HK1011965B - Substituted benzenesulfonylureas and-thioureas, process for their preparation, their use as medicament or diagnostic agent, as well as medicaments containing them - Google Patents

Description

The invention relates to substituted benzene sulphonylurea and thiourea of formula I which means: R(1) Hydrogen, methyl or trifluoromethyl;R(2) Alkoxy with 4, 5, 6, 7, 8, 9 or 10 C atoms, with 1 to 6 carbon atoms replaced by the heteroatoms O, S or NH;Oxygen or sulphur;Y-[CR(3) 2)1-4; R(3) Hydrogen or alkyl with 1 or 2 C atoms;XHydrogen, halides or alkyl with 1, 2, 3, 4, 5 or 6 C atoms;ZNitro halides, alkoxides with 1, 2, 3 or 4 C atoms or alkyl with 1, 2, 3 or 4 C atoms; and their pharmaceutically compatible salts.

Sulfonylurea substances are known from the German disclosure 2413514, the German patent 1518 874. There is described their blood sugar-lowering effect. As a prototype of such blood sugar-lowering sulfonylurea substances, the glibenclamide, which is used as a means to treat diabetes mellitus therapeutically and in research serves as a much-respected tool for research of so-called ATP-sensitive caliber channels. In addition to its blood sugar-lowering effect, the glibenclamide has other effects that can not yet be used therapeutically, but all of which can be attributed to blockade of this ATP-sensitive potassium channel.

European disclosure note 0 612 724 (HOE 93/F 056) already describes compounds with reduced blood sugar lowering effect, but these are not yet sufficient for many purposes.

The present invention was therefore designed to synthesize compounds which exhibit a similarly good cardiac effect to glibenclamide but which do not affect blood sugar at cardiacally effective doses or concentrations or which have a significantly lower effect than glibenclamide.

This objective was achieved by the compounds described at the beginning.

The preferred compounds are those in which the R(1) Hydrogen, methyl or trifluoromethyl;R(2) Alkoxy with 4, 5, 6, 7, 8, 9 or 10 C atoms, in which one to six carbon atoms have been replaced by the heteroatoms O, NH or S;Oxygen or sulphur;A straight hydrocarbon residue with or without substitution of the formula: -[CR(3)1-42); R(3) Hydrogen or alkyl with 1 or 2 C atoms;XHydrogen, chlorine, fluorine or alkyl with 1, 2, 3 or 4 C atoms;ZNitro, fluorine, chlorine, alkyl with 1, 2, 3 or 4 C atoms or alkoxy with 1, 2, 3 or 4 C atoms; and their pharmaceutically compatible salts.

In particular, preference is given to compounds I, where: R(1) Hydrogen or methyl;R(2) Alkoxy with 4, 5, 6, 7, 8, 9 or 10 C atoms, in which 1 to 6 carbon atoms have been replaced by the heteroatoms O, S or NH;Eoxygen or sulphur;Y-[CR(3) 2)1-4; R(3) Hydrogen or alkyl with 1 or 2 C atoms;XHydrogen, fluorine, chlorine or alkyl with 1, 2, 3 or 4 C atoms;ZChlorine, fluorine, alkyl with 1, 2, 3 or 4 C atoms or alkoxy with 1, 2, 3 or 4 C atoms; and their pharmaceutically compatible salts.

In particular, preference shall be given to compounds of formula I, where: R (r) (hydrogen or methyl) (r) (methoxy or methoxy) (oxygen or sulphur) (Y-[CR]) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) (r) ( R ()) 3) Hydrogen or methyl;X Hydrogen, fluorine, chlorine or alkyl with 1, 2 or 3 C atoms;ZFluorine, chlorine, alkyl with 1, 2 or 3 C atoms or alkoxy with 1, 2 or 3 C atoms; and their pharmaceutically compatible salts.

Alkyl means, unless expressly stated otherwise, straight chain, branched or cyclic saturated hydrocarbon residues with one to six carbon atoms. The term alkoxy refers to an ether substituent with a straight chain, branched or cyclic saturated hydrocarbon residue of one to ten carbon atoms. The elements fluorine, chlorine, bromine and iodine can be used as halogen substituents. The carbon atoms of the alkyl side chain Y and the alkoxy side chain can be asymmetrically substituted.

The invention relates to compounds of one or the other enantiomer and a racemic mixture or mixtures of the two antibodies in different proportions. Furthermore, compounds with two chiral centres in the alkyl side chain Y and the alkoxy chain may occur. In this case, the invention covers both the individual antibodies themselves and a mixture of the two enantiomers in different proportions, as well as the corresponding mesocompositions.

The compounds of the invention are valuable medicinal products for the treatment of cardiac arrhythmias of various origins and for the prevention of arrhythmic sudden cardiac death and can therefore be used as antiarrhythmic agents. Examples of cardiac arrhythmias are supraventricular arrhythmias such as atrial tachycardia, atrial flatulence, or paroxysmal supraventricular arrhythmias or ventricular arrhythmias such as ventricular extrasythmia, but particularly life-threatening ventricular tachycardia or particularly dangerous cardiac fibrillation. They are therefore particularly suitable for cases where arrhythmias are the result of a narrowing of a coronary artery, for example during a cardiac arrest or a sudden or chronic cardiac arrest, and are therefore more suitable for patients with chronic cardiac arrhythmias or hypertension, for example during a heart attack or a sudden cardiac arrest.

In addition, the compounds can have a positive effect on a decreased contractility of the heart. This can be a disease-related decrease in heart contractility, such as in heart failure, but also in acute cases such as heart failure in shock effects. Similarly, in a heart transplant, the heart can resume its performance after surgery more quickly and reliably. The same applies to heart operations that require a temporary shutdown of heart activity by cardioplegic solutions.

The compounds may therefore be used as active substances in human and veterinary medicine and may be used as intermediates for the manufacture of other active substances.

The invention also relates to a process for the manufacture of compounds I characterized by the use of a (a) an aromatic sulphonamide of formula II or its salt of formula III with an R(1) substituted isocyanate of formula IV Other R (n) = C (O) IV Other The Commission has decided to initiate the procedure laid down in Article 2 (2) of Regulation (EC) No 1272/2008 in respect of the transposition of the provisions of Regulation (EC) No 1272/2008 into the Annex to this Regulation. Alkali and alkaline ammonium and tetraalkyl ammonium ions are considered as M cations in the salts of formula III. Equivalent to the R(1) substituted isocyanates IV, R(1) substituted carbamic acid esters, R(1) substituted carbamic acid halides or R(1) substituted urea can be used. (b) An unsubstituted benzolsulfonil urea I a [R(1) = H] can be obtained by conversion of an aromatic benzolsulfonamide of formula II or its salt III with trialkyl silyl isocyanate or silicon tetraisocyanate and hydrolysis of the primary silicon substituted benzolsulfonil urea.It is also possible to form a benzoyl sulfonamide II or its salt III by transformation with a halogen cyan and hydrolysis of the primary N-cyanosulfonamide with mineral acids at 0°C to 100°C. (c) A benzoyl sulphonyl urea I a can be obtained from an aromatic benzoyl sulfonamide II or its salt III with an R-substituted trichloracetamide of formula V Other The following information shall be provided in the form of a summary of the results of the analysis: Other in the presence of a base in an inert solvent according to synthesis 1987, 734-735 at 25°C to 150°C. For example, alkali metal or mineral metal hydroxides, hydrides, amides or alcohols such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methylate, sodium ethanolate, potassium methylate or potassium methanolate are suitable as bases.Dioxane, ethylene glycoldimethyl ether (diglyme), ketones such as acetone or butane, nitriles such as acetonitrile, nitrous compounds such as nitromethane, esters such as ethylacetate, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), phosphoric acid hexamethyl trimaide, sulfoxides such as DMSO, sulphones such as sulfolane, hydrocarbons such as benzene, toluene, xyloles. (d) A benzene sulphonyl thio resin I b is obtained from a benzoyl sulfonamide II or its salt III and a R ((1) substituted thioisocyanate VI Other R (n) -N = C = S VI Other An unsubstituted benzolsulfonylthiocyanate I b [R(1) = H] can be produced by conversion of an aromatic benzolsulfonamide II or its salt III with trimethylsilylisothiocyanate or silicon tetra-trisothiocyanate and hydrolysis of the primary silicon-substituted benzolsulfonyl uranium. It is also possible to convert an aromatic benzolsulfonamide II or its salt III with benzoylisothiocyanate and to convert the intermediate benzolsulfonamide II with aqueous mineral acid to I b [R(1) = H].Similar processes are described in J. Med. Chem. 1992, 35, 1137-1144. (e) A substituted benzene sulphonylurea of formula I a can be produced by a conversion reaction from a benzene sulphonylurea of structure I b. The substitution of an oxygen atom for the sulphur atom in the substituted benzene sulphonylurea can be achieved, for example, by means of oxides or salts of heavy metals or by the application of oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid. Substances can also be produced by treatment with phosphorus oxygen or phosphorus pentachloride.Isothiocyanate urines behave like thiocyanate urines in the process of desulphurisation and can therefore also be used as starting materials for these reactions. The trialkylsilyl protective group can be removed from the resulting (trialkylsilyl) benzoyl sulphonyl urine by standard methods. Furthermore, sulphonic acid chloride VII can be converted with parabans to benzoyl sulphonyl parabanes, whose hydrolysis with mineral acids gives the corresponding benzoyl sulphonyl urine I a. Similarly, amines R ((1) -NH2 can be converted to the compounds I a by benzolsulfonyl carbamide esters, benzolsulfonyl carbamide halides or benzolsulfonyl urea I a [with R ((1) = H].(h) A benzene sulphonyl thioethylene resin I b is prepared by conversion of an amine of formula R (1) -NH2 with a benzene sulphonyl isothiocyanate of formula IX Similarly, amines R(1)-NH2 can be converted to the compound Ib by a benzoyl sulphonyl carbamide thioester or a benzoyl carbamide ethiohalogenide.

The compounds I and their physiologically harmless salts are valuable therapeutics, suitable not only as antiarrhythmic agents but also as prophylaxis for cardiovascular disorders, heart failure, heart transplantation or cerebrovascular diseases in humans or mammals (e.g. monkeys, dogs, mice, rats, rabbits, guinea pigs and cats).

Physiologically harmless salts of compounds I are defined as compounds of formula XI, according to Remmington's Pharmaceutical Science, 17th edition, 1985, pp. 14-18. which can be formed from non-toxic organic and inorganic bases and substituted benzoyl sulphonylurea I. Preferably salts in which M is sodium, potassium, rubidium, calcium, magnesium, ammonium ions in formula XI, and the acid addition products of basic amino acids such as lysine or arginine.

The starting compounds for the above-mentioned synthesis processes of benzoyl sulphonylurea I are produced by known methods as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and in the patent publications mentioned above) under reaction conditions known and suitable for the above-mentioned transformations. Other

Thus, substituted amines of the general formula XII can be acylated according to Scheme 1 and subjected to a halogen sulfonation. As acylating agents for the acylation of amino groups, the alkylesters, halogenides (for example, chlorides or bromides) or anhydrides of carbon acids of the formula R(4)-COB are suitable. R(4) here stands for a trihalogen methyl residue, a (C1-C4) alkyl or a benzoic acid derivative. The benzoic acid derivative can be substituted or replaced by one or two similar or different residues, Zured X. A possible substitute for hydrogen is (C1-C4) -alkyl or a substituent for hydrogen, halogen (C1-C1-C4) -alkyl, or a fluid such as halogen (C1-C1-C4) -alkyl, or a halogen (C1-C4-C1-C4).Trihalogen acetate, (C1-C4) carboxylate. Examples are acetanid, trihalogen acetane hydride, acetyl halogenide, trihalogen acetyl halogenide, propionyl chloride, isobutyryl bromide and chloride, formic acid/acetic anhydride, benzoyl chloride, 5-chloro-2-methoxybenzoic acid or -anhydride, and -C1-C4-alkylaster or 2,5-difluor benzoic chloride. The synthesis of compound XIII is carried out by adding a tertiary base such as pyridoxine or tetraethyl benzolamine in the presence or absence of a solvent, with a catalytic component such as dimethyl amethylamine. The compound can be used as a preservative, for example, in the case of a solution of up to 160°C. The protective group can be used as a diluentry, for example, in the case of amethylamine, at temperatures of up to about 20°C.Dioxane, glycolite ethers such as ethylene glycolmonomethyl or monoethyl ethers (methyl glycol or ethyl glycol), ethylene glycoldimethyl ethers (diglyme), ketones such as acetone or butane, nitriles such as acetonitrile, nitrous compounds such as nitromethane, esters such as ethylacetate, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), phosphoric acid hexamethyl triamide, sulfoxides such as DMSO, chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1,2-dichlorethane or carbon tetrachloride, hydrocarbons such as benzene, benzene, Xylal. These compounds are also directly related to each other. The amine XIII acylated in Scheme 1 can be converted to sulfonamide XIV in a known manner in Scheme 2. The sulfonamide XIV is produced by known methods under reaction conditions known and suitable for the above conversions.In particular, preference is given to processes in which acylated amine XII is transferred by electrophilic reactions in the presence or absence of inert solvents at temperatures of -10°C to 120°C, preferably 0°C to 100°C, to aromatic sulphonic acids and their derivatives, such as sulphonic acid halides. For example, sulfonations with sulphuric acids or oleum, halogen sulfonations with halogen sulphonic acids, reactions with sulfuryl halogen in the presence of anhydrous oxides or thiol halogen in the presence of oxide containing methanol, may be carried out in a primary sulphonic acid reaction, which is carried out in the presence of oxide oxides containing methanol.they can be converted into sulphonic acid by acid halides, such as phosphorus trihalogenide, phosphorentahalogenide, phosphoroxychloride, thionyl halides, oxalic halides, either directly or by treatment with tertiary amines such as pyridine or trialkylamines or with alkaline or alkaline hydroxides or reagents forming these basic compounds in situ. The conversion of sulphonic acid derivatives into sulphonic acid is known in the literature, preferably by conversion of sulphonic acid chlorides in inert solutions at temperatures of 0 to 100 °C with water. However, aromatic sulphonic acid can be obtained by the Ammonium ammonium process at temperatures of 1 to 50 °C or by further conversion of sulphonic acid inert solutions inert gases and ammonium ammonium compounds obtained by the Ammonium process at temperatures of 1 to 100 °C with water.preferably at -100 °C to 30 °C, with sulphur dioxide and then heat treatment with amidosulfonic acid.

The acyl group acts as a protective group for amin XIII, and sulfonamide XIV can be separated with acids or bases after presentation. The acidic salt can be formed by cleavage with aqueous acids or acids in inert solvents. For this implementation, for example, sulfuric acid, nitric acid, halogenated hydrocarbons such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfonamide, and organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic acids, can be formed by one or more disulfide-based carbonic acids or sulfuric acids, for example, benzoic acid, lauric acid, kalium nitrate, kalium nitrate, diethyl nitrate, sulfuric acid, sulfuric acid, nitric acid, methanol, nitric acid, methanol, nitric acid, methanol, nitric acid, methanol, nitric acid, methanol, nitric acid, methanol, nitric acid, methanol, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid, nitric acid,

The aromatic benzoyl sulfonamides of formula III are produced from the sulfonamide substituted amines or their acid addition compounds as mentioned above. Depending on the nature of the members R (1), R (2), R (3), X, Y and Z, in individual cases one or other of the above methods will be unsuitable for the production of compounds I or at least require measures to protect the active groups. Such relatively rare cases can be easily detected by the professional and it is not difficult to successfully apply another route of synthesis described in such cases.

The compounds I can have one or more chiral centers. They can therefore be obtained in the form of racemate or in the form of optically active substances if optically active starting materials are used. If the compounds have two or more chiral centers, they can be obtained in the synthesis as a mixture of racemates from which the individual isomers can be isolated in a pure form, for example by recrystallization from inert solvents. The resulting racemates can, if desired, be separated by known mechanisms or chemically in their enantiomers.

The compounds I and their physiologically harmless salts may be used in the manufacture of pharmaceutical preparations, in particular by non-chemical means, in which case they may be used together with at least one solid or liquid vehicle or auxiliary, alone or in combination with other cardiovascular medicinal products, such as calcium antagonists, NO donors or ACE inhibitors, in an appropriate dosage form. These preparations may be used as medicinal products in human or veterinary medicine. Organic substances or inorganic substances suitable for enteral (e.g. oral), parenteral (e.g. intravenous) application, or topical applications and not reacting with water, such as oil, are suitable.For oral use, in particular tablets, tablets, tablets, capsules, syrups, juices or drops, for rectal use, solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants for topical use, ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (e.g. in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanol or their intermixtures or mixtures with water) or powders.contain stabilisers and/or net agents, emulsifiers, salts and/or excipients such as lubricants, preservatives, osmotic pressure agents, buffers, colouring and flavouring agents and/or flavourings, and may, if desired, contain one or more additional active substances, such as one or more vitamins.

The dosage range required to treat arrhythmias with compounds I depends on whether acute or prophylactic therapy is being used. Usually, a dose range of at least 0.1, preferably at least 1 mg to at most 100, and preferably at most 10 mg per kg per day is recommended for prophylaxis. A dose range of 1 to 10 mg per kg per day is preferred for an adult weighing about 75 kg. The dose may be administered as a single oral or parenteral dose, but may be divided into up to four single doses. The following substances are to be classified in the same category as the product: (1) 2-Methoxy-5-chlor-{N-2-[3-sulfonylamino-N-(methylaminocarbonyl) -4-methoxyethyl]phenyl-benzamide, (2) 2-Methoxy-5-fluor-{N-2-[3-sulfonylamino-N-(methylaminocarbonyl) -4-methoxyethyl-benzamide, (3) 2-Methoxy-5-fluor-{N-2-[3-sulfonylamino-N-(methylaminocarbonyl) -4-methoxyethyl-benzamide, and

Example 1

The use of the active substance in the manufacture of the active substance is authorised. 670 mg 2-Methoxy-5-chlor-{N-2-[-3-sulfonylamino-4-methoxyethoxyphenyl]-ethyl}-benzamide is dissolved in 10 ml of absolute DMF and mixed with 70 mg of 60% NaH. Stir for 20 min at room temperature and drip 1.6 ml of a 1-molar methyl isothiocyanate solution into DMF. Heat at 80°C for 1.5 h and drip the reaction solution after cooling to 100 ml of 1 N hydrochloric acid. Extract with acetic acid, dry and remove the solvent in a vacuum. The resulting solid is dissolved in a little ethanol and cooled with water. The yield is 720 mg, at 134°C.

Example 2

The use of the active substance in the manufacture of the active substance is authorised. 390 mg 2-Methoxy-5-chlor-{N-2-[-3-sulfonylamino-4-methoxyethoxyphenyl]-ethyl}-benzamide is dissolved in 6 ml DMF and mixed with 35 mg 60% NaH. Stir for 20 min at room temperature and drip 0.8 ml of 1-molar methyl isothiocyanate solution in DMF. Heat at 80°C for 1.5 h and drip the reaction solution to 50 ml 1 N hydrochloric acid after cooling. Extract with acetic acid, dry and remove the solvent in a vacuum. It's 108 degrees.

Pharmacological data:

The following models can be used to suggest the therapeutic properties of compounds I:

(1) Action potential duration on the papilla of guinea pig: (a) The introduction

ATP deficiency states, as seen during ischaemia in the heart muscle cell, lead to a shortening of the action potential duration. They are considered to be one of the causes of so-called reentry arrhythmias, which can cause sudden cardiac death.

(b) Method

To measure the action potential, a standard microelectrode technique is used: guinea pigs of both sexes are killed by a blow to the head, their hearts removed, the papillary muscles removed and suspended in an organ bath. The organ bath is rinsed with ring solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl2, 0.02% NaHCO3 and 0.1% glucose) and sprayed with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36°C. The muscle is stimulated via an electrode with rectangular pulses of 1 V and 1 ms and a frequency of 2 Hz. The action potential is detected and recorded by an intravascularly inserted glass electrode filled with 3 mL L-Cl solution.The substances to be tested were added to the Ringer solution at a concentration of 2.2·10-5 mol per litre. The action potential is amplified with an amplifier by Hugo Sachs and shown on the oscilloscope. The duration of the action potential is determined at a 95% degree of repolarization (APD95). Action potential reductions are prevented either by adding a 1 μM solution of the potassium channel opener Hoe 234 [J. Kaiser, H. Gögelein, Naunyn-Schmiedeberg, Ph.D., 1991, 343, R59] or by adding 2-deoxyglucose. The action potential reducing effect of these substances was produced by the simultaneous addition of the measuring substances or by adding 30 substances to the bath.Glibenclamide was the standard in these measurements.

(c) Results:

The following values were measured: Other

Beispiel Nr.	APD95-Anfang [ms]	APD95-30 min [ms]
1	160 ± 13	150 ± 14

Claims (13)

1. A substituted benzenesulfonylurea or -thiourea of the formula I in which:

   R(1)   is hydrogen, methyl or trifluoromethyl;

   R(2)   is alkoxy having 4, 5, 6, 7, 8, 9 or 10 carbon atoms, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S or NH;

   E   is oxygen or sulfur;

   Y   is - [CR(3)₂]_1-4;

   R(3)   is hydrogen or alkyl having 1 or 2 carbon atoms;

   X   is hydrogen, halogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;

   Z   is nitro, halogen, alkoxy having 1, 2, 3 or 4 carbon atoms or alkyl having 1, 2, 3 or 4 carbon atoms;

   or its pharmaceutically tolerable salts.
2. A compound of the formula I as claimed in claim 1, wherein:

   R(1)   is hydrogen, methyl or trifluoromethyl;

   R(2)   is alkoxy having 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in which one to six carbon atoms are replaced by the heteroatoms O, NH or S;

   E   is oxygen or sulfur;

   Y   is a straight substituted or unsubstituted hydrocarbon radical of the formula:         -[CR(3)₂]_1-4;

   R(3)   is hydrogen or alkyl having 1 or 2 carbon atoms;

   X   is hydrogen, chlorine, fluorine or alkyl having 1, 2, 3 or 4 carbon atoms;

   Z   is nitro, fluorine, chlorine, alkyl having 1, 2, 3 or 4 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms;

   or its pharmaceutically tolerable salts.
3. A compound of the formula I as claimed in at least one of claims 1 and 2, wherein:

   R(1)   is hydrogen or methyl;

   R(2)   is alkoxy having 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in which 1 to 6 carbon atoms are replaced by the heteroatoms O, S or NH;

   E   is oxygen or sulfur;

   Y   is -[CR(3)₂]_1-4;

   R(3)   is hydrogen or alkyl having 1 or 2 carbon atoms;

   X   is hydrogen, fluorine, chlorine or alkyl having 1, 2, 3 or 4 carbon atoms;

   Z   is chlorine, fluorine, alkyl having 1, 2, 3 or 4 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms;

   or its pharmaceutically tolerable salts.
4. A compound of the formula I as claimed in at least one of claims 1 to 3, wherein:

   R(1)   is hydrogen or methyl;

   R(2)   is methoxyethoxy or methoxyethoxyethoxy;

   E   is oxygen or sulfur;

   Y   is - [CR(3)₂]_2-3;

   R(3)   is hydrogen or methyl;

   X   is hydrogen, fluorine, chlorine or alkyl having 1, 2 or 3 carbon atoms;

   Z   is fluorine, chlorine, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1, 2 or 3 carbon atoms;

   or its pharmaceutically tolerable salts.
5. A compound of the formula I as claimed in at least one of claims 1 to 4, which is the compound of the formula or its pharmaceutically tolerable salts.
6. A compound of the formula I as claimed in at least one of claims 1 to 4, which is the compound of the formula or its pharmaceutically tolerable salts.
7. A process for the preparation of a compound I as claimed in claims 1 to 6, which comprises

   (a) reacting an aromatic sulfonamide of the formula II or its salt of the formula III with an R(1)-substituted isocyanate of the formula IV         R(1)-N=C=O     IV to give a substituted benzenesulfonylurea I a, where R(1), R(2), X, Y and Z have the meanings indicated in claims 1 to 6 and where M is an alkali metal, alkaline earth metal, ammonium or tetraalkylammonium ion; or

   (b) preparing an unsubstituted benzenesulfonylurea I a [R(1) = H] by reaction of an aromatic benzenesulfonamide of the formula II or its salt III with trialkylsilyl isocyanate or silicon tetraisocyanate and hydrolysis of the primary silicon-substituted benzenesulfonylureas; or

   (c) preparing a benzenesulfonylurea I a from an aromatic benzenesulfonamide II or its salts III using an R(1)-substituted trichloroacetamide of the formula V         Cl₃C-C(=O)-NHR(1)     V in the presence of a base; or

   (d) preparing a benzenesulfonylthiourea I b from a benzenesulfonamide II or its salt III and an R(1)-substituted isothiocyanate VI         R(1)-N=C=S     VI; or

   (e) preparing a substituted benzenesulfonylurea of the formula I a by conversion reaction from a benzenesulfonylthiourea of the structure I b; or

   (f) preparing a benzenesulfonylurea I a from a benzenesulfonyl halide of the formula VII using an R(1)-substituted urea or an R(1)-substituted bis(trialkylsilyl)urea; or

   (g) preparing a benzenesulfonylurea I a by reaction of an amine of the formula R(1)-NH₂ with a benzenesulfonyl isocyanate of the formula VIII or

   (h) preparing a benzenesulfonylthiourea I b by reaction of an amine of the formula R(1)-NH₂ with a benzenesulfonyl isothiocyanate of the formula IX or

   (i) oxidizing a substituted benzenesulfenyl- or -sulfinylurea to give a benzenesulfonylurea I a,

   and optionally converting the compound I into the pharmaceutically tolerable salt.
8. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof for the production of a medicament for the treatment of cardiac arrhythmias.
9. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof for the production of a medicament for the prevention of sudden heart death.
10. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof for the production of a medicament for the treatment of ischemic conditions of the heart.
11. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof for the production of a medicament for the treatment of weakened myocardial contractile force.
12. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof for the production of a medicament for the improvement of heart function after heart transplantation.
13. A medicament comprising an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 6 or of a pharmaceutically tolerable salt thereof.