MXPA99001995A - New derivatives of oxilic acid, its obtaining and use in quality of mixed antagonists of receivers eta / - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of the formula I (See Formula) in which the radicals have the meanings indicated in the description, as well as to the use thereof as medicament.

Description

ue'vos er va e c o car ox co, its o enc n and use as mixed antagonists of ETA / ETß receptors Description The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide composed of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isomeric forms: ET-1, ET-2 and ET-3. In the following, the term "endothelin" or "ET" will mean one or all of the isomeric forms of endothelin. Endothelin is a potent va-soconstrictor and has a strong effect on vascular tone. It is known that this vasoconstriction is produced by the link between endothelin and its receptor (Nature, -332, 411-415, 1988, FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys, Res. Commun., 154 , 868-875, 1988).

An increased or abnormal libration of endothelin causes a prolonged contraction of peripheral blood vessels, kidney and brain, which can lead to diseases. As the literature teaches, high levels of endothelin have been found in the plasma of patients with hypertonia, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, apoplectic attack, prostate hypertrophy, atherosclerosis, and asthma (J Vascular Med. Biology 2., 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344. 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 2 ?, 904 (1994), Nature 265, 759 (1993), J. Mol. Cell, Cardiol. A234 (1995); Canger Research 56, 663 (1996)).

At least two subtypes of endothelin receptors, the ETA and ETB receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). According to this, the substances that inhibit the binding of endothelin with the two receptors antagonize the physiological effects of endothelin, which is why they represent valuable drugs.

WO 96/11914 discloses carboxylic acid derivatives which bind with high affinity to the ETA receptor, but with considerably lower affinity with the ETB receptor (called ETA-specific antagonists). ns ace, whose ana with receptor A is at least ve ne vee.es higher than the affinity with the ETB receptor- Therefore, the invention is intended to provide antagonists of endothelin receptors that are linked to approximately the same affinity with the ETA receptor and the ETB receiver (called mixed antiarrhythmics).

There is approximately the same affinity with the two receptors when the quotient of the affinities ETA: ETB is higher than 0.1 and lower than 2, preferably lower than 10.

The object of the present invention are carboxylic acid derivatives of the formula I where R 1 signifies tetrazole or a group O I C R dorde R have the following meanings: a) a radical OR7, where R7 means: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion, such as, for example, C? -C4-alkylammonium or the ammonium ion; C3-Cs- cycloalkyl, Ci-Cβ-alkyl, CH2-phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C? -C4-alkyl, C? -C -haloalkyl, hydroxy , C? -C4-alkoxy, mercapto, C? -C4-alkylthio, amino, carboxy, H (C? -C -alkyl), N (C? -C4-alkyl) 2; - a C3-C6-alkenyl or C3-C6-alkynyl group, whose groups can in turn carry from one to five halogen atoms, - one or three halogen atoms and one to three of the following radicals: nitro , cyano, C? -C4-alkyl, Ci-C "4-halogenoalkyl, hydroxy, C? -C4-alkoxy, mercapto, C? -C -alcjuiltio, amino, NH (C? -C4-alkyl), N ( C? -C4-alkyl) 2; b) a five-membered heteroaromatic linked via a nitrogen atom, such as, for example, pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms, or one or two C3-C4-alkyl groups or one or two cL-C-alkoxy groups. c) a group where k has the values 0, 1 and 2, p has the values 1, 2, 3 and 4, and R8 means C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl, which may be substituted by one or more, eg. from one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C? -C4-haloalkyl, hydroxy, C? -C4-alkoxy, C? -C4-alkylthio, mercapto, amino, carboxy, NH (C? -C4-alkanol), N (C1-C4 -alkyl) 2-d) a radical where R9 singnifica: C? -C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, C1-C4-halogenoalkyl, whose radicals can carry a C? -C4-alkoxy radical, C1-C4-alkylthio and / or a phenyl radical as mentioned in c), - phenyl, optionally substituted, especially those mentioned above. e) in addition, R1 can mean -N \ R14 where R13 and R14 can be identical or different and have the following meanings: hydrogen, C-Cs-alkyl, C3_C8-Cycloalkyl, C3_C8_alkenyl, C3-.C8-alkynyl, benzyl, phenyl, which can carry from one to five halogen atoms and / or from one to three of the following radicals: nitro, cyano , C? -C4-alkyl, C? _C4_haloalkyl, hydroxy, C? -C4_alkoxy, mercapto, Ci-C ^ -alkyl, amino, NH (C1-C4-alkyl), N (C? _C4_alkyl) 2, or R13 and R14 together form an alkylene chain of from 4 to 7 ^ carbon atoms closed forming a ring, which may be substituted by C1-C4..alkyl and in which an alkylene group may be substituted by oxygen, sulfur or nitrogen, such as - (CH2) 4-, - (CH) 5-, - (CH2.6-, - (CH2) 2_C- (CH2) 2-. - (CH2) 7_, -CH2_S- ( CH2) 2-, _ = CH2_NH- (CH2) 2_, - (CH2) 2_N- (CH2) 2_; R 2 hydrogen, hydroxy, NH 2, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2. Halogen, C? -C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl C? -C4-haloalkyl, C? -C4-alkoxy, C1-C4-haloalkoxy or C1 -C4 -alkylthio, or CR2 is linked with CR10 in the form indicated below forming a six-membered ring.

X nitrogen or methine.

And nitrogen or methine.

Z nitrogen or CR10, where R10 signifies hydrogen or C1-C-alkyl or CR10 together with CR2 or CR3 forms a 5 or 6 membered alkylene or alkenylene ring, which may be substituted by one or two C1-C4 groups -alkyl and where one or more methylene groups may be substituted by oxygen, sulfur, -NH or -N (C1-C4-alkyl) 2-NC1_4-alkyl.

At least one of the ring members X, Y or Z denotes nitrogen.

R3 hydrogen, hydroxy, NH2, NH. { C1-C4 -alkyl), N (C1-C4 -alkyl) 2, halogen, C1-C4-alkanoyl, C-C4-alkenyl, C2-C4-alkynyl,, -CR10 in the above-mentioned form forming a ring of 5 or 6 members.

R4 and R5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C? -C4-alkyl, C-C-alkenyl, C, -C4-hydroxyalkyl, C2-C4- to < 3 -inyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, carboxy, C1-C4-haloalkoxy, C? -C4-alkylthio, amino, NH (C1-C4 -alkyl), N (C? -C -alkyl) 2) or phenyl, which may be mono or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C3.-C4-alkyl, C1-C4-haloalkyl, C? -C4-alkoxy, C1-C4- haloalkoxy or C? -C4-alkylthio; or phenyl or naphthyl, which are linked to each other in ortho position via a direct bond, a methylene group, ethylene or an oxygen or sulfur atom or a group S02, NH or N-alkyl; C3 -Ce -cycloalkyl- R6 C3-Ce-cycloalkyl, the radicals of which can be mono- to polysubstituted by: halogen, R15, hydroxy, mercapto, carboxy, nitro, cyano, C? -C4-alkoxy, C? -C4-alkyl, C2-C4 -alkyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkylalkyloxy, C1-C4 -alkylthio, C? -C4-haloalkoxy, C1-C4-alkylalkyl, C1-C4-alkoxycarbonyl, C3- C 8 -alkylcarbonyloalkyl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 or phenyl, which may be mono to polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, C1-C4-haloalkyl, C? -C-alkoxy, C? -C-haloalkoxy or C? -C4-alkylthio; phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C? -C4-alkyl, C4-alkenyl, C2-C4-alkynyl , C3-C6-alkenyloxy, C1-C4-haloalkyl, C3-C6-alkynyloxy, C1-C -alkylcarbonyl, C? -C4-alkoxycarbonyl, C? -C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1 -C 4 -alkaryl, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, dioxomethylene, dioxoethylene or phenyl, which may be mono or polysubstituted, eg mono to trisubstituted by halogen, nitro , cyano, C?-C4-alkyl, C?-C4-haloalkyl, "C?-C4-alkoxy, C?-C4-haloalkoxy or C?-C4-alkylthio; ngen and oxygen, which can carry from one to four halogen atoms and / or one to two of the following radicals: C1-C4 -alkyl, C -C-alkenyl, C1-C4 -halogenoalkyl, C1-C -alkoxy, C? -C4-halogenoalkoxy, C? -C-alkylthio, phenyl or phenoxy, the phenyl radicals of which in turn can carry from one to five halogen atoms and / or from one to three of the following radicals: C? -C4-? alkyl, C 1 -Chaloalkyl, C x -C 4 -alkoxy, C 4 -Chaloalkoxy and / or C 4 -Calkylthio; R15 C? -C4-alkyl, C? -C4-alkylthio, C? -C-alkoxy, which may carry one of the following radicals: hydroxy, carboxy, amino, NH- (C? -C4-alkyl), N- (C? -C-alkyl) 2, carboxamide or CON (C? -C4-alkyl) 2; W sulfur or oxygen.

Q a spacer with a length that corresponds to la of a C2-C4 chain. The function of Q is to create in the compounds of formula I a defined distance between the groups R6 and W. This distance must correspond to the length of a chain of C2-C4-alkyl. This can be achieved with a large number of chemical radicals, for example with C2-C4 -alkyl, C3-C -alkenyl, C3-C4 -alkynyl, -S-CH2 -CH2-, -0-CH2-CH -, -N- CO-CH2-0-, whose radicals can be mono- or polysubstituted by: halogen, hydroxy, mercapto, C1-C-alkyl, C-C4-alkenyl, C2-C4-alkynyl, carboxy , nitro, cyano, Cx-CValkoxy, -Ce-alkenyloxy, C3-e-alkynyloxy, C? -C4-alkylthio, C? -C -haloalkoxy, C? -C4 -alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-8-alkylcarbonyloalkyl, H (C? -C4-alkyl), N (C? -C4-alkyl) 2, phenyl, which may be mono- or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, "C? -C4-alkyl, C? -C -haloalkyl, C? -C4-alkoxy, C1-C4-haloalkoxy or C? -C4-alkylthio. or the spacer Q forms part of a ring of 5-7 members, hetero or carbocyclic, to which R6 is attached.

Here are the following definitions: An alkali metal is, for example, lithium, sodium, potassium; An alkaline earth metal is eg calcium, magnesium, barium; , C 1 -C 4 -haloalkyl can be linear or branched, for example fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-rifluoroethyl, 2-chloro-2, 2-di-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl; C-e-haloalkoxy can be linear or branched, for example difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, - chloro-1, 1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoro-roetoxy; ci "(- 4" alkyl can be linear or branched such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-pro-pyl, 1-butyl or 2-butyl; C2-C4-alkenyl can be linear or branched, for example ethenyl, l-ptropen-3-yl, l-propen-2-yl, 1-propenyl-yl, 2-methyl-1-propenyl, -butenyl or 2-butenyl; C2-4-Alkynyl can be linear or branched, for example ethynyl, 1-propynyl-yl, 1-propin-3-yl, l-butyne-4-yl or 2-butyne-4-yl; C? -C-4-alkoxy can be linear or branched such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C3-C6-alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; C? -C4-hydroxyalkyl, can be linear or branched, such as, for example, hydroxymethyl, l-hydroxy-2-yl, C3-C-6-alkynyloxy can be linear or branched, such as, for example, 2-pro-pin-1-yloxy. 2-butyn-l-yloxy or 3-butin-2-yloxy; C 1 -C 4 -alkylthio may be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio; C? -C4-alkylcarbonyl can be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl; ,, -, - -bonyl or n-butoxycarbonyl; C 3 -Cg-alkylcarbonyloalkyl can be linear or branched, for example 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl Cx-Cs-alkyl can be linear or branched, such as, for example, C -Cal-qullo, pentyl, hexyl, heptyl or octyl; halogen is, for example, fluorine, chlorine, bromine, iodine.

Another object of the invention are those compounds from which the compounds of the formula I (called predrugs) can be released.

Those prodrugs are preferred, in which the libration takes place under conditions that predominate in certain compartments of the body, eg in the stomach, intestine, blood circulation, liver.

The compounds and also the intermediates for their preparation, such as, for example, II, III and IV, may possess one or more substituted asymmetric carbon atoms. Such compounds can be present as pure enantiomers or diastereomers or also in the form of their mixtures. It is preferred to use in pure enantiomeric compound.

Another object of the present invention is the use of the aforementioned carboxylic acid derivatives for the production of medicaments, especially for obtaining inhibitors for the E A and E ß receptors. The compounds of the invention are suitable as mixed antagonists, as defined at the beginning.

The compounds of the general formula IV, in which W means sulfur or oxygen - also in pure enantiomeric form - can be obtained in the manner described in WO 96/11914. R4 - 0 .R1 R4 \ C / \ / + R6 Q W H .- »- R6 Q W C 1 CH OH R / s R i, 5 R '1 II III IV. . corresponding or their esters or applying other known methods.

The carboxylic acid derivatives of the general formula VI can be prepared by reacting a compound of the formula Via with an alcohol or thiol of the formula VII under acid catalysis. R16 Via VII R16 SAW The specified radicals have the following values: R1 has the meanings indicated for the general formula Ri6 and Ri ?, which may be identical or different, mean hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl each time optionally substituted, R18 hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl each time optionally substituted, Ri9 hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl each time optionally substituted, preferably, they will have the following meanings: R1 COOR7,,, substituted, R18 alkyl, phenyl, cycloalkyl each time optionally substituted, RiQ alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, each time optionally substituted, the following radicals being preferred Rl C00CH3 Rl6 r R4 R7 R5 R18 optionally substituted alkyl, especially methyl Rl9 R6_Q.

The carboxylic acid derivatives of the general formula rv can be prepared according to this process, by reacting a compound of the formula IVa with an alcohol or phenol of the formula III under acid catalysis R4 vat III R4 IV For this purpose, the compounds IVa and III are mixed in substance or in an inert solvent for this reaction and catalytic amounts of an acid are added, such as, for example, p-toluenesulfonic acid. Examples of these inert solvents are methylene chloride, benzene or toluene. Those solvents, methyl, are also suitable.

The reaction mixture is then stirred at between room temperature and boiling temperature of the solvent. The alcohol R18OH formed is removed by distillation or application of a vacuum. This method is suitable for obtaining pure IV enantiomers, provided that it starts from pure enantiomers IVa.

The compounds of formula IVa are known and are described, for example, in WO 96/11914.

The compounds of the invention, in which the substituents have the meanings indicated for the general formula I can be obtained, for example, by reacting the carboxylic acid derivatives of the general formula IV, where the substituents have the indicasos meanings, with compounds of the general formula V.

V In the formula V means R11 halogen or R12-S? 2-, where R12 can be C? -C-alkyl, C? -C4-allogenoalkyl or phenyl. In addition, it represents at least one of the ring members X or Y or Z nitrogen. The reaction is preferably carried out in an inert solvent or diluent by adding an appropriate base, namely a base which prids the deprotonation of intermediate IV, in a temperature range from room temperature to the boiling point of the solvent.

Compounds of type I with R1 = COOH can be obtained directly by deprotonating intermediate IV, where R1 means COOH, with two equivalents of an appropriate base and is transformed with compounds of the general formula V. The reaction is also carried out here an inert solvent and in a temperature range from room temperature to the boiling point of the solvent.

Examples of solvents or diluents of this type are aliphatic, alicyclic and aromatic hydrocarbons, which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petrolther, ligroin, benzene, toluene, xylene, metrichloroethylene chloride, ethers, example, diisopropyl ether, dibutyl ether, methyl-tert. -butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles, for example acetonitrile and pro-pionytryl, acid amides, for example, dimethylformamide, dinethylacetamide and N-methylpyrrolidone, sulfoxides and sulphones, for example dimethyl sulfoxide and sulfolane The compounds of formula V are known, partly commercially available, or can be prepared according to generally known methods.

As the base, an alkali metal or alkaline earth metal hydride, such as, for example, sodium hydride, potassium hydride or calcium hydride, a carbonate, for example an alkali metal or alkaline earth metal carbonate, is suitable. sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide, a metal-organic compound, such as eg butyllithium or an alkali metal amide, eg lithium isopropylamide or lithium amide.

The compounds of the formula I can also be obtained starting from the corresponding carboxylic acids, ie, compounds of the formula I, where x means COOH and forming them, first, usually in the active form, eg. acid halide, an anhydride or an imidazolide, and then transforming it with a corresponding hydroxyl compound HOR7. This reaction can be carried out in the usual solvents and requires the addition of a base, with one of the abovementioned being considered as such. These two steps can be simplified when the carboxylic acid is activated in the presence of a water separating agent, for example a carbodiimide, on the hydroxyl compound.

In addition, the compounds of the formula I can also be obtained, starting from the salts of the corresponding carboxylic acids, that is to say, of compounds of the formula I, in which R 1 means a group COR and R singifies OM, and m can be a alkali metal cation or the equivalent of an alkaline earth cation. These salts can be transformed with many compounds of the formula RA, A being a typical nucleophilic cleavable group, for example halogen, such as chlorine, bromine, iodine or arylsulfonyl or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, eg toluenesulfonyl and methylsulfonyl or other equivalent dissociative group. Compounds of the formula R-A with a reactant substituent A are known or can easily be obtained with general skill. This reaction can be carried out with the usual solvents, as mentioned above.

The compounds of the formula I in which R 1 means tetrazole can be obtained in the manner described in WO 96/11914.

In some cases it is necessary to obtain the compounds I to apply known protecting group technique. For example, if R6 = hydroxyphenyl, then the hydroxy group can be protected, first, as benzyl ether, which is then separated at an appropriate stage from the reaction sequence.

With respect to their biological action, the carboxylic acid derivatives of the general formula I are preferred - both as pure enantiomers or diastereomers or their mixtures -, in which the substituents have the following meanings: R2 hydrogen, hydroxy, halogen, N (C? -C4-alkyl) 2, C? -C4-alkyl, C? -C4-alkoxy, Cx-C4-alkylthio, C? -C4-haloalkyl, C? C4-halogenoalkoxy, or CR2 is linked with CR10 in the form indicated below to form a 5- or 6-membered ring; X nitrogen or methine; And nitrogen or methine; Z nitrogen or CR10, where R10 signifies hydrogen or C? _4 -alkyl or CRi ° together with CR2 or CR3 forms a 5 or 6 membered alkylene or alkenylene ring which can be substituted by two methyl groups and where a methylene group can respectively be replaced by oxygen or sulfur, eg -CH2-CH2-0-, -CH2-CH2-CH2-O-, -CH = CH-0-, -CH = CH-CH20-, -CH (CH3) -CH (CH3) -O-, -CH = C (CH3) -O-, -C (CH3) = C (CH3) -O-, or - "C (CH3) = C (CH3) -S; At least one annular member X, Y or Z means nitrogen.

R3 hydrogen, hydroxy, halogen, N (C? -C4-alkyl) 2, C? -C-alkyl, C? -C4-alkoxy, C? -C4-alkylthio, C? -C4-haloalkyl, C? -C4 -halogenoalkoxy, or CR3 is linked with CR10 in the above manner forming a ring of 5 or 6 members, - R4 and R5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C? -C-alkyl, C? -C4-haloalkyl, qu, NH? -4 - what is it or NC? -C4 - what 2 or in o, which can be mono or polysubstituted, eg mono up to trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, C? -C4 -halogenoalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy or C1-C4-alkylthio; or phenyl or naphthyl, which can be linked together in the ortho position via a direct bond to a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N-alkyl group C3-C8-cycloalkyl; C3-C8-cycloalkyl, whose radicals can be mono- or poly-substituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C? -C-alkoxy, C? -C4-alkyl, C2-C4-alkenyl, C2 -C4-al-ejuinyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C? -C4-alkylthio, C? -C4-halogenoalkoxy, CX-C4-alkyI-carbonyl, CX-C4-alkoxycarbonyl , NH (C1-C4 -alkyl), N (Cx-C4-alkyl) 2 or phenyl, which may be mono- or polysubstituted, eg mono up to trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, C 1 -C 4 -halo-rioalkyl, C 1 -C 4 -alkoxy, C 4 -Chaloalkoxy or C 4 -C 4 -alkylthio; phenyl or naphthyl, which may be mono- or polysubstituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C? -C4-alkyl, C2-C4-alkenyl, C2- C4 -alkynyl, C3-C6-alkenyloxy, C? -C4-haloalkyl, C3-C6-alkynyloxy, C? -C4-alkylcarbonyl, C? -C4-alkoxycarbonyl, C? -C4-alkoxy, C? -C4 -halogenoalkoxy, phenoxy, C? -C4-alkylthio, NH (C1-C4-alkyl), N (C? -C4-al-? -kyl) 2, dioxomethylene, dioxoethylene or phenyl, which may be mono- or polysubstituted, mono-to-trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, C1-C4-haloalkyl, C? -C4-alkoxy, C-C4-haloalkoxy or C? -C4-alkylthio; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which may carry from one to four halogen atoms and / or one to two of the following radicals: C ? -C4-alkyl, C? -C4 -halogenoalkyl, C? -C -alkoxy, C? -C -haloalkoxy, C? -C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, whose phenyl radicals can in turn carry one to five halogen atoms and / or from one to three of the following radicals: C1-C4-alkyl, C? -C4-haloalkyl, C? -C4-alkoxy, R15 -methyl, ethyl, methoxy or ethoxy, which may carry one of the following radicals: hydroxy, carboxy, amino, NH (C? -C4-alkyl), N (C? -C4-alkyl) 2, carboxamide or C0N (C? -C4-alkyl) 2; W sulfur or oxygen; Q C2-C4-alkyl, C3-C4-alkenyl, C3-C-alkynyl, -S-CH2-CH2-, -0-CH2-CH-, the radicals of which may be mono- or polysubstituted by: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C? -C4-alkyl, C? -C4-alkoxy, C? -C4-alkylthio, C? -C4-halogenoalkoxy, C? -C4-alkoxycarbonyl, NH (C? -C -alkyl), N (C? -C4-alkyl) 2 or phenyl, which may be mono- or polysubstituted, eg mono up to trisubstituted by halogen, nitro, cyano, C? -C4 -alkyl , C? -C -halogenoalkyl, C? -C4-alkoxy, C? -C -haloalkoxy or C? -C4-alkylthio, or Q forms together with R6 the following ring systems; Indan-2-yl, indan-3-yl, 1, 2, 3, 4-tetrahydronaphth-2-yl, 1, 2, 3, 4-tetrahydronaphth-3-yl, the phenyl rings can be in each case substituted by: halogen, hydroxy. mercapto, carboxy, nitro, cyano, C? -C4-alkoxy, C? -C4-alkyl, "C? -C4-alkenyl, C? -C4-alkynyl, C2-C3-alkenyloxy, C3-C6 ~ alkynyloxy? , C? -C4-alkylthio, C? -C4-haloalumino, C? -C-alkylcarbonyl, C? -C4-alkoxycarbonyl, amino, NH (C? -C -alkyl), N (C? C4-alkyl) 2 or phenyl.

Especially preferred are the compounds of the formula I - the pure enantiomers or the pure diastereomers as well as their mixtures - in which the substituents have the following meanings: R 2 -fluoromethyl, C 1 -C 4 -alkyl, C 1 -C -alkoxy, C 1 -C -alkylthio, or CR 2 is linked with CR 10 in the form indicated below to form a 5- or 6-membered ring, X nitrogen or methine; And nitrogen or methine; Z nitrogen or CR10, where R10 means hydrogen or C? _4-alkyl- or CR10 forms together with CR2 or CR3 a 5 or 6 membered alkylene or alkenylene ring, which may be substituted by one or two methyl groups and where one group methylene respectively is substituted by oxygen or sulfur, eg -CH2-CH -0-, r -CH2-CH2-CH2-O-, -CH = CH-0-, -CH = CH-CH20-, -CH (CH3) -CH (CH3) -0-, At least one of the ring members X, Y or Z is nitrogen R3 trifluoromethyl, C? -C4-alkyl, C? -C-alkoxy, Cx C4-alkylthio, or CR3 is linked with CR10 in the above-mentioned manner to form a 5- or 6-membered ring; R4 and R5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more radicals of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C? -C -alkyl, C? -C4-haloalkyl, C? -C -alkoxy, C? -C4-halogenoalkoxy, phenoxy, C? -C4-alkylthio, NH (C? -C -alkyl) or N (C1-C4-alkyl) 2 or phenyl, which may be mono- or polysubstituted, eg monohasta trisubstituted by halogen, nitro, cyano, C1-C4 -alkyl , C1-C4-haloalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy or C? -C4-alkylthio; or phenyl or naphthyl, which are linked together in the ortho position via a direct bond, a methylene group, ethylene, an oxygen or sulfur atom or a SO2, NH or N-alkyl group C5-C-cycloalkyl; R6 C5-C-cycloalkyl, the radicals of which may be mono- or poly-substituted by: C? -C4-alkoxy, C? -C4-alkyl, Cx-C4-alkylthio, halogen, hydroxy, carboxy, cyano, trifluoromethyl, acetyl, or phenyl, which may be mono- or polysubstituted, eg mono to trisubstituted by halogen, cyano, C? C4-alkyl, C? -C-haloalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy or C? -C-alkylthio; phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C? -C4-alkyl, C-C-haloalkyl, acetyl, C? -C-alkoxycarbonyl, C? -C4-alkoxy, C? -C4-haloalkoxy, phenoxy, C? -C4-alkylthio, NH (C1-C4-alkyl), N (C? -C4-alkyl) 2, dioxomethylene, dioxoethylene or phenyl, which may be mono- or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C? -C4 alkyl, C? -C4 haloalkyl, C? -C4 alkoxy, C? -C4 -halogenoalkoxy or C? -C4-alkylthio; ,,, 1- 4-, N (C? -C4-alkyl) 2, carboxamide or CO (C? -C4-alkyl) 2; a heteroaromatic of five or six members, containing one to three nitrogen atoms and / or a sulfur or oxygen atom, which may carry from one to four halogen atoms and / or one to two of the following radicals: C ? -C4-alkyl, C? -C4-halogenoalkyl, C? -C4-alkoxy, trifluoromethoxy, C? -C4-al- (juylthio, phenyl or phenoxy, whose phenyl radicals in turn can carry from one to five carbon atoms) halogen and / or one to three of the following radicals: C? -C4-alkyl, C? -C4-halogenoalenyl, C? -C4-alkoxy, C1-C4-haloalkoxy and / or C? -C4- alkyl uncle; W sulfur or oxygen; Q C2-C -alkyl, C3-C4-alkenyl, C3-C-alkynyl,, -S-CH2-CH2-, -O-CH2-CH2-, whose radicals can be mono- or polysubstituted by: halogen, hydroxy , mercapto, carboxy, C1-C4-alkyl, C? -C4-alkoxy, C? -C4-alkylthio, or phenyl, which may be mono- or polysubstituted, eg mono to trisubstituted by halogen, nitro, cyano, C ? -C4-alkyl, C-C4 -halogenoalkyl, C? -C4-alkoxy, C1-C4-halogenoalkoxy or C? -C4-alkylthio or Q forms together with R6 the following ring systems; Indan-2-yl, indan-3-yl, 1, 2, 3, 4-tetrahydronaphth-2-yl, 1, 2,3,4-tetrahydronaphth-3-yl, the phenyl rings can be in each case substituted by: halogen, hydroxy. mercapto, carboxy, nitro, cyano, C? -C4-alkoxy, C? -C4-alkyl, C? -C-alkenyl, C? -C4-alkynyl, C2-C3-alkenyloxy, C3-C6- l- quiniloxy, C? -C4-alkylthio, C? -C4-haloalumino, C? -C -alkylcarbonyl, C? -C4-alkoxycarbonyl, amino, NH (C? -C4-alkyl) 7 N (C? -C-alkyl) 2 or phenyl.

The compounds of the present invention offer a new therapeutic potential for the treatment of hypertonia, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic renal failure, re nal failure, cerebral vasospasm, cerebral ischemia, secondary hemorrhage. arachnoid, migraine, asthma, atherosclerosis, endotoxic shock, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty, benign hyperplasia of the prostate, ischemic renal failure and produced by intoxication or hypertonia, mesenchymal growth and metastasis, .

The compounds according to the invention surprisingly have, in part, also an antagonistic effect against the neurokinin receptor.

This is especially true for the compounds of the formula I, in which R1 means Another object of the invention are combined preparations from antagonists of the endothelin receptors of the formula I and inhibitors of the queen-angiotensin system. The inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and, above all, angiotensin-converting enzymes (ACE inhibitors).

Another object of the invention are combined preparations from β blockers and the endothelin receptor antagonists indicated above, as well as from mixed inhibitors of ACE / neutral endopeptidase (NEP) and the endothelin receptor antagonists indicated above.

The combined preparations can also be administered in a single galenic form or else in separate forms. The administration can be simultaneous or temporarily graduated.

The dose in case of the combination can be up to the maximum amount of the respective individual doses. However, it is also possible to use lower doses than in the corresponding individual therapy.

These combined preparations are suitable, above all, for the treatment and prophylaxis of hypertension and its secondary diseases, as well as for the treatment of heart failure.

The good effects of the compounds can be checked in the following examples: For the linkage study, human CHO cells, cloned, expressing ETA or ETB receptors were used.

Preparation of the membrane The CHO cells with expression of the ETA and ETB receptors were multiplied in the DMEM NUT 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 μg streptomycin (Gibco, Sigma No. P-0781). After 48 h the cells were washed with PBS and incubated for 5 minutes at 37 ° C with 0.05% PBS containing trypsin. Then, it was neutralized with medium and the cells were collected by centrifugation at 300 x g.

For the preparation of the membrane the cells were regulated at a concentration of 10 8 cells / ml of buffer (50 mM tris-HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant / output 20).

Linkage assays For the ligation test with the ETA and ETB receptors, the membranes were suspended in the incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 μg / ml bacitracin and 0.2% BSA ) at a concentration of 50 μg of protein per test substance, and incubated at 25 ° C with 25 pM 125J-ET? (assay with ETA receptor) or 25 pM 125J-ET3 (assay with ETB receptor), in the presence or absence of the test substance. The non-specific binding was determined with 10 ~ 7 M E x. After 30 min, the free radioligand and the radioligand bound by filtration were separated on a "glass fiber GF / B" filter (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 by means of a Packard 2200 CA liquid scintillation counter.

Assay of ET antagonists in vivo Male SD rats of 250-300 g were drugged with Amobarbi-tal, connected to artificial respiration, vagotomized and depi-nalized. The carotid artery and the jugularis vein were probed. , it lasted for a prolonged period.

The test animals were injected with the test substances (1 nl / kg) intravenously 5 min before the ETl administration. To determine the ET antagonist properties, the increase in blood pressure in the test animals was compared with that of the test animals. of the control animals. p.o - trial of the mixed antagonists etA and etj Male normotonous rats of 250-300 g (Sprague Dawley, Janvier) were orally pretreated with the test substances. 80 minutes later the rats were narcotized with urethane and A. carotis (to measure blood pressure) was catheterized, as well as V. jugularis (application of endothelin big / endothelin 1).

After a stabilization phase, endothelin big (20 μg / kg, vol of api.0.5 ml / kg) or etl (0.3 μg / kg, volume of api 0.5 ml / kg) was administered intravenously. Blood pressure and cardiac freeiuency were recorded continuously for 30 minutes. The marked and prolonged changes in blood pressure were calculated as a surface under the curve (AUC). In order to terminate the antagonistic effect of the test substances, the AUC of the animals treated with the substances was compared with the AUC of the control animals.

The compounds of the invention can be administered in a customary manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). They can also be applied by means of vapors or sprays through the naso-far Lngea cavity.

The dose depends on the age, condition and weight of the patient, as well as on the form of application. As a general rule, the two daily Ls of active substance amount to between approx. 0.5 and 50 mg / kg of body weight in oral administration, and at between approx. 0.1 and 10 mg / kg of body weight in parenteral administration.

The new compounds can be used in the usual solid and liquid galenic application forms, eg as compresses, film tablets, capsules, powders, granules, dragees, superfoods, solutions, ointments, creams or sprays. These are prepared in a customary manner, and the active substances can be prepared with customary galenic auxiliaries, such as tablet exudates, fillers, preservatives, preservatives, anti-oxidants and / or gasses (see H. Sucker et al. .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The application forms thus obtained contain the substance normally in an amount of 0.1 to 90% by weight.

Synthesis examples Example 1: Methyl ester of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid 7 g (27.5 mmol) of 3,3-diphenyl-2,3-epoxy-propionic acid methyl ester and 5.5 g (30.2 mmol) of 2- (3,4-dimethoxyphenyl) ethanol are dissolved in 20 ml of dichloromethane and at room temperature 5 drops of boric trifluoride etherate are added. The solution is stirred for two hours. The solvent is then distilled off and the residue (10.7 g, 89%) is used directly for further reactions.

Example 2: 2-Hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid 12 g (27.5 mmol) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) -ethoxy) -3,3-diphenyl-propionic acid methyl ester are dissolved in 110 ml of dioxane and mixed with 55 ml of 1N NaOH solution. The mixture is stirred for two hours at 80 ° C. Water is added to the preparation and the aqueous phase is extracted twice. The aqueous phase is acidified with IN aqueous HCl, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled. The residue is recrystallized from ether / n-hexane, 10.2 g (87%) of colorless crystals being isolated. p.f. : 133-135 ° C Example 3: 2- (4-Methoxy -6-methyl-pyrimidin-2-yloxy) -3 - (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid (1-482) 1 g (2.3 mmol) of 2-hydroxy -3- (2 - (3,4-dimethoxyphenyl-ethoxy) -3,3-diphenylpropionic acid are pre- sented in 10 ml of DMF and mixed with the mixture. mg e-methoxy-methyl-2-methylsulfonylpyrimidine and stirring for three hours at room temperature The mixture is mixed with water and the reaction mixture is extracted with ether.The aqueous phase is acidified with 1 N aqueous HCl, it is extracted with ether and dried over magnesium sulfate, the solvent is distilled off, the residue is purified by MPLC and after recrystallization from ether / n-hexane, 655 mg (52 '%) of colorless powder are isolated. iH-NMR (200 MHz): 7.2 ppm (10 H, m), 6.8 (3 H, m), 6.2 (1 H, s), 6.18 (1 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.7 (1 H, m), 2.85 (2 fí, tr), 2.2 (3 H, s).

ESI-MS: M + = 544 Example 4: Methyl ester of 3,3-di (4-ethylphenyl) -2, 3-epoxypropionic acid To a suspension of 9.1 g (168 mmol) of sodium methanolate in 80 ml of THF is added in drops at -10 ° C a solution of 15 ml (168 mmol) of methyl chloroacetate and 20 g (84 mmol) of 4 , 4'-diethylbenzophenone in 20 ml of THF. The mixture is heated to room temperature and stirred for 2 hours. The preparation is poured into water and extracted with ether. The organic phase is washed with sodium hydrogencarbonate solution and citric acid solution, magnesium sulfate and the solvent is distilled. 15.4 g of a crude oil is isolated which is used directly for further reactions.

Example 5: Methyl ester of 2-hydroxy-3- (2- (3,4-dimethoxypheneyl) -3,3-di (4-ethyl-phenyl) propionic acid 6 g (19.3 mmol) of 3,3-di (4-ethyl-phenyl) -2,3-epoxypropionic acid methyl ester (crude) and 3.52 g (19.3 mmol) of 2- (3-methyl) , 4-dimethoxy-phenyl) ethanol are dissolved in 20 ml of dichloromethane and at room temperature 5 drops of boron trifluoride etherate are added. The solution is stirred for 1.5 hours. Subsequently, the solvent is distilled and the residue is used, a yellowish ligenting oil (8.66 g, 91%), directly for subsequent reactions. 2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-di (4-ethylphenyl) propionic acid 9.2 9.2 g (19.3 mmol) of methyl ester of 2 - i-3- (2- (3,4-dimethoxyphenyl) -ethoxy) -3,3-di (4-ethylphenyl) propionic acid are dissolved in 26 ml of dioxan and mixed with 13 ml of NaOH solution 3 N. The mixture is stirred for three hours at 10 60 ° C. Water is added to the preparation and the aqueous phase is extracted twice with ether. The aqueous phase is acidified with 1 N aqueous HCl, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled. 6.5 g (71%) of a yellow oil which is used directly for ultralight reactions are isolated.

Example 7: Acid 2- (4-methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxy-20 phenyl) ethoxy) -3,3-di (4-ethylphenyl) propionic acid (1 -116) 1.8 g (3.8 mmoles) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) -ethoxy) -3,3-di (4-ethylphenyl) ropionic acid are present in 20 ml of DMF and 554 mg of NaH (50% suspension) are added. After 15 The mixture is mixed with 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and stirred for three hours at room temperature. The preparation is mixed with water and the reaction mixture is extracted with ether. The aqueous phase is acidified with 1 N aqueous HClit is extracted with ether and dried over magnesium sulfate. The solvent is distilled and after recrystallization from ether / n-hexane, 540 mg (23%) of colorless powder - iH-NMR (200 MHz) is isolated: 7.0-7.4 ppm (10 H, m), 6.8 (2 H) , d), 6.2 (1 H, 35 s), 6.15 (1 H, s), 3.9 (3 H, s), 3.8 (3 H, s), 3.7 (1 H, m), 3.5 (1 H, m), 2.9 (2 H, tr), 2.6 (4 H, m), 2.3 (3 H, s), 1.2 (6 H, m).ESI-MS: M + = 600 40 Example 8: 2 - (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3-phenylprop- (2E) -enoxi) -3,3-diphenylpropionic acid (1-27) 45 To a suspension of 432 mg mmoles, 50%) of NaH in 20 ml of DMF are added 1.12 g (3 mmoles) of 2-hydroxy-3- (3-phenyl- 4,6-dimethyl-1-methyl-sulfonylpyrimidine) is stirred for 16 hours. hours, then diluted with 200 ml of water, acidified with 1 N hydrochloride acid and extracted with ether.The ether phase is extracted with 1 N sodium hydroxide solution, the aqueous phase is acidified again and the product is extracted The organic phase is dried over magnesium sulfate, filtered and the solvent is distilled off. The residue is recrystallized from ether / hexane and 927 mg (65%) of the crystalline product are isolated. p.f .: 128-133 ° C iH-NMR (200 MHz): 7.3 ppm (15 H, m), 6.74 (1 H, s), 6.7 (1 H, d), 6.3 (1 H, s), 6.2 (1 H, dtr, 4.3 ( 1 H, dd), 4.1 (1 H, dd), 2.3 (6 3, s).

ESI-MS: M + = 480 Example 9: 4,6-dimethyl-1-methylthio-pyrimidine 15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH are dissolved in 175 ml of water. To this mixture 12 ml (128 mmol) of dedimethyl sulfate are added dropwise within 10 minutes at room temperature. After one hour the aqueous phase is extracted three times with ether, dried over magnesium sulfate and the solvent is distilled. 15.9 g (97%) of crude product are isolated. iH-NMR (270 MHz): 6.7 ppm (1 H, s), 2.5 (3 H, s), 2.3 (6 H, s).

Example 10: 4, 6-dimethyl-1-methyl-sulfonyl-pyrimidine 15.9 g (103 mmol) of 4,6-dimethyl-l-methylthio-pyrimidine are present in 120 ml of dichloromethane and 110 ml of water. At 0 ° C chlorine gas is introduced until saturation (yellow coloration). After the complete conversion, the excess chlorine is removed with nitrogen, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate. The solution is concentrated and the product is completely crystallized by adding ether (14 g, 73%). ; & H-NMR (270 MHz): 7.2 ppm (1 H, s), 3.4 (3 H, s), 2.6 (6 H, s).

Ejetiplo 11: (S) methyl 2-hydroxy-3-methoxy-3, 3-diphenylpropionate In 300 ml of DMF, 54.4 g (200 mmoles) of (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid are present with 10.8 g (200 mmoles) of sodium methylate. To this suspension, 21 ml (210 moles) of dimethyl sulfate are added dropwise within 15 minutes, increasing the temperature to 50 ° C and making the suspension more and more liquid. The mixture is stirred further during the night and then poured into 1.5 1 of water and ice. The aqueous phase is extracted twice with 500 ml of ether and the ether phase is washed twice with water. The organic phase is dried over magnesium sulfate, the drying agent is filtered and the solvent is distilled off. 55.8 g of an oil is isolated, which is used directly for further transformations.

Ejetiplo 12: (S) -2-hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropio-nato methyl Variant A: In a flask, 27.9 g of methyl (S) -2-hydroxy-3-methoxy-3, 3-di-phenylpropionate (100 mmol) are mixed with 1 g of p-toluenesulfonic acid and 18.2 g of 2 - (3,4-dimethoxyphenyl) ethanol (100 mmol) and heated to 60 ° C. A vacuum is applied in the flask to distill the forming methanol, and it is stirred for another 5 hours at 60 ° C .; For further processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is washed first with sodium hydrogen carbonate solution and then several times with water, then dried with magnesium sulfate, filtered the drying agent and the solvent is distilled, a residue of 43 g of oil is isolated, which can be used directly in the subsequent synthesis.

Variant B: In a flask, 27.9 g of methyl (S) -2-hydroxy-3-methoxy-3, 3-diphenylpropionate (100 mmol), 1 g p-toluene sulfonic acid and 18.2 g (100 mmol) are dissolved. ) of 2- (3,4-dimethoxyphenyl) ethanol in 75 -il of dichloromethane. The solution is heated and the distillate is stirred for a further 5 hours at 60 ° C. For further processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is washed, first with sodium hydrogen carbonate solution and several times with water. The magnesium sulfate is then dried, the drying agent is distilled off and the solvent is distilled off. A residue of 43 g of oil is isolated, which can be used directly for the subsequent synthesis. 10 Example 13: (S) -2-Hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid To a solution of 74 g (170 mmol) of (S) -2-hydroxy-3 - (methyl 2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionate in 510 ml of dioxane is added 255 ml of 1 N sodium hydroxide solution and the suspension is stirred for two hours at 50 ° C. The mixture is diluted 20 with 2.5 1 of water and neutralized with citric acid. The aqueous phase is extracted twice with 500 ml of ether. The organic phase is then washed with water, dried over magnesium sulfate and after filtering the ether, it is distilled. The residue is purified by crystallization from ether / n-hexane and isolated 25 70 g of srictal. iH-NMR (200 MHz): 7.3 ppm (10 H, m), 6.8 (1 H, dbr), 6.7 (1 H, dbr), 6.6 (1 H, sbr), 5.0 (1 H, s), 3.9 (3 H, s), 3.85 (3 H, s), 3.6 (1 H, dt), 3.4 (1 H, OH), 3.2 (1 H, dt), 2.8 (2 H, t). 30 [a] 20 = 8.3 (1; ethanol) Example 14: 35 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid (1-445) and acid (S) -2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic (1-445 (S) -enantiomer) 40 A an initial charge from 9 g (390 mmol) of lithium amide in 35 ml of DMF is added 55 g (130 mmol) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) acid -3,3-Diphenylpropionic acid, dissolved in 150 ml of DMF in the course of 15 minutes. For that end, 45 25 g (137 mmol) of 2-methylsul-fon-4,6-dimethylpyrimidine, dissolved in 75 ml of DMF are slowly added dropwise and the mixture is stirred at room temperature for 18 hours. For further processing it will be They are filtered by suction and washed with water. The wet crystals are dissolved in dichloromethane, the solution is dried over magnesium sulfate, filtered and the solvent is distilled. The oily residue is absorbed in it, extracted with 130 ml of 1 N sodium hydroxide solution and the aqueous phase is neutralized with 130 ml of 1 N hydrochloric acid, precipitating crystals. After drying, 64 g of product are isolated.

H-NMR (200 MHz): 7.3 ppm (10 H, m), 6.7 (4 H, m), 6.3 (1 H, s), 3.9 (3 H, s), 3.85 (3 H, s), 3.7 (1 H, dt), 3.6 (1 H, dt), 2.8 (2 H, t), 2.3 (6 H, s). p.f,: 125-130 ° C decomp. ESI-MS: M + = 528 In analogy it is prepared from (S) -2-hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid and 2-methylsulfon-4,6-dimethylpyrimidine in the presence of of lithium amide, (S) -2- (4,6-dimethyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid. [aP ° = 111 (1; ethanol) Example 15: The following compounds are prepared in analogy Example 8 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methoxyphenyl) ethoxy) -3,3-di (4-ethylphenyl) ropionic acid (1-147) p.f. : 150-155 ° C ESI-MS: M + = 570 2- (4-Methoxy-5,6-dihydrofuro- (2, 3d) -pyrimidin-2-yloxy) -3- (2- 4 -chlorophenyl) ethoxy) -3,3-diphenylpropionic acid (1-651) p.f. : 150-152 ° C ESI-MS: M + = 546 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (4-chlorophenyl) ethoxy) -3,3-diphenylpropionic acid (1-713) p.f .: 108 ° C decomp. ESI-MS: M + = 502, p.f .: 165-167 ° C ESI-MS: M + = 534 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-chloro-phe-nyl) -ethoxy) -3,3-diphenyl-propionic acid (1-746) p.f. : 93-98 ° C ESI.-M-37 ~ M + = 518 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (4-methoxyphenyl) ethoxy) -3,3-di (4-ethylphenyl) propionic acid (1-148) p.f .: 130-133 ° C ESI-MS: M + = 554 2 - (Methoxy -6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid (1-710) p.f .: 90-100 ° C ESI-MS: M + = 566 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3,3-diphenylpro-poxy) -3,3-di (4-chlorophenyl) ropionic acid ! H-NMR (200 MHz): 7.3 ppm (18 H, m), 6.25 (1 H, s), 6.0 (1 H, s), 4.0 (1 H, tr), 3.8 (3 H, s), 3.4 (2 H, m), 2.2 (5 H, m).

ESI-MS: M + = 642 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3,4-dimethoxy-phenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid (1-) 699) p.f. : 100-110 ° C ESI-MS: M + = 612 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (2-methoxy-phe-nyl) -ethoxy) -3,3-di (4-chlorophenyl) -propionic acid (1) -487) p.f .: 85-90 ° C ESI-MS: M + = 582, - - - p.f .: 190-195 ° C ESI-MS: M + = 610 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2-phenylethylthio) -3,3-di (4-chlorophenyl) propionic acid p.f. : __ 173-175 ° C iH-NMR (200): 7.0-7.4 ppm (13 H, m), 6.0 (1 H, s), 4.7 (2 H, tr), 3.8 (3 H, s), 3.1 (2 H, tr), 2.5 (4 H, m) 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2- (3, 4-dimethoxyphenyl) ethoxy) -3,3-di (4 -) acid chlorophenyl) propionic (1-635) p.f .: 100-110 ° C ESI-MS: M + = 640 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2- (3,5-dimethoxyphenyl) ethoxy) -3,3-di (4) acid chlorophenyl) propionic (1-593) p.f .: 90-100 ° C ESI-MS: M + = 640 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2- (2-methoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) acid propionic (1-164) p.f .: 135-145 ° C ESI-MS: M + = 610 2 - (4-Methoxy-5,6-dihydrofuro- (2, 3d) -pyrimid-2-yloxy) -3- (3, 3-diphenylpropoxy) -3,3-di (4-chlorophenyl) propionic acid p.f., _: _ 125-127 ° C ESI-MS: M + = 670 2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (3, -diphenylpropoxy) -3,3-di (4-chlorophenyl) propionic acid p.f. : 135-140 ° C ESI-MS: M + = 668, - p.f .: 135-140 ° C H-NMR (200): 7.0-7.5 ppm (13 H, m), 5.9 (1 H, s), 3.9 (3 H, s), 2.6-2.8 (8 H, m), 2.1 (2 H, m ). 2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2- (2-methoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid p.f .: 105-115 ° C ESI-MS: M + = 608 2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2- (3-methoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid p.f .: 110-120 ° C ESI-MS: M + = 608 2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2- (4-dimethylaminophenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic acid p.f .: 135-140 ° C ESI-MS: M + = 621 2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) acid propionic p.f .: 125-130 ° C ESI-MS: M + = 638 Acid 2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3- (2- (3,5-dimethoxyphenyl) ethoxy) -3,3-di (4-chlorophenyl) propionic p.f .: 125-130 ° C ESI-MS: M + = 638 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin--yloxy) -3- (2- (4-methylphenyl) ethoxy) -3,3-diphenylpropionic acid (1-370) p.f .: 128-130 ° C ESI-MS: M + = 526, - - p.f .: 155 ° C decomp. ESI-MS: M + = 484 2- (4,6-Dimethoxy-pyrimidin-2-yloxy) -3- (2-phenylethoxy) -3,3-di-phenpropionic acid p.f .: 203 ° C decomp. ESI-MS: M + = 500 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2-phenylethoxy) -3,3-di-phenylpropionic acid (1-720) p.f .: 130-133 ° C ESI-MS: M + = 468 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2-phenylethoxy) -3,3-diphenyl-propionic acid (1-657) p.f .: 138-142 ° C ESI-MS: M + = 512 2- (4,6-Dimethoxy-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) -ethoxy) -3,3-diphenylpropionic acid p.f .: 155-158 ° C ESI-MS: M + = 514 2- (4-Methoxy -6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-465) p.f .: 145-147 ° C ESI-MS: M + = 498 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3- (4-methoxyphenyl-N-propoxy) -3,3-diphenyl-propionic acid (1-554) p.f. : 160-165 ° C ESI -MS: M + = 528 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3- (4-methoxyphenyl) pro-poxy) -3,3-diphenylpropionic acid (1-555) mp: 165-170 ° C 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3- (3, 4, 5 -trimethoxy-phenyl) propoxy) -3,3-diphenylpropionic acid (1-335) XH-: MMR (200): 7.2-7.4 ppm (10 H, m), 6.3 (2 H, s), 6.2 (2 H, s), 3.8 (3 H, s), 3.75 (10 H, s) , 3.4 (2 H, m), 2.6 (2 H, m), 2.25 (3 H, s), 1.9 (2 H, m).

ESI-MS: M + = 588 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3- (3,4,5-trimethoxyphenyl) -propoxy) -3,3-diphenylpropionic acid (1-336) iH-MR (200): 7.2-7.5 ppm (10 H, m), 6.6 Cl H, s), 6.3 (3 H, s), 3.8 (9 H, s), 3.4 (2 H, m), 2.6 (2 H, m), 2.3 (6 H, s), 1.9 (2 H, m).

ESI-MS: M + = 572. 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3- (2-chlorophenyl) -propoxy) -3,3-diphenylpropionic acid (1-383) iH-NMR (200): 7.1-7.5 ppm (14 H, m), 6.24 (1 H, s), 6.23 (1 H, s), 3.8. { 3 H, s), 3.4 (2 H, m), 2.75 (2 H, m), 2.25 (3 H, s), 1.9 (2 H, m).

ESI-MS: M + = 532 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3- (2-chlorophenyl) -propoxy) -3,3-diphenyl-propionic acid (1-384) p.f .: 172-178 ° C ESI-MS: M + = 516 2 - (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3- (4-chlorophenyl) -propoxy) -3,3-diphenylpropionic acid (1-251) iH-MR (200): 7.0-7.4 ppm (14 H, m), 6.6 (1 H, s), 6.3 (1 H, s), 3.5 (2 H, m), 2.7 (2 H, m), 2.3 (6 H, s), 1.9 (2 H, m). ESI-MS: M + = 516 2 - (4,6-Dimethyl-pyrimidin-2-yloxy) -3 - (3 - (3, -dimethoxyphenyl) -propoxy) -3,3-diphenylpropionic acid (1-490)) fí-NMR (200): 7.1-7.5 ppm (10 H, m), 6.74 (1 H, s), 6.7 (3 H, s), 6.3 (1 H, s), 3.8 (6 H, s), 3.5 (2 H, m), 2.7 (2 H, m), 2.3 (6 H, ESI-MS: M + = 542 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (-propoxyphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-69) p.f ".: 115-119 ° C ESI-MS: M + = 542 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-butoxife-nyl) -ethoxy) -3,3-diphenyl-propionic acid (1-71) p.f .: 118-122 ° C ESI-MS: M + = 556 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (4-butoxyphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-70) p.f. : 122-125 ° C ESI-MS: M + = 540 2- (4-Methoxy -6-methyl-pyrimidin-2-yloxy) -3- (3-phenylprop- (2E) enoxy) -3,3-diphenylpropionic acid (1-44) p.f .: 171-174 ° C ESI -MS: M + = 496 Ac 2 - (4-methoxy -6-methyl-pyrimidin--yloxy) -3- (3- (2-methylphenyl) propoxy) -3,3-diphenylpropionic acid (1-107) Decomposition: 144-146 ° C ES] -MS: M + = 512 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3 - (3 - (2-methylphenyl) -propoxy) -3,3-diphenylpropionic acid (1-90) decomposition: 173-176 ° C ESI -MS: M + = 496 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3- (4-methylphenyl) propoxy) -3,3-diphenylpropionic acid (1-363) Decomposition: 158-161 ° C ESI-MS: M + = 512 Decomposition: 163-167 ° C ESI-MS: M + = 496 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methylthio-phe-nyl) -ethoxy) -3,3-diphenyl-propionic acid (1-246) Decomposition: 136-138 ° C ESI-MS: M + = 530 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (4-methylthiophenyl) -ethoxy) -3,3-diphenylpropionic acid (1-217) Decomposition: 166-169 ° C ESI-MS: M + = 514 2- (4-Methoxy -6-methyl-pyrimidin-2-yloxy) -3 - (2- (4-ethoxy-3-methyl-3-phenyl) ethoxy) -3,3-diphenyl-propionic acid (1-145) Decomposition: 141-145 ° C ESI-MS: M + = 558 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-ethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid (1-510) Destruction: 131-135 ° C ESI MS: M + = 528 2- (4-Methoxy-6-yl-pyrimidin-2-yloxy) -3- (2- (4-y-propyl-phen.l) ethoxy) -3,3-diphenylpropionic acid (1-705) iH-MMR (200 MHz, DMSO): 7.0-7.35 ppm (14 H, m), 6.35 (1 H, s), 6.1 (1 H, s), 4.0 (1 H, m), 3.9 (3 H, s), 3.8 (3 H, s), 3.7 (1 H, m), 2.9 (3 H, m), 2.2 (3 H, s), 1.1 (6 H, d).

ESI MS: M + = 526 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (3,4-methylenedioxy-phenyl) ethoxy) -3,3-diphenylpropionic acid (1-568) Decomposition: 146-148 ° C ESI MS: M + = 528, Decomposition: 145-149 ° C ESI-MS: M + = 556 2 - (4-Methoxy-5,6-dihydrofuro- (2, 3d) -pyrimidin-2-yloxy) -3 - (2- (4-ethoxy-3-methoxyphenyl) ethoxy) -3,3-diphenylpropionic acid ( 1-735) 1 H-NMR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m), 6.85 (2 H, m), 6.7 (1 H, d), 6.1 (1 H, s), 4.6 (2 H, tr), 4.0 (3 H, m), 3.85 (3 H, s), 3.75 (3 H, s), 3.65 (1 H, m), 3.05 (2 H, tr), 2.8 (2 H, m) , 1.25 (3 H, m).

ESI-MS: M + = 586 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimid-2-yloxy) -3- (2- (4-ethoxyphenyl) ethoxy) -3,3-diphenylpropionic acid (1-) 407) 1H-.TOR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (2 H, d), 6.1 (1 H, s), 4.65 (2 H, tr), 3.95 (3 H , m), 3.8 (3 H, s), 3.65 (1 H, m), 3.05 (2 H, tr), 2.8 (2 H, m), 1.25 (3 H, m).

ESI-MS: M + = 556 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (2- (4-ethoxy-3-methoxy-phenyl-Detox) -3,3-diphenyl-propionic acid (1-146) Decomposition: 129-134 ° C ESI-MS: M + = 542 2- (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (-2- (3,4-methylenedioxyphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-569) H-MR (270 MHz, DMSO): 7.1-7.4 ppm (10 H, m), 6.9 (1 H, s), 6.8 (2 H,), 6.7 (1 H, d), 6.2 (1 H, s ), 6.0 (2 H, s), 3.95 (3 H, m), 3.65 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s).

ESI-MS: M + = 512 x -, - in prop n co - decomposition: 145-148 ° C ESI-MS: M + = 512 2- (4-Methoxy-5,6-dihydrofuro- (2,3d) -pyrimidin-2-yloxy) -3- (2- (4-i-propylphenyl) ethoxy) -3,3-diphenylpropionic acid (1-) 604) -LH-NMR (270 MHz, DMSO): 7.1-7.4 ppm (14 H, m), 6.1 (1 H, s), 4.6 (2 H, tr), 3.9 (1 H, m), 3.8 (3 H , s), 3.6 (1 H, m), 3.0 (2 H, tr), 2.8 (3 H, m), 1.1 (6 H, d).

ESI-MS: M + = 554 Acid 2- (4,6-dimethyl-1-pyrimidin-2-yloxy) -3- (2- (4-propylphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-672) decomposition: 156-160 ° C ESI -MS: M + = 510 ACI or 2- (4-methoxy-5,6-dihydrofuro- (2, 3d) -pyrimid-2-yloxy) -3- (2- (4-methoxyphenyl) ethoxy) -3,3-di (4 -methylphenyl) -propionic (1-517) H-NMR (200 MHz, DMSO): 7.0-7.3 ppm (10 H, m), 6.8 (2 H, d), 6.0 (1 H, s), 4.6 (2 H, tr), 3.85 (3 H , s), 3.8 (1 H, m), 3.7 (3 H, s), 3.6 (1 H, m), 3.0 (2 H, tr), 2.8 (2 H, tr), 1.1 (6 H, d ).

ESI -MS: M + = 570 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (2- (4-methoxyphenyl) -ethoxy) -3,3-diphenylpropionic acid (1-622) iH-NMR (270 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (2 H, d), 6.4 (1 H, s), 6.1 (1 H, s), 4.0 (1 H, m), 3.7 (3 H, s), 3.7 (1 H, m), 2.8 (2 H, tr), 2.3 (3 H, s).

ESII-MS: M + = 514 -, - in co-iH-NMR (200 MHz, DMSO): 7.1-7.4 ppm (12 H, m), 6.8 (3 H, m), 6.1 (1 H, s), 4.0 (1 H,), 3.7 (3 H, s), 3.6 (1 H, m), 2.8 (2 H, tr), 2.3 (6 H, s).

ESI -MS: M + = 498 2- (4-Methoxy-6-methyl-pyrimidin-2-yloxy) -3- (3-phenylpropoxy) -3,3-diphenylpropionic acid (1-499) Decomposition: 153-155 ° C ESI-MS: M + = 498 2 - (4,6-Dimethyl-pyrimidin-2-yloxy) -3- (3-phenylpro-poxL) -3,3-diphenylpropionic acid (1-500) Decomposition: 148-151 ° C ESI-MS: M + = 482 Analogously or in the manner described in the general part, the related compounds can be obtained in Table 1.

Table I or lí *. H1 4 t F" U1 n .

F. OR Ül o 01 t 01 lí * -. a Ul 0 * 1 Ul OO l O t 0 * > in Ul 0 * > 0 * 1 I heard 01 00 s-, O Using the linkage test described above, the data of the receptor-binding are measured for the compounds indicated below. the results are represented in Table 2 below.

Table 2 Linkage data to the receivers (K¿ values)

Claims (3)

1. Acrylic acid derivatives of the formula I where R1 means tetrazole or a group O ~ c ~ R where R has the following meanings: a) a radical OR7, where R7 means: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion; C3 -Ce-cycloalkyl, C? -C8-alkyl, - CH2-optionally substituted phenyl; a C3-Ce-alkenyl or C3-C6-alkynyl group optionally substituted, or phenyl optionally substituted. b) a five-membered heteroaromatic linked via a nitrogen atom. c) a group where k has the values 0, 1 and 2, p has the values 1, 2, 3 and 4, and R8 means . d) a radical O NH S R9 O where R9 singnifica: C? -C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, which radicals can carry a C? -C4-alkoxy, C? -C4-alkylthio radical and / or a phenyl radical; phenyl optionally substituted. e) a radical / R13 where R13 and R14 can be identical or different and have the following meanings: hydrogen, C? -C8-alkyl, C3-C8-Cycloalkyl, C3-C8-alkyl, C-C8-alkynyl, benzyl, optionally substituted phenyl or R13 and R14 together form an alkylene chain of 4 to 7 carbon atoms closed to form a ring, optionally substituted, which may contain a heteoatome. R2 hydrogen, hydroxy, NH2, NH (C? -C4 -alkyl), N (C? -C4-alkyl) 2, halogen, C? -C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C C4-haloalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy or C? -C4-alkylthio, or CR2 is linked with CR10 in the form indicated below to form a six-membered ring. X nitrogen or methine. And nitrogen or methine. or a 5-membered or 6-membered alkenylene or an o-ene or alkenylene group, which may be substituted by one or two C-C-alkyl groups and where one or more methylene groups may be substituted by oxygen, sulfur , -NH or -NC? -4-alkyl. R3 hydrogen, hydroxy, NH2, NH (C -C4 -alkyl), N (C? -C4-alkyl) 2, halogen, C? -C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C? -C4-hydroxyalkyl, C? -C4-haloalkyl, C? -C4-alkoxy, C? -C4-haloalkoxy, C-C4-alkylthio, or CR3 is linked with CR10 in the above-mentioned manner to form a ring of 5 or 6 members . R4 and R5 (which may be identical or different): phenyl or naphthyl optionally substituted, or phenyl or naphthyl, which are linked to each other in ortho position via a direct bond, a methylene group, ethylene or an oxygen or sulfur atom or a group S02, NH or N-alkyl; C3-C8-optionally substituted cycloalkyl; R6 C3-C8-cycloalkyl optionally substituted; optionally substituted phenyl or naphthyl; a five or six member heteroaromatic containing one to three nitrogen atoms and / or a sulfur or oxygen atom and which may, if necessary, be substituted; W sulfur or oxygen. Q a spacer with a length corresponding to la of a carbon chain with 2 to 4 carbon atoms, as well as the physiologically tolerated salts and the pure enantiomeric forms.

2. Drug preparations for peroral, parenteral and intraperitoneal application, containing, together with the auxiliary substances for usual medicaments, at least one carboxylic acid derivative I according to claim 1.

3. Use of the carboxylic acid derivatives according to claim 1 for the treatment of diseases. . Use of the carboxylic acid derivatives I according to claim 1 for the production of medicaments for the treatment of diseases in which high levels of endothelin are present. Use of the carboxylic acid derivatives I according to claim 1 for the treatment of chronic heart failure, restenosis, hypertension, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer . Use of the carboxylic acid derivatives I according to claim 1 in combination with inhibitors of the re-nina-angiotensin system, mixed inhibitors of ACE / neutral endopep idase (NEP); ß blockers. Use of the compounds of formula IV R4 wherein the radicals R1, R4, R5, R6, Q and W have the meanings indicated in claim 1, as starting materials for the synthesis of mixed ERA / ETB receptor antagonists. A structural fragment of the formula R4 wherein the radicals Rx, R4, R5, R6, Q and W have the meanings indicated in claim 1, as structural elements in a mixed ERA / ETB receptor antagonist. Process for the preparation of carboxylic acid derivatives of the general formula IV reacting compounds of the formula IVa R4 with an alcohol or thiol of formula III Rd Q-W -H ni wherein the radicals R ', R4, R5, R6, Q, W have the meanings indicated in claim 1 and R18 represents an open chain or phenyl cyclic alkyl, which is optionally substituted, under acid catalysis.