MXPA00000755A - Benzothia(oxa)diazol derivatives and their use as endothelin-receptor antagonists - Google Patents

Abstract

The invention relates to novel compounds of formula (I), wherein R represents group (1), X stands for O or S, and R1, R2, R3, R4, R5 and R6 have the meaning citedin Claim 1, or a tauomeric cyclized form. The invention further relates to (E) isomers and their salts. Said novel derivatives exhibit endothelin-receptor antagonistic properties.

Description

DERIVATIVES OF BENZOTIA (OXA) DI AZOL AND ITS USE AS ANTAGONISTS OF THE ENDOTHELIAL RECEPTOR DESCRIPTION OF THE INVENTION The invention relates to the compounds of formula I, R where R represents X represents O or S, R1 represents H, Hal, OA or A, REF .: 32269 R2, R3, R5, R6 independently represent H, Hal, A, OA or R4, R4 represents -0- (CH2) n-Cy, Cy represents cycloalkyl of 3 to 8 C atoms, A represents alkyl of 1 to 6 atoms of C, where one or two CH2 groups may be replaced by 0 or S atoms or by groups -CR5 = CR5 'and / or 1 to 7 H atoms may be replaced by F, R5 and R5 independently represent H, F or A, Hal represents fluorine, chlorine, bromine or iodine, n is 0, 1 or 2, or a cyclic tautomeric form, and isomers (E) and salts of all isomers. The cyclic tautomeric form of hydroxylactone occurs when the compounds of formula I are isolated as carboxylic acids. If the compounds of formula I are present as salts (carboxylates), then the open chain tautomer is obtained. In the world patent no. 95/05376 similar compounds are disclosed. The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I and their salts possess valuable pharmacological properties and are well tolerated. In particular, they exhibit endothelial receptor antagonist properties and, therefore, can be used for the treatment of diseases such as hypertonia, heart failure, coronary disease, renal, cerebral and myocardial ischemia, renal insufficiency, cerebral infarction, subarachnoid hemorrhage. , arteriosclerosis, pulmonary hypertension, inflammations, asthma, hyperplasia of the prostate, endotoxic shock and complications after the administration of substance such as, for example, cyclosporine, and others, which produce diseases associated with endothelial activity.

The compounds exhibit, among other things, a high affinity for the endothelial sub-receptors ETA and ETB. These effects can be checked by usual methods in vi tro or in vi ve, as described, for example, P.D. Stein et al., In J. Med. Chem., 37_, 1994, p. 329 to 331, and E. Ohlstein et al., In Proc. Nati Acad. Sci. USA 91_, 1994, p. 8052 to 8056. M. K. Bazil et al., And J. Lange et al., Describe an adequate method to determine the hypotensive effect in J. Cardiovasc. Pharmacol. 22, 1993, p. 897 to 905, and in Lab. Animal 2_0, 1991, Appl. Note 1016, respectively. The compounds of formula I can be used in medicine and veterinary medicine as active substances of drugs, in particular for the prophylaxis and / or therapy of cardiac and circulatory diseases and of angiopathy, and mainly of hypertonia and heart failure . The object of the invention is constituted by the compounds of formula I and their salts, and also a process for preparing the compounds of formula I, according to claim 1, and their salts, characterized in that a compound of formula II is reacted wherein R1, R5, R6 and X have the meaning indicated in claim 1, and A represents alkyl of 1 to 4 carbon atoms or benzyl, with a compound of formula III eleven! wherein R2, R3, R4 have the meaning indicated in claim 1, and then the ester is cleaved, and / or a base or an acid of formula I is transformed into one of its salts. The meanings of all the remains that appear repeatedly in the present text, for example R3, R4 or R5, are independent of each other. The remains or parameters R, X, R1, R2, R3, R4, R5, R6, A and n indicated in this text have the meanings indicated for formulas I to III, unless otherwise indicated. In the formulas indicated above, A represents alkyl of 1 to 6, preferably of 1, 2, 3 or 4 C atoms. The preferred meanings of A are methyl, then ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertbutyl, and then 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, then trifluoromethyl, pentafluoroethyl, allyl or crotyl.

Cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Hal is preferably F, Cl or Br, but also I. R1 preferably represents H, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, methoxymethyl, nitro, amino, formamido, acetamido, sulfonamido, methylsulfonamido, N-methylsulfonamido, cyano and then also formyl. R2, R3, R5, R6 independently represent H, fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, alkyl such as, for example, methyl, ethyl, propyl or isopropyl, then hydroxy , nitro, amino, N-methylamino, dimethylamino, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, N-methylacetamido , N-ethylacetamido, N-propylacetamido, N-butylacetamido, propionylamino, butyryla ino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, N-methyl-methylsulfonamido, N-methyl-ethylsulfonamido, N-ethyl-methylsulfonamido, N-ethyl-ethylsulfonamido, N-propyl-methylsulfonamido, N-propyl- ethylsulfonamido, N-butyl-methylsulfonamido, N-butyl-ethylsulfonamido, phenylsulfonamido, (4-methylphenyl) -sulfonamido, carbamido, ethylcarbamido, phenylcarbamido, methoxycarbonylamino, ethoxycarbonylamino, formyl, hydroxymethyl, methoxymethyl, ethoxymethyl, anilino, phenoxycarbonylamino, benzyloxycarbonyl, benzyl -sulfonamido, N, N-dimetilcarbamido, 1-piperidinyl-CONH, hidroxietoxicarbonilamino, metoxietoxicarbonilamino, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxymethyl, methoxycarbonylmethyl or ethoxycarbonylmethyl. The compounds of formula I may have one or more chiral centers and, therefore, have different stereoisomeric forms. Formula I covers all these forms. Particularly preferred are the Z isomers of formula I, ie the compounds in which the C = C double bond of the radical R is in the Z-configuration. Accordingly, the compounds of the formula I which at least one of the mentioned residues has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the partial formulas la and Ib which are indicated below, which correspond to the formula I and in which the radicals which are not explicitly detailed have the meanings for the formula I, namely: in the R 1 represent H , X represent S, R2, R3, R4, R5 independently represent H, Hal, A or OA, A represents alkyl of 1 to 6 C atoms and R4 represents cycloalkyl of 3 to 6 C atoms, in Ib R1 represents H, X represents O, R2, R3, R4, R5 independently represent H, Hal, A or OA, A represents alkyl of 1 to 6 C atoms and R4 represents cycloalkyl of 3 to 6 C atoms. In general, the compounds of Formula I and the starting materials for its preparation are prepared according to known methods, as described in the literature (for example, in works standard such as those of Houben-Weyl, "Methoden der organischen Che ie" (Methods of Organic Chemistry), Gerog-Thieme-Verlag, Stuttgart;) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods that are not detailed in this text. If desired, the starting materials can be prepared in themselves, but in such a way that instead of isolating them from the reaction mixture they are directly reacted to form the compounds of formula I. The compounds of formula I can be prepared preferably by reaction of compounds of formula II with compounds of formula III, and by subsequent cleavage of the ester. Generally, the reaction is carried out in an inert solvent, preferably in the presence of a base such as, for example, a potassium or sodium alkoxide such as sodium or potassium methoxide, ethoxide or terbutoxide. As the solvent, the respective alcohols are particularly preferred. The reaction times are comprised, according to the conditions used, between a few minutes and 14 days, the temperatures of The reaction is between about 0 ° and 150 °, usually between 20 ° and 130 °. Suitable inert solvents include, 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; esters such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether (methyl glycol) or ethylene glycol monoethyl ether (ethylene glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone, amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide (DMSO); carbon sulfide; carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned.

In general, the starting compounds of formula II are new, whereas those of formula III are known. However, the compounds of formula II can be obtained according to methods known per se. Thus, for example, ethyl 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-methoxy phenyl) -4-oxobutanoate can be obtained by the reaction of 2- (2,1,3) -benzothiadiazol-5-yl) -acetic acid ethyl ester with 2'-bromo-4-methoxy-acetophenone in an inert solvent and adding an acid capturing agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, or either by adding some other alkaline or alkaline earth salt of a weak acid, preferably a salt of potassium, sodium, calcium or cesium. It may also be convenient to add an organic base such as triethylamine, dimethylamine, pyridine or quinoline. It is conveniently worked at temperatures between 0 ° and 150 °. The solvents mentioned above can be used as the inert solvent. Methyl 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -acetate can be prepared, for example, from 4,6-dimethyl-2,3,1-benzothiadiazole as follows : 1. by regioselective deprotonation with diisopropyl-lithium amide and 1,3-dimethyl-tetrahydro-pyrimidin-2-one in THF. 2. by reaction with C02. 3. by esterification with methyl iodide and potassium carbonate in DMF. The esters can be saponified with, for example, acetic acid or with NaOH or KOH in water, water-THF or water-dioxane, at temperatures between 0 and 100 °. A "base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol, and then by evaporation of the latter. In particular, acids which form physiologically acceptable salts are suitable for this reaction, therefore, inorganic acids, such as, for example, sulfuric acid, nitric acid, hydrocides such as acid, can be used. hydrochloric or hydrobromic, phosphoric acids such as orthophosphoric acid, sulfamic acid, then also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids such as, for example, Formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, naphthalene disulfonic and lauryl sulfuric. The salts of acids not acceptable from the physiological point of view, for example the picrates, can be used to isolate and / or purify the compounds of formula I. Furthermore, the compounds of formula I can be transformed with bases (for example, sodium or potassium hydroxide or carbonate) into their salts metal, in particular the alkali metal or alkaline earth metal salts, or in their respective ammonium salts. The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts in the preparation of pharmaceutical preparations, in particular by a non-chemical route. For these purposes, the compounds can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid auxiliary excipient or auxiliary product and, optionally, in combination with one or more additional active substances. Another object of the present invention are pharmaceutical preparations containing at least one compound of formula I and / or one of its physiologically acceptable salts. These preparations can be used in medicine and in veterinary medicine as a medicine. Among the excipients there may be mentioned organic or inorganic substances which are suitable for enteral (eg oral), parenteral or topical administration and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, tablets, pills, capsules, powders, granules, syrups, juices or drops are used in particular for rectal administration, for suppositories, for parenteral administration, solutions, preferably oily solutions or aqueous, and also suspensions, emulsions or implants, and for Topical application ointments, creams or powders. The new compounds can also be lyophilised and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The aforementioned preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing osmotic pressure, pH regulating substances, dyes, taste-correcting substances and / or various additional active substances, for example, one or several vitamins. The compounds of formula I and their physiologically acceptable salts can be used to combat diseases, in particular hypertonia and heart failure. In general, the substances of the invention are preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dose is preferably comprised between approximately 0.02 and 10 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, of the effectiveness of the special compound used, of age, body weight, general state of health, sex, diet, time and method of administration, speed of excretion, combination of medications and the severity of the particular disease to which the therapy is applied. Oral administration is preferred. All temperatures indicated in this text are 'given in ° C. In the examples that follow, the expression "one works (or treats) in a usual manner" means the following: if necessary, water is added, if necessary it is adjusted, according to the constitution of the final product, to pH values comprised between 2 and 10, it is extracted with ethyl acetate or dichloromethane, the phases are separated and the organic phase is dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallization. The Rf values are given on silica gel; mobile phase: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): The (ionization by electronic impact) M + FAB (Fast Atom Bombardment) (rapid bombardment of atoms) (M + H) + EXAMPLE 1 To a solution of 34 mg of sodium in 10 ml of ethanol are added 0.368 g of 4-cyclopentyloxy-3,5-dimethoxybenzaldehyde ("A") and 0.52 g of 2- (2, 1, 3-benzo-thiadiazole). -5-yl) -4- (4-methoxyphenyl) -4-oxo-butanoate ethyl, mp 89 ° (obtained by reaction for 18 hours and with heating under reflux of 5.5 g of 2- (2, 1, 3-benzo-thiadiazol-5-yl) -acetic acid ethyl ester with 5.5 g of 2'-bromo-4- methoxyacetophenone and 4 g of potassium carbonate in 200 ml of acetone; ethyl 2- (2, 1, 3-benzothiadiazol-5-yl) -acetate, m.p. 40-41 °, is obtained by reaction for 4 hours and with refluxing of 24.3 g of ethyl 3,4-diaminophenylacetate with 26.9 ml of thionylaniline in 80 ml of toluene), and then the mixture is heated under reflux for one hour. hour. 1.4 ml of acetic acid are added and heating is continued for a further 16 hours. The solvent is removed and the mixture is worked in the usual manner. 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl-5H-furan-2- is obtained ona, FAB 575. Analogously, it is obtained by reaction of "" with 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoate of ethyl. 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyl-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H -furan-2-one, with ethyl 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (2, 5-dimethoxy-phenyl) -4-oxo-butanoate, 3- (2, 1,3-benzothiadiazol-5-yl) -4- (4-cyclopentyl-3,7-dimethoxybenzyl) -5-hydroxy-5- (2,5-dimethoxyphenyl) -5H-furan-2-one, with 2- (7-Methyl-2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoate, ethyl, 3- (7-methyl-2-2, 1,3-benzothiadiazol-5-yl) -4- (4-cyclo-pentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H-furan-2-one, mp 159-160 °. Analogously, it is obtained by reacting 3-cyclopentyloxy-4,5-dimethoxybenzaldehyde with 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-methoxy phenyl) -4-oxo-butanoate. ethyl, 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-cyclopentyl-4,5-dimethoxy-benzyl) -5-hydroxy-5- (4-methoxy-phenyl) -5H-furan-2-one, FAB 575. Analogously, it is obtained by reacting 4-cyclopropyl-methyloxy-4,5-dimethoxybenzaldehyde with 2- (2, 1, 3-benzothiadiazol-5-yl) -4 - ethyl (4-methoxyphenyl) -4-oxo-butanoate, 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-cyclo-propylmethyloxy-4,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan-2 -one; with ethyl 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoate, 3- (2, 1, 3-benzothiadiazol-5) -yl) -4- (4-cyclo-propylmethyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxy phenyl) -5H-furan-2-one; with ethyl 2- (2, 1, 3-benzothiadiazol-5-yl) -4- (2, 5-dimethoxy-phenyl) -4-oxo-butanoate, 3- (2, 1, 3-benzothiadiazol-5) -yl) -4- (4-cyclopropyl-methyloxy-3,5-dimethoxyphenyl) -5-hydroxy-5- (2,5-dimethoxy-phenyl) -5H-furan-2-one and with 2- (7- methyl-2, 1,3-benzothiadiazol-5-yl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo-butanoate ethyl, the 3- (7-methyl 1-2, 1, 3- benzothiadiazol-5-yl) -4- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H-furan-2-one, mp 156-158 °. Analogously, 3- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -4- (4-cyclohexyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro) is obtained. -4-methoxyphenyl) -5H-furan-2-one, mp 163-164 °.

Example 2 To a suspension of 30 mg of 3- (2,1,3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxy-benzyl) -5-hydroxy-5- (4- methoxyphenyl) -5H-furan-2-one in 1 ml of methanol are added equimolar amounts of 0.1 N NaOH and the mixture is stirred at room temperature. The solvent is removed, the residue is partitioned between water and diethyl ether and the aqueous phase is lyophilized. The sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2 acid is obtained -butenoic By analogous treatment with NaOH of the furan derivatives mentioned in Example 1, the sodium salts of the corresponding open-chain 4-oxo-2-butenoic acid derivatives are obtained: sodium salt of 2- (2, 1, 3- benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxy phenyl) -4-oxo-2-butenoic acid; Sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (2,5-dimethoxy phenyl) -4-oxo-2 acid -butenoic; Sodium salt of 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) - 4-oxo-2-butenoic; sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (3-cyclopentyloxy-4,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid; Sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (3-cyclopropylmethyloxy-4,5-dimethoxybenzyl) -4- (4-methoxyphenyl) -4-oxo-2-butenoic acid; Sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxyphenyl) -4-oxo- 2-butenoic; Sodium salt of 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -4- (2,5-dimethoxyphenyl) -4-oxo-2- acid butenoic acid and sodium salt of 2- (7-methyl-2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopropylmethyloxy-3,5-dimethoxybenzyl) -4- (3-fluoro-4-methoxy) phenyl) -4-oxo-2-butenoic acid. The following examples refer to pharmaceutical preparations: Example A: vials for injections The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to 6.5 with 2 N hydrochloric acid, then filtered under sterile conditions , fill the jars with the solution, lyophilize and close the jars in sterile conditions. Each bottle for injection contains 5 mg of the active substance.

Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, then the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance.

Example C: solution A solution is prepared with 1 g of an active substance of formula I, 9.38 g of NaH2P0 x 2H20, 28.48 g of Na2HP04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to 1 1 volume and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment Under aseptic conditions 500 mg of an active substance of formula I are mixed with 99.5 g of Vaseline.

Example E: Tablets A mixture composed of 1 kg of an active substance of 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 in the form of tablets, so such that each tablet contains 10 mg of the active substance.

Example F: Dragees The tablets are formed analogously to that described in Example E and are then coated in a usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsules With 2 kg of an active substance of formula I, hard gelatine capsules are filled, so that each capsule contains 20 mg of the active substance.

Example H: ampoules A solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water is filtered under sterile conditions. The ampoules are filled with this solution and then lyophilized and closed in sterile conditions. Each ampoule contains 10 mg of the active substance.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds of formula I characterized because R represents X represents O or S, R1 represents H, Hal, OA or A, R2, R3, R5, R6 independently represent H, Hal, A, OA or R4, R4 represents -O- (CH2) n-Cy, Cy represents cycloalkyl from 3 to 8 carbon atoms, A represents alkyl of 1 to 6 carbon atoms, wherein one or two groups of CH2 can be replaced by O or S atoms or by groups -CR5 = CR5 'and / or 1 to 7 H atoms can be replaced by F, R5 and R5 independently represent H, F or A, Hal represents fluorine, chlorine, bromine or iodine, nn is 0, 1 or 2, or a cyclic tautomeric form, and isomers (E) and salts of all isomers.

2. Compounds of formula I, according to claim 1 a) 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyl-oxy-3,5-dimethoxybenzyl) -4- (4) acid -methoxyphenyl) -4- oxo-2-butene ico; b) 2- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyl-3,7-dimethoxybenzyl) -4- (3-fluoro-4-methoxy-ifenyl) -4- oxo-2-butenoic; c) 3- (2, 1, 3-benzothiadiazol-5-yl) -3- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (4-methoxyphenyl) -5H-furan-2- ona; d) 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H- furan-2-one; e) 3- (2, 1, 3-benzothiadiazol-5-yl) -4- (3-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) -5H- furan-2-one; f) 3- (7-methy1-2, 1,3-benzothiadiazol-5-yl) -4- (4-cyclopentyloxy-3,5-dimethoxybenzyl) -5-hydroxy-5- (3-fluoro-4-methoxyphenyl) ) -5H-furan-2-one; and its salts.

3. Process for preparing the compounds of formula I, according to claim 1, and their salts, characterized in that a compound of formula II is reacted wherein R1, R5, R6 and X have the meaning indicated in claim 1, and A represents alkyl of 1 to 4 carbon atoms or benzyl, with a compound of formula III wherein R2, R3, R4 have the meaning indicated in claim 1, and then the ester is cleaved, and / or a base or an acid of formula I is transformed into one of its salts.

4. A process for obtaining pharmaceutical preparations, characterized in that a compound of the formula according to claim 1 is carried, and / or one of its salts physiologically acceptable to a suitable dosage form, together with at least one excipient or solid, liquid or semi-liquid auxiliary product.

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

6. Compounds of formula I, according to claim 1, and their physiologically acceptable salts, which combat hypertonia, heart failure, renal failure, cerebral infarction, coronary heart disease, renal, cerebral ischemia and of myocardium, subarachnoid hemorrhage, inflammations, asthma and endotoxic shock.

7. Medicaments of formula I, according to claim 1, and physiologically acceptable salts thereof which are endothelial receptor antagonists.

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

9. Use of the compounds of formula I, according to claim 1, and / or their physiologically acceptable salts to combat hypertonia, heart failure, renal insufficiency, cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage, inflammations, asthma and endotoxic shock.