SK832001A3 - New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists - Google Patents

Abstract

The invention relates to new carboxylic acid derivatives of the formula (I), where the substituents have the meaning given in the description, their production and their use as endothelin-receptor antagonists.

Description

Carboxylic acid derivatives bearing side keto chains, their preparation and their use as endothelin receptor antagonists

Technical field

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

BACKGROUND OF THE INVENTION

Endothelin is a 21 amino acid peptide that is synthesized and released through 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 a potent effect 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 vascular contraction in peripheral, renal and cerebral blood vessels, which can lead to disease. As reported in the literature, endothelin is involved in a variety of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344. 114 (1990), N. Engl J. Med 322. 205 (1989) N. Engl J. Med 328, 1732 (1993), Nephron 66, 373 (1994) Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol Cell, Cardiol 27, A234 (1995), Cancer Research 56,663 (1996)).

At least two endothelin receptor subtypes, the ET _A and ET _B receptor, have been described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, agents that exhibit endothelin binding to both receptors could antagonize the physiological effects of endothelin and therefore be valuable pharmaceutical agents.

Mixed endothelin receptor antagonists are those that bind to the ET _A and ET _B receptors with approximately the same affinity. Approximately the same

The affinity for receptors exists when the affinity quotient is greater than 0.05 (preferably 0.1) and less than 20 (preferably 10).

Patent application DE 19636046.3 describes mixed ET _A / ET _B receptor antagonists. Spacer Q (see formula XX), which corresponds to the length C ₂ -C ₄ alkyl chain, is important for these compounds.

R (XX)

Mixed receptor antagonists are also obtained with a spacer of Q = COCR ⁷ R ⁸ (see Formula I).

It is an object of the present invention to identify compounds that bind with approximately the same affinity to the ET _A and ET _B receptor and have more advantageous properties than the mixed endothelin receptor antagonists known to date.

SUMMARY OF THE INVENTION

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

wherein the substituents have the following meanings:

R ¹ represents tetrazolyl or a group o II

C ^- R

R represents

(a) a residue of OR ⁹ in which R ⁹ represents:

····

-3 ···································· Hydrogen, an alkali metal cation, an alkaline earth metal cation, a physiologically acceptable organic ammonium ion, such as a tertiary C 1 -C ₄ -alkylammonium or ammonium ion;

C ₃ -C ₈ -cycloalkyl, C 1 -C ₈ -alkyl, CH ₂ -phenyl, which may be substituted by one or more of the following radicals, such as: halogen, nitro, cyano, C 1 -C ₄ -alkyl, Cr

C ₄ -haloalkyl, hydroxyl, Ci-C ₄ -alkoxy, mercapto, C ₄ -alkylthio, amino, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2;

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

a phenyl radical which may carry one to five halogen atoms and / or one to three of the following radicals, such as: nitro, cyano,

Ci-C ₄ -alkyl, C _r C ₄ -haloalkyl, hydroxyl, Ci-C ₄ -alkoxy, mercapto, C ₁ -C ₄ -alkylthio, amino, NH _(Ci-C4 alkyl), N (-C _4- alkyl) ₂ ;

b) a 5-membered heteroaromatic ring which is bonded by a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl and which may bear 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) a group

T ¹¹ 10 - O _'(CH2) p-S' R in which k can assume the values 0, 1 or 2, p can assume the values 1, 2, 3 or 4 and R ¹⁰ is

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, for example one to three, from the following residues such as:

-4 ···· halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C 1 -C ₄ haloalkyl, hydroxyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, mercapto, amino, NH (C 1 -C 4) _4- alkyl), N-C 1 -C 1 -alkylh;

(d) the remainder by

II ii —N — S — RH ¹¹

O in which R ¹¹ means:

C ₁ -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C ₃ -C 6 -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, these radicals may carry C ₁ -C ₄ an alkoxy group, a C ₁ -C ₄ -alkylthio group and / or a phenyl radical as mentioned under c);

phenyl which may be substituted with one to three of the following radicals such as: halogen, nitro, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, hydroxyl, C 1 -C ₄ alkoxy, C 1 -C ₄ -alkyl; C ₄ alkylthio, mercapto, amino, NH _(Ci-C4 alkyl), N _(Ci-C4 alkyl) _2;

R ² 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 _{A 4-} alkynyl group, a C ₁ -C ₄ -hydroxyalkyl group, a C 1 -C ₄ -haloalkyl group, a C 1 -C ₄ -alkoxy group, a C 1 -C ₄ -haloalkoxy group or a C 1 -C ₄ -alkylthio group, or CR ² is attached to R ¹² as shown under Z to form a 5- or 6-membered ring;

X is nitrogen or methine;

Y is nitrogen or methine;

Z represents nitrogen or CR ¹² in which R ¹² represents hydrogen, halogen, C 1 -C 4 haloalkyl or C 1 -C 4 -alkyl, or CR ¹² , together with CR ² or CR ³ , forms a 5- or 6-membered alkylene or alkenylene a ring which may be substituted by one or two C 1 -C 4 -alkyls

B · · · · · · · · · ·

- in groups and in which one or more methylene groups can always be replaced by oxygen, sulfur, -NH or N (C 1 -C ₄ -alkyl), wherein at least one of the ring members X, Y or Z is nitrogen;

R ³ is 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, C 1 -C 4 haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -hydroxyalkyl, C 1 -C ₄ -alkylthio, or CR ³ is bonded to CR ¹² , as shown under Z, to form a 5- or 6-membered ring;

R ⁴ and R ^s (which may be the same or different) mean:

phenyl or naphthyl, each of which may be substituted with one or more of the following radicals such as: halogen, nitro, cyano, hydroxyl, mercapto, C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ C ₄ -alkynyl, C ₄ -haloalkyl group, a Ci-C ₄ -alkoxy, phenoxy, carboxyl, C _r C ₄ -halogénalkoxylová group, a Ci-C ₄ alkylthio group, amino, NH (C -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) ₂ or phenyl, which may be mono- or polysubstituted, for example mono- to trisubstituted, with a substituent such as 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 -group;

phenyl or naphthyl, which are linked to each other in the ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, or by SO ₂ , NH or N-alkyl; C ₃ -C ₈ -cycloalkyl;

R ⁶ represents a C ₃ -C ₈ -cycloalkyl group, which residues may in each case be mono- or polysubstituted with a substituent such as:

halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, _Ci-C4 alkoxy group, Ci-C ₄ -alkyl, C 2 -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₃ - C ₆ -alkenyl • ····································

- Q - Oxide, C ₃ -C ₆ -alkyloxy, C ₁ -C ₄ -alkylthio -group, Cr _C4 -halogénalkoxylová group, a C ₁ -C ₄ -alkylcarbonyl, C ₄ alkoxycarbonyl, C ₃ -C ₈ -alkylkarbonylalkylová group, carboxamide, NH _(Ci-C4 alkyl), N ( C 1 -C ₄ -alkyl) ₂ or phenyl, which may be mono- or polysubstituted, for example mono- to trisubstituted with a substituent such as halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -haloalkyl C ₄ -alkoxy, C 1 -C ₄ haloalkoxy 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, R ¹⁵ , 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 6 haloalkyl, C ₃ -C ₆ -alkyloxy, C ₁ -C ₄ -alkylcarbonyl, C 1 -C ₄ -alkoxycarbonyl group, a carboxamide group, C ₄ alkoxy, _Ci-4 -halogénalkoxylová, phenoxy, _Ci-4 alkylthio group, a NH (C ₁ -C ₄ alkyl), N (C _r C ₄ -alkyl) ₂ , dioxomethylene, dioxoethylene or phenyl, which may be mono- or polysubstituted, for example mono- to trisubstituted with a substituent such as halogen, nitro, cyano, C ₁ -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy a C 1 -C ₄ -haloalkoxy group; o C 1 -C 4 alkylthio;

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, such as: C 1 -C ₄ -alkyl group, a C ₂ -C ₄ -alkenyl, C ₁ -C ₄ -haloalkyl group, a Ci-C ₄ -alkoxy, C ₄ -halogénalkoxylová group, a Ci-C ₄ alkylthio group, phenyl or phenoxy, wherein phenyl radicals may themselves carry one to five halogen atoms and / or one to three 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 and / or or Ci-C ₄ alkylthio group;

-7 ····································· ·······················

R ⁷ and R ⁸ (which may be the same or different) mean:

is hydrogen, Ci-C ₄ alkyl group;

^{1 S} R is a _Ci-4 alkyl group, _Ci-4 alkylthio, _Ci-4 alkoxy, each of which carries one of the following radicals: hydroxyl, carboxyl, amino, NH _(Ci-4 - alkyl), N (C ₁ -C ₄ -alkyl) ₂ , carboxamide or CON (C 1 -C ₄ -alkyl) ₂ ;

W is sulfur or oxygen.

Here and in the following, the following definitions are used:

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

the alkaline earth metal is, for example, calcium, magnesium or barium;

C ₃ -C ₈ -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C _r 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;

The C 1 -C ₄ -haloalkoxy group 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- chloro-1,1,2-trifluoroethoxy,

2-fluoroethoxy or pentafluoroethoxy;

The C 1 -C ₄ -alkyl group 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 group 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 can be linear or branched such as, for example, ethynyl, propyn-1-yl, 1-propynyl-3-yl, 1-butyn-4-yl or 2-butyn-4-yl ;

• ··············

8 «· ······

- · · · · · · · · · · · · · · · · · · · · · · ·

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

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

The C ₃ -C ₆ -alkynyloxy group may be linear or branched, such as

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

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

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

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

The C ₃ -C ₈ -alkylcarbonylalkyl group may be linear or branched, such as 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

Ci-C ₈ alkyl group can be linear or branched such as C _r C ₄ alkyl, pentyl, hexyl, heptyl or octyl;

halogen is, for example, fluorine, chlorine, bromine or iodine.

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

Preferred precursors are those in which the release takes place under conditions that predominate in certain body compartments, such as the stomach, intestine, bloodstream, or liver.

Compounds of formula I as well as intermediates for their preparation, such as compounds of formula II, III, IV, V and VI, may contain one or more asymmetrically

-9 ································· Substituted carbon atoms. Such compounds may exist as pure enantiomers or pure diastereoisomers or as a mixture thereof. The use of an enantiomerically pure compound as an active compound is preferred.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors for ETA and _ETB receptors. The compounds of the present invention are useful as mixed antagonists as defined in the introduction.

The preparation of compounds of formula IV in which W is sulfur or oxygen can be carried out as described in WO 96/11914.

In this reaction, the later keto group is protected as a cyclic acetal; however, other protecting groups such as dimethylacetal may also be envisaged.

ri ⁸ ° x / °?

R (II) III

Π e o P?

(IV)

The compounds of formula IV can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of formula II and reacting them with compounds of formula III as described in WO 96/11914.

In addition, the enantiomeric compounds of formula IV can be obtained by carrying out classical resolution with appropriate enantiomerically pure bases using racemic or diastereomeric compounds of formula IV. Suitable bases of this type are, for example, 4-chlorophenylethylamine and such bases as disclosed in WO 96/11914.

The preparation of compounds of formula II has been described in WO 96/11914, while compounds of formula III are either known or can be synthesized using generally known procedures, such as:

-10- • ·· • • • ··· ···· • • • • • ·· · ·· · • · · · ··· • · · · · · · · • · · ···· · · · · • · · · · · ·· · ·· ··· 8 / = \ <1 8 clay v MeO. , C-C-W— ' V / 1.) R MaBr _B «X? IN 2) Removal of the protecting group 3.) Acetalization c β 'R c b R W H (III)

The carboxylic acid derivatives of formula (IV) can then be reacted with compounds of formula (V) to give compounds of type VI.

(iv) +

(VI)

In formula V, R ¹⁶ is halogen or R ¹⁷ -SO 2 -, wherein R ¹⁷ can represent 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 causes deprotonation of intermediate IV, at a temperature range from room temperature to the boiling point of the solvent.

Compounds of type VI, where R ¹ = COOH, can be obtained directly in this manner if intermediate IV, in which R ¹ is COOH, is deprotonated using two equivalents of a suitable base and reacted with compounds of formula V. reaction in an inert solvent and in a temperature range from room temperature to the temperature of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, trichlorethylene. such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides ···

-11 ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Acids such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, and sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.

The compounds of formula V are known, in some cases commercially available, or can be prepared using generally known procedures.

The base used 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 metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as hydroxide sodium or potassium hydroxide; an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.

The compounds of the present invention in which the substituents have the meanings defined by the general formula (I) can finally be prepared by the removal of the keto-protecting group in the compounds of the formula VI. In the case of ethylene glycol acetal, this can be accomplished by acid hydrolysis.

(VI)

J 'V HΓ - C - C' W - CC ^- O '\ z' 7 Is L

R R R 3

R (I)

Type I compounds can be further synthesized using compounds having the general formula VIIa?

(IN)

1) (II) -

2.) (VII)

-12 • ············································ · · ·

Compounds of formula VII can then be reacted with Grignard reagents to give compounds of formula I (VII)

R Mg B r

Compounds of formula I may also be prepared starting from the corresponding carboxylic acids, i.e. compounds of formula I in which R ¹ is COOH, and these are first converted in the customary manner to an activated form such as an acid halide, anhydride or imidazolide and this is then reacted with a suitable hydroxyl compound HOR ⁹ . This reaction can be carried out in conventional solvents and often requires the addition of a base, with the above-mentioned bases being suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as carbodiimide.

In addition, the compounds of formula I may also be prepared starting from salts of the corresponding carboxylic acids, i.e., compounds of formula I wherein R ¹ represents a COOM group, wherein M may be an alkali metal cation or an alkaline earth metal cation equivalent. These salts can be reacted with a number of compounds of the formula R ⁹ 'A, wherein A is a conventional nucleophagic leaving group, for example halogen, such as chlorine, bromine, iodine or aryl or alkylsulfonyl, optionally substituted with a substituent such as halogen, alkyl or haloalkyl such as toluenesulfonyl and methylsulfonyl or other equivalent leaving group. Compounds of formula R ⁹ 'A which contain a reactive substituent A are known or can be readily prepared using general knowledge. This reaction can be carried out in conventional solvents and is preferably carried out with the addition of a base, the above-mentioned base being preferred.

In some cases, the use of commonly known protecting group procedures is essential for the preparation of compounds of Formula I of the present invention.

-13 ······································· Invention. For example, when R ^e is to be 4-hydroxyphenyl, the hydroxyl group may first be protected as a benzyl ether, which is then cleaved off at a suitable stage in the reaction sequence.

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

With respect to biological activity, preferred are the carboxylic acid derivatives of the formula I - both as pure enantiomers or pure diastereoisomers or mixtures thereof - in which the substituents have the following meanings:

R ² is hydrogen, N _(Ci-C4 alkyl) _2, C ₄ alkyl group, C ₄ -alkoxy, C ₄ alkylthio, C ₄ -haloalkyl, C ₄ haloalkoxy a group, a hydroxymethyl group or CR ² is attached to CR ¹² as mentioned under Z to form a 5- or 6-membered ring;

X represents nitrogen or methine;

Y is nitrogen or methine;

Z represents nitrogen or CR ¹² in which R ¹² represents hydrogen, fluoro, trifluoromethyl or methyl or CR ¹² , together with CR ² or CR ³ , forms 5- or

A 6-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups and in which one methylene group may in each case 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 ) -O-, -CH = C (CH ₃ ) - O-, -C (CH ₃ ) = C (CH ₃ ) -O- or C (CH ₃ ) = C (CH ₃ ) -S;

at least one of the ring members X, Y or Z is nitrogen;

R ³ is hydrogen, N _(Ci-C4 alkyl) 2, C _r C ₄ -alkyl, C ₄ -alkoxy, C ₄ alkylthio, -C ₄ -haloalkyl, C ₁ -C ₄ group -halogénalkoxylovú a hydroxymethyl group or CR ³ is bonded to CR ¹² as indicated under Z to form a 5- or 6-membered ring;

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

···· · · • • · • · • • • • • • • · • • • • · • • • · • ···· • · • • • · • • • · · · • · · • • · · · ·

phenyl or naphthyl, each of which may be mono- to tri-substituted with a substituent such as halogen, cyano, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C 4 -alkoxy, phenoxy, C 1 -C ₄ -alkylthio, NH 1 C 1 -C ₄ -alkyl; alkyl) or N _(Ci-4 alkyl) ₂ or phenyl which can be mono- to trisubstituted by halogen, cyano, _Ci-4 alkyl, C ₁ -C ₄ -haloalkyl group, a _Ci-4 -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ alkylthio; or phenyl or naphthyl, which may be bonded to one another in the ortho position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom, or a SO ₂ , NH or N-alkyl group; C 5 -C 6 -cycloalkyl;

R ⁶ represents a C ₃ -C ₈ -cycloalkyl group, which radical may in each case be mono- to trisubstituted by a substituent such as: halogen, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C 1 -C ₄ - alkylthio, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkoxycarbonyl or phenyl which may be mono- to tri-substituted with a substituent such as halogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -haloalkyl; -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy or C 1 -C ₄ -alkylthio;

phenyl or naphthyl, each of which may be mono- to tri-substituted with a substituent such as halogen, R ¹⁵ , cyano, hydroxyl, C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C 1 -C ₄ -alkylcarbonyl, C _r C ₄ -alkoxycarbonyl, Ci-C ₄ -alkoxy, -C ₄ -halogénalkoxylová, phenoxy, -C ^ alkylthio, NH _(Ci-C4 alkyl), N (C ₂ -C ₄ alkyl) _2, dioxomethylene , dioxoethylene or phenyl, which can be mono- to trisubstituted by halogen, cyano, Ci-C ₄ -alkyl, C ₄ -haloalkyl group, a C ₁ -C ₄ -alkoxy, C ₄ - haloalkoxy or C 1 -C ₄ -alkylthio;

-15 · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 A five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or a sulfur or oxygen atom which may carry one or two halogen atoms and / or one or two of the following radicals such as is: C 1 -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethoxy, C ₁ -C ₄ -alkylthio, phenyl or phenoxy, wherein the phenyl radicals may themselves carry one to five halogen atoms and / or one to three of the following radicals: _Cl-C4 alkyl, -C ₄ -alkoxy and / or C -C ₄ -alkylthio;

R ⁷ and R ⁸ (which may be the same or different) mean:

is hydrogen, Ci-C ₄ alkyl group;

R ¹⁵ represents methyl, ethyl, methoxy or ethoxy, each bearing one of the following radicals, such as: hydroxyl, carboxyl, amino, NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ -alkyl) _2, carboxamido, or CON _(Ci-C4 alkyl) _2;

W is sulfur or oxygen.

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

R ² is trifluoromethyl, C ₁ -C ₄ -alkyl, C ₄ -alkoxy, C ₄ alkylthio, or ^CR2 is linked to ^CR12 as indicated under Z to give a 5- or 6 -member ring;

X represents nitrogen or methine;

Y is nitrogen or methine;

Z represents nitrogen or CR ¹² in which R ¹² represents hydrogen, fluoro or methyl or CR ¹² , together with CR ² or CR ³ , forms a 5- or 6-membered alkylene or alkenylene ring, in which one methylene group may be present in each optionally replaced with oxygen or sulfur such as -CH ₂ CH ₂ -S-, -CH = CH-O-, -CH ₂ -CH ₂ -S-;

at least one of the ring members X, Y or Z is nitrogen;

-16 ···························· ·· ·· · ·· ···

R ³ is trifluoromethyl, C ₁ -C ₄ -alkyl, C 1 -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio or CR ³ is attached to CR ¹² as mentioned under Z to form a 5- or 6-membered ring;

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

phenyl or naphthyl, each of which can be mono- to trisubstituted by halogen, Ci-C ₄ -alkyl, C ₄ -alkoxy, phenoxy or phenyl which can be mono- to trisubstituted by halogen, C -C ₄ -alkyl or C 1 -C ₄ alkoxy; or phenyl or naphthyl, which may be bonded to one another in the ortho position by a direct bond, a methylene, ethylene or ethenylene group or a SO ₂ group;

a cyclohexyl group;

R ⁶ represents a cyclohexyl group which may be mono- to trisubstituted with a substituent such as C ₁ -C ₄ -alkoxy, C 1 -C ₄ alkyl, halogen or phenyl, which may be mono- to trisubstituted with halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl; -C ₄ -alkoxy;

phenyl or naphthyl, which in each case may be mono- to trisubstituted by a substituent such as halogen, R ¹⁵ , C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, acetyl, C 1 -C ₄ -alkoxycarbonyl, C 1 -C ₄ -alkoxy, phenoxy, C 1 -C ₄ -alkylthio, dioxomethylene, dioxoethylene or phenyl, which may be mono- to trisubstituted by halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or C 1 -C 4 -alkylthio;

R ⁷ and R ⁸ (which may be the same or different) mean:

is hydrogen, Ci-C ₄ alkyl group;

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

R ¹⁵ is methoxy or ethoxy, each bearing one of the following radicals such as: hydroxyl, carboxyl, carboxamide or CON (C 1 -C ₄ -alkyl) ₂ ;

W is sulfur or oxygen.

The compounds of the present invention provide novel therapeutic potential for the treatment of hypertension, pulmonary high blood pressure, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebral ischemia, haemorrhage, subarachmia , atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass surgery, benign prostatic hyperplasia, ischemic renal failure or hypertension and renal failure or hypertension caused by intoxication, metastasis caused by intoxication, pancreatitis and gastrointestinal ulcers.

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

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

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

The invention further relates to combinations of endothelin receptor antagonists of formula I and agents that block the effect of VEGF (vascular endothelial growth factor). Such agents are, for example, antibodies directed against VEGF or specific binding proteins, or alternatively low molecular weight agents that can specifically inhibit VEGF release or receptor binding.

-18 · t t ···· 9

9 9 9 9999 9 99

9

999 9 99 9 999

The above combinations may be administered concurrently or sequentially. They can be used both in a simple pharmaceutical preparation and alternatively in separate preparations. The forms of administration may also be varied, for example, endothelin receptor antagonists may be administered orally, and VEGF inhibitors may be administered parenterally.

These combination preparations are particularly suitable for the treatment and prevention of hypertension and its consequences and for the treatment of cardiac insufficiency.

The invention further relates to a structural fragment of the formula. ίϊ H H,

R - C ^- C ^- W - C C Ο Τ ~

I7 Is <1

R RR f

wherein the radicals R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and W are as defined above.

Such structural fragments are useful as structural components of endothelin receptor antagonists, especially mixed endothelin receptor antagonists.

The invention further relates to endothelin receptor antagonists consisting of a structural fragment of the formula

wherein the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , W, X, Y and Z have the aforementioned meanings, covalently bonded to a group having a molecular weight of at least 40, preferably at least 77th

The good effect of the compounds may be demonstrated in the following experiments: Receptor Binding Studies

In receptor binding studies cloned human ET _A or ET _B receptor expressing CHO cells were used.

-19 ································

Preparation of membranes

ETA or _ETB receptor-expressing CHO cells were proliferated in DMEM NUT MIX F12 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 mg / ml streptomycin (Gibco, Sigma No. P0781). After 48 hours, cells were washed with PBS and incubated at 37 ° C for 5 minutes with 0.05% trypsin-containing PBS. The mixture was then neutralized with medium and the cells were collected by centrifugation at 300 x g.

To prepare the membranes, cells were adjusted to a concentration of 10 ⁸ cells / ml buffer (50 mM Tris HCl buffer, pH 4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds / constant output 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 mg protein per test. and incubated at 25 ° C with 25 µM [125 I] -ETi (ET _A 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 with 10 ⁷ M ET 1. After 30 minutes, free and bound radioligands were separated by filtration through GF / B glass fiber filters (Whatman, England) on a Skatron cell sampler (Skatron, Lier, Norway) and the filters were washed with ice-cold tris HCl buffer, pH 7.4 containing 0.2% BSA. The radioactivity trapped on the filters was determined quantitatively using a Packard 2200 CA liquid scintillation counter.

In vivo testing of ET antagonists:

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

In control animals, intravenous administration of 1 mg / kg ET1 resulted in a marked increase in blood pressure that persisted over a relatively long period.

• ········································

- X (J --··············································

Test compounds were injected intravenously (1 mg / kg) to test animals 30 minutes prior to ET1 administration. To determine ET-antagonistic properties, the blood pressure changes of the test animals were compared to the blood pressure values of the control animals.

Oral testing of mixed ET _A and ET _B antagonists:

Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) were orally pretreated with test substances. 80 minutes later, the animals were anesthetized with urethane and the cervical artery was catheterized (for blood pressure measurement) as well as the jugular vein (administration of big endothelin / endothelin 1).

After the stabilization phase, big endothelin (20 mg / kg, administered volume 0.5 ml / kg) or ET1 (0.3 mg / kg, administered volume 0.5 ml / kg) was administered intravenously. Blood pressure and heart rate were recorded continuously for 30 minutes. Obvious and prolonged changes in blood pressure were calculated as the area under the curve (AUC). To determine the antagonist effect of the test substances, the AUC of the treated animals was compared to the AUC of the control animals.

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

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

The novel compounds can be used in solid or liquid form in conventional pharmaceutical forms of administration, for example, as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, lace, solutions, ointments, creams or sprays. These are prepared in the usual manner. In this case, the active compounds may be formulated using conventional pharmaceutical excipients such as tablet binders, fillers, preservatives

-21 ··················································· Substances, tablet disintegrators, flow control agents, plasticizers, wetting agents, dispersing agents, emulsifying agents, solvents, delaying agents, antioxidants and / or propellants (cf. H. Sucker et al., Pharmazeutische [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1991). The forms of administration thus obtained usually contain the active compound in an amount of from 0.1 to 90% by weight.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis examples

Example 1

2-Hydroxy-3,3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-yl-methoxy) -propionic acid methyl ester

P-Toluenesulfonic acid (0.50 g, 0.27 mmol) was added under cooling to a solution of 2-phenyl- [1,3] -dioxolan-2-ylmethanol (1.98 g, 11.0 mmol) and methyl ester. 3,3-diphenyl-2,3-epoxypropionic (4.71 g, 13.2 mmol; HPLC purity: 71%) in anhydrous dichloromethane (100 mL) and stirred at 0 ° C for 15 min. The resulting solution was washed with sodium bicarbonate solution and the organic phase was separated and dried over magnesium sulfate. After filtering off the drying agent, the solvent was removed by distillation; the remaining crude oil (4.70 g) was reacted without further purification.

Example 2

2-Hydroxy-3,3-diphenyl-3- (2-phenyl- [1,3] dioxolan-2-ylmethoxy) propionic acid

2-Hydroxy-3- (2-phenyl) - [1,3] -dioxolan-2-ylmethoxy) -3,3-diphenyl-propionic acid methyl ester (4.60 g, crude product) was dissolved in dioxane / water 2: 1 (45 mL) and treated with sodium hydroxide (300 mg, 7.50 mmol). The mixture was heated to 40 ° C and stirred for one hour. For work-up, it was diluted with water (150 ml) and extracted twice with ethyl acetate. The aqueous phase was acidified with citric acid and extracted twice with ethyl acetate. The extracts obtained after acidification were dried over magnesium sulfate and the solvent was removed by distillation. 4.00 g of a crude oil was obtained, which was reacted without further purification.

-22Example 3

2- (4-Methoxy-6-methylpyrimidin-2-yloxy) -3,3-diphenyl-3- (2-phenyl- [1,3] dioxolan-2-ylmethoxy) propionic acid, sodium hydride (240 mg, 5.00 mmol) was added in 3 portions over 3 minutes to a solution of 2-hydroxy-3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) -3,3-diphenylpropionic acid (1.00 mmol). g, 1.62 mmol at 68% purity by HPLC) in anhydrous DMF (15 mL). The mixture was stirred for 5 minutes and then 2-methanesulfonyl-4,6-dimethylpyrimidine (421 mg, 2.00 mmol) was added portionwise. The mixture was stirred at room temperature for 16 hours. For working up, the contents of the flask were poured into ice water, then acidified with citric acid and extracted twice with ether. The organic extracts were dried over magnesium sulfate and the solvent removed by distillation. 1.75 g of an oil remained, which was further purified by flash chromatography and subsequently crystallized from ether / n-hexane. The title compound was obtained as a colorless solid (750 mg, 85% yield).

¹ H-NMR (200 MHz, CDCl ₃ ): 7.5-7.7 ppm (2H, m), 7.2-7.4 (13H, m), 6.3 (1H, s) 6.2 (1H, s), 4.2-4.4 (2H, m), 4.1 (1H, d), 3.9 (3H, s), 3.8-4 O (2H, m), 3.6 (1H, d), 2.4 (3H, s).

Example 4

2- (4-Methoxy-6-methylpyrimidin-2-yloxy) -3- (2-oxo-2-phenylethoxy) -3,3-diphenylpropionic acid

P-Toluenesulfonic acid (50 mg) was added to a solution of 2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3- (2-phenyl- [1,3] dioxolan-2-ylmethoxy) -3, Of 3-diphenylpropionic acid (600 mg, 1.11 mmol) in dioxane / water 1: 1 (20 mL) and the resulting mixture was stirred at 80 ° C for 2 h. After cooling, the mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulfate and the solvent was removed by distillation. The residue (550 mg) remaining as a residue was purified by crystallization from ether / n-hexane, then subjected to flash chromatography and crystallized again from ether / n-hexane.

····

-23 ······························ · · · · ·· · ·· · ·· ···

The title compound was obtained as a crystalline solid (163 mg, 30% yield).

¹ H-NMR (200 MHz, CDCl ₃ ): 7.2-7.9 ppm (15H, m), 6.2 (2H, s br), 5.1 (2H,

m), 3.7 (3H, s), 2.2 (3H, s).

ESI-MS: M + = 498

The following compounds were prepared analogously:

Example 5

2- (4,6-dimethylpyrimidin-2-yloxy) -3- (2-oxo-2-phenylethoxy) -3,3-diphenylpropionic acid ¹ H-NMR (200 MHz, CDCl ₃ ): 7.8 ppm (2 H, d), 7.2-7.7 (13H, m), 6.7 (1H,

s), 6.3 (1H, s), 5.2 (1H, d), 4.9 (1H, d), 2.3 (6H, s).

ESI-MS: M ^&lt; ⁺ &^gt; = 482

Example 6

3- [2- (4-bromophenyl) -2-oxo-ethoxy] -2- (4,6-dimethyl-2-yloxy) -3 ₁ 3-diphenylpropionic acid * ^1H-NMR (200 MHz, _CDCl3): 7 7 ppm (2H, d), 7.6 (2H, d), 7.2 - 7.5 (10H,

m), 6.7 (1H, s), 6.2 (1H, s), 5.1 (1H, d), 4.9 (1H, d), 2.3 (6H, s), with).

ESI-MS: M <+> = 560

Example 7

3- [2- (4-Bromophenyl) -2-oxoethoxy] -2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid 1 H-NMR (200 MHz, CDCl ₃ ): 7 7 ppm (2H, d), 7.6 (2H, d), 7.2 - 7.5 (10H,

m), 6.2 (1H, s), 6.0 (1H, s), 5.2 (1H, d), 4.9 (1H, d), 3.7 (3H, s), s), 2.2 (3H, s).

ESI-MS: M ⁺ = 576 * In the synthesis of 4-bromophenyl-substituted derivatives, boron trifluoride diethyl etherate was used in place of p-toluenesulfonic acid for final acetal cleavage.

Example 8

-24 · 4 ··· · 4 · 4 ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2-Hydroxy-3 - [(methoxymethylcarbamoyl) methoxy] -3,3-diphenylpropionic acid benzyl ester

Boron trifluoride diethyl etherate (0.10 mL) was slowly added to a solution cooled to -78 ° C, 2-hydroxy- N -methoxy- N -methylacetamide (1.19 g, 10.0 mmol) and benzylic acid ester. 3,3-diphenyl-2,3-epoxypropionic acid (3.88 g, 11.0 mmol; HPLC purity: 94%) in anhydrous dichloromethane (100 mL). The mixture was stirred for two hours, during which time it was gradually warmed to -20 ° C, and the reaction was quenched by the careful addition of aqueous sodium bicarbonate solution. The organic phase was washed with sodium bicarbonate solution and dried over magnesium sulfate. After filtering off the drying agent, the solvent was removed by distillation; The remaining crude oil (5.50 g) was reacted further without further purification.

Example 9

3 - [(Methoxymethylcarbamoyl) methoxy] -2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid benzyl ester

A solution of 2-hydroxy-3 - [(methoxymethylcarbamoyl) methoxy] -3,3-diphenylpropionic acid benzyl ester (1.35 g, crude product) was treated with potassium carbonate (365 mg, 2.64 mmol) and ice, after 10 minutes, with 2-methanesulfonyl-4-methoxy-6-methylpyrimidine (320 mg, 1.45 mmol). It was then stirred at 0 ° C for 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water, acidified with citric acid and extracted twice with ether. The combined organic phases were backwashed with water and dried over magnesium sulfate. After distilling off the solvent, a foam (1.60 g) remained, which was purified by flash chromatography followed by crystallization from ether / n-hexane to give 650 mg of the title compound.

Example 10

3- (2- (3,4-Dimethoxyphenyl) -2-oxoethoxy] -2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid benzyl ester

A one molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 mL) was added to a solution of benzyl ester 3 at room temperature at 50 ° C. _nf - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- - [- (Methoxymethylcarbamoyl) methoxy] -2- (4-methoxy) 6-methylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid (250 mg, 0.38 mmol, HPLC purity: 86%) in anhydrous tetrahydrofuran (25 mL). After stirring for 10 minutes, only partial conversion was observed, therefore a 1 molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 mL) was added dropwise again. The mixture was stirred for an additional 10 minutes, then the solvent was evaporated. The residue was taken up in ethyl acetate / ether 1: 2. After insoluble matter was filtered off, the solvent was removed by distillation and the oily residue (400 mg) was purified by flash chromatography. The title compound was obtained as a foam (125 mg, 49% yield with 95% purity by HPLC).

¹ H-NMR (400 MHz, CDCl ₃ ): 7.5-7.7 ppm (4H, m), 7.4 (2H, d), 7.2-7.3 (9H, m) 6.9 (2H, d), 6.8 (1H, d), 6.3 (1H, s), 6.2 (1H, s), 5.4 (1H, d) 5.0 (2H, m),

4.7 (1H, d), 3.9 (6H, s), 3.7 (3H, s), 2.3 (3H, s).

The compounds listed in Table I may be prepared analogously or as described in the general section.

Example 11

Receptor binding data for the compounds listed below was measured as described above in the binding assays.

The results are shown in Table 2.

Table 2

Receptor Binding Data (K-Values)

compound ET _Ä [nM] ET _B [nM] Example 4 10 114 Example 5 31 119 Example 6 18 168 Example 7 13 106 1-10 1.7 20 1-114 1.3 21

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Table 1

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-28 **

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ο about about ABOUT about ABOUT ABOUT ABOUT about ABOUT ABOUT about about about ω ABOUT about about about WHAT about about about about CD ABOUT CD CD ABOUT from from from FROM from from FROM FROM from from FROM from from from from FROM from from from FROM from from from from FROM FROM from from FROM X from from from from from from FROM from from from from from from from from FROM from from from FROM from from from from FROM FROM from from about about CM ω CM o 1 CM about about WHAT X CO x o 1 CM about x x x x o N x x x X o t CM x x x x X Q x CM X x CM T C-C x X C-F about 1 o x X Q x CN X x about about about about about about about Q about about 1 CM about about about about about ABOUT about 1 CM about about CM about from from x x X CM CM X about 1 about 1 about 1 X o X o about 1 X u (0 LL (U d) p (M X o d) Φ Me N X o d) Φ d) d) CM X o from· t o 1 o « LL Φ d> Me d) x o Me 1 ω d) p > » Me about with about with with ABOUT with WITH with with UJ UJ about with x WITH ABOUT with about about UJ ABOUT X 0) d) d) d) d> Φ Φ ABOUT d) d) d) > d) d) m d) d) >. φ Σ Φ from with Σ d) Σ Σ with x Σ with Σ Σ Σ Φ X d) d) Σ with Σ Σ ABOUT with about about about with ABOUT about about about about UJ about UJ about UI ABOUT about with x about x with with about about about UJ ABOUT x x x x x x x x x x x x x X x x x x x x x x x x x x x x x d) d) d) x x x x with x x x with x x x x x x x x x x x x x x with x x x x x > >> c J? c (D «- x > > about 1 > >. phenyl N C C C phenyl phenyl phenyl phenyl > > > >> CH x o ó d) «♦ j · d) > C d) Ύ Φ CN e-fe c d) C «? C «? c Φ • ♦ y Ύ o O O s o ž cn c d) M— > > c LL · exy > c C ·? > S O ra c 1 ΙΛΙ0 phenyl phenyl phenyl C-F C-F C-F C-F ABOUT about 1 about 1 ABOUT 1 1 Q from in 1 Q L-fei 1 x: d) * T d) 1 d) 1 d> CD CD 1 1 1 1 d) Φ Φ Φ CM 0) about > about about with c Cd Q «Cd Σ Q Ύ in * T Q Q Q Q > < WITH with with 1 with x X FROM LL c d) about 4_ > about about 1 from 1 X FROM 1 ABOUT 1 N ABOUT 1 about 1 about 1 what 4 4 4 c d) X, in xr 4 WHAT WHAT N what' IN" Ν ' LL N ^- WHAT* about Ν ' CN WHAT* CN in WHAT* CN WHAT in CN * WHAT* WHAT WHAT LL WHAT WHAT what what > » > « C £ > > C Cd C 1 U- C C C Q) 1 C Φ d) -0Me-1 N phenyl d) T ll 1 hexyl hexyl «T—> c phenyl > c H > C phenyl, phenyl phenyl > c > C (2) | To < Q > > > about about IN <D Φ IN > > > > > > and in in > >. (U v 4 c Φ C d) c d) c d) > ^ E. > u_ with LL U- with about c d) about c d) c d) C d) c d) c d) C d) c d) LL I LL I o t c Φ LLJ 1 c Φ LL WHAT LL U- U- LL ABOUT about CN WHAT Ν ' Ν ' WHAT U- N ^- LL U- U- U- LL LL U- WHAT N ' «R LL Ν ' LL Ν ' Φ Φ x X X É X x x WITH X X X X X x X X x x o N Cd X X x X X x X X X 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 about about about about about ABOUT about about about ABOUT ABOUT about about about about ABOUT about about ABOUT about (D about about ABOUT ABOUT about about about about about about about Q about ABOUT about about about about about about about about about ABOUT at about ABOUT about F about about ω about about about about about about about CN WHAT 'φ IO WHAT b- WHAT ABOUT) about T CN WHAT Ν ' and WHAT b- 00 o> about CN WHAT N · m CD 1 → WHAT CD m 1 U) T and ID 1 10 1 and and m 1 lO 1 CD WHAT 1 WHAT 1 WHAT 1 WHAT 1 what what 1 WHAT 1 WHAT 1 WHAT 1 b- 1 1 1 b- 1 h- 1 b- b- 1 b. 1 b- b-

· -29 ♦

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about ω about about about about about ABOUT about ω about about about ABOUT about it about about ABOUT what about about about about about about about about about from from from from from from from FROM from from from from from from from from from from from from from from from from from from from from from from x x x ω from from from about from from from from from from from from from about from from from from from from from from from from about from from from o 1 CM about CO x about CM about about 1 CM about CO x CO x from from x x C-F X o 1 CM CM X x at 1 x x x x x X Q CM T x X o CM X x x ω 1 about x from about about about from about about about about about about from from about about about t CM about about 1 (M about about about from about ύ about from CM X CM X CM about X about X about J- Φ p φ S 1 about Me CM about CM ABOUT Φ Φ d> d) d> x o about d) d) d) d) Φ d) Φ Φ X o about from- CH about Φ WHAT LL · Φ Φ φ > » WITH with about WITH ABOUT with WITH with with WITH with with with ABOUT with with UJ with about with 2 iii X d> 0) about d) d) d) d) d) d) d) Φ d) d) φ > Φ n LL WITH WITH > r d) x with with from WITH Φ d) WITH Ξ with with with Φ WITH Σ about T ABOUT ABOUT UJ about x x UJ with about about about about ABOUT with x x WHAT ABOUT about (0 about about about UJ x x x x from x x x x x x x x x x x x x x x X X Me x x x x x x φ -from' T x from from x x x x x x x x x x x x x x x x x x WITH x x LU x x x phenyl > > » Φ C phenyl e-phenyl > f- phenyl C le-phenyl > C hexyl phenyl jhexyl cyclohexyl > f o T3 C phenyl > Γ phenyl e-phenyl naphthyl) phenyl C CM X ω x o 1 CM X o ύ o > c M- Q. O i-OM (D ž- e-Cl Ύ CO ll > c Φ • t- e-4M c Ä > i-F-phenyl le-Cl e-fer 4 · * c (d) Q. cycle i-cycles idyll idyll ^: enyl c ·? d) letylé opylf stylfei □ OC i-OM Φ 1 o T o o z Φ ** - CO UL n. Q Φ o 4-F about > WITH C > Q about WITH WITH cyclo φ u_ > U.> about with from · L. £ L Φ C) φ Q 1 Φ ABOUT about .J. 't <: about LU ABOUT u. c d) xr > ABOUT WITH ABOUT about. Q. F WHAT 4 <: WITH 4 CXJ with about about WHAT WHAT what 4 WHAT n 4 U- what about what XT ω xr xr CXI WHAT CXJ what xr WHAT what WHAT WHAT XT xr phenyl ·? about > > 1 > phenyl • phenyl > C phen > Φ M- c Q) > > Φ Ύ > > > > > c d) c d) > > > C d) > > < > > Φ > » > » >. φ Φ > d> in Ύ with C C with C C C C C C C with || 11 C C C 1 I C C C C what 1 C C C C C about u. 0) 0) d) d) d) d) d) d) d) 1 1 | φ d) Φ 1 d) Φ d) Φ d) Φ Φ Φ Φ 1 xr LL U- CM LL LL LL LL LL LL LL CXJ XF XT LL U- U- XT U- ll LL LL xr U- LL LL LL LL WHAT d> about from X x X X X WITH X X X X x X x X N x x x X X X x x X X X X X ABOUT about about about about about ABOUT about ABOUT about about ABOUT ABOUT ABOUT about (0 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 ABOUT about Φ 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 ABOUT about 1- ABOUT ABOUT ABOUT about about about about ABOUT ABOUT about about about about about in- CXI WHAT xt m CD N- oo about IN" CM WHAT ID CD F WHAT CD about CXI what XT uo CD L'- 00 CD about about Q about about about ABOUT about about WHAT 1 00 1 oo 1 OO 1 00 1 WHAT 1 00 oo f 00 1 00 1 σ> t σ> 1 9 0> 1 about 1 0) 1 ABOUT) 1 CD - Φ 1 σ> 1 V “f 1 1 1 1 1 1 1 T “f

· -30 »

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about ω about about about about about about about about about ω about about about about about about about about about about about about from from from from from from from from from from from from from from from from from from from from from from from from x x from from from from from from from from from from about about from from from from from from from from from from from from WHAT I about 1 CM ω what x CO x about CM about ω x x x X o 1 CM x CM X o Q x x about x x X Q x CM X x x x x x ύ about about about about about about about from from about about about 1 CM about about about about about at from about (D Φ p Φ Φ X o CM X o Φ CM X o 1 o Φ Φ Φ p CO LL X o 1 CM X o Φ CM x o 1 ω Φ Φ Φ Φ w (ABOUT x o FROM about with with with here with x with about x x about with with with with with from x Φ Φ Φ Φ φ with Φ CM CO x Φ (L WHAT LL Φ Φ with Φ Φ Φ with with Σ Φ Σ Φ about with x x with about with with about with with x with about about x about x with about UJ with with m from about Φ Φ φ x x with with x x x x x x x x x x x x x WITH x x x x x x (D Φ φ Φ Φ x x with with x x x x x x x x x x x x x WITH x with x x x with > < > > > e-fen e-fen phenyl phenyl phenyl phenyl phenyl phenyl le-fer phenyl > < > > c snyl le-fer > c S O phenyl > c S O > c > c v o ** T ô -r o about 1 about about 1 WITH *>. Q. ž ¹ s WHAT M ^- C Ä > 4? step LI l (D 1 0) Φ 1 1 1 Φ φ Φ φ ABOUT Φ u_ U- Φ 1 ro (0 Q from* Ύ Q in in Q Q Q with WITH with WITH Q_ with Φ υ ABOUT WITH c Φ Q from from 4 LU ω 1 N about 1 about what · Μ _ 4_ 'sr ABOUT 1 about 1 $ ABOUT ljj ABOUT 1 LL 1 L. Φ 4 CN WHAT WHAT CM WHAT WHAT in cn what what what what WHAT WHAT Ν ' M what N WHAT WHAT Ν ' LL what > > inyl, phenyl Cl-fen > > phenyl > c phenyl Me-fen snyl r H l-phenyl phenyl phenyl > l-phenyl WITH £ -'t C Φ C Φ 0) 4? LL 1 ABOUT 4f 0) about 1 V φ Ί Φ C Φ at 1 C .c. Φ x: Φ > > 4 >. > with <0 LL Q Ý > Φ Φ Q >> UJ 'V § WITH U- Q about about Φ c Φ c Φ c d) ϋ about c Φ c Φ about ABOUT LL UJ with with 4_ C Φ U- ω about ABOUT N; > > ? LL u. U- n- M · U- LL WHAT M · WHAT WHAT M ^- CN CM what LL M ^- M ^- WHAT M ^- what ABOUT ABOUT WHAT X x x x X x Ô N X X x X X X X x X X X X X X x X x ABOUT ABOUT ABOUT about ABOUT about (C about ABOUT ABOUT about ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT ABOUT about ABOUT about about ABOUT about ABOUT ABOUT about about ABOUT <D about about ABOUT about about about about ABOUT about about about about about about about about ABOUT about ABOUT ABOUT about about ABOUT h- about about ABOUT about about about about about about about about about about about about about ABOUT cn about CM cn M ^- m WHAT b- WHAT ABOUT) about CM WHAT N LD WHAT b- 00 OT about y- CN about t T IN" CM CN CN CN CN CN CN CN CN CN what WHAT WHAT in X " 1 1 1 in 1 1 F 1 in 1 1 1 1 1 1 1 ^ 7 1 1 1 1 IN" 1

Claims (11)

A carboxylic acid derivative of the formula I * in which the substituents have the following meanings: L ^R1 is tetrazolyl or a group of II c ^- R R represents (a) an OR ⁹ radical in which R ⁹ represents 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 ₈ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, CH ₂ -phenyl or phenyl, each of which is optionally substituted; b) a 5-membered heteroaromatic ring which is bonded via a nitrogen atom; (c) the group 'F ¹¹ 10' O '(CH ₂ ) p -S' R in which k may be 0, 1 or 2, p may be 1, 2, 3 or 4 and R ¹⁰ is C 1 -C ₄ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl or optionally substituted phenyl; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · d) the remainder fl u -ys- ^R o * wherein R ¹¹ is C 1 -C ₄ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, which radicals may carry C ₁ -C ₄ -alkoxy, C 1 -C 4 -alkylthio and / or a phenyl residue; phenyl which may be optionally substituted; R ² is hydrogen, hydroxyl, NH ₂ , NH (C 1 -C ₄ -alkyl), N (C 1 -C ₄ alkyl) ₂₁ halogen, C 1 -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ C ₄ -alkynyl, C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, -C ₄ -halogénalkoxylovú group or a _Ci-C4 alkylthio, or ^CR2 is linked to R ¹² as provided below, to form 5- or A 6-membered ring; X is nitrogen or methine; Y is nitrogen or methine; Z is nitrogen or CR ¹² in which R ¹² represents hydrogen or C 1 -C 4 alkyl, or CR ¹² , together with CR ² or CR ³ , forms a 5- or 6-membered alkylene or alkenylene ring, which may be optionally substituted, and wherein one or more methylene groups may each be replaced by oxygen, sulfur, -NH or N (C 1 -C 4 alkyl); R ³ is 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, C 1 -C ₄ -haloalkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -haloalkoxy, C 1 -C ₄ -alkylthio; or -33 ··· ······· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· · ·· · ·· ··· CR ³ is bonded to CR ¹² 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, each of which may be optionally substituted phenyl or naphthyl, which are bonded to one another in the vorto position through a direct bond, a methylene, ethylene or ethenylene group, an atom oxygen or sulfur or by SO ₂ , NH or N-alkyl t; C ₃ -C ₈ -cycloalkyl optionally substituted; R ⁶ represents an optionally substituted C ₃ -C ₈ -cycloalkyl group; phenyl or naphthyl, which is optionally substituted; a five- or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or a sulfur or oxygen atom which may be optionally substituted; R ⁷ and R ⁸ (which may be the same or different) represent hydrogen or C 1 -C 6 -alkyl; W represents sulfur or oxygen. Pharmaceutical preparation, characterized in that it contains at least one carboxylic acid derivative of the formula I according to claim 1. * · Use of carboxylic acid derivatives 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 the carboxylic acid derivatives of the formula I according to claim 1 for the preparation of medicaments for the treatment of diseases in which elevated levels of endothelin occur. Use according to claim 5, for the treatment of chronic cardiac insufficiency, restenosis, high blood pressure, pulmonary high blood pressure, -34 · ············································· ··· acute / chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer. A pharmaceutical combination comprising a carboxylic acid derivative according to claim 1 and a renin-angiotensin system inhibitor or a mixed ACE / neutral endopeptidase (NEP) inhibitor or a β-blocker. Use of a compound of formula IV 8 4 R ^- C ^- C ^- W - CC - OH (IV), I7 I s11 R RR wherein the residues R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and W have the meanings given in claim 1 as intermediates in the synthesis of endothelin receptor antagonists. Use of a structural fragment of the formula wherein the residues R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and W have the meanings set forth in claim 1 as a structural component of an endothelin receptor antagonist. 10. Use of a structural fragment of the formula 4th A compound of formula VIa wherein the residues R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , W, X, Y and Z have the meanings set forth in claim 1 as a structural component of an endothelin receptor antagonist. (VIa) wherein the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , W, X, Y and Z are as defined in claim 1 and R ¹⁸ and R ¹⁹ have the following meanings R ¹⁸ and R ¹⁹ (which may be the same or different) mean C 1 -C ₄ -alkyl or R ¹⁸ , together with R ¹⁹ , form an ethylene or propylene bridge, which may be optionally substituted with one to four methyl groups.