HRP970503A2 - Novel carboxylic acid derivatives, their production and their use as mixed eta/etb receptor antagonists - Google Patents

Description

The proposed invention relates to new carboxylic acid derivatives, their production 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. Hereinafter, one or all of the isomeric forms of endothelin are referred to as "endothelin" or "ET". 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, 868-875, 1988 ).

Elevated or abnormal release of endothelin causes permanent vasoconstriction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As is known from the literature, endothelin is involved in a number of diseases. These include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic 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 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996)).

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

In WO 96/11914, carboxylic acid derivatives are described, which bind to the ETA-receptor with high affinity, and bind to the ETB-receptor with significantly lower affinity (so-called ETA-specific antagonists).

"ETA-specific" antagonists are defined here as such antagonists whose affinity for the ETA-receptor is at least twenty times higher than its affinity for the ETB-receptor.

There was a need for the preparation of endothelin receptor antagonists, which bind to ETA- and ETB-receptor with approximately equal affinity (so-called mixed antagonists).

Approximately equal receptor affinity exists if the ETB:ETB affinity quotient is greater than 0.1 and less than 20, preferably less than 10.

The subject of the invention are derivatives of carboxylic acids of formula I

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where

R1 represents a tetrazole or a group

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where R has the following meaning:

a) residue OR7, where R7 has the following meaning:

hydrogen, alkali metal cation, alkaline earth metal cation, physiologically tolerable organic ammonium ion, such as 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 substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4 -Alkoxy, mercapto, C1-C4-alkylthio, amino, carboxy, NH (C1-C4-alkyl), N (C1-C4-alkyl)2;

C3-C6-alkenyl or C3-C6-alkynyl group, whereby this group can carry one to five halogen atoms;

R7 can further 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-alkylthiophene amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;

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

c) group

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where

k has the value 0, 1 and 2,

p has the value 1, 2, 3 and 4, a

R8 represents C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl, which may be substituted with one or more, for example with one to three of the following residues: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, carboxy, NH (C1-C4-alkyl) , N (C1-C4-alkyl ) 2;

d) the remainder

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in which

R9 represents C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, C1-C4-haloalkyl, whereby these residues can carry C1-C4-alkoxy C1-C4-alkylthio and/ or a phenyl radical as under c);

phenyl, optionally substituted, especially as previously stated,

e) R1 can also be

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where

R13 and R14 can be the same or different and have the following meaning:

hydrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl, which may bear one to three of the following residues: 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-alkyl chain which is closed in a ring, which is substituted with C1-C4-alkyl and in which one alkylene group can be replaced by -(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 represents hydrogen, hydroxy, 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 the group CR2 together with CR10, as indicated below, is connected in a five- or six-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two C1-C4-alkyl groups and where one or more methylene groups may be substituted with oxygen, sulfur, -NH or N (C1-C4-alkyl) 2 ;

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 together with CR10 as mentioned above, connected in a five- or six-membered ring;

R4 and R5 (which can be the same or different) represent:

phenyl or naphthyl, 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-haloalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or phenyl which may be mono- or multi-substituted, eg mono- to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenal alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or

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

C3-C8-cycloalkyl;

R6 represents C3-C8-cycloalkyl, whereby these residues can be mono- or multi-substituted with halogen hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2- ( C1-C4-alkyl),

N (C1-C4-alkyl) 2 or with phenyl which can be mono- or multi-substituted, e.g. mono- to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halo-alkyl, C1-C4-alkoxy , C1-C4-halogenalkoxy or C1-C4-alkylthio;

phenyl or naphthyl, which may be substituted with one or more of the following residues: 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 substituted, e.g. singly to triply with halogen nitro, cyano, C1-C4-alkyl, C1- C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

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

R15 is C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which can carry one of the following residues: 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, which corresponds to the length of the C2-C4 chain. The function of the group Q in the compounds of formula I is to create a defined distance between the groups R6 and W. The distance must correspond to the length of the C2-C4-alkyl chain. This can be achieved with a variety of chemical residues, for example with C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, -N-CO -CH2-O-, whereby these residues can be singly or multiply 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-Haloalkyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C3-C8- Alkylcarbonylalkyl, NH (C1-C4 -alkyl), N (C1-C4-alkyl) 2, phenyl which can be single or multiple substituted, e.g. single to triple with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halo-alkyl, C1- C4-Alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio.

Or, the spacer group Q represents part of a five- to seven-membered, hetero- or carbocyclic ring, which is fused to R 6 .

The following definitions apply below:

An alkali metal is, for example, lithium, sodium, potassium.

Alkaline earth metal is, for example, calcium, magnesium, barium.

C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C1-C4-haloalkyl can be linear or branched, such as 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-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, 1-propen-2-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-hydroxyether-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 can 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 pentyl, hexyl, heptyl or oxytyl.

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).

Preference is given to such prodrugs in which the release takes place under such conditions as those prevailing in certain parts of the body, eg in the stomach, intestines, blood stream, liver.

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

The subject of the invention is "further 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 according to the invention are particularly suitable as mixed antagonists, as defined in the introduction.

The production of compounds of the general formula IV, in which Z represents sulfur or oxygen, can be carried out - also in enantiomerically pure form - as described in WO 96/11914.

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Compounds of general formula III are known or can be synthesized, for example, by reduction of the corresponding carboxylic acids, i.e. their esters, or also by some other generally known method.

Derivatives of carboxylic acids of general formula IV can be prepared by reacting a compound of formula IVa with an alcohol or thiol of formula VII under acid catalyzed conditions.

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The listed residues have the following meanings:

R 1 has the meaning given for the general formula I;

R16 and R17, which may be the same or different, represent hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which may be substituted if necessary,

R18 represents hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,

R19 represents hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,

The following meanings of the rests are:

R1 is COOR7;

R16 and R17, which can be the same or different, represent alkyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,

R18 represents alkyl, phenyl, cycloalkyl, which can be substituted if necessary,

R19 represents alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, which can be substituted if necessary,

The special meanings of the rests are as follows:

R1 is COOR7;

R 16 is R 4 ;

R17 is R5;

R18 is alkyl, optionally substituted, especially methyl,

R19 is Q.

Derivatives of carboxylic acids of the general formula IV can be produced by a process in which a compound of the formula IVa is reacted with an alcohol or a thiol of the formula III under conditions of acid catalysis

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For this purpose, compounds IVa and III are mixed as substances or mixed in a solvent inert for this reaction and a catalytic amount of an acid, for example p-toluenesulfonic acid, is added. Examples of inert solvents are methylene chloride, benzene or toluene. Also suitable are such inert solvents that form a 1 fi azeotropic mixture with alcohol R18OH. In the case of methanol (R18 = CH3) these are, for example, chloroform or acetic acid methyl ester.

The reaction mixture is then stirred at a temperature between room temperature and the boiling point of the solvent. The resulting i-p alcohol R18OH is distilled off or removed using a vacuum. This method is suitable for the production of enantiomerically pure compounds IV if starting from enantiomerically pure compounds IVa.

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

Compounds according to the invention, in which the substituents have the meanings specified for the general formula I, can be produced, for example, by reacting the carboxylic acid derivative of the general formula IV, in which the substituents have the specified meanings, with the compound of the general formula V.

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In formula V, R11 represents halogen or R12-SO2-, where R12 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. Furthermore, at least one of the ring members, X or Y or Z, is nitrogen. The reaction takes place primarily in an inert solution or diluent with the addition of a suitable base, i.e. of bases that support the deprotonation of intermediate products, in the temperature range from room temperature to the boiling point of the solvent.

Compounds of type I with R1 = COOH can also be obtained directly if the intermediate IV, in which R1 is COOH, is deprotonated with two equivalents of the appropriate base and the compounds of the general formula V are reacted. The reaction also takes place in an inert solvent and in the temperature range from room temperature to the boiling point of the solvent.

Examples of such solvents, i.e. diluents, are aliphatic, alicyclic and aromatic hydrocarbons, which can be chlorinated if necessary, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethylene 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-methyl-pyrrolidone, sulfoxides and sulfones, such as dimethylsulfoxide and sulfolane.

Compounds of formula V are known, are partially commercially available or can be produced by generally known methods.

Alkaline or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, carbonate such as alkali carbonate, e.g. sodium or potassium carbonate, alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, organometallic compound such as butyl can serve as a base. -lithium or alkali amide, such as lithium diisopropylamide or lithium amide.

Compounds of formula I can also be produced by dividing them 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 imidazole, and they are then chemically converted with the corresponding hydroxyl compound HOR7. This conversion can be carried out in common solvents and often requires the addition of a base, where the above come into play. Both steps can also be simplified by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water releasing agent such as carbodiimide.

In addition, the compounds of formula I can also be prepared by dividing them from the salts of the corresponding carboxylic acids, i.e. compounds of formula I in which R represents the group COR and R is OM, where M can be an alkali metal cation or an equivalent of an earth cation. alkali metal. These salts can be reacted with many compounds of the formula R-A, where A represents a common nucleophilic starting group, for example halogen, such as chlorine, bromine, iodine, or, if necessary, halogen, alkyl or haloalkyl substituted aryl or alkyl sulfonyl, such as e.g. toluenesulfonyl and methylsulfonyl or some other equivalent starting group. Compounds of the formula R-A with substituents A, capable of reaction, are known or can be easily obtained on the basis of general expert knowledge. This conversion can be carried out in common solvents and is carried out primarily with the addition of a base, whereby the above mentioned are taken into account.

In some cases, for the production of compounds I according to the invention, generally known methods of protecting groups should be applied. If, for example, R6 represents a 4-hydroxyphenyl group, then the hydroxy group should first be protected as a benzyl ether, which is then cleaved off in a suitable reaction step.

Compounds of formula I, in which R 1 represents a tetrazole, can be prepared as described in WO/11914.

As far as biological action is concerned, preference is given to derivatives of carboxylic acids of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures -, in which the substituents have the following meaning:

R 2 represents 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 -Haloalkyl, or is CR 2 together with CR10, as indicated below, linked in a five- or six-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or with CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two methyl groups and where the methylene group can be substituted with oxygen or with sulfur, as -CH2-CH2-O-, -CH2-CH2-CH2-O-,

-CH=CH-O-, -CH=CH-CH2-O-, -CH (CH3) -CH (CH3) -O-,

-CH=C(CH3)-O-, -C(CH3)=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 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 -haloalkyloxy or is CR 3 together with CR10, as above, linked in a five- or six-membered ring;

R4 and R5 (which can be the same or different) represent:

phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, nitro, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-halogenoalkyl, carboxy, C1-C4-alkoxy, C1-C4 -halogenalkoxy, phenoxy, C1-C4-alkylthio, NH (C1-C4-alkyl) or N (C1-C4-alkyl) 2 or phenyl, which can be mono- or multi-substituted, e.g. mono to tri-substituted, with halogen nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or with C1-C4-alkylthio; or

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

C3-C8-cycloalkyl;

R6 represents C3-C8-cycloalkyl, whereby these residues can be mono- or multi-substituted with halogen hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2- C4-Alkynel, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxy-carbonyl, NH (C1-C4-Alkyl) , N (C1-C4-alkyl) 2 or phenyl, which can be mono- or multi-substituted, e.g. mono- to tri-substituted, with nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy , C1-C4-halogenalkoxy or C1-C4-alkylthio;

phenyl or naphthyl, which may be substituted with one or more of the following residues: 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 substituted, e.g. singly to triply with halogenated nitro, cyano, C1-C4-alkyl, C1 -C4-halogenal alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio;

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

R15 is methyl, ethyl, methoxy or ethoxy, bearing one of the following residues: 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 C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, where these residues can be mono- or multi-substituted with halogen, hydroxy . C1-C4-alkyl) 2 or with phenyl, which can be singly or multiply substituted, e.g. singly to triply with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1 -C4-halogenalkoxy or C1-C4-alkylthio; or

Q together with R6 forms the following ring systems: indan-2-yl, indan-3-yl, 1,2,3,4-tetrahydro naphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl, wherein the phenyl ring 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-halogenalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, amino, NH (C1-C4-alkyl),N(C1-C4-alkyl) 2 or with phenyl.

Particularly preferred compounds of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures - are those in which the substituents have the following meanings:

R 2 represents trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 2 together with CR 10 , as indicated below, is connected in a five- or six-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or with CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two methyl groups and where the methylene group can be substituted with oxygen or with sulfur, as -CH2-CH2-O-,

-CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2O-,

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

-C(CH3) = (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 3 together with CR 10 , as mentioned above, is connected in a five-membered or six-membered ring;

R4 and R5 (which may be the same or different) represent;

phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, nitro, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy, C1-C4-haloalkyloxy . -C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or

phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or one SO2-, NH- or N-alkyl group;

C5-C7-cycloalkyl;

R6 represents C5-C7-cycloalkyl, whereby these residues can be mono- or multi-substituted with C1-C4-alkoxy, C1-C4-alkyl, C1-C4-alkylthio, halogen hydroxy, carboxy, cyano, trifluoromethyl, acetyl or phenyl, which may be mono- or multi-substituted, for example mono- to tri-substituted with halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-halogenoalkyl, acetyl, C1-C4-alkoxycarbonyl . mono- or multi-substituted, eg mono to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;

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

R15 is methoxy or ethoxy, which can carry one of the following residues: 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 C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, where these residues can be mono- or multi-substituted with halogen, hydroxy , mercapto, carboxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or phenyl, which may be singly or multiply substituted, e.g. singly to triply with halogen, nitro, cyano, C1-C4-alkyl , C1-C4-halo-alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or

Q together with R6 forms the following ring system: indan-2-yl, indan-3-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl, at where the phenyl ring may 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-alkylcarbonyl, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or with phenyl.

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

The compounds according to the invention show a surprising, occasionally also antagonistic action against the neurokinin receptor.

This is particularly the case with compounds of formula I in which R1 represents

[image]

A further subject of the invention are combined preparations of 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, above all, angiotensin-converting enzyme (AGE)-inhibitors.

A further subject of the invention are combined preparations from β-blockers and the above-mentioned endothelin-receptor antagonists, as well as mixed ACE-neutral (NEP) endopeptidase inhibitors and the above-mentioned endothelin-receptor antagonists.

Combined preparations can be given in a single galenic form or also in spatially separate forms. Administration can be done simultaneously or time-graded.

In the case of a combination, the dosage can go up to the highest amount of the individual dose in question. However, lower doses can also be administered than with the individual therapy concerned.

These combined preparations are suitable above all for the treatment and suppression of hypertension and diseases resulting from it, and for the treatment of heart failure.

The good performance of the compounds can be demonstrated in the following experiments:

Study of receptor binding

Cloned CHO cells expressing the ETA- or ETB-receptor are used for binding studies.

Preparation of membranes

CHO cells expressing the ETA- or ETB-receptor were propagated 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 are washed with PBS and incubated for 5 minutes with PBS containing 0.05% trypsin. After that, they are neutralized with the medium and the cells are harvested by centrifugation at 300 x g.

To prepare the membranes, cells are 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/constant/power 20).

Binding tests

To test the binding of ETA- and ETB-receptors, membranes are suspended in 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 protein per test mixture and are incubated at 25°C with 25 pM 125J-ET1 (ETA-receptor assay) or 25 pM 125J-RZ3 (ETB-receptor assay) in the presence and absence of the test substance. Non-specific binding is determined by 10-7 M ET1. After 30 minutes, free and bound radioligand are separated by filtration through a GF/B glass fiber filter (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway) and the filter is washed with ice-cold Tris-HCl buffer, pH 7.4 with 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 a group of control animals, intravenous administration of 1 µg/kg ET1 led to a clear increase in blood pressure, which was sustained over a longer period of 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.

per. - testing of mixed ETA- and ETB-antagonists:

Male normotensive rats weighing 250-350 g (Sprague Dawley, Janvier) were first orally administered the test substances. 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, apl. vol. 0.5 ml/kg) or ET1 (0.3 µg/kg, apl. vol. 0.5 ml/kg) was given 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 control animals.

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

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 substance is between 0.5 and 50 mg/kg of body weight for oral administration and between 0.1 and 10 mg/kg of body weight for parenteral administration.

The new compounds can be administered in usable solid or liquid galenic application forms, eg as tablets, film-coated tablets, capsules, powder, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are prepared in the usual way. In doing so, the active substances can be processed with the usual galenic auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, softeners, cross-linking agents, dispersing agents, emulsifiers, solvents, extended-release agents. active substances, antioxidants and/or propellant gases (compare 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

2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid methyl ester

7 g (27.5 mmol) of methyl ester of 3,3-epoxypropionic acid and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)-ethanol are dissolved in 20 ml of dichloromethane and added at room temperature 5 drops of boron trifluoride etherate. The solution is stirred for two hours. The solvent is then distilled off and the residue (10.7 g, 89%) is converted directly further.

Example 2

2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3, 3-diphenyl-propionic acid

12 g (27.5 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid methyl ester are dissolved in 110 ml of dioxane and mixed with 55 ml of 1N with NaOH solution. The mixture is stirred for two hours at 80°C. Water is added to the mixture and the aqueous phase is extracted twice with ether. The aqueous phase is acidified with 1N aqueous acetic acid, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled off. The residue was recrystallized from ether/n-hexane and 10.2 g (87%) of colorless crystals could be isolated.

Melting point: 133-135°C.

Example 3

2-(4-Methoxy-6-methyl)-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-482)

1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic acid is placed in 10 ml of DMF and 340 mg of NaH (50 % suspension). After stirring for 15 minutes, the mixture was mixed with 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and stirred for three hours at room temperature. The mixture was mixed with water and the reaction mixture was extracted with ether. The aqueous phase is acidified with 1N aqueous HCl, 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 a colorless powder is isolated.

1H-NMR (200 MHz): 7.2 ppm (10 H, m); 6, 8 (3H, m); 6.2 (1H, s); 6.18 (1H, s); 3.9 (9H, m); 3.8 (1H, m); 3.7 (1H, m); 2.85 (2H, tr); 2.2 (3H, s) .

ESI-MS: M+ = 544

Example 4

3,3-di(4-ethylphenyl)-2,3-epoxypropionic acid methyl ester

A solution of 15 ml (168 mmol) methyl ester of chloroacetic acid and 20 g (84 mmol) of 4,4'- of diethylbenzophenone in 20 ml of THF. The mixture is stirred for 2 hours at room temperature. The mixture is then transferred to water and extracted with ether. The organic phase is washed with sodium hydrogen carbonate solution and citric acid solution, dried over magnesium sulfate and the solvent is distilled off. 15.4 g of crude oil can be isolated, which is directly used further.

Example 5

2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid methyl ester

6 g (19.3 mmol) methyl ester of 3,3-di(4-ethylphenyl)-2,3-epoxypropionic acid (crude) and 3.52 g (19.3 mmol) 2-(3,4-dimethoxyphenyl) of ethanol is dissolved in 20 ml of dichloromethane and 5 drops of boron trifluoride ether are added at room temperature. The solution is stirred for 1.5 hours. The solvent is then distilled off and the residue, a pale yellow oil (8.66 g, 91%) is directly further chemically converted.

Example 6

2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid

9.2 g (19.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid methyl ester were dissolved in 26 ml of dioxane and it is mixed with 13 ml of 3N NaOH solution. The mixture is stirred for 3 hours at 60°C. Water is added to the reaction mixture and the aqueous phase is extracted twice with ether. The aqueous phase is acidified with 1N aqueous HCl and extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled off. 6.5 g (71%) of a yellowish oil is isolated, which is directly further chemically converted.

Example 7

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3, 4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid (I- 116)

1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid is placed in 20 ml of DMF- and 554 mg of NaH (50% suspension) is added. After stirring for 15 minutes, the mixture was mixed with 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonyl-pyrimidine and stirred for 3 hours at room temperature. The mixture is mixed with water and extracted with ether. The aqueous phase is acidified with 1N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent is distilled off and after recrystallization from ether/n-hexane, 540 mg (23%) of a colorless powder is isolated.

1H-NMR (200 MHz): 7.0-7.4 ppm (10 H, m); 6.8 (2H, d); 6.2 (1H, s); 6.15 (1H, s); 3.9 (3H, s); 3.8 (3H, s); 3.7 (1H, m); 3.5 (1H, m); 2.9 (2H, tr) ; 2.6 (4H, m); 2.3 (3H, s); 1.2 (6H, m).

ESI-MS: M+ = 600

Example 8

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-phenylprop-(2E)-enoxy)-3,3-diphenylpropionic acid (I-27)

To a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF was added 1.12 g (3 mmol) of 2-hydroxy-3-(3-phenylprop-(2E)-enoxy)-3,3 -diphenylpropionic acid and mixed for 10 minutes at room temperature. After the addition of 614 mg (3.3 mmol) of 4, 6-dimethyl-1-methyl-sulfonylpyrimidine, it is stirred for 16 hours, then diluted with 200 ml of water, acidified with 1N hydrochloric acid and extracted with ether. The ether phase is extracted with 1N sodium hydroxide solution, the aqueous phase is acidified again and the product is extracted with ether. The organic phase is dried over magnesium sulfate, filtered and the solvent is distilled off. The residue was recrystallized from ether/hexane and 927 mg (65%) of the crystalline product was isolated.

Melting point: 128-133°C.

1H-NMR (200 MHz): 7.3 ppm (15 H, m); 6.74 (1H, s); 6.7 (1H, d); 6.3 (1H, s); 6.2 (1H, dtr) ; 4.3 (1H, dd) ; 4.1 (1H, dd); 2.3 (6H, 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. 12 ml (128 mmol) of dimethyl sulfate was added dropwise to this mixture at room temperature for 10 minutes. After one hour, the aqueous phase is extracted three times with ether, dried over magnesium sulfate and the solvent is distilled off. 15.9 g (97%) of crude product can be isolated.

1H-NMR (270 MHz): 6.7 (1H, s); 2.5 (3H, s); 2.3 (6H, s).

Example 10

4, 6-dimethyl-1-methylsulfonyl-pyrimidine

15.9 g (103 mmol) of 4,6-dimethyl-1-methylthio-pyrimidine are placed in 120 ml of dichloromethane and 110 ml of water. At 0°C, gaseous chlorine is introduced until saturation (yellow coloration). After complete chemical conversion, chlorine is expelled with nitrogen, the aqueous phase is extracted with dichloromethane and the collected organic phase is dried over magnesium sulfate. The solution is concentrated and the product is crystallized by adding ether (14.0 g, 73%).

Melting point: 79-80°C.

1H-NMR (270 MHz): 7.2 ppm (1H, s); 3.4 (3H, s); 2.6 (6H, s) .

Example 11

(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester

54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with 10.8 g (200 mmol) of sodium methylate are added to 300 ml of DMF. 21 ml (210 mmol) of dimethyl sulfate are added dropwise to this suspension over 15 minutes, during which the temperature rises to 50°C and the suspension becomes low-viscosity. The mixture is stirred overnight and then poured over 1.5 l of water and ice. The aqueous phase is extracted twice with 500 ml of ether and the ether phase is washed again twice with 200 ml of water. The organic phase is dried over magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. 55.8 g of oil is isolated, which is further processed directly.

Example 12

(S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid methyl ester

Version A:

In a flask, 27.9 g of (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid methyl ester (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 connected to the flask to distill off the resulting methanol and it is stirred for another 5 hours at 60°C. For processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is first washed with sodium hydrogen carbonate solution and then several times with water. It is then dried with magnesium sulfate, the solvent is filtered off and the solvent is distilled off. A residue of 43 g of oil is isolated, which can be used directly in the next synthesis.

Version B:

27.9 g of methyl ester (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid (100 mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) are dissolved in the flask. of 2-(3,4-dimethoxyphenyl)ethanol in 75 ml of dichloromethane. The solution is heated and dichloromethane is distilled off while dichloromethane is added dropwise to distill off the resulting methanol and it is stirred for another 5 hours at 60°C. For processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is first washed with sodium hydrogen carbonate solution and then several times with water. It is then dried with magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. A residue of 43 g of oil is isolated, which can be used directly in the next synthesis.

Example 13

(S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid

To a solution of 74 g (170 mmol) methyl ester (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid in 510 ml of dioxane, add 255 ml 1N sodium hydroxide solution and the suspension is stirred for two hours at 50°C. The mixture is diluted with 2.5 l of water and neutralized with citric acid. The aqueous phases are extracted twice with 500 ml of ether. Then the aqueous phase is washed with water, dried over magnesium sulfate and after filtration the ether is distilled off. The residue was purified by crystallization from ether/n-hexane and 70 g of crystals were isolated.

1H-NMR (200 MHz): 7.3 ppm, (10H, m); 6.8 (1H, dbr) ; 6.7 (1H, dbr); 6.6 (1H, sbr) ; 5.0 (1H, s); 3.9 (3H, s); 3.85 (3H, s); 3.6 (1H, dt) ; 3.4 (1H, OH) ; 3.2 (1H, dt) ; 2.8 (2H, t) .

[α]20 - 8.3 (1; ethanol) .

Example 14

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-445) and

(S)-2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-445 (S)-enantiomers )

55 g (130 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl- of propionic acid, dissolved in 150 ml of DMF. To this, 25 g (137 mmol) of 2-methylsulfone-4,6-dimethylpyrimidine dissolved in 75 ml of DMF were slowly added dropwise and stirred for 18 hours at room temperature. For processing, the mixture is poured over 2 liters of ice water and citric acid is added for neutralization. The secreted crystals are sucked off and washed with water. Wet crystals are dissolved in dichloromethane, the solution is dried over magnesium sulfate, filtered and the solvent is distilled off. The oily residue is taken up in ether, extracted with 130 ml of 1 N sodium hydroxide solution and the aqueous phase is neutralized with 130 ml of 1 N hydrochloric acid, during which crystals are separated. After drying, 64 g of the product is isolated.

1H-NMR (200 MHz): 7.3 ppm, (10H, m); 6.7 (4H, m); (6.3 (1H, s); 3.9 (3H, s); 3.85 (3H, s); 3.7 (1H, dt) ; 3.6 (1H, dt) ; 2.8 ( 2H, t); 2.3 (6H, s).

Melting point: 125-130°C (approx.).

ESI-MS: M+ = 528

Analogously, (S)-2-hydroxy-3-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid and 2-methyl-sulfone-4,6-dimethylpyrimidine in the presence of lithium amide was produced (S )-2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid.

[α]20 = 111 (1; ethanol) .

Example 15

The following compounds were produced analogously to example 8.

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid (I-147) Melting point: 150-155°C

ESI-MS: M+ = 570

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I- 651) Melting point: 150-152°C

ESI-MS: M+ = 546

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I-713)

Melting point: 108°C (dec.)

ESI-MS: M+ = 502

2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid

Melting point: 165-167°C

ESI-MS: M+ = 534

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I-746)

Melting point: 93-98°C

ESI-MS: M+ = 518

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid (I-148)

Melting point: 130-133°C

ESI-MS: M+ = 554

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (I-710)

Melting point: 90-100°C

ESI-MS: M+ = 566

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(chlorophenyl)propionic acid

1H-NMR (200 MHz): 7.3 ppm, (18H, m); 6.25 (1H, s); 6.0 (1H, s); 4.0 (1H, tr) ; 3.8 (3H, s); 3.4 (2H, m); 2.2 (5H, m). ESI-MS: M+ = 642

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (1-699) Melting point: 100-110°C

ESI-MS: M+ - 612

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (I-487)

Melting point: 85-90°C

ESI-MS: M+ = 582

2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(chlorophenyl)- propionic acid (I-486)

Melting point: 190-195°C

ESI-MS: M+ = 610

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-phenylethylthio)-3,3-di(chlorophenyl)propionic acid

Melting point: 173-175°C

1H-NMR (200 MHz): 7.0-7.4 ppm, (13H, m); 6.0 (1H, s); 4.7 (2H, tr); 3.8 (3H, s); 3.1 (2H, tr); 2.5 (4H, m).

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(chlorophenyl )-propionic acid (I-635)

Melting point: 100-110°C

ESI-MS: M+ = 640

2-(4-Methoxy-5,6-dihydrofuro-(2, 3d)-pyrimidin-2-yl-oxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3, 3-di(chlorophenyl ) propionic acid (I-593)

Melting point: 90-100°C

ESI-MS: M+ = 640

2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl )-propionic acid (I-164)

Melting point: 135-145°C

ESI-MS: M+ = 610

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)-propionic acid Melting point: 125-127°C

ESI-MS: M+ = 670

2-(4-Methoxy-5,6-dihydrofuro-5H-cyclopentylpyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)-propionic acid

Melting point: 135-140°C

ESI-MS: M+ = 668

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-phenylethylthio)-3, 3-di(4-chlorophenyl)propionic acid

Melting point: 135-140°C

1H-NMR (200 MHz): 7.0-7.5 ppm, (13H, m); 5.9 (1H, s); 3.9 (3H, s); 2.6-2.8 (8H, m); 2.1 (2H, m).

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)-propionic acid

Melting point: 105-115°C

ESI-MS: M+ = 608

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3-methoxyphenyl)ethoxy)-3, 3-di(4-chlorophenyl)-propionic acid

Melting point: 110-120°C

ESI-MS: M* = 608

2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(4-dimethylaminophenyl)ethoxy)-3,3-di(4-chlorophenyl) propionic acid

Melting point: 135-140°C

ESI-MS: M+ = 621

2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)- propionic acid

Melting point: 125-130°C

ESI-MS: M+ = 638

2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)- propionic acid

Melting point: 125-130°C

ESI-MS: M+ - 638

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid (1- 370)

Melting point: 128-130°C

ESI-MS: M+ = 526

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-phenyl-ethoxy)-3,3-diphenylpropionic acid (I-719)

Melting point: 155°C (exp.)

ESI-MS: M+ = 484

2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-phenyl-ethoxy)-3,3-diphenylpropionic acid

Melting point: 203°C (dec.)

ESI-MS: M+ = 500

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic acid (I-720)

Melting point: 130-133°C

ESI-MS: M+ = 468

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic acid (I-657)

Melting point: 138-142°C

ESI-MS: M+ = 512

2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid

Melting point: 155-158°C

ESI-MS: M+ = 514

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid (I-465)

Melting point: 145-147°C

ESI-MS: M+ = 498

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-554)

Melting point: 160-165°C

ESI-MS: M+ = 528

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)propoxy)-3,3-diphenylpropionic acid (I-555)

Melting point: 165-170°C

ESI-MS: M+ = 512

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-335)

1H-NMR (200 MHz): 7.2-7.4 ppm, (10H, m); 6.3 (2H, s); 6.2 (2H, s); 3.8 (1H, s); 3.75 (10H, s); 3.4 (2H, m); 2.6 (2H, m); 2.25 (3H, s); 1.9 (2H, m).

ESI-MS: M+ = 588

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-336)

1H-NMR (200 MHz): 7.2-7.5 ppm, (10H, m); 6.6 (IH, s); 6.3 (3H, s); 3.8 (9H, s); 3.4 (2H, m); 2.6 (2H, m); 2.3 (6H, s); 1.9 (2H, m) .

ESI-MS: M+ = 572

2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionic acid (I-383)

1H-NMR (200 MHz): 7.1-7.5 ppm, (14H, m); 6.24 (1H, s); 6.23 (1H, s); 3.8 (3H, s); 3.4 (2H, m); 2.75 (2H, m); 2.25 (3H, s); 1.9 (2H, m) .

ESI-MS: M+ = 532

2-(4, 6-dimethyl-pyrimidin-2-yloxy)-3-(3-(2-chlorophenyl)-propoxy)-3,3-diphenylpropionic acid (I-384)

Melting point: 172-178°C

ESI-MS: M+ = 516

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(4-chlorophenyl)-propoxy)-3,3-diphenylpropionic acid (I-251)

1H-NMR (200 MHz): 7.0-7.4 ppm, (14H, m); 6.6 (1H, s); 6.3 (1H, s); 3.5 (2H, s); 2.7 (2H, m); 2.3 (6H, s); 1.9 (2H, m).

ESI-MS: M+ = 516

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(3,4-dimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-490)

1H-NMR (200 MHz): 7.1-7.5 ppm, (10H, m); 6.74 (IH, s); 6.7 (3H, s); 6.3 (1H, s); 3.8 (6H, s); 3.5 (2H, m); 2.7 (2H, m); 2.3 (6H, s); 1.9 (2H, m).

ESI-MS: M+ = 542

2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-propoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-69)

Melting point: 115-119°C

ESI-MS: M+ = 542

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-71)

Melting point: 118-122°C

ESI-MS: M+ = 556

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-butoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-70)

Melting point: 122-125°C

ESI-MS: M+ = 540

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-phenyl-prop-(2E)-enoxy)-3,3-diphenylpropionic acid (I-44)

Melting point: 171-174°C

ESI-MS: M+ = 496

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(2-methylphenyl)-propoxy-3,3-diphenylpropionic acid (I-107)

Decomposition: 144-146°C

ESI-MS: M+ = 512

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(2-methyl-phenyl)-propoxy-3,3-diphenylpropionic acid (I-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 (I-363)

Decomposition: 158-161°C

ESI-MS: M+ = 512

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(4-methyl-phenyl)-propoxy-3, 3-diphenylpropionic acid (I-346)

Decomposition: 163-167°C

ESI-MS: M+ = 496

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylthio-phenyl)ethoxy-3,3-diphenylpropionic acid (I-246)

Decomposition: 136-138°C

ESI-MS: M+ = 530

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methylthio-phenyl)-ethoxy-3,3-diphenylpropionic acid (I-217)

Decomposition: 166-169°C

ESI-MS: M+ = 514

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy-3,3-diphenylpropionic acid (I-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 (I-510)

Decomposition: 131-135°C

ESI-MS: M+ = 528

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic acid (I-705)

1H-NMR (200 MHz, DMSO): 7.0-7.35 ppm, (14H, m); 6.35 (1H, s); 6.1 (1H, s); 4.0 (1H, m); 3.9 (3H, s); 3.8 (3H, s); 3.7 (1H, m); 2.9 (3H, m); 2.2 (3H, s); 1.1 (6H, d).

ESI-MS: M+ = 526

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-568)

Decomposition: 146-148°C

ESI-MS: M+ = 528

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid ( I-501)

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 ( I-735)

1H-NMR (200 MHz, DMSO): 7.1-7.4 ppm, (10H, m); 6.85 (2H, m); 6.7 (1H, d); 6.1 (1H, s); 4.6 (2H, tr) ; 4.0 (3H, m); 3.85 (3H, s); 3.75 (3H, s); 3.65 (1H, m); 3.05 (2H, tr) ; 2.8 (2H, m); 1.25 (3H, m-) .

ESI-MS: M+ = 586

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3, 3-diphenylpropionic acid

(I-407)

1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (12H, m); 6.8 (2H, d); 6.1 (1H, s); 4.65 (2H, tr); 3.95 (3H, m); 3.8 (3H, s); 3.65 (1H, m); 3.05 (2H, tr) ; 2.8 (2H, m); 1.25 (3H, m).

ESI-MS: M+ - 556

2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-146)

Decomposition: 129-134°C

ESI-MS: M+ - 542

2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-569)

1H-H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (10H, m); 6.9 (1H, s); 6.8 (2H, m); 6.7 (1H, d); 6.0 (2H, s); 3.95 (3H, m); 3.65 (1H, m); 2.8 (2H, m); 2.3 (6H, s).

ESI-MS: M+ = 512

2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-ethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-473)

Decomposition: 145-148°C

ESI-MS: M+ = 512

2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic acid

(I-604)

1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (14H, m); 6.1 (1H, s); 4.6 (2H, tr) ; 3.9 (3H, s); 3.8 (3H, s); 3.6 (1H, m); 3.0 (2H, tr); 2.8 (3H, m); 1.1 (6H, d).

ESI-MS: M+ = 554

2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-i-propyl-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-672)

Decomposition: 156-160°C

ESI-MS: M+ = 510

2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-methylphenyl )-propionic acid (I-517)

1H-NMR (200 MHz, DMSO): 7.0-7.3 ppm, (10H, m); 6.8 (2H, d); 6.0 (1H, s); 4.6 (2H, tr) ; 3.85 (3H, s); 3.8 (1H, m); 3.7 (3H, s); 3.6 (1H, m); 3.0 (2H, tr); 2.8 (3H, tr); 1.1 (6H, d) .

ESI-MS: M+ - 570

2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-622)

1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (12H, m); 6.8 (2H, d); 6.4 (1H, s); 6.1 (1H, s); 4.0 (1H, m); 3.7 (3H, s); 3.7 (1H, m); 2.8 (2H, tr); 2.3 (3H, s).

ESI-MS: M+ = 514

2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-585)

1 H-NMR (200 MHz, DMSO): 7.1-7.4 ppm, (12 H, m); 6.8 (3H, m); 6.1 (1H, s); 4.0 (1H, m); 3.7 (3H, s); 3.6 (1H, m); 2.8

(2H, tr); 2.3 (3H, s).

ESI-MS: M+ - 498

2-(4-Methoxy-6-methylpyrimidin-2-yloxy)-3-(3-phenyl-propoxy)-3,3-diphenylpropionic acid (I-499)

Decomposition: 153-155°C

ESI-MS: M+ = 498

2-(4,6-dimethylpyrimidin-2-yloxy)-3-(3-phenyl-propoxy)-3,3-diphenylpropionic acid (I-500)

Decomposition: 148-151°C

ESI-MS: M+ = 482

Analogously, or as described in the general section, the compounds listed in Table 1 can be produced.

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Example 16

In accordance with the binding assay described above, receptor binding values were measured for the following listed compounds.

The results are shown in the following table.

Table 2

Receptor binding values (Ki-values)

[image]

Claims (10)

1. Carbonic acid derivatives of formula I [image] indicated by that R1 represents a tetrazole or a group [image] where R has the following meaning: a) residue OR7, where R7 represents hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerable organic 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 linked via a nitrogen atom; c) group [image] where k has the value 0, 1 and 2, p has the value 1, 2, 3 and 4, and R8 represents C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or optionally substituted phenyl; d) the remainder [image] in which R9 represents C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cyclo-alkyl, whereby these residues can carry one C1-C4- alkoxy, C1-C4-alkylthio and/or one phenyl residue ; phenyl, optionally substituted; e) the remainder [image] where R13 and R14 can be the same or different and have the following meaning: hydrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl, which can be substituted if necessary, or R13 and R14 together form an optionally substituted C4-C7-alkyl chain, which is closed in a ring, which may contain one heteroatom; R2 represents 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 or C1-C4-alkylthio, or CR2 together with CR10 is connected in a five- or six-membered ring, as indicated below; X is nitrogen or methine; Y is nitrogen or methine; Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl/ or CR10 together with CR2 or CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted if necessary, and where one or more methylene groups can be substituted with oxygen, sulfur, -NH or with -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-halogenalkoxy, C1-C4-alkylthio; or CR3 is joined together with CR10 in a five- or six-membered ring, as stated above; R4 and R5 (which can be the same or different) represent: phenyl or naphthyl, optionally substituted, or phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or one SO2-, NH- or N-alkyl group, C3-C8-cycloalkyl, optionally substituted; R6 represents optionally substituted C3-C8-cyclo-alkyl, phenyl or naphthyl, optionally substituted; a five- or six-membered heteroaroamt containing one to three nitrogen atoms and/or a sulfur or oxygen atom, and which can be substituted if necessary; W is sulfur or oxygen; Q is a spacer group, which corresponds to the length of the C2-C4 chain, and their physiologically tolerable salts, and enantiomerically pure as well as diastereomerically pure forms. 2. Medicinal preparations for peroral, parenteral and intraparenteral administration, characterized by the fact that, in addition to the usual excipients for medicines, they contain at least one derivative of carboxylic acid I according to claim 1. 3. Use of carboxylic acid derivatives according to claim 1, characterized in that they are used for the treatment of diseases. 4. Use of compounds I according to claim 1, characterized in that they are used as endothelin receptor antagonists. 5. Use of carboxylic acid derivatives I according to claim 1, characterized in that they are used for the production of drugs for the treatment of diseases in which an elevated level of endothelin appears. 6. Use of carboxylic acid derivatives I according to claim 1, characterized in that they are used for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute and chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and cancer prostate. 7. Use of carboxylic acid derivatives I according to claim 1, characterized in that they are used in combination with renin-angiotensin system inhibitors mixed AGE and neutral endopeptidase inhibitors, (NEP)-inhibitors; β-blockers. 8. Use of compounds of formula IV [image] in which the residues R1, R4, R5, R6, Q and W have the meaning specified in claim 1, indicated that they are used as starting material for the synthesis of mixed ETA/ETB-receptor antagonists. 9. Fragment of the structure of the formula [image] in which the residues R1, R4, R5, R6, Q and W have the meaning stated in claim 1, characterized by the fact that it represents a structural element in a mixed ETA/ETB-receptor antagonist. 10. Process for the production of carboxylic acid derivatives of the general formula IV [image] characterized by the fact that the compounds of formula IVa [image] under the conditions of acid catalysis, they are chemically converted with alcohol or thiol of formula III [image] in which the residues R 1 , R 4 , R 5 , R 6 , Q and W have the meaning specified in claim 1, and R 18 represents cyclic alkyl or open chain alkyl or phenyl, which can be substituted if necessary.