HRP20000602A2 - 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists - Google Patents

Description

The proposed invention relates to new carboxylic acid derivatives with a 5-substituted pyrimidine ring, 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, Nature Medicine 1, (1995) ), 944).

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.

Carboxylic acid derivatives and their use as endothelin antagonists are described in WO 95/26716, WO 96/11914, WO 97/9294, WO97/12878, WO 97/38980, WO/38981. These compounds carry a nitrogen atom or group

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in the 5-position of the heterocycle.

In contrast, the compounds according to the invention have a group in that position

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wherein X represents halogen, hydroxy or C1-C4-halo-alkyl. Compared to known endothelin antagonists, the compounds according to the invention are distinguished, for example, by being much better metabolized in the body.

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

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where

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 can 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 linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms, or one or 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-Halo-Alkyl, Hydroxy, C1-C4-Alkoxy, C1-C4-Alkylthio, Mercapto, Amino, NH (C1-C4-Alkyl), N (C1 -C4-alkyl)2;

d) the radical of the formula

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where

R9 is C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cyclo-alkyl, where these radicals can carry C1-C4-alkoxy, C1-C4-alkylthio and/or phenyl radical defined as under c);

phenyl may be substituted with one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH (C1 -C4-alkyl), N (C1-C4-alkyl)2.

Other substituents have the following meanings:

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-halogenalkoxy or C1-C4-alkylthio, morpholine;

X is halogen, C1-C4-haloalkyl, hydroxy;

R3 is hydrogen, hydroxy, NH, 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, -NH-O-C1-C4-Alkyl, C1-C4-Alkylthio;

R2 and R3 (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, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, phenoxy, mercapto , alkylcarbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2; 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; or

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

or C3-C7-cycloalkyl;

R6 is hydrogen,

C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, whereby these radicals can in each case be mono- or multi-substituted with hydroxy, mercapto, carboxy, halogen, nitro, cyano, C1-C4-Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C3-C3-Alkylcarbonylalkyl, Amino, NH (C1-C4-alkyl), N (C1-C4-alkyl)2, phenoxy or phenyl, wherein the above-mentioned aryl residues can be mono- or multi-substituted, e.g. phenyl or phenoxy mono- to tri-substituted with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy, mercapto, carboxy, hydroxy, amino, R12, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl) , N(C1-C4-alkyl)2, dioxomethylene, dioxoethylene or with C1-C4-alkylthio;

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

halogen, nitro, cyano, hydroxy, amino, C1-C4--alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl ), N (C1-C4-alkyl)2 or dioxomethylene or dioxoethylene;

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

provided that R 6 can only be hydrogen if Z is not a single bond;

R12 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)3, carboxyamide or CON(C1-C4-alkyl)2;

Z is sulfur, oxygen, or a single bond.

The following definitions apply here and in the following:

Alkali metal is, for example, lithium, sodium, potassium:

alkaline earth metal is, for example, calcium, magnesium, barium;

organic ammonium ions are protonated amines, such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;

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

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;

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 1 can be released (so-called prodrugs).

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

The compounds, and also the intermediates for their production, such as for example II and IV, can 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 invention further relates to the use of the above-mentioned carboxylic acid derivatives for the production of drugs, especially for the production of endothelin receptor inhibitors.

Compounds of the general formula IV, wherein Z represents sulfur or oxygen (IVa) can be prepared as described in WO 96/11914.

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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.

Compounds of formula IVa can be obtained in enantiomerically pure form by acid-catalyzed transesterification, as described in DE 19636046.3.

In addition, enantiomerically pure compounds of formula IVa can be obtained by classical resolution of racemic or diastereomeric compounds of formula IVa using suitable enantiomerically pure bases. Examples of suitable bases of this type are, for example, 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.

Compounds of the general formula IV, in which Z represents a single bond (IVb), can be obtained in racemic and also in enantiomerically pure form, as described in WO 97/38981.

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Compounds according to the invention in which the substituents are defined as for formula I, can be produced, for example, by reacting a carboxylic acid derivative of formula IV, in which the substituents have the stated meaning, with compounds of general formula V.

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R 10 in formula V is halogen or R 11 SO 2 -, where R 11 can be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl. 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 R is COOH, using two equivalents of the appropriate base and reacting with compounds of general formula V. This reaction also takes place in inert solvent and at a 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.

Compounds of formula I can also be produced by dividing them from the corresponding carboxylic acids, i.e. compounds of formula I in which R 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 react with the corresponding hydroxyl compound HOR. This reaction can be carried out in common solvents and the addition of a base is often required, whereby for example triethylamine, pyridine, imidazole or diazabicycloundecane come into consideration. Both 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, the compounds of formula 1 can also be produced by dividing them from salts of the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents the COOM group, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can react with many compounds of the formula R7-A, where A represents a common nucleophilic leaving group, for example halogen, such as chlorine, bromine, iodine, or optionally with halogen, alkyl or haloalkyl substituted aryl- or alkylsulfonyl, such as e.g. toluenesulfonyl and methylsulfonyl, or with another equivalent leaving group. Compounds of formula R7-A with reactive substituent A are known or can be easily obtained based on general knowledge of the art. This reaction can be carried out in common solvents and takes place preferably with the addition of a base, whereby the above mentioned are taken into account.

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 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 1 as pure enantiomers, i.e. pure diastereomers or as their mixtures, in which the substituents have the following meanings:

R 2 is hydrogen, hydroxy, N (C 1 -C 4 -alkyl) 3 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyloxy, C 1 -C 4 -haloalkyloxy, C 1 -C 4 -alkylthio, halogen;

X is halogen, trifluoromethyl;

R 3 is hydrogen, hydroxy, N(C 1 -C 4 -alkyl) 2 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyloxy, C 1 -C 4 -alkylthio, halogen;

R4 and R5 represent phenyl or naphthyl, which may be substituted with one or more, for example with one to three of the following radicals: halogen, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1- C4-Alkoxy, C1-C4-Halo-Alkoxy, C1-C4-Alkylthio, NH (C1-C4-Alkyl)2, N(C1-C4-Alkyl)2, C1-C4-Alkylcarbonyl, C1-C4-Alkoxy-carbonyl;

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(C1-C4-alkyl) group;

a five- or six-membered heteroatom containing one or two nitrogen atoms and/or a sulfur or oxygen atom, which can carry one to two halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-alkoxy, phenyl , which can carry one to three halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;

or C3-C7-cycloalkyl;

R6 is C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, whereby these radicals can in any case be singly or multiply substituted with halogen, hydroxy, cyano, C1-C4- Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkylcarbonyl, Hydroxycarbonyl, C1-C4-Alkoxy-carbonyl, NH(C1-C4-Alkyl) 2, N (C1-C4-alkyl)2, phenoxy or phenyl, wherein the above-mentioned aryl radicals can be singly or multiply substituted, for example singly to triply with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1 -C4-Alkoxy, C1-C4-halogenalkoxy, R12, C1-C4-Alkoxycarbonyl, dioxomethylene, dioxoethylene or with C1-C4-alkylthio, phenyl or phenoxy;

phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy, C1-C4-halogenalkoxy, phenoxy , C1-C4-alkylthio, NH(C1-C4-alkyl)2, N(C1-C4-alkyl)2;

a five- or six-membered heteroatom containing one to three nitrogen atoms and/or one sulfur or oxygen atom that 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, C1-C4-halogenalkoxy, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, 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;

R 12 is C 1 -C 4 -alkyl, C 1 -C 4 -Alkoxy, which can carry one of the following radicals: hydroxy, carboxamide or CON(C 1 -C 4 -alkyl) 3 ;

Z is sulfur, oxygen, or a single bond.

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 C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, especially methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

X is fluorine, trifluoromethyl;

R 3 is C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, especially methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

R4 and R5, the same or different, represent phenyl and may be substituted with one or more, for example with one to three of the following radicals: halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or

R4 and R5 represent phenyl groups that 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(C1-C4-alkyl) group; or

thiazole, oxazole, thiophene or furan, wherein the above-mentioned heteroatoms can be mono- to doubly substituted with halogen, C1-C4-alkyl, C1-C4-alkoxy;

R4 and R5 represent cyclohexyl;

R6 is C1-C8-alkyl, C3-C6-alkenyl or C3-C8-cycloalkyl, whereby these radicals can in any case be mono- or multi-substituted with halogen, hydroxy, cyano, C1-C4-alkoxy, C3-C6- alkenyloxy, C1-C4-alkylthio, phenoxy or phenyl, wherein the above-mentioned aryl radicals can be mono- or poly-substituted, for example mono- to tri-substituted with C1-C4-alkyl, C1-C4-alkoxy, dioxo-methylene, dioxoethylene or with C1-C4-alkylthio;

phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, phenoxy , C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;

a five- or six-membered heteroatom containing a nitrogen atom and/or a sulfur or oxygen atom, 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, C1-C4-alkylthio, phenyl, phenoxy or phenylcarbonyl, 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 and/or C1-C4-Alkylthio;

Y is sulfur, oxygen, or a single bond.

The compounds of the proposed invention offer a new therapeutic option for the treatment of hypertension, high pulmonary pressure, myocardial infarction, angina pectoris, arrhythmia, acute/chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis , endotoxic shock, endotoxin-induced organ failure, 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, contrast-induced kidney failure, pancreatitis, gastrointestinal ulcers and erectile dysfunction.

The invention further relates to combinations 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 angiotensin-converting enzyme (ACE) inhibitors (e. Angiotensin-Converting-Enzyme). Combinations of endothelin receptor antagonists of formula 1 and ACE inhibitors are preferred.

The invention further relates to combinations of endothelin receptor antagonists of formula I and beta blockers.

The invention further relates to combinations of endothelin receptor antagonists of formula I and diuretics.

The invention further relates to combinations of endothelin receptor antagonists of formula I and substances that block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF, or specific binding proteins, or also low molecular weight substances that can specifically inhibit VEGF release or receptor binding.

The combinations mentioned above can be given simultaneously or separately. They can be used in a single pharmaceutical formulation or in separate formulations. The method of application can also be different, for example, endothelin receptor antagonists can be given orally, and VEGF inhibitors parenterally.

These combined preparations are particularly suitable for the treatment and prevention of hypertension and its consequences, and also 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, which reproduce 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 10 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 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 μq protein per test mixture and incubated at 25°C with 25 pM 125J-ET1 (ETA-125 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.

Functional test on blood vessels for endothelin receptor antagonists

Rabbit aorta segments, after initial stress of 2 g and unloading time of 1 hour in Krebs-Henseleit solution at 37°C and pH 7.3-7.4, were first induced to contract with K+. After washout, a dose effect curve was constructed against endothelin up to the maximum.

Potential endothelin antagonists were applied to other preparations of the same vessel 15 minutes before the start of drawing the dose effect curve to endothelin. Effects towards endothelin were calculated as % contraction caused by K+. Effective endothelin antagonists cause a shift to the right of the endothelin dose-effect curve.

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 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.

per. - 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). Applications can also be made 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 (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-(4,6-dimethoxy-5-fluoropyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester

1.0 g (3.5 mmol) methyl ester of 2-hydroxy-3- of methoxy-3,3-diphenyl-propionic acid, dissolved in DMF. The mixture was stirred for 30 minutes at room temperature and then mixed with 830 mg (4.8 mmol) of 4,6-dimethoxy-5-fluoro-2-methylsulfonyl-pyrimidine in 10 ml of DMF and stirred for 2 hours at room temperature. . The reaction mixture was poured into ice-water and extracted three times with diethyl ether. The ether phase is dried with magnesium sulfate, then filtered and the solvent is removed under vacuum. The brown residue (1.7 g) was purified by MPLC to give 1.3 g of the desired product, which was directly reacted further.

Example 2

2-(4,6-dimethoxy-5-fluoro-pyrimidin-2-yloxy)-2-methoxy-3,3-diphenylpropionic acid (A) and

2-(4-methoxy-5-fluoro-6-hydroxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (B)

1.3 g (2.9 mmol) of 2-(4,6-dimethoxy-5-fluoro-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester are dissolved in 10 ml of dioxane and mixed with 5.9 ml of 1N KOH solution. The mixture is stirred for 4 hours under reflux. 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. The residue was taken up in ether, whereby 100 mg of product B crystallized. The mother liquor was mixed with n-hexane to give 400 mg of product A as a solid.

A: 1H-NMR (CDCl 3 , 500 MHz): 7.2-7.45 (m, 10H); 6.05 (s, 1H); 3.95 (s, 6H); 3.3 (s, 3H), melting point: 167-170°C.

B: 1H-NMR (DMSO, 250 MHz): 7.1-7.4 (m, 10H); 6.05 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H), melting point: 115-110°C.

Example 3

Benzyl ester of 2-(4-morpholino-5-fluoro-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

3.3 g (9 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid benzyl ester and 4- of morpholino-5-fluoro-2-chloropyrimidine, dissolved in DMF. The mixture is stirred for 3 hours at 90°C and then for 3 hours at 130°C. The reaction mixture was poured into ice-water and extracted three times with ethyl acetate. The ethyl acetate phase was dried with magnesium sulfate and then filtered and the solvent removed under vacuum. The brown residue (5.72 g) is purified by MPLC, and it is directly reacted further.

Example 4

2-(4-morpholino-5-fluoro-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

A solution of 0.9 g of 2-(4-morpholino-5-fluoro-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid benzyl ester in 30 ml of ethyl acetate is hydrogenated using 300 mg of palladium on activated carbon. (10%) with hydrogen for 3 hours at room temperature under atmospheric pressure. The reaction mixture was filtered, concentrated and the residue (900 mg) was purified by MPLC.

1 H-NMR (CDCl 3 , 500 MHz): 8.95 (d, 1H); 7.2-7.5 (m, 10H); 6.05 (s, 1H); 3.8 (s, 8H); 3.3 (s, 3H), melting point: 174-175°C.

The compounds listed in Table I can be produced in the same way.

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Example 5

In accordance with the binding assay described above, receptor binding data were obtained for the compounds listed below.

The results are shown in the following table 3.

Table 3

Receptor binding data (Ki-values)

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Claims (8)

1. Carboxylic acid derivatives of formula I [image] indicated by that 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 or an ammonium ion; C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, which can 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 linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, 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 [image] where k can have a value of 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-Halo-Alkyl, Hydroxy, C1-C4-Alkoxy, C1-C4-Alkylthio, Mercapto, Amino, NH (C1-C4-Alkyl), N (C1 -C4-alkyl)2; d) the radical of the formula [image] where R9 represents C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, whereby these radicals can carry C1-C4- alkoxy, C1-C4-alkylthio and/or a phenyl radical defined as under c); phenyl, which may be substituted with one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH (C1-C4-alkyl), N(C1-C4-alkyl)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-halogenalkoxy or C1-C4-alkylthio, morpholine; X is halogen, C1-C4-haloalkyl, hydroxy; 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, -NH-O-C1-C4-Alkyl, C1-C4-Alkylthio; R2 and R3 (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, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, phenoxy, mercapto , alkyl-carbonyl, alkoxycarbonyl, C1-C4-alkylthio, amino, NH(C1-C4-alkyl) , N(C1-C4-alkyl)2; 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; or a five- or six-membered heteroatom, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl . C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio; or C3-C7-cycloalkyl; R 6 is hydrogen; C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, whereby these radicals can in each case be mono- or multi-substituted with hydroxy, mercapto, carboxy, halogen, 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, Amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenyl or phenoxy, which may be singly or multiply substituted, for example singly to triply with halogen, nitro, cyano, C1-C4-alkyl, C1 -C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy or C1-C4-alkylthio, or phenoxy; phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) , N(C1-C4-alkyl)2 or dioxomethylene or dioxoethylene; a five- or six-membered heteroatom, containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl . C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio; provided that R 6 can only be hydrogen if Z is not a single bond; Z is sulfur, oxygen or a single bond; and their physiologically tolerable salts, and enantiomerically pure and diastereomerically pure forms. 2. Use of carboxylic acid derivatives I according to claim 1, characterized in that they are used for the treatment of diseases. 3. Use of compounds I according to claim 2, characterized in that they are used as endothelin receptor antagonists. 4. The use of carboxylic acid derivatives I according to claim 1, characterized in that they are used for the production of drugs or for the treatment of diseases in which an elevated level of endothelin appears. 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 endothelin contributes to the occurrence and/or progression of the disease. 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, high pulmonary pressure, acute/chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer. 7. Combination, characterized in that it contains carboxylic acid derivatives I according to claim 1 and one or more active substances, selected from the group consisting of inhibitors of the renin-angiotensin system, such as renin inhibitors, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors ), mixed ACE/neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, calcium antagonists, and VEGF-blocking agents. 8. Pharmaceutical preparation for peroral, parenteral and intraparenteral use, characterized by the fact that in a single dose, apart from the usual excipients for medicines, it contains at least one carboxylic acid derivative I according to claim 1.