EP1140867A1 - Nouveaux derives d'acides beta-amido- et beta-sulfonamidocarboxyliques, leur production et leur utilisation comme antagonistes des recepteurs d'endotheline - Google Patents

Nouveaux derives d'acides beta-amido- et beta-sulfonamidocarboxyliques, leur production et leur utilisation comme antagonistes des recepteurs d'endotheline

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Publication number
EP1140867A1
EP1140867A1 EP99964533A EP99964533A EP1140867A1 EP 1140867 A1 EP1140867 A1 EP 1140867A1 EP 99964533 A EP99964533 A EP 99964533A EP 99964533 A EP99964533 A EP 99964533A EP 1140867 A1 EP1140867 A1 EP 1140867A1
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Prior art keywords
methoxy
yloxy
alkyl
benzoylamino
diphenylpropionic acid
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German (de)
English (en)
Inventor
Wilhelm Amberg
Rolf Jansen
Georg Kettschau
Hartmut Riechers
Ernst Baumann
Stefan Hergenröder
Manfred Raschack
Liliane Unger
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Abbott GmbH and Co KG
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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

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., 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 prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 2 4, 2868 (1990), Nature ll !, 11 (1990), N. Engl. J. Med. 322., 205 (1989), N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • the invention relates to ß-amido and ß-sulfonamidocarboxylic 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 4 -C 4 alkyl ammonium or the ammonium ion;
  • R 6 may furthermore be a phenyl radical which one to five halogen atoms and / or can carry one to three of the following radicals: nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 - Alkoxy, mercapto, Ci-Gj alkylthio, amino, NH (C 1 -C 4 alkyl), Nfd-C ⁇ 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.
  • R 8 means:
  • W and Z which can be the same or different:
  • Y is nitrogen or CR ";
  • Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, dC 4 alkyl, C 2 -C 4 alkenyl, C 2 _C alkynyl,
  • -C-C 4 -haloalkyl -C-C 4 _alkoxy, phenoxy, -C-C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, amino, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 or phenyl, which can be mono- or polysubstituted, 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 1 -C 4 -Halogenalkoxy or C ⁇ _C 4 alkylthio; or
  • Phenyl or naphthyl which are connected 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 5 _C 6 -cycloalkyl where these radicals in each case may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C 4 alkyl, C 2 -C 4 alkenyl,
  • R 12 phenyl, naphthyl or a five- or six-membered heteroaromatic containing one to three
  • R 5 is hydrogen, C 1 -C 4 alkyl
  • R 9 and R 10 (which may be the same or different)
  • CR 9 or CR 10 is linked to CR 11 as stated under R 11 to form a 5- or 6-membered ring;
  • R 11 is hydrogen, halogen, C ⁇ _C 4 -alkoxy, C Haiogen- alkoxy, C 3 .C 6 _Alkenyloxy, C 3 -C 6 alkynyloxy, C ⁇ _C 4 _Alkyl- thio, C 1 -C_Alkylcarbonyl, C ⁇ -C Alkoxycarbonyl, NH (C 1 _C 4 -alkyl), N (C ⁇ _C 4 _alkyl) 2 , hydroxy, carboxy, cyano, amino, mercapto;
  • CR 9 or CR 10 forms together with CR 9 or CR 10 a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C ⁇ _ 4 alkyl groups, and in which one or more methylene groups by oxygen, sulfur, -NH or
  • An alkali metal is e.g. Lithium, sodium, potassium;
  • alkaline earth metal is e.g. Calcium, magnesium, barium;
  • Organic ammonium ions are protonated amines such as e.g. Ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;
  • 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 4 haloalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoro-ethoxy, 2, 2-difluoroethoxy, 1, 1, 2, 2-tetrafluoroethoxy, 2,2,2-tri-fluoroethoxy , 2-chloro-l, 1, 2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
  • C 1 -C 4 -alkyl can be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
  • C 2 -C 4 alkenyl can be linear or branched, such as, for example, ethenyl, l-propen-3-yl, l-propen-2-yl, 1-propen-l-yl, 2-methyl-l-propenyl, 1- Butenyl or 2-butenyl;
  • C 2 -C 4 alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
  • C ⁇ -C 4 alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy;
  • CC 6 -alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
  • C 3 -C 6 alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
  • C 1 -C 4 -Alkylthio can be linear or branched such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1, 1-dimethylethylthio;
  • C 5 -C 5 -alkylcarbonyl can be linear or branched, for example
  • C 1 -C 8 -alkyl can be linear or branched, such as C 1 -C 4 -alkyl, pentyl, hexyl, heptyl or octyl;
  • C 3 -C 8 alkenyl can be linear or branched, such as l-propen-3-yl, l-propen-2-yl, 1-propen-l-yl, 2-methyl-l-propenyl, l-butene 4-yl, 2-buten-3-yl, l-pentene-5-yl, l-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl or l-octene 8-yl;
  • C 3 -C R -alkynyl can be linear or branched, for example 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 2-pentyn 5-yl, 3-hexin-6-yl, 3-heptin-7-yl, 2-octin-8-yl;
  • 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 and III can have one or more asymmetrically substituted carbon atoms.
  • 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 above-mentioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for ET A and / or ET B receptors.
  • the compounds according to the invention are suitable as antagonists as defined at the outset.
  • the compounds of the formula I according to the invention can be prepared in the ways described in DE 19726146.9. Alternatively, production via intermediates of the general formula III is possible; these derivatives can be synthesized either by reducing azides of the formula II (see DE 19726146.9) using generally known methods or by opening the oxazoline derivatives of the general formula IV described in WO 95/07266.
  • the oxazoline derivatives of the formula IV can be opened by treating them with aqueous solutions of strong acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid in the presence of a suitable solubilizer.
  • strong acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid in the presence of a suitable solubilizer.
  • All water-miscible solvents can be used for this purpose, provided they are inert towards the reagents used.
  • solubilizers examples include alcohols, such as methanol, ethanol, n-propanol, isopropanol; Ethers such as tetrahydrofuran or dioxane; Nitriles, such as acetonitrile or propionitrile; Acid amides, such as dimethylformamide or dimethylacetamide; Sulfoxides and sulfones such as dimethyl sulfoxide; Carboxylic acids, such as acetic acid or propionic acid.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol
  • Ethers such as tetrahydrofuran or dioxane
  • Nitriles such as acetonitrile or propionitrile
  • Acid amides such as dimethylformamide or dimethylacetamide
  • Sulfoxides and sulfones such as dimethyl sulfoxide
  • Carboxylic acids such as acetic acid or propionic acid.
  • the reaction is preferably carried out in a temperature range between 0 ° C. and the boiling point of the solvent or solvent mixture.
  • R 4 R 5 N denotes an aromatic or heteroaromatic carboxamide
  • R 4 R 5 N denotes an aromatic or heteroaromatic carboxamide
  • acylating III on nitrogen or, alternatively, acylating both the amino and the hydroxyl group in III and subsequently the ester acyl cleaves group using well known methods.
  • the compound of general formula III is reacted with the acylating reagent in a molar ratio of 1: 1 to 1: 6 in the presence of a suitable diluent. All solvents which are inert to the reagents used can be used for this purpose.
  • III V
  • 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, ethyl chloride and trichlorethylene, Ethers, such as diisopropyl ether, dibutyl ether, methyl tert. Butyl ether, dioxane and tetrahydrofuran,
  • Nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.
  • the reaction is preferably carried out in a temperature range between 0 ° C. and the boiling point of the solvent or solvent mixture.
  • reaction catalyst can be advantageous.
  • Dimethylaminopyridine for example, can be used as the catalyst.
  • the resulting compounds of the general formula V are converted into the ⁇ -amidocarboxylic acid derivatives according to the invention by reacting the compounds of the general formula V with heterocycles of the general formula VI.
  • R 14 is halogen or R 15 -S0 2 -, where R 15
  • C may be 4 -haloalkyl or phenyl, and apply the above-mentioned conditions for W, X, Y, Z and Q.
  • 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.
  • 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.
  • Compounds of the formula VI are known, some are commercially available or can be prepared in a generally known manner.
  • R 1 in compounds of general form Ia is an ester
  • the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.
  • An alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, for example 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 can serve as the base .
  • the compounds of the general formula I according to the invention in which R 4 R 5 N is a sulfonamide can be obtained from amines of the general formula VII, the preparation of which is described in DE 19726146.9. For this purpose, VII is reacted with sulfonic acid halides by generally known methods and subsequently, if R 1 is an ester, the ester group is split acidic, basic or hydrogenolytically.
  • 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 starting them in an activated form, such as an acid halide, in the usual way Anhydride or imidazolide transferred and then reacted with a corresponding hydroxyl compound H ⁇ R 6 or sulfonamide H 2 NS0 2 R 8 .
  • This reaction can be carried out in the customary solvents and often requires the addition of a base, the above-mentioned being possible.
  • compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 is a group COR and R is OM, where M is an alkali metal cation or the Can be equivalent to an alkaline earth metal cation.
  • salts can be reacted with many compounds of the formula RD, where D is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group.
  • D is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl or one other equivalent leaving group.
  • D is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl
  • 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 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 4 -C 4 alkyl ammonium or the ammonium ion;
  • R 6 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: -C 4 -alkyl, C ⁇ -C-haloalkyl, hydroxy, C x -C alkoxy, mercapto, C ⁇ -C 4 -Alkylthio, NH (-C-C 4 alkyl), N (-C-C 4 alkyl) 2 ;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as 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 C 1 -C 4 -alkyl, hydroxy, C x -C 4 -alkoxy, -C-C 4 -alkylthio, NH (-C-C 4 -alkyl), N (-C-C 4 -alkyl) 2 , mercapto.
  • R 8 means:
  • Y is nitrogen or CR ";
  • R 2 and R 3 (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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 _alkoxy, phenoxy, C 1 -C 4 haloalkoxy, Amino, NH (-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, cyano, -C 4 alkyl , -C ⁇ C 4 -haloalkyl, C 1 _C 4 -alkoxy, C ⁇ -C_Halogenalkoxy or C ⁇ _C-alkylthio; or
  • Phenyl or naphthyl which are connected to one another in the ortho position 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 5 is hydrogen, methyl
  • R 9 and R 10 (which may be the same or different):
  • R 11 is hydrogen, halogen, C ⁇ _C 4 _Alkoxy, C ⁇ -C -haloalkoxy, C ⁇ -C4-alkylthio, NH (4 C ⁇ _C _Alkyl), N (C 1 _C 4 _Alkyl) 2, cyano;
  • CR 9 or CR 10 forms together with CR 9 or CR 10 a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C ⁇ _ 4 alkyl groups, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (C 1 -C 4 alkyl) can be replaced;
  • R 1 stands for tetrazole or for a group
  • R 6 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: -C ⁇ C 4 alkyl, -C ⁇ C 4 haloalkyl, -C -C 4 alkoxy;
  • a 5-membered heteroaromatic linked via a nitrogen atom such as imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C 4 -alkyl or one to two C 1 -C 4 alkoxy groups.
  • a group such as imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C 1 -C 4 -alkyl or one to two C 1 -C 4 alkoxy groups.
  • R 8 means:
  • Y is nitrogen or CR ";
  • R 2 and R 3 (which may be the same or different):
  • Phenyl groups by one or more of the following radicals can be: halo, C ⁇ -C alkyl, C ⁇ _C 4 haloalkyl, C ⁇ -C_Alkoxy, phenoxy, C 1 -C 4 alkylthio,
  • Phenyl groups which are connected to one another in the ortho position 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 12 phenyl or a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, it being possible for the radicals mentioned to be substituted one or more times by: halogen, hydroxy, C 1 -C 4 -alkyl, C ⁇ -C4-haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, phenoxy,
  • C ⁇ -C4-alkylthio NH (C ⁇ -C4 alkyl), N (C ⁇ -C4 alkyl) 2, (C 1 -C 4 -alkyl) NHS0 2, (C ⁇ -C4 alkyl) 2 NS0 2 or phenyl, which can be substituted one or more times, for. B. one to three times by halogen, -C-C 4 alkyl, -C-C 4 haloalkyl,
  • R 5 hydrogen f, methyl
  • R 9 and R 10 (which may be the same or different):
  • CR 9 or CR 10 is linked to CR 11 as stated under R 11 to form a 5- or 6-membered ring;
  • R 11 is hydrogen, C 4 -C alkoxy, Ci-C ⁇ alkylthio, cyano;
  • CR 9 or CR 10 forms together with CR 9 or CR 10 a 5- or 6-membered alkylene or alkenylene ring, which can be substituted by one or two C ⁇ _ 4 alkyl groups, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (C ⁇ _C_Alkyl), can be replaced;
  • the compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic kidney failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma Atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, ischemic and intoxication-related kidney failure or hypertension, cyclosporin-induced kidney failure, erectile dysfunction, metastasis, metastasis Cancer, prostate cancer, contrast-induced kidney failure, pancreatitis, gastrointestinal ulcers.
  • the invention further relates to combination preparations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 ⁇ g / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 ⁇ g.
  • the cells were adjusted to a concentration of 10 8 lines / ml buffer (50 mM Tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds / constant / output 20).
  • the membranes were incubated in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml bacitracin and 0.2% BSA) in a concentration of 50 ⁇ g Protein per test batch suspended and at 25 ° C with 25 pM [125J1-ET ! (ET A receptor test) or 25 pM [125J] -ET 3 (ET B _ receptor test) in the presence and absence of test substance.
  • the non-specific binding was determined with 10 -7 M ETi. After 30 minutes, the free and bound radioligand were removed by filtration through GF / B glass fiber filters
  • 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.
  • the animals are anesthetized with urethane and the carotid artery (for measuring blood pressure) and the jugular vein (application of big endothelin / endothelin 1) are catheterized.
  • 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 clear and persistent blood pressure changes are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotonically). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance 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 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.
  • Benzyl 2-methyl-4,4,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate (13.5 g; crude) was added in a mixture of methanol (25 ml), water (50 ml) and concentrated hydrochloric acid (50 ml) stirred for 60 hours at room temperature. The undissolved part was then decanted; the residue was stirred for another three hours in the above mixture. It was decanted again; the remaining residue was discarded. The two liquid phases were combined and adjusted to pH 8-9 with sodium hydroxide solution, whereupon crystallization began. The crystals were washed with ether and suction filtered; 4.65 g of the desired amino alcohol were obtained in 97% purity.
  • the mixture was diluted with ether and washed successively with dilute citric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution.
  • the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo.
  • the citric acid extract was neutralized and extracted with ether; the organic phases obtained from this were dried and evaporated as described above. The residue (206 mg) was used without further processing.

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Abstract

L'invention concerne des dérivés d'acide carboxylique de formule (I) où les substituants ont la signification suivante: R<1> représente du tétrazol ou un groupe (a), W et Z sont identiques ou différents et représentent de l'azote ou de la méthine; sachant que si W et Z représentent de la méthine, Q représente de l'azote; X représente de l'azote ou CR<9>; Y représente de l'azote ou CR<10>; Q représente de l'azote ou CR<11>; sachant que si Q représente de l'azote, X représente CR<9> et YCR<10>; R<2> et R<3> sont identiques ou différents et représentent phényle ou naphthyle éventuellement substitués, ou phényle ou naphthyle, qui sont reliés entre eux dans une ortho-position par une liaison directe, un groupe méthylène, éthylène ou éthénylène, un atome d'oxygène ou de souffre ou un groupe SO2-, NH- ou N-alkyle, ou cycloalkyle C5-C6 éventuellement substitué; R<4>, représente un reste (b) ou (c); R<5> représente hydrogène, alkyle C1-C4-. L'invention concerne leur production et leur utilisation comme antagonistes des récepteurs d'endothéline; les composés de formule (II). Un fragment structurel de formule (d) où les restes R<1>, R<2>, R<3>, R<4> et R<5> ont la signification donnée dans la 1ère revendication, comme élément structurel dans un antagoniste des récepteurs d'endothéline.
EP99964533A 1998-12-18 1999-12-09 Nouveaux derives d'acides beta-amido- et beta-sulfonamidocarboxyliques, leur production et leur utilisation comme antagonistes des recepteurs d'endotheline Withdrawn EP1140867A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19858779A DE19858779A1 (de) 1998-12-18 1998-12-18 Neue ß-Amido und ß-Sulfonamidocarbonsäurederivate, ihre Herstellung und Verwendung als Endothelinrezeptorantagonisten
DE19858779 1998-12-18
PCT/EP1999/009679 WO2000037450A1 (fr) 1998-12-18 1999-12-09 NOUVEAUX DERIVES D'ACIDES β-AMIDO- ET β-SULFONAMIDOCARBOXYLIQUES, LEUR PRODUCTION ET LEUR UTILISATION COMME ANTAGONISTES DES RECEPTEURS D'ENDOTHELINE

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JP (1) JP2002533330A (fr)
KR (1) KR20010101279A (fr)
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AR (1) AR023353A1 (fr)
AU (1) AU3036400A (fr)
BG (1) BG105618A (fr)
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CA (1) CA2355251A1 (fr)
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DE (1) DE19858779A1 (fr)
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IL (1) IL143451A0 (fr)
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CA2429106A1 (fr) * 2000-11-17 2002-05-23 Warner-Lambert Company Llc Traitement de dysfonctionnements sexuels
US7790770B2 (en) 2005-11-23 2010-09-07 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
WO2011004402A2 (fr) * 2009-07-10 2011-01-13 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés

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DE4329911A1 (de) * 1993-09-04 1995-03-09 Basf Ag Substituierte Milchsäurederivate mit einem N-organischen Rest in beta-Position
HUP0000553A3 (en) * 1996-12-18 2001-08-28 Abbott Gmbh & Co Kg Sixmembered nitrogencontained heteroaromatic carboxylic acid derivatives, pharmaceutical compositions containing them, and their use for producing pharmaceutical compositions
DE19726146A1 (de) * 1997-06-19 1998-12-24 Basf Ag Neue ß-Amino und ß-Azidopcarbonsäurederivate, ihre Herstellung und Verwendung als Endothelinrezeptorantagonisten

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NO20013000L (no) 2001-08-15
CN1334806A (zh) 2002-02-06
AU3036400A (en) 2000-07-12
BR9916331A (pt) 2001-09-11
BG105618A (en) 2002-01-31
IL143451A0 (en) 2002-04-21
HUP0201321A3 (en) 2003-02-28
WO2000037450A1 (fr) 2000-06-29
CZ20012186A3 (cs) 2002-07-17
TR200101780T2 (tr) 2001-11-21
JP2002533330A (ja) 2002-10-08
DE19858779A1 (de) 2000-06-21
CA2355251A1 (fr) 2000-06-29
KR20010101279A (ko) 2001-11-14
HUP0201321A2 (hu) 2002-12-28
AR023353A1 (es) 2002-09-04
SK8682001A3 (en) 2002-08-06
NO20013000D0 (no) 2001-06-15
HK1042095A1 (zh) 2002-08-02

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