MXPA00004506A - NOVEL HETEROCYCLICALLY SUBSTITUTED&agr;-HYDROXYCARBOXLIC ACID DERIVATIVES, METHOD FOR PRODUCING THE SAME AND THEIR USE AS ENDOTHELIN RECEPTOR ANTAGONISTS - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein A represents NR8R9, azido, OR10, SR10 or C1-C4 alkyl, R1 representstetrazole or a group (1), wherein R has the following meaning:a) a radical OR5;b) a 5-membered heteroaromat bonded by a nitrogen atom;c) a group (2);d) a radical (3), and the remaining substituents have the meanings given in the description. The invention also relates to production of the inventive derivatives and to their use as endothelin receptor antagonists.

Description

NOVEDOSOS DERIVATIVES OF ACID a-H DROXICARBOX CO HETEROCICLICALLY SUBSTITUTED, PREPARED AND USED AS ENDOTHELIN RECEPTOR ANTAGONISTS The present invention relates to novel carboxylic acid derivatives, their preparation and use. Endothelin is a peptide constructed from 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, "endothelin" or "ET" designates one or all of the endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332 (1988), 411-415; FEBS Letters, 231 (1988), 440-444 and Biochem. Biophys., Res. Commun., -154 (1988), 868-875). An increased or abnormal release of endothelin causes a prolonged vascular contraction in peripheral blood vessels, kidney and brain, which can lead to diseases. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, seizure, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2 (1990), 207, J. Am. Med.

Association 264 (1990), 2868, Nature 344 (1990), 114, N.

Engl. J. Med. 322 (1989), 205, N. Engl. J. Med. 328 (1993), 1732, Nephron 66 (1994), 373, Stroke 25 (1994), 904, Nature 365 (1993), 759, J. Mol. Cell. Cardiol. 27 (1995), A234; Cancer Research 56 (1996), 663, Nature Medicine 1 (1995), 944). At least two end telin receptor subtypes, ETA and ETB receptors, have now been described in the literature (Nature 348 (1990), 730, Nature 348 (1990), 732). Accordingly, substances that inhibit the binding of endothelin to one or both receptors must antagonize the physiological effects of endothelium and therefore be useful pharmaceutical products. An object of the present invention is to provide endothelin receptor antagonists that bind to the ETA receptor and / or the ETB receptor. We have found that this object is achieved by heterocyclicly substituted α-hydroxycarboxylic acid derivatives of the formula I R2 R1 is tetrazole or a group 0 C - R wherein R has the following meanings: a) a radical OR 5, wherein R 5 is: hydrogen, the cation of an alkali metal, the cation of a terrestrial alkali earth, a physiologically tolerable organic ammonium ion such as alkyl with 1 to 4 carbon atoms-tertiary ammonium or el- -Lon ammonium; cycloalkyl with 3 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms, CH 2 -phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, alkyl having 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, hydroxyl, alkoxy with 1 to 4 carbon atoms, mercapto, alkylthio with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1) to 4 carbon atoms) 2; an alkenyl group with 3 to 8 carbon atoms or an alkynyl group with 3 to 8 carbon atoms, it being possible for these groups to carry one to five halogen atoms; R5 can also be a phenyl radical which can carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, hydroxyl alkoxy with 1 to 4 carbon atoms, mercapto, alkylthio with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2. b) a 5-membered heteroaromatic linked by a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl or triazolyl, which can carry one or two halogen atoms, or one or two alkyl groups with 1 to 4 carbon atoms or one or two groups alkoxy with 1 to 4 carbon atoms. c) a group (O) - O (CH2 2) 1 'R ° wherein k can assume values 0, 1 or 2, p values 1, 2, 3 or 4 and R6 is alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms or phenyl, which may be mono- to tri-substituted by: halogen, nitro, cyano, alkyl with 1 to 4 atoms carbon, hydroxyl, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, mercapto. d) a radical O - N - S - R7 H [| Or where R7 is: alkyl with 1 to 4 carbon atoms, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals to transport a radical alkoxy with 1 to 4 carbon atoms and / or phenyl as mentioned under c); haloalkyl with 1 to 4 carbon atoms or phenyl, which may be substituted as mentioned under c). The other substituents have the following meanings: A is NR8R9, azido, OR10, SR10 or alkyl with 1 to 4 carbon atoms. - - X is oxygen, sulfur, CR11 or NR12; with the proviso that if X = CR11, then Y = oxygen or sulfur or NR1.

And it is oxygen, sulfur, CR13 or NR14; with the proviso that if Y = oxygen or sulfur or NR14, then X = CR11. R3 (which may be identical or different): they are phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, alkyl having 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, phenoxy, haloalkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4) alkyl 2 or phenyl, which may be mono- or poly-substituted, for example mono- to tri- substituted, by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio carbon atoms; or phenyl or naphthyl, which are connected to each other in the ortho- position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N group (alkyl with 1 to 4 carbon atoms). carbon); cycloalkyl with 5 to 6 carbon atoms, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, and R11 (which may be identical or different) : are hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkenyloxy with 3 to 6 carbon atoms, alkynyloxy with 3 to 6 carbon atoms, alkylthio with 1 to 4 carbon atoms , alkylcarbonyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, hydroxyl, NH2, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2 alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms carbon, it being possible that these radicals are substituted by halogen, hydroxyl, mercapto, carboxyl, cyano; or CR4, together with CR11, form an alkylene or alkenylene ring with 5- or 6-members which may be unsubstituted or substituted, and wherein in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or - N (alkyl having 1 to 4 carbon atoms). is hydrogen, alkyl having 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms or alkynyl with 3 to 8 carbon atoms, alkylcarbonyl with 1 to 5 carbon atoms, it being possible for these radicals in each case to be mono- or poly-substituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, alkoxy with 1 to 4 carbon atoms, alkenyloxy with 3 to 6 carbon atoms, alkynyloxy with 3 to 6 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, alkylcarbonylalkyl with 3 to 8 carbon atoms, NH (alkyl with 1) to 4 carbon atoms), N (C 1 -C 4) alkyl 2, cycloalkyl with 3 to 8 carbon atoms, phenoxy or phenyl, it being possible for the aforementioned aryl radicals to be mono- or poly-substituted , for example mono- to tri-substituted by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms) no), N (alkyl with L to 4 carbon atoms) 2, phenyl or alkylthio with 1 to 4 carbon atoms; phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, alkylthio with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, dioxomethylene or dioxoethylene; cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono- or poly-substituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms. to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms; R8, together with R9, form an alkylene chain with 3 to 7 carbon atoms, closed to give a ring, which may be mono- or poly-substituted by alkyl with 1 to 4 carbon atoms, alkylthio with 1-4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, and in which case alkylene group can be replaced by oxygen or sulfur, such as - (CH2) 4-, - (CH2) 5-, - (CH ^ T) 6-, - (CH2) 7-, - (CH2) 2-0- (CH2) 2-, - (CH2) 2-S- (CH2) 2-. R3 is hydrogen, alkyl having 1 to 4 carbon atoms; R9 is as indicated under R8 linked with R8 to give a ring. R 10 is hydrogen, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms or alkynyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono- or poly-substituted by: halogen, hydroxyl, mercapto, carboxylOj. nitro, amino, cyano, alkoxy with 1 to 4 carbon atoms, alkenyloxy with 3 to 6 carbon atoms, alkynyloxy with 3 to 6 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, alkylcarbonylalkyl with 3 to 8 carbon atoms, carboxamide, CONH (alkyl with 1 to 4 carbon atoms), CON (alkyl with 1 to 4 carbon atoms) 2, CONR15R16, NH (alkyl having 1 to 4 carbon atoms), N (C 1 -C 4 alkyl) 2, C 3 -C 8 cycloalkyl, heteroaryloxy or heteroaryl, having five or six members, comprising one to three nitrogen atoms and / or sulfur or oxygen atoms, phenoxy or phenyl, it being possible for all said aryl radicals, for their part, to be mono- or poly-substituted, for example mono- to tri-substituted, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, alkylcarboxyl with 1 to 4 carbon atoms, R19, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, amino, NH (alkyl with 1) to 4 carbon atoms), N (C 1 -C 4 alkyl) 2, phenyl or alkylthio with 1 to 4 carbon atoms; phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, alkylthio with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms- 2-dioxomethylene or dioxoethylene; cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be tri-substituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, alkyl with 1 to 4 atoms carbon, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms; is hydrogen, alkyl having 1 to 4 carbon atoms, or NR12, together with CR4, forms an alkylene ring at 5- or 6-membered CN-members which may be mono- to tri-substituted by alkyl having 1 to 4 carbon atoms, and wherein in each case one or more methylene groups may be replaced by oxygen or sulfur.

R 13 is hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, it being possible for these radicals to be substituted halogen. R1 is hydrogen, alkyl having 1 to 4 carbon atoms.

R1 and R16: R15 and R16 together form an alkylene chain with 3 to 7 carbon atoms or alkenylene with 4 to 7 carbon atoms, closed to give a ring which is operated on a phenyl ring which may be mono- to tri- substituted by halogen, alkyl with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, hydroxyl , carboxyl, amino. R 19 is alkyl with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, which can carry one of the following radicals: hydroxyl, carboxyl, alkoxycarbonyl with 1 to 4 carbon atoms carbon, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, carboxamide or CON (alkyl with 1 to 4 carbon atoms) 2. The following definitions apply here and in the following text: an alkali metal is for example lithium, sodium, potassium; an alkaline earth metal is for example calcium, magnesium, barium; Cycloalkyl with 3 to 8 carbon atoms for example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; Haloalkyl with 1 to 4 carbon atoms can be linear or branched such as for example fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, l-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; Haloalkoxy with 1 to 4 carbon atoms can be linear or branched such as for example difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-f luoroethoxy or pentaf luoroethoxy; Alkyl with 1 to 4 carbon atoms can be linear or branched such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl; Alkenyl having 2 to 4 carbon atoms can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 2-propen-3-yl, 1-propene-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl; Alkynyl with 2 to 4 carbon atoms can be linear or branched such as, for example, ethynyl, 1-propynyl-yl, l-propyne-3-yl, l-butyne-4-yl or 2-butyne-4- il ?; Alkoxy with 1 to 4 carbon atoms can be linear or branched such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-mepropropoxy, 2-methylpropoxy or 1,1-dimethyletoxy; C 3 -C 6 alkenyloxy can be linear or branched such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; Alkynyloxy having 3 to 6 carbon atoms can be linear or branched, such as, for example, 2-propynyl-yloxy, 2-butyne-1-yloxy or 3-butyne-2-yloxy; Alkylthio having 1 to 4 carbon atoms can be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylthioethyl, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; Alkylcarbonyl having 1 to 4 carbon atoms can be linear or branched, such as, for example, 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; Alkylcarbonylalkyl with 3 to 8 carbon atoms can be linear or branched, such as, for example, 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl; Alkyl with 1 to 8 carbon atoms can be linear or branched, such as, for example, alkyl having 1 to 4 carbon atoms, pentyl, hexyl, heptyl or octyl; Halogen is, for example, fluorine, chlorine, bromine, iodine. The invention also relates to those compounds from which the compounds of the formula I (prodrugs) can be released. Preferred prodrugs are those in which release proceeds under conditions such as predominance in certain compartments of the body, for example in the stomach, intestine, blood circulation, liver. The invention further relates to the use of the aforementioned carboxylic acid derivatives for the preparation of prodrugs, in particular for the production of inhibitors for ETA and ETB receptors. The compounds I and also the intermediates for their preparation, such as, for example, II, may have one or more asymmetrically substituted carbon atoms. These compounds can be present as pure enantiomers or pure diaesteromers or as a mixture thereof. The use of an enantiomerically pure compound as the active compound is preferred. Compounds having the formula lia wherein A is alkyl having 1 to 4 carbon atoms, azido, SR10 or OR10, can be prepared as described in WO 9611914, DE 19614533.3 or DE 19726164.9. R2 -CH-OH lia R3 R1 The compounds of the formula IIb wherein A is SR10 or OR10 can be obtained in an enantiomerically pure form by an acid catalyzed transesterification, as described in DE 19636046.3.

The enantiomerically pure compounds of the formula II can also be obtained by performing a classical resolution with racemic or diastereomeric compounds of the formula II, using suitable enantiomerically pure bases. Suitable bases of this type are 4-chlorophenylethylamine and the bases mentioned in WO 96/11914. The compounds according to the invention, wherein A is alkyl with 1 to 4 carbon atoms, azido, SR10 or OR10 and the other substituents have the meaning given under formula I, can be prepared by example by reacting the acid derivatives carboxylic acid of the formula lia, wherein the substituents have the given meaning, with compounds of the formula III. ~ In formula III, R17 is halogen, or R18S02, it being possible for R18 to be alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms or phenyl. The preferred reaction is carried out in an inert solvent or diluent with the addition of a suitable base, ie a base which achieves deprotonation of the bundled intermediate, in a temperature range from room temperature to the boiling point of the solvent. Compounds of the type wherein R1 = COOH can be obtained directly in this manner if the intermediate is where R1 is COOH, is deprotonated using two equivalents of a convenient base and reacts with compounds of the formula III. Here again, the reaction is carried out in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent. Examples of these solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, which in each case may or may not be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride, and trichlorethylene, ethers, such as for example diisopropyl ether, dibutyl ether, methyl terbutyl ether, propylene oxide, dioxane, and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides, such as, for example, dimethyl formamide, dimethyl acetamide, and N-methyl pyrrolidone, sulfoxides and sulphones, such as for example dimethyl sulfoxide, and sulfolane. Compounds of formula III are known or can be prepared in a generally known form such as, for example: H. Erlenmeyer, G. Bischoff, Helv. Chim. Acta, 2_9 (1946), 280-283, G. Kjellin, J. Sandstrom, Acta Chim. Scand. , 23. (1969), 2879, E. R. Buchmann, A. 0. Reims, H. Sargent, J. Org. Chem., 6. (1941), 20 764-766, F. C. James, ~ H. D. Krebs, Aust. J. Chem., 35 (1982), 385-391, GR Humphrey, SHB Wright, J. Heterocyclic Chem., 26 (1989), 23. The base employed can be alkali metal hydride or alkaline earth metal such as hydride sodium, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, for example sodium or potassium carbonate, an alkali metal hydroxide or alkaline earth metal, such as sodium or potassium hydroxide, an organometallic compound such such as butyl lithium or alkali metal amide, such as lithium diisopropyl amide, or lithium amide. Compounds of the formula Ilb can be reacted similarly to the methods described in DE 19726164.9 to give the compounds Ib. 11b Compounds of the formula I can also be prepared from the corresponding carboxylic acids, ie compounds of the formula I wherein R 1 is COOH, and converting these first in a conventional manner to an active structure such as an acid halide, an anhydride or imidazolide and then reacting it with an appropriate hydroxyl compound HOR5. This reaction can be carried out in the usual solvents and often requires the addition of a base, those mentioned above are adequate. These two steps can also be simplified, for example by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as carbodiimide. Additionally, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie, of compound of the formula I, wherein R 1 is a COOM group, it being possible for M to be an alkali metal cation, or the equivalent of an alkaline earth metal cation, these salts can be reacted with many compounds of the formula RW, wherein W is a usual nucleofugic leaving group, for example a halogen, such as chlorine, iodine, bromine or aryl- or alkyl -sulfonyl, which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as for example toluenesulfonyl and methyl sulfonyl, or other equivalent leaving group. Compounds of the formula R-W, which have a reactive substituent W are known p are easy to obtain using common dexterous knowledge. This reaction can be carried out in the usual solvents and is advantageously carried out with addition of a base, those mentioned above are suitable. In some cases, the use of generally known protecting group techniques is necessary to prepare the compounds I according to the invention. If, for example R 10 = 4-hydroxyphenyl, the hydroxyl group can be first protected as a benzyl ether, which is then broken at a convenient stage in the reaction sequence. Compounds of the formula I wherein R 1 is tetrazole can be prepared as described in WO 99/11914. With respect to the biological action, carboxylic acid derivatives of the formula I - both pure comatomers and diaesteromers or as a mixture thereof - are preferred, wherein the substituents have the following meanings: A is NR8R9, azido, OR10, SR10 or alkyl with 1 to 4 carbon atoms. X is oxygen, sulfur, CR11 or NR12; with the proviso that if X = CR11, then Y = oxygen or sulfur or NR14.

And it is oxygen, sulfur, CR13 or NR14; with the proviso that if Y = oxygen or sulfur or NR14, then X = CR11. R2 and R3 (which may be identical or different): they are phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, alkyl with 1 to 4 carbon atoms , haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, alkylthio with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2 or phenyl, which may be mono- to tri-substituted, by halogen, cyano, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms or alkylthio with 1 to 4 carbon atoms; or phenyl or naphthyl, which are connected to each other in the ortho- position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N group (alkyl having 1 to 4 carbon atoms). carbon); cycloalkyl with 5 to 6 carbon atoms, it being possible for these radicals in each case to be mono- to tri-substituted by: halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms. and R11 (which may be identical or different): they are alkyl with 1 to 4 carbon atoms, it being possible for these radicals to be substituted by halogen, hydroxyl; hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, hydroxyl, NH2, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; 0 CR4, together with CR11, forms an alkylene or alkenylene ring of 5- or 6- membered which can be mono-to tri-substituted by alkyl having 1 to 4 carbon atoms and wherein in each case one to three methylene groups can be replaced by oxygen or sulfur. is hydrogen, alkyl having 1 to 8 carbon atoms, alkylcarbonyl having 1 to 5 carbon atoms, it being possible for these radicals in each case to be mono-to tri-substituted by: halogen, hydroxyl, carboxyl, amino, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, cycloalkyl with 5 to 6 carbon atoms, phenoxy or phenyl, it being possible for said aryl radicals, for their part, to be mono- to tri-substituted by halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2 / phenyl or alkylthio with 1 to 4 carbon atoms; phenyl or naphthyl, which in each case can be mono-to tri-substituted by halogen, hydroxyl, amino, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, alkylthio with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2? dioxomethylene or dioxoethylene; cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono-to tri-substituted by: halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms; or R8, together with R9, form an alkylene chain with 4 to 6 carbon atoms, closed to give a ring, which may be mono- to tri-substituted by alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, and wherein an alkylene group may be replaced by oxygen or sulfur such as - (CH2) 4-, - (CH2) 5-, - (CH2) 6-, - (CH2) 2-0- (CH2 ) 2-, - (CH2) 2-S- (CH2) 2-.

Ry - is hydrogen, alkyl having 1 to 4 carbon atoms; or R9 is as given under R8 linked with R8 to give a ring. R 10 is hydrogen, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms or alkynyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono- to tri-substituted by: halogen, hydroxyl, mercapto, carboxyl, amino, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, carboxamide, CONH (alkyl with ia 4 carbon atoms), CON (alkyl with 1 to 4 carbon atoms) 2, CONR15R16 , NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, C 5 -C 6 -cycloalkyl, phenoxy or phenyl, it being possible for the aforementioned aryl radicals to be mono- to tri-substituted by halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, alkylcarboxyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, amino, NH (alkyl having 1 to 4 carbon atoms), N (alkyl having 1 to 4 carbon atoms) 2 / phenyl, alkylthio having 1 to 4 carbon atoms or R19; phenyl or naphthyl, which in each case may be mono-to tri-substituted by: halogen, hydroxyl, amino, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms , haloalkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, dioxomethylene dioxoethylene; cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono-a-tri-substituted by: halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms. it's hydrogen, methyl; or NR 12, together with CR 4, forms an alkylene ring with 5-to 6-membered which may be mono- to tri-substituted by methyl.

R 13 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, it being possible for these radicals to be mono- to tri-substituted by halogen. R1 is hydrogen, methyl. R15 and R16: R15 and R16 together form an alkylene chain with 3 to 7 carbon atoms or alkenylene chain with 4 to 7 carbon atoms closed to give a ring, to which a phenyl ring, such as 7-azabicyclo, is fused. [4.2.0] -octa-1, 3, 5-triene, 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1,2,4,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible in each case that the phenyl ring is mono- to tri-substituted by halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms. R19 is methyl, ethyl, methoxy or ethoxy, which carries one of the following radicals: hydroxyl, carboxyl, alkoxycarbonyl with 1 to 4 carbon atoms, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, carboxamide or CON (C 1 -C 4 alkyl) 2. Particularly preferred compounds of formula I (as well as pure enantiomers or pure diastereomers or mixtures thereof are those in which the substituents have the following meanings: A is NR8R9, azido, OR10, SR10 or alkyl having 1 to 4 carbon atoms X is oxygen, sulfur or CR11; that if X = CR11, then Y = oxygen or sulfur, I is oxygen, sulfur or CR13, with the proviso that if I = oxygen or sulfur then X = CR11. R2 and R3 (which can be identical or different): they are phenyl or naphthyl, which in each case can be mono- to tri-substituted by: halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 atoms carbon, C 1 -C 4 -alkoxy, haloalkoxy with 1 to 4 carbon atoms, NH (C 1 -C 4 -alkyl), N (alkyl with 1 to 4 carbon atoms) 2, phenoxy or phenyl, which may be mono- to tri-substituted by halogen, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms carbon or haloalkoxy with 1 to 4 carbon atoms; or phenyl or naphthyl, connected together in the ortho- position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N group (alkyl with 1 to 4 carbon atoms) ); cyclohexyl. R4 and R11 (which may be identical or different): they are hydrogen, halogen, alkyl with 1 to 4 carbon atoms, trifluoromethyl, hydroxymethylene, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N ( alkyl with 1 to 4 carbon atoms) 2; or CR 4, together with CR 11, forms an alkylene or alkenylene ring with 5- to 6-membered, which may be branched or disubstituted by methyl, and wherein in each case a methylene group may be replaced by oxygen; R8 - is hydrogen, alkyl with 1 to 4 carbon atoms, alkylcarbonyl with 1 to 4 carbon atoms, it being possible for these radicals to be mono- to tri-substituted by: halogen, hydroxyl, carboxyl, amino, alkoxy with 1 to 4. carbon atoms, alkylthio with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4) carbon atoms) 2, cycloalkyl with 5 to 6 carbon atoms, phenyl, which for its part mono- to tri-substituted by halogen, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms; phenyl which may be mono- to tri-substituted by halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, trifluoromethyl, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, dioxomethylene or dioxoethylene; cycloalkyl with 5 to 6 carbon atoms, it being possible for these radicals in each case to be mono-a-tri-substituted by: halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms; or R8, together with R9, form an alkylene chain with 4 to 6 carbon atoms closed to give a ring that may be mono- to tri-substituted by alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4"carbon atoms. carbon, and wherein an alkylene group may be replaced by oxygen such as - (CH2) 4-, - (CH2) 5-, - (CH2) 6-, - (CH2) 2-0- (CH2) 2-. is hydrogen, alkyl having 1 to 4 carbon atoms, or R9 is as indicated under R8 linked with R8 to give a ring, it is hydrogen, alkyl having 1 to 4 carbon atoms, it being possible for these radicals in each case to be mono - a tri-substituted by: halogen, hydroxyl, carboxyl, alkoxy with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, carboxamide, CONH (alkyl with 1 to 4 carbon atoms), CON (alkyl with 1) to 4 carbon atoms) 2, CONR15R16, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, C 5 -C 6 cycloalkyl, phenyl, which may be mono- to tri-substituted by halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, alkylcarboxyl with 1 to 4 carbon atoms, trifluoromethyl, alkoxy with 1 to 4 carbon atoms, NH (alkyl with 1 to 4 carbon atoms) ), R19, N (C1-C4 alkyl) 2, phenyl or alkylthio with 1 to 4 carbon atoms; phenyl which may be mono- to tri-substituted by halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms , NH (alkyl having 1 to 4 carbon atoms), N (alkyl having 1 to 4 carbon atoms) 2, dioxomethylene or dioxoethylene; cycloalkyl with 3 to 8 carbon atoms, it being possible for these radicals in each case to be mono- or poly-substituted by: halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, R 13 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, trifluoromethyl. R15 and R1 R15 and R16 together form an alkylene chain with 3 to 7 carbon atoms closed to give a ring, to which a phenyl ring is fused, such as 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1, 2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible for the phenyl ring in each case to be mono- to tri-substituted by halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxyl; R 19 is methoxy or ethoxy, which carries one of the following radicals: hydroxyl, carboxyl, alkoxycarbonyl with 1 to 4 carbon atoms, amino, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 atoms) carbon) 2, carboxamide or CON (C 1 -C 4 alkyl) 2- The compounds of the present invention offer a novel therapeutic potential for the treatment of hypertension, high pulmonary pressure, myocardial infarction, angina pectoris, arrhythmia , chronic / acute renal failure, chronic heart failure, renal insufficiency, cerebral vasospasm, and cerebral schema, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty operations and referral, benign prostatic hyperplasia, renal failure or hypertension caused by ischemia and intoxication, metastasis and growth of mesenchymal tumors such as or prostate carcinoma, renal failure induced by contrast agent, pancreatitis, gastrointestinal ulcers. The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Renin-angiotensin system inhibitors are renin inhibitors, angiotensin II antagonists and angiotensin converting enzyme inhibitors (ACE - Angiotension-Converting Enzyme). Combinations of the endothelin receptor antagonists of the formula I and ACE inhibitors are preferred. The invention further relates to combinations of endothelin receptor antagonists of the formula I and calcium antagonists such as verapamil. 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 furthermore relates to combinations of endothelin receptor antagonists of the formula I and substances that block the action of vascular endothelial growth factor (VEGF). These substances, for example, are di-rigid antibodies against VEGF or specific binding proteins or alternatively low molecular weight substances which can specifically inhibit the release of VEGF or receptor binding. The above-mentioned combinations can be administered simultaneously or sequentially. They can be used in either a simple pharmaceutical formulation or alternatively in separate formulations. The administration form may also be different, for example, endothelin receptor antagonists may be administered orally and VEGF inhibitors parenterally. These combination preparations are especially suitable for the treatment and prevention of hypertension and its sequelae and also for the treatment of heart failure. _ __ __ _ The good action of the compounds can be seen in the following experiments: Receptor binding studies For binding studies, CHO cells expressing ETA and ETB were used. Membrane preparation CHO cells expressing ETA and ETB were proliferated in DMEM NUT MIX F12 medium (Gibco, No. 21331-020), using 10% fetal bovine serum (PAA Laboratories GmbH, Linz, No. A15-022), glutamine lmM (Gibco, No. P-25030-024), 100 U / ml penicillin and 100 μg / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated at 37 ° C for 5 minutes with PBS containing 0.05% trypsin. Neutralization with medium was then carried out and the cells were harvested by centrifugation at 300 x g. For membrane preparation, the cells were adjusted to a concentration of 10 8 cells / ml of buffer (Tri buffer, 50 mM HCl, pH 7.4) and then disintegrated by a Branson 250 sonicator 40-70 seconds / constant / output [ sic] 20). Binding tests For the ETA and ETB receptor binding test, the membranes were suspended 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 μg protein per test batch and incubated at 25 ° C with 25 pM

[1251] -ETX (ETA receptor test) or 25 pM [1251] -ET3 (ETB receptor test) in the presence or absence of test substance. The non-specific binding was determined with ETX 10 ~ 7 M. After 30 min, the free and ligated radioligand were separated by filtration through glass fiber filters GF / B (Whatman, England) in a Skatron cell collector ( Skatron, Lier, Norway) and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid flash counter. Test of ET antagonists in vivo: Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and uncharacterized. The carotid artery and the jugular vein were catheterized. In control animals, intravenous administration of 1 mg / kg of ET1 leads to a clear increase in blood pressure, which lasts for a relatively long period. The test animals were injected i.v. (1 ml / kg) with the test compounds, 30 minutes before ET1 administration. To determine the ET antagonist properties, the blood pressure changes in the test animals were compared with those in the control animals. Test p.o. of the mixed ETA and ETB antagonists: Male normotonic tests (Sprague Dawley, Janvier) weighing 250-350 g, are pretreated orally with the test substances. 80 Minutes later, the animals are anesthetized with urethane and the carotid artery is catheterized (for blood pressure measurement) and also the jugular vein (administration of great endothelin / endothelin 1). After a stabilization phase, large endothelin (20 μg / kg, adm., 0.5 ml / kg) or ET1 (0.3 g / kg, adm., 0.5 ml / kg) is administered intravenously. The blood pressure and heart rate are continuously recorded for 30 minutes. Clear and long-term blood pressure changes are calculated as the area under the curve (AUC = Under the Curve Area). To determine the antagonistic action of the test substances, the AUC of the animals treated with substances is compared with the AUC of the control animals. The compounds according to the invention can be administered orally or parentally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. Administration through the nasopharynx can also be carried out using vapors or sprays. The dose depends on the age, condition and weight of the patient and also on the form of administration. As a rule, the dose of the daily active compound is from about 0.5 to 100 mg / kg of body weight in the case of oral administration and from about 0.1 to 10 mg / kg of body weight in the case of parenteral administration. The novel compounds can be administered in solid or liquid form in conventional pharmaceutical administration forms, for example as tablets, film coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointment, creams or sprays. These are prepared in the usual way. The active compounds can in this case be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, delaying agents, antioxidants. and / or propellants (see H. Sucker et al .: Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1991). The application forms thus obtained normally contain the active compound in an amount of 0.1 to 90% by weight. Synthesis examples Example 1: 2-Methylsulfonyl-4,5-dimethylthiazole 2.7 G of 2-methylmercapto-4, 5-dimethylthiazole were initially introduced into methylene chloride at ice temperature and 5.9 g of mCPBA were added. The batch was stirred at room temperature for 16 hours and then extracted once with sodium carbonate solution and with sodium thiolsulfate solution. The organic phase was dried over magnesium sulfate, the solvent was distilled off and 2.88 g of oil were isolated, which were used directly in addition. NMR-XH (200 MHz): 3.25 ppm (3 H, s), 2.50 (3 H, s), 2.40 (3 H, s). ESI-MS: M + = 191 Example 2: 2-Methylmercapto-4, 5-cyclopententiazole 10.4 G of ammonium dithiocarbamate were initially introduced into ethanol and 7.5 g of 2-chlorocyclopentanone were added. After 30 minutes, the reaction is complete and the reaction mixture is added to the water. The aqueous phase is strongly alkaline, using sodium hydroxide solution, extracted with methylene chloride and then adjusted to pH 2 using concentrated hydrochloric acid. The aqueous phase is extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and the solvent is distilled off. The residue is recovered in toluene, a tip filled with a spatula is added with p-toluenesulfonic acid and the solvent is distilled off at 60 ° C. 7.9 G of oil is dissolved in 75 ml of water and 2.4 g of NaOH and 5.7 ml of dimethyl sulfate were added rapidly by droplets. After one hour, the reaction is complete and the mixture is added to the water. The aqueous phase is extracted with ether, the organic phase is dried with magnesium sulfate and the solvent is distilled off. The residue is used in the next reaction without further purification. Example 3: 2-Methylsulfonyl-4,5-cyclopententhiazole 1.9 G of 2-methylmercapto-4,5-cyclopententhiazole were initially introduced at ice temperature into methylene chloride and 7.3 g of mCPBA were added. The batch was stirred at room temperature for 16 hours and then extracted once with 1 N sodium hydroxide solution, and with sodium thiosulfate solution. The organic phase was dried over magnesium sulfate. The solvent was distilled off and 2.25 g of oil were isolated, which were used more directly. RMN-1 !! (200 MHz): 3.26 ppm (3 H, s), 3.05 (2 H, dd), 2.95 (2 H, dd), 2.55 (2 H, dddd). ESI-MS: M + = 203 Example 4: 2-Methylsulfonyl-4,5-dimethyloxazole 3 G of 2-methylthio-4,5-dimethyloxazole are dissolved in 100 ml of methylene chloride and 13 g of mCPBA are added at room temperature of ice. The batch was stirred for three hours and then added to sodium thiosulfate solution. It was neutralized with sodium acid carbonate and the product was extracted with methylene chloride; after drying over magnesium sulfate, the solvent was distilled off and 2 g of crude product were isolated, which was directly possible to use more. NMR ^ H (200 MHz): 3.30 ppm (3 H, s), 2.35 (3 H, s), 2.15 (3 H, s). ESI-MS: M + = 175 Example 5: Acid (S) -2 - (4,5-Dimethylthiazol-2-yloxy) -3-methoxy-3,3-diphenyl-propionic acid (1-1) 320 Mg of? 55% aH were added to an initial mixture of 1 g of S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid in 20 ml of THF / 20 ml of DMF and the mixture was stirred for 15 minutes. 700 mg of 2-methylsulfonyl-4,5-dimethylthiazole was added to this mixture and stirred at room temperature for 16 hours. The batch was then treated with water, the mixture was acidified with citric acid and the product was extracted with ether. After drying over magnesium sulfate and distilling off the solvent, it was purified chromatographically and the product was crystallized from ether / n-hexane. 522 Mg crystals were isolated. RM? - H (200 MHz): 7.35-7.20 ppm (10 H, m), 6.25 (1 H, s), 3.30 (3 H, s), 2.25 (3 H, s), 2.20 (3 H, s) ). ESI-MS: M + = 383 Example 6: 2- (4,5-Cyclopententiazol-2-yloxy) -3- (2- (3,4-dimethoxy-enyl) -ethoxy) -3,3-diphenyl-propionic acid (1 -17) NMR-XH (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.25 (1 H, s), 3.85 (3 H, s), 3.80 ( 3 H, s), 3.70-3.40 (2 H, m), 2.9-2.6 (4 H, m), 2.30-2.25 (2 H, m). ESI-MS: M + = 545 2 - (4, 5 -Dimet i 1 oxazol-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) -ethoxy) -3,3-diphenyl-propionic acid (1- 15) RM? H (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.00 (1 H, s), 3.85 (3 H, s), 3.80 ( 3 H, s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.10 (3 H, s), 1.90 (3 H, s). ESI-MS: M + = 517 Acic or (S) -2- (Benzothiazol-2-yloxy) -3-methoxy-3,3-diphenylpropionic (1-6) RM? H (200 MHz): 7.70-7.50 ( 2 H, m), 7.35-7.20 (12 H, m), 6. 50 (1H, s), 3.30 (3 H, s). ESI-MS: M + = 405 (S) -2- (4,5-Cyclopententiazol-2-yloxy) -3-methoxy-3, 3-diphenyl-propionic acid (1-5) RM? H (200 MHz) : 7.50-7.20 ppm (10 H, m), 6.40 (1 H, s), 3.30 (3 H, s), 2.80-2.60 (4 H, m), 2.30 (2 H, m). ESI-MS: M + = 395 (S) -2- (4,5-Dimethyloxazol-2-yloxy) -3-methoxy-3, 3-diphenyl-propionic acid (1-4) NMR-XH (200 MHz): 7.50-7.20 ppm (10 H, m), 6.10 (1 H, s), 3. 25 (3H, s), 2.1 (3H, s), 1.90 (3 H, s). ESI-MS: M + = 367 2- (4,5-Dimethylthiazol-2-yloxy) -3- (2- (3,4-dimethoxy-phenyl) -ethoxy) -3,3-diphenyl-propionic acid (1-13) RM ^ H (200 MHz): 7.30-7.20 ppm (10 H, m), 6.70-6.50 (3 H, m), 6.20 (1 H, s), 3.90 (3 H, s), 3.85 (3 H, s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.20 (3 H, s), 1.15 (3 H, s). ESI-MS: M + = 533. The compounds in Table I can be prepared similarly or as described in the general section.

R2 Table I R3 R1 fifteen twenty fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen 79 15 fifteen Example 7: According to the binding test described above, the receptor binding data were measured for the compounds shown below. The results are illustrated in Table 2. Table 2 Receiver binding data (values

Claims (9)

1. A heterocyclic substituted-hydroxycarboxylic acid derivative R2 wherein R1 is tetrazole or an O group C-R wherein R has the following meanings: a) a radical OR 5, wherein R 5 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerable organic ammonium ion; cycloalkyl with 3 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms, CH 2 -phenyl, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms or phenyl, in each case unsubstituted or substituted, b) a 5-membered heteroaromatic linked by a nitrogen atom, c) a group (0) k wherein k can acquire the values 0, 1 or 2, p can acquire the values 1, 2, 3 or 4 and R6 is alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 3 a 8 carbon atoms, alkynyl with 3 to 8 carbon atoms or unsubstituted or substituted phenyl; d) a radical O - N - S - R 'H 11 O wherein R 7 is: alkyl having 1 to 4 carbon atoms, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms, cycloalkyl with 3 to 8 carbon atoms , it being possible for these radicals to transport an alkoxy radical with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms and / or phenyl; haloalkyl with 1 to 4 carbon atoms or unsubstituted or substituted phenyl; A is NR8R9, azido, OR10, SR10 or alkyl with 1 to 4 carbon atoms. X is oxygen, sulfur, CR11 or NR12; with the proviso that if X = CR11, then Y = oxygen or sulfur or NR14; And it is oxygen, sulfur, CR13 or NR14; with the proviso that if Y = oxygen or sulfur or NR14, then X = CR11; R2 and R3 (which may be identical or different): they are phenyl or naphthyl, they are unsubstituted or substituted, or phenyl or naphthyl, connected to each other in the ortho position by a direct bond, a methylene, ethylene or ethylene group, an atom of oxygen or sulfur or a group S02, NH or N (alkyl with 1 to 4 carbon atoms), cycloalkyl with 5 to 6 carbon atoms, unsubstituted or substituted; R4 and R11 (which may be identical or different): they are hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, alkenyloxy with 3 to 6 carbon atoms, alkynyloxy with 3 to 6 atoms carbon, alkylthio with 1 to 4 carbon atoms, alkylcarbonyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms, hydroxyl, NH2, NH (alkyl with 1 to 4 carbon atoms), N (alkyl with 1 to 4 carbon atoms) 2, alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, it being possible for these radicals to be unsubstituted or substituted; or CR, together with CR11, form an alkylene or alkenylene ring with 5- or 6-members which may be unsubstituted or substituted and wherein in each case one or more of the methylene groups may be replaced by oxygen, sulfur, -NH or -N (alkyl having 1 to 4 carbon atoms); R8 is hydrogen, alkyl having 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms, alkylcarbonyl with 1 to 5 carbon atoms, it being possible that these radicals are unsubstituted or substituted; phenyl or naphthyl, which is unsubstituted or substituted; C3-C8-cycloalkyl, unsubstituted or substituted; or R8, together with R9, form an alkylene chain with 3 to 7 carbon atoms, which may be unsubstituted or substituted and closed to give a ring, wherein an alkylene group may be replaced by oxygen or sulfur; R9 is hydrogen, alkyl having 1 to 4 carbon atoms; or R9 linked to R8 as indicated under R8 to give a ring; 10 is hydrogen, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, alkynyl with 3 to 8 carbon atoms, it being possible for these radicals to be unsubstituted or substituted; phenyl or naphthyl that is unsubstituted or substituted; cycloalkyl with 3 to 8 carbon atoms unsubstituted or substituted; R 12 is hydrogen, alkyl having 1 to 4 carbon atoms; or NR12 together with CR4, forms a 5- or 6-membered alkylene or alkenylene ring, which may be unsubstituted or substituted and wherein in each case one or more methylene groups may be replaced by oxygen or sulfur; R13 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms, alkynyl with 2 to 4 carbon atoms, it being possible for these radicals to be unsubstituted or substituted; R 14 is hydrogen, alkyl having 1 to 4 carbon atoms; and the physiologically tolerable salts, and the possible enantiomerically pure and diastereoisomerically pure forms.

2. The use of heterocyclicly substituted α-hydroxycarboxylic acid derivatives I according to claim 1, for the treatment of diseases.

3. The use of compounds I according to claim 2, as endothelin receptor antagonists.

4. The use of heterocyclicly substituted α-hydroxycarboxylic acid derivatives I according to claim 1, for the production of drugs in the treatment of diseases in which high levels of endothelin occur.

5. The use of heterocyclic substituted substituted hydroxycarboxylic acid derivatives I according to claim 1, for the production of drugs for treating diseases wherein endothelin contributes to formation and / or progress.

6. The use of heterocyclicly substituted hydroxycarboxylic acid derivatives I according to claim 1, for treating chronic heart failure, restenosis, high blood pressure, high pulmonary pressure, acute / chronic renal failure, cerebral ischemia, asthma, prostatic hyperplasia benign and prostate cancer.

7. A combination of heterocyclicly substituted α-hydroxycarboxylic acid derivatives I according to claim 1, and one or more active compounds selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists, enzyme inhibitors that converts to angiotensin (ACE), neutral endopeptidase / mixed ACE (NEP) inhibitors, ß-blockers, diuretics, calcium channel blockers and VEGF blocking substances.

8. A pharmaceutical preparation for oral and parenteral use, comprising by individual dose in addition to the usual drug auxiliaries, at least one carboxylic acid derivative I according to claim 1.

9. A structural fragment of the formula R2 R3 R1 wherein the radicals R, R, R, R, X and Y have the meanings given in claim 1, as a structural fragment in an endothelin receptor antagonist.