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
• • 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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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Heart & Thoracic Surgery (AREA)
• Hospice & Palliative Care (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Plural Heterocyclic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

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• 1998
  • 1998-08-10 DE DE19836044A patent/DE19836044A1/de not_active Withdrawn
• 1999
  • 1999-08-07 HU HU0104007A patent/HUP0104007A3/hu unknown
  • 1999-08-07 IL IL14091599A patent/IL140915A0/xx unknown
  • 1999-08-07 AU AU53741/99A patent/AU5374199A/en not_active Abandoned
  • 1999-08-07 WO PCT/EP1999/005728 patent/WO2000009489A1/de not_active Application Discontinuation
  • 1999-08-07 CA CA002340167A patent/CA2340167A1/en not_active Abandoned
  • 1999-08-07 BR BR9912889-6A patent/BR9912889A/pt not_active Application Discontinuation
  • 1999-08-07 EP EP99939457A patent/EP1104410A1/de not_active Withdrawn
  • 1999-08-07 PL PL99345998A patent/PL345998A1/xx not_active Application Discontinuation
  • 1999-08-07 ID IDW20010326A patent/ID27965A/id unknown
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  • 1999-08-07 KR KR1020017001731A patent/KR20010072378A/ko not_active Application Discontinuation
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  • 1999-08-07 JP JP2000564942A patent/JP2002522531A/ja active Pending
  • 1999-08-07 CN CN99811981A patent/CN1323298A/zh active Pending
  • 1999-08-10 CO CO99050715A patent/CO5261504A1/es not_active Application Discontinuation
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• 2001
  • 2001-02-06 NO NO20010622A patent/NO20010622D0/no not_active Application Discontinuation
  • 2001-02-09 BG BG105236A patent/BG105236A/xx unknown
  • 2001-03-08 HR HR20010164A patent/HRP20010164A2/hr not_active Application Discontinuation
  • 2001-03-09 ZA ZA200101975A patent/ZA200101975B/en unknown
• 2002
  • 2002-05-15 HK HK02103679.0A patent/HK1042086A1/zh unknown

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