SK772002A3 - Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists - Google Patents

Abstract

The invention relates to compounds of formula (I), whereby the substituents have the meaning cited in the description. The invention also relates to the utilization of said derivatives.

Description

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, 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 caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988). .

Increased or abnormal release of endothelin causes sustained vasoconstriction in peripheral, renal and cerebral vessels, which may lead to disorders. As reported in the literature, endothelin is involved in several disorders. 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, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl, J. Med., 322, 205 (1989), N. Engl, J. Med., 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol Cell Cell, 27, A234 (1995), Cancer Research 56, 663 (1996), Nature Medicine 1, 944 , (1995)).

To date, at least two endothelin receptor subtypes, ET _A and ET _B 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 receptors should antagonize the physiological effects of endothelin and thus represent valuable drugs.

The preparation and use of endothelin receptor antagonists has already been described in WO 95/26716, WO 96/11914, WO 97/09294, WO97 / 12878, WO 97/38980, WO97 / 38981, WO 97/38982, WO98 / 09953, WO98 / 27070 , DE 19726146.9, DE 19748238.4, DE 19750529.5, DE 19806438.1, DE 19809144.3 and DE 19836044.4. Further research has revealed that related compounds with a 5,6-substituted pyrimidine ring have advantageous properties in relation to receptor affinity and receptor binding profile. The present invention relates to their preparation and use.

SUMMARY OF THE INVENTION

The invention relates to carboxylic acid derivatives I

(0 where R 'is tetrazolyl or a group wherein R has the following meaning:

(a) the radical OR ⁷ , where R ⁷ is:

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

C ₃ -C ₈ -cycloalkyl, Ο, -C 6 -alkyl, CH ₂ -phenyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, Ο _Γ alkyl ₄ alkyl, C 1 -C 4 haloalkyl, hydroxyl , C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino,

NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ;

C ₃ -C ₆ -alkenyl or C ₃ -C ₆ -alkynyl, which groups in turn may carry one to five halogen atoms;

R ⁷ may also 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, 0, -O, haloalkyl, hydroxyl, C ₁ -C ₄ alkoxy, mercapto, C ^ C ^ alkylthio, amino, NH-C ^ alkyl), N (C _r C ₄ -alkyl) _2;

b) a 5-membered heteroaromatic system, for example pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which is attached via a nitrogen atom and which may carry one to two halogen atoms or one or two C 1 -C 4 alkyl or two C 1 -C 6 alkoxy groups;

(c) group (0) _k

---- --- O _{(CH2) p} --- S --- R 8 wherein k is 0,1 or 2, p is 1,2, 3 and 4, and ^R8 is

C ₁ -C ₄ -alkyl, C ₃ -C _e cycloalkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ alkynyl or phenyl, optionally substituted by one or more, e.g. one to three of the following radicals: halogen, nitro, cyano, C ₁ -C ₄ -haloalkyl, hydroxyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, mercapto, amino, NH 2 C ₁ -C ₄ alkyl), N (C 1 -C ₄ alkyl) ₂ ;

d) radical

ABOUT

II

--- N --- S --- R9 ^H II o where R ⁹ is:

C, -C ₄ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C _B cycloalkyl, where these radicals can carry a C, -C ₄ -alkoxy, C ^ C ^ - an alkylthio and / or phenyl radical as mentioned under c);

phenyl, which may be substituted by one to three of the following radicals: halogen, nitro, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ -haloalkyl, hydroxyl, Ο, Ο ₄ alkoxy, 0, -04-alkylthio, mercapto , amino, NH 4 -C 1-4 alkyl), N (C ₁ -C ₄ alkyl) ₂ .

Other substituents have the following meanings:

I

R ² is hydroxy, NH 2, NH (C, -C4 alkyl), N (C4 alkyl) 2, C ^ alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, C, -C 4 hydroxyalkyl, C ^ -haloalkyl , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 -alkylthio, or CR ² together with CR ^{3 form a} 5- or 6-membered alkylene or alkenylene ring, which may be substituted with one or two C 1 -C 4 -alkyls and wherein in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N (C 1 -C 4 -alkyl).

R ³ is hydroxyl, NH ₂ , NH (C 1 -C ₄ -alkyl), N 1 -C 4 -alkyl), halogen, C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C _4- alkynyl, C ₃ -C ₆ -alkenyloxy, C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ alkoxycarbonyl, C 1 -C ₄ -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy, C 1 - C ₄ -haloalkoxy, -NH-O-C 1 -C ₄ alkyl, C 1 -C ₄ -alkylthio, or CR ³ forms, as mentioned under R ² , together with CR ^{2 a} 5- or 6-membered ring;

R ⁴ and R ⁵ (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, 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, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ; or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 _2, NH or N-alkyl;

or C ₃ -C ₇ -cycloalkyl;

R ⁶ is hydrogen,

C 3 -C ₈ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, each of which may be substituted one or more times with the following:

hydroxyl, mercapto, carboxyl, halogen, nitro, cyano, C ₁ -C ₄ -alkoxy, C ₃ -C ₆ -alkenyloxy, C ₃ -C ₆ -alkyloxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -haloalkoxy, C 1 -C ₄ -alkylcarbonyl, O, O-alkoxycarbonyl, (C 1 -C 4 -alkylONHcarbonyl, (C ₁ -C ₄ -alkyl) Ncarbonyl, C ₃ -C ₈ -alkylcarbonylalkyl, amino, NH (C ₁ -C ₄ -alkyl) , N 1 -C 1-6 alkyl, 1a, phenoxy or phenyl, wherein the aryl radicals may be substituted one or more times, e.g., one to three times, by the following: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 0, -O C 1 -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, mercapto, carboxy, hydroxyl, amino, R ¹⁰ , C 1 -C ₄ alkoxycarbonyl, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , methylenedioxy, ethylenedioxy, or phenyl or phenoxy substituted with C, -C ₄ alkylthio;

phenyl or naphthyl, each of which is optionally substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C _r C ₄ alkyl, -C haloalkyl, C, -C ₄ -alkoxy, C ₄ -C -haloalkoxy, phenoxy, CLC alkylthio, NH (C, _{-C 4} alkyl), N (C _r C ₄ alkyl) ₂ or methylenedioxy or ethylenedioxy;

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom and which may carry one to four halogen atoms and / or one to two of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 C 1 -C ₄ -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyls in turn may carry one to five halogen atoms and / or one to three of the following radicals: C 1 -C 4 _4- alkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy and / or C 1 -C ₄ -alkylthio;

R ¹⁰ is CLC alkyl, C, -C ₄ alkylthio or C _r C ₄ -alkoxy, each of which carries one of the following radicals: hydroxyl, carboxyl, amino, NH (C ₁ -C ₄ alkyl), N ( C, _{-C 4} alkyl) _2, carboxamide or CON (C ₁ -C ₄ -alkyl) _2;

Z is sulfur or oxygen.

The following definitions apply in this context and beyond:

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

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

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

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

The 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, 2,2dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C 1 -C ₄ -haloalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2 -chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

C 1 -C 4 alkyl may be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C ₂ -C ₄ -alkenyl may be linear or branched, such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;

C ₂ -C ₄ -alkynyl may be linear or branched, such as ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl;

C 1 -C 6 alkoxy may be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C ₃ -C ₆ -alkenyloxy may be linear or branched, such as allyloxy,

2-buten-1-yloxy or 3-buten-2-yloxy;

C ₃ -C ₆ -alkynyloxy may be linear or branched, such as 2-propyne-

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

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

1,1-dimethylethylthio;

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

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

C ₃ -C -alkylkarbonylalkyl _B may be linear or branched, e.g. 2oxoprop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl;

C _r -C ₈ alkyl may be linear or branched, such as C-C alkyl, pentyl, hexyl, heptyl or octyl;

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 be in the form of pure enantiomers or pure diastereomers or mixtures thereof. It is preferred to use an 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 endothelin receptor inhibitors.

Compounds of formula IV in which Z is sulfur or oxygen (IV) can be prepared as described in WO 96/11914.

R6 — Z-H (H1)

R 4 H - R ⁶ - Z - C - OH

R5 R1 (IV)

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

Compounds of formula IV may be obtained in enantiomerically pure form by acid catalyzed transetherification as described in WO 98/09953.

Enantiomerically pure compounds of formula IV may also be obtained by carrying out conventional resolution of racemates of racemic or diastereomeric compounds of formula IV with suitable enantiomerically pure bases. Examples of suitable bases of this type are 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.

Novel compounds in which the substituents are as defined for formula (I) can be prepared, for example, by reacting the carboxylic acid derivatives of formula (IV) in which the substituents are as defined with compounds of formula (V).

(IN)

V is halogen or R ¹² -SO ² -, wherein R ¹² can be C 1 -C 4 alkyl, C 1 -C ₄ -haloalkyl or phenyl. The reaction is preferably carried out in an inert solvent or diluent with the addition of a suitable base, i.e. a base which deprotonates intermediate IV, at a temperature ranging from ambient temperature to the boiling point of the solvent.

When R ^{1 is} an ester, compounds with R ¹ = COOH can be prepared by acidic, basic or catalytic cleavage of the ester group.

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

Examples of such solvents or diluents include aliphatic, alicyclic and aromatic hydrocarbons, which may also be chlorinated, for example hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfone such as dimethylsulfoxide and sulfolane.

The compounds of formula V are known and some of them can be purchased or prepared in a manner known per se. 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 carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide, for example sodium hydroxide or potassium hydroxide, an organometallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide.

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 an activated form, for example a halide, anhydride or imidazolide, and then reacting it with a suitable hydroxyl compound HOR ^7. . This reaction can be carried out in conventional solvents and often requires the addition of a base such as triethylamine, pyridine, imidazole or diazabicycloundecene. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as carbodiimide.

In addition, the compounds of formula I may also be prepared starting from salts of the corresponding carboxylic acids, 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 many compounds of formula R ⁷ -A, wherein A is a conventional nucleofusion leaving group, for example halogen such as chlorine, bromine, iodine, or optionally halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl, for example toluenesulfonyl and methylsulfonyl, or another equivalent outgoing group. The compounds of the formula R ⁷ -A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction may be carried out in conventional solvents, preferably with the addition of a base, with the abovementioned bases being suitable.

In some cases, it is necessary to employ generally known protecting group techniques to prepare the novel compounds. For example, when R ⁶ = 4-hydroxyphenyl, the hydroxyl group can be initially protected as benzyl ether, which is then cleaved at a suitable stage of the reaction sequence.

Compounds of formula I wherein R ¹ is tetrazolyl can be prepared as described in WO 96/11914.

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

R ² hydroxy, N (Cl-C4-alkyl) 2, C ^ C ^ alkyl, C ^^ - haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C ^ C ^ alkylthio, or ^CR2 forms together with CR ^{3 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 methylenes may in each case be replaced by oxygen, sulfur, -NH or -N ? -C? alkyl);

R ³ hydroxyl, N (C ₁ -C ₄ -alkyl) ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₄ -alkylthio, halogen, or CR ³ forms, as indicated for R ² , together with CR ^{2 a} 5- or 6-membered ring;

R ⁴ and R ⁵ are phenyl or naphthyl, each of which may be substituted with one or more, for example one to three, of the following radicals:

halogen, cyano, hydroxyl, mercapto, amino, C, _-C4 alkyl, C, -C ₄ haloalkyl, C, -C ₄ alkoxy, C ₁ -C ₄ -haloalkoxy, C, -C ₄ alkylthio, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , C 1 -C ₄ alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl;

phenyl or naphthyl, which are linked to each other in ortho positions by direct bonding, methylene, ethylene or ethenylene, an oxygen or sulfur atom or an SO ₂ , NH or N (C ₁ -C ₄ -alkyl) group;

or C ₃ -C ₇ -cycloalkyl;

R ^{6 is} C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, each of which may be substituted one or more times with the following: halogen, hydroxyl, cyano, C 1 -C 4 - alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylcarbonyl, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, NH (C 1 -C 4 -alkyl), N ( (C 1 -C 4 -alkyl) 2) phenoxy or phenyl, wherein the aryl radicals 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, C 1 -C 4 -haloalkoxy, R ¹⁰ , C 1 -C 4 -alkoxycarbonyl, methylenedioxy, ethylenedioxy, C 1 - C ₄ -alkylthio, phenyl or phenoxy;

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

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom and which may carry one to four halogen atoms and / or one to two of the following radicals: C 1 -C ₄ -alkyl, C , -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyls may in turn carry one to five halogen atoms and / or one to three of the following radicals: C, -C ₄ alkyl, C, -C ₄ haloalkyl, C, -C ₄ alkoxy, C, -C ₄ -haloalkoxy and / or C, -C ₄ alkylthio;

R ^{10 is} C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy which bears one of the following radicals: hydroxyl, carbamoyl or CON (C 1 -C ₄ -alkyl) ₂ ;

Sulfur or oxygen.

Particularly preferred compounds of formula I - either in the form of pure enantiomers or pure diastereomers or mixtures thereof - are those in which the substituents have the following meanings:

R ² C 1 -C 4 alkyl, C 1 -C 4 alkoxy, especially methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, or CR ² together with CR ³ forms a 5-membered alkylene or alkenylene ring which may be substituted by one or two methyl and in which in each case one or more methylene groups may be replaced by oxygen or sulfur;

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, or CR ³ forms, as mentioned for R ² , together with CR ² 5-membered ring;

R ⁴ and R ⁵ are phenyl (identical or different) which may be substituted by one or more, e.g. one to three of the following radicals: halogen, hydroxy, C ^ O ^ alkyl, C _t -C ₄ alkoxy, C ₁ -C _4- alkylthio;

R ⁴ and R ⁵ are phenyl which are connected to each other at ortho positions by direct coupling, methylene, ethylene or ethenylene, an oxygen or sulfur atom, or an SO ₂ , NH or N (C ₁ -C ₄ -alkyl) group; or

R ⁴ and R ⁵ are cyclohexyl;

R ⁶ Ο, -C 6 -alkyl, C ₃ -C ₆ -alkenyl or C ₃ -C ₈ -cycloalkyl, each of which may be substituted one or more times with the following: halogen, hydroxyl, cyano, C 1-6 -alkoxy, C ₃ -C ₆ -alkenyloxy, C 1 -C 4 -alkylthio, phenoxy or phenyl, wherein the aryl radicals may be substituted one or more times, for example one to three times, by the following: C 1 -C 4 -alkyl, C 1 -C ₄ -alkoxy, methylenedioxy, ethylenedioxy, C C 1 -C ₄ -alkylthio;

phenyl or naphthyl, which may 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 ^ C ^ alkylthio, -C ₄ alkylamino or C ^^ - dialkylamino;

a five- or six-membered heteroaromatic system containing one nitrogen atom and / or one sulfur or oxygen atom and which may carry one to four halogen atoms and / or one to two of the following radicals: C 1 -C 4 alkyl, C, C ₄ - haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C 6 -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyls in turn may carry one to five halogen atoms and / or one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 alkyl; haloalkyl, C _r C ₄ -alkoxy and / or C, - alkylthio;

Sulfur or oxygen.

The compounds of the present invention offer novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, haemorrhage, subaracherosis, subaracherias, subaracherias , endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostate hyperplasia, liver cirrhosis, erectile dysfunction, ischemic and intoxication-induced renal failure or mesenchymal growth, metastasis, metastasis, pancreatitis, especially acute pancreatitis, gastrointestinal ulcers.

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

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

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

The invention further relates to combinations of endothelin receptor antagonists of formula I and agents that block VEGF (vascular endothelial growth factor) action. Examples of such agents are antibodies directed against VEGF or specific binding proteins or thereafter low molecular weight agents capable of specifically inhibiting the release or binding of VEGF receptors.

The above combinations may be administered simultaneously or sequentially. They can be used either in a single pharmaceutical preparation or in special preparations. The dosage form may also vary; endothelin receptor antagonists can be administered, for example, orally, and VEGF inhibitors parenterally.

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

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

Receptor Binding Studies

Cloned human CHO cells secreting the ET _A or ET _B receptor were used for binding studies.

Preparation of membrane

ET _A or ET _B receptor secreting CHO cells were cultured in DMEM NUT MIX F, ₂ (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 (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.

For membrane preparation, cells were adjusted to a concentration of 10 ⁸ cells / ml buffer (50 mM Tris-HCl, 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 mg / ml bacitracin and 0.2% BSA) at a concentration of 50 gg of protein to the assay and incubated with 25 µM [ ¹²⁵ I] -ET, (ET _A receptor assay) or 25 µM [ ¹²⁵ I] -ET ₃ (ET _B receptor assay) in the presence and absence of test substance at 25 ° C. 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.

Functional blood vessel assay for endothelin receptor antagonists

After biasing the segments with rabbit aorta 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37 ° C and pH between 7.3 and 7.4, contraction by K ⁺ is first induced. After washing, a dose-response curve of endothelin to the maximum is constructed.

Potential endothelin antagonists are administered to other samples of the same vessel 15 minutes before the start of the dose-effect curve of endothelin. The effects of endothelin are calculated as a percentage of K ⁺ -induced contraction. For potent endothelin antagonists, there is a shift to the right of the endothelin effect curve.

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 gg / 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 mixed ET _A and ET _B 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 gg / kg, administered volume 0.5 ml / kg) or ET1 (0.3 gg / 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 nasopharyngeal 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. 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

Example 1 ¹ 2-Methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine

4.9 g (44 mmol) of 2-oxocyclopentanecarbaldehyde dissolved in 100 ml of water were added over 1 hour to a solution of 16.4 g of potassium carbonate (119 mmol) and 42.3 g of S-methylisothiourea sulfate (152 mmol) and after stirring with stirring at room temperature overnight, the mixture was heated at 65 ° C for 6 hours. The aqueous solution was extracted with pentane, the organic phase was concentrated and the residue was chromatographed on silica gel (heptane / ethyl acetate 8: 2) to give 0.93 g of the target compound as a solid.

Example 2

2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine

A solution of 9.9 g (16.1 mmol) of Oxone in 70 ml of water and 4M sodium hydroxide solution were added alternately to a solution of 0.85 g (5.1 mmol) of 2-methylsulfanyl-6,7-dihydro-5H-cyclopentapyrimidine in 20 ml. of methanol at 0 ° C while maintaining a pH of 2-3. After the addition was complete, the mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporated. The solid residue (0.93 g) was used without further purification.

Example 3

Benzyl 2- (6,7-dihydro-5,7-cyclopentapyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionate

0.6 g (1.6 mmol) of benzyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate dissolved in DMF was added dropwise to a suspension of 0.1 g of NaH (3.3 mmol, 80% in white oil) in 10 ml DMF at 0 ° C. After stirring the mixture for 30 minutes, 420 mg (2.1 mmol) of 2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine in 10 mL of DMF was added and the mixture was stirred at room temperature overnight. It was then poured into ice-water and extracted three times with diethyl ether. The ether phases were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The yellow residue (0.54 g) was chromatographed on silica gel to give 243 mg of the desired product.

MS (API): 503 (M + Na) ^< ^{+ >.}

Example 4

2- (6,7-Dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-136)

A solution of 0.23 g of benzyl 2- (6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionate in 15 mL of ethyl acetate-methanol 2: 1 was hydrogenated with hydrogen under atmospheric pressure using 60 mg palladium on activated carbon (10%) at room temperature for 24 hours. The mixture was filtered and concentrated and the residue (177 mg) was taken up in diethyl ether, filtered and dried. 95 mg of the target product was isolated.

¹ H-NMR (d ₆ -DMSO, 200 MHz): 8.3 (s, 1H), 7.2-7.4 (m, 10H); 6.15 (s, 1 H);

3.3 (s. 3H); 2.8 (m, 4H); 2.1 (m, 2H).

Example 5

2-Chloro-4-methoxy-5-methylpyrimidine

A solution of 25 g 2,4-dichloro-5-methylpyrimidine in methanol was cooled to 0 ° C, 28.5 ml sodium methoxide solution (30% in methanol) was added and the mixture was stirred at 0 ° C for one hour and then at at room temperature for 2 hours. The resulting suspension was freed from solvent, dissolved in water and extracted with ether. The organic phases were dried over sodium sulfate, filtered and concentrated, and the resulting residue was chromatographed on silica gel to give 11.4 g of the target compound.

Example 6

2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-isopropoxy-3,3-diphenylpropionic acid (I-5)

0.76 g (2.5 mmol) of 2-hydroxy-3-isopropoxy-3,3-diphenylpropionic acid dissolved in DMF was added dropwise to a suspension of 0.23 g of sodium hydride (7.6 mmol, 80% in white oil) ) in 20 ml DMF at 0 ° C. After stirring the mixture for 30 minutes, 0.6 g (3.8 mmol) of 2-chloro-4-methoxy-5-methylpyrimidine in 10 mL of DMF was added and the mixture was then stirred at room temperature overnight and then at 40 ° C 8 hours. It was then poured into ice-water, adjusted to pH 1 with 2N HCl and extracted three times with diethyl ether. The ether phases were extracted with 1 N KOH, the alkaline aqueous phase was again adjusted to pH 1 with 2 N HCl and re-extracted with ether. The ether phases thus obtained were dried over magnesium sulphate, filtered and the solvent was evaporated under reduced pressure. The yellowish residue (0.8 g) was chromatographed on silica gel to isolate 0.19 g of the desired product.

¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H); 7.5-7.6 (m. 2H); 7.2-7.4 (m. 8H); 6.3 (s, 1 H); 3.9 (m, IH); 3.9 (s. 3H); 2.0 (s. 3H); 1.1 (m, 6H).

MS (API): 423 (M + H) < ⁺ > ^.

Example 7

2-methylsulfanyl-4-methoxy-5-methylpyrimidine

7.2 g (102 mmol) of sodium thiomethanolate was added to a solution of 14.8 g (93 mmol) of 2-chloro-4-methoxy-5-methylpyrimidine in 100 ml of acetonitrile and the resulting suspension was refluxed for four hours. The solvent was then removed and the residue was dissolved in water and extracted with ether. The organic phases were dried over sodium sulfate, filtered and concentrated and the residue (13.4 g) was reacted without further purification.

Example 8

2-methylsulfanyl-4-methoxy-5-methylpyrimidine

A solution of 62.4 g (101 mmol) of Oxone in water and 4 M sodium hydroxide solution (approximately 40 mL) was added to a solution of 13.3 g (78.1 mmol) of 2-methylsulfanyl.

Of 4-methoxy-5-methylpyrimidine in 80 mL of methanol at 0 ° C while maintaining a pH of 2-

3. After the addition was complete, the mixture was stirred at room temperature for 2 hours and after removing the methanol, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporated. The solid residue (14.7 g) was stirred in diethyl ether for two hours, filtered and dried to give 13.5 g of pure target product.

Example 9

2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-benzyloxy-3,3-diphenylpropionic acid (I-47)

1.0 g (2.5 mmol) of 2-hydroxy-3-benzyloxy-3,3-diphenylpropionic acid dissolved in DMF was added dropwise to a suspension of 0.27 g of sodium hydride (9 mmol, 80% in white oil) in 20 ml DMF at 0 ° C. After stirring the mixture for 30 minutes, 0.79 g (3.9 mmol) of 2-methylsulfonyl-4-methoxy-5-methylpyrimidine in 10 mL of DMF was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water, the pH was adjusted to 1 with 2 N HCl and extracted three times with diethyl ether. The ether phases were extracted with 1 N KOH, the alkaline aqueous phase was again adjusted to pH 1 with 2 N HCl and extracted with ether. The obtained ether phases were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The yellowish residue (1.2 g) was mixed with 10 ml diethyl ether and stirred at room temperature for 3 hours. The precipitated solid was filtered off with suction and dried to give 0.6 g of the target compound.

¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H), 7.2-7.45 (m, 10H); 6.2 (s, 1 H); 4.7 (d, 1H); 4.55 (d, 1H); 3.85 (s, 3H); 2.1 (s. 3H).

MS (API): 471 (M + H) < ⁺ > ^.

Example 10

2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -3-hydroxy-3 ₁ 3-diphenylpropionic acid (I29)

A solution of 440 mg (0.94 mmol) of 2- (4-methoxy-5-methylpyrimidin-2-yloxy) -

3-Benzyloxy-3,3-diphenylpropionic acid in 20 ml of ethyl acetate was hydrogenated with hydrogen at atmospheric pressure at room temperature with 80 mg of palladium on charcoal (10%) for 3 days. The mixture was filtered and concentrated and the residue (430 mg) was chromatographed on silica gel to give 39 mg of the desired target product.

¹ H-NMR (d ₆ -DMSO, 200 MHz): 8.0 (s, 1H); 7.6 (m. 2H); 7.0-7.5 (m, 45H); 5.6 (s, 1H); 3.8 (s, 3 H); 1.9 (s, 3 H).

Example 11

(S) -2- (4-Methoxy-5-methylpyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (I-2) g (36.7 mmol) of (S) -2-hydroxy acid -3-Methoxy-3,3-diphenylpropionic acid dissolved in 40 mL of DMF was added dropwise to a suspension of 3.3 g of sodium hydride (110 mmol, 80% in white oil) in 40 mL of DMF at 0 ° C. After stirring the mixture for 60 minutes, 9.6 g (47.7 mmol) of 2-methylsulfonyl-4-methoxy-5-methylpyrimidine in 20 mL of DMF was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water, the pH was adjusted to 1 with 2 N HCl and extracted three times with diethyl ether. The ether phases were extracted with 1 N KOH, the alkaline aqueous phase was again adjusted to pH 1 with 2 N HCl and extracted with ether. The obtained ether phases were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue (17.1 g) was stirred overnight in diethyl ether, filtered and dried. The solid thus obtained (12.1 g) was chromatographed on silica gel to isolate 11.4 g of the desired product.

¹ H-NMR (CDCl _3> 270 MHz); 8.0 (s, 1H), 7.2-7.45 (m, 10H); 6.1 (s, 1 H); 3.85 ⁽¹ s, 3 H); 3.3 (s. 3H); 2.0 (s, 3 H).

Mp: 134 ° C (dec.)

MS (ESI) 394 (M + H) < ⁺ > ^.

The following compounds were prepared analogously to the above examples:

Example 12

3-Ethoxy-2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) -3,3-diphenylpropionic Acid (I-4) ¹ H-NMR (CDCl _{3 I} 200 MHz): 8.0 (s, 1H) 7.1-7.5 (m, 10H); 6.2 (s, 1 H); 3.9 (s. 3H); 3.5 (m. 2H); 2.0 (s. 3H); 1.1 (t, 3 H).

MS (API): 409 (M + H) < ⁺ > ^.

Example 13

3- (2- (3,4-dimethoxyphenyl) ethoxy] -2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid ¹ H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H), 7.1-7.4 (m, 10H), 6.6-6.8 (m, 3H);

6.3 (s, 1 H); 3.9 (s. 3H); 3.8 (m, 7 H); 3.5-3.65 (m, IH); 2.7-2.9 (m. 2H); 2.0 (s. 3H); 1.1 (t, 3 H).

MS (ESI): 555 (M + H) < ⁺ > ^.

Example 14

3- (2- (3,4-Dimethoxyphenyl) ethoxy] -2- (9-methyl-9H-purin-2-yloxy) -3,3-diphenylpropionic acid (1-150) ¹ H-NMR (CDCl ₃ , 200 MHz) .Delta .: 8.2 (s, 1H), 7.9 (s, 1H), 7.1-7.4 (m, 10H), 6.6-6.8 (m, 3H), 6.3 ( s, 1H); 3.9 (s, 3H); 3.8 (m, 7H); 3.5-3.65 (m, 1H); 2.7-2.9 (m, 2H); 0.1 (s, 3H), 1.1 (t, 3H).

MS (ESI): 555 (M + H) < ⁺ > ^.

Example 15

3,3-Bis (4-fluorophenyl) -3-methoxy-2- (4-methoxy-5-methyl-pyrimidin-2-yloxy) propionic acid (1-61) ¹ H-NMR (CDCIg, 400 MHz): 8.0 ( s, 1H), 7.4-7.5 (m, 2H); 7.25-7.35 (m, 2 H);

6.9-7.0 (m, 4H); 6.05 (s, 1 H); 3.9 (s. 3H); 3.3 (s. 3H); 30 2.05 (s, 3H).

MS (API): 431 (M + H) < ⁺ > ^.

Example 16

3- (3,4-Dimethylbenzyloxy) -2- (4-methoxy-5-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid (1-149)

1 H-NMR (CDCl ₃ , 200 MHz): 8.0 (s, 1H), 7.1-7.5 (m, 10H); 6.2 (s, 1 H); 4.6 (d,

H); 4.4 (d, 1H); 3.85 (s, 3H); 2.2 (s. 6H); 2.0 (s, 3 H).

MS (API): 498 (M + H) < ⁺ > ^.

The compounds listed in Table 1 can be prepared analogously.

Example 17

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

The results are shown in Table 2.

Table 2

Receptor Binding Data (KJ values)

compound ET _and [nM] I-2 0.6 I-4 1.8 I-5 3

1-29 175 1-47 8.7 1-61 3.1 1-136 22 1-149 5 1-150 2200

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Table II

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Claims (8)

PATENT CLAIMS A compound of formula I wherein R ¹ is tetrazolyl or a group wherein R is as follows: (a) the radical OR ⁷ , where R ⁷ is: hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically tolerated organic ammonium ion, for example a tertiary C ₁ -C ₄ -alkylammonium or ammonium ion; C ₃ -C ₈ -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 -alkoxy, mercapto, C ^ C ^ alkylthio, amino, NH (C, -C ₄ -alkyl), N (C, -C ₄ alkyl) _2; C ₃ -C ₆ -alkenyl or C ₃ -C ₆ -alkynyl, which groups in turn may carry one to five halogen atoms; R ⁷ may also be phenyl, which may bear one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C ₁ -C ₄ -alkyl, 0, -O, haloalkyl, hydroxyl, C ₁ -C ₄ -alkyl; alkoxy, mercapto, C ₁ -C ₄ alkylthio, amino, NH (C _r C ₄ alkyl), NiCrCo alkyl) ^ b) 5-membered heteroaromatic such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is attached via a nitrogen atom and which may carry one to two halogen atoms or one or two O ^ C ^ alkyl, or two _R C C ₄ alkoxy group ; (c) group (O) _k --- O- (CH ₂ ) _P - _S - R 8 where k has values of 0,1 and 2, p has values of 1,2, 3 and 4, and R ⁸ is C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or phenyl which may be substituted by one or more, for example one to three of the following radicals: halogen, nitro , cyano, C ^ C ^ alkyl, C ^ C haloalkyl, hydroxy, C, -C ₄ -alkoxy, C ₁ -C ₄ alkylthio, mercapto, amino, NH ^ C-alkyl), nothing, C ₄ -alkyl) ₂ ; d) radical ABOUT --N-S - 9 H || Where R ⁹ is: C ₁ -C ₆ alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, which radicals may carry C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylthio and / or phenyl a radical as mentioned under c); phenyl, optionally substituted by one to three of the following radicals: halogen, nitro, cyano, CLC alkyl, C ^ C ^ haloalkyl, hydroxy, C, -C ₄ alkoxy, C ^ C ^ alkylthio, mercapto, amino, NH? -C 1-6 alkyl), N 1 -C 1-6 alkylOg; R ² is hydroxyl, NH 2, NH (C 1 -C 4 -alkyl), N (C 1 -C 4 -alkyl) 2, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio, or CR ² together with CR ^{3 form a} 5- or 6-membered alkylene or alkenylene ring, which may be substituted with one or two C 1 -C 4 -alkyls and wherein in each case one or more methylene groups may be replaced by oxygen, sulfur, -NH or -N (C 1 -C ₄ -alkyl); R ³ is hydroxyl, NH ₂ , NH (C 1 -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , halogen, O, O- ₄ alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₃ -C ₆ -alkenyloxy, C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ alkoxycarbonyl, C 1 -C ₄ -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C ₄ -alkoxy, C , -C ₄ haloalkoxy, -NH-O-C 1 -C 4 alkyl, C 1 -C ₄ -alkylthio, or CR ³ forms, as mentioned under R ² , together with CR ^{2 a} 5- or 6-membered ring; R ⁴ and R ⁵ (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, 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, amino, NH (C 1 -C ₄ -alkyl), N 3 -C 4 -alkyl 4; or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an S0 _2, NH or N-alkyl; or C ₃ -C ₇ -cycloalkyl; R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, each of which may be substituted one or more times with the following: hydroxyl, mercapto, carboxyl, halogen, nitro , cyano, C 1 -C ₄ -alkoxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ -alkyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ haloalkoxy, Ο, _-4 alkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, (C 1 -C 4 alkyl) NHCarbonyl, (C 1 -C 4 alkyl) ₂ Ncarbonyl, C ₃ -C ₀ -alkylcarbonylalkyl, amino, NH 1 -C 4 alkyl), N (C 1 -C ₄ alkyl) ₂ , phenoxy or phenyl, wherein the aryl radicals may be substituted one or more times; phenyl or naphthyl, each of which may be substituted with 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 1-4 alkylthio, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ or methylenedioxy or ethylenedioxy; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom and which may carry one to four halogen atoms and / or one to two of the following radicals: C 1 -C ₄ -alkyl, C 1 -C ₄ -alkyl; haloalkyl, C ₁ -C ₄ -alkoxy, C ₄ -haloalkoxy, -C alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals in turn to carry one to five halogen atoms and / or one to three of the following radicals: C - C ₄ alkyl, C 1 -C 4 haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C 4 haloalkoxy and / or -C ₄ -alkylthio; Z is sulfur or oxygen, and physiologically tolerated salts, tautomeric forms, and enantiomerically pure and diastereomerically pure forms. Use of compounds I according to claim 1 for the treatment of diseases. Use of the compounds I according to claim 1 as endothelin receptor antagonists. Use of compounds I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which elevated endothelin levels occur. Use of the compounds I according to claim 1 for the manufacture of medicaments for the treatment of diseases in which endothelin contributes to the development and / or progression. Use of compounds I according to claim 1 for the treatment of chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostate hyperplasia, prostate cancer and acute pancreatitis. A combination of compounds I according to claim 1 and one or more active ingredients selected from inhibitors of the renin-angiotensin system, such as renin inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE / neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, blockers Calcium channel I and VEGF blocking agents. A pharmaceutical preparation for. oral or parenteral use, characterized in that it comprises at least one compound I according to claim 1 in a single dose in addition to conventional pharmaceutical excipients.