SK11512000A3 - 5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula (I), wherein the substituents have the following meanings; R<1>= tetrazole or a group (1); R = a radical OR<7>(2), (3), a 5-membe red heteroaromatic bonded by a nitrogen atom such a pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R<2>, R<3> = hydrogen, hydroxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-halogen alkyl, C1-C4-alkoxy, C1-C4-halogen alkoxy or C1-C4-alkythio; X = halogen, C1-C4-halogen alkyl, hydroxy; R<4> and R<5> = phenyl or naphthyl, C3-C7-cycloalkyl, phenyl or naphthyl which are bonded in ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2-NH or an N-alkyl group or a 5-membered or 6-membered heteroaromatic; R<6> = hydrogen, phenyl or naphthyl, a five or six-membered heteroaromatic, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkinyl or C3-C8-cycloalkyl, whereby said radicals can be substituted once or many times, with the proviso that R<6> can only stand for hydrogen if Z does not represent a single bond; Z = sulfur, oxygen or a single bond, in addition to the physiologically compatible salts and the enantiomeric-pure and diastereomeric-pure forms. The novel compounds are suitable for combating diseases, especially as endothelin antagonists.

Description

Technical field

The present invention relates to novel carboxylic acid derivatives containing a 5-substituted pyrimidine ring, their preparation and use.

to

BACKGROUND OF THE INVENTION

I

Endothelin is a peptide consisting of 21 amino acids and synthesized by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET2 and ET-3. In the following, "endothelin" or "ET" refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vascular tone. This vasoconstriction is known to be due to 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) ).

Increased or excessive release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which can lead to diseases. Endothelin has been reported to be involved in a variety of diseases, including hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, cerebral angiospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma, asthma and asthma. 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), Nature Medicine 1, 944 (1995)).

At least two endothelin receptor subtypes, ETa and ETb receptors, are currently described in the literature (Nature 348 730 (1990), Nature 348, 732 (1990)). Thus, agents that inhibit the binding of endothelin to one or both receptors could antagonize the physiological effects of endothelin and could therefore be valuable drugs.

-2-Carboxylic acid derivatives and their use as endothelin antagonists are described in WO 95/26716, WO 96/11914, WO 97/9294, WO 97/12878,

WO 97/38980; WO 97/38981. These compounds carry a nitrogen atom or a group

C 1 ^H at the 5-position of the heterocycle.

In contrast, the compounds of the invention contain an x group at this position

wherein X is halogen, hydroxyl or C ₁ -C ₄ -haloalkyl. In comparison, endothelin antagonists are known, for example, the compounds of the invention are more conveniently metabolized in the body.

SUMMARY OF THE INVENTION

The present invention relates to carboxylic acid derivatives of the general formula I ^{6 H-} v-z-c-o-y-x

RR x 3 (I), wherein R ¹ is tetrazole or a group wherein R is:

(a) radical OR ⁷ where R ⁷ represents:

hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, such as a tertiary C 1 -C 6 -alkylammonium or an ammonium ion;

-3Cä -C cykloalkylpvú group -C ₈ -alkyl, _CH2 -phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C _r C ₄ -alkyl, C _r C ₄ -haloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, mercapto, C ₁ -C ₄ -alkylthio, amino, NH (C 1 -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ;

A C 5 -C 6 -alkenyl group or a C 3 -C 6 -alkynyl group, which groups themselves may carry one to five halogen atoms;

^R7 may furthermore be phenyl, which may carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano C _r C ₄ -alkyl, C ₄ -haloalkyl, hydroxyl C 1 -C 4 alkoxy, mercapto, C ₁ -C ₄ -alkylthio, amino, NH (C ₁ -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ;

b) a 5-membered heteroaromatic radical such as a pyrrolyl, pyrazolyl, and imidazolyl triazolyl which is attached via N and which carry one or two halogen, one or two C _r C ₄ alkyl- or one or two -C ₄ - alkoxy groups.

(c) a group

- o- (ch ₂ ) _p -s-r ⁸ in which k can be 0, 1 or 2, p can be 1, 2, 3 or 4 and R ⁸ is

₄ C _r C alkyl group, a C _{3 -C8} cycloalkyl group, C ₃ -C ₆ -alkenyl, C3 -C6 alkynyl or phenyl, which may be substituted by one or more, e.g. one to three of the following radicals: halogen, nitro, cyano, C _r C ₄ -alkyl, CrC ₄ -haloalkyl, hydroxyl, C _r C ₄ alkoxy group, C ₄ -alkylthio, mercapto, amino, NH (C ₁ -C ₄ alkyl), N (Ci-C ₄ alkyl) _second

(d) the rest

--L · ^H II o

where R ⁹ represents:

C 1 -C ₄ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, these radicals may carry C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkyl an alkylthiol and / or phenyl radical as mentioned under c);

phenyl, which may be substituted with one to three of the following radicals, such as: halogen, nitro, cyano, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, hydroxyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ - alkylthio, mercapto, amino, NH (C ₁ -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) 2.

Other substituents are as below:

^R2 is H, OH, _NH2, NH _(Ci-C4 alkyl), N (C _R C ₄ alkyl) _2, halo, C _R C ₄ alkyl group, a _C2-C4 -alkenyl. C ₂ -C ₄ alkynyl, C _r C ₄ -hydroxyalkylovú group -C ₄ -haloalkyl, C _r C ₄ alkoxy group, -C ₄ -halogénalkoxylovú group or a _Ci-C4 alkylthio, morpholine;

X is halogen, Ci-C ₄ -haloalkyl, hydroxyl;

R ³ represents hydrogen, hydroxyl, NH ₂ NH (CrC ₄ -alkyl), N (C 1 -C 6 -alkyl); ₄ alkyl) ₂ , halogen, C _r C ₄ an alkyl group, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ alkynyl, C 1 -C 6 ₄ -hydroxyalkyl, C 1 -C 6 ₄ a haloalkyl group, CrC ₄ an alkoxy group, C _r C ₄ -haloalkoxy, -NH-O-C1-C ₄ an alkyl group, CrC ₄ alkylthio;

R ⁴ and R ⁵ (which may be the same or different) represent:

a phenyl or naphthyl group which may be substituted by one or more of the following radicals, such as: halogen, nitro,

-5-cyano, hydroxyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C ₁ -C ₄ -alkylthio, amino,

NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ; or a phenyl or naphthyl group which are ortho-linked to each other by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, or an SO2-, NH- or Nalkyl group; or a five- or six-membered heteroaromatic radical containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following radicals, such as: C 1 -C ₄ - alkyl, -C ₄ -haloalkyl group, a Ci-C ₄ -alkoxy, C ₄ -halogénalkoxylová group, a C _r C ₄ alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: C _r C ₄ -alkyl, -C ₄ -haloalkyl group, a C _r C ₄ alkoxy group, -C ₄ -halo-alkoxy and / or C _r C ₄ - alkylthio;

or a C ₃ -C 7 -cycloalkyl group;

R ⁶ is hydrogen,

C 1 -C 6 -alkyl, C ₃ -C 6 -alkenyl, C ₃ -C 6 -alkynyl or C ₃ -C 6 -cycloalkyl, these radicals in each case being mono- or polysubstituted by a substituent such as hydroxyl, mercapto, carboxyl , halo, nitro, cyano, C _r C ₄ -alkoxy, C ₃ -C ₆ alkenyloxy group, a C ₃ -C 6 alkynyloxy, C _r C ₄ -alkylthio, -C ₄ -halo-alkoxy, C _4- alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₃ -C ₈ -alkylcarbonylalkyl, amino, NHC 1 -C 4 alkyl), N (C 1 -C ₄ -alkyl) ₂ , phenoxy or phenyl, wherein the above aryl residues may be

-6R ¹² mono- or polysubstituted, for example phenyl or phenoxy mono- to trisubstituted with a substituent such as halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, mercapto, carboxyl, hydroxyl, amino, R ¹² , C ₁ -C ₄ -alkoxycarbonyl, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) 2, dioxomethylene, dioxoethylene or C ₁ -C ₄ -alkylthio;

phenyl or naphthyl, each of which may be substituted by one or more of the following radicals, such as: halogen, nitro, cyano, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy , -C ₄ -halogénalkoxylová, phenoxy, Cr _C4 alkylthio group, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) ₂ or dioxo-methylene or dioxoethylene;

a five- or six-membered heteroaromatic radical containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following radicals, such as: C 1 -C ₄ -alkyl group, a C -C ₄ -haloalkyl group, -C ₄ alkoxy group, C ₄ -halogénalkoxylová group, a C _r C ₄ alkylthio, phenyl, phenoxy, phenylcarbonyl or, where the phenyl radicals for their part may for their part carry one to five halogen atoms and / or one to three of the following radicals: -C ₄ -alkyl, C ₄ -haloalkyl group, -C ₄ alkoxy, -C ₄ -halogénalkoxylová group and / or C _r C ₄ alkylthio;

with the proviso that R ⁶ can only represent hydrogen if Z is not a single bond;

is Ci-C ₄ -alkyl, -C ₄ alkylthio, C _r C ₄ alkoxy, which carry one of the following radicals: hydroxyl, carboxyl, amino, NH (C _r C ₄ alkyl), N (C ₁ -C ₄ alkyl) _2, carboxamide or CON (alkyl -C _{4) 2,}

-7Z represents sulfur, oxygen or a single bond.

The following definitions apply to these and the following:

an alkali metal is, for example, lithium, sodium, potassium;

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

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

C ₃ -C ₇ -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

Ci-C ₄ -haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 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;

C _r C ₄ -halogénalkoxylová can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2difluóretoxy, 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, 2 chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

The C 1 -C ₄ -alkyl group 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;

The C 2 -C ₄ -alkenyl group may 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;

C ₂ -C ₄ -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 ;

The C ₁ -C ₄ -alkoxy group may be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

The C 3 -C 6 -alkenyloxy group may be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

The -8C ₃ -C ₆ -alkynyloxy group may be linear or branched, such as 2-propin-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;

C ₁ -C ₄ -alkylthio may be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

The C 1 -C 4 -alkylcarbonyl group may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

The C 1 -C 4 -alkoxycarbonyl group may be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-propoxycarbonyl or n-butoxycarbonyl;

The C ₃ -C ₈ -alkylcarbonylalkyl group may be linear or branched, such as 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

The C 1 -C 5 -alkyl group may be linear or branched, such as C 1 -C 4 alkyl, pentyl, hexyl, heptyl or octyl;

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

The invention further relates to such compounds from which the compounds of formula I can be released (precursors).

Preferred are those precursors in which release occurs under conditions that predominate in certain parts of the body, for example, in the stomach, intestines, bloodstream, or liver.

The compounds as well as intermediates for their preparation, such as compounds II and IV, may contain one or more asymmetrically substituted carbon atoms. Such compounds may be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as an active compound is preferred.

The invention further relates to the use of the aforementioned carboxylic acid derivatives for the preparation of a medicament, in particular for the preparation of inhibitors for endothelin receptors.

-9mozu

(IVa)

Compounds of formula IV wherein Z is sulfur can be prepared as described in WO 96/11914.

- ⁴ XZA / ^r1 _{+ r6} - _z - _h

R ⁵ (II) III

Compounds of formula III are either known or can be synthesized, for example, by reduction of the corresponding carboxylic acids or esters thereof, or using other generally known procedures.

The compounds of formula IVa can be prepared in enantiomerically pure form by means of acid-catalyzed transetherification as described in DE 19636046.3.

In addition, enantiomerically pure compounds of formula IVa can be prepared by performing classical racemate separation on racemic or diastereomeric compounds of formula IVa using suitable enantiomerically pure bases. Suitable bases are, for example, 4-chlorophenylethylamine and the bases disclosed in WO 96/11914.

Compounds of formula IV in which Z is a single bond (IVb) can be prepared both vemememically and in enantiomerically pure form as described in WO 97/38981.

(IVb)

H

C - OH

I

The compounds of the present invention in which the substituents have the meanings defined in formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IV in which the substituents have the meanings defined, with compounds of the formula V.

In formula V, R ¹⁰ is halogen or R ¹¹ -SO ² -, and R ¹¹ can be C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl or phenyl. The reaction is preferably carried out in an inert solvent or diluent with the addition of a suitable base, ie, a base which causes deprotonation of intermediate IV, in a temperature range from room temperature to the temperature of the solvent variation.

Compounds of type I in which R ^{@ 1} = COOH can be further prepared directly if intermediate IV in which R ^{@ 1} is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of formula V. The reaction is again carried out in an inert reaction. solvent, and at a temperature range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, which may in any case be chlorinated, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylether. such as diisopropyl ether, diisobutyl 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 dimethyl sulfolane.

The compounds of formula V are known and some of them are commercially available or can be prepared using generally known procedures.

Alkali metal hydride or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, carbonate such as alkali metal carbonate such as sodium carbonate or potassium carbonate, alkali metal hydroxide or alkaline earth metal hydroxide such as sodium hydroxide or hydroxide potassium, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide may serve as a base.

Compounds of formula I may also be prepared starting from the corresponding carboxylic acids, i.e., compounds of formula I in which R ¹ is COOH, and these are first converted to an activated form, such as an acid halide, acid anhydride, in the usual manner. or an acid imidazolide, and then reacted with a suitable hydroxyl compound of formula HOR ⁷ . This reaction can be carried out in conventional solvents and often requires the addition of a base such as triethylamine, pyridine, imidazole or diazabicycloundecane. These two steps can also be simplified, for example by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as carbodiimide.

In addition, the compounds of formula I may also be prepared starting from salts of the corresponding carboxylic acids, ie compounds of formula I in which R ¹ represents a COOM group in which M may be an alkali metal cation or an equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R ⁷ -A, wherein A is a customary nucleofugic leaving group, e.g. a halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl, for example, toluenesulfonyl and methylsulfonyl that may be substituted halogen, alkyl or haloalkyl, or other equivalent leaving group. Compounds of formula R ⁷ -A that contain a reactive substituent A are known or can be readily prepared using general knowledge. This reaction can be carried out in the usual solvents and a base addition is preferred, in which case the abovementioned bases are suitable.

In some cases, it is necessary to use generally known methods using protecting groups for the preparation of the compounds of formula I according to the invention. If, for example, R ⁶ = 4-hydroxyphenyl, the hydroxyl group may initially be protected as a benzyl ether, which is then cleaved off at a suitable stage in the reaction process. Compounds of formula I wherein R ¹ is tetrazole can be prepared as described in WO 96/11914.

From the viewpoint of biological activity, such carboxylic acid derivatives of the formula I are preferred - both pure enantiomers and pure diastereoisomers or mixtures thereof - in which the substituents have the meanings defined below:

-12r ² is hydrogen, hydroxy, N (-C ₄ alkyl) 2, -C ₄ -alkyl, -C ₄ -haloalkyl, _Ci-4 alkoxy group, -C ₄ haloalkoxy, -C ₄ alkylthio, halogen;

X is halogen, trifluoromethyl;

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

R ⁴ and R ⁵ are phenyl or naphthyl which may be substituted by one or more, for example one or three, of the following radicals such as: halogen, cyano, hydroxy, mercapto, amino, C 1 -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₄ -alkylthio, NH (C 1 -C ₄ -alkyl) 2, N (C 1 -C ₄ -alkyl) ₂ , C 1 -C ₄ alkylcarbonyl, C 1 -C _{4 A 4-} alkoxycarbonyl group;

a phenyl or naphthyl group ortho-bonded to each other by a direct bond, and a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, or an SO ₂ , NH or N (C ₁ -C ₄ alkyl) group;

a five-membered heteroaromatic radical containing one or two nitrogen atoms and / or a sulfur or oxygen atom which may carry one or two halogen atoms and / or one or two of the following radicals, such as; -C ₄ -alkyl, C _r C ₄ alkoxy group, a phenyl group which in turn can carry one to three halogen atoms and / or one to three of the following radicals: -C ₄ -alkyl, -C ₄ - alkoxy or C ₁ -C ₄ -alkylthio;

or a C3-C7-cycloalkyl group;

R ⁶ represents a C ₃ -C ₆ -alkyl group, a C ₃ -C ₆ -alkenyl group, a C ₃ -C ₆ alkynyl group or a C ₃ -C ₈ -cycloalkyl group, which residues may in each case be mono- or polysubstituted by a substituent such as: halogen, hydroxy, cyano, C _r C ₄ -alkoxy, C ₃ -C ₆ -alkenyloxylová group, a C ₃ -C ₆ alkynyloxy

-13skupina, C4-alkylthio, _Ci-C4 -halogénalkoxylová group, a C 1 -C 4 alkyl-carbonyl, hydroxycarbonyl, Ci-C4-alkoxycarbonyl, NH _(Cl-C4 alkyl) 2, N _(Ci-C4 alkyl) 2, phenoxy or phenyl, wherein the above aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted, with a substituent such as: halogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -haloalkyl; C4-alkoxy, C4-haloalkoxy, R ^12, C ₄ -alkoxycarbonyl, dioxomethylene, ethylene-dioxo, C1 -C4 alkylthio, phenyl or phenoxy;

phenyl or naphthyl which may be substituted by one or more of the following radicals such as: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 alkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, phenoxy, C 1 -C ₄ -alkylthio, NH (C 1 -C 4 -alkyl) 2, N (C 1 -C ₄ -alkyl) ₂ ;

a five- or six-membered heteroaromatic radical 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 radicals, such as: C 1 -C ₄ -alkyl group, a C ₁ -C ₄ -haloalkyl, C1 to C4 alkoxy group, a C ₁ -C ₄ -halogénalkoxylová group, a C -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five of the carbon halogen and / or one to three of the following radicals: C _r -C 4 alkyl, -C ₄ -haloalkyl group, a Ci-C ₄ alkoxy group, a C -C ₄ -halo-alkoxy and / or -C ₄ -alkylthio;

R ¹² represents a C ₁ -C ₄ -alkyl group, a C ₁ -C ₄ -alkoxy group which may carry one of the following radicals, such as: hydroxyl, carboxamide or CON (C ₁ -C 4 -alkyl) ₂ ;

means sulfur, oxygen or a single bond.

Particularly preferred are compounds of formula I - both pure enantiomers and pure diastereomers or mixtures thereof - in which the substituents have the meanings defined below:

R ² represents C ₄ -alkyl, C _r C 4 alkoxy, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

X is fluoro, trifluoromethyl;

R ³ represents C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

R ⁴ and R ⁵ represent a phenyl group (the same or different) which may be substituted by one or more, for example one to three, of the following radicals, such as: halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 -alkoxy, C C ₁ -C ₄ -alkylthio;

R ⁴ and R ⁵ are phenyl groups which are ortho-bonded to each other by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO ₂ , NH or N (C 1 -C 4 alkyl) group; or a thiazole, oxazole, thiophene or furan, wherein the above heteroaromatic radicals may be mono- to disubstituted by halogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy;

R ⁴ and R ⁵ is cyclohexyl;

R ⁶ is C 1 -C 6 -alkyl, C ₃ -C 6 -alkenyl or C ₃ -C ₈ -cycloalkyl, these radicals in each case being mono- or polysubstituted by a substituent such as: halogen, hydroxyl, cyano, C 1 -C ₄ -alkoxy, C ₃ -C ₆ alkenyloxy, C ₁ -C 4 -alkylthio, phenoxy or phenyl, wherein the above aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted with a substituent such as, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, dioxomethylene, dioxoethylene, C 1 -C 4 -alkylthio;

-15-phenyl or naphthyl which may be substituted by one or more of the following radicals, such as: halogen, nitro, cyano, hydroxyl, amino, C ₁ -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ - alkoxy, _halo-Ci-C4 alkoxy, phenoxy, -C ₄ -alkylthio, C ₄ alkylamino, or -C ₄ -dialkylamino;

five- or six-membered heteroaromatic radicals which contain a nitrogen atom and / or a sulfur or oxygen atom, which may carry one to four halogen atoms and / or one to two of the following radicals, such as: C 1 -C ₄ -alkyl, C 1 -C _{4 4-} haloalkyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals, such as: C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy and / or C ₁ -C ₄ -alkylthio;

Y is sulfur, oxygen or a single bond.

The compounds of the present invention provide novel therapeutic options for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral angiospasm, cerebral ischemia, haemosclerosis, subarachteria, subarachteria , endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, hypertension or renal failure caused by ischemia or intoxication, metastasis and growth of mesenchymal renal tumors, pancreatic ulcer, dysfunction.

The invention further relates to combinations of endothelin receptor antagonists of formula I and inhibitors of the renin-angiotensin system. The reninangiotensin system inhibitors are renin inhibitors, angiotensin-11 antagonists and angiotensin converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of formula I and ACE inhibitors are preferred.

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

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

Still further, the invention relates to combinations of endothelin receptor antagonists of formula I and agents that block the effect of VEGF (vascular endothelial growth factor). Such agents are, for example, antibodies directed against VEGF or specific binding proteins or other low molecular weight agents capable of inhibiting the release of VEGF or specific receptor binding.

The above combinations may be administered concurrently or one after the other at different times. They can be used either in a simple pharmaceutical preparation or in separate preparations. The forms of use may also vary, for example, endothelin receptor antagonists may be administered orally and VEGF inhibitors parenterally.

These combination preparations are particularly suitable for the treatment and prevention of hypertension and the resulting diseases, as well as for the treatment of cardiac insufficiency.

The high potency of the compounds can be demonstrated by the following experiments:

Receptor Binding Studies

In receptor binding studies Cloned human ET _A or ET _B receptor-expressing CHO cells.

Preparation of membranes

ET _A or ET _b receptor-expressing CHO cells were cultured in DMEM NUT MIX F ₁₂ medium (Gibco, No. 21331-020) containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM. glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100g / ml streptomycin (Gibco, Sigma No. P-0781). Mon 48

For 17 hours, cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.

For membrane preparation, cells were diluted to a concentration of 10 ⁸ cells / ml buffer (50 mM trisHCl buffer, pH 7.4) and then disintegrated by sonication using Branson Sonifier 250, for 40-70 seconds / constant 20.

Bonding tests

For ET _and and ET _B receptor binding assays, membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl 2, 40 mg / ml bacitracin and 0.2% BSA) at a concentration of 50 µg protein per mixture. samples and incubated at 25 ° C with 25 µM [ ¹²⁵ J] ET 1 (ETα receptor sample) or 25 µM [ ¹²⁵ J] ET 3 (ETb receptor sample) in the presence and absence of test compound. Non-specific binding was determined using 10 ' ⁷ M ET 4 After 30 minutes filtration through GF / B glass fiber filters (Whatman, England) was performed in a Skatron cell collector (Skatron, Lier, Norway) to separate free and bound radioligands. and the filters were washed with ice-cold tris-HCl buffer, pH 7.4, containing 0.2% BSA. The radioactivity retained on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional blood vessel assay to determine endothelin receptor antagonists

Rabbit aorta segments were initially induced to contract with K ⁺ after an initial tension of 2 g and a relaxation time of 1 hour in Krebs-Henseleit solution at 37 ° C and pH 7.3-7.4. After washing, the endothelin dose effect diagram was constructed to the maximum.

A potential endothelin antagonist is administered to other formulations within the same vessel 15 minutes before the start of recording the effect of the endothelin dose. The effects of endothelin were calculated as a percentage of the K ⁺ -induced contraction. Effective endothelin antagonists caused a shift to the right in the endothelin dose effect diagram.

In vivo testing of ET antagonists:

-18 Samples of SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and sacrificed. The carotid artery and jugular vein were catheterized.

In control animals, intravenous administration of 1 mg / kg ET1 resulted in a clear increase in blood pressure that persisted over a relatively long period.

Test animals received an intravenous injection of test compound (1 ml / kg) 30 minutes prior to ET1 administration. To determine ET-antagonistic properties, changes in blood pressure in the test animals were compared with the values for the control animals.

Oral testing of mixed ET _A and ET _B antagonists:

Male rats weighing 250-350 g with normal tone (Sprague Dawley, Janvier) were pretreated orally with test substances. 80 minutes later, the animals were anesthetized with urethane and A. carotis (for blood pressure measurement) and V. jugularis (administration of large amounts of endothelin / endothelin 1) were catheterized.

After the stabilization phase, a large amount of endothelin (20 gg / kg, injection volume 0.5 ml / kg) or ET1 (0.3 mg / kg, injection volume 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were continuously recorded for a period of 30 minutes. Obvious and persistent changes in blood pressure were calculated as the area under the curve (AUC). To determine the antagonist effect of the test substances, the AUC of the treated animals was compared to the AUC of the control animals.

The compounds of the present invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) by conventional means. Administration can also be by vapor or spray through the nasopharynx cavity.

The dose depends on the age, condition and weight of the patient and the route of administration. The daily dose of active ingredient is about 0.5 to 50 mg / kg body weight for oral administration and about 0.1 to 10 mg / kg body weight for parenteral administration.

The novel compounds may be used in conventional solid or liquid pharmaceutical forms of administration, for example, as uncoated or film-coated tablets, capsules, powders, granules, lace, solutions, ointments, creams or sprays. These are prepared in the usual manner. For this purpose, the active substances may be formulated with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release retardants, antioxidants and / or propellants (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way usually contain from 0.1 to 90% by weight of active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis examples

Example 1

2- (4,6-Dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid methyl ester

1.0 g (3.5 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester dissolved in DMF was added dropwise to a suspension of 0.18 g NaH (4.2 mmol, 55% in DMF). white mineral oil) in 10 ml DMF. The mixture was stirred at room temperature for 30 minutes and then mixed with 830 mg (4.8 mmol) of 4,6-dimethoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 mL of DMF and stirred at room temperature for 2 hours. The reaction mixture was poured onto ice-water and extracted three times with diethyl ether. The ether phases were dried with magnesium sulfate and then filtered, and the solvent was removed under reduced pressure. The brown residue (1.7 g) was purified by MPLC to give 1.3 g of the desired product which was used directly in the next reaction.

Example 2

2- (4,6-Dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (A) and

-20 2- (4-Methoxy-5-fluoro-6-hydroxypyrimidin-2-yloxy) -3-methoxy-3,3-diphenyl-propionic acid (B)

1.3 g (2.9 mmol) of 2- ( _4L 6-dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid methyl ester were dissolved in 10 ml of dioxane and mixed with

5.9 ml of 1 N KOH solution. The mixture was stirred under reflux for four hours. Water was added to the reaction mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The residue was taken up in ether and 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: ¹ H NMR (CDCl ₃ , 500 MHz): 7.2-7.45 (m, 10H); 6.05 (s, 1 H); 3.95 (s, 6H); 3.3 (s, 3H)

Melting point: 168-170 ° C

B: ¹ H NMR (DMSO, 250 MHz): 7.1-7.4 (m, 10H); 6.05 (s, 1 H); 3.9 (s. 3H); 3.3 (s, 3H)

M.p .: 115-117 ° C

Example 3

2- (4-Morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid benzyl ester

3.3 g (9 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid benzyl ester and 4-morpholino-5-fluoro-2-chloropyrimidine dissolved in DMF were added dropwise to a suspension of 9.96 g of K ₂ CO ₃ (72 mmol) in 40 mL DMF. The mixture was stirred initially at 90 ° C for 3 hours and then at 130 ° C for 3 hours. The reaction mixture was poured onto ice-water and extracted three times with ethyl acetate. The ethyl acetate phase was dried using magnesium sulfate and then filtered, and the solvent was removed under reduced pressure. The brown residue (5.72 g) was purified by MPLC and used directly in the next reaction.

Example 4

2- (4-Morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid

-21 Using 300 mg of palladium on charcoal (10%), a solution of 0.9 g of 2- (4-morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid benzyl ester in 30 ml of ethyl acetate was hydrogenated with hydrogen at atmospheric pressure at room temperature for 3 hours. The reaction mixture was filtered and 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, 1 H); 3.8 (s. 8H);

3.3 (s, 3H)

Melting point: 174-175 ° C

The compounds listed in Table 1 can be prepared in a similar manner.

CM CM

I

Table 1

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about about about about 1 about about about about about 1 1 about ABOUT ll LL LL LL LL LL LL LL LL LL LL LL LL LL ω S Φ Σ n LL Φ rt U_ Φ 0) Φ Φ Φ WITH Φ S Φ p Φ about ABOUT about with about 5 with WITH WITH about ύί about about with Φ 5 O a) S LU O s o Φ Σ O φ 5 φ s UJ UJ φ S O LLJ Φ o O s o O s o > > Ί >> > >, Q. Σ >> > > >> Q. Q. *> » 4-4 *> 4-4 Φ 0) 0) Π) about Φ <u φ <u Φ about p Φ (D E E E E Q. E E E E E Q Q E E -phenyl | Mephenyl I > c > c • « e-phenyl > c φ T LL ABOUT LL > C > c > c > c > c > c > c > c LL 1 CO 1 CO Φ 1 CO Ä <D φ H Ä d) H Φ ** - Φ Ä 1 CO I T x x x HSOzphenyl «X o O ω x WHAT FROM <*) X o <<4 O ω x >, O N (0 x x x x about about about about ABOUT from from about from about ABOUT about about about about about about about about ABOUT about about C ABOUT about about about about about about about about about about Q about about υ about about about about CM WHAT m WHAT b- WHAT a> about IN" C \ | what b * b- b- b- b * b- b- b- b * · WHAT WHAT 00 WHAT T " 1 1 in « in in 1 * 7 1 7 1 1 1 in

ΟΧΙ

I

Table 2

N ABOUT about about about about about about about about about about about about X LL u. LL LL U- LL ll U- ll ll ll ll u. 0> m (U ra ra ra ra ra ra ra ra ra ra WITH WITH 5 WITH WITH 5 WITH WITH Σ WITH WITH WITH WITH qí about ABOUT ABOUT ABOUT ABOUT 0 ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ω ω ra ra ra ra cu d) d) d) Φ Φ d) with WITH 5 5 WITH WITH WITH Σ with with with with 0L about ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about about about about about > 1 » x L X c d) about ABOUT L 1 > > and o x o > Q o Q 1 ¼ > > > > > about Q O > N cm n Q O <D ra ra ra Q) 0) d) about > 0I E E E E E E E .y Á .and d) ABOUT ABOUT CM X X cn x x x x ra at about (Λ ra ra it C) <) C) xa L II xa xa xa II 11 II N x x x X N N N X x X < > about about about ABOUT ω from > > > about about about I T x x X x x x x x x x x about about about about about about about about about about about about about about about about about about about about about about ABOUT about about about oL about about about about about about about about about U at about about about CM WHAT T " CM WHAT T it 0? b- 00 cp ▼ T " * 7 •ABOUT 1 1 1 1 1 1 1 1 1 1

-29Example 5

Using the binding assays described above, receptor binding data for the compounds listed below was measured.

The results are summarized in Table 3.

Table 3

Receptor Binding Data (K; values)

compound ET _A [nM] ET _B [nM] 1-2 7.4 1200 1-121 61 > 10000 1-168 4000 > 7000

Claims (8)

A carboxylic acid derivative of the formula I PV 1151-2000 in which ^R1 is tetrazole or a group of II C-R R represents: (a) radical OR ⁷ where R ⁷ represents: hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion or an ammonium ion; C -C cycloalkyl group, a dripping-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C _r C ₄ -alkyl, C ₄ -haloalkyl group, a hydroxyl group, a C _r C ₄ alkoxy, mercapto, _{Ci-C4-alkylthio,} amino, NH _(Ci-C4 alkyl), N (C ₁ -C ₄ -alkyl) _2; A C ₃ -C 6 -alkenyl or a C ₃ -C ₆ -alkynyl group, which groups themselves may carry one to five halogen atoms; R ⁷ may further represent a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals, such as nitro, cyano, C 1 -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, hydroxyl, C ₁ -C ₄ alkoxy, mercapto, _Ci-C4 -alkylthio, amino, NH (C _r C ₄ alkyl), N _(Ci-C4 alkyl) _2; b) 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms, or a single or two Ci-C ₄ -alkyl or one or two -C ^ alkoxy groups. c) - o- <ch ₂ ) _p -s-r ⁸ wherein k can be 0, 1 or 2, p can be 1, 2, 3 or 4 and R ⁸ is C 1 -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or phenyl which may be substituted by one or more, for example one to three, of the following radicals, such as halogen, nitro, cyano, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, mercapto, amino, NH (C 1 -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) 2. (d) the rest -.- L · ^H II on where R ⁹ represents: C ₁ -C ₄ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C 6 -alkynyl, C ₃ -C ₈ -cycloalkyl, these radicals may carry C ₁ -C ₄ -alkoxy, C 1 -C ₄ -alkylthio and / or or a phenyl radical as mentioned under c); phenyl, which may be substituted by one to three of the following radicals such as halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C 1 -C 4 -haloalkyl, hydroxyl -32skupina, C4-alkoxy, -C ₄ -alkylthio, mercapto, amino, NH (C _r C ₄ alkyl), N _(Ci-C4 alkyl) _second R ² is H, OH, NH _2, NH (C _{r C4} alkyl), N _(Ci-C4 alkyl) _2, halo, C _R -C ₄ alkyl group, a C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -hydroxyalkylovú group -C ₄ haloalkyl, _Ci-C4 alkoxy group, -C ₄ haloalkoxy or C ₁ -C ₄ alkylthio, morpholine; X represents halogen, C ₁ -C ₄ -haloalkyl, hydroxyl; R ³ is H, OH, NH ₂₁ NH (-C ₄ alkyl), N (C _r C ₄ alkyl) _2, halo, C _r C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ C ₄ -alkynyl, -C ₄ -hydroxyalkylovú group, a Ci-C ₄ haloalkyl, C _r C ₄ alkoxy group, C ₄ haloalkoxy, -NH-OC- | -C ₄ -alkyl, -C ₄ alkylthio; R ⁴ and R ⁵ (which may be the same or different) represents a phenyl or naphthyl group which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C _r C ₄ alkyl, C _r C ₄ haloalkyl group, a C _r C ₄ alkoxy group, C ₄ -halogénalkoxylová, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C4-alkylthio, amino, NH _(Ci-C4 alkyl), N (C _r C ₄ -alkyl) _2; or phenyl or naphthyl which are ortho-linked to each other via a direct bond, methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an _SO2 -, NH-- or Nalkylovej group; or a five- or six-membered heteroaromatic radical containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following: -33zvyškov as C _r C ₄ -alkyl, -C ₄ -haloalkyl group, -C ₄ -alkoxy, -C ₄ -halogénalkoxylová group, a C _r C ₄ alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals in turn can carry one to five halogen atoms and / or one to three of the following radicals: -C ₄ -alkyl, -C ₄ -haloalkyl group, $ -C ₄ -alkoxy, _Ci-4 -halogénalkoxylová group and / or _CR C ₄ -alkylthio; * or a C3-C7-cycloalkyl group; R ⁶ is hydrogen, C ₁ -C ₈ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, these radicals in each case being mono- or polysubstituted by a substituent such as hydroxyl , mercapto, carboxyl, halogen, nitro, cyano, C _r C ₄ -alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ -alkinyloxylová group, a C _r C ₄ alkylthio group -C ₄ -halogénalkoxylová, -C ₄ -alkylcarbonyl, C _r C ₄ -alkoxycarbonyl, C ₃ -C ₈ alkylcarbonylalkyl, amino, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2, phenyl or phenoxy which may be mono- or polysubstituted, for example phenyl or phenoxy which may be mono- to trisubstituted by halogen, nitro, cyano, C _r • C ₄ alkyl, -C ₄ -haloalkyl group, -C ₄ -alkoxy, C _r C ₄ -haloalkoxy or C ₁ -C ₄ -alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C _r C ₄ -alkyl, -C ₄ -haloalkyl group, a C ₄ -alkoxy Cr group, a C _r C ₄ -halogénalkoxylová, phenoxy, C ₄ -alkylthio, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) ₂ or dioxomethylene or dioxoethylene; -34 five- or six-membered heteroaromatic radical containing one to three nitrogen atoms and / or one sulfur or oxygen atom, which may carry one to four halogen atoms and / or one to two of the following radicals, such as a C 1 -C 4 -alkyl group , -C ₄ -haloalkyl group, -C ₄ -alkoxy, -C ₄ -halo-alkoxy, C _r C ₄ alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals for their part may for their part carry one to five of the carbon halogen and / or one to three the following radicals: -C ₄ alkyl, -C ₄ haloalkyl, -C ₄ -alkoxy-, C _r -C ₄ haloalkoxy, and / or -C ₄ -alkylthio; with the proviso that R ⁶ can only represent hydrogen if Z is not a single bond; Z is sulfur, oxygen or a single bond. and physiologically acceptable salts and enantiomerically pure as well as diastereomerically pure forms. Use of the carboxylic acid derivatives of the formula I according to claim 1 for the treatment of diseases. Use of compounds of formula I according to claim 1 as endothelin receptor antagonists. Use of the carboxylic acid derivatives of formula I according to claim 1 for the preparation of medicaments for the treatment of diseases associated with elevated endothelin levels. Use of the carboxylic acid derivatives of formula I according to claim 1 for the preparation of medicaments for the treatment of diseases in which endothelin contributes to the development and / or progression. Use of the carboxylic acid derivatives of formula I according to claim 1, for the treatment of chronic cardiac insufficiency, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. A combination comprising carboxylic acid derivatives of formula I according to claim 1 and one or more active compounds selected from inhibitors of the renin-angiotensin system, such as renin inhibitors, angiotensin-11 antagonists, angiotensin converting enzyme (ACE) inhibitors ), mixed ACE / neutral endopeptidase (NEP) inhibitors, beta-blockers, diuretics, calcium antagonists and VEGF-blocking agents. * 8. The preparation of medicaments for oral, parenteral and intraparenteral administration which: With a single dose, in addition to the usual pharmaceutical excipients, it comprises at least one carboxylic acid derivative of the formula I according to claim 1.