET1 (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 approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
• the new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (cf. H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
• the aqueous phase was extracted with ether, the organic phase thus obtained was discarded, then the aqueous phase was adjusted to pH 1 with hydrochloric acid and extracted with ether.
• the organic phase was dried over sodium sulfate, the solvent was distilled off and the residue was chromatographed on silica gel (methylene chloride / methanol 9: 1). Yield 14.0 g of white foam.

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