MXPA98001698A - New derivatives of carboxilic acid, its obtaining and - Google Patents

Abstract

Derivatives of the carboxylic acid of the formula I (See Formula) in which R 1 signifies a tetrazole, nitrile, a COOH group or a hydrolysable COOH radical, and the other substituents have the meanings indicated in the description

Description

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

Endothelin is a peptide composed of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isomeric forms: ET-1, ET-2 and ET-3. In the following, the term "endothelin" or "ET" will mean one or all of the isomeric forms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. It is known that this vasoconstriction is produced by the link between endothelin and its receptor (Nature, 332. 411-415, 1988, FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

An increased or abnormal libration of endothelin causes a prolonged contraction of the peripheral blood vessels, kidney and brain, which can lead to diseases. As the literature teaches, high levels of endothelin have been found in the plasma of patients with hypertonia, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, atherosclerosis, and in the respiratory tract of asthmatics (Japan J. Hypertension, 12 , 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990)).

So it is to be assumed that the substances that specifically inhibit the binding of endothelin with the receptor are also capable of antagonizing the physiological effects of endothelin, being, therefore, valuable drugs.

It has been found (Wo 94/02474), that certain carboxylic acid derivatives of the general formula Q are good inhibitors for endothelin receptors.

RC = = COOH i. to .

But here the compounds with a double bond in the Molecule are predominantly taken into account. In addition to RA and RB, a maximum of one hydrogen atom is admitted in the β center.

Surprisingly, it has now been found that this hydrogen atom can be substituted by alkyl radicals. A ß-quaternary center is formed, which at the same time achieves a marked increase in efficiency against endothelin receptors. (see the examples).

The object of the present invention are carboxylic acid derivatives of the formula I R 2 R 5 C CH (I), R 3"^ ^ (CH 2) n R 4 in which R 1 signifies a tetrazole, nitrile, a COOH group or a hydrolysable COOH radical, and the other substituents have the following meanings: R2 and R3 (which can be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, cyano, N02, hydroxy, C? -C-alkyl, C? -C-halogenoalkyl, C? -C-alkoxy, C? -C-halogenoalkoxy, phenoxy, C? -C-alkylthio, amino, benzyloxy, C? -C-alkylamino or C? -C-dialkylamino; or phenyl or naphthyl, which are linked to each other in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom; R4 phenyl or naphthyl, methylenedioxyphenyl, ethylenedioxyphenyl, indian, indolyl, pyridyl, benzopyranyl, furanyl, benzofuryl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyrimidinyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl , C3-C7-cycloalkyl, thienyl, oxazolyl, thiazolyl, which may be substituted by one or more of the following radicals: halogen, cyano, hydroxy, N02, C1-C-alkyl, C? -C4-haloalkyl, C? C4-alkoxy, C? -C-halogenoalkoxy, phenoxy, C? -C-alkylthio, amino, benzyloxy, C? -C-alkylamino oder C? -C4-dialkylamino, the alkyl radicals being able to form a ring together; R5 Ci-Ca-alkyl, C3-Cd-alkenyl, C3-Ce-alkynyl or C3-C8-cyClO-alkyl, the radicals of which may be mono- or polysubstituted by: halogen, C? -C4-alkoxy, C? -C- alkylthio, C? -C -alkylamino, di-C1-C4-alkylamino; phenyl, benzyl, 1-methylnaphthyl, 2-methylnaphthyl or naphthyl, which can each be substituted by one or more of the following radicals: halogen, cyano, hydroxy, amino, C? -C4-alkyl, C? -C4-alkoxy , phenoxy, C? -C4-alkylthio, dioxometrylene or dioxoethylene; n 1 - 2 The compounds and also the intermediates for their obtention, such as, for example, Va, may possess one or more substituted asymmetric carbon atoms. Such compounds can be present as pure enantiomers or diastereomers or also in the form of their mixtures. It is preferred to use in pure enantiomeric compound.

Another object of the present invention is the use of the above-mentioned carboxylic acid derivatives for the preparation of medicaments, especially for the preparation of inhibitors for endothelin receptors.

The compounds of the formula I can be prepared by first reacting a type III ketone in the presence of a base to give the compounds of the formula I. O II + (Et20) POCH2COOR R2 'R5 (II) (III ) (IV) Suitable polar solvents are, for example, DMF or THF.

As the base, an alkali metal or alkaline earth metal hydride, such as, for example, sodium hydride, potassium hydride or calcium hydride, a carbonate, for example an alkali metal or alkaline earth metal carbonate, for example carbonate sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide, eg sodium hydroxide or potassium hydroxide, an organic metal compound, eg butyl lithium, an alkali metal alcoholate, eg sodium ethanolate or potassium tert-butanolate, or an alkaline amide, eg lithium isopropylamide.

The reaction is carried out, preferably at a temperature range of between 0 ° C and the boiling point of the solvent or solvent mixture.

The compounds of type IV can then be reacted with aromatic compounds in the presence of a catalyst to give the carboxylic acid derivatives of the general formula Va.

(IV) (va) Strong inorganic acids, such as Lewis acids, are suitable as catalysts here. Exemplary examples may be sulfuric acid, aluminum trichloride, zinc chloride or iron trichloride. When sulfuric acid is used, the free acid can be obtained directly.

Alternatively, symmetrical carboxylic acid derivatives of the formula Vb can be prepared from a β-dicarbonyl compound VI and an aromatic compound, in the presence of a catalyst.

(VI) (Vb) Strong inorganic acids are suitable as catalysts. Examples are, inter alia, sulfuric acid, aluminum trichloride, zinc chloride or iron trichloride (see also: Gogte G.R. et al., J. Univ. Bombay, Sect. A, 27, 1958, 41).

Another possibility for obtaining compounds of type Va consists of starting with a ketone VII, (VII) R ^ R2 which can be transformed with Meldrum acid, in the presence of a base, such as, for example, pyridone or sodium hydride, giving the compounds of type VIII When the compounds of type VIII are reacted in di-ethyl ether with a Grignard reagent of the general formula I R3- Mg Y (IX) YY == BBrr ,, CC: l, I compounds of type X are obtained, it may be advantageous to additionally use copper salts, such as copper chloride, copper bromide, copper iodide or copper cyanide and work in the presence of a Lewis acid, such as, for example, trimethylsilyl chloride or boric trifluoride etherate.

The hydrolysis of the compounds of the formula X with mineral acids, such as hydrochloric acid or sulfuric acid, can then supply the compounds Va (R = OH).

Other possibilities for obtaining the Va compounds can be carried out in analogy to the prescriptions of Zimmermann H.E. et al. J. Am. Chem, Soc. 82., 1961, 1196 or of Yu A.J. et al. J. Org. Chem. 21, 1958, 1004.

The compounds of the formula Va, b can be converted at -78 ° C to room temperature with a strong base, such as, for example, butyl-lithium or lithium di-diisopropylamide, in an inert solvent, for example diethyl ether or tetrahydrofuran. and under inert gas, eg nitrogen or argon, in the anion (or the dianion for R = H. This anion reacts with type VII alkylating agents at -78 ° C to room temperature.) After quenching with NH4C1 or dilute mineral acid, eg HCl, the compounds of the formula I are obtained (Va, b) (XI) (I) Z = halogen, trialkylamine Compounds of type I with R1 = tetrazole can be synthesized, starting from the carboxylic acids I (R1 = COOH) For this purpose, the carboxylic acid is reacted with thionyl chloride at room temperature in the acid chloride and transformed, then, with aqueous ammonia solution in the acid amide of formula XII.

Amides of the formula XII can be transformed with oxalyl chloride or phosphorus trichloride or trifluoroacetic acid anhydride in DMF or pyridine at 0 ° C to room temperature, giving the nitriles of the formula XIII R5 CN (XIII) R2 R4 The nitriles of the formula XIII are reacted with sodium triazide or trimethylsilyl azide in an appropriate solvent, for example dimethylformamide, tetrahydrofuran or l-methyl-2-pyrrolidinone, in the presence of a catalyst, e.g. aluminum chloride (see also: Bernsteim PR et al., Synthesis, 1987, 1133), the tetrazoles XIV being obtained at room temperature or elevated. The compounds of the formula I can also be obtained, starting from the corresponding carboxylic acids, i.e. of compounds of the formula I, wherein R 1 = COOH, and by transforming these, first, in a customary manner into the active form, such as, for example, an acid halide, an anhydride or an imidazolide and reacting this, then, with a compound of corresponding hydrixyl HOR. This reaction can be carried out in the usual solvents and frequently requires the presence of a base, with the above mentioned being considered as such. These two steps can be simplified, for example, by reacting the carboxylic acid in the presence of a water-separating agent, such as, for example, a carbodiimide, on the hydroxyl compound.

In addition, the compounds of the formula I can also be obtained starting from the salts of the corresponding carboxylic acids, namely of compounds of the formula I, in which R 1 signifies a group COR and R represents OM, where M can mean a cation of alkali metal. These salts can be reacted with numerous compounds of the formula RA, meaning A a conventional nucleophilic dissociable group, for example halogen, such as chlorine, bromine, iodine or, optionally, aryl or alkylsulfonyl substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent dissociative group. Compounds of the formula R-A with a reactant substituent A are known or can be prepared without problem by applying the methods generally known to the expert. This reaction can be carried out with the usual solvents and it will be advantageously carried out by adding a base, taking into consideration those mentioned above.

Pure enantiomeric compounds of the formula I can be obtained by subjecting the racemic or diastereomeric compounds of the formula VI to a classical separation of racemates with pure enanthimer bases, such as brucine, strychnine, quinine, quiñi-dine, cincnidine, cinchonine, yohimbine, morphine, dehidroabieti-lamina, ephedrine (-), (+), deoxiefedrine (-), (+), threo-2-amino-l- (p-nitrophenyl) -1, 3 -propanediol (-) , (+), threo-2- (N, N-dimethylamino) -1- (p-nitrophenyl) -1, 3 -propanediol (+), (-) threo-2-amino-l-phenyl-1,3 -propanediol (+), (-) a-methylbenzylamine (+), (-), a- (1-naphthyl) ethylamine (+), (-), a- (2-naphthyl) eti-lamel (+ ), (-), aminomethylpinan, N, N-dimethyl-l-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norseudoephedrine, amino acid derivatives, peptide derivatives.

The radical R1 in formula I is widely variable. R1 represents, for example, a group 0 where R has the following meanings: a) a succinylimidoxy group; b) a five-membered heteroaromatic linked via a nitrogen atom, such as, for example, pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may contain one or two halogen atoms, especially fluorine, chlorine and / or one to two the following radicals: C? -C4-alkyl, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl; C? -C-haloalkyl, especially C? -C2-haloalkyl, such as, for example, 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 and pentafluoroethyl; C? -C4-halogenoalkoxy, especially C? -C2-halogenoalkoxy wie difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2.2 , 2-trifluoroethoxy, 2-chloro-l, 1,2-trifluoroethoxy and pentafluoroethoxy, especially trifluoromethoxy; C 1 -C 4 -alkoxy, such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, especially methoxy, ethoxy, 1-methylethoxy; C? -C-alkylthio, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, especially methylthio and ethylthio; c) R means, in addition, a radical R where m is 0 or 1 and R6 and R7, which may be the same or different, have the following meanings: hydrogen Ci-Cβ-alkyl, especially C? -C4-alkyl, such as, for example, those mentioned above; C3-C6-alkenyl, such as, for example, 2-propenyl, 2-butenyl, 3-bute-nyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, -pentenyl, l-methyl-2-butenyl, 2-methyl-2-bute-nyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-bute-nyl, 3-methyl -3-butenyl, 1, l-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, l-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl , l-methyl-2-pentenyl, 2-methyl-2-pente-nyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3 -pentenyl, l-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pente-nyl, 1,1-dimethyl-2-butenyl, 1, -dimethyl-3-butenyl, 1,2-di-methyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-bute-nyl, 1,3-dimethyl-3-butenyl , 2, 2-dimethyl-3-butenyl, 2,3-di-methyl-2-butenyl, 2,3-dimethyl-3-butenyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2 ethyl 2-butenyl, 2-ethyl-3-butenyl, 1,1-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, special nte 2-propenyl, 2-bu-tenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl; C-C6-alkynyl, such as, for example, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl -3-butynyl, 2-methyl-3-butynyl, l-methyl-2-buty-nyl, 1, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexy-nyl, 3-hexynyl , 4-hexynyl, 5-hexynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, l-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4 -pentinyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1, l-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl , 2, 2-dimethyl-3-buty-nyl, l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl and l-ethyl-l-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, l-methyl-2-propynyl and l-methyl-2-butynyl, especially 2-propynyl C 3 -C 8 -cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl , cyclooctyl, whose alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry from one to five halogen atoms, especially fluorine or chlorine and / or one to two of the following groups: C1-C4-alkyl, C? -C4-alkoxy, C1-C4-alkylthio, Ci? -haloalkoxy, such as, for example, those mentioned above, C3-C6-alkenyloxy, C3-C6-alkenylthio, C-C6 -alkynyloxy, C3-C6-alkynylthio, having the alkenyl and alkynyl components contained in these radicals, preferably the meanings indicated above; C? -C4-alkylcarbonyl, such as, for example, methylcarbo-nyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbo-nyl, 1,1-dimethylethylcarbonyl; C? -C-alkoxycarbonyl, such as, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, 1, 1-dimethylethoxycarbonyl; C3-C6-alkenylcarbonyl, C3-C6-alkynylcarbonyl, C3-Cβ-alkenyloxycarbonyl and C3-C6-alkynyloxycarbonyl, the alkenyl or alkynyl radicals preferably having the above defined meanings; phenyl, optionally mono- or polysubstituted, eg mono- to trisubstituted by halogen, nitro, cyano, C? -C4-alkyl, C? -C-halogenoalkyl, C? -C-alkoxy, C? -C4-halogenoalkoxy or C C 4 -alkylthio, such as, for example, 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methyl-phenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl; di-C? -C4-alkylamino, such as, for example, dimethylamino, diproylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropyl- N-ethylamino, N-isopropy1-N-propylamino; R6 and R7 also represent phenyl, which may be substituted by one or more, eg one to three of the following radicals: halogen, nitro, cyano, C? -C4-alkyl, C? -C4-haloalkyl, C? -C4-alkoxy, C1-C4-haloalkoxy or C? -C4-alkylthio, as, for example, especially those mentioned above; or R6 and R7 together form a closed ring optionally substituted, for example by a C4-C-alkylene chain substituted by C? -C4-alkyl and which may contain a heteroatom selected from the group oxygen, sulfur or nitrogen, such as - (CH2) -, - (CH2) 5-, - (CH2) 6-, - (CH2) 7-, - (CH2) 2-0- (CH2) 2-, -CH2-S - (CH2) 3-, - (CH2) 2-0- (CH2) 3-, -NH- (CH2) 3-, -CH2-NH- (CH2) 2 ~, -CH2-CH = CH-CH2- , -CH = CH- (CH2) 3-; d) R means, in addition, a group where k represents the values 0, 1 and 2, p the values 1, 2, 3 and 4 and RB means C? -C4-alkyl, C? -C-haloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or optionally substituted phenyl, such as, for example, especially those mentioned above. e) R also means a radical OR9, where R9 means: hydrogen, the cation of an alkali metal, such as, for example, lithium, sodium, potassium, or the cation of an alkaline earth metal, such as, for example, calcium, magnesium and barium or an organic ammonium ion, compatible with the environment, such as, for example, a C1-C4-tertiary alkyl ammonium or the ammonium ion; C3-Cβ-cycloalkyl, such as, for example, those mentioned above, which can carry from one to three C? -C-alkyl groups; Ci-Cβ-alkyl, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethyl-butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-3- dimethylbutyl, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, l-ethyl-2-methylpropyl, which can carry one to five halogen atoms, especially fluorine and chlorine and / or one of the following radicals: C? -C4-alkoxy, C? -C4-alkylthio, cyano, C? -C4-alkylcarbonyl, c3-C8-cycloalkyl, C? -C-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, whose aromatic radicals can lead to its ve from one to five halogen atoms and / or from one to three of the following radicals: nitro, cyano, C? -C4-alkyl, C? -C4-halogenoalkyl, C? -C4-alkoxy, C? -C4-halogenoalkoxy and / or C? -C4-alkylthio, as, for example, especially those mentioned above; a Ci-Cg-alkyl group, such as, for example, those mentioned above, and which can carry from one to five halogen atoms, especially fluorine and / or chlorine, and which bears one of the following radicals: a heteroaromatic of five members containing a nitrogen atom and an oxygen or sulfur atom, and which can carry from one to four halogen atoms and / or from one to two of the following radicals: nitro, cyano, C? -C4-alkyl, C? -C-haloalkyl, Cx-C4-al-coxy, phenyl, C? -C4-haloalkoxy and / or C? -C4-alkylthio. They are mentioned, especially: 1-pyrazolyl, 3-methyl-l-pyrazolyl, 4-methyl-l-pyrazolyl, 3,5-dimethyl-l-pyrazolyl, 3-phe nyl-1-pyrazolyl, 4-phenyl -1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1, 2,4-triazol-1-yl, 3-methyl-1, 2, 4 -triazol-1-yl, 5-methyl-1, 2,4-triazol-1-yl, 1-benztriazolyl, 3-isopropyl-isoxa-zol-5-yl, 3-methylisoxazol-5-yl, oxazole-2 -yl, thiazol-2-yl, imidazol-2-yl, 3-ethyl-isoxazol-5-yl, 3-phenylisoxazol-5-yl, 3-tert. -butyl-isoxazol-5-yl; a C2-C6-alkyl group carries in position 2 one of the following radicals: C? -C4-alkoxyimino, C3-C6-alkynyloxyimino, C3-C6-haloalkenyloxyimino or benzyloxyimino; a C3-C6-alkenyl group or a C3-C6-alkynyl group, which groups can in turn carry from one to five halogen atoms; R9 further denotes a phenol radical which can carry from one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C? -C4-alkyl, C? -C4-halogenoalkyl, C ? -C-alkoxy, C? -C4-haloalkoxy and / or C? -C-alkylthio, as, for example, especially those mentioned above; a five-membered heteroaromatic linked via a nitrogen atom, containing one to three nitrogen atoms and one to two halogen atoms and / or one to two of the following radicals: C1-C4-alkyl, C C4-haloalkyl, C? -C4-alkoxy, phenyl, C? -C4-haloalkoxy and / or C? -C-al-quiltio. They are mentioned, especially: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl -1-pyrazolyl, 4-chloro-l-pyrazolyl, 4-bromo-l-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1, 2,4-triazol-l-yl, 3-methyl-l, 2,4 -tria-zol-1-yl, 5-methyl-l, 2,4-triazol-1-yl, 1-benztriazolyl, 3,4-dichloroimidazol-1-yl; R9 also means a group where R10 and R11, which may be the same or different, mean: C? -C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-CB-cycloalkyl, whose radicals can carry a C? -C4-alkoxy, C? -C4-alkylthio radical and / or a optionally substituted phenyl radical, as, for example, especially those mentioned above; phenyl, which may be substituted by one or more, eg one to three of the following radicals: halogen, nitro, cyano, C1-C-alkyl, C? -C4-haloalkyl, C? -C4-alkoxy, C? -C4-halogenoalkoxy or C? -C-alkylthio, these radicals corresponding, especially, to those mentioned above; or R10 and R11 together form a C3-C12-alkylene chain which can carry one to three C? -C4-alkyl groups and one heteroatom of the oxygen, sulfur and nitrogen group, such as, for example, those mentioned for R6 and R7 R means, in addition, a radical OR -NH, 12 Or where R12 means: C? -C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C? -cycloalkyl, especially the aforementioned radicals, the radicals of which can contain a C? -C4-alkoxy, C1-C- radical? alkylthio and / or a phenyl radical, such as those mentioned above; phenyl optionally substituted, especially those mentioned above. g) R means a radical 0 < tt2 0 where R12 has the meanings indicated above.

R1 may also be tetrazole or nitrile.

With respect to their biological action, the carboxylic acid derivatives of the general formula I are preferred - both as enantiomers or pure diastereomers, and also their mixtures - in which the substituents have the following meanings: R1 tetrazole, COOH or a hydrolysable COOH radical; R2 and R3 (which may be the same or different); phenyl or naphthyl, which may be substituted by one or more of the following radicals: F, Cl, Br, I, cyano, N02, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, 2, 2, 2-trifluoroethyl , methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyloxy, phenoxy, methylthio, ethylthio, benzyloxy, amino, methylamino, dimethylamino; R4 phenyl, methylenedioxyphenyl, ethylenedioxyphenyl, indanyl, pyridyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzothienyl, 2-pyrimidinyl, 4-pyrimidinyl, 2,3-dihydrobenzothienyl, which may be substituted by one or more of the following radicals: F, Cl, Br, I, cyano, N02, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, tert. -butyloxy, trifluoromethyloxy, phenoxy, methylthio, ethylthio, propylthio, benzyloxy, amino, methylamino, dimethylamino; R5 methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, tert. -butyl, pentyl, 3-methylbutyl, hexyl, pent-3-yl, 4-methylpentyl, 2-ethylbutyl, which may be mono- or polysubstituted each time by: cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio , ethylthio, propylthio, isopropylthio, amino, methylamino, dimethylamino; allyl, vinyl, trifluoromethyl, 2,2,2-trifluoroethyl; phenyl, benzyl, which can each carry one or more of the following radicals: F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, dioxomethylene, dioxoethylene; n 1 - 2 Examples of preferred compounds are listed in the following table: 00 OR to ( t to a to to t 00 to UJ or U) to Ul u > UJ J > 00 Ul vo t OJ bundle Ul rf » rf » ao The compounds of the present invention offer a new therapeutic potential for the treatment of hypertonia, pulmonary hypertension, myocardial infarction, angina pectoris, acute renal failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, endotoxic shock, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty, benign hyperplasia of the prostate, ischemic renal failure and produced by intoxication or hypertonia.

The good effects of the compounds can be checked in the following examples: Linkage studies to receptors For the linkage study, human CHO cells, cloned, expressing ETA receptors and cerebellar membranes from guinea pigs with > 60% of ETB, compared to ETA receivers.

Preparation of the membrane CHO cells with expression of ETA receptors were multiplied in F? 2 medium with 10% fetal calf serum, 1% glutamine, 100 U / ml penicillin and 0.2% streptomycin (Gibco BRL , Gaithersburg, MD, USA). After 48 h the cells were washed with PBS and incubated for 5 minutes with 0.05% PBS containing trypsin. Then, neutralized with medium F? and the cells were collected by centrifugation at 300 x g. For lysis of the cells the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycine) and then incubated for 30 min at 4 ° C at a concentration of 107 cells / ml of lysis buffer. The membranes were centrifuged for 10 min at 20,000 x g and the pellet was stored in liquid nitrogen.

The cerebellum of the guinea pigs were homogenized in the Potter-Elvejhem homogenizer and generated by differential centrifugation of 10 min at 1,000 x g and repeated centrifugation of the supernatant from 10 min at 20,000 x.

Linkage assays For the ligation test with the ETA and ETB receptors, the membranes were suspended in the incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 μg / ml bacitracin and 0.2% BSA ) at a concentration of 50 μg of protein per test substance, and incubated at 25 ° C with '25 pM [125J] -ETi (assay with ETA receptor) or 25 pM [125J] -RZ3 (assay with ETB receptor) , in the presence or absence of the test substance. The specific binding was determined with 10"7 M ETi.After 30 min, the free radioligand and the radioligand bound by filtration on a GF / B glass fiber filter (Whatman, England) were separated in a Skatron cell collector. (Skatron, Lier, Norway), and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA The radioactivity collected on the filters was quantified by means of a Packard liquid scintillation counter. 2200 CA.

Functional in vitro assay system for finding endothelin receptor antagonists (subtype A) This assay system is a functional test for endothelin receptors, which is based on cells. Certain cells exhibit an increase in the intracellular calcium concentration when stimulated with endothelin 1 (ET1). This increase can be measured in intact cells, loaded with calcium-sensitive dyes. 1-fibroblasts isolated from rats, in which an endogenous endothelin receptor of subtype A was detected were loaded with the fluorescent dye fura 2-an in the following manner: after trypsinization the cells were resuspended in buffer A (120 mM NaCl, 5 mM of KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2 x 106 / ml and incubated for 30 min at 37 ° C. C in the dark with fura 2-am (2 μM), Pluronics F-127 (0.04%) and DMSO (0.2%). The cells were then washed twice with buffer A and resuspended at 2 x 10 6 / ml.

The fluorescence signal of 2 x 10 5 cells per ml was recorded continuously at 30 ° C with Ex / Em 380/510. The test substances were added to the cells and after a 3 min incubation time with ET1 the maximum change in fluorescence was determined. Controlling the response of the cells to ET1 without prior addition of a test substance, and this response was set equal to 100%.

Assay of ET antagonists in vivo SD rats of 250-300 g were narcotized with Amobarbital, connected to artificial respiration, vagotomized and after-dosed. The carotid artery and the jugularis vein were probed.

In control animals the intravenous administration of 1 μg / kg of ET1 produced a marked increase in blood pressure, which lasted for a prolonged period.

The test animals were injected with the test substances (1 ml / kg) intravenously 5 min before ET1 administration. To determine the antagonist properties of ET, the increase in blood pressure in the test animals was compared with that of the control animals.

"Sudden death" induced by endothelin in rats The principle of the assay is based on the inhibition of the sudden cardiac death of the mouse produced by endothelin, which is probably due to a constriction of the coronary arteries, by pretreatment with endothelin receptor antagonists. After intravenous injection of 10 nmol / kg of endothelin in the volume of 5 ml / kg of body weight, the death of the animals occurs within a few minutes.

The lethal dose of endothelin-1 is examined each time in a small collective of animals. When the test substance is applied intravenously, injection of lethal endothelin-1 into the reference group is generally applied 5 minutes later. In the other types of application, the lethal application is carried out, if necessary, until a few hours later.

The percentage of survival is documented and the active doses that protect 50% of the animals 24 hours or more of sudden cardiac death induced by endothelin (ED 50) are determined.

Functional assay of vessels for endothelin receptor antagonists In segments of the rabbit aorta, after a pretension of 2 g and a relaxation time of 1 h in a Krebs conductive solution, they are induced at 37 ° C and a pH value of between 7.3 and 7.4, firstly a contraction of K +. After washing, an endothelin dose-effect curve is drawn up to the maximum.

Potential endothelin antagonists are applied in other preparations of the same vessel 15 min before the beginning of the endothelin dose-effect curve. The effects of endothelin are calculated in% of the K + contraction. In the efficient endothelin antagonists there is a shift to the right of the endothelin dose-effect cuve.

The compounds of the invention can be administered in a customary manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). They can also be applied by means of vapors or sprays through the nasopharyngeal cavity.

The dose depends on the age, the state and weight of the patient, as well as the way of application. As a general rule, the daily dose of active substance is increased to between approx. 0.5 and 50 mg / kg of body weight in oral administration, and at between approx. 0.1 and 10 mg / kg body weight in the parenteral administration.

The new compounds can be used in the usual solid and liquid galenic application forms, eg as compresses, film tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner, being able to prepare the active substances with customary galenic auxiliaries, such as tablet exudates, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, humectants, dispersants, solvent emulsifiers, retarders. -suppliers, antioxidants and / or blowing gases (see H. Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The application forms thus obtained contain the active substance, usually in an amount of 0.1 to 90% by weight.

Synthesis examples Example 1 3, 3-Bis (4-methoxyphenyl) butanoic acid a) (2E, Z) Ethyl 3- (4-methoxyphenyl) but-2-enoate (6.6 g, 30 mmol) are dissolved at 0 ° C in anisole (4.9 g, 45 mmol), and mixed carefully with 50 ml of 80% H2SO4. The biphasic mixture is intensively stirred for 20 h at room temperature, then poured on ice and the product extracted with ethyl acetate. The organic phase is dried (Na 2 SO), filtered and concentrated, the residue is taken up in ether, extracted with 2N sodium hydroxide solution and the ether phase is discarded. The alkaline phase is adjusted with 2N HCl to pH 2 and the product is extracted with ethyl acetate. The organic phase is dried (Na 2 SO), filtered, concentrated and the dried residue is stirred with diisopropyl ether. The product is filtered by suction and dried. 5.1 g of a white powder (56%) remain. Melting point: 161-164 ° C The mother liquor is further processed, obtaining another 1.1 g (12%) of the acid.

Alternatively, the acid can be prepared in the following manner: b) At 0 ° C 32 ml of anisole (294 mmole) are mixed with 33 ml of ethyl acetoacetate (258 mmole), carefully mixed with 150 ml of 70% H2SO4, and the biphasic mixture thus obtained is stirred vigorously. 72 at room temperature. The mixture is then poured onto ice and further worked up as indicated in). The residue is recrystallized from diisopropyl ether. 15.3 g (35%) of a white solid remain. c) Analogously, proceed to obtain 3,3-diphenylbutanoic acid (Example 3,4) Example 2 Acid (2R, S) -3, 3-bis- (4-methoxyphenyl) -2- (3 ', 4'-methylenedioxybenzyl) -butanoic acid A solution of diisopropylamine (3.1 ml, 22 mmol) in 50 ml of dry tetrahydrofuran is mixed under nitrogen at -10 ° C with bu-tillithium (13.8 ml, 22 mmol, 1.6M in hexane), stirred by 5 min at -10 ° C, and then 3, 3-bis (4-methoxy-phenyl) butanoic acid (3.0 g, 10 mmol) in 15 ml of absolute THF is added dropwise at 0 ° C. After the addition is complete, stir for 1 h at room temperature, cool to -20 ° C, add piperonyl bromide (2.6 g, 12 mmol) in 10 mL of THF and then stir for 72 h at room temperature. Then, the preparation is quenched with saturated NH 4 Cl solution, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried (Na 2 S 4), filtered and concentrated in the rotary evaporator. The brown residue is purified chromatographically on silica gel (methanol / CH2C12 1:19), obtaining 1.3 g (30%) of product as a white foam. Melting point: 137-140 ° C (from diisopropyl ether) EXAMPLE 3 Ethyl 3, 3-diphenyl-butanoate At 0 ° C, 65 g of A1C13 (487 mmoles) are suspended in 500 ml of benzene and slowly mixed with 61.7 g of ethyl (2E, Z) 3-phenyl-but-2-enoate. The dark red solution is stirred for 20 h at ambient temperature and then poured onto an ice / conc. HCl mixture. The organic phase is separated, the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with NaOH, then dried (Na 2 SO 4), filtered and concentrated (66.8 g of dark brown oil). 56.5 g of this oil are distilled, obtaining 46.3 g of product as a colorless oil.

EXAMPLE 4 3,3-Diphenylbutanoic Acid In 30 ml of dioxane, 4.9 g of ethyl 3, 3-diphenylbutanoate (18.3 mmol) are dissolved, mixed with 36 ml of 1M KOH and stirred for 6 hours. it has 60-70 ° C.

Next, the dioxane is evaporated on the rotary evaporator, the residue is diluted with water and extracted with diethyl ether. The aqueous phase is then adjusted to pH 1 and extracted with ethyl acetate. The organic phase is dried (Na 2 SO 4), filtered and concentrated. The dry residue is stirred with hexane, obtaining 2.35 g of a white powder (55%). The mother liquor is not purified further.

Example 5: Acid (2R, S) 3,3-diphenyl-2- (3 ', 4'-methylenedioxybenzylbutanoic) To a solution of 3, 3-diphenylbutanoic acid (2.4 g, 10 mmol) in 40 ml of absolute THF are added dropwise at -20 ° C 15 ml of butyl lithium (24 mmol, 1.6 M in hexane). ), and then stir 1 h between -10 and -20 ° C. Then piperonyl chloride (2.2 g, 40 mmoles) in 10 ml of THF, stirred 16 h at room temperature and then quenched with saturated NH 4 Cl solution. The organic phase is separated, the aqueous phase is extracted with ethyl acetate, then the combined organic extracts are dried (Na 2 SO 4), filtered and concentrated. The residue is chromatographically purified in 45 silica gel (CH2Cl2 / MeOH 19: 1), obtaining 2.4 g of the desired product (65%).

The acid is dissolved in CH2C12 and stirred with saturated sodium carbonate solution. The organic phase (!) Is separated, dried (Na2SO4), and concentrated. 2.5 g of the sodium salt of the acid are obtained. Melting point: 308-310 ° C (decomp.) Example 6: 3, 3-Bis (4-methoxy-3-methylphenyl) butanoic acid It is prepared as in example Ib. But in this case the corresponding ethyl ester is mainly isolated, so that a subsequent saponification is necessary (in analogy to example 4). Melting point: 121-124 ° C Example 7 Acid (2R, S) 3, 3-bis (4-methoxy-3-methylphenyl) -2- (3 ', 4'-methylenedio-xybenzyl) butanoic acid Prepared in analogy to Example 2. 3.25 ml of diisopropylamine (23 mmoles), 15.6 ml of butyllithium (23 mmoles, 1.5 M in hexane), 3.28 g of 3, 3-bis (4) acid -me-tox-3-methylphenyl) butanoic (10 mmol), 2.19 g of piperonyl chloride (13 mmol), give 4.1 g of crude product. Chromatography on silica gel (CH2Cl2 / MeOH 19: 1) gives 1.6 g of product (35%) Melting point: 152-153 ° C Example 8 Acid (2R, S) 3, 3-diphenyl-2- (3 ', 4'-dimethoxybenzyl) butanoic acid Prepared as in Example 5. 2.4 g of 3, 3-diphenylbutanyl acid (10 mmoles), 15.6 ml of butyllithium (23 mmoles, in 1.5 M hexane, 2.2 g of sodium chloride). 3,4-dimethoxybenzyl (13 mmol) gives 3.8 g of crude product Purification in silica gel (heptane / ethyl acetate 1: 1) 2.1 g Produkt (54%) Melting point: 141-143 ° C EXAMPLE 9 3,3 bis- (4-methoxyphenyl) pentanoic acid (2E, Z) ethyl 3- (4-methoxyphenyl) pent-2-enoate (7.0 g, 30 mmol) are dissolved at 0 ° C in anisole (4.9 g, 45 mmol) g and mixed thoroughly with 50 ml of 80% H2SO4. The biphasic mixture is agitated intensively for 30 h at room temperature, then poured on ice and the product is extracted with methylene chloride. The organic phase is dried (Na 2 SO), filtered, concentrated, the residue is taken up in ether, extracted with 2N sodium hydroxide solution and the ether phase is discarded. The alkaline phase is adjusted with 2N HCl to pH 2 and the product is extracted with ethyl acetate. The organic phase is now dried (Na 2 SO 4), filtered, concentrated and the solid residue is stirred with heptane. The product is filtered by suction and dried. There remain 6.8 g of a white powder (72%). Melting point: 136-139 ° C Example 10 10 Acid (2R, S) 3,3-bis- (4-methoxypheniDepntanoic) To a solution of 3, 3-bis- (4-methoxy-phenyl) -pentanoic acid (6.2 g, 20 mmol) in 100 ml of absolute THF are added in drops at -20 ° C 29 ml of butyllithium (46 mmol, 1.6 M in hexane) and then stirred 1 h at room temperature. Then, piperonyl chloride (4.4 g, 24 mmol) in 10 ml of THF is added at -10 ° C, stirred for 72 h at room temperature and quenched with saturated NH 4 Cl solution. The organic phase is separated, the aqueous phase is extracted with ethyl acetate, then the combined organic extracts are dried (Na2SO4), filtered and concentrated. The residue (11.2 g) is chromatographically purified on silica gel (CH2Cl2 / MeOH 24: 1) to obtain 3.1 g of the desired product (34%). Melting point: 84-86 ° C (stirred in heptane) Example 11 Methyl 3, 3-bis- (4-methoxyphenyl) hexanoate. .

Anisole (6.6 g, 61 mmol) is dissolved in 200 ml of dichloroethane, at 0 ° C aluminum trochloride (12.3 g, 3092 mmoles) and then dropwise added under stirring (2E, Z) methyl 3- (4-methoxyphenyl) hex-2-enoate (18 g, 61 mmol). The reaction mixture is stirred 2 h at 5 ° C and then 2 days at room temperature. For further processing pour the mixture onto ice, extract with CH2C12, wash the organic phases combined with saturated NaCl solution and dried over MgSO4. The residue remaining after concentration is purified by chromatography on silica gel (n-heptane / ethyl acetate 7.5%). In this way, 5.2 g (25%) of a colorless oil are obtained. iH-NMR (CDCl 3). d: 0.9 (m, 3H), 1.1 and 2.2 (per m, 2H), 3.08 40 (s, 2H), 3.4 (s, 3H) (s, 6H), 6 , 8 and 7.1 (per m, 4H) ppm.

Example 12 3,3-Bis- (4-methoxyphenyl) hexanoic acid 45 Methyl 3,3-bis- (4-methoxyphenyl) hexanoate (5.2 g, 15.2 mmol) are present in 20 ml of dioxane, KOH (1.05 g, 18.2 mmol) is added and boil approx. 1 hour. The mixture is diluted, then with water, washed with ethyl acetate, the aqueous phase is then regulated with HCl diluted to pH 3 and extracted with ethyl acetate. The organic phase is then washed with saturated NaCl solution, dried over MgSO4 and concentrated. After chromatography on silica gel (CH2Cl2 / 3% methanol), 4.1 g of a slightly yellowish oil (84%) are obtained. iH-MR (CDC13), d: 0.9 (m, 3H), 1.1 and 2.2 (per m, 2H), 3.1 (s, 3H), 3.8 (s, 6H), 6.8 and 7.1 per m, 4H) ppm.

Example 13 The following compounds are prepared analogously to Example 5.

Acid (2R, S) 3, 3-diphenyl-2- (methylnaphth-2'-diButanoic melting point: 163-166 ° C FAB-MS: 380 (M +) Acid (2R, S) 3, 3-diphenyl-2- (3 ', 5'-dimethylbenzDbutanoic melting point: 141-143 ° C FAB-MS: 358 (M +) Acid (2R, S) 3,3-diphenyl-2- (4'-benzyloxy-3'-methoxybenzyl) butanoic Melting point: 163-166 ° C FAB-MS: 466 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (4'-benzyloxy -3-methoxybenzyl) butanoic Melting point: 137-140 ° C FAB-MS: 526 (M +) Acid (2R, S) 3, 3 -diphenyl -2- (4'-hydroxy-3'-methoxybenzydbutanoic melting point: 153-155 ° C FAB-MS: 376 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (4'-hydroxy-3-methoxybenzyl) -butanoic Melting point: 157-160 ° C FAB-MS: 436 (M +) Acid (2R, S) 3,3-bis- (4-methoxy -3-methylphenyl) -2- (3 ', 5'-dimethylbenzDbutanoic melting point: 150-152 ° C FAB-MS: 446 (M +) Acid (2R, S) 3, 3 -bis- (4-methoxyphenyl) -2- (methylnaphth-2'-yl) butanoic Melting point: 162-164 ° C FAB-MS: 440 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (3 ', 5'-dimethylbenzDbuta-noic) Melting point: 125-128 ° C FAB-MS: 418 (M +) Acid (2R, S) 3,3-bis- (4-methoxy-3-methylphenyl) -2- (3 ', 4'-dimethoxy-benzyl) butanoic Melting point: 155-157 ° C FAB-MS: 478 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (3 ', 4'-dimethoxybenzyl) butanoic Melting point: 148-150 ° C FAB-MS: 450 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (5'-methoxy-3 ', 4'-methylene-dioxybenzyl) pentanoic Melting point: 138-141 ° C FAB-MS: 478 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (5'-methoxy-3 ', 4'-methylene-dioxybenzyl) butanoic Melting point: 134-136 ° C FAB-MS: 464 (M +) Acid (2R, S) 3,3-diphenyl-2- (5'-methoxy-3 ', 4'-methylenedioxybenzyl) -butanoic Melting point: 135-138 ° C FAB-MS: 464 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (3 ', 4'-ethylenedioxybenzyl) -pentanoic acid Melting point: 168-170 ° C FAB-MS: 462 (M +) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (3 ', 4'-ethylenedioxybenzyl) -butanoic Melting point: 161-163 ° C FAB-MS: 448 (M +) Acid (2R, S) 3, 3-bis- (4-methoxyphenyl) -2 - (3 ', 4'-methylenedioxybenzyl) -hexanoic Melting point: 142-145 ° C (from n-heptane) Acid (2R, S) 3,3-bis- (4-methoxyphenyl) -2- (3 ', 4'-ethylenedioxybenzyl) -hexanoic Melting point: 163-165 ° C (from n-heptane / diethyl ether) Acid (2R, S) 3, 3-bis- (4-methoxyphenyl) -2 - (3 ', 4'-methylenedioxy-5' me-toxibenzyl) hexanoic Melting point: 180-182 ° C (from n -heptane / diethyl ether) Example 14 The compounds obtained in examples 2 to 10 were examined by the procedures described above with respect to their affinity with the endothelin receptor. As the comparative substance, a compound known from WO 94/02474 was used. The result is described in the following table.

Claims (1)

1. Claiming Derivatives of the carboxylic acid of the formula I R 2 R 1 R 5 C CH (I), R 3 2 (CH 2) n R 4 in which R 1 signifies a tetrazole, nitrile, a COOH group or a hydrolysable COOH radical, and the Other substituents have the following meanings: R2 and R3 (which can be identical or different): • * • - > phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, cyano, N02, hydroxy, C? -C4-alkyl, C? -C4-haloalkyl, C1-C-alkoxy, C? -C4- haloalkoxy, phenoxy, C? -C4-alkylthio, amino, benzyloxy, C? -C4-alkylamino or C? -C4-dialkylamino; or phenyl or naphthyl, which are linked to each other in the ortho position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom; "R4 phenyl or naphthyl, methylenedioxyphenyl, ethylenedioxyphenyl, indian, indolyl, pyridyl, benzopyranyl, furanyl, benzofurranyl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyrimidinyl, 2,3-dihydrobenzofuranyl, benzothienyl, quinolinyl, C3-O7- cycloalkyl, thienyl, oxazolyl, thiazolyl, which 30 may be substituted by one or more of the following radicals: halogen, cyano, hydroxy, N02, C? -C4-alkyl, C? -C4-halogenoalkyl, C? -C4-alkoxy, C? -C4-halogenoalkoxy, phenoxy , C? -C4-alkylthio, amino, benzyloxy, C? -C-alkylamino or C? -C4-dialkylamino, the alkyl radicals being able to form "together a ring; R5 C? -C8-alkyl, C3-Ce-alkenyl, C3-C6-alkynyl or C3-C8-cycloalkyl, the radicals of which may be mono- or polysubstituted by: halogen, C? -C4 -alkoxy, C? C4-alkylthio, C? -C4-alkylamin-40, di-C1-C4-alkylamino; Phenyl, benzyl, 1-methylnaphthyl, 2-methylnaphthyl or naphthyl, which may be substituted each time by one or more of the following radicals: halogen, cyano, hydroxy, amino, C? -C4-alkyl, C? -C4- alkoxy, phenoxy, C? -C4-alkylthio, di-oxo-methylene or dioxoethylene; n