HRP20000650A2 - Novel unsymmetrically substituted carboxylic acid derivatives, method for producing them, and their use as mixed et<->a<p>/et<->b<p> receptor antafonists - Google Patents

Description

The proposed invention relates to new carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide made 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. As used herein, the term "endothelin" or "ET" refers to one or all of the isomeric forms of endothelin. Endothelin is a strong vasoconstrictor and has a strong effect on blood vessel tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, (1988), 868 -875).

Elevated or abnormal release of endothelin causes permanent narrowing in peripheral, renal and cerebral blood vessels, which can lead to health disorders. It is known from the literature that endothelin is involved in numerous health disorders. These are hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic 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.

So far, at least two subtypes of endothelin receptors, ETA and ETB receptors, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Therefore, substances that inhibit the binding of endothelin to one or both receptors antagonize the physiological effects of endothelin and therefore represent valuable drugs.

WO 95/26716 describes compound XX as an endothelin receptor antagonist.

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In contrast, the aim of the proposed invention is to provide so-called mixed endothelin receptor antagonists. Mixed endothelin receptor antagonists bind with approximately equal affinity to ETA and ETB receptors. There is approximately equal affinity for the receptors when the ETA : ETB affinity ratio is greater than 0.05, preferably greater than 0.1, and less than 20, preferably less than 10.

DE describes carboxylic acid derivatives that bind with high affinity to the ETA receptor to the ETB receptor. One characteristic of these compounds is, for example, symmetrical substitution with two phenyl rings at the β center. We have now found, quite surprisingly, that mixed receptor antagonists can be obtained even with unsymmetrical substitution of the β center (for example methyl/phenyl).

The invention relates to carboxylic acid derivatives of formula I

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in which the substituents have the following meanings:

R1 represents a tetrazole or a group

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where

R has the following meanings:

a) radical OR7 in which R7 represents:

hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic ammonium ion, such as a tertiary C1-C4-alkylammonium or ammonium ion;

C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, which may be substituted with one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4 -Alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N (C1-C4-alkyl)2;

C3-C6-alkenyl or C3-C6-alkynyl group, whereby these groups, for their part, can carry one to five halogen atoms;

R7 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, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxy, C1-C4-alkoxy, mercapto, C1 -C4-alkylthio, amino, NH(C1-C4-alkyl), N (C1-C4-alkyl)2;

b) a five-membered heteroaromatic system such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl connected via a nitrogen atom, which can carry one or two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4- alkoxy groups;

c) group

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where k can have the value 0, 1 and 2, p can be 1, 2, 3 and 4 and

R 8 is C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or phenyl, which can be mono or poly, for example mono to tri substituted with the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH (C1-C4-alkyl), N (C1-C4-alkylom)2;

d) the radical of the formula

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in which R9 is

C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cyclo-alkyl, C1-C4-haloalkyl, wherein these radicals can carry C1-C4-alkoxy, C1-C4-alkylthio and / or phenyl radical defined as under c);

phenyl, optionally substituted as mentioned above,

e) group

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in which R13 and R14 can be the same or different and have the following meanings:

hydrogen, nitrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl, which can carry one to five halogen atoms and/or one to three of the following radicals: nitro , Cyano, C1-C4-Alkyl, C1-C4-Haloalkyl, Hydroxy, C1-C4-Alkoxy, Mercapto, C1-C4-Alkylthio, Amino, NH (C1-C4-Alkyl), N (C1-C4-Alkyl) 2,

or R13 and R14 together form a C4-C7-alkylene chain which is ring-closed and may be substituted with C1-C4-alkyl and in which one alkylene group may be replaced by oxygen, sulfur or nitrogen, such as

-(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)2-O-(CH2)2-, -(CH2)7-, -CH2-S-(CH2) 2-, -CH2-NH-(CH2)2-, -(CH2)2-N-(CH2)2-;

R2 is hydrogen, hydroxy, NH2, NH (C1-C4-alkyl), N(C1-C4-alkyl)2 halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio, or CR2 is linked to CR10 as shown below to form a five- or six-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, in which R10 represents hydrogen, halogen, hydroxy, C1-C4-haloalkyl or C1-C4-alkyl, or CR10 together with CR2 or with CR3 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C1-C4-alkyl groups and in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or by N(C1-C4-alkyl);

at least one of the ring members X, Y or Z is nitrogen;

R3 is hydrogen, hydroxy, NH2, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-hydroxyalkyl, C1-C4-alkylthio, or CR3 is linked to CR10 as mentioned above, thus giving a 5- or 6-membered ring;

R4 is C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl, which may be substituted with one or more of the following radicals: halogen, cyano, hydroxy, mercapto, C1-C4- alkoxy, phenoxy, carboxy, C1 -C4-haloalkyloxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or alkylcarbonyl;

C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl, which is connected to R5 by a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur or SO2-, NH-, or N-alkyl group;

R5 is phenyl or naphthyl, each of which may be substituted with one or more of the following radicals:

halogen, nitro, cyano, hydroxy, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-hydroxyalkyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, carboxy, C1-C4-halogenalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl), N(C1-C4-alkyl) 2 or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with halogen , nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio; or

phenyl or naphthyl which are linked in the ortho position to R4 via a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or a single SO2-, NH- or N-alkyl group; or

C3-C8-cycloalkyl;

R6 is C3-C8-cycloalkyl, whereby these radicals can in any case be singly or multiply substituted with the following substituents: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2 -C4-alkenyl, C2-C4-alkynyl, C2-C4-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkyl-carbonyl, C1-C4-alkoxycarbonyl, C3 -C8-alkylcarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl, which can be singly or multiply, for example singly to triply substituted with halogen, nitro, cyano, C1-C4- alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl or C 1 -C 4 -alkylthio;

phenyl or naphthyl, each of which may carry one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3 -C6-Alkenyloxy, C1-C4-Haloalkyl, C2-C4-Alkynyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, Phenoxy, C1-C4-Alkylthio, NH (C1-C4-alkyl), N(C1-C4-alkyl)2. dioxomethylene, dioxoethylen, or phenyl, which may be mono or poly, for example mono to tri substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyl or C1-C4-alkylthio, provided that if R6 represents an unsubstituted phenyl radical, then R2 and R3 cannot simultaneously be OCH3;

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4- alkenyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl radicals can carry one to five halogen atoms and/or one to three the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy and/or C1-C4-alkylthio;

R15 is C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which can carry one or more of the following radicals: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4- alkyl)2, carboxy-amide or CON(C1-C4-alkyl)2;

W is sulfur or oxygen;

Q is a spacer group that corresponds to the length of the chain that has C2-C4 atoms. The function of the group Q is to provide a defined distance between the group R6 and W in the compounds of formula I. This distance must correspond to the length of the C2-C4-alkyl chain. This can be achieved with a large number of chemical radicals, for example with C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl,

-S-CH2-CH2-, -O-CH2-CH2-, -N-CO-CH2-, -CO-N-CH2-CH2-, -CO-N (C1-C4-alkyl)-CH2-CH2- , -SO2-N (C1-C4-alkyl) -CH2-CH2-, -SO2-NH-CH2-CH2-, whereby these radicals can in any case be single or multiple substituted with halogen, hydroxy, mercapto, C1- C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkynyl, Carboxy, Nitro, Cyano, C1-C4-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4- haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C6-alkylcarbonylalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl, which may be single or multiple, for example mono- to tri-substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy or C1-C4-alkylthio;

or the spacer Q is part of a 5- to 7-membered ring, hetero- or carbocyclic, to which R 6 is fused. The following definitions apply here and in the following:

An alkali metal is, for example, lithium, sodium, potassium. Alkaline earth metal is, for example, calcium, magnesium, barium.

C3-C7-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

C1-C4-haloalkyl can be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-difluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C1-C4-halogenalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

C1-C4-alkyl may be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C2-C4-alkenyl can be linear or branched, such as ethenyl, 1-propen-3-yl, 2-propen-3-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- butenyl or 2-butenyl;

C2-C4-alkynyl can be linear or branched, such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;

C1-C4-Alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C3-C6-alkenyloxy can be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten~2-yloxy;

C1-C4-hydroxyalkyl may be linear or branched, such as hydroxymethyl, 1-hydroxyethet-2-yl;

C3-C6-alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C1-C4-alkylthio can be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C1-C4-alkylcarbonyl may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

C1-C4-Alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C3-C8-alkylcarbonylalkyl may be linear or branched, such as 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;

C1-C8-alkyl may be linear or branched, such as C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;

halogen is, for example, fluorine, chlorine, bromine, iodine.

A further subject of the invention are such compounds from which the compounds of formula I can be released (so-called prodrugs).

Preferable are such prodrugs in which the release takes place under the conditions prevailing in certain parts of the body, eg in the stomach, intestines, bloodstream, liver.

Compounds and intermediates for their production, such as II, III and IV, may have one or more asymmetrically substituted carbon atoms. Such compounds can exist as pure enantiomers, i.e. as pure diastereomers or as a mixture thereof. When used as an active substance, preference is given to using an enantiomerically pure compound.

The preparation of such compounds is described in the examples.

The invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of drugs, especially for the production of ETA and ETB receptor inhibitors. The compounds of the invention are particularly suitable as mixed antagonists as defined in the introduction.

Compounds of the general formula IV, in which Z represents sulfur or oxygen, can be prepared, also in enantiomerically pure form, as described in WO 96/11914 or DE 19636046.3.

Compounds of the general formula III are known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or their esters, or by generally known methods.

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A further possibility for obtaining enantiomerically pure compounds of formula IV is the classical separation of racemates with racemic or diastereomeric compounds of formula IV using suitable enantiomerically pure bases. Suitable bases of this type are, for example, 4-chlorophenylethylamine and the bases mentioned in Wo 96/11914.

The compounds according to the invention in which the substituents have the meanings given under the general formula I, can be produced, for example, by the reaction of the carboxylic acid derivatives of the formula IV, in which the substituents have the given meanings, with the compounds of the general formula V.

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R 11 in formula V is halogen or R 12 -SO 2 -, where R 12 can be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction takes place preferably in an inert solvent or diluent, with the addition of a suitable base, i.e. a base that causes deprotonation of the intermediate product IV, at a temperature in the range from room temperature to the boiling point of the solvent.

Compounds of type I, where R1 is COOH, can be obtained directly by deprotonating intermediate IV, where R1 is COOH, with two equivalents of a suitable base and reacting with compounds of general formula V. This reaction also takes place in an inert solvent and at temperature in the range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone , sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.

Compounds of formula V are known, and some of them can be purchased, or can be prepared by generally known methods.

Alkali or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, carbonate such as alkali metal carbonate, e.g. sodium or potassium carbonate, alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, organometallic compound such as butyllithium or an alkali metal amide, such as lithium diisopropylamide or lithium amide.

Compounds of formula I can also be produced by starting from the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents COOH, and they are first converted in the usual way into an activated form, such as an acid halide, anhydride or imidazolide, and the latter then reacts with the corresponding hydroxyl compound HOR7. This reaction can be carried out in common solvents and often requires the addition of a base, in which case those mentioned above are suitable. 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.

In addition, compounds of formula I can also be produced starting from salts of the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents the group COR, and R is OM, where M can be an alkali metal cation or the equivalent of an earth cation. alkali metal. These salts can react with many compounds of the formula R-A, where A represents a common nucleophilic leaving group, for example halogen, such as chlorine, bromine, iodine, or, where appropriate, halogen, alkyl or haloalkyl substituted aryl- or alkylsulfonyl, such as, for example, toluenesulfonyl and methylsulfonyl, or with another equivalent leaving group- Compounds of the formula R-A with a reactive substituent A are known or can be easily obtained on the basis of general expert knowledge. This reaction can be carried out in common solvents and takes place preferably with the addition of a base, in which case the above are suitable.

In some cases, for the preparation of compounds I according to the invention, generally known procedures with protecting groups must be applied. If, for example, R 6 represents 4-hydroxyphenyl, then the hydroxyl group may first be protected as a benzyl ether, which is then cleaved off in an appropriate reaction step.

Compounds of formula I, wherein R 1 is tetrazole, can be prepared as described in WO 96/11914.

As far as biological activity is concerned, preference is given to carboxylic acid derivatives of formula I as pure enantiomers, i.e. pure diastereomers or as their mixtures, in which the substituents have the following meanings:

R 2 is hydrogen, hydroxy, halogen N (C 1 -C 4 -alkyl) 2 , C 1 -C 4 -alkyl, C 1 -C 4 -Alkoxy, C 1 -C 4 -Alkylthio, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Halo alkoxy or CR 2 is linked to CR10 as indicated below, giving a 5- or 6-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, in which R10 represents hydrogen, halogen, hydroxy, C1-C4-haloalkyl or C1-C4-alkyl, or CR10 forms together with CR2 or with CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted with one or two methyl groups and in each case one or two methylene groups may be replaced by oxygen or sulfur, as –CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH=CH-O -, -CH=CH-CH2-O-, -CH(CH3)-CH(CH3)-O-, -C(CH3)-O-, or -C(CH3)=C(CH3)-S;

at least one of the ring members X, Y or Z is nitrogen;

R3 is hydrogen, hydroxy, halogen, NH (C1-C4-alkyl), C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, or is CR3 connected to CR10 as above to give a 5- or 6-membered ring;

R4 is C1-C4-alkyl or C2-C4-alkenyl, which may be substituted with one or more of the following radicals:

Halogen, Cyano, Hydroxy, Mercapto, C1-C4-Alkoxy, Phenoxy, Carboxy, C1-C4-Haloalkyloxy, C1-C4-Alkylthio, Amino, NH(C1-C4-Alkyl), N (C1-C4-Alkyl)2 or C1-C4-alkylcarbonyl;

R5 is phenyl or naphthyl, each of which may be substituted with one or more of the following radicals:

halogen, nitro, cyano, hydroxy, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-halogenalkoxy, C1-C4-alkoxy, phenoxy, carboxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N (C1-C4-alkyl)2 or phenyl, which may be singly or multiply, for example singly to triply substituted with halogen, nitro, cyano, C1 -C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or C3-C8-cycloalkyl;

R6 is C3-C8-cycloalkyl, whereby these radicals can in any case be singly or multiply substituted with the following substituents: halogen, hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2 -C4-alkenyl, C2-C4-alkynyl, C3-C4-alkenyloxy, C3-C6-alkynyl-oxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkyl-carbonyl, C1-C4-alkoxycarbonyl , NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl, which can be singly or multiply, for example singly to triply substituted with halogen, nitro, cyano, C1-C4-alkyl, C1- C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

phenyl or naphthyl, each of which may carry one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3 -C6-Alkenyloxy, C1-C4-Haloalkyl, C3-C6-Alkynyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, Phenoxy, C1-C4-Alkylthio, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene, dioxoethylene, or phenyl, which may be singly or multiply, for example singly to triply substituted with halogen, nitro, cyano, C1-C4-alkyl , C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy or C1-C4-alkylthio, provided that if R6 represents an unsubstituted phenyl ring, then CR10 together with CR2 or CR3 must form a 5-membered alkylene a ring in which one or two methylene groups may be replaced by O or S;

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4- haloalkyl, C1-C4-alkoxy, trifluoro-methoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl radicals can carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl , C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio;

R15 is methyl, ethyl, methoxy or ethoxy, bearing one of the following radicals: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxyamide or CON(C1-C4- alkyl)2;

W is sulfur or oxygen;

Q is C2-C4-alkyl, C3-alkenyl, -S-CH2-CH2-, -O-CH2-CH2, whereby these radicals can in any case be singly or multiply substituted with halogen, hydroxy, mercapto, cyano, C1 -C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylthio, C1-C4-Haloalkyl, C1-C4-Alkoxy-carbonyl, NH(C1-C4-Alkyl), N(C1-C4-Alkyl) 2, phenyl, which can be singly or multiply, for example singly to triply substituted with halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio;

or the spacer Q together with R6 forms the following ring systems: 2-indanyl, 3-indanyl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3yl, wherein the phenyl ring in each case they may be substituted with halogen, hydroxy, mercapto, carboxy, nitro, cyano, C1-C4- alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3 -C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-alkylcarbyl, C1-C4-alkoxycarbonyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl.

Particular preference is given to compounds of formula I as pure enantiomers, i.e. pure diastereomers or as their mixtures, in which the substituents have the following meanings:

R 2 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 2 is linked to CR 10 as shown below to form a 5- or 6-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, in which R10 represents hydrogen, fluorine or methyl, or CR10 forms together with CR2 or with CR3 a 5- or 6-membered alkylene or alkenylene ring which may be substituted with one or two methyl groups and in which in each case one methylene group can be replaced by oxygen or sulfur, as –CH2-CH2-O-,

-CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2-O-,

-CH(CH3)-CH(CH3)-O-, -C(CH3)-O-, or -C(CH3)=C(CH3)-S;

at least one of the ring members X, Y or Z is nitrogen;

R 3 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 2 is linked to CR 10 as shown above to form a 5- or 6-membered ring;

R 4 is C 1 -C 4 -alkyl which may be substituted with one or more of the following radicals: halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenalkoxy;

R5 is phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-halogenalkoxy, C1 -C4-Alkoxy, Phenoxy, C1-C4-Alkylthio, NH(C1-C4-Alkyl), N(C1-C4-Alkyl)2 or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

or phenyl or naphthyl, which is linked in the ortho position to R4 by a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom, or SO2, NH or N-alkyl group;

cyclohexyl;

R6 is cyclohexyl which can be mono- or multi-substituted with the following substituents: C4-Alkoxy, C1-C4-alkyl, halogen or phenyl, which can be mono- or multi-substituted, for example mono- to tri-substituted with halogen, C1-C4-alkyl or C1-C4-Alkoxy;

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, R15, C1-C4-alkyl, C1-C4-halogenoalkyl, acetyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, phenoxy, C1 -C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene, dioxo-ethylene, or phenyl, which may be mono- or multi-substituted, for example mono- to tri-substituted with halogen, cyano , C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio, provided that if Q represents -CH2-CH2- and W is O, then the phenyl ring must have at least one substituent other than hydrogen;

R15 is methoxy or ethoxy, which carries one of the following radicals: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl) 2, carboxyamide or CON (C1-C4-alkyl)2;

W is sulfur or oxygen;

Q is C2-C3-alkyl, -S-CH2-CH2-, -O-CH2-CH2, whereby these radicals can in any case be mono- or multi-substituted with halogen, C1-C4-alkyl, C1-C4-alkoxy .

or group Q together with R6 forms the following ring systems: indan-2-yl, indan-3-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl , wherein the phenyl rings can in any case be substituted with halogen, hydroxy, mercapto, carboxy, cyano, C1-C4- alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6- alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkoxycarobyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl.

The compounds of the proposed invention offer a new therapeutic option for the treatment of hypertension, high pulmonary pressure, myocardial infarction, chronic heart failure, angina pectoris, arrhythmia, acute/chronic renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis , endotoxic shock, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostatic hyperplasia, kidney failure, i.e. hypertension caused by ischemia and intoxication, metastasis and growth of mesenchymal tumors, kidney failure induced by a contrast agent, pancreatitis, gastrointestinal ulcers.

In some cases, the compounds according to the invention surprisingly also show antagonistic activity towards the neurokinin receptor.

This particularly applies to compounds of formula I in which R1 represents

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The invention further relates to combinations containing endothelin receptor antagonists of formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and, in particular, inhibitors of the enzyme that converts angiotensin (ACE) (e. Angiotensin-Converting-Enzyme).

The invention further relates to a combination of products containing β and the above-mentioned endothelin receptor antagonists, and those containing mixed ACE-neutral endopeptidase (NEP) inhibitors and the above-mentioned endothelin receptor antagonists.

The combined preparation can be given in the form of a single pharmaceutical dose or in separate formulations. The application can be simultaneous or gradual.

The dosage of the combination can in any case go up to the maximum amount of a single dose. However, lower doses than in the individual therapy concerned may also be administered.

These combined preparations are particularly suitable for the treatment and prevention of hypertension and its consequences, and for the treatment of heart failure.

The good performance of compounds can be demonstrated by means of the following tests:

Study of receptor binding

Cloned CHO cells amplifying the human ETA or ETB receptor were used for binding studies.

Preparation of membranes

CHO cells expressing the ETA or ETB receptor were grown in DMEM NUT MIX F12 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/ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated for 5 minutes at 37°C with PBS containing 0.05% trypsin. After that, they were neutralized with medium and collected by centrifugation at 300 x g.

To prepare the membranes, cells were adjusted to a concentration of 108 cells/ml buffer (50 ml tris HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/power constant 20).

Binding tests

To test the binding of ETA and ETB receptors, membranes were suspended in incubation buffer (50 mM Tris HCl, pH 7.4 with 5 mM MnCl2, 40 mg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per test well. mixture and incubated at 25°C with 25 pM 125J-ET1 (ETA-receptor assay) or 25 pM 125J-ET3 (ETB-receptor assay) in the presence or absence of the test substance. Nonspecific binding was determined with 10-7 M ET1. After 30 min, free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway) and the filters were washed with ice-cold Tris HCl buffer, pH 7.4 for s 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Testing of ET-antagonists in vivo

Male SD rats, weighing 250-300 g, were anesthetized with amobarbital, connected to artificial respiration, vagotomized and de-spinalized. The carotid artery and jugular vein were catheterized.

In the group of control animals, intravenous administration of 1 μg/kg ET1 led to a clear increase in blood pressure, which was maintained for a relatively long time.

Experimental animals, 30 minutes before the administration of ET1, were injected with the test compounds i.v. (1 mg/kg). To determine the ET-antagonistic properties, the increase in blood pressure of experimental animals was compared with that of control animals.

Oral testing of mixed ETA- and ETB-antagonists

Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g first received test substances orally. 80 minutes later the animals were anesthetized with urethane, and the carotid artery (for blood pressure measurement) as well as the jugular vein (big endothelin/endothelin 1 application) were catheterized.

After the stabilization phase, big endothelin (20 μg/kg, applied volume 0.5 ml/kg) or ET1 (0.3 μg/kg, applied volume 0.5 ml/kg) was administered intravenously. Blood pressure and heart rate were registered continuously for 30 minutes. Clear and persistent changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals that received the test substances was compared with the AUC of the control animals.

The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). The application can also be performed with vapors or sprays through the nasopharynx.

The dosage depends on the age, condition and weight of the patient, and on the method of application. As a rule, the daily dose of the active compound is from approximately 0.5 to 50 mg/kg of body weight for oral administration and from approximately 0.1 to 10 mg/kg of body weight for parenteral administration.

The novel compounds may be provided in conventional solid or liquid pharmaceutical forms, eg as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are produced in the usual way. For this purpose, active substances can be processed with common pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, softeners, wetting agents, dispersants, emulsifiers, solvents, slow-release agents active substances, antioxidants and/or propellants (cf. H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Application forms obtained in this way contain the active substance usually in an amount of 0.1 to 90 wt. %.

EXAMPLES OF SYNTHESIS

Example 1

Methyl 2-hydroxy-3-(2-(4-chlorophenyl)ethoxy)-3-phenyl-butyrate (diastereomer I, predominantly 2s,3r)

8 drops of boron trifluoride etherate are added to a mixture of 5 g (26 mmol) of methyl trans-2,3-epoxy-3-phenylbutyrate and 4.0 g (26 mmol) of 2-(4-chlorophenyl)ethanol at room temperature, and the mixture is stirred for 2.5 hours at 30-35°C (if necessary, chloroform can be used as a solvent). To complete the reaction, add another 3 drops of boron trifluoride etherate and then continue stirring for another 15 hours at 30-35°C. Then the mixture is taken up in ether and extracted three times with 2N NaOH, the organic phase is dried over MgSO4 and filtered and then the solvent is distilled off. Residue: 8.7 g of yellowish oil reacts immediately.

Example 2

2-Hydroxy-3-(2-(4-chlorophenyl)ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

8.7 g of methyl (2s,3r)-2-hydroxy-3-(2-(4-chlorophenyl)-ethoxy)-3-phenylbutyrate (crude product from example 1) is dissolved in 50 ml of dioxane and, after the addition of 75 ml of 1M NaOH, stir for 3 hours at room temperature. Then water is added to the mixture and the aqueous phase is extracted with ether. The aqueous phase is acidified with HCl and extracted with ethyl acetate, the organic phase is dried over magnesium sulfate. After removing the solvent by distillation, 7.0 g of oil was isolated and it was used immediately (mixture of siastereomers) (2s,3r/2s,3s 80:20).

Example 3

2-(4,6-dimethyl-2-pyrimidinyloxy)-3-(2-(4-chlorophenyl)-ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

0.28 g of NaH (9 mmol, 80% in white oil) was placed in 10 ml of DMF under nitrogen. 1 g of 2-hydroxy-3-(2-(4-chloro-phenyl)ethoxy)-3-phenylbutyric acid (crude product) from example 2 dissolved in 5 ml of DMF was added drop by drop, and after 10 minutes added se 640 mg of 2-chloro-4,6-dimethyl-pyrimidine. Then the mixture is stirred for 4 days. Water is added and then the pH is adjusted to 2 with 2N HCl. The aqueous phase is extracted with ether. The combined organic phases are shaken three times with 2N NaOH, and the organic phase is discarded. The alkaline phase is adjusted to pH 2 with 2N HCl and then extracted with ether. The combined organic phases are dried over MgSO4 and filtered, then the solvent is distilled off and the residue (1.1 g of yellow foam is purified by chromatography (methylene chloride/methanol 9:1). Two fractions: 187 mg of a mixture of two diastereomers (2s,3r/2s ,3s 84:16); 400 mg of a mixture of two diastereomers (2s,3r/2s,3s 75:25).

ESI-MS: M+ = 440

Example 4

Methyl 2-hydroxy-3-(2-(4-chlorophenyl)ethoxy)-3-phenylbutyrate (diastereomer II, predominantly 2s,3s)

8 drops of boron trifluoride etherate were added to a mixture of 5 g (26 mmol) of methyl cis 2,3-epoxy-3-phenylbutyrate and 4.0 g (26 mmol) of 2-(4-chlorophenyl)ethanol at room temperature, and the mixture is stirred for 2.5 hours at 30-35°C (chloroform can be used as a solvent if necessary). Then, to complete the reaction, add another 9 drops of boron trifluoride ether and continue mixing for 3 hours at 30-35°C. Then the mixture is taken up in ether and extracted three times with 2N NaOH, the organic phase is dried over MgSO4 and filtered and then the solvent is distilled off. Residue: 8.1 g of yellowish oil which immediately reacts further.

Example 5

2-hydroxy-3-(2-(4-chlorophenyl)ethoxy)-3-phenylbutyric acid (diastereomer II, predominantly 2s,3s)

8.1 g of methyl (2s,3r)-2-hydroxy-3-(2-(4-chlorophenyl)-ethoxy)-3-phenylbutyrate (crude product from example 1) is dissolved in 50 ml of dioxane and after the addition of 69 ml 1M NaOH, stirred for 4 hours at room temperature. Water is then added to the mixture and the aqueous phase is extracted with ether. The aqueous phase is acidified with HCl and extracted with ethyl acetate, and then the organic phase is dried over magnesium sulfate. After removing the solvent by distillation, 5.8 g of oil (diastereomeric mixture (2s,3s/2s,3r 87:13)) was isolated. This crude product was stirred overnight in a little diisopropyl ether. The precipitate obtained was filtered off and after removing the solvent (2 .3 g of a white solid, diastereomerically pure, mp 94-95°C), reacts further in example 6.

Example 6

2-(4,6-dimethyl-2-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)-ethoxy)-3-phenylbutyric acid (diastereomer II, predominantly 2s,3s)

0.28 g of NaH (9 inmol, 80% in white oil) was placed in 10 ml of DMF under nitrogen, and 1 g of 2-hydroxy-3-(2-(4-chlorophenyl)ethoxy) was added dropwise. -3-phenylbutyric acid (3 mmol from example 5) dissolved in 5 ml of DMF and after 10 minutes, 640 mg of 2-chloro-4,6-dimethylpyrimidine was added dropwise. The mixture is then stirred overnight at room temperature. Water is added to the mixture and the pH is adjusted to 2 with 2N HCl. The aqueous phase is extracted with ether. The combined organic phases are shaken three times with 2N NaOH, and the organic phase is discarded. The alkaline phase is adjusted to pH 2 with 2N HCl and then extracted with ether. The combined organic phases are dried over MgSO4 and filtered and then the solvent is distilled off and the residue

(1.25 g of yellowish foam) was stirred in diisopropyl ether

(1.1 g product, diastereomerically pure).

1H NMR (270 MHz, DMSO): 12.5-13.0 ppm (1H, br); 7.15-7.4 (9H, m); 6.85 (1H, 8); 5.15 (1H, s); 3.50-3.65 (1H, m); 3.2-3.4 (1H, m); 2.7-2.85 (2H, m), 2.25 (6H, e); 1.65 (3H, S).

ESI-MS: M+ = 440

The following compounds were produced analogously to the examples described above.

Example 7

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methyl-phenyl)ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1 H NMR (200 MH 2 , CDCl 3 ): 7.0-7.5 ppm (9 H, m); 6.25 (1H, 8); 5.3 (1H, 8); 3.9 (3 H, d); 3.65-3.8 (1H, m); 3.4-3.6 (1H, m); 2.8-3.0 (2H, m) 2.3 (3H, s), 1.8 (3H, m),

Example 8

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methyl-phenyl)ethoxy)-3-phenylbutyric acid (diastereomer II, predominantly 2s,3s)

1 H NMR (250 MHz, CDCl 3 ): 7.0-7.5 ppm (9 H, m); 6.1 (1 H, s); 5.5 (1 H, B); 3.9 (3 H, d); 3.65-3.8 (1H, m); 3.4-3.6

(1H, m); 2.8 3.0 (2H, m) 2.3 (3H, e), 2.2 (6H, s); 1.8 (3H, m),

Example 9

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)-ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (200 MH2, DMSO): 12-13.5 ppm (1H, br); 7.0-7.3 (9H, m); 6.8 (1H, s); 5.3 (1H, s); 3.4-3.7 (2H, m); 2.7-2.9 (2H, m); 2.25 (6H, B); 2.2 (3H, s); 1.7 (3H, s),

ESI-MS: M+ = 420

Example 10

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-phenylpropoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (200 MHZ, DMSO): 12-13.5 ppm (1H, bl); 7.1-7.4 (9H, m); 6.8 (1H, B); 5.3 (1H, s); 3.2-3.6 (2H, m); 2.5-2.7 (2H, m); 2.25 (6H, s); 1.7 (3H, s); 1.7-1.9 (2H, m),

ESI-MS: M+ = 420

Example 11

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(naphth-2-yl)-ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (250 MHz, DMSO): 12-13.5 ppm (1H, br); 7.7-7.9 (4H, m); 7.1-7.5 (8H, m); 6.9 (IH, s); 5.3 (1H, s); 3.6-3.8 (1H, m); 3.4-3.6 (IH, m); 2.9-3.1 (2H, m); 2.3 (6H, s);

1.7 (3H, s),

ESI-MS: M+ = 456

Example 12

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(4-chlorophenyl)-propoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (270 MHz, DMSO): 12.5-13.0 ppm (1H, br); 7.15-7.5 (9H, m); 6.9 (1H, s); 5.2 (1H, s); 3.3-3.5 (1H, m); 3.1-3.3 (1H, m); 2.55-2.7 (2H, m); 2.3 (6H, s); 1.7 (3H, s); 1.65-1.9 (2H, m),

ESI-MS: M+ = 454

Example 13

2-(4,6-dimethyl-2-pyrimidinyloxy)-3-(2-(4-fluorophenyl)-ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (200 MHz, DMSO): 12.0-13.0 ppm (1H, br); 7.0-7.4 (9H, m); 6.8 (1H, s); 5.2 (1H, s); 3.5-3.7 (1H, m); 3,3-

3.5 (1H, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s), ESI-MS: M+ = 424

Example 14

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-fluorophenyl)-ethoxy)-3-phenyl-butyric (diastereomer II, predominantly 2s,3s)

1H NMR (200 MHZ, DMSO): 12.5-13.0 ppm (1H, bl); 7.0-7.4 (9H, m); 6.B (1H, s); 5.1 (1H, s); 3.5-3.7 (1H, m); 3.2-3.4 (1H, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.65 (3H, s).

ESI-MS: M+ = 424

Example 15

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(9-methoxyphenyl)-ethoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

1H NMR (200 MH2, DMSO): 12.0-13.0 ppm (1H, br); 7.2-7.9 (5H, m); 7.1 (2H, d); 6.9 (1H, s); 6.75 (2H, d); 5.2 (1H, s); 3.7 (3H, s); 3.4-3.6 (1H, m); 3.2-3.4 (1H, m); 2.7-2.85 (2H, m); 2.3 (6H, s); 1.7 (3H, s).

ESI-MS: M+ = 436

Example 16

2-(4,6-Dimethyl-pyrimidin-2-yloxy)-3-(3-(4-methoxyphenyl)-propoxy)-3-phenylbutyric acid (diastereomer I, predominantly 2s,3r)

m.p.: 153-156°C

ESI-MS: M+ = 450

The compounds listed in Table 1 can be produced analogously or in the manner described in the general section.

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Example 17

Receptor binding data were measured using the binding assay described above for the compounds listed below.

The results are presented in Table 2.

Table 2. Data on receptor binding (Ki values)

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Claims (9)

1. Carboxylic acid derivative of formula I [image] indicated that the substituents have the following meanings: R1 represents a tetrazole or a group [image] where R has the following meanings: a) radical OR7 in which R7 represents: hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic ammonium ion, such as a tertiary C1-C4-alkylammonium or ammonium ion; C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, optionally substituted; C3-C6-alkenyl or C3-C6-alkynyl group, optionally substituted, or phenyl, optionally substituted; b) a five-membered heteroaromatic system connected through a nitrogen atom; c) group [image] where k can have the value 0, 1 and 2, p can be 1, 2, 3 and 4 and R8 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C6-alkynyl or optionally substituted phenyl; d) the radical of the formula [image] in which R9 is C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, whereby these radicals can carry a C1-C4-alkoxy, C1-C4-alkylthio and/or phenyl radical: phenyl, optionally substituted; e) group [image] in which R13 and R14 can be the same or different and have the following meanings: hydrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl, optionally substituted; or R13 and R14 together form a C4-C7-alkylene chain which is closed in a ring and may contain a heteroatom; R2 is hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio, or CR2 is linked to CR10 as shown below, to form a five- or six-membered ring; X is nitrogen or methine; Y is nitrogen or methine; Z is nitrogen or CR10, in which R10 represents hydrogen, halogen, hydroxy, C1-C4-haloalkyl or C1-C4-alkyl, or CR10 forms together with CR2 or with CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C1-C4-alkyl groups and in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or by N(C1-C4-alkyl); R3 is hydrogen, hydroxy, NH2, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -Hydroxyalkyl, C1-C4-haloalkyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, C1-C4-Alkylthio, or CR3 is linked to CR10 as stated above, thus giving a 5- or 6-membered ring; R 4 is C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl or C 2 -C 4 -alkynyl, which may be substituted; R5 is phenyl or naphthyl, optionally substituted; or phenyl or naphthyl which is linked in the ortho position to R4 via a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or a SO2-, NH- or N-alkyl group; or C3-C8-cycloalkyl, optionally substituted; R 6 is optionally substituted C 3 -C 8 -cycloalkyl; phenyl or naphthyl, each of which may carry one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3 -C6-Alkenyloxy, C1-C4-Haloalkyl, C3-C6-Alkynyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, Phenoxy, C1-C4-Alkylthio, NH (C1-C4-alkyl), N (C1-C4-alkyl)2, dioxomethylene, dioxoethylen, or phenyl, which may be mono- or polysubstituted, for example mono- to tri-substituted with halogen, nitro, cyano, C1-C4-alkyl , C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy or C1-C4-alkylthio, provided that if R6 represents an unsubstituted phenyl radical, then R2 and R3 cannot simultaneously be OCH3; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, and which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C2-C4- alkenyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl radicals can carry one to five halogen atoms and/or one to three the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy and/or C1-C4-alkylthio; R15 is C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which can carry one or more of the following radicals: hydroxy, carboxy, amino, NH (C1-C4-alkyl), N (C1-C4- alkyl)2, carboxamide or CON(C1-C4-alkyl)2; W is sulfur or oxygen; Q is a spacer group that corresponds to the length of the chain that has C2-C4 atoms, and physiologically tolerable salts, and enantiomerically pure and diastereomerically pure forms. 2. Pharmaceutical preparation for oral, parenteral or intraperitoneal use, characterized in that, in addition to the usual pharmaceutical excipients, it contains at least one carboxylic acid derivative according to claim 1. 3. Use of carboxylic acid derivatives I according to claim 1, characterized in that they are used for the treatment of diseases. 4. Use of compound I according to claim 1, characterized in that it is used as an endothelin receptor antagonist. 5. Use of carboxylic acid derivative I according to claim 1, characterized in that it is used for the production of drugs or for the treatment of diseases in which an elevated level of endothelin occurs. 6. Use of carboxylic acid derivative I according to claim 1, characterized in that it is used for the treatment of chronic heart failure, myocardial infarction, atherosclerosis, arrhythmias, angina pectoris, restenosis, high blood pressure, high pulmonary pressure, acute/chronic kidney failure, kidney failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. 7. Use of carboxylic acid derivative I according to claim 1, characterized in that it is used in combination with renin-angiotensin system inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, β-blockers. 8. Use of compounds of formula IV [image] in which the radicals R1, R4, R5, R6, Q and W have the meaning stated in claim 1, indicated that they are used as starting material for the synthesis of ETA/ETB receptor antagonists. 9. Structural fragment of the formula [image] in which the radicals R1, R4, R5, R6, Q and W have the meaning specified in claim 1, indicated that it is a structural element in mixed ETA/ETB receptor antagonists.