Classifications

• • 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
  • C07D251/26—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 only hetero atoms directly attached to ring carbon atoms
  • C07D251/30—Only oxygen 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
• • 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
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—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
  • A61P35/00—Antineoplastic agents
• • 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
  • 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
• • 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

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- 4, 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 , 2868 (1990), Nature 144, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron £ 6. 373 ( 1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944, ( 1995)).
• 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)). Therefore 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 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 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, dC 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 alkoxy, Mercapto, C ⁇ -C 4 alkylthio, amino, NH (-C-C 4 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 has one or two halogen atoms or one or two
• -C-C 4 alkyl C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or phenyl, which can be substituted by one or more, for example one to three of the following radicals : halogen, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, hydroxy, C ⁇ -C 4 -alkoxy, C 4 alkylthio, mercapto, amino, NH (C ⁇ -C4 alkyl) , N (C 1 -C 4 alkyl) 2 .
• R 8 means:
• Phenyl which can be substituted by one to three of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl,
• R 2 is phenyl or phenoxy, benzyl, benzyloxy, where all aryl radicals can carry one to five halogen atoms and / or one to three of the following radicals: hydroxy, mercapto, carboxy, nitro, cyano, C 1 -C 4 alkyl, C 1 -C C 4 -haloalkyl, -C-C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -Cg alkynyloxy,
• a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, -C-C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, C ⁇ -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals or may carry one to three of the following radicals in turn one to five halogen atoms and / a: C ⁇ -C 4 -alkyl, -C-C 4 haloalkyl, -C-C 4 alkoxy, C ⁇ ⁇ C4-haloalkoxy and / or -C-C-alkylthio;
• C 3 -C 8 cycloalkyl which can carry one to three of the following radicals: -CC 4 alkyl, -C ⁇ C 4 -haloalkyl, -C ⁇ C 4 -alkoxy, -C-C 4 -haloalkoxy, C ⁇ -C 4 -Alkylthio.
• Phenyl or naphthyl which may be substituted by one or more of the following radicals in each case being: halogen, nitro, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl,
• a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom which has one to four halogen atoms and / or one may carry one to two of the following radicals: C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4-alkoxy, C ⁇ -C4-haloalkoxy, C ⁇ -C4 ⁇ alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn one to five halogen atoms and / or may carry one to three of the following radicals: C ⁇ -C4 ⁇ alkyl, C ⁇ -C 4 haloalkyl, C! -C 4 alkoxy, -C-C 4 haloalkoxy and / or -C-C 4 alkylthio.
• R 4 and R 5 (which may be the same or different):
• Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 - Haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 ; 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, NH or N-alkyl group;
• R 9 C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkoxy, which carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C 4 alkyl), N (C ⁇ - C 4 alkyl) 2 , carboxamide or CON (C ! -C 4 alkyl) 2 .
• R 10 is hydrogen, halogen, hydroxyl, NH 2 , NH (C ! -C alkyl),
• C ⁇ -C4-haloalkoxy or C ⁇ -C4-alkylthio or CR 10 forms together with CR11 a 5- or 6-membered alkylene or alkenylene ring, by one or two C ⁇ -C 4 alkyl groups may be substituted and wherein one or more methylene groups can each be replaced by oxygen, sulfur, -NH or -N (-CC 4 ⁇ alkyl); Phenyl, which can carry one to three of the following radicals: -C-alkyl, -C-C 4 -haloalkyl, C ! -C 4 -alkoxy, -C-C 4 -haloalkoxy, -C-C 4 -alkylthio.
• R 11 is hydrogen, hydroxyl, NH, NH (-CC 4 alkyl), N (-C-alkyl) 2 , halogen, -C-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -Alkynyl, CC 6 -alkenyloxy, -C-C 4 -alkylcarbonyl, -C-C 4 -alkoxycarbonyl, -C-C 4 -hydroxyalkyl, C ⁇ -C 4 -haloalkyl, -C-C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, -NH-0 -CC-C-alkyl, -CC-C-alkylthio, C 3 -C 8 cycloalkyl or CR 11 forms as indicated under R 10 together with CR 10 a 5- or 6-membered ring;
• Phenyl or phenoxy which to five halogens / or one and one to three of the following radicals: hydroxy, mercapto, carboxy, nitro, cyano, C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4 ⁇ Alkoxy, C 3 -Cg-alkenyloxy, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, C ⁇ -C 4 -alkylcarbonyl, R 9 , C ⁇ -C 4 -alkoxycarbonyl, (C ⁇ -C 4 alkyl) - NHCarbonyl, (-C-C 4 ⁇ alkyl) NCarbonyl, C 3 -C 8 -alkylcarbonylalkyl, amino, NH (C ⁇ -C-alkyl), N (C ⁇ -C 4 alkyl), phenoxy or phenyl, where
• a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which can carry one to four halogen atoms and / or one or two of the following radicals: -CC 4 alkyl, -C-C 4 - haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy,
• C ⁇ -C 4 alkylthio phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals or may carry one to three of the following radicals in turn one to five halogen atoms and / a: C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy and / or C! -C 4 alkylthio.
• a sulfur or oxygen is
• 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 ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;
• C 3 -Cg cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
• C ! -C 4 -Halogenalkyl 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-chloro 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 ⁇ -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;
• C 3 -C 6 alkenyloxy can be linear or branched, 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;
• Ci-C 4 alkylthio can be linear or branched such as methyl thio, ethyl thio, propyl thio, 1-methyl ethyl thio, butyl thio, 1-methyl propyl thio, 2-methyl propyl thio or 1, 1-dimethyl ethyl thio;
• 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, for example Metoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
• C 3 -C 6 -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-Cg-alkyl can be linear or branched such as -CC 4 alkyl, pentyl, hexyl, heptyl or octyl;
• Halogen is e.g. Fluorine, chlorine, bromine, iodine.
• the invention further relates to those compounds from which the compounds of the formula I can be released (so-called prodrugs), e.g. Amides of the acids included in Formula I.
• prodrugs in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
• the compounds and also the intermediates for their preparation, e.g. II and IV, can have one or more asymmetric substituted carbon atoms.
• Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
• the use of an enantiomerically pure compound as the active ingredient is preferred.
• the invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of medicaments, in particular for the production of inhibitors for endothelin receptors.
• Compounds of the general formula III are either known or can be synthesized, for example, by reducing the corresponding carboxylic acids or their esters, or by other generally known methods.
• Compounds of the formula IV can be obtained in enantiomerically pure form via an acid-catalyzed transetherification, as described in WO 98/09953.
• enantiomerically pure compounds of the formula IV can be obtained by carrying out a classic racemate resolution with suitable enantiomerically pure bases with racemic or diastereomeric compounds of the formula IV.
• bases are e.g. 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
• R 12 denotes halogen or R 13 -S0-, where R 13
• C ⁇ -C 4 -alkyl, C ⁇ 4 haloalkyl or phenyl may be.
• 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.
• R 1 is an ester
• solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which can optionally be chlorinated, such as 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 hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene
• ethers such as diisopropyl ether, dibutyl ether, methyl tert.
• nitriles such as, for example, acetonitrile and propionitrile
• acid amides such as, for example, dimethylformamide, 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.
• 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 7 .
• This reaction can be carried out in the customary solvents and often requires the addition of a base such as triethylamine, pyridine, imidazole or diazabicycloundecane to be considered.
• a base such as triethylamine, pyridine, imidazole or diazabicycloundecane
• compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formula I in which R 1 represents a group COOM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
• R 1 represents a group COOM
• M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
• D 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.
• R 6 is 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 phenyl or phenoxy, which is one to three of the following
• C ⁇ C ⁇ -C-C halogen, 4 alkyl, 4 haloalkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 alkylthio, C ⁇ -C4-haloalkoxy, C ⁇ -C alkyl-carbonyl, C ⁇ -C: can carry radicals -Alkoxycarbonyl, (-CC alkyl) - NHCarbonyl, (-C-alkyl) NCarbonyl, NH (C 1 -C 4 alkyl), N (-C 4 alkyl) 2 ;
• a five- or six-membered heteroaromatic containing a nitrogen atom and / or a sulfur or oxygen atom and which can carry one to two of the following radicals: halogen, C ⁇ -C 4 alkyl, C 1 -C 4 haloalkyl, C ⁇ -C 4 -alkoxy, C 4 haloalkoxy, C ⁇ ⁇ C 4 alkylthio, phenyl, which for its part can carry one to three of the following radicals: halogen, C ⁇ -C4 alkyl, Ci-C4-haloalkyl, C ⁇ -C 4 -Alkoxy, -CC 4 ⁇ halogen alkoxy, -C-C 4 ⁇ alkylthio;
• R 3 is hydrogen
• Phenyl or naphthyl which may be substituted by one or more of the following radicals in each case being: halogen, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C 4 alkoxy, C x -C 4 halo-alkoxy, -CC alkylthio, NH (-C 4 alkyl), N (-C 4 alkyl) 2 , dioxomethylene or dioxoethylene;
• a five- or six-membered heteroaromatic containing one to three nitrogen atoms and / or one sulfur or oxygen atom and which can carry one to two of the following radicals: C 4 -alkyl, C 4 haloalkyl, C ⁇ -C4 ⁇ Alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, phenyl, which in turn can carry one to five halogen atoms and / or one to three of the following radicals: -C-C 4 -alkyl, C ⁇ -C 4 -halogen- alkyl, C ⁇ ⁇ C 4 -alkoxy, C 4 haloalkoxy, C ⁇ -C 4 -alkylthio.
• R 4 and R 5 (which may be the same or different):
• Phenyl or naphthyl which may be substituted by one or more of the following radicals: halogen, C ⁇ -C 4 -alkyl, C 4 haloalkyl, C ⁇ -C alkoxy, C! -C 4 halo-aikoxy, -C-C 4 alkylthio; or
• Phenyl or naphthyl which are ortho-linked via a direct bond, a methylene, ethylene or ethenylene group; or
• R 10 is hydrogen, halogen, C ⁇ -C-alkyl, C ⁇ -C 4 -haloalkyl,
• R 11 is hydrogen, NH (C ⁇ -C-alkyl), N (C ⁇ -C 4 -alkyl) 2 , CC 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 ⁇ alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C-alkylthio, C 5 -C 6 cycloalkyl or CR 11 forms, as indicated under R 10 together with CR 10, a 5- or 6-membered ring;
• Phenyl or phenoxy which can carry one to three of the following radicals: halogen, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -alkylthio, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkylcarbonyl, C ⁇ -C 4 -alkoxy - carbonyl, (C ⁇ -C-alkyl) NH carbonyl, (C ⁇ -C-alkyl) 2 NCarbonyl, NH (C ⁇ -C 4 alkyl), N (C ⁇ -C-alkyl) 2 ;
• a five- or six-membered heteroaromatic containing a nitrogen atom and / or a sulfur or oxygen atom which can carry one or two of the following radicals: halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 ⁇ haloalkyl, C ⁇ -C 4 - Alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 -alkylthio, phenyl, which in turn can carry one to three of the following radicals: halogen,
• a sulfur or oxygen is
• R 2 is phenyl or phenoxy, which is one to three of the following
• Residues can carry: halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -alkylthio, C ⁇ -C 4 -haloalkoxy;
• a five- or six-membered heteroaromatic containing a nitrogen atom and / or a sulfur or oxygen atom which can carry one or two of the following radicals: Halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C-alkylthio;
• R 3 is hydrogen
• C ⁇ -C 8 alkyl, or C 3 -C 6 cycloalkyl where these radicals can each be mono- to trisubstituted by: hydroxy, halogen, C ⁇ -C 4 alkoxy, C ⁇ -C4-alkylthio, C ⁇ -C4- Halogenalkoxy, phenoxy, phenyl, heteroaryl, five- or six-membered, containing a nitrogen atom and / or a sulfur or oxygen atom, it being possible for the aryl and hetaryl radicals mentioned to be mono- to trisubstituted by: halogen, C C-C 4 -alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 ⁇ haloalkoxy, R 9 , dioxomethylene, dioxoethylene, C ⁇ -C 4 ⁇ alkylthio;
• Phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 alkylthio, dioxomethylene or dioxoethylene;
• a five-membered heteroaromatic containing a sulfur or oxygen atom which can carry one or two of the following radicals: C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ -C 4 alkylthio.
• 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, C ⁇ -C-alkyl, C ⁇ -C 4 -haloalkyl, C -C 4 -alkoxy, CC 4 -haloalkoxy, C ⁇ -C 4 - Alkylthio; or
• Phenyl or naphthyl which are ortho-linked via a direct bond or a methylene group.
• R 9 C ⁇ -C 4 alkyl, C ⁇ -C 4 alkylthio, C ⁇ -C 4 alkoxy, each of which can carry a hydroxy group.
• R 10 hydrogen, halogen, methyl, trifluoromethyl, methoxy, or CR 10 together with CR 11 forms a 5- or 6-membered alkylene ring, which can be substituted by one or two methyl groups, and in each case one or more methylene groups by oxygen or sulfur can be replaced.
• R 11 is hydrogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 ⁇ alkoxy, C ⁇ -C 4 -haloalkoxy, C--C-alkylthio, C 5 -C 6 cycloalkyl or CR 11 forms as specified under R 10 together with CR 10 a 5- or 6-membered ring.
• a sulfur or oxygen is
• 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, kidney failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, plastic surgery and restenosis after pro-angio Hyperplasia, erectile dysfunction, glaucoma, ischemic and intoxication-related kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-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.
• ACE angiotensin converting enzyme
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor).
• VEGF vascular endothelial growth factor
• substances are, for example, antibodies directed against VEGF or specific binding proteins or else low-molecular substances which specifically release VEGF or receptor Can inhibit.
• the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
• the form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally.
• the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 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 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). Binding tests
• the membranes were incubated at 50 in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 mg / ml 5 bacitracin and 0.2% BSA) ig protein suspended per test batch and incubated at 25 ° C with 25 pM [125J] -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 ETx.
• Radioactivity was quantified using a Packard 2200 CA liquid scintillation counter.
• endothelin antagonists are applied to other preparations in the same vessel 15 min before the endothelin dose-effect curve begins.
• the effects of endothelin are calculated in% of the K + contracture.
• the endothelin dose-effect curve is shifted to the right.
• test animals were injected with the test compounds iv 30 min before the ETI administration (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. 5 po - testing of mixed ET A and ET B antagonists:
• mice Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 10 80 minutes later, 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, 15 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 20 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 orally or parenterally (subcutaneously, intravenously, intramuscularly, intra-perotoneally) in the customary manner. 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 active ingredient dose 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 galenical 5 application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, dragées, 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). 5
• the application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 90% by weight.
• the ethereal extracts were extracted with 1 molar potassium hydroxide solution; the alkaline aqueous extracts were combined and acidified again and extracted three times with ether.
• the ethereal extracts obtained therefrom were dried over magnesium sulfate and, after adding a little hexane, evaporated at low temperature. 317 mg (0.67 mmol, 92% yield) of the target compound were obtained.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pulmonology (AREA)
• Urology & Nephrology (AREA)
• Hospice & Palliative Care (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pyridine Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (13)

Applications Claiming Priority (2)

Publications (2)

Family

ID=7909761

Family Applications (1)

Country Status (20)

Cited By (1)

Citations (6)

• 1999
  • 1999-06-01 DE DE19924892A patent/DE19924892A1/de not_active Withdrawn
• 2000
  • 2000-05-19 EP EP00938660A patent/EP1181281A2/de not_active Withdrawn
  • 2000-05-19 CZ CZ20014312A patent/CZ20014312A3/cs unknown
  • 2000-05-19 WO PCT/EP2000/004571 patent/WO2000073276A2/de not_active Application Discontinuation
  • 2000-05-19 CA CA002375666A patent/CA2375666A1/en not_active Abandoned
  • 2000-05-19 CN CN00809738A patent/CN1359376A/zh active Pending
  • 2000-05-19 BR BR0011105-8A patent/BR0011105A/pt not_active IP Right Cessation
  • 2000-05-19 MX MXPA01012284A patent/MXPA01012284A/es unknown
  • 2000-05-19 PL PL00355112A patent/PL355112A1/xx not_active Application Discontinuation
  • 2000-05-19 JP JP2000621342A patent/JP2003500476A/ja active Pending
  • 2000-05-19 AU AU53959/00A patent/AU765345B2/en not_active Ceased
  • 2000-05-19 IL IL14680000A patent/IL146800A0/xx unknown
  • 2000-05-19 KR KR1020017015482A patent/KR20020006049A/ko not_active Application Discontinuation
  • 2000-05-19 TR TR2001/03475T patent/TR200103475T2/xx unknown
  • 2000-05-19 SK SK1755-2001A patent/SK17552001A3/sk unknown
  • 2000-05-19 HU HU0201387A patent/HUP0201387A3/hu unknown
  • 2000-05-30 AR ARP000102660A patent/AR022047A1/es unknown
• 2001
  • 2001-11-26 NO NO20015762A patent/NO20015762L/no not_active Application Discontinuation
  • 2001-11-27 BG BG106154A patent/BG106154A/xx unknown
• 2002
  • 2002-11-29 HK HK02108677.1A patent/HK1047102A1/zh unknown

Patent Citations (6)

Also Published As

Similar Documents

Legal Events