WO1998027091A1

WO1998027091A1 - Endothelin receptor antagonists as pesticides

Info

Publication number: WO1998027091A1
Application number: PCT/EP1997/007047
Authority: WO
Inventors: Werner Mederski; Mathias Osswald; Dieter Dorsch; Claudia Wilm; Maria Christadler; Claus Jochen Schmitges
Original assignee: Merck Patent Gmbh
Priority date: 1996-12-19
Filing date: 1997-12-15
Publication date: 1998-06-25
Also published as: AR008716A1; DE19653024A1; AU5758398A

Abstract

New compounds of the formula (I), in which R is an unsubstituted, an R3 mono-, di-, or trisubstituted, or an R5 substituted phenyl, or unsubstituted or simply R2 substituted 2,1,3-benzothiadiazolyl; R1 is A, in which 1-7 H atoms can be replaced by F, -S-A, -A-A, unsubstituted or simply R3 substituted phenyl, -alkylene-phenyl or unsubstituted or simply R3 substituted thienyl; R2 is A, F, Cl, Br or -O-A; R?3, R4, R5¿ are, independently, A, -O-A, -S-A, -O-alkylene-COOH, -alkylene-COOH or COOH; R?3 and R4¿ together can also mean -O-CH¿2?-O-; and A is alkyl with 1-7 C atoms, as well as their salts, have endothelin receptors antagonistic properties.

Description

ENDOTHELINE RECEPTOR ANTAGONISTS AS PESTICIDES

The invention relates to compounds of the formula I.

wherein

R is unsubstituted or mono-, di- or trisubstituted by R ^3, R ⁴ or R ⁵ substituted phenyl, or unsubstituted or monosubstituted by R ² 2,1,3-benzothiadiazolyl,

R ¹ A, in which 1-7 H atoms can be replaced by F, -SA, -OA, unsubstituted or simply substituted by R ^3, phenyl, alkylene-phenyl or unsubstituted or simply substituted by R ³ ,

R ² A, F, Cl, Br or -OA,

R ³ , R ⁴ , R ⁵ each independently of one another A, -OA, -SA, -O-alkylene-COOH, -alkylene-COOH or COOH,

R ³ and R ⁴ together also -O-CH ₂ -O- and

A alkyl with 1-7 C atoms,

means

as well as their salts. Similar compounds are known, for example, from EP 0 526 708, EP 0 617 001, WO 93/08799 or WO 96/12706.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show endothelin receptor-antagonistic properties and can therefore be used to treat diseases such as hypertension, heart failure, coronary heart disease, renal, cerebral and myocardial ischemia, renal failure, cerebral infarction, subarachnoid hemorrhage, arteriosclerosis, pulmonary high pressure, inflammation, endahyroidism, asthma Shock and complications after the administration of substances such as Cyclosporin, as well as other diseases associated with endothelin activities.

The connections show i.a. a high affinity for the endothelin

Subreceptors ET _A and ET _B. In particular, they have an affinity for the endothelin subtype receptor B.

These effects can be determined by conventional in vitro or in vivo methods, e.g. described by P.D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein et al., Proc. Natl. Acad. Be. USA 91, 1994, 8052-8056.

A suitable method for determining the hypotensive effect is e.g. B. described by M.K. Bazil et al., J. Cardiovasc. Pharmacol. 22, 1993, 897-905 and J. Lange et al., Lab Animal

20, 1991, appl. Note 1016.

The compounds of the formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of cardiovascular and vascular diseases, especially hypertension and heart failure. The invention relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and their salts,

characterized in that a compound of formula II

wherein

R ¹ and R ^{2 have} the meaning given in claim 1, and A denotes alkyl having 1-4 C atoms or benzyl,

with a compound of the formula IM

R-CH ₂ -NH-NH ₂ wherein

R has the meaning given in claim 1,

implements

and then cleaves the ester,

and / or converts a compound of formula I into one of its salts.

For all residues that occur several times, such as B. R ³ , R ⁴ or R ⁵ applies that their meanings are independent of each other. Above and below, the radicals or parameters R, R ¹ , R ² and A have the meanings given in the formulas I to III, unless expressly stated otherwise.

In the above formulas, A is alkyl and has 1 to 7, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1 -, 2- or 3-methylbutyl, 1, 1 -, 1, 2- or 2 , 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-,

1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1 , 1, 2- or 1, 2,2-trimethylpropyl.

If R ^{1 is} alkyl, alkyl also has the following preferred meanings in addition to the preferred meanings mentioned:

Trifluoromethyl, pentafluoroethyl, heptafluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Alkylene preferably means methylene, ethylene, propylene, butylene, furthermore pentylene or hexylene.

Alkylene-phenyl is especially benzyl or phenethyl.

O-A preferably means e.g. Methoxy, ethoxy, propoxy or butoxy, also isopropoxy or tert-butoxy.

R is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p- ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methylthiophenyl, o-, m- or p-carboxymethoxyphenyl, o-, m- or p-carboxymethylphenyl, 2,3-, 2,4-2,5 - or 2,6-dimethoxyphenyl, 2-carboxy-methoxy-4-methoxy-phenyl, 3,4,5-trimethoxyphenyl, 1, 3-benzodioxol-5-yl, more preferably unsubstituted or monosubstituted 2,1,3-benzo - thiadiazol-5-yl, in particular preferably 4-, 6- or 7-chloro-benzothiadiazol-5-yl, 4-, 6- or 7-methyl-benzothiadiazol-5-yl, 4-, 6- or 7- Bromobenzothiadiazol-5-yl, 4, 6- or 7-fluoro-benzothiadiazol-5-yl, 4, 6- or 7-methoxy-benzothiadiazol-5-yl.

The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.

Formula I encompasses all of these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.

Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ic, which correspond to the formula I and in which the radicals which are not specified have the meaning given for the formula I, but in which

in la R unsubstituted or single, double or triple by R ³ ,

R ⁴ or R ⁵ substituted phenyl and R ¹ A, in which 1-7 H atoms can be replaced by F,

-OA, unsubstituted or simply substituted by R ³ phenyl, benzyl or thienyl and

R ³ , R ⁴ , R ⁵ each independently represent A, -OA, -SA, -O-CH ₂ -COOH, -CH ₂ -COOH or COOH;

in Ib R unsubstituted or simply substituted by R ²

2,1,3-benzothiadiazol-5-yl radical and R ¹ A, in which 1-7 H atoms can be replaced by F,

-OA, unsubstituted or simply substituted by R ³ phenyl, benzyl or thienyl, mean and

in Ic R unsubstituted or single, double or triple by R 3,

R ⁴ or R ⁵ substituted phenyl; R ^{1 is} methyl, ethyl, propyl, butyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, unsubstituted or simply substituted by R ^3, phenyl, benzyl or thienyl; R, R, R each independently of one another A, -OA, -SA,

-O-CH ₂ -COOH, -CH ₂ -COOH or COOH and R ³ and R ⁴ together also mean -O-CH ₂ -O-.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III and then cleaving the ester.

The reaction is usually carried out in an inert solvent or solvent mixture, preferably in the presence of e.g. of glacial acetic acid Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about 0 ° and 160 °, normally between 20 ° and 140 °.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

When the compounds of the formula II are reacted with the compounds of the formula III, regioisomeric 1 H-pyrazole-3-carboxylic acid esters of the formula IV are formed as by-products

wherein

R, R ¹ , R ² and A have the meaning given in claim 1.

The corresponding 1 H-pyrazole-3-carboxylic acids show no affinity for r diaent P EnriΛdlnotthhαelliirni - DRαez-Tαeop + tΛoirrαein- »

The starting compounds of formula II are usually new, while those of formula III are generally known.

However, the compounds of formula II can be prepared by methods known per se. For example, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -2-methoxyimino-4-oxo-octanoate by reacting 5-bromomethyl-2,1, 3-benzothiadiazole with 2-methoxyimino-4-oxo - ethyl octanoate (WT Ashton and GA Doss in J. Heterocyclic Chem. 30, 307 (1993)) in an inert solvent with the addition of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt weak acid of the alkali or alkaline earth metals, preferably the Potassium, sodium, calcium or cesium can be obtained. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable.

Preferably one works at temperatures between 0 ° and 150 °. Suitable inert solvents are those already mentioned above.

Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

An acid of the formula I can be converted with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating. Bases that provide physiologically acceptable salts are particularly suitable for this implementation.

Thus, the acid of formula I can be converted with a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.

On the other hand, a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, eg formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanoic acid or Ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.

The invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.

Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, Contain buffer substances, coloring, flavoring and / or several other active ingredients, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used in the control of diseases, in particular

Hypertension and heart failure can be used.

The substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: heptane / ethyl acetate 9: 1. Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺ Example 1

6.52 g of potassium carbonate are added to a solution of 9.0 g of 2-methoxyimino-4-oxo-octanoic acid ethyl ester and 9.44 g of 5-bromomethyl-2,1,3-benzothiadiazole in 60 ml of dimethylformamide and stirred for 20 hours in a room - temperature. The mixture is worked up in the customary manner and 15.5 g of ethyl 3- (2,1,3-benzothiadiazol-5-ylmethyl) -2-methoxyimino-4-oxo-octanoate ("A") are obtained. 11.37 g of benzylhydrazine dihydrochloride are added to a solution of 14.7 g of "A" in 100 ml of ethylene glycol monomethyl ether and 200 ml of glacial acetic acid, and the mixture is heated at 110 ° for 24 hours.

After customary working up and chromatography on silica gel, 1.33 g of 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester and 2.0 g are obtained of the regioisomeric 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-5-butyl-1 H-pyrazole-3-carboxylic acid ethyl ester.

Analogously, by converting "A"

with (3-methoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3-methoxybenzyl) -3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2,4-dimethoxybenzyl) -3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (3,4,5-trimethoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (2-carboxybenzyl) -3-butyl-

1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethylbenzyl) -3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (1, 3-benzodioxol-5-ylmethyl) hydrazine 4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-ylmethyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2, 1, 3-benzothiadiazol-5-ylmethyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2, 1, 3-benzothiadiazol-5-ylmethyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

and the regioisomeric 1 H-pyrazole-5-butyl-3-carboxylic acid ethyl ester derivatives.

Analogously, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -4-cyclohexyl-2-methoxyimino-4-oxo-butyrate is obtained by reaction

with benzylhydrazine 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-cyclohexyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (3-methoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2,4-dimethoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (3,4,5-trimethoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethylbenzyl) -3-cyclohexyl-1 H-pyrazole-5-carboxylic acid ethyl ester; with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (1, 3-benzodioxol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (1, 3-benzodioxol-5-ylmethyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2, 1, 3-benzothiadiazol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (1, 3-benzothiadiazol-5-ylmethyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid ethyl ester;

and the regioisomeric 1 H-pyrazole-5-cyclohexyl-3-carboxylic acid ethyl ester derivatives.

Analogously, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -4-propoxy-2-methoxyimino-4-oxo-butyrate is obtained by reaction

with benzylhydrazine

Ethyl 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-propoxy-1H-pyrazole-5-carboxylate;

with (3-methoxybenzyl) hydrazine 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2,4-dimethoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (3,4,5-trimethoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine 4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (1, 3-benzodioxol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-ylmethyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2,1, 3-benzothiadiazol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2,1, 3-benzothiadiazol-5-ylmethyl) -3-propoxy-1H-pyrazole-5-carboxylic acid ethyl ester;

and the regioisomeric 1 H-pyrazole-5-propoxy-3-carboxylic acid ethyl ester derivatives.

Analogously, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -4- (2-thienyl) -2-methoxyimino-4-oxo-butyrate is obtained by reaction

with benzylhydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1-benzyl-3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (3-methoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-

(2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester; with (3,4,5-trimethoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-yimethyl) -1- (2-carboxymethylbenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3- (2-thienyl) -1 H -pyrazole-5-carboxylic acid ethyl ester;

with (1, 3-benzodioxol-5-ylmethyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2,1, 3-benzothiadiazol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2,1, 3-benzothiadiazol-5-ylmethyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid ethyl ester;

and the regioisomeric 1 H-pyrazole-5- (2-thienyl) -3-carboxylic acid ethyl ester derivatives.

Analogously, ethyl 3- (2,1, 3-benzothiadiazol-5-ylmethyl) -4-phenyl-2-methoxyimino-4-oxo-butyrate is obtained by reaction

with benzylhydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1-benzyl-3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (3-methoxybenzyl) hydrazine 4- (2,1, 3-Benzothiadiazol-5-yimethyl) -1- (3-methoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (2,4-dimethoxybenzyl) -3-phenyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (3,4,5-trimethoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (1,3-benzodioxol-5-yimethyl) hydrazine 4- (2,1,3-benzothiadiazol-5-ylmethyl) -1 - (1,3-benzodioxol-5-ylmethyl) -3-phenyl-1H -pyrazole-5-carboxylic acid ethyl ester;

with (2, 1, 3-benzothiadiazol-5-ylmethyl) hydrazine

4- (2,1, 3-Benzothiadiazol-5-ylmethyl) -1- (2,1, 3-benzothiadiazol-5-ylmethyl) -3-phenyl-1H-pyrazole-5-carboxylic acid ethyl ester;

and the regioisomeric 1 H-pyrazole-5-phenyl-3-carboxylic acid ethyl ester derivatives.

Analogously, ethyl 3- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -2-methoxyimino-4-oxo-octanoate is obtained by reaction with benzylhydrazine

Ethyl 4- (2, 1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1-benzyl-3-butyl-1H-pyrazole-5-carboxylate;

with (3-methoxybenzyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1 - (3-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2,4-dimethoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (3,4,5-trimethoxybenzyl) hydrazine 4- (2, 1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3-butyl-1 H -pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1- (2-carboxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethylbenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (2-methoxycarbonylmethoxy-4-methoxybenzyl) hydrazine

4- (2,1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid ethyl ester;

with (1, 3-benzodioxol-5-ylmethyl) hydrazine

4- (2, 1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester;

with (2,1, 3-benzothiadiazol-5-ylmethyl) hydrazine 4- (2, 1,3-benzothiadiazol-6-chloro-5-ylmethyl) -1 - (2,1, 3-benzothiadiazol-5-ylmethyl ) -3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester; and the regioisomeric 1 H-pyrazole-5-butyl-3-carboxylic acid ethyl ester derivatives.

Example 2

A solution of 1, 3 g of 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-butyl-1 H-pyrazole-5-carboxylic acid ethyl ester in 20 ml of ethanol and 5 ml of THF is mixed with 5 ml of NaOH (c = 2 mol / L) are added and the mixture is stirred at room temperature for 12 hours. You work up as usual and receive

Crystallization from heptane 0.75 g of yellow crystals 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-butyl-1 H-pyrazole-5-carboxylic acid, mp 122-124 °.

The following compounds are obtained analogously from the 1 H-pyrazole-5-carboxylic acid ester derivatives listed in Example 1

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethylbenzyl) -3-butyl-1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-ylmethyl) -3-butyl-1H-pyrazole-5-carboxylic acid; 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,1, 3-benzothiadiazol-5-ylmethyl) -3-butyl-1 H -pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxybenzyl) -3-cyclohexyl-1 H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyi) -1 - (2-carboxymethylbenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-yimethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3-cyclohexyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3-cyclohexyl-1 H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2, 1, 3-benzothiadiazol-5-ylmethyl) -3-cyclohexyl-1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3-methoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid; 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethylbenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2, 1, 3-benzothiadiazol-5-ylmethyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2,4-dimethoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid; 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxybenzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (1, 3-benzodioxol-5-ylmethyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (2, 1, 3-benzothiadiazol-5-ylmethyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1-benzyl-3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3,4,5-trimethoxybenzyl) -3-phenyl-1H-pyrazoI-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3-phenyl-1H-pyrazole-5-carboxylic acid; 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,1, 3-benzothiadiazol-5-ylmethyl) -3-phenyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1-benzyl-3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1- (3-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1 - (3,4,5-trimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1- (2-carboxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1- (2-carboxymethylbenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1 - (2-carboxymethoxy-4-methoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid;

4- (2, 1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1 - (1, 3-benzodioxol-5-ylmethyl) -3-butyl-1 H-pyrazole-5-carboxylic acid and

4- (2,1, 3-Benzothiadiazol-6-chloro-5-ylmethyl) -1 - (2,1, 3-benzothiadiazol-5-ylmethyl) -3-butyl-1 H-pyrazole-5-carboxylic acid. The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

R unsubstituted or one, two or three times by R,

R ⁴ or R ⁵ substituted phenyl or unsubstituted or simply substituted by R ² 2,1,3-benzothidiazoiyl,

R ¹ A, in which 1-7 H atoms can be replaced by F, ⁰ -SA, -OA, unsubstituted or simply substituted by R ^3, phenyl, alkylene-phenyl or unsubstituted or simply substituted by R ³ ,

R ^ A, F, Cl, Br or -O-A, 5

R ³ , R ⁴ , R ⁵ each independently of one another A, -OA, -SA, -O-alkylene-COÖH, -alkylene-COOH or COOH,

R ³ and R ⁴ together also -O-CH ₂ -O- and 0

A alkyl with 1-7 C atoms,

means

⁵ and their salts.

2. Compounds of formula I according to claim 1

a) 4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1-benzyl-3-butyl-1 H-pyrazole-5-carboxylic acid; b) 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxy-benzyl) -3-butyl-1H-pyrazole-5-carboxylic acid; c) 4- (2,1, 3-benzothiadiazol-6-chloro-5-ylmethyl) -1- (3-methoxy-benzyl) -3-butyl-1H-pyrazole-5-carboxylic acid; d) 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxy-benzyl) -3-butyl-1H-pyrazole-5-carboxylic acid; e) 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2,4-dimethoxybenzyl) -3-butyl-1H-pyrazole-5-carboxylic acid; f) 4- (2, 1, 3-benzothiadiazol-5-ylmethyl) -1 - (3-methoxy-benzyl) -3-phenyl-1H-pyrazole-5-carboxylic acid; g) 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (3-methoxy-benzyl) -3- (2-thienyl) -1 H-pyrazole-5-carboxylic acid; h) 4- (2, 1, 3-Benzothiadiazol-5-ylmethyl) -1 - (3-methoxy-benzyl) -3-cyclohexyl-1 H-pyrazole-5-carboxylic acid; j) 4- (2,1, 3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxy-benzyl) -3-propoxy-1H-pyrazole-5-carboxylic acid;

as well as their salts.

3. A process for the preparation of compounds of the formula I as claimed in claim 1 and their salts,

characterized in that a compound of formula II

wherein

with a compound of the formula IM

R-CH ₂ -NH-NH, wherein

R has the meaning given in claim 1,

implements

and then cleaves the ester,

and / or converts a compound of formula I into one of its salts.

4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of formula I according to claim 1 and / or one of its physiologically acceptable

Brings salts together with at least one solid, liquid or semi-liquid carrier or auxiliary into a suitable dosage form.

5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating hypertension, heart failure, kidney failure, cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage, arteriosclerosis, inflammation, asthma and endotoxic shock.

7. Medicament of formula I according to claim 1 and their physiologically acceptable salts as endothelin receptor antagonists.

8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the

Combat hypertension, heart failure, kidney failure, cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage, arteriosclerosis, inflammation, asthma and endotoxic shock.