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  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • 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
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  • 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
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  • 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

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. In the following, "endothelin” or “ET” denotes one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 15 ⁇ , 868-875, 1988).
• endothelin causes persistent vascular contraction in peripheral, renal, and cerebral blood vessels, which can lead to disease.
• endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 2 £ A, 2868 (1990), Nature i, 114 (1990), N. Engl. J. Med. 221, 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 task was to provide endothelin receptor antagonists that bind to the ET A and / or the ET B receptor.
• the invention relates to ⁇ -amino and ⁇ -azidocarboxylic acid derivatives of the formula I.
• R 1 stands for tetrazole or for a group 0
• 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 4 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, C 1 -C 4 -alkylthio, amino, NH (C 1 -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 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 .
• Halogen nitro, cyano, C 1 -C 4 -alkyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , Mercapto.
• R 6 means:
• R 2 and R 3 (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 2 -C 4 alkynyl, C -Ci-hydroxyalkyl, -C-C 4 -haloalkyl, C ⁇ -C-alkoxy, phenoxy, C ⁇ -C 4 -haloalkoxy, C ⁇ ⁇ C-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 ⁇ -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C ⁇ - C 4 haloalkoxy 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;
• Cs-C ⁇ -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, C 2 - C-alkynyl, -CC 4 alkoxy, -C-C 4 alkylthio, -C-C 4 halo-alkoxy;
• R 7 is hydrogen, -CC 8 -alkyl, C 3 -C ⁇ - alkenyl or C 3 -C 8 -alkynyl,
• Ci-Cs-alkylcarbonyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, amino, cyano, C 1 -C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C 6 -alkynyloxy, -C-C 4 -alkylthio, -C-C 4 -haloalkoxy, C ⁇ -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonyl- alkyl, NH (C ⁇ -C -alkyl), N (C 3 .C 4 -alkyl) 2 , C 3 -C 8 -cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, phenoxy or phenyl, all of the aryl radicals mentioned being one
• 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 1 -C 4 haloalkyl,
• C 3 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, CC 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, -CC 4 alkoxy, -C-C 4 alkylthio, -C-C 4 haloalkoxy, or;
• R 7 is linked to R 8 via 4 or 5 CH 2 groups to form a 5 or 6-membered ring;
• R 8 is hydrogen, -CC 4 alkyl
• R 8 is linked to R 7 via 4 or 5 CH 2 groups to form a 5 or 6-membered ring;
• 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, -CC 4 -alkoxy, -C-C 4 -haloalkoxy, C 3 -C 6 -alkenyloxy, C 3 -C6 ⁇ alkynyloxy, -C-C -alkylthio, -C-C 4 -alkylcarbonyl, C ⁇ - C 4 -alkoxycarbonyl, NH (-C-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 1 -C 4 -alkyl groups, and in each case one or more methylene groups by oxygen, Sulfur, -NH or -N (-C ⁇ C 4 alkyl), can be replaced;
• 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-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-chloro-2, 2-difluoroethyl, 2, 2- Dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl;
• C ⁇ -C-haloalkoxy can be linear or branched, e.g. Difluoromethoxy, trifluoromethoxy, chlorodluoromethoxy, 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, e.g. 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 1 -C 4 -alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethyloxy;
• C 3 -C 6 ⁇ alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
• C 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;
• Ci-Cs-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, for example, 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
• 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, for example, l-propen-3-yl, l-propen-2-yl, 1-propen-l-yl,
• C 3 -C 8 alkynyl can be linear or branched, for example
• 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).
• the compounds I and also the intermediates for their preparation, such as, for example, II and III, 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 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 preparation of the compounds of the general formula II, in which A is an azido group (Ha), is based on the epoxides III, which are e.g. can be synthesized in WO 96/11914. These epoxides III can then be treated with an azide, e.g. Sodium azide. For this purpose, the compounds of the general formula III are reacted with the azide, in a molar ratio of about 1: 1 to 1: 7, at a temperature of 20 to 150 ° C. to Ha.
• the reaction can also take place in the presence of a diluent.
• a diluent for this purpose, all solvents which are inert to the reagents used can be used.
• 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, ether, such as diisopropyl ether, dibutyl ether, methyl tert.
• chlorinated such as, for example, hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and trichlorethylene, ether, 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.
• 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. Strong organic and inorganic acids and Lewis acids can be used as catalysts. Examples include sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluene sulfonic acid, boron trifluoride etherate and rare earth triflates.
• the compounds according to the invention having the general formula I in which A is an azido group (Ia) can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula Ha in which the substituents have the meaning given with compounds of the general formula IV brings about a reaction.
• R 12 is halogen or R 13 -S0 2 -, where R 13 can be C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl or phenyl, and for W, X, Y, Z and Q those mentioned at the outset Conditions apply.
• 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 Ha, 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, 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 metal such as lithium diisopropylamide or lithium amide.
• the compounds Ia according to the invention with the general formula I in which A is an amino group (Ib) are prepared from the compounds Ia.
• the compounds Ia can be converted to Ib in the presence of triphenylphosphine.
• R 1 is an ester
• the amino group in Ib can be alkylated or converted into the amide by generally known methods.
• the ester group can then be split acidic or basic to the carboxylic acid.
• the compounds with the general formula II in which A is a substituted amine can also be prepared directly from the epoxide III by opening with an amine.
• the substances IIc can then be reacted with IV as described above to give the compounds I according to the invention.
• 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 this then reacted with a corresponding hydroxyl compound H ⁇ R 4 or sulfonamide H 2 NS0 2 R 6 .
• 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 allowing the carboxylic acid to act on the hydroxyl compound or the sulfonamide in the presence of a water-releasing agent such as a carbodiimide.
• 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 can be the equivalent of an alkaline earth metal cation.
• These 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 another equivalent leaving group.
• 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:
• Phenyl or naphthyl which can be substituted by one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C ! -C 4 alkyl, -C-C 4 haloalkyl,
• 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 7 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl,
• C 1 -C 5 -alkylcarbonyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 alkynyloxy, C !
• -C 4 -alkyl hio, -C-C 4 -haloalkoxy, -C-C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkyl), N (C ⁇ -C 4 -alkyl) 2 , C 3 -Ca-cycloalkyl, Heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, phenoxy or phenyl, where the aryl radicals mentioned can themselves be substituted one or more times, for example one to three times by halogen, hydroxy, mercapto, carboxy, cyano, C 4 -alkyl, C 4 haloalkyl, C ⁇ -C alkoxy, C ⁇ -C -haloalkoxy, amino, NH (C. 3-C 4 -alkyl), N (C 1 -C 4 alkyl) 2 , or -CC 4 alky
• Phenyl or naphthyl each of which may be substituted by one or more of the following radicals: halogen, cyano, hydroxy, amino, C ⁇ -C 4 -alkyl, C 4 haloalkyl, phenoxy, C ⁇ -C 4 alkoxy, C ⁇ - C 4 haloalkoxy, C ! -C 4 alkylthio, dioxomethylene, NH (C ⁇ -C 4 alkyl), N (-C-C 4 alkyl) 2 or dioxoethylene;
• C 3 -C 8 cycloalkyl where these radicals can each be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, C 1 -C 4 -alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , -C -C alkoxy, Cj.-C 4 alkylthio, -C ⁇ C-haloalkoxy;
• R 8 is hydrogen; R 9 and R 10 (which may be the same as different):
• CR 9 or CR 10 is linked to CR 11 as stated under R 11 to form a 5- or 6-membered ring;
• Rii hydrogen, halogen, C 4 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 4 C 4 alkylthio, NH (C 4 C 4 alkyl), N (C 1 -C 4 alkyl) 2 »cyano; C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, where these radicals can each be mono- or polysubstituted by: halogen, cyano, C 1 -C 4 -alkyxy;
• 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 1 -C 4 -alkyl groups, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (-CC 4 alkyl), can be replaced;
• Y is nitrogen or CR 1 ";
• R 2 and R 3 (which may be the same or different):
• Phenyl by one or more of the following groups may be substituted: 4 -alkyl halogen, C ⁇ -C, C ⁇ -C 4 halo-alkyl, C ⁇ -C 4 alkoxy, phenoxy, C ⁇ -C4-alkylthio, NH (C ⁇ -C 4 alkyl), N (-C 4 alkyl) 2 or phenyl, which can be mono- or polysubstituted, for example one to three times by halogen, -C 4 alkyl, -C -C haloalkyl, -C -C alkoxy or C ⁇ -C 4 alkyl thio; or
• R 7 is hydrogen, -CC 8 -alkyl, C 3 -C 8 -alkenyl or C 3 -C 8 -alkynyl,
• C 1 -C 5 alkylcarbonyl where these radicals may each be mono- or polysubstituted by: halogen, hydroxyl, carboxy, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkoxycarbonyl , NH (-CC alkyl), N (-C 4 alkyl) 2 , C 3 -C 8 cycloalkyl, heteroaryloxy or heteroaryl, five- or six-membered, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, Phenoxy or phenyl, where the aryl radicals mentioned may in turn be mono- or polysubstituted, for example one to three times by halogen, hydroxyl,
• Phenyl or naphthyl which may be substituted by one or more of the following radicals in each case being: halogen, cyano, C 4 -alkyl, C 4 haloalkyl, phenoxy, C ⁇ -C alkoxy, C ⁇ -C 4 alkylthio, Dioxomethylene or dioxoethylene;
• C 5 -C 6 cycloalkyl where these radicals can each be mono- or polysubstituted by: C ⁇ -C-alkyl, -C-C 4 alkoxy;
• R 8 is hydrogen
• R 9 and R 10 (which may be the same as 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 1 -C alkoxy, C 1 -C 4 alkylthio, cyano; C ⁇ -C alkyl, where these radicals can be substituted one or more times by halogen;
• 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 1 -C 4 -alkyl groups, and in each case one or more methylene groups by oxygen, sulfur, -NH or -N (-CC 4 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, sub-arachnoid 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, metastasis and growth of mesenchymal tumors
• 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 combinations can be applied in a common galenical form or separately in time and space.
• Another object of the invention is the use of the compounds according to the invention for photoaffinity labeling of the endothelin receptors.
• Compounds of the formula I in which A is azido are particularly suitable for this purpose.
• the good effects of the compounds can be shown in the following experiments:
• the ET A or ET B receptor-expressing CHO cells were in DMEM NUT MIX F ⁇ 2 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 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 2 , 40 ⁇ g / ml bacitracin and 0.2% BSA) in a concentration of 50 ⁇ g 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 ETi.
• test animals were given the test compounds i.v. 30 min before the administration of ET1. 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.
• mice Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are orally pretreated with the test substances. 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, Appl. Vol. 0.5 ml / kg) or ET1 (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and persistent changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
• the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, 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.

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