SK176299A3 - New 'beta'-amino and 'beta'-azidocarboxylic acid derivatives, the production thereof and the use thereof as endothelin receptor antagonists - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein the constituents have the meaning given in the description. The invention also relates to the production of said derivatives, and to their use as endothelin receptor antagonists.

Description

Novel β-amino- and β-azidocarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists

Technical field

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

BACKGROUND OF THE INVENTION. Endothelin is a peptide of 21 amino acids that is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, both ET-2 and ET-3. Endothelin "or" ET "will hereinafter refer to one or all of the endothelin isoforms. 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 (1988) 411-415; FEBS Letters, 231).

(1988) 440-444, and Biochem. Biophys. Res. Commun., 154, (1988) 868-875).

Increased or abnormal release of endothelin causes sustained vasoconstriction in peripheral, renal and cerebral vessels, which can lead to disease. As reported in the literature, endothelin is involved in several diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868, Nature 344.

(1990) 114, N. Engl. J. Med. 322. (1989) 205, N. Engl. J. Med. 328 (1993) 1732.

Nephron 66, (1994) 373, Stroke 25, (1994) 904, Nature 365. (1993) 759, J. Mol. Cell. Cardiol. 27, (1995) A234; Cancer Research 56, (1996) 663, Nature Medicine 1, (1995) 944).

To date, at least two endothelin receptor subtypes, ET _A and ET _B receptors, have been described in the literature (Nature 348. (1990) 730, Nature 348. (1990) 732). Accordingly, substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and thus represent valuable drugs.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide endothelin receptor antagonists that bind to the ETa and / or ETb receptor. The invention relates to βamino and β-azidocarboxylic acid derivatives of the formula I

R ² WX

A-C-CH-O- (

II \!

R 3 R 1 Z-Y wherein R ¹ is tetrazolyl or a group

ABOUT

II

C-R where R is as follows:

(a) the radical OR ⁴ , where R ⁴ is:

hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerated organic ammonium ion, for example a tertiary C 1 -C ₄ -alkylammonium or ammonium ion;

C 1 -C 6 -cycloalkyl, C 1 -C 6 -alkyl, CH 2 -phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, hydroxyl, C 1 -C ₄ -haloalkyl -C ₄ -alkoxy, mercapto, C 1 -C ₄ -alkylthio, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ;

I '' I · * I _t

C 3 -C ₈ -alkenyl or C ₃ -C 8 -alkynyl, where these groups in turn to carry one to five halogen atoms;

R ⁴ may additionally be phenyl, which may carry one to five halogen atoms and / or one to three of the following radicals:

nitro, cyano, C 1 -C ₄ -alkyl, C 1 -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);

b) a 5-membered heteroaromatic system attached through a nitrogen atom, for example pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one to two halogen atoms or one or two C 1 -C 4 -alkyl or two C 1 -C ₄ -alkoxy groups;

c) the group (°) k -O- (CH ₂ ) _p -S-R 5 where k can be values of 0.1 and 2, p values of 1, 2, 3 and 4, and R ⁵ is

C 1 -C 4 -alkyl, C ₃ -C 8 -cycloalkyl, C ₃ -C 8 -alkenyl, C ₃ -C ₈ -alkynyl or phenyl which may be substituted by one or more, for example one to three of the following radicals:

d) radical

O _NH — — — R ⁶ 6 where R ⁶ is:

C, -C4-alkyl, C ₃ -C 8 -alkenyl, C ₃ -C 8 -alkynyl, _C3 -Ca-cycloalkyl, where these radicals can carry a C, -C4-alkoxy, _{Ci-C4-alkylthio} and / or a phenyl radical, as mentioned under c);

Ci-C4-haloalkyl or phenyl, unsubstituted or substituted, in particular, a * ¹ and II mentioned under c).

Other substituents have the following meanings:

A is NR ⁷ R ⁸ or azido;

W and Z (which may be identical or different) are:

nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;

X is nitrogen or CR ⁹ ;

Y is nitrogen or CR ¹⁰ ;

Q is nitrogen or CR ¹¹ ; with the proviso that X = CR ⁹ and Y = CR ¹⁰ when Q = nitrogen R ² and R ³ (which may be identical or different) are:

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C ₁ -C 4 -alkyl, C ₂ -C 4 -alkenyl, C ₂ -C 4 -alkynyl, C 1 -C 4 ₄ hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, phenoxy, C ^ -haloalkoxy, Ci-C4-alkylthio, amino, NH (C, -C4-alkyl), N (C ₁ -C ₄ - alkyl) 2 or phenyl, which may be substituted one or more times, e.g. one to three times, halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C 4 -alkylthio; or phenyl or naphthyl, which are linked to each other in ortho positions by direct coupling, methylene, ethylene or ethenylene, an oxygen or sulfur atom, or an SO2, NH or N-alkyl group;

C 5 -C 6 -cycloalkyl, which radicals may in each case be substituted one or more times with the following radicals: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C ₂ -C 4 - alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C ₁ -C ₄ -haloalkoxy;

R ⁷ is hydrogen, C 1 -C ₈ -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl, C 1 -C ₅ -alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by the following radicals: halogen , hydroxyl, mercapto, carboxyl, nitro, amino, cyano, Ci-C4-alkoxy, _C3-C6 alkenyloxy, _{C3-C6-alkynyloxy,} C4-alkylthio, C _r C 4 haloalkoxy, _Ci-C4 -alkoxycarbonyl, C ₃ -C ₈ -alkylcarbonylalkyl, NH (C 1 -C 4 -alkyl), N (C 1 -C ₄ -alkyl) ₂ , C ₃ -C ₈ -cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three atoms nitrogen and / or one sulfur or oxygen atom, phenoxy or phenyl, wherein all said aryl radicals may in turn be substituted one or more times, e.g. one to three times, by the following radicals: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, _Ci-C4-alkyl, Ci-C4-haloalkyl, C4-alkoxy, C _r C 4 haloalkoxy, amino, NH (C ₄ -C -alkyl), N (C 1 -C 4 -alkyl) 2, phenyl or C 1 -C 4 -alkylthio;

phenyl or naphthyl, which may in each case be substituted by one or more of the following radicals: 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, carboxyl, NH (C 1 -C ₄ -alkyl), N (C 1 -C 4 -alkyl) ₂ , methylenedioxy or ethylenedioxy;

C ₃ -C 6 -cycloalkyl, these radicals may in each case be substituted one or more times with the following radicals: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C ₄ -alkyl, C ₂ -C 4 -alkenyl, C ₂ -C ₄ -alkynyl, C 1 -C ₄ -alkoxy, C 1 -C 4 -alkylthio, C 1 -C ₄ -haloalkoxy; or

R ⁷ is linked to R ⁸ through 4 or 5 CH ₂ groups to form a 5- or 6-membered ring;

R ⁸ is hydrogen, C 1 -C 6 -alkyl;

or R ⁸ is linked to R ⁷ through 4 or 5 CH ₂ groups to form a 5- or 6-membered ring;

R ⁹ and R ¹⁰ (which may be identical or different) are:

hydrogen, halogen, _{Ci-C4-alkoxy,} C4-haloalkoxy, C 3 -C ₆ alkenyloxy, C -C alkynyloxy, C ₁ -C ₄ -alkylthio, C ₁ .C4-alkylcarbonyl, _Ci-C4 -alkoxycarbonyl, hydroxyl, NH ₂ , NH (C 1 -C ₄ -alkyl), N 1 -C 4 -alkylh

C 1 -C 4 -alkyl, C ₂ -C 4 -alkenyl, C ₂ -C ₄ -alkynyl, which radicals may be substituted by the following radicals: halogen, hydroxyl, mercapto, carboxyl, cyano;

or CR ⁹ or CR ¹⁰ is attached to CR ¹¹ as indicated for R ¹¹ to form a 5- or 6-membered ring,

R ¹¹ is hydrogen, halogen, C ₁ -C ₄ -alkoxy, -C ₄ -haloalkoxy, C ₃ .C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₄ alkylthio, Ci.C4-alkylcarbonyl, C -C ₄ -alkoxycarbonyl, NH (C 1 -C 4 -alkyl), N (C ₁ -C 4 -alkyl) ₂ , hydroxyl, carboxyl, cyano, amino, mercapto;

C 1 -C 4 -alkyl, C 2 -C ₄ -alkenyl, C 2 -C ₄ -alkynyl, which radicals may be substituted one or more times with the following radicals: halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C 1 -C ₄ -alkoxy ;

or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring, which may be substituted with one or two C 1 -C ₄ -alkyls and in which case one or more methylene groups may in each case be replaced by oxygen , sulfur, -NH or -N (C 1 -C ₄ -alkyl).

The terms used herein have the following meaning:

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

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

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

r

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

C ₁ -C ₄ -haloalkyl may be linear or branched, e.g. 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 1 -C ₄ -haloalkoxy may be linear or branched, 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;

C 1 -C ₄ -alkyl may be linear or branched, e.g. methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C ₂ -C ₄ -alkenyl may be linear or branched, e.g. 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 may be linear or branched, e.g. ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butin-4-yl or 2-butin-4-yl;

The C ₁ -C ₄ -alkoxy may be linear or branched, e.g. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

I

C 3 -C ₆ -alkenyloxy may be linear or branched, e.g. allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

The C 6 -C 6 -alkynyloxy may be linear or branched, e.g. 2-propyn-1-yloxy,

2-butin-1-yloxy or 3-butin-2-yloxy;

The C ₁ -C ₄ -alkylthio may be linear or branched, e.g. methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C 1 -C 5 -alkylcarbonyl may be linear or branched, e.g. acetyl, ethylcarbonyl or 2-propylcarbonyl;

C 1 -C ₄ -alkoxycarbonyl may be linear or branched, e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C 3 -C 6 -alkylcarbonylalkyl may be linear or branched, e.g. 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl

C 1 -C 6 -alkyl may be linear or branched, e.g. C 1 -C ₄ -alkyl, pentyl, hexyl, heptyl or octyl;

C 3 -C 6 -alkenyl may be linear or branched, e.g. 1-Propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-buten-4-yl, 2-buten-3-yl, 1- penten-5-yl, 1-hexen-6-yl, 3-hexen-6-yl, 2-hepten-7-yl, or 1-octen-8-yl;

C 3 -C 6 -alkynyl may be linear or branched, e.g. 1-propyn-1-yl,

1-propyn-3-yl, 1-butin-4-yl, 2-butin-4-yl, 2-pentin-5-yl, 3-hexin-6-yl, 3-heptin-7-yl,

2-Octin-8-yl;

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

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

Preferred precursors are those whose release takes place under conditions prevailing in certain parts of the body, e.g. in the stomach, intestines, blood circulation, liver.

Compounds I and intermediates for their preparation, e.g. II and III, may have one or more asymmetrically substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereomers or as mixtures thereof. It is preferred to use the enantiomerically pure compound as the active ingredient.

The invention further relates to the use of the aforementioned carboxylic acid derivatives for the manufacture of medicaments, in particular for the manufacture of ETa and / or ETb receptor inhibitors. The novel compounds are useful as antagonists as defined above.

The preparation of compounds of formula II wherein A is an azido group (IIa) is based on epoxides III which can be synthesized, for example, as described in WO 96/11914. These • l. The epoxides III can then be reacted with an azide, for example sodium azide. This is accomplished by reacting compounds of formula III with azide in a molar ratio of about 1: 1 to 1: 7 at 20 to 150 ° C to give 11a.

_{R 1} R 2 H Y_ \ X ^R + N ₃ Na

R

III

N ₃ R 2

H

NO-OH

R3 R1 11a

The reaction may also be carried out in the presence of a diluent. All solvents which are inert to the reagents can be used for this purpose.

Such solvents or diluents include aliphatic, alicyclic and aromatic hydrocarbons which may be chlorinated, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, dichloromethane, chloroform, ethyl chloride and trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, dibutyl ether, dibutyl ether, dibutyl ether. dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethyiformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethylsulfoxide and sulfolane.

In addition, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent or solvent mixture.

The presence of a catalyst may be advantageous. Suitable catalysts are strong organic and inorganic acids and Lewis acids. Examples are sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and rare earth triflates.

The novel compounds of formula I wherein A is an azido group (Ia) can be prepared, for example, by reacting carboxylic acid derivatives of formula IIa, where the substituents have the meanings indicated, with compounds of formula IV.

W-X

Ha + R 12 — q Ζ-Ύ * N ₃

R 2

H

No-0

R3 R1

W-X {Z-Y

IV la

R ¹² in formula IV is halogen or R ¹³ -SO ² -, wherein R ¹³ can be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl, and W, X, Y, Z and Q are as defined above. The reaction is preferably carried out in an inert solvent or diluent with the addition of a suitable base, e.g. a base which deprotonates intermediate IIa at a temperature ranging from ambient temperature to the boiling point of the solvent.

The compounds of formula IV are known and some of them can be purchased or prepared in a manner known per se.

Compounds of type Ia wherein R ¹ = COOH can be obtained directly by deprotonation of intermediate IIa, where R ¹ is COOH, with two equivalents of a suitable base and reaction with compounds of formula IV. This reaction also takes place in an inert solvent at a temperature ranging from room temperature to the boiling point of the solvent.

The base which can be used is an alkali metal or alkaline earth metal hydride, for example sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide, for example sodium or potassium hydroxide, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide or lithium amide.

The novel compounds of formula I wherein A is amino (1b) are prepared

I starting from compounds Ia. This is accomplished by reacting compounds of Formula Ia with hydrogen in the presence of a catalyst such as palladium or platinum in a solvent at 20 to 100 ° C. Compounds 1a can also be converted to 1b in the presence of triphenylphosphine.

N3

R 2

H —C-O R3 R1

W-X t <

Z ^ -Y * h ₂ n ^{r 2} h

--C-0

R3 R1

W-X f / '

Z — Y to lb

When R ^{1 is} an ester, the amino group in 1b can be alkylated or converted to an amide by generally known methods. The ester group may then be cleaved with acid ¹ or a base to give the carboxylic acid.

Compounds of formula II wherein A is a substituted amino group (IIc) can also be prepared directly from epoxide III by amine opening. Compounds IIc can then be reacted with IV as described above to give novel compounds I.

Compounds of formula I may also be prepared starting from the corresponding carboxylic acids, i.e. compounds of formula I, wherein R ¹ is COOH, first by converting them conventionally into activated forpy, for example a halide, anhydride or imidazolide, and then reacting it with a suitable hydroxyl compound HOR ⁴ sulfonamide or H2NSO2R ^6th This reaction can be carried out in conventional solvents and often requires the addition of a base, the above-mentioned bases being suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on a hydroxyl compound or sulfonamide in the presence of a dehydrating agent, for example a carbodiimide.

In addition, the compounds of formula I may also be prepared starting from salts of the corresponding carboxylic acids, i.e. compounds of formula I, wherein R ¹ is COOM, where

M may be an alkali metal cation or an equivalent of an alkaline earth metal cation. These salts can be reacted with a number of compounds of formula RD wherein D is a conventional nucleofusion leaving group, for example halogen such as chlorine, bromine, iodine, or aryl- or alkylsulfonyl, which is unsubstituted or substituted by halogen, alkyl or haloalkyl, e.g. toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of formula RD with a reactive substituent D are known or can be readily obtained in the art. This reaction may be carried out in conventional solvents, preferably with the addition of a base, with the abovementioned bases being suitable. Compounds of formula I wherein R ¹ is tetrazolyl can be prepared by methods similar to those described in WO 96/11914 from the corresponding carboxylic acids (of formula I with R ¹ = COOH).

In some cases, it is necessary to employ generally known protecting group techniques to prepare the novel compounds. For example, if A is to be HOCH 2 CONH-, the hydroxyl group may first be protected as a benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.

f '' ', I

Compounds of formulas I and II may be obtained in enantiomerically pure form from the racemic or diastereomeric compounds of formulas I and II by carrying out the classical resolution of the racemate with the appropriate enantiomerically pure bases as described, for example, in WO 96/11914.

In view of their biological activity, preferred carboxylic acid derivatives of formula I, in the form of pure enantiomers and pure diastereomers or mixtures thereof, are those where the substituents have the following meanings:

A is NR ⁷ R ⁸ or azido;

W and Z (which may be identical or different) are:

nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;

X is nitrogen or CR ⁹ ;

Y is nitrogen or CR ¹⁰ ;

Q is nitrogen or CR ¹¹ ; with the proviso that X = CR ⁹ and Y = CR ¹⁰ when Q = nitrogen further Q, for which in addition to the above conditions the following applies: Y = CR ^{10 or} X = CR ⁹ if Q = CR ¹¹ .

R ² and R ³ (which may be identical or different) are:

phenyl or naphthyl, each of which is optionally substituted by one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, _Ci-C4-alkyl, Ci-C ₄ haloalkyl, C ₁ -C ₄ -alkoxy, phenoxy, -C _4- haloalkoxy, C 1 -C ₄ alkylthio, amino, NH (C 1 -C ₄ -alkyl), Ν (Ο ₃ -C ₄ -alkyl) ₂ or phenyl, which may be substituted one or more times, e.g. one to three times, by halo, cyano, -C ₄ alkyl, C _r C ₄ haloalkyl, Ci-C ₄ -alkoxy, C ₄ -haloalkoxy or C _r C ₄ alkylthio; or phenyl or naphthyl, which are linked to each other in ortho positions by direct coupling, methylene, ethylene or ethenylene, an oxygen or sulfur atom or an SO ₂ , NH or N-alkyl group;

R ⁷ is hydrogen, C 1 -C ₈ -alkyl, C ₃ -C ₈ -alkenyl or C ₃ -C ₈ -alkynyl, C ₃ -C ₈ -alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by the following groups: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1 -C ₄ -alkoxy, C ₃ -C ₈ -alkenyloxy, C ₃ -C ₈ -alkyloxy, C ₁ -C ₄ -alkylthio, C 1 -C ₄ -haloalkoxy, C 1 -C 4 _4- alkoxycarbonyl, NH 4 -CU-alkyl), N (C 1 -C ₄ -alkyl) ₂ , C ₃ -C ₈ -cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and / or one a sulfur or oxygen atom, a phenoxy or a phenyl, wherein all said aryl radicals may in turn be substituted one or more times, e.g. one to three times, by halogen, hydroxyl, mercapto, carboxyl, cyano, C _r C ₄ -alkyl, C ₄ haloalkyl, "Ci-C ₄ -alkoxy, C _r C ₄ -haloalkoxy, amino, NH ( -C ₄ alkyl), N _(Ci-C4 alkyl) _2, phenyl and _{Ci-C4-alkylthio;}

phenyl or naphthyl, which in each case may be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, phenoxy, C 1 -C ₄ -alkoxy, C 1 -C 4 _4- haloalkoxy, methylenedioxy, C 1 -C ₄ -alkylthio, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ or ethylenedioxy;

C ₃ -C 8 -cycloalkyl, where these radicals may in each case be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, C, -C ₄ -alkyl, C ₂ .C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ^ C ^ alkoxy, C, -C ₄ alkylthio, C _r C _4-ha! oalkoxy;

R ⁸ is hydrogen;

R ⁹ and R ¹⁰ (which may be identical or different):

hydrogen, halogen, C ₁ .C ₄ alkoxy, CrC ^ haloalkoxy, _{Ci-C4-alkylthio,} NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2;

C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, which radicals may be substituted by the following radicals: halogen, hydroxyl, mercapto, cyano;

or CR ⁹ or CR ¹⁰ is attached to CR ¹¹ as shown for R ¹¹ to form a 5- or 6-membered ring;

R ¹¹ is hydrogen, halogen, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₄ -alkylthio, NH (C 1 -C ₄ alkyl), N (C 1 -C ₄ -alkyl) ₂ , cyano;

C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, which radicals may in each case be substituted one or more times with the following: halogen, cyano, C 1 -C ₄ -alkoxy;

or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring, which may be substituted by one or two C 1 -C ₄ -alkyls, and in which case one or more methylene groups may in each case be replaced by oxygen , sulfur, -NH or -N (C ₁ -C ₄ -alkyl);

Particularly preferred compounds of formula I, in the form of pure enantiomers and pure diastereomers, or mixtures thereof, are those wherein the substituents have the following meanings:

A is NR ⁷ R ⁸ or azido;

W and Z (which may be identical or different) are:

nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;

X is nitrogen or CR ⁹ ;

Y is nitrogen or CR ¹⁰ ;

Q is nitrogen or CR ¹¹ ; with the proviso that X = CR ⁹ and Y = CR 10 when Q = nitrogen, and Y = CR ¹⁰ or X = CR ⁹ if Q = CR ¹¹ ;

, i

R ² and R ³ (which may be identical or different) are:

phenyl, which may be substituted by one or more of the following radicals: halogen, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, phenoxy, C ₁ -C ₄ -alkylthio, NH (C ₁ -C 4- alkyl), N (C 1 -C ₄ -alkyl) ₂ or phenyl, which may be substituted one or more times, e.g. one to three times as follows: halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy or C 1 -C 4 -alkylthio; and phenyl groups which are connected together in the o- positions by direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an _SO2, NH or N-alkyl;

R ⁷ is hydrogen, C 1 -C 6 -alkyl, C ₃ -C 6 -alkenyl or C ₃ -C ₈ -alkynyl, C ₁ -C ₅ -alkylcarbonyl, it being possible for these radicals to be substituted in each case one or more times by the following: halogen, hydroxyl, carboxyl, amino, cyano, C4-alkoxy, _{Ci-C4-alkylthio, Ci-C4-alkoxycarbonyl,} NH (C ₁ -C ₄ alkyl), N _(Ci-C4 alkyl) _2, C ₃ -C 6 -cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, phenoxy or phenyl, wherein all said aryl radicals may in turn be substituted one or more times, e.g. one to three times, with the following: halogen, hydroxyl, mercapto, carboxyl, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C ₁ -C 4 -alkoxy, amino, NH (C ₁ -C 4 -alkyl), N (C 1 -C 4 -alkyl) ₂₁ phenyl or C 1 -C 4 -alkylthio;

phenyl or naphthyl, each of which is optionally substituted by one or more of the following radicals: halogen, cyano, Ci-C4-alkyl, C1-C4 haloalkyl, phenoxy, C _r C 4 alkoxy, -C ₄ -alkylthio, methylenedioxy or ethylenedioxy;

C 5 -C 6 -cycloalkyl, which radicals may in each case be substituted one or more times with the following groups: C 1 -C 4 -alkyl, C 1 -C 4 alkoxy;

R ⁸ is hydrogen;

R ⁹ and R ¹⁰ (which may be the same or different) are: hydrogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, N (C 1 -C ₄ -alkyl) 2;

C 1 -C 4 -alkyl, which radicals may be substituted by halogen;

or CR ⁹ or CR ¹⁰ is attached to CR ¹¹ as shown for R ¹¹ to form a 5- or 6-membered ring;

R ¹¹ is hydrogen, C ₁ -C 4 -alkoxy, C 1 -C 4 -alkylthio, cyano;

C 1 -C ₄ -alkyl, wherein the radicals may in each case be substituted one or more times with halogen;

or CR ¹¹ together with CR ⁹ or CR ¹⁰ forms a 5- or 6-membered alkylene or alkenylene ring, which may be substituted by one or two C 1 -C 4 alkyls, and in which case one or more methylene groups may in each case be replaced by oxygen, sulfur, -NH or -N (C 1 -C ₄ -alkyl);

The compounds of the present invention offer novel potential treatments for hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute / chronic renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid haemorrhage, subarachnoid haemorrhage, subarachnoid haemorrhage, subarachnoid haemorrhage, endotoxin-induced renal failure, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, ischemic and intoxication-induced renal failure or hypertension, cyclosporin-induced failure of> t * 1, kidney, prostate cancer, cancer metastasis, and cancer growth, contrast agents, pancreatitis, gastrointestinal ulcers.

The invention further relates to combination products consisting of endothelin receptor antagonists of formula I and inhibitors of the renin angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists, and in particular angiotensin converting enzyme (ACE) inhibitors.

The combinations may be administered together in a single pharmaceutical form or separately temporally and spatially.

The factors to be considered for the dosage and regimen are the same as for the individual substances.

I

These combination products are particularly suitable for the treatment and prevention of hypertension and its consequences and for the treatment of heart failure.

The invention further relates to the use of the novel compounds for photoaffinity labeling of endothelin receptors. Particularly suitable for this purpose are compounds of formula I wherein A is azido.

The beneficial effect of these compounds can be shown in the following tests:

Receptor Binding Studies

For binding studies, cloned human CHO cells secreting the ETa or ETb receptor were used.

»» ¹ '

Preparation of membrane

ET _A or ET _B receptor secreting CHO cells were cultured in DMEM NUT MIX F ₁₂ medium (Gibco, # 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, # A15-022), 1 mM glutamine (Gibco # 25030-024), 100 U / ml penicillin and 100 µg / ml streptomycin (Gibco, Sigma # P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% PBS containing trypsin at 37 ° C for 5 minutes. Following neutralization with medium, the cells were collected by centrifugation at 300 x g.

Q

For membrane preparation, cells were adjusted to a concentration of 10 cells / ml buffer (50 mM TrisHCl, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant output 20).

Binding tests

For the ET _A 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 µg / ml bacitracin and 0.2% BSA) at a concentration of 50 µg protein. and incubated with 25 µM [ ¹²⁵ I] -ET1 (ETα receptor assay) or 25 µM [ ¹²⁵ I] -ET3 (ETb receptor assay) in the presence and absence of test substance at 25 ° C. Non-specific binding was determined using 10 ⁷ M ETi. After 30 minutes, free and bound radioligand was separated by filtration through GF / B glass fiber filters (Whatman, England) in a Skatron cell separator (Skatron, Lier, Norway) and the filters were washed with ice cold Tris-HCl buffer, pH 7.4 with 0 , 2% BSA. The radioactivity retained on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

In vivo testing of ET antagonists:

Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and ligated. Carotid and jugular vein were catheterized.

In control animals, intravenous administration of 1 µg / kg ET1 resulted in a significant increase in blood pressure that persisted for a long time.

Test animals received an intravenous injection (1 ml / kg) of test compounds 30 minutes before ET1 administration. To determine the properties of ET antagonism, changes in blood pressure of the test animals were compared to changes in pressure of the control animals.

Oral testing of ET receptor antagonists:

Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g were orally pretreated with test compounds. After 80 minutes, the animals were anesthetized with urethane and the carotid (for blood pressure measurement) and jugular vein (administration of large endothelin / endothelin 1) were catheterized.

After the stabilization period, large endothelin (20 µg / kg, administered volume 0.5 ml / kg) or ET1 (0.3 µg / kg, administered volume 0.5 ml / kg) was administered intravenously. Blood pressure and pulse are recorded continuously over 30 minutes. Significant and long-term changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonist effect of the test substances, the AUC for the animals treated with the substance was compared with the AUC for the control animals.

The novel compounds may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. Administration can also be by vapor or spray through the nasopharynx space.

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

The novel compounds may be administered in conventional solid or liquid dosage forms, e.g. such as uncoated or coated tablets, capsules, powders, granules, supositories, solutions, ointments, creams or sprays. These are produced in a conventional manner. For this purpose, the active ingredients may be formulated with conventional pharmaceutical excipients such as tablet binders, bulking agents, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release retardants, antioxidants and / or dispensing gases ( see H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The dosage forms thus obtained usually contain from 0.1 to 90% by weight of active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Synthetic examples

Example 1

Methyl 2-hydroxy-3-azido-3,3-diphenylpropionate

3.8 g (59.0 mmol) of sodium azide and 3.1 g (59.0 mmol) of ammonium chloride were introduced into 80 ml of methanol. To this suspension was added 5 g (19.7 mmol) of methyl

3,3-diphenyl-2,3-epoxypropionate and the mixture was then stirred at room temperature for 48 hours. The mixture was concentrated, water was added and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were then dried over magnesium sulfate, the solvent was distilled off and the residue was purified by chromatography. 1.2 g (4 mmol, 21% yield) of pure product was isolated.

Melting point: 102-103 ° C ¹ H-NMR (200 MHz): 7.2 ppm (10 H, m), 5.1 (1H, d), 3.5 (3 H, s), 3, 4 (1H, d).

Example 2

Methyl 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3-azido-3,3-diphenylpropionate

930 mg (6.7 mmol) of potassium carbonate, 1.4 g (6.7 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and 2.0 g (6.7 mmol) of methyl 2-hydroxy-3-azido- 3,3-diphenylpropionate was mixed in 20 ml DMF. The mixture was stirred at 80 ° C for two hours. Cooling and addition of water was followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. 2.9 g of a crude oil was isolated and used immediately in the next reaction.

Example 3 t

Methyl 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionate

2.8 g (6.7 mmol) of methyl 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3-azido-3,3-diphenylpropionate was dissolved in 20 mL (40 mL) of methanol / ethyl acetate and added to the palladium spatula tip on carbon. The apparatus was then purged with nitrogen and then with hydrogen and the solution was stirred at atmospheric pressure at room temperature for three hours. After the conversion was complete, the palladium on carbon was filtered off and the solvent was distilled off. 2.9 g of crystals were isolated and used immediately in the next reaction.

• I

Example 4

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionic acid (I375)

840 mg (2.1 mmol) of methyl 2- (4-methoxy-6-methyl-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionate was added to a mixture of 6.4 ml dioxane and 3.2 ml 1 N hydroxide solution The mixture was stirred at 80 ° C for two hours. Cooling, addition of water and acidification were followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. The residue was stirred with ether, allowing 190 mg (0.5 mmol, 25% yield) of crystals to be isolated.

Z-ΝΜ ^ δΟ MHZ / DMSO / 303K): 7.7 ppm (1H, br), 7.4 (4H, m), 7.2 (6H, m),

5.9 (1H, br), 5.1 (1H, s), 3.2 (3H, br), 2.1 (3H, s).

¹ H-NMR (360 MHz / DMSO / 323 K): 7.7 ppm (1H, br), 7.4 (4H, m), 7.2 (6H, m), 5.9 (1H) H, s), 5.1 (1H, s), 3.2 (3H, s), 2.1 (3H, s).

Example 5

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3-azido-3,3-diphenylpropionic acid (I-542)

1.1 g (2.5 mmol) of methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-azido-3,3-diphenylpropionate were added to a mixture of 11 ml of dioxane and 5 ml of 1 N potassium hydroxide solution and it was stirred at 50 ° C for three hours. Cooling, addition of water and acidification were followed by extraction with ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. 900 mg (2.1

1 mmol, 85% yield) of crystals. .

Melting point: 164-165 ° C

ESI-MS: M ^&lt; ⁺ &^gt; = 421

Example 6

Methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-acetylamino-3,3-diphenylpropionate

A catalytic amount of DMAP and 1 g (2.4 mmol) of methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionate were dissolved in 10 ml of pyridine. With cooling in ice, 0.26 ml (3.7 mmol) of acetyl chloride was added dropwise and the mixture was stirred at room temperature for 12 hours. Water was added and the mixture was extracted with ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. The residue was treated with ether and the compound started to crystallize after a short time (1 g, 2.2 mmol, 90% yield). The compound could be used without further purification.

Example 7

2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-acetylamino-3,3-diphenylpropionic acid (1-174) g (2.2 mmol) methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) 3-Acetylamino-3,3-diphenylpropionate was added to a mixture of 8.8 ml dioxane and 4.4 ml 1 N potassium hydroxide solution and the mixture was stirred at 80 ° C for 1 hour. Cooling and addition of water was followed by extraction with ether (once). Acidification was followed by extraction with methyl tert-butyl ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. The residue was stirred with ether, allowing 640 mg (1.5 mmol, 67% yield) of crystals to be isolated.

Melting point: 120-121 ° C

ESI-MS: M ^&lt; ⁺ &^gt; = 437

Example 8

Methyl 2- (4-methoxy-6 _I 7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-azido-3,3difenylpropionát

743 mg (5.4 mmol) of potassium carbonate, 2.5 g (10.8 mmol) of 4-methoxy-6,7-dihydro-5H-cyclopenta-2-methylsulfonylpyrimidine and 3.0 g (10.8 mmol) of methyl 2-hydroxy- 3-Azido-3,3-diphenylpropionate was mixed in 20 mL DMF. The mixture was stirred at 60 ° C for three hours. Cooling and addition of water was followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. 3.7 g (8.3 mmol, 77% yield) of crystals were isolated and used immediately in the next reaction.

Example 9

2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-azido-3,3-diphenylpropionic acid (1-518)

3.7 g (8.3 mmol) of methyl 2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2yloxy) -3-azido-3,3-diphenylpropionate were added to a mixture of 33 ml dioxane and 17 ml 1 N potassium hydroxide solution and the mixture was stirred at 50 ° C for two hours and then at room temperature for 12 hours. Water was added and the impurities were extracted with ether. The acidification was followed by extraction with ether. The combined organic phases were dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized from a mixture of ether and n-hexane, allowing 2.6 g (5 mmol, 60% yield) of crystals to be isolated.

¹ I ¹

Melting point: 143-144 ^e C ESI-MS: M + = 431

Example 10

The following compounds were prepared in a similar manner to the compounds in the above-described examples.

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3-amino-3,3-diphenylpropionic acid (I354)

Melting point: 159-160 ° C ESI-MS: M ⁺ = 395

2- (4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-amino-3,3-diphenylpropionic acid (I-334)

Melting point: 119-120 ° C ESI-MS: M ⁺ = 405

2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methoxyacetylamino-3,3-diphenylpropionic acid (I-535) ^1, I

Melting point: 187-188 ° C ESI-MS: M ⁺ = 467

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3- (2,2-dimethylpropylcarbonylamino) -3,3-diphenylpropionic acid (I-388)

Melting point: 198-199 ° C ¹ H-NMR (200 MHz): 7.5 ppm (2H, m), 7.2 (8H, m), 6.7 (1H, s), 6.5 (1H, s),

5.7 (1H, s), 3.8 (6H, s), 2.1 (2H, s), 1.0 (9H, s).

2- (4 _L 6-dimethoxy-2-pyrimidinyloxy) -3-cyclopropylcarbonylamino-3 3difenylpropiónová ₁ (1-227)

Melting point: 206-207 ° C ESI-MS: M ⁺ = 463

2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3-p-nitro-benzoylamino-3 _I, 3-diphenylpropionic acid (1-541)

Melting point: 219-220 ° C ESI-MS: M ⁺ = 544

The compounds listed in Table 1 can be prepared in a similar manner or as described in the general section.

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N CH from from from from from from from FROM d) d) 0) fl> d) d) d) d> > - from 2 2 about 1 about 2 2 1 about 2 2 2 ABOUT about about about about ABOUT Q) d) σ 2 1 about CH CH 2 1 about from CH CH from FROM Q) -Me φ -Me d> 2 1 d) d) ethyl x 2 ABOUT 1 about 2 ABOUT 1 about from 2 ABOUT 1 about C-OM ABOUT about about ABOUT g from from from from CH from from CH CH 1 X T from < CI-phenyl-CONH Phenyl-NH- Phenyl-NH- OH-phenyl-CO Phenyl-CONH- n from m from Phenyl-CONH- _2- Phenyl-CONH b about- ώ about 1 ABOUT 1 ABOUT from 3,4- 2 ABOUT WHAT CM 1 WHAT 1 [*> OJ > » >. >. ps > » >. > » > » C C C C C C C C C N " d) (U d> d) in d) (U d> d) saith U- LL LL LL LL LL LL LL LL I X X X X X X X X r * ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about ABOUT OI ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about about about about about about ABOUT cn about in CM WHAT T WHAT WHAT N- • and WHAT WHAT WHAT WHAT WHAT what what WHAT •about and 1 IO 1 and 1 and 1 m 1 m 1 m 1 and and 1

Example 11

Receptor binding data was measured by the binding assay described above for the compounds listed below.

The results are shown in Table 2.

I 1

Table 2

Receptor Binding Data (K i Values)

compound ET _and [nM] ET _b [nM] 1-174 83 > 7000 I-227 225 2800 I-334 600 6400 I-354 50 > 6400 I-375 300 7300 I-388 1000 7000 1-518 14 460 I-535 35 7000 1-541 1000 > 7000 I-542 60 2200

Claims (10)

A β-amino or β-azidocarboxylic acid derivative of the formula I R 2 W-X -CH-OR 3 R 1 Wherein R ¹ is tetrazolyl or a group wherein R is as follows: (a) the radical OR ⁴ , where R ⁴ is: hydrogen, an alkali metal cation, an alkaline earth metal cation, or a physiologically tolerated organic ammonium ion; C ₃ -C ₈ -cycloalkyl, dripped alkyl, unsubstituted or substituted _CH2-phenyl, unsubstituted or substituted, -CE C ₃ -alkenyl or C ₃ -C 8 alkynyl, unsubstituted or substituted, or phenyl, unsubstituted or substituted, (b) a 5-membered heteroaromatic system attached through a nitrogen atom; c) a group, (O) k -O- (CH ₂ ) _p -S-R ⁵ where k can be values of 0.1 and 2, p values of 1, 2, 3 and 4, and R ⁵ is C 1 -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl or unsubstituted or substituted phenyl, d) radical Ο — NH-S-R6 II Ο where R ⁶ is: C _r C ₄ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, C ₃ -C ₈ -cycloalkyl, where these radicals can carry a C ₁ -C ₄ alkoxy, alkylthio, and CpG / or a phenyl radical; C 1 -C 4 -haloalkyl or phenyl, unsubstituted or substituted; A is NR ⁷ R ⁸ or azido; W and Z (which may be identical or different) are: nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine; X is nitrogen or CR ⁹ ; Y is nitrogen or CR ¹⁰ ; Q is nitrogen or, CR ¹¹ ; with the proviso that X = CR ⁹ and Y = CR ¹⁰ when Q = nitrogen R ² and R ³ (which may be identical or different) are: phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl, which are connected to each other in ortho positions by direct coupling, methylene, ethylene or ethenylene, an oxygen or sulfur atom or an SO ₂ , NH or N-alkyl group; C ₅ -C ₆ -cycloalkyl, unsubstituted or substituted; R ⁷ is hydrogen, C ₈ alkyl, C ₃ -C ₈ -alkenyl, C ₃ -Ca alkynyl, C ₅ alkylcarbonyl, these radicals to be unsubstituted or substituted; phenyl or naphthyl, unsubstituted or substituted; unsubstituted or substituted C ₃ -C ₈ -cycloalkyl; or R ⁷ is linked to R ⁸ through 4 or 5 CH ₂ groups to form a 5 or 6-membered ring; R ⁸ is hydrogen, C 1 -C 4 -alkyl; or R ⁸ is linked to R ⁷ through 4 or 5 CH ₂ groups to form a 5 or 6-membered ring; R ⁹ and R ¹⁰ (which may be identical or different) are: hydrogen, halogen, _{Ci-C4-alkoxy,} C4-haloalkoxy, C3-6-alkenyloxy, C3-C6alkinyloxy, C, -C4-alkylthio, Ci.C ₄ -alkylcarbonyl, C, -C4-alkoxycarbonyl, hydroxyl, _NH2, NH (C ₁ -C ₄ alkyl), N (Cl-4 alkyl) ₂ C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C 4 -alkynyl, which radicals may be unsubstituted or substituted; or CR ⁹ or CR ¹⁰ is attached to CR ¹¹ as shown below to form a 5- or 6-membered ring, R ¹¹ is hydrogen, halo, C, -C4-alkoxy, C4-haloalkoxy, C3.Ce-alkenyloxy, C ₃ -C alkynyloxy, C, -C4-alkylthio, Ci.C4 alkylcarbonyl, Ci-C4-alkoxycarbonyl, NH (C4 -alkyl), N (C 1 -C 4 -alkyl) ₂ , hydroxyl, carboxyl, cyano, amino, mercapto; T C 1 -C 4 -alkyl, C ₂ -C 4 -alkenyl, C ₂ -C 4 -alkynyl, which radicals may be unsubstituted or substituted; or CR ¹¹ together with CR ⁹ or CR ^{10 form a} 5- or 6-membered alkylene or alkenylene ring, which may be unsubstituted or substituted, and in which case one or more methylene groups may in each case be replaced by oxygen, sulfur, -NH or - N (C 1 -C ₄ -alkyl); and physiologically tolerated salts and possible enantiomerically pure and diastereomerically pure forms. Use of a β-amino or β-azidocarboxylic acid derivative according to claim 1 for the treatment of diseases. Use of compounds I according to claim 2 as endothelin receptor antagonists. Use of a β-amino or β-azidocarboxylic acid derivative according to claim 1 for the manufacture of a medicament for the treatment of diseases in which elevated endothelin levels occur. Use of a β-amino or β-azidocarboxylic acid derivative according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer. Use of the β-amino or β-azidocarboxylic acid derivative according to claim 1 in combination with: renin-angiotensin system inhibitors such as renin inhibitors, angiotensin II antagonists and in particular angiotensin converting enzyme (ACE) inhibitors; mixed ACE / neutral endopeptidase (NEP) inhibitors; β-blockers. Medicament for oral, parenteral or intraperitoneal administration, characterized in that it contains a single dose in addition to the conventional. at least one carboxylic acid derivative I according to claim 1. A compound of formula II R 2 CH-OH R3 R1 Wherein the radicals R, R, R and A are as defined in claim 1. ' ¹ . * 1 9. Use of compounds of formula II: R 2 CH-OH R 3 R 1 wherein the radicals R ¹ , R ² , R ³ and A are as defined in claim 1 as starting materials for the synthesis of endothelin receptor antagonists. 10. Structural fragment of the formula R 2 R3 R1 H *, - ° T where the radicals R ^1, R ^2, R ³ and A are as defined in Claim 1, as a structural element of an endothelin receptor.