CZ20002963A3 - Novel derivatives of carboxylic acid containing 5-substituted pyrimidine ring, process of their preparation and use - Google Patents

Abstract

The present invention relates to carboxylic acid derivatives of the general formula I, in which R R-R6, X and Z have the specific meaning and their meanings preparation. The new compounds are useful in the treatment of disorders, especially as endothelin antagonists.

Description

Novel carboxylic acid derivatives, containing

5-substituted pyrimidine ring, their preparation and use

Technical field

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

BACKGROUND OF THE INVENTION

Endothelin is a 21 amino acid peptide that is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, endothelin or ET refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has potent effects on vascular tone. This vasoconstriction is known to be due to the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may lead to disorders. It has been reported in the literature that endothelin is one of the causes of many disorders; these disorders include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, cerebral vasospasm, stroke, benign prostate hypertrophy, atheriosclerosis, asthma and prostate cancer (J.

* * · · · ·

Vascular Med. Biology 2, 207 (1990), J. Am. Copper. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944, (1995)).

At least two endothelin receptor subtypes, ET _A and ET _B receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Consequently, substances that inhibit endothelin binding to one or both receptors should act as antagonists of the physiological effects of endothelin and should therefore be valuable drugs.

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

- H at the 5-position of the heterocycle.

In contrast, the compounds of the present invention have a c-x group at this position wherein X represents a halogen atom, a hydroxy group or a C 1 -C ₄ -haloalkyl group. Compared to known endothelin antagonists, for example, the compounds of the present invention are more advantageously metabolized in the body.

SUMMARY OF THE INVENTION

The present invention relates to carboxylic acid derivatives of the general formula I

wherein R ¹ represents tetrazole or a group

O li

C-R wherein R represents:

(a) a residue of OR ⁷ in which R ⁷ represents:

a hydrogen atom, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, such as a tertiary C 1 -C 4 -alkylammonium ion, or 9 9 99

9 9

9 9

9 9

9 9 9

9 9 9 ammonium ion;

C3 ^- C8 cycloalkyl, Ci-Cg-alkyl, CH2-phenyl which may be substituted by one or more of the following radicals: halogen, nitro, cyano, _Ci-C4 alkyl, _Ci-C4 haloalkyl, hydroxy, C 1 -C ₄ -alkoxy, mercapto, C 1 -C ₄ -alkylthio, amino,

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

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

R ⁷ may further represent a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C ₄ -alkyl,

_Ci-C4 haloalkyl, hydroxy, _{Ci-C4-alkoxy,} mercapto, _Ci-C4 alkylthio, amino,

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

b) a 5-membered heteroaromatic ring such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is bonded via a nitrogen atom and which may carry one or two halogen atoms or one or two C 1 -C ₄ -alkyl groups or one or two C 1 -C 4 _4- alkoxy groups.

(c) a group

Φ φ · · · · · · φ • ΦΦ φφ ··· · · · * <°> _K - O- _{(CH2) p} -S - ^R8 in which k may be 0, 1 or 2, p it may be 1, 2, 3 or 4 and R ⁸ represents

C 1 -C ₄ -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, e.g. one, one to three, of the following radicals:

halogen atom, group

_Ci-C4 haloalkyl, _Ci-C4 alkylthio, mercapto, nitro, cyano, _Ci-C4 alkyl, hydroxy, _Ci-C4 alkoxy, amino,

NH (C, -C ₄ -alkyl), N _(Ci-C4 alkyl) _second

(d) the rest

O

II, - N-S - R 'II o

wherein R ⁹ represents:

C 1 -C ₄ -alkyl,

C ₃ -C ₆ -alkenyl,

C ₃ -C 6 -alkynyl, ♦ * · ·

I · 9 4 «9» 9

9 9 4 9

9 9 f

9 9 9

C ₃ -C ₈ -cycloalkyl, wherein these radicals may carry a C ₁ -C ₂ -alkoxy, C 1 -C ₄ -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, _Ci-C4 alkyl, _Ci-C4 haloalkyl, hydroxy, Ci-C ₄ -alkoxy, C ₁ -C ₄ -alkylthio , mercapto, amino,

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

Other substituents are defined below:

R ² represents hydrogen, hydroxy, _NH2, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2, halogen, _Ci-C4 alkyl,

C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₄ hydroxyalkyl,

C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ -alkylthio, morpholine;

X is halogen, _Ci-C4 haloalkyl, hydroxy;

R ³ represents a hydrogen atom, hydroxy, NH ₂ , NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) 2, a halogen atom, C 1 -C ₄ -alkyl,

C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₄ hydroxyalkyl, C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₄ -haloalkoxy, -NH-O-C -C ₄ -alkyl, C 1 -C ₄ -alkylthio;

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

phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl,

_Ci-C4 alkoxy, _Ci-C4 haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, _Ci-C4 alkylthio, amino, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) ₂ ; or phenyl or naphthyl which are ortho-linked to each other via a direct bond, methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a group S0 _2, NH or N-alkyl; or a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following residues: _Ci-C4 alkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy,

C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals: C 1 -C ₄ -alkyl, C 1 -C _{4 4-} haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy and / or

C 1 -C ₄ -alkylthio;

or C3- _C7- cycloalkyl;

R ⁵ represents a hydrogen atom,

C 1 -C 8 -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, wherein these radicals may be mono- or polysubstituted by: hydroxy, mercapto, carboxy, halogen, nitro, cyano, C, -C ₄ -alkoxy, C ₃ -Cg-alkenyloxy, C ₃ -C ₆ -alkínyloxy,

_Ci-C4-al thio alkyl, C-j-halogenabkoxy,

C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl,

C ₃ -C ₈ -alkylcarbonylalkyl, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , phenoxy or phenyl, wherein the above aryl radicals may be mono- or polysubstituted, for example phenyl or phenoxy mono- to trisubstituted by halogen, nitro, cyano, _Ci-C4 alkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy, Ci-C ₄ -haloalkoxy, mercapto, carboxy, hydroxy, amino, R ¹² ,

C 1 -C ₄ -alkoxycarbonyl, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , dioxomethylene, dioxoethylene or C 1 -C ₄ -alkylthio;

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkoxy C ₄ -haloalkoxy, phenoxy, _Ci-C4 alkylthio, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2, or dioxomethylen or dioxoethylen;

five or six membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following residues: _Ci-C4 alkyl, _Ci-C4 - haloalkyl, C 1 -C ₄ -alkoxy,

C 1 -C ₄ -haloalkoxy, C ₁ -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three consecutive C 1 -C ₄ -alkyl radicals, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy and / or

C 1 -C ₄ -alkylthio;

with the proviso that if Z is not a single bond, R6 is a single bond, R6 is a single bond, R6 It can only be a hydrogen atom;

R ¹² represents C 1 -C ₄ -alkyl, C 1 -C ₄ -alkylthio, C 1 -C ₄ -alkoxy which may carry one of the following radicals: hydroxy, carboxy, amino, NH (C 1 -C ₄ -alkyl),

N (C 1 -C ₄ -alkyl) ₂ , carboxamide or CON (C 1 -C ₄ -alkyl) ₂ ;

Z represents a sulfur atom, an oxygen atom or a single bond.

The following definitions apply throughout the text:

an 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;

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

C 1 -C ₄ -haloalkyl may have a straight or branched chain such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl,

2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,

2.2.2- trichloroethyl or pentafluoroethyl;

• · * φ φ φ φ φ φ φ φ φ

C 1 -C ₄ -haloalkoxy may have a straight or branched chain 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 have a straight or branched chain 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 have a straight or branched chain 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 have a straight or branched chain such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butin-4-yl or 2-butin-4-yl;

C 1 -C ₄ -alkoxy may have a straight or branched chain such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy,

1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C 3 -C 6 -alkenyloxy may have a straight or branched chain such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C ₃ -C ₆ -alkynyloxy may have a straight or branched chain such as 2-propyn-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;

The C 1 -C ₄ -alkylthio may have a straight or branched chain, such as methylthio, ethylthio, propylthio, and the like. · • • »» »

1-methylethylthio, butylthio, 1-methylpropylthio,

2-methylpropylthio or 1,1-dimethylethylthio;

C 1 -C ₄ -alkylcarbonyl may have a straight or branched chain such as acetyl, ethylcarbonyl or 2-propylcarbonyl;

C 1 -C ₄ -alkoxycarbonyl may have a straight or branched chain such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C ₃ -C ₈ -alkylcarbonylalkyl may have a straight or branched chain such as 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

C 1 -C 8 -alkyl may have a straight or branched chain such as C 1 -C ₄ -alkyl, pentyl, hexyl, heptyl or octyl;

a halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.

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

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

Compounds and also intermediates for their preparation, such as

4 · Φ

Φ ♦ Φ

For example, compounds of formulas II and IV may have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers or pure diastereomers or as mixtures thereof. The use of enantiomerically pure compounds as active compounds is preferred.

The present invention further relates to the use of the aforementioned carboxylic acid derivatives for the preparation of medicaments, in particular for the preparation of endothelin receptor inhibitors.

Compounds of formula IV in which Z represents a sulfur atom or an oxygen atom (IVa) can be prepared according to WO 96/11914.

III iva

The compounds of formula (III) are either known or can be synthesized, for example, by reduction of their corresponding carboxylic acids or esters, or by other generally known methods.

The compounds of the formula IVa can be obtained in enantiomerically pure form by transetherification with acid catalysis as described in DE 19636046,3.

Further, enantiomerically pure compounds of formula (IVa) can be obtained by carrying out the classical racemate separation on the

· * * 0 ♦ · ··

4 4 · · ·

The racemic or diastereomeric compounds of formula (IVa) using suitable enantiomerically pure bases. Suitable bases are, for example, 4-chlorophenylethylamine and the bases which are disclosed in WO 96/11914.

Compounds of formula IV wherein Z represents a single bond (IVb) may be prepared both racemically and in enantiomerically pure form as described in WO 97/38981.

R ⁴

v ivb

Compounds of the present invention in which the substituents are as defined in formula (I) may be prepared, for example, by reacting a carboxylic acid derivative of formula (IV) wherein the substituents are as defined for compounds of formula (V).

IV +

In the general formula, VR ¹⁰ represents a halogen atom or R ¹¹ -SO 2 -, and R ¹¹ can be C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl or phenyl. The reaction is preferably conducted in an inert solvent, • · · · · · «··· • φ" and φφφ · ··> _«v or diluent with addition of a suitable base, i.e. a base which provides a deprotonation of intermediate IV, in a temperature range from ambient temperature to the boiling point of the solvent.

Compounds of type I where ^R1 = COOH can furthermore be obtained directly if the intermediate IV in which ^R1 is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. The reaction is again carried out in an inert solvent and in the temperature range from ambient to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons which may be chlorinated, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, ethers such as diisopropyl ether diisobutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and Nmethylpyrrolidone, sulfoxides and sulfones such as dimethylsulfoxide and sulfolane.

The compounds of formula (V) are known and some of them are commercially available or can be prepared in a manner known per se.

The base may be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali carbonate

Φ «« «• • • • • • • • φ

a metal such as sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as 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, and their initial conversion to an activated form by a conventional method such as an acid halide, anhydride or imidazolide followed by reaction 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 diazabicycloundecane. These two steps can be simplified, for example, by allowing the carboxylic acid to act on the hydroxy compound in the presence of a dehydrating agent such as carbodiimide.

In addition, compounds of formula I may be prepared starting from salts of the corresponding carboxylic acids, i.e., compounds of formula I, wherein R ¹ represents a COOM group in which M may be an alkali metal cation or an equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R ⁷ -A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl such as toluenesulfonyl and methylsulfonyl, which may be substituted with a halogen atom, an alkyl group or a haloalkyl group, or which may be substituted with a halogen atom, an alkyl group or a haloalkyl group; or another equivalent leaving group. Compounds of formula R ⁷ -A that contain a reactive substituent A are known or can be readily obtained with general knowledge in the art. This reaction can be carried out in conventional solvents and is preferably carried out with the addition of a base; in this case, the bases mentioned above are suitable.

In some cases, known protecting group techniques need to be used to prepare compounds of the present invention. For example, when R ⁶ = 4-hydroxyphenyl, the hydroxy group may initially be protected as a benzyl ether, which may then be cleaved at a suitable stage in the reaction sequence.

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

With respect to biological activity, those carboxylic acid derivatives of formula I - as both pure enantiomers or pure diastereomers or mixtures thereof - are preferred, in which the substituents are defined as follows:

R ² is hydrogen, hydroxy, N _(Ci-C4 alkyl) 2 / _{Ci-C4-alkyl, Ci-C4} haloalkyl,

C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylthio, halogen;

X is halogen, trifluoromethyl;

R ³ represents a hydrogen atom, hydroxy, N (C 1 -C ₄ -alkyl) _2r, and it is 9;

C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy,

_Ci-C4 haloalkoxy, _Ci-C4 alkylthio, halogen;

R ⁴ and R ⁵ represent phenyl or naphthyl which may be substituted by one or more, for example one to three, of the following radicals: halogen, cyano, hydroxy, mercapto, amino, C 1 -C ₄ -alkyl,

_Ci-C4 haloalkyl, _Ci-C4 alkoxy, _Ci-C4 haloalkoxy, _Ci-C4 alkylthio, NH _(Ci-C4 alkyl) _2, N _(Ci-C4 alkyl) _2, C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl;

phenyl or naphthyl bonded to each other through a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, or a SO ₂ , NH or N (C 1 -C ₄ -alkyl) group, a five-membered heteroaromatic ring containing one or two nitrogen atoms and / or a sulfur or oxygen atom which can carry one or two halogen atoms and / or one or two of the following residues: _Ci-C4 alkyl,

C 1 -C ₄ -alkoxy, phenyl, which itself may carry one to three halogen atoms and / or one to three of the following radicals: C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy or C 1 -C ₄ -alkylthio;

or C ₃ -C 7 cycloalkyl;

R ⁶ represents C 1 -C ₈ -alkyl, C ₃ -C 6 -alkenyl, C ₃ -C 6 -alkynyl or C ₃ -C 8 -cycloalkyl, wherein the radicals may be mono- or polysubstituted by: halogen, hydroxy, cyano, C 1 -C ₄ -alkoxy, C ₃ -C 6 -alkenyloxy, C ₃ -C 6 -alkynyloxy, C 1 -C ₄ -alkylthio, C 1 -C ₄ -haloalkoxy, ♦ ·· · · · · · · · · · · * * * * * * * * · * · · · · · · · ·

C 1 -C ₄ -alkylcarbonyl, hydroxycarbonyl,

C 1 -C ₄ -alkoxycarbonyl, NH (C 1 -C ₄ -alkyl) ₂ , N (C 1 -C ₄ -alkyl) ₂ , phenoxy or phenyl, wherein the above aryl radicals may be mono- or polysubstituted, for example mono- to trisubstituted , with halo, _Ci-C4 alkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy,

_Ci-C4 -haloalkoxy, ^R12, _Ci-C4 -alkoxycarbonyl, dioxomethylen, dioxoethylen, _Ci-C4 alkylthio, phenyl or phenoxy;

phenyl or naphthyl, which may be substituted by one or more of the following: halogen, nitro, cyano, hydroxy, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C _{4 4} -haloalkoxy, phenoxy, _Ci-C4 alkylthio, NH _(Ci-C4 alkyl) _2,

N (C 1 -C ₄ -alkyl) ₂ ;

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

C 1 -C ₄ -alkylthio;

R ¹² represents C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy bearing one of the following: hydroxy, carboxamide or

CON (C 1 -C ₄ -alkyl) ₂ ;

Z represents a sulfur atom, an oxygen atom or a single bond.

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

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

X represents a fluorine atom, trifluoromethyl;

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

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

R ⁴ and R ⁵ represent phenyl groups which are bonded to each other through a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO ₂ , NH or N (C 1 -C ₄ -alkyl) group; or

A »AA AA

thiazole, oxazole, thiophene or furan, wherein the above heteroaromatic groups may be mono- to disubstituted with the following radicals: halogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy;

R ⁴ and R ⁵ represent cyclohexyl;

R ⁶ represents C 1 -C ₈ -alkyl, C 3 -C ₆ -alkenyl or

C 3 -C ₈ -cycloalkyl, wherein the radicals may be mono- or polysubstituted by halogen, hydroxy, cyano, C 1 -C ₄ -alkoxy, C 3 -C 6 -alkenyloxy, C 1 -C ₄ -alkylthio, phenoxy or phenyl, wherein the aforementioned aryl radicals can be mono- or polysubstituted, for example mono- to trisubstituted, by radicals Ci-C ₄ -alkyl, C _x -C ₄ -alkoxy, dioxomethylen, dioxoethylen,

C 1 -C ₄ -alkylthio;

phenyl or naphthyl, which may be substituted by one or more of the following: halogen, nitro, cyano, hydroxy, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C _{4 4} -haloalkoxy, phenoxy, C 1 -C ₄ -alkyithio, C 1 -C ₄ -alkylamino or

_Ci-C4 alkylamino -dialky;

five or six membered heteroaromatic ring containing a nitrogen atom and / or a sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following residues: _Ci-C4 alkyl, _Ci-C4 haloalkyl, C -C ₄ -alkoxy, C 1 -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals can themselves carry one to five halogen atoms and / or φ · φ φ · · · · φφ φφφφ • · φφφ φφ φ one to three of the following radicals: _Cl-C4 alkyl,

C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy and / or C 1 -C ₄ -alkylthio;

Y represents a sulfur atom, an oxygen atom or a single bond.

The compounds of the present invention provide novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, asthma, migraine , endotoxic shock, endotoxic-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass, benign prostatic hyperplasia, hypertension or renal failure caused by ischemia or intoxication, metastasis and growth of mesenchymal tumors, contrast-induced renal failure, pancreatic intestinal gastrointestinal gastrointestinal gastro and erectile dysfunction.

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

- 22 - • »·· ·· ·· · · · • · · · · · • e «· · · • · · t · ··· ··· " • · * » • · · · · • · · e • · · · · · • · · · <· » Submitted the invention further relates combinations antagonists receptors endothelin of the general formula I and diuretics • Submitted the invention further relates combinations antagonists

endothelin receptors of formula I and agents that block VEGF (vascular endothelial growth factor) activity. Such agents are, for example, anti-VEGF antibodies or specific binding proteins or also low molecular weight agents which are capable of specifically inhibiting the release of VEGF or receptor binding.

The above combinations may be administered simultaneously or one at a time at different times. They can be used as a single pharmaceutical preparation or as separate preparations. The dosage form may also vary, for example, endothelin receptor antagonists may be administered orally and VEGF inhibitors parenterally.

These combinations of preparations are particularly suitable for the treatment and prevention of hypertension and disorders arising therefrom, as well as for the treatment of cardiac insufficiency.

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

Receptor binding studies

In these binding studies, cloned CHO cells expressing ET _A or ET _B receptors were used.

• 9 · 9

Preparation of membranes

CHO cells expressing ET _A or ET _B receptors were grown in DMEM NUT MIX F12 medium (Gibco, # 21331-020) containing 10% fetal calf serum (PAA Laboratories GmbH, Linz, # A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 units / ml penicillin and 100 μς / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37 ° C for 5 minutes. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.

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

Binding tests

For 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 µg protein per test. mixture and incubated at 25 ° C with 25 µM [ ¹²⁵ I] ET 1 (ETA receptor assay) or 25 µM [ ¹²⁵ I] ET 3 (ET _B receptor assay) in the presence and absence of test substance. Non-specific binding was determined using 10 ^-7 M ETi. 30θ 30 minutes were filtered through GF / B glass fiber filters (Whatman, England) in a Skatron cell coliector (Skatron, Lier, Norway) for

- 24 ·: -I “J * · * ·· ** ·· ··· ··· * · »*** • · · • «· ♦ • · · 0 • · · φ • · · *> · Β department free and bound radioligand and filters were washed ice cold Tris-HCl buffer, pH 7.4,

containing 0.2% BSA. The radioactivity collected on the filters was measured using a Packard 2200 CA liquid scintillation counter.

Functional test of endothelin receptor antagonists on blood vessels

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

Potential endothelin antagonists were administered to other preparations from the same vessel 15 minutes prior to the start of determining the effect of the dose on endothelin. The effect of endothelin was calculated as% K ⁺ -induced contraction. Effective endothelin antagonists cause a shift to the right of the endothelin dose-response curve.

In vivo testing of ET antagonists:

Male SD rats weighing 250-300 g were anesthetized with amobarbital, with artificial respiration, vagotomization, and were sacrificed by puncturing the spinal cord. The carotid and jugular vessels were catheterized.

In control animals, intravenous administration of 1 gg / kg ETi resulted in a marked increase in blood pressure that persisted for a relatively long time.

• 9 • 9 • 9

The test animals received i.v. injection of test compounds (1 mL / kg) 30 minutes prior to ETi administration. To determine the properties of ET-antagonism, changes in blood pressure in test animals were compared with changes in control animals.

Oral testing of mixed ET _A and ET _B antagonists:

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

After the stabilization phase, large endothelin (20 pg / kg, application volume 0.5 ml / kg) or ETI (0.3 pg / kg, application volume 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were continuously recorded for 30 minutes. Different and persistent changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonist effect of the test substances, the AUC of the animals treated with the test substance was compared with the AUC of the control animals.

The compounds of the present invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the usual manner. Administration can also be by vapor or spray to the nasopharynx space.

J • *

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

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1:

Methyl 2- (4,6-dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionate

1.0 (3.5 mmol) methyl-2-hydroxy-3-methoxy27

3.3-Diphenylpropionate, dissolved in DMF, was added dropwise to a suspension of 0.18 g NaH (4.2 mmol, 55% in white mineral oil) in 10 mL DMF. The mixture was stirred at ambient temperature for 30 minutes and then mixed with 830 mg (4.8 mmol).

4,6-dimethoxy-5-fluoro-2-methylsulfonylpyrimidine in 10 mL of DMF and stirred at ambient temperature for 2 hours. The reaction mixture was poured into ice-water and extracted three times with diethyl ether. The ether phases were dried over magnesium sulfate and then filtered, and the solvent was removed under reduced pressure. The brown residue (1.7 g) was purified by MPLC to give 1.3 g of the desired product, which was used directly in subsequent reactions.

Example 2:

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

1.3 g (2.9 mmol) of methyl 2- (4,6-dimethoxy-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionate were dissolved in 10 ml dioxane and mixed with 5.9 ml solution of 1 N KOH. The mixture was stirred at reflux for four hours. Water was added to the reaction mixture and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate and the solvent was distilled off. The residue was taken up in ether, crystallized and 100 mg of product B. The mother liquor was mixed with n-hexane to give 400 mg of product A as a solid.

• ·

Α: ^{Χ Η} NMR (CDC1 _3, 500 MHz): 7.2-7.45 (m, 10H); 6.05 (s, 1H); 3.9 (s, 6H); 3.3 (s, 3 H).

Melting point: 168-170 ° C

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

3.9 (s, 3H); 3.3 (s, 3 H).

Melting point: 115-117 ° C

Example 3:

Benzyl 2- (4-morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionate

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

Example 4:

2- (4-Morpholino-5-fluoropyrimidin-2-yloxy) -3-methoxy-

3,3-diphenylpropionic

Using 300 mg of palladium on charcoal (10%), a solution of 0.9 g of benzyl 2- (4-morpholino-5-fluoropyrimidin-2-yloxy) 3-methoxy-3,3-diphenylpropionate in 30 ml of ethyl acetate was hydrogenated with hydrogen atmospheric pressure at ambient temperature for 3 hours. The reaction mixture was filtered and concentrated and the residue (900 ^X 1 HNMR (CDCl _3, 500 MHz): 8.95 (s, 1H); 3.8 (s, 8H), 3.3 (s,

Melting point: 174-175 ° C (mg) was purified by MPLC.

(d, 1 H); 7.2-7.5 (m. 10H); 6.05 3H)

The compounds listed in Table I may be prepared in a conventional manner.

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CŠI C0 ο ο ο ο Ο Ο ο ο ο ο ο AND ο ο ο ο ο Ο 1 ο ο ο ω ο ο ο X X X Cm Cm Cm Cm Cm Cm Cm Cm Cm Cm X X X X X X X X X X χ Uí X X Φ Φ 07 / Φ Φ Φ Φ Φ φ φ 07 / 07 / φ φ φ φ 07 / φ £ φ £ £ Ρ £ £ £ Φ 1-1 £ £ £ X ι — 1 υ φ £ φ £ χ with 2 X X £ Ο £ Ο Ο Ο ω Ο Ο ϋ £ υ Ο Ο Ο υ ο ο £ Ο £ Ο X ο ο Ο ο ι — 1 > 1 in ι — 1 --4 ο Ρ φ Φ 07 / Φ Φ φ Φ φ Φ X φ φ φ φ β φ (Ν £ £ Φ Φ pL | Ρ 4-> £ £ £ £ £ £ Ρ £ £ £ φ Φ Φ Φ £ 0 X £ Φ Ρ CÚ Ο Ο £ £ at ω ω Ο ϋ Ο Ο Ο Ο φ Ο Ο Ο £ £ £ £ Ο £ υ Ο £ ω Ρ ί> 7 β φ Ρ 0 in 1—1 £ ι— | I-1 > 1 Φ 1-1 1 1> 1 ι — 1 ί> 7 I-1 «—Ι > 1 £ ι— | > 1 ι — 1 ο Γ — ί > 1 β Ο | ο β Ο Ν > 1 X I-1 Ο Ν φ Ν Φ β Ρ ί> 7 Ρ CN Φ 44 Φ 1-1 Ό φ φ ι — 1 Ρ 1-1 1-1 1-1 1 X ι — 1 1—1 ι — 1 1-1 ι — 1 • Η Ρ '—1 1 • Η ι — I ί> 1 1-1 • Η 1— | Ρ £ ί> 7 β > 1 > 1 Γ-4 υ > 1 > 1 ί> Ί ^L > 7 ί> 7 χ > 7 ί> 7 β X X £ £> 7 1 Ρ X φ X X ί> 7 X X χ υ 1 β β β β β 4-> β β X 4-1 X Ρ β Η β X X 0 X Ρ Ρ β Ρ Ρ Ρ 40 1 ο φ φ φ φ φ 1 φ φ 1 1 4-1 φ φ AND φ 1 AND β AND φ Φ φ φ φ φ Λ (Ό χ 44 44 44 44 44 CM 44 44 • šf ’ΜΡ φ £ Ρ Ρ Ρ Ρ (Μ X β £ £ Ρ £ £ £ ι — 1 '—1 χ * 7 ι — 1 > 1 1—1 > 1 1-1 I-1 Π > 1 ι — 1 β >, β > 1 ί> 7 φ X ί> 7 φ β φ β β Μ-ί AND φ β Ρ φ 44 φ φ X φ 1 1-1 1-1 ι — 1 1-1 1 — I 1-1 ι — 1 1-1 44 1 ι — I ι — 1 ι — 1 Ρ Ρ ι — 1 07 / 1- [ 1-1 1-1 ι — 1 0 Γ — ί Ρ φ > 1 > 7 > 1 > 1 7> 7 > 1 7> 7 1 1—1 ί> 7 Ι> Ί 7> 7 1 1 > 1 X ί> 1 > 7 > 1 ι — 1 > 1 > 7 1 £ β β β β β β β β Cm υ β β β X X β ο β β β β X β β X Ο 1 β «Σρ 0) φ φ φ φ φ φ φ 1 1 φ φ φ 1 1 φ 1 φ φ φ φ > 1 φ φ 1 φ Λ 4-1 44 44 44 44 44 44 44 CM ω 44 44 44 Ρ Ρ Ρ Ρ Ρ Ρ ϋ Ρ Ρ η ΡΟ Ρ ι— | ι — 1 > 7 β β φ φ Ρ Ρ 07 / U7 X 07 / LT7 Ε <Ν Ο U7 Κ CM Ο 07 / ιη X! χ CN X ΓΊ ω (Ν ω X CN X χ X X X X X X υ υ υ Ο X X X Ο X ο Ο χ X X X X X X X Ο ο Ο ο ο ο Ο Ο ο ο ο ο Ο ο χ ο X ο ο ο ο ο ο ο ο ο Ο i — 1 ο ο ο ο ο ο ο Ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο X υ ο υ υ υ υ υ υ υ υ υ υ υ ο ο υ υ ο ο υ ο υ ο ο ο ο ο 40 Ρ C0 σ> ο ι — 1 CM (Ό LO 40 Γ- 00 σι ο τ — 1 CM η LO 40 Γ'- C0 σ> ο ι — 1 CM «ΧΤ * šT sr LT) LO LO LO LT) LD LO LT) LD LD 40 40 40 40 40 40 40 40 40 40 γ- Ρ Γ- 1 — I ι — 1 ί — 1 ? —Ι γ — 1 5—1 ι — 1 ι — 1 ι — ι ί — 1 5—1 γ — 1 5—1 Ρ γΗ χ — 1 γΗ r ~ 1 Ρ τ-Η γΗ γ-1 r — 1 γΗ ϊ — ι Γ - ί t—! > ο Η 1—1 Η Η Η Ρ Μ Η Μ Μ Η) Η ΙΗ Η Η Μ ΗΗ Η Η Η Η Μ 1 H Η1 AND Η 1 Η 1 ΗΗ

IX] O 1 O O O O O 1 1 Ο Ο X X X Cu Cu X X tx-i X X X X rc (1) φ φ rc 0) pour Φ and) Φ Φ £ X £ £ α; IX with α with £ £ £ O X Ο Ο £ φ φ Φ φ Φ Φ CM £ with Φ Φ X X £ X £ £ £ Ά O O £ £ ω X O ω Ο Ο Ο 1-1 1—1 i — 1 1-1 1—1 1-1 X X 1—1 X ι— | > 1 ί> Ί > 1 > 1 ί> Ί > 1 > 1 !> ι > 1 X cl X X X X X CL X X X X 0 X X X X X Ο ο X X LD Φ β Φ Φ Φ Φ Φ Μ β φ φ Honors G CL G with £ WITH β CL X WITH WITH 1 — ί 1-1 ί> Ί I — 1 > Ί β >. α φ β φ X φ honors X i — 1 1—1 1-1 1-1 I— | X 1-1 1-1 1 X 1 > 1 > 1 I> i Í> 1 ^> Ί Ι> Ί > 1 (1) 1 X α honors β β β β β β £ X 1 φ Φ Φ Φ Φ φ φ φ 1 1 honors what x X X X X X X X WHAT 1-1 > 1 β rc rc ί—} Φ X X χΝ X O O 1—1 (N CM CM 0 O O O Ν w ω what ω Φ X X X X X X β X X X X O O WITH X O X X ο ο ϋ ο rH O O O O O O Φ ο ο Ο ϋ Honors AT O O O at O X υ υ υ ο what LO what t- ~ what σ> ο τ — 1 WHAT WHAT r ~~ Γ r- r- ~ r ~~ r- ~ X 00 00 03 / C0 , —1 τ — 1 1 — 1 t — 1 i — 1 5—1 , —1 ι — 1 1—1 t — 1 X > ó H H H H H X Η X X X X

• · ··· «« · ♦ 9 ·

• * »·

Table II

Ν O O O O O O O O O O O O O X fcl Cu IP IP P IP IP IP IP IP IP IP IP <D 0) Φ Φ Φ ω Φ (1) Cl) Cl) Cl) Φ CD ω £ £ £ £ £ £ £ £ £ £ £ £ £ OC O O O O O O O O O O O O O CD 0) CD Φ CD Φ Φ Φ Φ Cl) CD Cl) CD CM £ with £ £ £ £ £ £ £ £ £ £ £ it O O O O O O O O O O O O O l-1 ί> Ί CM iC AND CC Φ CM O P CC 1 <-1 O j — 1 > 1 1 Í> 1 i — 1 G. CM G Ϊ> Ί O X O G. P O P and-( 1 — i I — 1 1—1 I — 1 1 — t 1 — t O G. i — 1 AND G ί> Ί >, Σ> ί í> l > 1 Í> 1 P O > 1 l — t O rc Λ PC rc rC rC 4C CL. what N Ι> Ί WHAT 1-1 P P P Fri P P P O • H řC rc CC P <£> Φ Φ ω Cl) ω Φ Cl) ω 1 0) P O > 1 G G G G G G G • r-J 0. X) φ O CM X! what rc (r) CC CC Π3 WHAT ro CC CC CC Λ 7 at O b X! Xi O O O N CM CM II ^s - ' N N N II II II rtS CC CC CC CC (Π what (AT CC CC CC < > O O O O ω £ > í> > O O O X CC CC CC CC CC CC CC CC CC cc CC CC O O O O O O O O O O O O O rd O O O O O O O O O O O O O tž O at O O O at at O O O at O O O ,-AND CM oo r — 1 CN what LQ r- what σ> i — 1 x — 1 Γ — '1 τ — 1 « H H H H H H H H l · —1 H 1—1 > u 1—1 H H H H H H HJ H H H IH 1—1

• ·

Example 5

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

The results are summarized in Table 3.

Table 3

Receptor Binding Data (Ki values)

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

Represented by:

Dr. Otakar Švorčík

- 40 JUDr. Otakar Švorčík attorney

120 00 Prague 2, Halkova 2

Claims (8)

A carboxylic acid derivative of the general formula I R = Z = C R 1 H> 5 <1 R ⁵ R ¹ in which: R ¹ represents tetrazole or a group O II CR is OR ⁷ wherein R ⁷ is; a hydrogen atom, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, or an ammonium ion; C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl, CH 2 -phenyl, optionally substituted by one or more of the following: halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, hydroxy, 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 ; · · ". ·· ♦ · ·· * * · · · ·. ϊ * * * »*» »» »* ΒΒ A C ₃ -C ₆ -alkenyl or C ₃ -C ₆ -alkynyl group, which groups may optionally carry one to five halogen atoms; R ⁷ may further represent a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C ₄ -alkyl, _Ci-C4 haloalkyl, hydroxy, _{Ci-C4-alkoxy,} mercapto, _Ci-C4 alkylthio, amino, NH (C 1 -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ ; b) a 5-membered heteroaromatic ring such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl which is bonded via a nitrogen atom and which may carry one or two halogen atoms or one or two C 1 -C ₄ -alkyl groups or one or two C 1 -C ₄ -alkoxy groups, (c) group (9), (CHJ 2'p in which k can be 0, 1 or 2, p can be 1, 2, 3 or 4 and R ⁸ represents C 1 -C ₄ -alkyl, C 5 -C 8 -cycloalkyl, C3-C6-alkenyl, 4, 44, 4, 4 4 4 4 C ₃ -C ₆ -alkynyl or phenyl, possibly substituted by one or more, for example one to three, of the following radicals: halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, hydroxy, C 1 -C ₄ -alkoxy, Ci-C ₄ alkylthio, mercapto, amino, NH (C _x -C ₄ -alkyl), N (C _x -C ₄ -alkyl) _2, (d) the rest O II, - NS — R ^H II o wherein R ⁹ represents: C 1 -C ₄ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, wherein these radicals may carry a C 1 -C ₄ -alkoxy radical, a C 1 -C ₄ -alkylthio and / or a phenyl radical as mentioned under c); phenyl which may be substituted by one to three of the following radicals: halogen, nitro, cyano, _Ci-C4 alkyl, _Ci-C4 haloalkyl, hydroxy, _Ci-C4 alkoxy, _Ci-C4 -alkylthio, mercapto, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , R ² is hydrogen, hydroxy, NH _2, 0 · 0 · 0 0 NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2, halogen, C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, _Ci-C4 hydroxyalkyl, _{Ci-C4-haloalkyl, Ci-C4} alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ -alkylthio, morpholine; X is halogen, _Ci-C4 haloalkyl, hydroxy; R is hydrogen, hydroxy, NH ₂ , NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , halogen atom, a C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, _Ci-C4 hydroxyalkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy, _Ci-C4 haloalkoxy, _{-NH-O-Ci-C4-alkyl, Ci-C4} alkylthio; R ⁴ and R ⁵ (which may be the same or different) represent: phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxy, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ - haloalkoxy, phenoxy, mercapto, alkylcarbonyl, alkoxycarbonyl, C 1 -C ₄ -alkylthio, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ ; or phenyl or naphthyl which are ortho-linked to each other through _a direct bond, methylene, ethylene or ethenylene group, an oxygen atom or a sulfur atom, • or a group S0 _2, NH or N-alkyl; or a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one or four halogen atoms; the two following radicals: 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, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals: _Cl-C4 alkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy, _Ci-C4 -haloalkoxy and / or C 1 -C ₄ -alkylthio; or C ₃ -C 7 cycloalkyl; R ⁶ represents a hydrogen atom, C 1 -C 6 -alkyl, C ₃ -C 6 -alkenyl, C ₃ -C 6 -alkynyl or C ₃ -C ₆ -cycloalkyl, wherein the radicals may be mono- or polysubstituted by: hydroxy, mercapto, carboxy, halogen, nitro, cyano, C 1 -C ₄ -alkoxy, C ₃ -C 6 -alkenyloxy, C ₃ -C 6 -alkynyloxy, C 1 -C ₄ -alkylthio, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl, C ₃ -C 8 -alkylcarbonylalkyl, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , phenyl mono- or polysubstituted, for example phenyl or phenoxy, which are mono- to trisubstituted by halogen, nitro, cyano, _Ci-C4 alkyl, _Ci-C4 haloalkyl, _Ci-C4 alkoxy, _Ci-C4 haloalkoxy or _Ci-C4 alkylthio; phenyl or naphthyl, which may be substituted by one or more of the following: halogen, nitro, cyano, hydroxy, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C _{4 4} -haloalkoxy, phenoxy, C 1 -C ₄ -alkylthio, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ • · φ «► φ ·» Nebo Φ · 9 or dioxomethylene or dioxoethylene; five or six membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur or oxygen atom which can carry one to four halogen atoms and / or one or two of the following residues: _Ci-C4 alkyl, _Ci-C4 - haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals: C 1 -C ₄ -alkyl, C 1 -C _{4 4-} haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy and / or C 1 -C ₄ -alkylthio; with the proviso that if Z is not a single bond, R 6 can only be a hydrogen atom; Z represents a sulfur atom, an oxygen atom or a single bond, and physiologically acceptable salts and enantiomerically pure and diastereomerically pure forms. Use of a carboxylic acid derivative of the formula I according to claim 1 for the treatment of diseases. Use of the compounds of formula I according to claim 1 as endothelin receptor antagonists. Use of a carboxylic acid derivative of the formula I according to claim 1 for the preparation of medicaments for the treatment of diseases associated with elevated endothelin levels. Use of a carboxylic acid derivative of the formula I according to claim 1 for the preparation of medicaments for the treatment of diseases in which endothelin contributes to their development and / or progression. Use of a carboxylic acid derivative of the formula I according to claim 1 for the treatment of chronic cardiac insufficiency, restenosis, high blood pressure, pulmonary hypertension, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer. A combination of a carboxylic acid derivative of the formula I according to claim 1 and one or more active compounds selected from reninangiotensin system inhibitors such as renin inhibitors, angiogensin-II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE / neutral inhibitors endopeptidases (NEPs), β-blockers, diuretics, calcium antagonists and VEGF-blocking agents. A medicament for oral, parenteral and intraparenteral administration comprising, in a single substance, in addition to the usual excipients, at least one carboxylic acid derivative of the formula I according to claim 1.