BG104577A - 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 wherein the substituents have the following meaning: R1 = tetrazole or a group R = a radical OR7 a 5-member red heteroaromatic bonded by a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and trizolyl; R2, R3 = hydrogen, hydroxy, NH2, NH2(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen,C1-C4-alkyl, C2-C4-alkenyl,C2-C4-alkinyl, C1-C4-hydoxyalkyl, C1-C4-alkpxy, C1-C4 halogen alkyl, C1-C4-alkoxy, C1-C4 halogen alkoxy, or C1-C4-alkylthio; X = halogen,C1-C4-halogen alkyl, hydroxy; R4 and R5 = phenyl or naphthyl, C3-C7-cycloalkyl, phenyl or naphthyl which are bonded in ortho position by a direct bond, a methylene, ethylene or ethylene group, an oxygen or sulfur atom or an SO2-NH or an N-alkyl group or a 5-membered or 6-membered heteroaromatic; R6 = hydrogen, phenyl or naphthyl, a five or six-membered heteroaromatic, C1-C8-alkyl,C3-C6-alkenyl,C3-C6 alkynyl or C3-C8-cycloalkyl, whereby said radicals can be substituted once or many times, with the proviso that R6 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. 8 claims

Description

Technical field

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

BACKGROUND OF THE INVENTION

Endothelin is a peptide made up of 21 amino acids that is synthesized and released by the endothelium of the vascular system. It exists in three isomeric forms, designated ET-1, ET-2 and ET-3. In the following description, endothelin or abbreviation ET means one or all isomeric forms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on the tone of the vessels. This vasoconstrictor effect is known to be caused by binding of the 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 abnormal endothelin secretion causes strong contractions in the peripheral, renal or cerebral blood vessels, which can lead to disease. As described in the literature, endothelin plays a role in a number of diseases. Such are, for example, hypertension, acute

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myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, cerebral hemorrhage, benign prostatic hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 1 14 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1 732 (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, namely the ETd- and ΕΤβ-receptors, have been described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to one or both of these receptors are required to antagonize the physiological effects of endothelin and thus be valuable pharmaceutically active agents.

WO 95/26716, WO 96/11914, WO 97/9294, WO 97/12878, WO 97/38980, WO 97/38981 describe carboxylic acid derivatives and their use as andotelin antagonists. These compounds have the N-atom or group at the 5-position of the heterocycle

The compounds of the present invention, in contrast to the above, are grouped in the 5th position

- X in which X is halogen, hydroxy and C 1 -C 4 haloalkyl.

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The compounds of the invention show more favorable metabolic degradation in the body than known endothelin antagonists.

SUMMARY OF THE INVENTION

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

in which R has the following meanings:

(a) a residue OR ⁷ in which R ⁷ means:

hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, such as a tertiary C 1 -C 4 alkylammonium or ammonium ion;

C3-C4-cycloalkyl, C1-C8-alkyl, CH3-phenyl, which may be substituted by one or more of the following substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy , C 1 -C 4 -alkoxy, mercapto, C 1 -C 4 alkylthio, amino,

NH (C1-C4-alkyl), N (C1-C4-alkyl) 2!

A C3-C6-alkenyl or C3-C6-alkynyl group, which in turn may be substituted by one to five halogen atoms,

R ⁷ may also mean a phenyl moiety which may be substituted by one to five halogen atoms and / or one to

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Three of the following substituents: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, Cf-C 4 alkoxy, mercapto, C 1 -C 4 ^alkyl * thio, amino,

NH (C- | -C4 -alkyl ^l), N (C- | - C4-alkyl) 2!

b) bonded by a nitrogen atom to a 5-membered heteroaromatic ring, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may be substituted by one to two halogen atoms, or by one to two C 1 -C 4 -alkyl groups or by one to two C1-C4-alkoxy groups;

c) the group ⁽ item

--- O-- (CH ₂ ) _P - S --- R ⁸ in which k is the number 0,1 and 2, p is the number 1, 2, 3 and 4 and

R ⁸ means

C1-C4-alkyl, C3-C3-cycloalkyl, C3-C3-alkenyl, C3-C3-alkynyl or phenyl, which may be substituted by one or more, e.g. with one to three of the following substituents:

halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, Cf-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH (C1-C4-alkyl), N (C - (C 4 -alkyl) 2,

d) the remainder

Oh

II-, --NS --R ^{9 n} II o

in which R ® means

C1-C4-alkyl, C3-C3-alkenyl, C3-C3-alkynyl, C3-C3-cycloalkyl, wherein these residues may be substituted by one

00/1 49/02-PB ·· · ·· ···· ·· ·· ft · · ·· · ft ft · ft ···· · ft · ft ··· • · ft ··· ·· · · · · · · · · · · · · · · · · · · · · · · · · ·

C 1 -C 4 alkoxy, C 1 -C 4 -alkylthio and / or phenyl residue as indicated in c), phenyl optionally substituted by one to three of the following substituents: halogen, nitro, cyano, -C 1-4 alkyl , C 1 -C 4 -halogenalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylthio, mercapto, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2 ·

Other substitutes have the following meanings:

R2 is hydrogen, hydroxy, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C 1 -C 4 ^and DR ^oxyalkyl -C 4 -haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 -halogenoxy or C 1 -C 4 -alkylthio, morpholine;

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

R 3 is hydrogen, hydroxy, amino, N (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoxy, -N-O-C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio;

R ⁴ and R ⁵ (which may be the same or different) have the following meanings:

phenyl or naphthyl which may be substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, -C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or phenyl or naphthyl which are linked together in orthography by direct bonding, by the methylene, ethylene or ethylene groups, by oxygen or sulfur, or by the SO2-, NH- or N-alkyl group;

a five or six membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom which

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has as one substituent one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoalkoxy, C 1 - C 1-6 alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl moieties may, in turn, have as substituents one to five halogen atoms and / or one to three of the following residues: C 1 -C 6 -alkyl, C-C 6 -haloalkyl, C - C 1 -C 6 -alkoxy, C 1 -C 4 -halogenoalkoxy and / or C- | -C1-6 alkylthio;

or C3-Sucycloalkyl;

R ⁶ is hydrogen,

C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 6 cycloalkyl wherein these moieties may be substituted by one or more of the following substituents: hydroxy, mercapto, carboxy, halogen, nitro, cyano , C 1 -C 4 -alkoxy, C ₃ -C 6 -alkenyloxy, C ₃ -C 4 -alkynyloxy, C ₁ -C 4 -alkylthio, C 1 -C 6 -halogenoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 6 - alkoxycarbonyl, C ₃ -C ₆ alkylcarbonylalkyl, amino, NH (C 1 -C 6 alkyl), N (C 1 -C 6 alkyl) 2, phenoxy or phenyl, wherein said aryl moieties may in turn be substituted once or repeatedly, e.g. with one to three of the following substituents: halogen, nitro, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, C 1 -C 6 alkoxy, C 1 -C 6 halogenalkoxy, mercapto, carboxy, hydroxy, amino, R ¹² , C- C 1-6 alkoxycarbonyl, NH (C 1 -C 6 alkyl), N (C 1 -C 6 alkyl) 2, dioxomethylene, dioxoethylene, C 1 -C 6 alkylthio, substituted phenyl or phenoxy;

phenyl or naphthyl, which may be optionally substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, amino, C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, C 1 -C 4 -alkoxy, C- | -C 1 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio,

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• · · · · · · · · ·

· · · · · · · · · · · · · · · · · · · ·

NH (C1-C4-alkyl), N (C1-C6-alkyl), dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom having as a substituent one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C - C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl moieties may in turn have as substituents one up to five halogen atoms and / or one to three of the following residues: C 1 -C 4 alkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy and / or C 1 -C 4 -al kiltio, provided that R6 can mean hydrogen only when Z does not mean a simple bond;

Fd 2 is C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxy, which may be substituted by one of the following residues: hydroxy, carboxy, amino, NH (C 1 -C 4 - alkoxy). C4-alkyl), N (C1-C4-alkyl) 2, carboxamide or CON ((C1-C4-alkyl) 2!

Z is sulfur, oxygen or a simple bond.

The following definitions apply here:

The alkali metal is e.g. cast, sodium, potassium. Alkaline earth metal is e.g. calcium, magnesium, barium. Organic ammonium ions are protonated amines, such as e.g. ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine;

C3-Sucycloalkyl is e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The C 1 -C 4 haloalkyl group may be straight or branched carbon, e.g. fluoromethyl, difluoromethyl,

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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- Trifluoroethyl or pentafluoroethyl.

The C 1 -C 6 -halogenalkoxy group may be straight or branched carbon, e.g. 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.

The Cf-C4 alkyl group may be straight or branched carbon, such as e.g. methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl.

The C2-C4 * alkenyl group may be straight or branched carbon, such as e.g. ethenyl, 1-propen-3-yl,

1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or

2- Butenyl.

The C2-C4-alkynyl group may be straight or branched carbon, such as e.g. ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl.

The C 1 -C 4 -alkoxy group may be straight or branched carbon, such as e.g. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1 dimethylethoxy.

The C3-C6-alkenyloxy group may be straight or branched carbon, such as e.g. allyloxy, 2-buten-1yloxy or 3-buten-2-yloxy.

The C3-C3-alkynyloxy group may be straight or branched carbon, such as 2-propin-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy.

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The C 1 -C 4 -alkylthio group may be straight or branched carbon, such as e.g. methylthio, ethylthio, propylthio, 1methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio.

The C1-C6-alkylcarbonyl group may be straight or branched carbon, such as e.g. acetyl, ethylcarbonyl or 2-propylcarbonyl.

The C 1 -C 4 -alkoxycarbonyl group may be straight or branched carbon, such as e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl.

The C3-C6-alkylcarbonylalkyl group may be straight or branched carbon, such as e.g. 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl.

C -] - Cd-al carbyl group may be straight or branched carbon, such as e.g. C1-C6-alkyl, pentyl, hexyl, heptyl or octyl.

The halogen atom is e.g. fluorine, chlorine, bromine, iodine.

Another object of the invention are compounds which can release compounds of formula I (so-called precursors).

Such precursors are preferred to release the active compounds under conditions that exist in certain organs of the body, e.g. in the stomach, intestines, circulation, liver.

The compounds of formula I, as well as intermediates for the preparation thereof, e.g. compounds of formulas II and IV may contain one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers, respectively pure diastereomers or as their

00/1 49/02-PB • · · · · · · · mixtures. It is preferred to use the pure enantiomers of the compounds as active substances.

It is also an object of the invention to use the carboxylic acid derivatives described above for the preparation of medicaments, in particular for the preparation of endothelin receptor inhibitors.

The preparation of compounds of general formula IV in which Z is sulfur or oxygen (formula IVa) can be carried out as described in WO 96/11914.

The compounds of general formula III are known or may be prepared e.g. by reduction of the corresponding carboxylic acids, their esters, or by other methods known per se.

The compounds of formula IVa can be obtained in the enantiomerically pure form by acid catalytic transesterification, as described in patent specification DE 19636046.3.

In addition, enantiomerically pure compounds of formula IVa may be obtained upon leaving racemic or diastereomeric compounds of formula IVa, which are subjected to classical racemate separation using appropriate enantiomerically pure bases. Such bases are suitable e.g. 4J chlorophenylethylamine as well as the bases specified in the patent

J | Description WO 96/11914.

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Compounds of general formula IV, in which Ζ means a simple bond (formula IVb) can also be prepared in racemic and enantiomerically pure form by the method described in patent description WO 97/38981, by the following scheme:

R ⁴

N.

C = O

R ⁴

N with — he

R ¹

IVb

The compounds of the invention in which the substituents have the meanings given in formula I can be obtained e.g. by reacting carboxylic acid derivatives of general formula IV, in which the meanings of the substituents are indicated above with compounds of general formula V.

In Formula V, the substituent R 1 θ is halogen or R ¹¹ -SO 2 -, wherein R ¹¹ is C 1 -C 4 -alkyl, C 1 -C 6 -halogenalkyl or phenyl. The reaction is preferably carried out in an inert solvent or diluent with the addition of a base, i.e. a base which is deprotonating on the intermediate of Formula IV, within the temperature range from room temperature to the boiling point of the solvent.

Compounds of the type of formula I in which R1 is COOH can also be prepared directly by deprotonation of

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• 9

9999

···· • · ·· • 9 99

9 99

9 99

9999 is an intermediate of formula IV in which R ¹ is COOH with two equivalents of a suitable base and reacted with compounds of general formula V. Here, too, the reaction is carried out in an inert solvent and at a temperature ranging from room to temperature.

the solvent boiling round.

Examples of such solvents or diluents, respectively, are aliphatic, alicyclic or aromatic hydrocarbons, which may optionally be chlorinated, e.g. hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, tetrachloromethane, ethyl chloride and trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert. butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile, propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.

The compounds of formula V are known, some of which are commercially available or can be prepared in a known manner.

As 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, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali amide, such as lithium diisopropylamide.

Compounds of formula I may also be prepared by use as starting materials of the corresponding carboxylic acids, i.e., compounds of formula I in which R 1 is COOH, which in a known manner is converted to the active form, e.g. acid halide, anhydride or imidazole derivative which thereafter

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is reacted with the corresponding hydroxyl derivative of formula HOR ⁷ . This interaction takes place in conventional solvents and the addition of a base such as e.g. triethylamine, pyridine, imidazole or diazabicycloundecane. These two steps may e.g. are easier to carry out when the carboxylic acid is allowed to react with the hydroxyl derivative in the presence of a water-withdrawing agent such as carbodiimide.

In addition, the compounds of formula I can be prepared when salts of the corresponding carboxylic acids are used as starting materials, i. compounds of formula I in which R ¹ is the COOM group, wherein M is an alkali metal cation or an alkaline earth metal cation equivalent. These salts can be reacted with many compounds of formula R ⁷ -A, wherein A represents a conventional nucleic-bound cleavage group, e.g. halogen, such as chlorine, bromine, iodine or optionally substituted by halogen, alkyl or halogenoalkyl aryl or alkylsulfonyl, such as e.g. toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of formula R ⁷ -A containing reactive substituent A are known or can be readily prepared by methods known to those skilled in the art. This interaction can be carried out in conventional solvents and is advantageous to occur in the presence of a base, having regard to the bases mentioned above.

In some cases, the preparation of the compounds of the invention of formula I requires the use of commonly known protecting group protection techniques. Thus, for example, if R ⁶ represents a 4-hydroxy group, then this hydroxy group may be protected initially as a benzyl ether and then in a suitable

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• ·

step in the reaction sequence the protecting group cleaves.

The compounds of formula I wherein R ¹ is tetrazole can be prepared as described in patent WO 96/11914.

In terms of their biological activity, preferred compounds of formula I - both as pure enantiomers, respectively pure diastereomers, and as mixtures thereof, are those compounds in which the substituents have the following meanings:

R 2 represents hydrogen, hydroxy, N (C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoxy, 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 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoxy, C 1 -C 4 alkylthio, halogen;

R ⁴ and R ⁵ are phenyl or naphthyl which may be substituted by one or more of the following substituents: halogen, cyano, hydroxy, mercapto, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, Cf-C 4 -alkoxy, C 1 -C 4 -halogenoxy, C 1 -C 4 -alkylthio, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, C 1 -C 4 -alkylcarbonyl, C-1 -C4alkoxycarbonyl;

phenyl or naphthyl, which are bonded to each other by direct bonding, by a methylene, ethylene or ethenylene group, by oxygen or sulfur, or by a SO2-, NH- or N (C1-C4-alkyl) group;

a five-membered heteroaromatic ring containing one or two nitrogen atoms and / or one sulfur or oxygen atom having as a substituent one to two halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C 1 - C4-alkoxy, phenyl, which

MB

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may in turn be substituted by one to three halogen atoms and / or one to three of the following residues: C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -alkylthio, or C 3 -C 9 cycloalkyl ;

R ^{6 is} C 1 -C ⁶ -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 cycloalkyl wherein these residues may be substituted by one or more of the following substituents: halogen, hydroxy, cyano, C 1 -C 6 -alkoxy , C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C6-haloalkoxy, C1-C6-alkylcarbonyl, hydroxycarbonyl, C1-C6-alkoxycarbonyl, NH (C1-C6) -alkyl), N (C 1 -C 4 -alkyl) 2, phenoxy, phenyl, wherein said aryl moieties may in turn be substituted once or repeatedly, e.g. with one to three of the following substituents: halogen, C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoxy, R ² , C 1 -C 6 -alkoxycarbonyl, dioxomethylene , dioxoethylene, C 1 -C 4 -alkylthio, phenyl or phenoxy;

phenyl or naphthyl, which may be optionally substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, amino, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C - C 1 -C 10 halogenoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 6 alkyl) 2;

a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom having, as a substituent, one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C - C 1 -C 10 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl moieties may in their turn have one to five halogen atoms as substituents and / or one to three of the following residues: C 1 -C 4 -alkyl,

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• · · ·

C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -halogenoalkoxy and / or C- | -C1-6 alkylthio;

R 12 is C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, which may be substituted by one of the following residues: hydroxy, carboxamide or CON ((C 1 -C 4 -alkyl) 2:

Z is sulfur, oxygen or a simple bond.

Particularly preferred compounds of formula I - both as pure enantiomers, respectively pure diastereomers, and as mixtures thereof, are those compounds in which the substituents have the following meanings:

R 2 represents C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, in particular 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, in particular methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

R ⁴ and R ⁵ are phenyl (simultaneously or separately) which may be substituted by one or more, e.g. with one to three of the following substituents: halogen, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -alkylthio, or

R ⁴ and R ⁵ are phenyl groups which are bonded to each other in the ortho position through a direct bond, through a methylene, ethylene or ethylene ethylene group, with oxygen or sulfur or through a SO 2 -, NH - or N (C 1 -C 4) group -alkyl); or thiazole, oxazole, thiophene or furan, wherein said heteroaromatic compounds may be mono- or polysubstituted with halogen, C1-C4-alkyl, C1-C4-alkoxy,

R ⁴ and R ⁵ are cyclohexyl;

ILHMMC

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R ⁶ is C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -cycloalkyl wherein these residues may be substituted by one or more of the following substituents: halogen, hydroxy, cyano, C 1 -C 4 alkoxy, C 3- Cd-alkenyloxy, C 1 -C 4 -alkylthio, phenoxy or phenyl, wherein said aryl moieties may in turn be substituted once or repeatedly, e.g. with one to three of the following substituents: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, dioxomethylene, dioxoethylene, C 1 -C 4 alkylthio, phenyl or naphthyl, which may be optionally substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoxy, phenoxy, C- -C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;

a five- or six-membered heteroaromatic ring containing one nitrogen atom and / or one sulfur or oxygen atom having as substituents one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C- | -C 4 * halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl moieties may in their turn have as one substituent one to five halogen atoms and / or one to three of the following residues: C 1 -C 4 -alkyl, -C 4 -haloalkyl, C 1 -C 4 alkoxy and / or C 1 -C 4 -alkylthio,

Ζ is sulfur, oxygen or a simple bond.

The compounds according to the invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina, arrhythmia, acute / chronic acute renal failure, chronic heart failure, renal failure, cerebral vasospasmodial spasmodia ,

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migraine, asthma, atherosclerosis, endotoxin-induced shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, renal failure due to hyperoxia, ischemia, metastasis formation and growth of mesenchymal tumors, contrast-induced renal failure, pancreatitis, gastrointestinal ulcer, erectile dysfunction.

Another object of the invention are combinations containing endothelin receptor antagonists of formula I and inhibitors of the renin-angiotensin system. Reninangiotensin system inhibitors are renin inhibitors, angiotensin-antagonists and, above all, angiotensin-converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of formula I and ACE inhibitors are preferred.

Another object of the invention are combinations of endothelin receptor antagonists of formula I and beta-blockers.

Another object of the invention are combinations of endothelin receptor antagonists of formula I and diuretics.

Another object of the invention are 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 and specific binding proteins, as well as low molecular weight substances that release VEGF or may specifically inhibit receptor binding.

The active substances of the above combinations can be applied simultaneously or stepwise one after the other

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in the time. They may be contained in a single application form or in separate gallicum forms. The application forms may also be different. For example, the formulation containing endothelin receptor antagonists may be for oral administration and the VEGF inhibitor may be for parenteral administration.

These combination preparations are particularly suitable for the treatment and maintenance of treatment for high blood pressure and related diseases, as well as for the treatment of heart failure.

The good activity of the compounds can be demonstrated by the following attempts:

Receptor binding studies

Cloned human ETd- or ΕΤβ-receptor-expressing CHO cells are used to investigate receptor binding.

Preparation of membranes

ETd- or ΕΤβ-receptor-expressing CHO cells were grown in ^{DMEM NUT MIX F- | 2- c P®A} a (Gibco, Nr. 21331-020) c containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, Nr . A15 -022), 1 mM glutamine (Gibco, Nr. 25030-024), 100 U / ml penicillin and 100 µg / ml streptomycin (Gibco, Sigma Nr P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 minutes at 37 ° C. The medium was then neutralized and the cells were separated by centrifuge at 300 x g.

For the preparation of membrane preparations, cells, at a concentration of 10 ⁸ cells / ml buffer (50 mM Tris-HCl, pH 7.4)

00/149/02-PB • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · with Branson Sonifier 250, 40-70 seconds / constant / power 20.

Attempts to connect

For the study of ETd- and ΕΤβ-receptor binding, the membranes were suspended in incubation buffer (50 mM TrisHCI, pH 7.4 with 5 mM MnCl2, 40 µg / ml bacitrazine and 0.2% BSA) at a concentration of 50 µg protein per sample and incubated at 25 ° C with 25 pM [ ¹²⁵ J] ET- (ETd-receptortest) or with 25 pM [ ¹²⁵ J] ET3 (ΕΤβ-receptortest), in the presence or absence of the test compounds. Non-specific binding was determined by 10 ⁷ M ET-. After 30 minutes, the free and bound radioactive ligands were separated by filtration through a GF / B glass fiber filter (Whatman, England) in a cell tissue vessel (Skatron, Lier, Norwegen type) and the filter was washed with ice-cold Tris-HCI buffer, pH 7.4 with 0.2% BSA. The total radioactivity of the filters is determined by a Packard 2200 CA scintillator.

functional study of vessels for endothelin-receptor antagonists

Rabbit aortic segments after pre-release in 2 g and a relaxation time of 1 hour in Krebs-Henseleit solution at 37 ° C and pH between 7.3 and 7.4 quenched the K ⁺ contraction. After washing, the endothelin-active dose curve is constructed for maximum values.

Potential endothelin antagonists are administered to other preparations made from the same blood vessel segments, 15 minutes before the endothelin-active dose curve is administered. The effects of endothelin are defined as% of K ⁺ 21

00/149/02-PB contraction. In the presence of active endothelin antagonists, the endothelin-active dose curve shifts to the right.

In vivo study of ET antagonists

Male SD-type rats weighing 250 - 300 g were anesthetized with amobarbital, allowed artificial respiration, weighted, and immobilized. Catheters of Arteria carotis and Vena jugularis are inserted.

The study was performed by intravenously injecting 1 μg / kg of ET1 into control animals until a noticeable increase in blood pressure was observed, which persisted for a longer time.

Of the test animals 30 minutes before the introduction of

ET1 was injected intravenously (1 ml / kg) from the test compound. The determination of the endothelin-antagonist activity of the compounds was performed by comparing the blood pressure increase of the test animals compared with the control animals.

Investigation of mixed ETd- and ETb-receptor binding in oral (p.o.) administration

In male rats weighing 250 - 300 g (Sprague species)

Dawley, Janvier) orally tested compound is administered with normal muscle tone. 80 minutes later, the animals were anesthetized with urethane and catheters were placed on Arteria carotis (for blood pressure measurement) and for Vena jugularis (administration of total endothelin / endothelin 1).

After the stabilization phase, total endothelin (20 µg / kg, administered volume of 0.5 ml / kg) and ET1 (0.3 µg / kg, administered volume of 0.5 ml / kg) were administered intravenously. Blood pressure and heart rate are recorded every 30 minutes. Notable and continued00 / 149/02-PB • · ·· • ο · ·· • ·············

9

Blood pressure changes are calculated as the area under the curve (AUC). To determine the antagonistic activity of the test compounds, a comparison was made between the areas obtained in the treated animals and those obtained in the control animals.

The compounds of the invention can be administered in the usual way, orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). The administration can also be accomplished by inhalation or injection through the nasopharynx.

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

The novel compounds may be used in the form of conventional solid or liquid forms for pharmaceutical use, e.g. such as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are obtained in known ways. In this case, the active substance can be treated with the usual excipients such as tablet binders, fillers, preservatives, swelling agents, density regulators, softeners, binders, dispersants, emulsifiers, solvents, release agents, antioxidants and / or spray gas (see, e.g., N. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The formulations thus obtained typically contain the active substance in an amount of 0.1 to 90 wt. %.

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Examples of carrying out the invention

Examples of preparation

Example 1

2- (4,6-Dimethoxy-5-fluoro-pyrimidin-2-yloxy) -3-methoxy-3,3-diphenylmethylpropionate

To a suspension of 0.18 g NaH (4.2 mmol, 55% in light mineral oil) in 10 ml dimethylformamide was added dropwise 1.0 g (3.5 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylmethylpropionate dissolved in dimethylformamide. After stirring at room temperature for 30 minutes, the mixture was mixed with 830 mg (4.8 mmol) of 4,6-dimethoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 ml of dimethylformamide and the reaction mixture was stirred for 2 hours at room temperature. It is then poured onto ice water and extracted three times with diethyl ether. The ether phases were dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The resulting brown residue (1.7 g) was purified by medium pressure liquid chromatography to isolate 1.3 g of the desired product, which was used directly in the next reaction.

Example 2

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

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

Dissolve 1.3 g (2.9 mmol) of 2- (4,6-dimethoxy-5-fluoro-pyrimidin-2-yloxy) -3-methoxy-3,3-diphenylmethylpropionate in 10 ml of dioxane and add a solution of 5.9 ml of 1N solution. of potassium • · ·· · • ·

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the basis. The mixture was stirred for 4 hours at reflux. Water was added to the mixture and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous hydrochloric acid, extracted with ether, the organic phase dried over magnesium sulfate and the solvent removed by distillation. The residue was dissolved in ether to crystallize 100 mg of product B. The mother liquor was mixed with n-hexane to give 400 mg of product A. as a solid.

Product A: ¹ H-NMR (CDCl ₃ , 500 MHz): 7.2-7.45 (m, 10H), 6.05 (s, 1H), 3.95 (s, 6H), 3.3 (s, 3H).

M.P. Mp 168-170 ° C.

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

M.P. 115-117 ° C.

Example 3 2- (4-Morpholino-5-fluoro-pyrimidin-2-yloxy) -3-methoxy-3,3-diphenylbenzylpropionate

To a suspension of 9.96 g of potassium carbonate (72 mmol) in 40 ml of dimethylformamide was added dropwise 3.3 g (9 mmol) of 2-hydroxy3-methoxy-3,3-diphenylbenzylpropionate and 4-morpholino-5-fluoro2-chloropyrimidine in dimethylformamide. The mixture was then stirred initially 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 organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. A brown residue (5.72 g) was obtained which was purified by

00/149/02-PB · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · хро хро хро · те те хро хро хро течначначна ичначна и и и и и и и и и и и се се се се се се се се се се се се се се се се се се се се се се се използва използва се се

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-diphenylbenzylpropionate in 30 ml of ethyl acetate was hydrogenated with hydrogen using 300 mg of palladium on carbon as catalyst ( 10%) at normal pressure and at room temperature for 3 hours. The reaction mixture was filtered, concentrated, and the residue (900 mg) was purified by medium pressure liquid chromatography.

¹ H-NMR (CDCl ₃ , 500 MHz): 8.95 (d, 1H), 7.2-7.5 (m, 10H), 6.05 (s, 1 Η), 3.8 (s, 8H), 3.3 (s, 3H).

M.P. 1 74-1 75 ° C.

The following Table 1 lists the compounds which can be prepared analogously to the examples given.

MIMIC

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Hei-Qi A oi-o-oο

N

Table I

N Oh Fr. Fr. 1 Fr. Fr. ω Fr. Fr. Fr. Fr. 1 Fr. Fr. Fr. se LL X LL LL and_ LL LL LL LL LL LL LL LL LL LL LL Oh F. F. f F. F. F. F. F. F. F. F. f F. f η Z * f 2E about I Z> ss Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Mr Fr. Oh f f f f f f f f f f f f f f N f OS Fr. Fr. Fr. Fr. Fr. Fr. Oh Fr. Fr. Fr. Fr. Oh Fr. Fr. CX t Fr. Ex sche 1 schema T -CH cht t -CH and sche Fr. sche X CH 1 1 Sht CH SK T O X f -e- 1 CX About that cx I ω 1 Oh 1 s; X c \ o to sche ΞΕ O. drank OMe -CH- CX T o X Ф -Θ- -CH- =; X is; X with; is; and (L. is; oh =; 1 S sche that F. with; sche with about with about X> et et 1 about: I et is; X zop yen Ct 1 St se T. Oh se T Fr. et se T o and with 1 CL p OS 2 S Fr. 2 f X -e- CO., LTD Oh Tt 2 p p Fr. is; with; with; is; is; is; with; with: with: with; with; with; Εζ is; is; GHG X X X X X X X X X X X X X X X X I I X X X I X X I X X X X I 'D- f f F. F. f F. F. f f F. F. F. f f F. axis -Θ- -Θ- -Θ- -Θ- -e e -Θ- -e- -Θ- -e- -Θ- -e- & -e- & SG se I St T. Oh I T. T. t I Z t T. t T. t T. t Fr. Oh Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. axis Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. see 00 Yu Fr. Ύ— see co Yu <x> co century> ΊΤ- h— T " t— -t— T " 1 1 1 1 ¹ 1 1 1 1 1 1 1 1 t 1

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N 00 Fr. Fr. Fr. Fr. Fr. Fr. Fr. 1 Fr. Fr. Fr. co Fr. Fr. Fr. Fr. Fr. Fr. Fr. 1 Fr. Fr. Fr. ο ο X X X X IX IX X X X X X X X X i X X X X X X X X X X X X X GO Me 4— »w Me ф 3> f f f f is X f 2 f + - «w f ф z> f Is X 1— f f f f is X f f f Ξ * φ is X £ Mr Oh Oh Oh Oh Ζ> Fr. Oh Fr. S Fr. Fr. Oh Fr. f Oh Fr. Fr. Oh Ο f f f f f f f f f Well f f f se f f se hh 2 f f f Z * f w w S U. f Z> X f φ χ ' axis Oh Fr. Fr. Fr. Ζ> Fr. Oh Fr. 2> Oh Fr. Fr. Oh f Fr. Fr. Fr. Fr. 2> Fr. Fr. ο with \ 1 s \ X Well X Oh X 1 C \ Fr. < co with \ I X C \ l-CH 1 C \ t with \ en-be Fr. 1 C \ X X f is; V X about 1 Well 1 OR yen sn sn Is X n Fr. 1 s \ n f 2 X X Ф fan e-f Well 1 and l- IL IL C \ X F. 2 CH sche X C \ Well -Θ- 1 f IL- CE X ΙΕ X τ Ε X τ IL Is X Is X OM X n> ΙΟ CL ent ex Fr. 1 Fr. about who sn- Oh with \ (CH with about Q. oh rock X ф -Θ- Φ -θ ' Φ & Is X rock X n>. 1> \ Oh I> \ Oh Di- T. b thief is X LOP sucker ss <T. DIS with \ se -CH about C \ thief Is X 1 X SG IL Is X with about « f 2 Φ Ε X 1— x> tF with f ho 1 about co 30 F. Q. IR n f IR IR X about X about Fr. Fr. X x f m · 1F I f 3 t co 1 Ο 1 Φ 1 axis Mr p p X X 00 n EG 2 = Mr ET co X X rf X -Θ- CO 2 -Θ- co LO Well e e Well e e e Well e e =; Well Well Well Well Well Well Well Well “Well Well CE CE Well «Ε Ε OS X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X I X X I X X X X X X X X X X X X X X X X X F. f f F. f F. F. F. f F. Φ F. F. F. F. F. f f F. F. F. F. F. F. Φ φ axis -Θ- -Θ- - © · -Θ- -Θ- • e -Θ- -e -e- -Θ- -e • e -e- -e e -e -Θ- -Θ- -Θ- e -Θ · -θ ' -e- & -θ ' -e se X X X I X X x X X X X t X X X x X X X X X X Fr. X X X X Fr. Oh Fr. Fr. Fr. Fr. Fr. Fr. Fr. Oh Oh Fr. Fr. Fr. Oh Fr. Fr. Oh Fr. Fr. Fr. Fr. Fr. Fr. ο Ο D " Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Oh Fr. Fr. Fr. Oh Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. ο ο axis Fr. Fr. ω Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. ο ο co Mr- 00 σ> Fr. SEE co Yu co Mr- co C5) Fr. see co rf Yu co Mr- co σ> ο Fr. T " h— Ύ— Ύ— SEE see <m see see see see see see see co co CO co co co co co co co i 1 1 1 1 1 1 ¹ 1 1 1 ¹ 1 1 1 i i 1 ^{1 1} 1 1 1 I

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Ν Oh o ω ο ο ο 1 Ο ο Ο ο ο ω Ο Ο Ο Ο ο ο 1 Ο Ο Ο X LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL ο LL LL LL LL LL CE F S o F s o φ S Oh Φ Ο Φ Ζ> Ο Φ 2> Φ 2 Φ 2 Ο Φ Ξ Ο Φ Ο φ ο Φ Ζ> c; X Η φ Φ 2 Ο Φ Σ Ο Φ Ζ> CC LL Ο φ ο Φ ζ ο εζ X Η Φ Φ Ο X Φ Ο N CE F. 2 o F o φ S o Φ ο φ 5 ο Φ 5 Ζζ X Η Φ φ Ξ ο φ φ ο φ ζ> ο Φ c; X 1— φ φ ζ> ο φ Ο Φ Ο Φ Ο φ ο σ: LL Ο § Η φ φ φ ο φ Σ ο x> tr 2-Me-phenyl 2-C1-phenyl c; X H Φ r 3-Br-phenyl 4-P-phenyl ε; X X Φ -θ- 1 LL I Chf «=; X Ηφ 4-Me-phenyl ε; X X φ -θ- 1 C \ Ο ζ 1 co 2-HO-phenyl 3,4-di-OMe-phenyl ε; X X Φ 1 Φ ε; X (- Φ 2 Ο Ο ο X et co <=; X I— φ S 3,4,5-tri-OMe-phenyl benzyl 2-C1-benzyl C-Br-benzyl 4-P-benzyl 2-Me-benzyl ε; X I— φ 2 2-Me-benzyl ί <χ X ο with \ X Ο 1 ε; X X Φ -θ- 1 Φ 1 X et 1 CO., LTD 3-ethyl-benzyl sMM. t =; x X Ф -Θ- Ζζ X X Φ -Θ- 2-Me-phenyl ε; X X φ e with; X X φ -θ- is; X X φ -θ · =; X X φ -θ- ε; X X Φ -θ- c; X X Φ -θ- with; X X φ -θ- with; X X Φ is =; X I φ • e ε; X X Φ -θ- with; X X Φ -θ- ε; X X Φ & d X X φ -θ- with; X X Φ -θ- R X X Φ -θ ' ε ^ X X φ e ες X I Φ -θ- XΕ X X φ -θ · ες X X Φ -θ- ε; X X φ -θ- a: X o o o I O o o τ ο ο ο I ο Ο ο Τ Ο ο ο Τ Ο ο ο X Ο ο ο Τ Ο ο ο Τ Ο ο ο Τ Ο Ο ο τ ο ο ο τ ο ο ο Ο Ο ο Τ Ο ο ο X ο ο ο X Ο Ο ο X Ο ο ο X Ο ο ο X ο ο ο X Ο ο ο X Ο Ο ο X Ο ο ο C00H No Cd TJ- 1 CO., LTD τΤ 1 Yu 'Τ <Χ) Μ- ГτΓ 1 00 «hG I σ> 1 ο LO I ΙΟ CM Yu co ιο I 'Τ Yu I Yu Yu I <0 ιο I Yu I οο ΙΟ σ> ΙΟ 1 ο co <ο CM <ο I co co I Μ <0 1

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00/149/02-PB ·· · »·· • ·» • · · • · · · f f f f • ff ·

Ф ф ф ф ф ф ф ф ф....

N Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. 1 Oh Fr. Fr. Fr. Fr. Fr. Fr. Fr. ω Fr. Fr. Fr. Fr. Fr. Fr. X LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL OS Me OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe Me ethyl OMe Me OMe Me OMe ΘΙΛΙΟ OMe F o OMe F. 2 OMe ΛΙ 00 Me OMe Me f Oh f o f o f Fr. OMe f Oh OMe f Oh Me ethyl f Oh ethyl OMe ethyl f o OMe OMe OMe OMe ethyl f Oh x> axis 4-isopropyl-benzyl 4-OMe-3-propyl-benzyl | 2-Me-5-propyl-benzyl ! 2-Me-5-propyl-benzyl 4-Me-2-propyl-benzyl methyl methyl methyl | methyl methyl ethyl methyl hundred with \ T o 1 with; x I Φ & 1 F. Fr. J S 1 CO., LTD p-propyl 1 C \ I o 1 C \ And oh with; X X f -Θ- 1 f Fr. > n d «F co ethyl 3-OMe-phenyl-CHp-CH? - methyl ethyl methyl methyl methyl t with \ I about <c \ I o with; X I f -e i b 1 X d 1 m- CO., LTD hundred Hundred is; X X Ф -Θ- 1 b 1 X d co axis <4 · pers phenyl phenyl phenyl with; X I f -e- phenyl 4-B-phenyl 4-B-phenyl 4-Cl-phenyl 1 phenyl with; X I ф -Θ- I f S m- about X I ф -Θ- f Oh 1 <=: X I f -Θ- 1 f S phenyl with; X X Ф -Θ- 1 CC LL Oh CO., LTD phenyl «=; X X f -e- LL i phenyl phenyl 3-C1-phenyl 2-B-phenyl 2-B-phenyl 2-Me-phenyl phenyl phenyl £ Mr UNC UNC UNC UNC UNC UNC LCOOCHq UNC t О О о о I oh oh I oh oh UNC UNC UNC I oh oh UNC UNC COOHN3 UNC t o o o UNC UNC | UNC t o O oh No io <£> 1 <o <y 1 Ναό 1 00 <o 1 σ> co 1 oh g- 1 C \ 1 b- t 00 N. 1 Yu <£> Mr- 1 Mr- 1 00 σ> N 1 oh oo 1 00 1 see 00 00 00 1 -ςΤ 00 1 00 1 <o 00 I 00 1 00 00 1

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N Oh Fr. Fr. Fr. Fr. ω 1 ο ο ο ο ο Ο ο Ο ω ω ο Ο Ο ο ω ο X IX LL IX LL IX m_ LL LL LL LL LL LL IX IX IX IX LL LL LL IX IX IX IX IX η OS F. 2 o F. 2 4— »w O. + -L w Oh . F I 2 ζ o se ll oh oh se ll Ο Ο Φ 2 CC LL Ο Φ 2 Φ 2 Φ 2 Ο Φ 2 Φ 2 Ο φ 2 Φ 2 Ο φ 2 Ο φ 2 Φ 2 Ο Φ 2 Φ 2 Ο Φ 2 φ 2 Φ 2 Ο N axis f 2 o F. 2 f 2 Oh f 2 Oh f 2 Oh f 2 Oh φ 2 Ο φ 2 Φ 2 Ο φ 2 ε; X ι— φ φ 2 Ο ε; X Η Φ φ 2 Ο ε; X Η φ φ 2 Ο φ 2 Ο ε; X ι— Φ φ 2 Ο ε; X ι— φ Φ 2 Ο φ 2 Ο ε; X IF φ 2 Ο X) axis ε X 1f 2 with; X n f X if S is; X tf 2 is; X If with; X with about Q. with 1 £ Σ ε; X C ο ο. C ε; X C ο Ω. C ε; X ι— φ 2 is; X co X φ χο 1 X ο 1 C. X Ο ε; X X Φ -θ- 1 ο 1 CO., LTD 1 (X I ο ex χ ο 1 Ε X X φ -θ- 6 1 1 C \ χ ο 1 c \ X Ο 1 ε; X X Φ Ϋ Ο 1 S Ct '' D CO., LTD 1 CX X ο c \ X ο 1 ε; X X φ -θ- ι Ο I X Et ι «Φ CQ I <χ X ο 1 (X X ο 1 ε; X X Φ -θ- i Ο 1 X Et ι Yu CO., LTD I c \ X Ο 1 CX X Ο I ε; X X Φ -θ- φ 2 Ο X Et 1 Yu co is; X X Φ - & 1 <Χ X ο 1 <χ X ο 1 ε; X X φ -Θ- Ο 1 S Ct I 'd CO., LTD I C \ X ο c \ X ο 1 ε; X X Φ -Θ- φ 2 Ο 1 S Ct I '' d " CO., LTD c \ X Ο 1 C \ X ο ε; X Φ -θ- 1 φ 2 X Et 1 CO., LTD ex X Ο 1 ex X Ο Εζ X X Φ -θ 4— · W i S Ct I CO., LTD X ά X Ο 1 CX X ο 1 ε; X X Φ -θ- I φ 2 X Et 1 Μ CO., LTD I CX X ο 1 <Χ X ο 1 ε; X X Φ -θ- Εζ tz Ο ο. C ο co X 2MF is; x X f -e- 1 SS IX about »St with; X X f <=; X X f =; X X Ф E X X f Εζ X X Φ -θ ' 1 se ll oh oh 1 ^ d- ε; X X φ -θ- ε; X I φ · & ε; X I φ -θ- ε; X X Φ -θi LL t ε; X X Φ -θ- c; X X φ -θ- Εζ X X φ -θ- I -ct ε; X X Φ -θ · 1 4 $ · ε; X I φ θ · is; X X Φ -θ ' ε; X I φ -θ- Ci X I φ -θ- is; X I Φ - & ε; X Φ -θ is; X I φ -e ε; X X φ & IX Ci X X φ -θ- c; X X Φ -θ- Ό and and axis х о о о х о о о х о о о se I o o o o х о о о X О о о X Ο ο ο X Ο ο ο X Ο Ο Ο χ ο ο ο I ο ο ο I ο ο ο X Ο ο ο X ο ο ο X Ο Ο Ο X ο ο ο X Ο ο ο X Ο Ο ο X ο ο ο X Ο ο ο X Ο Ο ο X Ο ο ο X Ο Ο Ο X ο ο ο No σ> 00 1 about σ> 1 T " Oh 1 See <c> 1 co o 1 ^ r σ> 1 Yu σ> 1 <ο σ> 1 σ> 1 00 σ> 1 σ> σ> 1 ο ο ο I CM ο 1 CO ο τι 'dο 1 ΙΟ ο τι <ο ο Τι Ο » 00 ο I σ> ο I ο I 1 (XI I

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Ν Oh Fr. Fr. Fr. Fr. i Ο Ο Ο ο Ο ω ο Ο Ο I Ο Ο Ο Ο ω Ο ο X and_ m_ LL LL axis LL Oh LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL _ f f S about F S Е X 1— ф F. 3> CO LL Ο Φ Ζ> Φ 2> Ο X ο Φ Ο Φ S ο Φ 2Ε Φ Ο Ο Φ Ο Φ Φ 2 Ο Φ Φ 2 φ Φ 2 Ο Φ Ν 00 | =; X If f S about f f X n f F. Φ 2 Ο Φ Ζ> Ο φ S ο φ ο φ ο φ ο Φ Ο Φ Ο Φ Ο φ ο φ ο Is X Η Φ φ Ζ> Ο Φ S ο Φ Ο Ε X Η Φ φ Ο Ε X Η Φ X> OS 1 cx X Oh > c \ X Oh Well X X Ф -е- f 1 S cg 1 Tt co with \ t o 1 with \ X about 1 e x X f -Θ- 1 4— · w 1 is X 1— f 2 with; X 1— F 2 f X φ 2 Ε X 1— φ Ε X Η φ 2 ε: X I— φ 2 Ε X Η Φ 2 ε; X I— φ 2 Ε X Η Φ 2 Ε X X φ -θ- Ε X C ο Q. C ο co X Ε X 1— > \ ο 1 ω Ε X Η φ 2 Ε X Η φ i sche X ο ό. X ο 1 Ε χ X φ -θ- 1 Ο 1 X Εί 1 CO CM 2,3-di-OMe-phenyl-CH2-CH2- 1 s \ X ο 1 s \ X Ο 1 Ε X X Φ -θ 't φ ζ> 1 With CX 00 1 (X X ο 1 ο. X ο 1 Ε X X φ -θ · ι 4— * W X ΙΙ CO., LTD ι c \ X ο 1 C \ X ο 1 Ε X X φ -θδ 1 X ε £ 1 CD CM ι C \ X ο 1 <χ Τ Ο Ε X I φ e φ Ο 1 X ΕΙ And a CD CM 2,6-di-Me-phenyl-CHp-CH? - -Ω axis > 4 · pers E X I F Ό- 1 IX 1 Is X X Ф -е- is X X ф -Θ- Is X I ф -Θ- Well X I Ф -Θ- Ε X X φ -θ- Ε X I Φ -θ- Ε X Ο φ X ο ε X X ΣΤ Ε X X Φ -θ- ε; X X Φ -e ιΐ. 1 CM ε; X X φ -θ · I Ο 1 co c; X X Φ -θ- Ε X X φ -θ- Ε X X Φ -θ ' Ε X X Φ -θ- CO LL Ο 1 CO Ε X X Φ θ- Е X X Φ е Ε X X Φ -θ- Ε X χ Φ γ δ 1 Is X X Φ -θ- Is X X Φ -θ ' Is X X Φ -θ- Ε X X Φ θ ' about: х о о о And oh Q X О о о I Oh Oh and X about oh 1 CM Ο ω X =: X Ο φ Ο Ό- X ο ο ο X ο ο Ο X ο ο ο CO X Ο ο ο ο ι £ X ο. Ο Ο Ο Ο X Ο ο ο CC X Ο Ο ο ο ΙΓ X c \ Ο Ο Ο Ο cm Ο ω χ ζ ^s ί- ^χ Ο φ Ο -θ- CM Ω ω χ Θ φ θ -θ- χ Ο Ο Ο X ο ο ο X ο ο ο X ο ο ο X Ο ο ο X Ο ο ο X ο ο ο No co 1 tg t— T " 1 Yu <o Mr- T " οο τ “· I Ο) I ο CM I CM CM cm I 00 CM 4J CM 1 Yu CM I <ο CM GCM 'Γ' ' 1 οο CM I σ> CM I ο 00 I CO., LTD I CM οο 00 00 I C0 ιη C0 I

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Ν Fr. Fr. 1 Fr. Fr. Fr. Fr. ω o o ω o o o o o o o o o o o l o Oh X LL ll LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL X) £ D f o f 2 F s F. F Z> o F. F S φ Ξ Φ S o Φ φ O s o Φ Φ Oh CC LL O Φ 2> o C— · W Φ o Φ o Φ o Φ 2 δ Φ o Φ o Φ o С SS f Fr. f is; X n F F. f o F Z about f Fr. is; X Φ Φ o e; X I— Φ φ Oh Φ o Φ 5 Φ cr LL O - ♦ -J W 4— » LLl Φ o Φ 5 o Φ o Φ o Φ o Φ o e; X H Φ Φ o X> CE 1 with \ T O 1 s \ t o 1 is; X I Ф Ό- <δ 1 X Cf 1 Yu SEE with; X φ o Q. O> e; -θ ' X Q. N. with; X c o Ol c £ 2 1 with \ I about t o 1 about 1 С \ ΞΕ О ό т 1 Hundred 1 I o ό t hundred 1 about t HO-CHP- (HO-CH) -CH _? - 1 HUNDRED with \ I about i Fr. I o î I 1 C \ ZE o <k T o c \ ZE O t o T 1 C \ I o t c \ ZE o C \ And o and about I HO-CH _? -CH _? -CH _? - t =: X X Φ 1 C \ T o 1 c \ I t = X X Φ -Θ- t = X X Φ -Θ- c = X I Φ -Θ- t = X X φ Ό- c = X X Φ -θ ' e: X Εζ o co ¢ 0 X μι CM e; X X Φ -e e; X X Φ -Θ- e; X X Φ -Θ- 00 t 'd- r = X e; O co CB X I— 1 Kt c; X H Φ e; X 1— Φ s e; X X Φ -Θ- TJ 1 δ 1 CO., LTD o t o T iO SE CE with; X X f -e- X X f -Θ- d X I ф -е- with; X I Ф -е- is; X I f -e- | =: X X ф Ϋ о with; X X f -Θ- e; X X Φ -Θ- ες X X Φ -Θ- e; X X Φ -Θ- e; X X Φ -Θ- X I Φ -Θ- e; X X Φ -Θ- =; X I Φ -Θ- e; X X Φ -Θ- e; X X Φ -Θ- e; X X Φ -Θ- c; X X Φ θ ' X X Φ -Θ- 1 LL 1 CM e; X X Φ -e- 1 δ I CO e; X X Φ -Θ- e; X X Φ -Θ- X X Φ -Θ- C = X I Φ e; X X Φ in LL 1 Tt 1 LL 1 CE t o o o 1g t с \ О О О О О I oh oh t o o o I oh oh t o o o I О О О О I o o o I o o o ZE o o o I O o o ZE o o o I O O O I O o o ZE O O O ZE O o o T Oh Oh Oh ZE O o o CC I O o o o iC I c \ O O o o cc ZE o o o o o If I c \ O O o o ΞΕ O o o T o o o 1 CM o ω I =: Z Ο φ Ο -Θ- No CO 1 ΓΓΟ f co co D " co 1 Fr. 1 T “gf Ύ-— SEE t co Ύ “ 1 'T T 1 LO - ^ r T ^- 1 CD 1 Γ— co ^ r J o> ^ r 1 o Yu V " Yu 1 CM LO co Yu T " 1 Yu 'Τ- Ι Yu Yu < co uo 1 ΓΙΟ 1 oo Yu 1 ca Yu o co

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• ·

Ν Oh Fr. Fr. ο , Ο ο ο ω ο ο Ο Ο I ο Ο Ο Ο Ο 1 1 Ο ο X LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL LL η (X CC LL Oh Oh SS LL oh Φ Φ Ξ> Ο Φ Ζ> φ ο I σ: LL Ο Φ Ζ> Ο Φ Ο <Τ LL Ο Φ S CC LL Ο Φ Ζ> Φ Φ Ζ> Φ Φ Ξ> Ο εξ X 1— φ Φ L> Ο Φ Ζ> ο Φ Ξ> Ν CL F. Oh F Z> o ф z> φ φ Φ Ξ> φ ζ> ο -θ- _χ Ο- χ Ο εξ 5 Ο σ: LL ο φ ο φ Ξ ε; X I— Φ S ο Φ Ξ> Ο Φ Φ ε; X Η Φ εξ X I— φ φ ο Εξ X 1— φ φ 5 Ο φ ζ> ο Φ Ζ> Ο Χ> CE 4-imidazolyl =; X X ф Ό- is; X I F - © 1 LL 1 ^ r εξ X X φ • θ · ο X X r φ ε; X Η Φ 5 X ct I CXI Εξ X C ο ο. C εξ X 1— X Φ C c εξ X 1— φ 2 ε; X 1φ 5 Ιξ X X φ -θ- ε; X I— Φ 2 εξ X Η Φ 2 ε; X Η Φ 2 is; X 1φ 5 ε; X C ο ο. C ε; X Η Φ 2 ε; X I— φ 2 ε; X 1— φ 2 εξ X Η Φ 2 εξ X 1— φ 2 Εξ X C Ο α C Εξ X C ο ο. C ε; X 1— φ 2 ε; X Η Φ 2 axis > d · OS with; X I Ф -Θ- εξ X I Ф -Θ- 1 CO U_ O »XG Εξ X X f - © Εξ X X φ -θ- εξ X X Φ -θ- ε; X X Φ -θ- ε; X υ Sd φ X ο Εξ X X 3f ε; X X φ -θ- c; X X Φ -θ- εξ X X φ -θ- LL 1 co ε; X I φ -θ- 1 φ Ξ> ο 1 co Εξ X X φ -θ- with; X X Ф -θ- LL 1 co ε; X X Φ -θ- Εξ X X Φ & ε; X X Φ -θ- εξ X I φ -θ- ε; X X Φ -θ- εξ X X Φ -θ · Εξ X X φ -θ- Εξ X I φ -e- Εξ X X φ -θ- 1 φ 1 co εξ X X φ -θ- 1 LL 1 axis if I с \ О О О О О SM O ω 1 ² I O f Ο -Θ- SG I О о о о о If I C \ Ο Ο Ο Ο ΞΕ Ο ο ο Τ Ο ο ο τ Ο Ο Ο Τ ο ο ο I ο ο ο I ο ο ο τ ο ο ο ΞΕ Ο Ο Ο ΞΕ Ο Ο ο ΞΕ Ο Ο ο CM ο ω τ X Ο φ Ο -θ- CC X Ο Λ ο ω χ ζ ο ο (0 Ζ Ο ο ο CC I Ο ο. Ο SL X ζ ο ο εξ Ο GO to α I— φ Η I Ο Ο ο I ο ο ο ΞΕ Ο ο ο ΞΕ Ο Ο ο No <0 1 see co T " 1 co co Μ <Ρ 'D' 1 Y <0 I co co 1 Γ— <0 1 00 co 1 σ> co 1 ο G- 1 Γ- I CM r- t co G- I ^ Γ Γ- > to r- I CD I Γ- I co r- I σ> Τ- Ι ο 00 τι 00 I CM 00 1 co 00 I

· · · · ·

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SS,

Table II

N Fr. Fr. Fr. Oh Fr. Fr. Fr. Fr. Oh Oh Fr. Fr. Fr. X LL. LL LL LL and. LL LL LL LL LL and_ LL LL F. F. F. F. f F. F. f F. F. f F. F. GO 2 S Σ 2> axis Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. f f f f f f f f F. f f f f m 2> z> 2> OS Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. with; 1 S 1 with \ I with \ X F. X Fr. -Θ- Fr. 1 1 with; εζ S with \ S with: p X p S Fr. Oh 1 Fr. p a a Fr. p with; with \ t = <=; with; <=; with; with; with; Q. Fr. S Fr. S S S S S S S P 00 00 with; axis with; n 1- b- n n 1- 1- Oh S I S X X » f f Φ f f f F. CO., LTD 1 F. 1- Q S axis 2 2 2 2 2 2 2 S Q. \ o f yy F. f F. f in: 00 00 00 00 Q. 1 Q. a a are see are are are f X X SS “G. (0 F. F. X X X 1- Oh Oh -_L 1- n 1- Fr. Fr. Oh Ros Fr. I 1 see X II x Fr. I Ros oh oh about about Q. II X II II < P Fr. Oh Fr. Fr. ω Z p p p Fr. Fr. Fr. I x X I x X x X X X X X X Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Oh Oh Fr. Fr. Fr. D " Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. sg Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. Fr. V " see CO Fr. t— see co 'T. Yu CD 00 σ> T " 7— t- T " Z

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Example 5

In the assay described above to determine binding, the following receptor binding indicators for the compounds of the invention according to the invention were measured.

The results are presented in Table 3.

Table 3

Receptor binding indicators (Kj-values)

Compound ETd [nM] ET _B [nM] I-2 7.4 1200 1-121 61 > 10000 1-168 4000 > 7000

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Claims (8)

1. Carboxylic acid derivatives of formula I in which the substituents have the following meanings: R ¹ represents tetrazole or the group Oh C - R in which R means: (a) residue OR ⁷ in which R ⁷ is: hydrogen, an alkali metal cation or an alkaline earth metal cation, a physiologically acceptable organic ammonium ion or ammonium ion; C3-C3-cycloalkyl, C1-C3-alkyl, CH2-phenyl which may be substituted by one or more of the following substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C Haloalkyl, hydroxy, C 1 -C 4 -alkoxy, mercapto, -C 4 -alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 -alkyl) 2; A C3-C3-alkenyl or C3-C3-alkynyl group which in turn may be substituted by one to five halogen atoms, R ⁷ may also mean a phenyl moiety which may be substituted by one to five halogen atoms and / or by one to three of the following substituents: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, hydroxy, C 1 -C 4 -alkoxy, mercapto, C 1 -C 4 alkylthio, amino 00/1 49/02-PB · · · · · · · · · · · · · · · · · · · · · NH (C1-C4-alkyl), N (C1-C4-alkyl); b) bonded by a nitrogen atom to a 5-membered heteroaromatic ring, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may be substituted by one to two halogen atoms, or by one to two C 1 -C 6 -alkyl groups or by one to two C1-C4-alkoxy groups; c) the group <4 - O - (CH ₂ ) _P - SR ⁸ in which k is the number 0, 1 and 2, p is the number 1, 2, 3 and 4 and R8 means C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -alkenyl, C 3 -C 4 -alkynyl or phenyl, which may be substituted by one or more, e.g. with one to three of the following substituents: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -halogenalkyl, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, mercapto, amino, NH (C 1 -C 6 -alkyl) ), N (C 1 - C 1 -C 6 alkyl) 2, d) the remainder Oh II, --N s --R ^{9 n} II O in which R ⁹ means C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, wherein these moieties may be substituted by one C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl; an alkylthio and / or phenyl residue as indicated in c); phenyl optionally substituted by one to three of the following substituents: halogen, nitro, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -halogen 00/149/02-PB alkyl, hydroxy, C 1 -C 6 - alkoxy, C 1 -C 4 alkylthio, mercapto, amino, NH (C 1 -C 6 alkyl), N (C 1 -C 4 alkyl); R 2 represents hydrogen, hydroxy, amino, NH (C 1 -C 4 -alkyl), N (C 1 -C 6 -alkyl) 2, halogen, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl , C 1 -C 4 -hydroxyalkyl, C 1 -C 6 -halogenalkyl, C 1 -C 6 alkoxy, C 1 -C 6 -halogenoxy or C 1 -C 6 -alkylthio, morpholine; X is halogen, C1-C4-haloalkyl, hydroxy; R ³ is hydrogen, hydroxy, amino, NH (C 1 -C 6 -alkyl), N (C 1 -C 6 -alkyl) 2 'halogen, C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 6 - alkynyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoxy, -NH-OC-] -C 1 -alkyl, C 1 -C 4 -alkylthio; R ⁴ and R ⁵ (which may be the same or different) have the following meanings: phenyl or naphthyl which may be substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -halogenalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C 1 -C 6 -alkylthio, amino, NH (C 1 -C 6 -alkyl), N (C 1 -C 6 -alkyl) 2 or phenyl or naphthyl which are linked together in orthography by direct connection, by methylene, ethylene or ethylene ethylene, oxygen or sulfur or by SO2-, NH- or N-alkyl; or a five or six membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom having as a substituent one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -halogenalkoxy, C 1 -C 6 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl moieties may in their turn have one to five substituents 00/149/02-PB halogen atoms and / or one to three of the following residues: C 1 -C 4 alkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy and / or C- | -C 4 -alkylthio or C 3 -C 9 cycloalkyl; R6 is hydrogen, C1-C8-alkyl, C3-C3-alkenyl, C3-C6-alkynyl or C3-C6-cycloalkyl, wherein these residues may be substituted by one or more of the following substituents: hydroxy, mercapto, carboxy, halogen, nitro cyano, C1-C4-alkoxy, C3-C6-alkenylC1- C4-alkylthio, C- | - C4-haloalkalkoC- | - C4-Coke and carbonyl, C3-C3-alkyl oxy, C3-C6-alkynyloxy, C 1 -C 4 -alkylcarbonylalkyl, amino, NH (C 1 -C 4 -alkyl), N (C- | -C4-alkyl) 2, phenyl, which in turn can be substituted once or repeatedly, e.g. phenyl or phenoxy substituted with one to three of the following substituents: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -halogenoalkyl, C 1 -C 4 -alkoxy, Cf-C 4 -haloalkoxy, C 1 - C4 alkylthio; phenyl or naphthyl, which may be optionally substituted by one or more of the following substituents: halogen, nitro, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy , C 1 -C 4 -halogenoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, or dioxomethylene or dioxoethylene; a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom having as a substituent one to four halogen atoms and / or one to two of the following residues: C 1 -C 4 -alkyl, C - | -C4-haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl residues of 00/149/02-PB 999 9 9 9 99 9 9 9 9 99 9 9 9999 999 9 9 9 99 99 · 9 9 999 may optionally have one to five halogen atoms and / or one to three of the following residues: C 1 -C 4 alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkoxy and / or C 1 -C 4 -alkylthio, provided that R® can mean hydrogen only when Z does not mean a simple bond; Z is sulfur, oxygen or a simple bond. as well as their physiologically acceptable salts and enantiomerically pure as well as diastereomerically pure forms. Use of carboxylic acid derivatives of 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 carboxylic acid derivatives of formula I according to claim 1 for the preparation of medicaments for the treatment of diseases related to endothelin elevation. Use of 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 onset and / or progression of the disease. Use of carboxylic acid derivatives of formula I according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary high pressure, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and cancer prostate. 00/149/02-PB ·· · • · ··· Combinations of carboxylic acid derivatives of formula I according to claim 1 with one or more active substances selected from inhibitors of the renin-angiotensin system, such as renin inhibitors, angiotensin-β-antagonists, angiotensin-converting enzyme (ACE) inhibitors ), mixed ACE / neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, calcium antagonists and VEGF-blocking agents. 8. An oral, parenteral and intra-parenteral medicament comprising at least one compound of formula I according to claim 1, in a single dosage form, together with the usual medicament additives.