CZ220699A3

CZ220699A3 - Derivatives of heterocyclic carboxylic acid, process of their preparation and use as endothelin receptor antagonist

Info

Publication number: CZ220699A3
Application number: CZ19992206A
Authority: CZ
Inventors: Wilhelm Ambert; Rolf Jansen; Andreas Kling; Dagmar Klinge; Hartmut Riechers; Stefan Hergenröder; Manfred Raschack; Liliane Unger
Original assignee: Basf Aktiengesellschaft
Priority date: 1997-12-04
Filing date: 1997-12-04
Publication date: 2000-02-16

Description

F ΖΟ ΖΟ »♦ ♦ · i i i i i i i i i i i

Heterocyclic Carboxylic Acid Derivatives, Process for their Preparation and Use as Endo- Antagonists.

X thelin receptor

Technical field

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

BACKGROUND OF THE INVENTION

Endothelin is a peptide consisting of a total of amino acids up to 21, which is formed and released by vascular endothelin. Endothelin exists in three iso-forms, ET-1, ET-2 and ET-3. In the following, endothelin or ET means one or more endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong vascular tone effect. The binding of endothelin to its receptor is known to cause this vasoconstriction [Nature 332. 411-415 (1988), FEBS Letters 231, 440-444 (1988), and Biochem. Biophys. Res.

Commun., 154, 868-875 (1988)]. w

Increased or abnormal endothelin release causes persistent vascular contraction in peripheral, renal and cerebral vessels, which may cause disease. As reported in the literature, endothelin is involved in a number of diseases. These diseases 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. Copper. Association 264. 2868 (1990), Nature 344. 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. Nos. 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 in the literature are described in the literature: · · · · · · · · · · · · · · · · · · · · · · · endothelin receptor subtypes, ETA receptors and β [β [Nature 348. 730 (1990), Nature 348, 732 (1990)]. Accordingly, endothelin binding agents at either of these receptors or at both receptors should exhibit antagonistic effects on the physiological effects of endothelin and should therefore be useful as drugs. in

SUMMARY OF THE INVENTION It is an object of the present invention to provide endothelin receptor antagonists that bind to ETA and / or ΕΤβ receptors.

The present invention relates to a carboxylic acid derivative. the formula XY CH-I ° -c 1 N = Z R 1 (I) R 2 is a tetrazole group or O < 1 >

II

c —R in which R has the following meanings: a) OR 1, in which R 6 is: a hydrogen atom, an alkali metal cation or an alkaline earth metal cation, a physiologically tolerable organic ammonium ion such as a tertiary C 1 -C 4 alkylammonium ion or an ammonium ion, a C 3 -C 8 cycloalkyl group, a C 1 -C 10 alkyl group, a benzyl group which may be substituted by at least one of a halogen atom, a nitro group, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkyl group haloalkyl group, hydroxyl group, C 1 -C 4 alkoxy group, mercapto group, C 1 -C 4 alkylthio group, amino group, ((C 0 -C 4 alkyl group), alkyl group) 2 # c 3 C 8 alkenyl group or C 3 -C8 alkynyl, and these groups may carry one to five halogen atoms, R6 may further be a phenyl group which may carry one to five halogen atoms and / or one to three of the following groups: nitro, cyano, C1-C4 alkyl , C1-4 haloalkyl, hydroxyl, C1-4 C4 alkoxy, mercapto, C1-4 alkylthio, amino, NH4C1-6alkyl, N1C1-C4alkyl, b) 5-membered heteroaromatic attached by a nitrogen atom such as a pyrrole group, a pyrazolyl group, an imidazolyl group or a triazolyl group which may carry one to two halogen atoms, one to two C 1 -C 4 alkyl groups, or one to two C 1 -C 4 alkoxy groups. 4 c) group k O (CH 2) p S - R 7 where k is 0,1 and 2, p is 1, 2, 3 and 4 and R 7 is%

C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkenyl, C 3 -C 8 alkenyl or phenyl which may be substituted by one or more, e.g. one or three of the following substituents: 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; NH1C1-6 alkyl, N (C1-C4 alkyl) 2 d)

II. —NH — R8 I! op in which R °] e:

C 1 -C 4 alkyl group; A C 3 -C 8 alkenyl group, a C 3 -C 8 alkynyl group, a C 3 -C 8 cycloalkyl group, and these groups may bear alkoxy-h%

a C 1-6 alkylthio group and / or a phenyl group as mentioned under c), c 14 a haloalkyl group or an unsubstituted or substituted phenyl group, in particular as referred to under c). - 5 - • f · · ·. · · · · · · · · · · · · · ·

Other substituents have the following meanings: X is a nitrogen atom or a methine group provided that when X is a nitrogen atom, then Z is a nitrogen atom and if X is a methine group then at least one of the Y or Z ring members is a nitrogen atom, Y is a nitrogen atom or CR, z is nitrogen or CR10 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and each may be monosubstituted or polysubstituted by halogen, a hydroxyl group, a mercapto group, a carboxyl group, a cyano group, an amino group, a C 1 -C 4 alkoxy group, a hydrogen atom, a halogen atom, a C 1 -C 4 alkoxy group, a C 4 -C 4 haloalkoxy group, a C 3 -C 8 alkenyloxy group, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C (C 1-4 alkyl), N (C 1 -C 4 alkyl) 2, hydroxyl, carbonyl a group, a cyano group, an amino group, a mercapto group; CR 2 together with CR 1 or CR 1 ® form a five- or six-membered alkylene or alkenylene ring which may be substituted by one or more C 1 -C 4 alkyl groups and in each case one or more methylene groups may be replaced by an oxygen atom, a sulfur atom, an NH group or CC - ^ ^ ^ j))))) )· · · ·· •ffffffffffffffffffffffffffffffffffffff · · · ·· · · · 4· 4· 4 4· 9 ♦% ft - 6 - R 3 and R 4 (which may be identical or different) are: phenyl or naphthyl, which may be substituted by at least one of halogen, nitro, cyano, hydroxy , mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkenyl, haloalkyl,

C 1 -C 4 alkoxy, phenoxy, C 1 -C 4 halo-alkoxy, alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 or phenyl which may be monosubstituted or polysubstituted, for example, monosubstituted to trisubstituted by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 0 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio, or phenyl or naphthyl a group which is linked to each other at the ortho position by a direct bond, a methylene group, an ethylene group, or an ethenylene group, an oxygen atom or a sulfur atom, or a SO 2 -, NH- or N-alkyl group, a C 3 -C 8 cycloalkyl group, and these the groups may in each case be monosubstituted or poly-substituted with a halogen atom, a hydroxyl group, a mercapto group, a carboxyl group, a nitro group, a cyano group, a C 1-6 alkyl group, a C 2 -C 4 alkenyl group R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 alkenyl or C 3 -C 8 alkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkoxy, alkynyl, and each of these groups may be monosubstituted or polysubstituted by a halo atom, a hydroxy group, a mercapto group, a carboxyl group, a nitro group, an amino group, a cyano group, a C 1 -C 4 alkoxy group, a C 3 -C 8 alkenyloxy group, a C 3 - A C 8 alkynyloxy group, a C 1 -C 4 alkylthio group, a C 1 -C 4 haloalkoxy group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 alkoxy-carbonyl group, a C 3 -C 8 alkylcarbonylalkyl group, an NH group (C 1 -C 4 alkyl), N < 1 > C 1 -C 4 alkyl) 2 / C 3 -C 8 cycloalkyl, heteroaryloxy or heteroaryl, which is 5-membered or 6-membered and contains one to three nitrogen and / or sulfur atoms or an oxygen atom, a phenoxy group or a phenyl group; bý monosubstituted or polysubstituted, e.g. monosubstituted to trisubstituted by halo, hydroxy, 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, N, N, C 1 -C 4 alkyl, C 1 -C 4 -C 1-6 alkyl, 2 or C 1 -C 4 alkylthio, phenyl or naphthyl, each of which may be substituted with one or more of the following: halogen, a nitro group, a cyano group, a hydroxyl group, an amino group, a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkoxy group, a phenoxy group, a C 1 -C 4 -halo group; alkylthio, C1-6-alkylamino, C1-C4 dialkylamino, dioxymethylene or dioxyethylene;

- an 8 - or 5 - membered heteroaroroatic group containing one to three nitrogen and / or sulfur atoms or an oxygen atom that can carry one to four atoms halogen and / or one to two of the following: C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, alkoxy, C 1 -C 4 haloalkoxy, (C 4 -C 4 alkylthio, phenyl, phenoxy or phenylcarboxy) the carbonyl group and the phenyl groups may carry one to five halogen atoms and / or one to three of the following groups: a-C 1-4 alkyl group, a C-O-O 4 haloalkyl group, a C 1-4 alkoxy group, a C 1-4 -O 4 haloalkoxy and / or C 1-4 alkylthio, C 3 -C 8 cycloalkyl, which may be monosubstituted or polysubstituted by halogen, hydroxyl, mercaptosulfone, carboxyl, nitro, cyano, (C 4 -C 4 alkyl, C 2 -C 4) alkenyl, C 2 -C 4 alk C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, Q 1 R 4 and R xu (which may be the same or different) are: hydrogen atom, halogen atom, C 1-4 alkoxy group, cl_c4 haloalkoxy group , A C 3 -C 8 alkenyloxy group, a C 3 -C 6 alkynyloxy group, a C 1 -C 4 alkylthio group, a C 1 -C 4 alkylcarbonyl group, a C 1 -C 4 alkoxy-carbonyl group, an amino group, an NH group (C 1 -C 4 alkyl), a group N (C 1 -C 4 alkyl) 2 , A C 1 -C 4 alkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group and these groups may be substituted by a halogen atom, a hydroxyl group, a mercapto group, a carboxyl group, a cyano group; Or when CR9 or CR10 is attached to CR2, as shown for R2, with the provision of a five or six membered ring, W is a sulfur atom, an oxygen atom or a single bond, Q is an oxygen atom, or a nitrogen atom, with the proviso that when Q is nitrogen, then W is j simple bond. In this context, the following definitions apply: alkali metal is, for example, lithium, sodium potassium, alkaline earth metal such as calcium, magnesium, barium, organic ammonium ions are protonated amines such as ethanolamine, diethanolamine, ethylenediamine, diethylamine or piperazine, a C 3 -C 8 cycloalkyl group is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group, a C 1 -C 6 haloalkyl group may be linear or branched, such as a fluoromethyl group, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl a group, 2,2-dichloro-2-fluoroethyl, 2,2,2 trichloroethyl or penta-fluoroethyl group, - 10 - - 10 - • ·· · · • t • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · T ··· ···

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- chloro-1,1, 2-trifluoroethoxy, 2-fluoro-ethoxy or pentafluoroethoxy, C1-C4 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, C2-C4 alkenyl may be linear or branched, such as ethenyl, 1-propene-3 -yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl, C2-C4 alkynyl may be linear or branched, such as ethynyl, 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl or 2-butin-4-yl, C1-C4 alkoxy may be linear or branched, e.g. methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy,

The C 5 -C 8 alkenyloxy group may be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy, for example. - 11 - C 3 -C 6 alkynyloxy * - · - · · · · · · · · · · · · · · · · · · it may be linear or branched, such as 2-propin-1-yloxy, 2-butin-1-yloxy or 3-butin-2-yloxy, C1-C4 alkylthio may be linear or branched, such as methylthio ethylthio, propylthio, 1-methylethylthiosulfonyl, butylthio, 1-methylpropylthio, 2- methylpropylthio or 1,1-dimethylethylthio, cl_c4 alkylcarbonyl may be linear or branched, such as acetyl, ethylcarbonyl a group or a 2-propylcarbonyl group,

The C 1 -C 4 alkoxycarbonyl group may be linear or branched such as a C 1-4 alkoxycarbonyl group. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or n-butoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl may be linear or branched, e.g. 2-oxoprop-1-yl, 3-oxobut-1-yl a group or a 3-oxobut-2-yl group

The C 1 -C 8 alkyl group may be linear or branched, such as, for example, a C 1 -C 4 alkyl group, a pentyl group, a hexyl group, a heptyl group, or an octyl group, a C 3 -C 8 alkenyl group may be linear or branched such as e.g. 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-buten-4-yl, 2-butene-3 -yl group, 1-penten-5-yl group, 1-hexen-6-yl group, 3-hexen-6-yl group - 12 - ·· ·· · · · · · · · · · · · · · · · · · · · · · · · ·. The group, 2-hepten-7-yl or 1-octene-7-yl or 1-octene- The 8-yl group, the C3-C8 alkynyl group may be linear or branched, such as 1-propin-1-yl, 1-propin-3-yl, 1-butin-4-yl, 2-butyne -4-yl, 2-pentin-5-yl, 3-hexin-6-yl, 3-heptin-7-yl, 2-octin-8-yl, halogen is e.g. chlorine, bromine, iodine.

The invention further relates to those compounds from which compounds of formula I (prodrugs) 1 can be released

Preference is given to those precursors for which the release takes place under conditions that are predominant in a particular compartment of the body, e.g., in the stomach, in the blood vessel, in the bloodstream, in the liver.

Compound I and also intermediates for its preparation, such as compounds II, III, IV and V, may have one or more asymmetrically substituted carbon atoms. Compounds of this type may be present as pure enantiomers or pure diastereomers or as a mixture thereof. It is preferred to use the pure enantiomer as the active compound.

The invention further relates to the use of the above-described carboxylic acid derivatives for the preparation of medicaments, in particular for the preparation of ET 1 and / or ETg receptor inhibitors. The compound of the invention is useful as an antagonist as defined in the introduction. 13 ♦ · · · · Ψ ·%%% ♦ ♦ · · 9 9 9 9 9 9 9 · · · · · · The preparation of a compound of formula XV in which W is a sulfur atom or an oxygen atom and Q is an oxygen atom (IVa) may also be carried out in enantiomerically pure form as described in WO 96 / 11914. R4 / 'V * 1 c - + RS-W_H-R5-W-C-CH-OH / R3 j 1 R3 R1 (II) (III) (IVa)

The compound of formula (III) is either known or may be prepared, for example, by reduction of the corresponding carboxylic acid or ester thereof, or by other generally known methods (

A compound of formula IV wherein W is a single bond and Q is an oxygen atom (VIb) can be prepared in both racemic and enantiomerically pure form as described in DE 19614533.3. R4 R4

II

R5-C CH-O-R5 C-CH-OH

• I II R3 R3 R1 (V) (IVb)

On the other hand, compounds of formula IV wherein W is a single bond and Q is a nitrogen atom (IVc) can be prepared in racemic and enantiomerically pure form as described in DE 19536891.6.

R5 COOEt R4 / 1 C / = c R5 C-CH - NH ii R3 NC! i. R3 Ri (VIc) (IVc)

The compound of the invention in which the substituents of the formula I are as described can be prepared, for example, by reacting a carboxylic acid derivative of the formula IV wherein the substituents are as defined for the compound of the formula VII.

(VH) In formula VII, R 11 is a halogen atom or R 12 -SO 2 - in which R 12 may be a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group or a phenyl group, and for X, Y and Z applies the conditions described in the introduction. 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 the deprotection of intermediate (IV) ranging from room temperature to the boiling point of the solvent.

Further, a type I compound wherein R 1 = COOH can be obtained directly when intermediate IV, wherein R 1 is COOH, is deprotonated with two equivalents of a suitable base and reacted with a compound of formula V. Here, the reaction also occurs in an inert solvent and within the temperature range from room temperature to the boiling point of the solvent. Examples of solvents or diluents of this type are aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be free or chlorinated, such as hexane, cyclohexane, petroleum ether, naphthalene, benzene, toluene, xylene, metnylene chloride, chloroform , carbon tetrachloride, ethyl chloride and trichlorethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as e.g. dimethylformanide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethylsulfoxide and sulfolane.

Compounds of formula VII are well known, in some cases are commercially available or can be prepared by any of the generally known methods [e.g., a method similar to that described in J. Org. 52, 4280 (1987)].

The base used may be an alkali metal hydride or an 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, a hydroxide of an alkali metal or some metal alkaline earth metal such as sodium hydroxide or potassium hydroxide, some organometallic compound such as butyllithium or a salt of an alkali metal with an amide such as lithium diisopropylamide or lithium amide.

A compound of formula (I) may also be prepared using a carboxylic acid, i.e., a compound of formula (I), wherein R 1 is a carboxyl group and first converting the compound to an activated form, such as an acid halide, anhydride or imidazolide, 16 s by subsequent reaction of the compound with the appropriate hydroxyl compound HOR7. This reaction can be carried out in conventional solvents and often requires the addition of a base where the above-mentioned bases are suitable. These two steps can also be simplified, e.g. by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide. Further, a compound of formula I may also be prepared using salts of the corresponding carboxylic acid starting material, i.e., compounds of formula I wherein R 1 is COR and R is OM, wherein M may be an alkali metal cation or equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds, generally. of formula RA wherein A is a conventional nucleofugid leaving group, e.g., a halogen atom such as a chlorine atom, a bromine atom, an iodine atom or, if desired, an aryl or alkylsulfonyl group substituted by a halogen atom, an alkyl group or a haloalkyl group such as e.g. a toluenesulfonyl group and a methylsulfonyl group or another equivalent leaving group. A compound of formula RA having a reactive substituent A is known or can be readily obtained using general knowledge. This reaction can be carried out in conventional solvents and is preferably carried out with the addition of a base, wherein the above-mentioned bases are suitable for this purpose.

A compound of formula I wherein R 1 is a tetrazole group may be prepared as described in WO 96/11914. 17

· · · · · · · · ·

Due to the biological action, derivatives of the formula I are preferred as pure enantiomers

as pure diastereomers or in which the substituents have the following meanings: X is a nitrogen atom or a methine group, provided that when X is a nitrogen atom, then Z is a nitrogen atom, and if X is a methine group, then at least one of the members ring Y or Z is nitrogen, Y is nitrogen or CR 9, Z is nitrogen or CR 10, R 2 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl ... and each of these groups it may be monosubstituted to trisubstituted by halogen atom, hydroxyl group, mercaptosulfone, hydrogen atom, halogen atom, C1-4 alkoxy group, C1 -C4 haloalkoxy group, C1 -C4 alkylthio group, alkoxycarbonyl group, NH4 C1 -C4 alkyl group ), an alkyl) 2 / hydroxyl group, or R 2 together with CR 9 or CR 8 · R 5 forms a five membered alkylene or alkenylene ring which may be substituted by one or two C 1 -C 4 alkyl groups and wherein in each case one or more methylenes In the case of certain groups, the oxygen atom, the sulfur atom, the -NH group, or the N (C 1 -C 4 alkyl) group, R 2a and R 6, which may be the same or different, are: - 18 - · · ···· · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Phenyl or naphthyl, and these may be monosubstituted to tri-substituted with halogen, cyano, hydroxyl, C1-C4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4- C 4 haloalkoxy, C 1 -C 4 alkylthio, amino, NH 3 C 1-6 alkyl, N (C 1 -C 4 alkyl) 2, or phenyl which may be monosubstituted to trisubstituted by halogen, nitro, cyano, C 1 -C 4 C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, halo alkoxy or -C 4 alkylthio, or phenyl or naphtha In each of these groups, the group which binds to each other at the ortho position by a direct bond, a methylene group, an ethylene group, or an ethylene group, an oxygen atom or a sulfur atom, or a SO 2 -, NH- or N-alkyl group. C 8 -C 8 cycloalkyl monosubstituted to tri-substituted with halogen, hydroxyl, mercapto, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1-4 alkylthio, C 1 -C 4 haloalkoxy, is hydrogen , C 1 -C 8 alkyl, C 8 -C 8 alkenyl or C 8 -C 8 alkynyl and each of these groups may be monosubstituted to trisubstituted by halogen, hydroxyl, mercapto, carboxy, amino, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, 19 19

C 1 -C 4 haloalkoxy, (C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl,

NH (C 1 -C 4 alkyl) alkyl, C 3 -C 8 cycloalkyl, heteroaryloxy or heteroaryl, 5 or 6-membered containing one to three nitrogen atoms and / or sulfur or oxygen atom, phenoxy or phenyl group wherein said aryl radicals may be mono-substituted or trisubstituted by halogen, hydroxyl, mercapto > cyano, (C 1 -C 4 alkyl, (C 1-4) haloalkyl, (C 1-4 alkoxy, C 2-4) haloalkoxy, (C 1-4 alkylthio by NH 4 C 1-4 alkyl) or N (C 1 -C 4 alkyl) 2, phenyl or naphthyl, which in each case may be monosubstituted to trisubstituted by: halogen, cyano, hydroxyl, amino, α-alkyl, 0-40 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 2 -C 4 alkyl), 11 ((C 1-4 alkyl) dioxymethylene or dioxyethylene, 5 or 6 membered heteroaromatic a group containing one to three nitrogen atoms and / or a sulfur or oxygen atom which may carry one to four halogen atoms and / or one to two of the following groups: C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group, alkoxy group, C 1 -C 4 alkyl group C4 haloalkoxy, CL-C4 a th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th th The 20-nyl group and the phenyl groups may carry one to five halogen atoms and / or one to three of the following. C 1 -C 6 alkyl,

C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and / or C1-C4 alkylthio, C3-C8 cycloalkyl and these may in each case be monosubstituted to tri-substituted with halogen , a hydroxyl group, a mercaptopine, a C 1 -C 4 alkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylthio group, a C 1 -C 6 alkyl group, halbalkoxy, R 9 and R 10 (which may be the same or different) are: hydrogen, halogen, C 1 -C 4 alkoxy, haloalkoxy, alkylthio, -C 4 alkylcarbonyl, C 1 -C 4 alkoxy-carbonyl, amino, NH ( C 1 -C 4 alkyl, N 1 -C 4 alkyl, 2, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, c 2 -C 4 alkynyl, and these groups may be substituted by halogen, hydroxyl, mercapto, cyano or to connect CR9 or CR10 to CR2 as shown for R 2, with a 5-membered or 6-membered ring, W is a sulfur atom, an oxygen atom or a single bond, Q is an oxygen atom or a nitrogen atom, provided that when the nitrogen atom is W, it is a single bond.

Particularly preferred compounds of formula I in the form of pure enantiomers and pure diastereomers or mixtures thereof are those whose substituents have the following meanings: X is a nitrogen atom or a methine group provided that when X is a nitrogen atom then Z is the nitrogen atom and Y is CR 9 and if X is a methyl group, then Y is a nitrogen atom and Y is a group or Y is a group CR 9 and Z is a nitrogen atom, Y is a nitrogen atom or CR 9 Z is a nitrogen atom or a group CR 1, R is C 1-4 -alkyl, trifluoromethyl, hydrogen, fluoro, C 1 -C 4 alkoxy, trifluoromethoxy, alkylthio, or CR 3 together with CR 9 or CR 10 form a 5 or 6 membered an alkylene or alkenylene ring which may be substituted with one or two C 1 -C 4 alkyl groups, wherein in each case one or more methylene groups may be replaced by an oxygen or sulfur atom, R 3 and R 4 (which may are identical or different) are: phenyl or naphthyl, which may be substituted by one or more of halogen, cyano, C1-C4 alkyl, trifluoromethyl, C1-4 alkoxy, trifluoromethoxy, C1-6 alkoxy C 1-6 alkylthio or phenyl group which - 9 · 9 e ·

it may be monosubstituted to trisubstituted by halogen, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkoxy or C 1 -C 4 alkylthio or phenyl or naphthyl, which are attached in ortho position by direct bond, methylene, ethylene or ethoxy the alkylene group, a C 5 -C 6 cycloalkyl group which may in each case be monosubstituted to a trisubstituted: a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylthio group, R 5 is a hydrogen atom, C 1-6 alkyl group. C 1 -C 8 alkyl, C 3 -C 8 alkenyl or C 3 -C 8 alkynyl, each of which may be monosubstituted or trisubstituted by: halogen, hydroxyl, mercapto, carboxy, cyano, amino, C 1 -C 4 alkoxy , C 1 -C 4 alkylthio, C 1 -C 4 alkoxycarbonyl, NH (C 1 -C 4 alkyl), N 1 -C 4 -C 1-4 alkyl) 2, C 3 -C 8 cycloalkyl a five- or six-membered group containing one to three nitrogen atoms and / or a sulfur or oxygen atom, a phenoxy group or a phenyl group, and each of said aryl groups may be monosubstituted to a trisubstituted by a halogen atom, a cyano group, a hydroxyl group, C 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 or N (C 1 -C 4 alkyl) 2 >

F v ', - :: · · · · · · · · ·. ♦ · * · '"···.' * · #. -..... ¥ f -! · Ψ-- · ·

Phenyl or naphthyl, which may in each case be monosubstituted to tri-substituted by halogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy, C1-C4 a haloalkoxy, phenoxy, alkylthio, dioxomethylene or dioxoethylene group # a five-membered or six-membered heteroardmatic compound containing one to three nitrogen atoms and / or a sulfur or oxygen atom that can carry one to four halogen atoms and / or one to three . . . , from the following groups: alkyl, trifluoromethyl, (1-4C alkoxy, C1-C4 alkylthio, phenyl, phenoxy, and each of the phenyl groups may carry one to five halogen atoms and / or one to three of the following groups: a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a C 1 -C 4 alkylthio group, a C 3 -C 8 cycloalkyl group, and each of these groups may be monosubstituted to a trisubsubstituted halogen atom, (C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, C 1-4 -O 4) alkylthio, R 9 and R 10 (which may be the same or different) are: trifluoromethyl, trifluoromethoxy, hydrogen, C 1 -C 4 alkoxy, C 1-4 alkylthio, NH (C 1 -C 4 alkyl) C1-4 (C1-4 alkyl) 2, C1-4 alkyl, vinyl, or CR9 or CR10 are attached to CR2, as defined for R, to give a 5- to 6-membered ring, w is a sulfur atom, an oxygen atom or a single bond Q is an oxygen atom or a nitrogen atom, provided that when Q is a nitrogen atom, then W is a single bond. EXAMPLES Preparation Examples

For the preparation of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and 2-hydroxy-3,3-diphenylbutyric acid see WO 96/11914 and DE 19614533.3. Example 1

2- (6-Methylpyridazin-3-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-517), 3 g (4.8 mmol) of 2-hydroxy-3-methoxy-3, 3 diphenylpropiones dissolved in dimethylformamide are added dropwise to a suspension of 0.43 g of sodium hydride (14.3 mmol, 80% suspension in white oil) in dimethylformamide. After stirring at room temperature for 30 min, the mixture was treated with 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine in 10 ml dimethylformamide and stirred overnight at room temperature. To complete the reaction, 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine is added again and the mixture is maintained at 600C for 5 h. Next, the mixture is poured into ice water, extracted three times with ethyl acetate, pH of the aqueous phase. was adjusted to 2 with concentrated hydrochloric acid diluted 1: 1 and the deposited precipitate was extracted with ethyl acetate. The ethyl acetate phases were dried over magnesium sulfate and then filtered and the solvent was distilled off under reduced pressure. 800 mg of a brown residue (1.19 g) was purified by MPLC chromatography to give 198 mg of the desired product as a white solid. 1 H-NMR (200 MHz, DMSO): 7.5 ppm (1H, d), 7.2-7.3 (10H, m), 7.1 (1H, d), 6.3 (1H, s) , 3.3 (3H, s), 2.5 (3H, s).

FAB-MS: 365 (M + H +) Example 2 The following compounds were prepared similarly to Example 1.

2- (6-Methoxypyrazin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (1-384) 1 H-NMR (200 MHz, DMSO): 7.9 ppm (1H, s), 7.8 ppm ( 1H, s), 7.2-7.3 JOH, m), 3.9 (3H, s), 3.3 (3H, s).

FAB-MS: 380 (M + H < + >)

2- (6-Methoxypyridazin-3-yloxy) -3,3-diphenyl-butyric acid 1 H-NMR (200 MHz, DMSO): 12.3-12.6 ppm (broad, 1H), 7.0-7, 4 (12H, m), 6.0 (1H, s), 3.9 (3H, s), 1.8 (3H, s).

FAB-MS: 365 (M + H < + >)

The compounds listed in Table 1 may be prepared in a similar manner or as described in the general section. . «O * * * * · ψ * * 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26

Table I

(X. £ < / 3 O 1 1 OOO O OO O.O O O OOOOOOOOOOO OO - I * << 0 > SC / 3 < UX 9 < u X _ Z £ £ £ £ £ £ £ £ £ £ £ £ £ X X X X X X X X X X X X X X X X X ΓΜ X 1 1 < NX i e............ CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM 1 XX & DX & 1 1 1 1 1 1 1 1 1 1 T T T T T T T T T T £ £ £ £ £ £ £ £ £ CH CH CH , 1 í Pi rs 1 < N 1 ΓΜ 1 with IX u X o 1 with JJ X o 1 tn OS and < 4— < fi, < UP, o CL., &Lt; U * 4-H Methyl methyl methyl methyl methyl methyl methyl 0) s 0 1 (US O 1 methyl methyl methyl methyl methyl propyl 3 > 0 1 < N < u X 0 1 st -r P ri-phenyl 4 COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH _ (N @ +) -00 CN CN Ό-Ό-h lt H Η — — — lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt lt < k— > 4 »—4 k- ^ ►4 k — H k— < - 27 - 27 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 4 »'·' ··

o o OO 1 1 O CO OOO 1 1 OOOOOOO 1 OO OO OO OO OO OOOoooo O OOO N 2 OOO < υ 2 ú aaaa 0 1 < N o 1 u < N / -N mao ¥ uaaaaaaau ó au 1 fN 2 0 1 uaaaaaa eí 2 1 < L) 2 o * 4 > 2 0 1 u I 0 1 u 2 0 1 ua and O 2 5 5 w ΰ 4 > 2 0 1 uaa < N / • “N mauv — ✓% O / —N au 1 u > 2 0 1 o 4H < υ 2 0 1 1 < N fS a 1 X t > 5 < ua < ua ">< ua 1 * < υ & 1 rs / s s fN au?, < υ MH 1 O 2 0 1 • H Ό 1 cn 1 < N / NN < N au G *, < o Cm 1 2 0 1 < 4 • and < ua < D and • and 0) and § ω and I 'I 1 * (U and "> r3 ω and 1 < N &n; For < 4-i 1O 2 0 c H Ό 1 < 4 1 < N / N N rs and 1 TG 4 4H ώ 0 t • H Ό 1 cn >, G, O li G oa υ and ι · Η D and rS < D af > o 06 06 > »G« and " P. g 'and Ti g, a >< + H 1 fI-. 4g & g «and Ti g tv < + H 1 U-. 4 £ G and G and G ca »1 >> Gc and Ti and < 4H Ti g, a >< 4H 1 O 2 4 & ca i ca e? < 4H 1 4 Ti G, < υ ^ H 1 u 4 1? ca * > »G < a G« and G ca >> X 0 > -GO 2 o G < a >> Ca c ca C ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ou 00 00 00 00 00 00 00 ► ► ► ► ► ► ► ► ► ► ► ► < (N CN 1 m (N 1 M O 1 M * S)) 1 hH NO < N 1 I'-CN 00 (N 1 HH O OJ 1 HH O CO 1 HH cn 1 HH O m 1 HH cn HH Tj- cn 1 HH vs 1 HH with cn 1 HH r- c < s HH 00 cn 1 HH OS cn 1 HH O 1 HH (HH Ol 1 HH J * - 28 - 28 • · ···· • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ·· ·· # · £ O o O CZ) C / 5 1, OO O O OO 1, o OOOOOO 1 1 oooo OOOO O Ooo OO oo 1 < N ayi fN X a 1 O < u 2 y O 2 0 1 < ϋ 2 9 ó O 2 y $ 0 1 υ o 2 0 1 yo 2 < υ 2 0 1 ou 1 ( Λ 1 < N a 0 1 ua auaau 1 ÍN a υ 1 < N o 1 (N au O 1 < N auu 1 o U 1 0 te * u 1 < n aua 0 2 1 y < υ 2 0 1 y υ 2 1 yaa 06 and - a- -¾ z- Z &&Lt; D 2, yy 1 fN 1 1 ozza a- -55- zaaaa < N / N N and aa aaa * > »B 0 1 y OJ 2 0 1 y X o K u X y X y X y X y X yayaoayaoaoaua υ auaoaoauauaoayayayaya y 06 B < D and 1 < s? y 1 g, <+; + H á > 2 0 Ή 1 CO 1 < N ΓΝ X o 1 & , »with < ua +3 < ua I * oa Ί4 < υ &#< ua • 5 (U and 1 fN (N and 0 w 1 G, 4 >< 4H 1 < L > 2 0 1 t3 co 1 < N rs ay Nw 't. (U ¢ + -1 1 < D 2 0 1 • co 1 co 1 < N / - ~ N N n aok 1) aoa >>& B & B & P < - > B & B ' and <" and " a " 1 To G ^ + - 1 1 O 2 0 1 -3 1 CO * B < ua G rV Ut 1 O 2 0 1 • - ^ T3 1 CO * (U and • 5 < υ and 06 Pi and £ f < sg < 2 c < ag < S < G ' and G, 4 > 1 tx. < ac & a &&; c B To G 1 gt GB Ci Ci Ci Ci Ci 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 ouaoouaoo υ aoouaoooaoouaoouaoou 0) 2 oooaoo About oouaooyaooyaooyaooya ooy > c ht hh 1 M no t - < ^ f 1 00 1—1 ON 1 t — HO * 0 lO 1 t — H CN mt what i / o t —H Ttf- lo 1 1 HH VO lo 1 M r- 1 00 i / ~ > 1 HH ON lo 1— < O vo 1 M Ό H-4 < N NO 1 lH CO NO 1 M NO 1 ► " NO NO > 1 1 — H NO 1 > —1 ·· ···· «· · · · · · · · · · ·

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The compound of the present invention provides novel therapeutic options for the treatment of hypertension, high blood pressure in the lung, myocardial infarction, cardiac artery, arrhythmia, acute / chronic renal failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasm, cerebral ishememia, subarachnoid haemorrhage, migraine, asthma , athero-sclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, anesthesiosis, and bypass grafting, benign hyperplasia-prostate, ischemic renal failure and renal failure or hypertension due to repair, metastasis and mesenchymal tumor growth such as prostate cancer, contrast agent kidney failure, pancreatitis, gastrointerstinal ulcers.

The invention further relates to combinations of endothelin receptor antagonists of formula I and renin-angiotensin system inhibitors. Renin-angiotensin inhibitors 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 calcium antagonists such as verapamil.

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

The invention further relates to combinations of endothelin antagonists of formula I and diuretics. · · · · · · · · · · · · · · · · ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· · β - 50 -

The invention further relates to combinations of endothelin receptor antagonists of formula I and agents that block VEGF (vascular endothelial growth factor). Substances of this type are, for example, anti-VEGF antibodies or specific binding proteins or alternatively low molecular weight substances that can specifically inhibit VEGF release or receptor binding. The combinations described above may be administered simultaneously or sequentially. They can be used in a single pharmaceutical composition or alternatively in different compositions. The administration form may also be varied, for example, endothelin receptor antagonists may be administered orally and VEGF inhibitors may be administered parenterally.

These combination formulations are particularly suitable for the treatment and prevention of hypertension and its consequences and for the treatment of cardiac insufficiency. The following experiments show the beneficial effects of these compounds.

Receptor Binding Study

For binding studies, CHO cells expressed at ETA or ETF1 receptors are used. Preparation of membranes

CHO cells expressed at ETA or ΕΤβ receptors proliferate in DMEM NUT MIX F12 (Gibco, # 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, # A15-022), 1 mM glutamine ( Gibco # 25030-024), 100 µl / ml penicillin and 100 µg / ml streptomycin (Sigma # P 0781). After 48 hours, cells are washed with phosphate buffered saline and incubated for 5 min at 37 ° C with phosphate buffered saline containing trypsin. Then the mixture is neutralized with medium and the cells are separated by centrifugation at 300 g.

For membrane preparation, the cell concentration is adjusted to 10 8 cells / ml buffer (50 mM tris HCl buffer, pH 7.4) and then disrupted on a Branson Sonifier 250, 40-70 s / constant / output [sic3 20.

Binding tests

For ETA and ETB binding assays, membranes are suspended in incubation buffer (50 mM tris HCl, pH 7.4, with 5 mM manganese chloride, 40 mg / ml bacitracin and 0.2% BSA) at a concentration of 50 mg protein per test dose and incubate at 25 ° C with 25 µM [125 I] - ET · (ETA receptor assay) or 25 µM [125 I] -ET3 (ΕΤβ receptor assay) in the presence and absence of test substance. Non-specific binding is determined with ΙΟ-7 Μ ΕΤχ. After 30 min, the free and bound radioligand is separated by GF / B glass fiber filtering filters (Whatman, England) on a Skatron cell collector (Skatron * Lier, Norway) and the filters are washed with ice cold tris HCl buffer at pH 7.4 containing 0.2% bovine serum albumin.

Radioactivity separated on the filters is expressed quantitatively using a Packard 2200 CA liquid scintillation counter.

Testing ET antagonists in vivo

Male SD rats weighing 250-300 g are anesthetized with amobarbital in artificial respiration, vagotomy and destruction of the brain and spinal cord by a blunt needle inserted into the spinal canal. Carotid and jugular vein -52-

catheterize. In control animals, administration of 1 mg / kg ET4 results in a marked increase in blood pressure that persists for a relatively long period.

Test animals receive intravenous (1ml / kg) test substance 30 min prior to administration of ET4. Pro (Determination of ET antagonistic properties is compared to changes in blood pressure of experimental animals with changes in control animals.

Oral testing of ET receptor antagonists

Male blood pressure rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated with oral test substances. After 80 min, the animals are anesthetized with urethane and the carotid (blood pressure) and jugular vein (for total endothelin / endothelin 1) catheterized.

After the stabilization phase, total endothelin (20 μg / kg, 0.5 ml / kg administered volume) or E ^ (0.3 μg / kg, 0.5 ml / kg administered) is administered intravenously.

Blood pressure and heart rate are continuously measured for 30 min. Significant and long-term changes in blood pressure are calculated as the area under the curve. To determine the antagonistic action of the test substances, the areas under the curve in the animals treated with these substances are compared to the area under the control animals.

The compounds of the present invention may be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the usual manner - 53 · • · · · · · · · · · · · · · · · · · · · · · · · ·

bem. Administration may also be carried out by nasopharyngeal use using vapor or spray. The dosage depends on the age, condition and weight of the patient and on the route of administration. As a rule, the daily dose of the active ingredient is from about 0.5 to 100 mg / kg body weight on oral administration and from about 0.1 to 30 mg / kg body weight on parenteral administration. The compound of the invention can be used in liquid or solid form, in conventional pharmaceutical forms for administration such as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are prepared in the usual manner. In this case, the active ingredients can be formulated with conventional pharmaceutical excipients such as tabletting binders, fillers, preservatives, disintegrants, flow control agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, antioxidant release agents and / or vehicle. (cf. H. Sucker et al .: Pharmaceutical Technology [Pharmaceutical Technology], Thieme-Verlag,

Stuttgart, 1991). Thus, the administration forms obtained typically contain from 0.1 to 90% by weight of the active ingredient.

Claims

A carboxylic acid derivative of the formula I R 4 R 5 W — C-CH — Q v ·. R 1 is R 1 -X-Y N = Z (I) wherein R 1 is a tetrazole group or an O ... - IL - group. C - R in which R has the following meaning: - a) OR6 in which R6 is: a hydrogen atom, an alkali metal cation, an alkaline earth cation or a physiologically tolerable organic ammonium ion, a C3-C8 cycloalkyl group, a C1-C6 alkyl group , unsubstituted or substituted CH 2 -phenyl, unsubstituted or substituted C 3 -C 8 alkenyl or C 3 -C 8 alkynyl, or unsubstituted or substituted phenyl, N, C 3 -C 8 alkynyl or unsubstituted or substituted phenyl. B) - 55 - five-membered heteroaromatic group attached by nitrogen atom, c) group (°) to • II - o - · - · · · · · · · · · · · · · · · · · · · (CH 2) p -R 7 4 in which k may be 0,1 and 2, p may be 1,2,3 and 4 and R 7 is an alkyl group, C 3 -C 8 -cycloalkyl, C 3 -C 8 alkenyl group, C 3 -C 8 alkynyl group or unsubstituted or substituted phenyl group, d) s * group O P ...... L. . - NH - S - R 8 II 0 in which R ® is: C 1 -C 4 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, and these groups may have C 1 -C 4 alkoxy X is a nitrogen atom or a methine group, provided that when X is a nitrogen atom then Z is a nitrogen atom and when X is a methine group, X is a nitrogen atom or a haloalkyl group. , then at least one of the ring members Y or Z is a nitrogen atom, Y is a nitrogen atom or a CR group.

9 - M - 56 - Z is N or CR 10, R 6 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - 4 A C 4 alkynyl group and each of these groups may be unsubstituted or substituted, a hydrogen atom, a halogen atom, a C 1 -C 4 alkoxy group, & C 1 -C 4 haloalkoxy, C 3 -C 6 alkenyloxy, C 3 -C 8 alkynyloxy, C 1 -C 4 alkythio,% C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxy-carbonyl, NH (C 1 -C 4 alkyl), N 1 -C 4 -C 1-4 alkyl) 2, hydroxyl, carboxyl, amino, or CR 2 together with CR 1 or CR 10 form a five- or six-membered alkylene or alkenylene ring, which may be unsubstituted or substituted, and in each case one or more methylene groups may be replaced by an oxygen atom, a sulfur atom, NH or NtC 1 -C 6 alkyl), R 2 and R 4 (which may be the same or different) are: phenyl or naphthyl, unsubstituted or substituted, or - phenyl or naphthyl, attached to each other in ortho position by direct bond, methylene, ethylene or ethenylene group, oxygen or sulfur atom or SO 2 -, NH- or N-alkyl group another, - 57 ···· ··· ·· · · · · ♦

unsubstituted or substituted C 3 -C 8 cycloalkyl, R 5 is hydrogen, C 1 -C 8 -alkyl, C 3 -C 8 alkenyl or C 3 -C 8 alkynyl, and these groups may be unsubstituted or substituted, unsubstituted or substituted phenyl or a naphthyl group, a five- or six-membered heteroaromatic group containing one to three nitrogen and / or sulfur or oxygen atoms, and this group may be an unsubstituted or substituted, unsubstituted or substituted C 3 -C 8 cycloalkyl group, R 9 and R 10 (which may be the same or different) are: hydrogen atom, hydroxyl group, amino group, NH1C1-4alkyl group, or N (C1-C4 alkyl) 2, halogen atom, alkoxy group, halo-alkoxy group or C1-C4 alkylthio group, C1-C4 alkyl group, C2-6 alkyl group A C 4 alkenyl group, a C 2 -C 4 alkynyl group, and these groups may be unsubstituted or substituted, or CR 9 or CR 10 may be attached to CR 2 as in above, with the provision of a five or six membered ring, W is a sulfur atom, an oxygen atom or a single bond, Q is an oxygen atom or a nitrogen atom, provided that - 58 - · # ·················································. ♦ «♦ · · · · · · ·--------------------- when Q is nitrogen, then W is a single bond, and physiologically tolerable salts thereof, and enantiomerically pure and diastereomerically pure forms.

Use of a carboxylic acid derivative according to claim 1 for the treatment of a disease.

Use of a compound of formula (I) as claimed in claim 2 as an endothelin receptor antagonist.

Use of a carboxylic acid derivative of the formula I as claimed in claim 1 for the preparation of a medicament for the treatment of diseases in which endothelin levels increase.

Use of a carboxylic acid derivative of the formula I as claimed in claim 1 for the preparation of a medicament for the treatment of diseases in which endothelin is involved in the formation and / or continuation of the disease.

Use of a carboxylic acid derivative of the formula I as claimed in claim 1 for the treatment of chronic cardiac insufficiency, restenosis, high blood pressure, high blood pressure in the lung, acute / chronic renal failure, cerebral ischemia, asthma, benign prostatic hyperplasia and prostate cancer.

7. A combination of a carboxylic acid derivative of the formula I as claimed in claim 1, with one or more active ingredients selected from inhibitors 59.· ····.

renin-angiotensin system such as renin inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, mixed ACE inhibitors / neutral endopeptidases (NEP), β-blockers, diuretics, calcium antagonists, and VEGF blocking agents.

8. A medicament for oral and parenteral administration comprising a single dose of " in addition to conventional drug adjuvants, at least one carboxylic acid derivative of the formula I according to claim 1.

An endothelin receptor antagonist having a chemical structure comprising a structural fragment of the formula.

C-CH X-Y. (P = (N = Z R 3 R 1 in which R 1, R 2, R 3, R 4, X, Y, Z and Q are as defined in claim 1).