SK1522000A3 - Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists - Google Patents

Abstract

The invention relates to carboxylic acid derivatives of formula (I) wherein the radicals are defined in the description, and to the use of these derivatives as ETA/ETB endothelin-receptor antagonists.

Description

Carboxylic acid derivatives, their preparation and use as mixed endothelin receptor ETa / ETb antagonists

Technical field

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

BACKGROUND OF THE INVENTION

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

Increased or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which can lead to disease. It is reported in the literature that endothelin is involved in a number of diseases. These include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2 (1990) 207, J. Am. Med. Association 264 (1990) 2868, Nature 344 (1990) 114, N. Eg J. Med 322 (1989) 205, N. Eg J. Med 328 (1993) 1732, Nephron 66 (1994) 373, Strake 25 (1994) 904, Nature 365 (1993) 759, J Mol Cell Cardiol 27 (1995) A234; Cancer Research 56 (1996) 663).

The literature describes at least two endothelin receptor subtypes, the ETα and ETb receptors, (Nature 348 (1990) 730 and 732). Accordingly, agents that inhibit the binding of endothelin to the two receptors must antagonize the physiological effects of endothelin and therefore represent valuable drugs.

WO 96/11914 discloses carboxylic acid derivatives which, however, bind with a high affinity to the ETα receptor and with a much lower affinity for the ETb receptor (called ETA-specific antagonists).

We are talking about antagonists as ET _A -specific if their affinity for the ET _A receptor is at least ten times higher than their affinity for the ET _B receptor.

It is an object of the present invention to provide endothelin receptor antagonists that bind with approximately the same affinity to ET _A and ET _B receptors (called mixed antagonists).

Approximately the same affinity for receptors means that the affinity ratio is greater than 0.1 and less than 1.0.

SUMMARY OF THE INVENTION

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

Kde - O — Het wherein the substituents have the following meanings R represents tetrazole or the group represents the radical OR ⁷ in which

R ⁷ is hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically acceptable organic ammonium ion;

C 3 -C ₈ -cycloalkyl, C 1 -C 6 -alkyl;

CH2-phenyl, unsubstituted or substituted;

C3-C6-alkenyl or C3-C6-alkynyl, unsubstituted or substituted; or phenyl, unsubstituted or substituted,

-3R ² is H, OH, NH _2, NHÍC ^ C ^ alkyl), N _(Ci-C4 alkyl) _2, halo, C ₄ alkyl, C 2 -C ₄ -alkenyl, C 2 -C ₄ - alkynyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ -alkylthio, or CR is bound to CR as shown below to form a 5- or 6-membered ring, or when Het represents a five membered ring, CR ² together with CR ^{3 can} represent a 5- or 6-membered alkenyl or alkylenyl ring which is unsubstituted or substituted;

X is nitrogen or methine;

Y is nitrogen or methine;

W is nitrogen or CR ¹⁰ wherein R ¹⁰ is hydrogen or C _M alkyl, or ^CR10 forms together with ^CR2 or ^CR3 a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which in each case one or more methylene groups may be replaced by a substituent such as oxygen, sulfur, -NH or -N (C 1 -C 4 alkyl);

R ³ is H, OH, _NH2, NH _(Ci-C4 alkyl), N (C _r C ₄ alkyl) _2, halo, -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C 2 -C ₄ -alkynyl , _Ci-C4 haloalkyl, _Ci-C4 alkoxy, -C ₄ haloalkoxy, _{Ci-C4-alkylthio;} or CR ³ is attached to CR ¹⁰ as above to form a 5- or 6-membered ring;

R ⁴ and R ⁵ (which may be the same or different) denote phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl, which are bonded together in ortho positions by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or SO ₂ , NH or N-alkyl

C ₃ -C ₈ cycloalkyl, unsubstituted or substituted;

R ⁶ is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl, each of which may be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, amino , CN, C _r C ₄ -alkoxy, C ₃ -C 6 alkenyloxy, C ₃ -C ₆ alkynyloxy,

-4Ci -C ₄ alkylthio, _Ci-C4 haloalkoxy, _Ci-C4 alkylcarbonyl, -C ₄ -alkoxycarbonyl, C3.e-alkylcarbonylalkyl, NH _(Ci-C4 alkyl), N (C ₄ - alkyl) 2, C ₃ -C ₈ cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and / or one sulfur or oxygen atom, phenoxy or phenyl, wherein said aryl residues may themselves be substituted by one or by multiple substituents, for example one to three substituents selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ - haloalkoxy, amino, NH (C 1 -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ or C 1 -C ₄ -alkylthio;

phenyl or naphthyl, each of which may be substituted by one or more of the following radicals such as halogen, nitro, cyano, hydroxyl, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy C ₄ haloalkoxy, phenoxy, _Cl-C4 alkylthio, _Ci-C4 alkylamino, _{Ci-C4-dialkylamino,} dioxomethylene or dioxoethylene;

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following: C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl , C ₄ -alkoxy, C _r C ₄ -haloalkoxy, C ₄ alkylthio, phenyl, phenoxy or phenylcarbonyl, where the phenyl radicals themselves can carry one to five halogen atoms and / or one to three of the following radicals: it is _{Ci-C4-alkyl, Ci-C4} haloalkyl, _{Ci-C4-alkoxy, Ci-C4} -haloalkoxy and / or C1 -C4 -alkylthio;

C 3 -C 6 -cycloalkyl, which radicals may be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C ₄ -alkyl, C 2 -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl _{C4-alkynyl, Ci-4} alkoxy, _Ci-4 alkylthio, _Ci-4 haloalkoxy;

Z is sulfur or oxygen;

B is C 2 -C ₄ -alkylene;

-5Het represents a heterocyclic radical of formula Ia or 1b

la Ib where

T represents O, S, NR ⁸

R ⁸ represents C 1 -C ₆ -alkyl and physiologically acceptable salts and enantiomerically pure forms.

In this context and beyond, the following definitions apply:

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

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

C 3 -C 6 -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C 1 -C ₄ -haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2- chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C 1 -C 4 -haloalkoxy may be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-fluoroethoxy —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-propyn-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl;

-6-C ₁ -C ₄ -alkoxy may be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

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

C3-C6-alkynyloxy may be linear or branched, such as 2-propyn-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy;

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

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 6 -alkylcarbonylalkyl may be linear or branched, for example 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl

C 1 -C ₈ -alkyl may be linear or branched, such as C 1 -C ₄ -alkyl, pentyl, hexyl, heptyl or octyl;

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

The invention further relates to compounds from which compounds of formula I (so-called precursors) can be released.

Preferred precursors are those in which release occurs under conditions similar to those prevalent in certain body compartments, such as the stomach, intestines of the bloodstream, liver.

The compounds and intermediates for their preparation, such as II, III and IV, may contain one or more asymmetrically substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereoisomers or as mixtures thereof. The use of enantiomerically pure compounds as an active ingredient is preferred.

The invention further relates to the use of the aforementioned carboxylic acid derivatives for the preparation of medicaments, in particular the preparation of inhibitors of ET _A and ETb receptors. The compounds of the invention are particularly useful as mixed antagonists as defined in the introduction.

Compounds of formula IV in which Z is sulfur or oxygen can also be prepared in enantiomerically pure form as described in WO 96/11914.

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.

The compounds of the invention wherein the substituents have the meanings defined in formula I may be prepared, for example, by reacting the carboxylic acid derivatives of formula IV, where the substituents are as defined above, with the compounds of formula V.

¹¹ + H ¹¹

R ¹¹ in formula 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. In addition, at least one of the ring members X or Y or Z is nitrogen. 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 room temperature to the boiling point of the solvent.

Compounds of type I wherein R = COOH can additionally be obtained directly when intermediate IV, wherein R is COOH, is deprotonated with two equivalents of a suitable base and reacted with compounds of formula V.

It is also carried out in an inert solvent and at a temperature ranging from room temperature to the boiling point of the solvent.

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

Compounds of formula V are known or, in some cases, can be purchased or prepared using generally known procedures.

As the base, an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate such as sodium or potassium carbonate, an alkali metal or an alkaline earth metal hydroxide such as sodium hydroxide can be used. or a potassium, organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.

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 these are first converted in the conventional manner to an activated form, such as an acid halide, anhydride or imidazolide, and the form is then reacted with a suitable hydroxyl compound HOR ⁷ . This reaction can be carried out in conventional solvents and the addition of a base is often required, in which case the abovementioned bases are suitable. For example, these two steps can be simplified by treating the hydroxyl compound with a carboxylic acid in the presence of a dehydrating agent such as carbodiimide.

Furthermore, the compounds of formula I may also be prepared starting from salts of suitable carboxylic acids, i.e. compounds of formula I, wherein R ¹ represents a group

COR and R are OM, where M may be an alkali metal cation or an equivalent of an alkaline earth metal cation. These salts can be reacted with a number of compounds of formula R-A, wherein A is a conventional nucleophage leaving

A group such as halogen, such as chlorine, bromine, iodine or unsubstituted or halogen-, alkyl- or haloalkyl-substituted aryl or alkylsulfonyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of formula R-A with a reactive substituent A are known or readily obtained using general knowledge known to those skilled in the art. This reaction may be carried out in conventional solvents and preferably carried out with the addition of a base, in which case the abovementioned bases are suitable.

In terms of biological activity, preferred carboxylic acid derivatives of formula I, both pure enantiomers and pure diastereoisomers and mixtures thereof, are those in which the substituents have the following meanings:

R ¹ is COOR ⁷ wherein

R ⁷ represents hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically acceptable organic ammonium ion;

C 6 -C 6 -cycloalkyl, C 1 -C 6 -alkyl;

CH 2 -phenyl, unsubstituted or substituted;

C 3 -C 6 alkenyl or C ₃ -O6-alkynyl, unsubstituted or substituted; or phenyl, unsubstituted or substituted.

R ² is H, OH, halogen, N (Cl-4 alkyl) 2, CrCralkyl, Ci-C4-alkoxy, _{Ci-C4-alkylthio,} Ci-C4-haloalkyl, Ci-C4-haloalkoxy, or ^CR2 is bonded to CR ¹⁰ as shown below to form a 5- or 6-membered ring, or, when Het is a five-membered ring, CR ² may together with CR ³ represent a 5- or 6-membered alkenyl or alkylenyl ring that is unsubstituted or substituted ;

X represents nitrogen or methine;

Y is nitrogen or methine;

W represents nitrogen or CR ¹⁰ , wherein R ¹⁰ represents hydrogen or C 1-6 -alkyl, or CR ¹⁰ together with CR ² or CR ³ forms a 5- or 6-membered alkylene or alkenylene ring which may be substituted with one or two methyl groups and which in any case is methylene

The -10 group can be replaced by oxygen or sulfur, such as -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH = CH-O-, -CH = CH-CH ₂ O-, -CH ( CH ₃ ) -CH (CH ₃ ) 0 -, -CH = C (CH ₃ ) -O-, -C (CH ₃ ) = C (CH ₃ ) -O-, or -C (CH ₃ ) = C ( CH ₃₎ -S; finally, one of the ring members X, Y or W is nitrogen.

R ³ is hydrogen, hydroxyl, halogen, N (C ₁ -C ₄ -alkyl) ₂ , C 1 -C 4 -alkyl,

C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, or CR ³ is attached to CR ¹⁰ as above to form a 5- or 6-membered ring, or, when Het represents a five membered ring, CR ² together with CR ^{3 may} represent a 5- or 6-membered alkenyl or alkylenyl ring which is unsubstituted or substituted;

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

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals such as halogen, nitro, cyano, hydroxyl, mercapto, amino, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy , C ₄ haloalkoxy, phenoxy, C4-alkylthio, NH _(Ci-C4 alkyl) or N (Ci-C ₄ -alkyl) ₂ or phenyl which may be substituted one or more times, for example one to three substituents selected from halogen, nitro, cyano, C C4R-alkyl, _Ci-C4 haloalkyl, Ci-C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy or C-C ^ alkylthio; or phenyl or naphthyl which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a group S0 _2, NH or N-alkyl; C ₃ -C 6 -cycloalkyl;

R ⁶ represents C ₃ -C 6 -cycloalkyl, which residues may be substituted one or more times with a substituent selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C ₁ -C 4 -alkoxy, C 1 -C 4 -alkyl , C 2 -C 4 -alkenyl, C 2 -C ₄ -alkynyl, Cr-Ce-alkenyloxy, _{C3-C6-alkynyloxy,} Ci-C ₄ alkylthio, C1C ₄ -haloalkoxy, C ₄ -alkylcarbonyl, C ₄ -alkoxycarbonyl, NH (C ₁ -C ₄ alkyl), N (C 1 -C ₄ alkyl) 2 or phenyl which may be substituted

-11 once or more, e.g. one to three times by a substituent selected from halogen, nitro, cyano, Ci-C4-alkyl, _Ci-C4 haloalkyl, Ci-C4-alkoxy, Ci-C ₄ -haloalkoxy or C-C _4- alkylthio;

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals such as halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C ₄ -alkyl, C 2 -C ₄ -alkenyl, C 2 -C ₄ -alkynyl, C ₃ -C 6 -alkenyloxy, C 1 -C 4 -haloalkyl, C 3 -C 6 -alkynyloxy, C 1 -C ₄ -alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl, C 1 -C ₄ -alkoxy, C 1 -C 4 -haloalkoxy , phenoxy, C 1 -C 4 alkylthio, NH (Cl-4 alkyl), N _(Ci-C4 alkyl) 2, dioxomethylene, dioxoethylene or phenyl, which is optionally substituted one or more times, for example one to three times by a substituent selected from halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C 4 -alkylthio;

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following radicals, such as C 1 -C 4 -alkyl, C ₁ - C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ -alkylthio, phenyl, phenoxy or phenylcarbonyl, the phenyl radicals alone may carry one to five halogen atoms and / or one to three of the following radicals, such as _Ci-C4 alkyl, C1-C4 haloalkyl, _{Ci-C4-alkoxy, Ci-C4} -haloalkoxy and / or C1 -C4 -alkylthio;

Z is sulfur or oxygen;

B is C 2 -C 4 -alkylene;

Het represents a heterocyclic group of formula Ia or 1b, wherein T = O, S.

Particularly preferred compounds of formula I, both pure enantiomers and pure diastereoisomers and mixtures thereof, are those wherein the substituents have the following meanings:

R 'means COOH;

-12X, Y represent N;

W is CR ¹⁰ ;

R ^2, R ³ are hydrogen, hydroxyl, _NH2, NH (Ci-4 alkyl), N (C _r C4 alkyl) _2, halo, C ₄ alkyl, C ₂ -C ₄ -alkenyl C _{1 2} C4-alkynyl, Ci-C ₄ haloalkyl, C _r C 4 alkoxy, C ₄ -haloalkoxy or C _r C 4 alkylthio, or ^CR2 is linked to ^CR10 as indicated below to give a 5- or A 6-membered ring, or, when Het represents a five-membered ring, CR ² may together with CR ³ represent a 5- or 6-membered alkylene or alkylenyl ring which is unsubstituted or substituted;

R ⁴ represents phenyl, which may be substituted by one or more of the following radicals such as halogen, nitro, cyano, hydroxyl, mercapto, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ - alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 -alkyl) or N (C 1 -C 4 -alkyl) ₂ or phenyl, which may be substituted one or more times, for example one to three times, by a substituent selected from halogen, nitro, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl, _Ci-C4 alkoxy, C1 -C4 -haloalkoxy or C 1 -C ₄ alkylthio; or

R ⁵ represents phenyl or 3,4-dimethoxyphenyl

R ⁶ is C 5 -C ⁶ -cycloalkyl, which radicals may in each case be substituted one or more times with a substituent selected from the group consisting of C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkyl, C 1 -C 4 -alkylthio, halogen, hydroxyl , carboxy, cyano, trifluoromethyl, acetyl, or phenyl which can be substituted one or more times, e.g. one to three times by a substituent selected from halogen, cyano, C, -C4 alkyl, C, -C4-haloalkyl, C ₁ -C 4 -alkoxy, C ₁ -C ₄ -haloalkoxy or C 1 -C 4 -alkylthio;

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals such as halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C ₄ -haloalkyl, acetyl, (C 1-4 -alkoxycarbonyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, phenoxy, C 1 -C ₄ alkylthio, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , dioxomethylene, dioxoethylene or phenyl, which may be substituted one or more times, for example one to three times with a substituent selected from the group consisting of halogen, nitro, cyano, C 1 -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ - haloalkoxy or C ₁ -C ₄ -alkylthio;

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

Z is sulfur or oxygen;

B represents C 3 -alkylene;

Het is Ia, wherein R ² and R ³ are methyl and T = O, S.

The compounds of the present invention provide novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute / chronic renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid haemorrhages, endotoxic, asthma, asthma, asthma, asthma organ failure, intravascular coagulation, angioplasty restenosis, benign prostatic hypoplasia, ischemic and intoxication-induced renal failure and hypotension, mesenchymal tumor metastasis and growth, contrast-induced renal failure, pancreatitis, gastrointestinal tract.

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

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

The good effect of the compounds can be demonstrated in the following tests:

Receptor Binding Studies

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

Preparation of membrane

ETA or _ETB receptor-expressing CHO cells were grown in DMEM NUT MIX F ₁₂ medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 µg / 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. This was followed by neutralization with medium and cell capture 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 buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250.40 to 70 seconds / constant / power 20).

Bonding 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 µg / ml bacitracin and 0.2% BSA) at a concentration of 50 µg protein per well. assay mixture and incubated at 25 ° C with 25 µM [ ¹²⁵ J] -ET 3 (ETA receptor assay) or 25 µM [ ¹²⁵ J] -ET 3 (ET _b receptor assay) in the presence and absence of test substance. Non-specific binding was determined with 10 ⁷ M ET- ^γ . After 30 minutes, free radioligands were separated from bound radioligands by filtration through GF / B glass wool filters (Whatman, England) in a Skatron collector cell (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.

-15Test for ET antagonists in vivo:

Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized, and punctured with the spinal cord. The carotid artery and jugular vein were catheterized.

Intravenous administration of 1 µg / kg ETi to control animals resulted in a marked increase in blood pressure that persisted over a prolonged period.

Test animals were injected intravenously (1 ml / kg) of test compounds 30 minutes prior to ET-1 administration. To determine ET-antagonistic properties, the blood pressure changes of the test animals were compared with the values for the control animals.

Oral testing of mixed ETa and ETb antagonists:

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

After the stabilization period, coarse endothelin (20 µg / kg, 0.5 ml / kg administered volume) and E 2 (0.3 µg / kg, 0.5 ml / kg administered volume) were administered intravenously. Blood pressure and heart rate were recorded continuously for 30 minutes. Significant and prolonged changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonist effects of the test substances, the AUC for the treated animals was compared to the AUC for the control animals.

The compounds of the invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) by conventional means. Administration can also be accomplished using aerosols or sprays through the nasopharynx space.

The dose depends on the age, condition and weight of the patient and the route of administration.

The daily dose of the active compound is usually about 0.5 to 50 mg / kg body weight for oral administration and about 0.1 to 10 mg / kg body weight for parenteral administration.

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

EXAMPLES Example 1

2,3-epoxy-3,6-diphenylhexanoic acid methyl ester

1.4 g (31 mmol) of 50% sodium hydride were added portionwise over 8 hours to a solution of 4 g (17.8 mmol) of 1,4-diphenyl-1-butanone and 2.7 ml (31 mmol) of methyl acid ester. chloroacetic acid in 60 ml THF. After the ketone was fully reacted, the reaction mixture was added to ice-water and extracted with ether. The organic phase was dried over magnesium sulphate and after distilling off the solvent, 5.5 g of an oil were isolated, which was taken on to the next reaction.

Example 2

2-Hydroxy-3-methoxy-3,6-diphenylhexanoic acid methyl ester g (6.75 mmol) of 2,3-epoxy-3,6-diphenylhexanoic acid methyl ester was added with 0.5 ml of methanol in 20 ml of dichloromethane and added 5 drops of boron trifluoride diethyl etherate. After 2 hours the mixture was concentrated and the residue was purified by MPLC (cyclohexane / ethyl acetate gradient) to isolate 530 mg of one diastereoisomer, 720 mg of the other diastereoisomer and 800 mg of the mixed fraction.

-17Example 3

2-Hydroxy-3-methoxy-3,6-diphenylhexanoic acid (single diastereoisomer, stereohemia unknown)

The second diastereoisomer (720 mg, 2.2 mmol) was dissolved in 9 mL of dioxane and 4.5 mL of 1 N sodium hydroxide solution was added. The mixture was stirred for 16 hours and then, after addition of water, extracted with ether. The aqueous phase was acidified with citric acid and extracted with ether, the organic phase was dried over magnesium sulphate and the solvent was distilled off. 936 mg of an oil were isolated and immediately reacted in the next reaction.

Example 4

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3-methoxy-3,6-diphenylhexanoic acid (one diastereoisomer)

195 mg (4.4 mmol) of 50% sodium hydride, 465 mg (1.5 mmol) of 2-hydroxy-3-methoxy-3,6-diphenylhexanoic acid and 291 mg (1.5 mmol) of 3,4-dimethyl-2-methylsulfone- The pyrimidine was mixed in 20 ml DMF and stirred at room temperature for 2 hours. The reaction mixture was added to 100 mL ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was purified by MPLC (cyclohexane / ethyl acetate gradient) to isolate 103 mg of one diastereomer.

¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.5 ppm (10H, m), 6.2 (1H, s), 5.6 (1H, s), 3.8 (3H, s), 3.3 (3H, s), 2.5-2.8 (3H, m), 2.3 (3H, s), 2.0 (1H, m) , 1.5-1.8 (2H, m).

ESI MS: M < + > = 436

Example 5

2,3-epoxy-3-phenyl-6- (3,4-methoxyphenyl) hexanoic acid methyl ester (mixture of diastereoisomers):

12.6 g (44 mmol) of 1-phenyl-4- (3,4-dimethoxy) phenyl-1-butanone were dissolved together with 8.3 g of methyl chloroacetate in 50 ml of DMF and at room temperature

-18 3.7 g of 50% sodium hydride suspension were added in portions over 1 hour. The precursor reaction was complete after a total of 1.5 hours and the reaction solution was added to 300 mL of ice-water. The aqueous phase was acidified with citric acid and extracted several times with ether, and the organic phase was separated, washed and dried over magnesium sulfate. The solvent was distilled off to recover 13 g of an oil which could be used immediately in the next reaction.

Example 6

2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid methyl ester

A mixture of 3.6 g (10 mmol) of 2,3-epoxy-3-phenyl-6- (3,4-methoxyphenyl) hexanoic acid methyl ester, 1.8 g (10 mmol) of 2- (3,4-dimethoxy) ethanol and 100 g of methyl ester. mg of p-toluenesulfonic acid in 50 ml of dichloromethane was stirred for 1 hour under ice-cooling. The reaction solution was added to saturated sodium bicarbonate solution and the organic phase was separated and dried over magnesium sulfate. The solvent was distilled off and 4.7 g of the residue was purified by MPLC (gradient: cyclohexane / ethyl acetate) to isolate 750 mg of a mixture of diastereoisomers.

Example 7

2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid

2.1 ml of 1 N sodium hydroxide solution was added to 750 mg (1.4 mmol) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3, methyl ester) methyl ester. 4-dimethoxyphenyl) hexane dissolved in 4.2 ml dioxane and the mixture was stirred at room temperature for 16 hours. The mixture was then treated with 100 mL of water and extracted with ether. Subsequently, it was neutralized with hydrochloric acid, the aqueous phase was extracted with ether, the ether phase was dried with magnesium sulfate and the solvent was distilled off. 620 mg of an oil were isolated and used immediately for the next reaction.

-19Example 8

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid

164 mg (3.42 mmol) of sodium hydride, 600 mg (1.14 mmol) of 2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid and 223 mg (1.2 mmol) of 3,4-dimethyl-2-methylsulfonopyrimidine were mixed in 10 mL of DMF and stirred at room temperature for 6 hours. The reaction mixture was added to 100 mL ice-water, acidified with citric acid and extracted with ether. The organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was purified by flash chromatography (cyclohexane / ethyl acetate gradient) to isolate 115 mg of one crystalline diastereoisomer.

Diastereoisomer I:

Melting point: 93-96 ° C

ESI MS: M < + > = 630

Example 9

2- (4 _I 6-dimethyl-2-pyrimidinyloxy) -3- ₍₃₎ 4-dimethoxy) -3-phenyl-6- (3,4-Dimethoxyphenyl) hexanoic acid

Diastereoisomer I:

Melting point: 130-133 ° C

ESI MS: M < + > = 616

Example 10

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (4-methoxyphenoxy) -3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid

Diastereoisomer I:

Melting point: 118-122 ° C

ESI MS: M < + > = 572

-20Example 11

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3-methoxy-3-phenyl-6- (3,4-dimethoxyphenyl) hexanoic acid

Diastereoisomer I:

Melting point: 135-138 ° C

ESI MS: M < + > = 480

Diastereoisomer II:

M.p .: 128-134 ° C

ESI MS: M < + > = 480

Example 12

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3-methoxy-3,6-diphenylhexanoic acid ¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.5 ppm (10H, m) , 6.7 (1H, s), 5.8 (1H, s), 3.3 (3H, s), 2.5-2.7 (3H, m), 2.3 (6H) H, s), 2.0-2.1 (1H, m), 1.6-1.8 (2H, m).

ESI MS: M < + > = 420

Example 13

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3-hex-3E-enoxy-3,6-diphenylhexanoic acid Diastereoisomer I:

Melting point: 110-114 ° C

ESI MS: M < + > = 488

Diastereoisomer li:

ESI MS: M < + > = 488

Example 14

2- (4,6-dimethyl-2-pyrimidinyloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) _{-3-diphenyl-1} 6

-21 Diastereoisomer I:

Melting point: 87-88 ° C

ESI MS: M < + > = 570

Diastereoisomer II:

Melting point: 87-88 ° C

ESI MS: M < + > = 570

Example 15

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (3,4-dimethoxyphenyl) ethoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

M.p .: 141-142 ° C

ESI MS: M < + > = 586

Example 16

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (3,4-dimethoxybenzyloxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.5 ppm (10H, m), 6.9 (3H, m), 6.7 (1H, s), 5.8 (1H, s), 4.4 (1H, d), 4.3 (1H, d), 3.9 (3H, s), 3.85 (3H, s), 2.5 2.7 (3H, m), 2.3 (6H, s), 2.0-2.3 (1H, m), 1.7-1.9 (2H, m).

ESI MS: M < + > = 556

Example 17

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (3,4-dimethoxybenzyloxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

-22 ¹ H-NMR (200 MHz, _CDCl3): 7.1 to 7.5 ppm (10H, m), 6.9 (3H, m), 6.25 (1H, s), 5 , 75 (1H, s), 4.45 (1H, d), 4.35 (1H, d), 3.9 (3H, s), 3.85 (6H, s), 2 , 4-2.7 (3H, m), 2.3 (6H, s), 2.0-2.2 (1H, m), 1.7-1.9 (2H, m) .

ESI MS: M < + > = 572

Example 18

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (2-thiophenylethoxy) -3,6-diphenylhexanoic acid)

3: 1 diastereoisomer mixture:

Decomposition: 85 ° C

ESI MS: M < + > = 532

Example 19

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (3,4,5-trimethoxyphenyl) ethoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.0-7.3 ppm (10H, m), 6.65 (1H, m), 6.4 (2H, s), 5.75 (1H, s), 3.9 (3H, s), 3.85 (6H, s), 3.5-3.7 (2H, m), 2.8-2.9 (2 H, m), 2.3-2.5 (3H, m), 2.3 (6H, s), 2.0-2.3 (1H, m), 1.5-1.7 (2H, m).

ESI MS: M < + > = 600

Example 20

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (3,4,5-trimethoxyphenyl) ethoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

Mp: 153-155 ° C

ESI MS: M < + > = 616

-23Example 21

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (2- (4-hydroxy-3-methoxyphenyl) ethoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.0-7.4 ppm (10H, m), 6.9 (1H, dm), 6.6-6.75 (3H, m) , 5.8 (1H, s), 5.5 (OH), 3.9 (3H, s), 3.85 (3H, s), 3.5-3.7 (2H, m) ), 2.8-2.9 (2H, tr), 2.3-2.5 (3H, m), 2.3 (6H, s), 2.0-2.3 (1H) , m), 1.5-1.7 (2H, m).

ESI MS: M < + > = 556

Diastereoisomer II:

ESI MS: M < + > = 556

Example 22

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (2- (4-hydroxy-3-methoxyphenyl) ethoxy) 3,6-diphenylhexanoic acid

Diastereoisomer I:

Mp .: 154-157 ° C

ESI MS: M < + > = 572

Example 23

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (4-carboxybenzyloxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 8.0 (2H, d), 7.1-7.5 ppm (12H, m), 6.8 (1H, m), 6.8 (1

H, s), 4.6 (1H, d), 4.5 (1H, d), 2.5-2.7 (3H, m), 2.3 (6H, s), 2 1 - 2.25 (1H, m),

1.5-1.7 (2H, m).

ESI MS: M < + > = 540

Diastereoisomer II:

-24 Melting point: 160-167 ° C

ESI MS: M < + > = 540

Example 24

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (4-carboxybenzyloxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 8.0 (2H, d), 7.1-7.5 ppm (12H, m), 6.2 (1H, m), 5.6 (1H, s), 4.55 (1H, d), 4.45 (1H, d), 3.9 (3H, s), 2.5-2.7 (3H, m) 2.3 (3H, s), 2.1 2.25 (1H, m), 1.6-1.8 (2H, m).

ESI MS: M < + > = 556

Diastereoisomer II:

ESI MS: M < + > = 556

Example 25

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (4-methoxyphenoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.5 ppm (10H, m), 6.5-6.8 (5H, m), 5.9 (1H, s) 3.75 (3H, s), 2.2-2.7 (4H, m), 2.3 (6H, s), 1.5-1.7 (2H, m).

ESI MS: M < + > = 512

Diastereoisomer II:

ESI MS: M < + > = 512

Example 26

2- (4-Methoxy-6-methyl-2-pyrimidinyloxy) -3- (4-methoxyphenoxy) -3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.5 ppm (10H, m), 6.5-6.9 (4H, m), 6.2 (1H, s) , 5.75 (1H, s), 3.8 (3H, s), 3.75 (3H, s), 2.2-2.7 (4H, m), 2.3 (3H, s) H, s), 1.5-1.7 (2H, m).

-25ESI MS: M < + > = 528

Diastereoisomer II:

ESI MS: M < + > = 528

Example 27

2- (4,6-Dimethyl-2-pyrimidinyloxy) -3- (3- (3,4,5-trimethoxyphenyl) -2E-propenoxy) 3,6-diphenylhexanoic acid

Diastereoisomer I:

¹ H-NMR (200 MHz, CDCl ₃ ): 7.1-7.4 ppm (10H, m), 6.6 (1H, s), 6.55 (2H, s), 6.3 (1H, s), 6.2 (1H, dtr), 5.9 (1H, d), 4.0-4.2 (1H, m), 3.85 (3H, s) 3.8 (3H, s), 3.75 (3H, s), 3.4 (1H, m), 2.4-2.7 (3H, m), 2.3 (6H) H, s), 2.0-2.1 (1H, m), 1.5-1.7 (2H, m).

ESI MS: M < + > = 612

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

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1 1 1 T " cm 1 1 1 1 1 T " CM 1 1 1 CM 1 CM 1 1 cm 1 from from from 1 1 from from from from from 1 1 from FROM from from 1 1 from from 1 from from 1 from from from from 1 1 from from from from from 1 1 from FROM from from 1 1 from from 1 from from 1 from Me CH ? x 9 x υ about CM X about CM X about about 1 1 x about I about x about about CM X 9 x about x about ABOUT CM X about CM X about about «M * 1 1 x about x about about I 9 x ¥ about about CM X about CM X about about 1 1 x about x about 1 x about x about 1 I about 1 1 03 with 03 with 03 with 1 03 from 03 from 1 03 from 03 FROM 1 03 from 03 from 1 03 from OMe φ with about 03 WITH ABOUT 1 1 n LL ABOUT 03 WITH 03 from ABOUT 03 2 about 03 FROM ABOUT 1 1 03 FROM 03 from about 03 FROM about 03 FROM about 1 1 03 FROM 03 FROM about 1 0) FROM 0) from ABOUT 1 03 from CM X about n X about CM I about CM X about CM x about CM X about CM X about CM X about CM X about CM x about CM x about CM x about CM X about CM X about CM X about CM X about CM X about CM X about CM X about CM X about CM X about CM x ABOUT CM X about CM X about CM X about CM X about CM X about CM X about CM X about CM I about CM x about CM x about CM x about CM x about CM x about CM X about CM X about CM X about CM X about CM x about CM x about CM x about <M X about CM X about CM X about CM X about CM X about CM X about CM x about CM x about CM x about CM X about CM I about CM X about CM X about CM I ABOUT CM X about CM X about CM X about CM X about CM X about CM I about CM X about CM X about CM I about CM X about CM X about CM I about CM X about CM x about CM x about CM X about CM x about CM I about CM x about ABOUT about about ABOUT about ABOUT about about about ABOUT ABOUT about about ABOUT about ABOUT ABOUT about ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about 2- (4-OMe-phenyl) -ethyl 2- (4-OMe-phenyl) -ethyl 2- (4-OMe-phenyl) -ethyl 2- (4-OMe-phenyl) -ethyl 2- (4-OMe-phenyl) -ethyl 2- {4-OMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (3,4-diOMe-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-COOH-phenyl) -ethyl 2- (4-SMe-phenyl) -ethyl 2- (4-SMe-phenyl) -ethyl 2- (4-SMe-phenyl) -ethyl 2 · > » 5 j 2- (4-Cl-phenyl) -ethyl 2- (4-Cl-phenyl) -ethyl 2- (3,4-diC phenyl) ethyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl 3,4-diOMe-phenyl phenyl > » C 03 LL C d) ll > 1 C 0) ll > » C 03 LL >. C 03 U. > » C 03 LL > < C 0) LL > « C 0) LL > » C 0) LL >. C 03 LL > 1 C 03 LL > » C 03 LL C 03 LL > » C 03 LL C 03 LL > » C 03 LL > » C 0) LL >. C 03 LL C 03 LL > » C 0) LL > » C 03 LL > » C 03 LL > » C 03 LL C 03 LL COOH COOH COOH x ABOUT ABOUT ABOUT COOH COOH COOH I ABOUT ABOUT ABOUT COOH COOH COOH X ABOUT ABOUT ABOUT COOH COOH COOH COOH COOH 1 X about ABOUT about X about ABOUT about X ABOUT ABOUT ABOUT COOH X ABOUT about about COOH X about about about COOH 00 with 1 03 2 about CM X " CM CM CM CM CM 1 what CM <7 The M CM CM 1 m CM what CM WITH! h- CM CM 1 00 CM CM 1 03 CM CM 1 about what CM WITH CM WHAT CM 1 m m CM 1 with CM 1 and WHAT CM 1 it n IN 1 → WHAT CM 1 what WHAT 03 WHAT about Ό · CM CM • t CM 1

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CQ. ·

THB 1 1 c \ T 1 1 CM 1 1 1 Whose 1 1 from from 1 from from 1 FROM from from from from 1 l FROM 1 from from from from from from from from from 1 1 from 1 x about x about 1 x about x about 1 x about x about about x about CN I £ about about ol x about CN X about g I about 1 1 x about 1 Φ with ID with 1 (D with Φ from Φ WITH Φ with φ 2 ABOUT 1 1 Φ WITH 1 in with (D Σ ABOUT 1 (D 2 Φ with about 1 Φ WITH Φ with about Φ from about φ with about Φ with about 1 1 Φ WITH N x about M I about N x about N x about ol x about ol x about ol x about ol x about ol x about ol X about ol x about ol x about ol X about ol I about ol x about ol x about ol x about ol x about CN x about ol x about ol x about <M X about ol x about ol x about 01 x about ol x about ol x about ol X ABOUT ol x about ol x about ol x about ol x about ol x about ol x about 01 x about ol x about ol x about (M x about ol x about ol x □ ol x about ol x about 01 x ABOUT ol x about ol x about about about about about about about ABOUT about about ABOUT about about about about ABOUT 2 (3,4-diOMe-phenyl) -ethyl 2 - ( "thiophenyl) ethyl 2-ftiofenyl) ethyl 2 - ( "thiophenyl) ethyl 2- (3,4,5-trio-phenyl) -ethyl 2- (3,4,5-trio-phenyl) -ethyl 2- (3,4,5-trio-phenyl) -ethyl > » C 2 Ϊ Φ x > » C 2 1 Φ x Hex-phenyl-3E Hex-phenyl-3E Hex-3E-enyl | Hex-phenyl-3E Hex-phenyl-3E 2- (3,4-diOMe-phenyl) -ethyl phenyl >. C ω LL C Φ LL >. C (D LL > 1 C φ LL >. C φ LL > » C φ LL > « C Φ LL >% C 0) LL > » C Φ LL > » C φ LL φ LL > » C Φ LL > » C Φ LL 3,4-diOMe-phenyl 4-OMe phenyl > C in LL > » C (D LL >. C Φ LL > » C Φ LL >. C Φ LL > » C Φ LL >> C Φ LL > « C Φ LL C Φ LL > » C Φ LL C Φ LL > » C Φ LL > » C Φ LL >. C φ LL COOH X about about about X about about about X about about about X ABOUT about about X about about about X about about about X about about at X about about about X about about about X about about about X about about about X about about about X about about about X about about about 1-288 0) WHAT ol about ABOUT) ol o> ol 1 ol CD l what 03 ol 1 N · 03 ol 1 m 03 (0 03 ol 1 1 → 03 ol WHAT 03 ol 1 ABOUT) 03 ol about about n 1 T " about WHAT ol about what 1

>. í = “O

N O n n X (0 O S £ · £> Φ Q) i n

s s i i

OJ II II * «T- CM

-39Example 12

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

The results are summarized in Table 2.

Table 2

Receptor Binding Data (K i Values)

compound ET _and K, [nM] ET _b K [nM] I-2 one diastereoisomer 43 345 I-224 one diastereoisomer 33 6.8 1-171 one diastereoisomer 15.7 26.4 1-145 one diastereoisomer 1100 13.6 1-137 one diastereoisomer 60 11 1-1 one diastereoisomer 190 495 I-88 one diastereoisomer 50 10 I-89 one diastereoisomer 25 17 I-35 one diastereoisomer 400 250 I-36 one diastereoisomer 300 250 1-128 one diastereoisomer 46 9 1-129 one diastereoisomer 23 10 I-44 one diastereoisomer 205 365 I-45 one diastereoisomer 40 255 I-89 one diastereoisomer 35 93 1-10 one diastereoisomer 65 190 1-116 one diastereoisomer 9 43 I-290 one diastereoisomer 22 700 I-292 one diastereoisomer 1.8 170 I-293 one diastereoisomer 13 15 I-295 one diastereoisomer 215 1400

-4075 / 454-4000

Claims (2)

1. The carboxylic acid derivative of the general formula I 1 ' ^ Π ^Η ' B R O-Het R ⁵ wherein the substituents have the following meanings R is tetrazole or o R ¹ -C 1 R ¹ R ¹ represents the radical OR ⁷ in which R ⁷ is hydrogen, an alkali metal cation, an alkaline earth metal cation or a physiologically acceptable organic ammonium ion; C 5 -C 6 -cycloalkyl, C 1 -C 6 -alkyl; CH 2 -phenyl, unsubstituted or substituted; C ₃ -C 6 -alkenyl or C ₃ -C 6 -alkynyl, unsubstituted or substituted; or phenyl, unsubstituted or substituted, R ² represents hydrogen, hydroxyl, NH ₂ , NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ , halogen, C 1 -C ₄ -alkyl, C 2 -C ₄ -alkenyl, C2 -C ₄ -alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ alkylthio, or CR ² is attached to CR ¹⁰ as shown below to form 5- or 6 a-membered ring, or when Het represents a five-membered ring, CR ² together with CR ^{3 may} represent a 5- or 6-membered alkenyl or alkylenyl ring which is unsubstituted or substituted; X is nitrogen or methine; -41 Y represents nitrogen or methine; W represents nitrogen or CR ¹⁰ , wherein R ¹⁰ represents hydrogen, halogen or C 1-6 -alkyl, or CR ¹⁰ together with CR ² or CR ³ forms a 5- or 6-membered alkylene or alkenylene ring which is unsubstituted or substituted and in which case one or more methylene groups may be replaced by a substituent such as oxygen , sulfur, -NH or -N (C 1 -C 4 alkyl); R ³ represents hydrogen, hydroxyl, NH ₂ , NH (C 1 -C 4 -alkyl), N (C 1 -C ₄ -alkyl) ₂ , halogen, C 1 -C ₄ -alkyl, C 2 -C ₄ -alkenyl, C 2 -C 4 -alkynyl , _Ci-4 haloalkyl, _Ci-4 alkoxy, C _{i_C-4} haloalkoxy, _Ci-4 alkylthio; or CR ³ is attached to CR ¹⁰ as above to form a 5 or 6-membered ring; R ⁴ and R ⁵ (which may be the same or different) denote phenyl or naphthyl, unsubstituted or substituted, or phenyl or naphthyl, which are bonded together at various positions by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or SO ₂ , NH or N-alkyl C 5 -C 6 -cycloalkyl, unsubstituted or substituted; R ⁶ represents hydrogen, C 1 -C 6 -alkyl, C 3 -C ₈ -alkenyl or C 3 -C 6 -alkynyl, each of which may be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, -C ₄ -alkoxy, C 3 -C ₆ alkenyloxy, C 3 -C alkynyloxy, C ₄ alkylthio, _Ci-C4 haloalkoxy, -C ₄ alkylcarbonyl, -C ₄ -alkoxycarbonyl, C ^ -alkylcarbonylalkyl, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₂ , C ₃ -C ₈ -cycloalkyl, hetaryloxy or hetaryl, five- or six-membered, containing one to three nitrogen atoms and / or or one sulfur or oxygen atom, phenoxy or phenyl, wherein said aryl radicals may themselves be substituted by one or more substituents, for example one to three substituents selected from the group consisting of halogen, hydroxyl, mercapto-42 * FROM B Het * FROM B Het, carboxyl, nitro, cyano, C ₁ -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, amino, NH (C ₁ -C ₄ -alkyl), N (C ₁ -C ₄ -alkyl) ₁₂ or C ₁ -C ₄ -alkylthio; phenyl or naphthyl, each of which may be substituted with one or more of the following radicals such as halogen, nitro, cyano, hydroxyl, amino, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, phenoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ -alkylamino, C 1 -C ₄ -dialkylamino, dioxomethylene or dioxoethylene; a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and / or one sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following: 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, the phenyl radicals alone may carry one to five halogen atoms and / or one to three of the following radicals such as C-C ₄ -alkyl, C _r C ₄ haloalkyl, _Ci-C4 alkoxy, -C ₄ -haloalkoxy and / or _C-C4 alkylthio; C 3 -C 6 -cycloalkyl, which radicals may be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C 1 -C ₄ -alkyl, C 2 -C ₄ -alkenyl, C ₂ -C ₄ -alkenyl C ₄ -alkynyl, C ₄ alkoxy, C ₄ alkylthio, C ₁ -C ₄ -haloalkoxy; represents sulfur or oxygen; It refers to C 2 -C ₄ alkylene; represents a heterocyclic radical of formula Ia or 1b RLA ib -43kde T represents O, S, NR ⁸ ; R ⁸ represents C 1 -C 6 -alkyl and physiologically acceptable salts and enantiomerically pure forms. Use of the carboxylic acid derivatives according to claim 1 for the preparation of medicaments.