HETEROARYLACRYLOYLAMINOALKYL-SUBSTITUTED BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION, THEIR USE AND PHARMACEUTICAL PREPARATIONS COMPRISING THEM

Abstract: The present invention relates to heteroarylacryloylaminoalkyl-substituted benzenesulfonamide derivatives of the formula I, in which Het is 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, nitro, (C1-C4)-alkyl, (C1-C4)-alkoxy and trifluoromethyl; R(1), R(2), R(3), R(4), X, Y and Z have the meanings indicated in the claims. The compounds of the formula I are valuable pharmaceutical active compounds which have, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the vagal cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, cardiomyopathies, decreased contractility of the heart or vagal dysfunction of the heart, or for the prevention of sudden cardiac death. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical preparations comprising them.

Description: Heteroarylacryloylaminoalkyl-substituted benzenesulfonamide derivatives, their preparation, their use and pharmaceutical preparations comprising them The present invention relates to heteroarylacryloyiaminoalkyl-substituted benzenesulfonamide derivatives of the formula I, in which R(1), R(2), R(3), R(4), Het, X, Y and Z have the meanings indicated below. The compounds of the formula I are valuable pharmaceutical active compounds which have, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the vagal cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, cardiomyopathies, decreased contractility of the heart or vagal dysfunction of the heart, or for the prevention of sudden cardiac death. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use and pharmaceutical preparations comprising them. For certain benzenesulfonylureas, a blood-sugar-lowering action has been described. A prototype of such blood-sugar-lowering sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus. Glibenclamide blocks ATP-sensitive potassium channels and is used in research as a tool for the exploration of potassium channels of this type. In addition to its blood-sugar-lowering action, glibenclamide has other actions which are attributed to the blockade of precisely these ATP-sensitive potassium channels but which hitherto can still not be used therapeutically. These include, in particular, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide however, the marked blood-sugar-lowering simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient, so that glibenclamide is not suitable clinically as an antiarrhythmic. Various patent documents, for example US-A-5574069, US-A-5698596, US-A- 5476850, US-A-5652268 orWO-A-00/03978, disclose antifibrillatory benzenesulfonylureas and -thioureas having reduced blood-sugar-lowering action. WO-A-00/15204 describes the action of some of these compounds on the autonomic nervous system. The properties of these compounds, however, are still not satisfactory in various respects, and there is an ongoing need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile which are still better suited, in particular, to the treatment of a disturbed cardiac rhythm and its consequences such as sudden cardiac death or a weakened myocardial contractile force. Various benzenesulfonylureas having an acylaminoalkyl substituent, in which the acyl group can also be derived, inter alia, from cinnamic acids, and the blood-sugar- lowering action of these compounds are disclosed in DE-A-1443878, US-A-3454636, DE-A-1518877 and US-A-4066639. The benzenesulfonylureas which are described in GB-A-1116355 are just so characterized by a blood-sugar-lowering action, among them some specific benzenesulfonylureas which contain a heteroarylacryloyl- aminoalkyl group in the para position to the sulfonylurea group. In WO-A-00/71513 (international patent application PCT/EPOO/04091) certain cinnamoylaminoalkyl- substituted benzenesulfonamide derivatives are described which are distinguished by a marked action on ATP-sensitive potassium channels in the heart. Further investigations showed that the benzenesulfonamide derivatives of the present invention which contain a heteroarylacryloylaminoalkyl substituent in the meta position to the sulfonyl group show a particularly marked action on ATP-sensitive potassium channels of the cardiac muscle and/or of the vagal cardiac nerve, without having a marked action on pancreatic potassium channels and thus being valuable pharmaceutical active compounds, in particular for the treatment of disorders of the cardiovascular system. The present invention relates to compounds of the formula I, in which R(1) is 1) (C C 4 )-alkyl; or 2) -O-(C C )-alkyl which is unsubstituted or is substituted by 1 , 2 or 3 fluorine atoms; or 3) -O-(C 1 -C 4 )-aIkyl which is substituted by a substituent selected from the group consisting of nitro, ((Cι-C 4 )-alkyl)carbonylamino, (C-ι-C )-alkylamino, di((Cι-C )- alkyl)amino, hydroxycarbonyl, ((Cι-C )-alkoxy)carbonyl, piperidin-1-yl, morpholin- 4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl and phenoxy, where the phenyl group and the phenoxy group are unsubstituted or are substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C 4 )-aIkyl, (Cι-C )-alkoxy and trifluoromethyl; or 4) -O-(CrC 4 )-alkyl-E(1)-(C C 4 )-alkyl-D(1 ), in which D(1 ) is hydrogen or -E(2)-(C C 4 )-alkyl-D(2), in which D(2) is hydrogen or -E(3)-(Cι-C 4 )-alkyl, where E(1), E(2) and E(3), which are independent of one another and can be identical or different, are O, S or NH; or 5) -O-(C 1 -C 4 )-alkyl-0-(C -C 4 )-alkyl which is substituted by 1 , 2 or 3 fluorine atoms; or 6) -O-(C 2 -C 4 )-alkenyl; or 7) -O-phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C 4 )-alkyl, (C-t-C 4 )-alkoxy and trifluoromethyl; or 8) halogen; or 9) phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C )-alkyl, (C 1 -C 4 )- alkoxy, -S(0) m -(Ci-C )-alkyl, phenyl, amino, hydroxyl, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, ((CrC 4 )-alkoxy)carbonyl and formyl; or 10) (C 2 -Cg)-alkenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of phenyl, cyano, hydroxycarbonyl and ((Cι-C )- alkoxy)carbonyl; or 11) (C- 2 -C 5 )-alkynyl which is unsubstituted or is substituted by a substituent selected from the group consisting of phenyl and (Cι-C )-alkoxy; or 12) 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or 13) -S(O) m -phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (C-i-C 4 )-alkyl, (C-ι-C 4 )-alkoxy and trifluoromethyl; R(2) is hydrogen or (C-j-CβJ-alkyl, but is not hydrogen if Z is oxygen; the residues R(3) and R(4), which are independent of one another and can be identical or different, are hydrogen or (Cι-C 4 )-alkyl; the residues R(5), which are all independent of one another and can be identical or different, are hydrogen or (Cι-C 3 )-alkyl; Het is 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, nitro, (Cι-C )-alkyl, (C-i- C )-alkoxy and trifluoromethyl; X is oxygen or sulfur; Y is -(CR(5) 2 )n-; Z is NH or oxygen; m is 0, 1 or 2; n is 1 , 2, 3 or 4; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. If groups, residues, substituents or variables can occur several times in the compounds of the formula I, they can all independently of one another have the meanings indicated and can in each case be identical or different. The term alkyl denotes straight-chain or branched saturated hydrocarbon residues. This also applies to groups derived therefrom such as, for example, alkoxy, alkoxycarbonyl or the residue -S(O) m -alkyl. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyi, n-pentyl, 1-methyl- butyl, isopentyl, neopentyl, tert-pentyl, n-hexyl or isohexyl. Examples of alkoxy are methoxy, ethoxy, propoxy such as n-propoxy and isopropoxy, butoxy such as n-butoxy, isobutoxy and tert-butoxy, etc. The same applies correspondingly to substituted alkyl residues, for example phenylalkyl residues, and to divalent alkyl residues (alkanediyl residues), in all of which the substituents or the bonds, via which the residues are bonded to the neighboring groups, can be situated in any desired positions. Examples of alkyl residues of this type which are bonded to two neighboring groups are -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 - which, inter alia, can represent the group Y or can be present in a group -0-(Ci-C 4 )-alkyl which carries one substituent. Alkenyl and alkynyl are straight-chain or branched, monounsaturated or polyunsaturated hydrocarbon residues, in which the double bonds and/or triple bonds can be situated in any desired positions. Preferably, the residues alkenyl and alkynyl contain one double bond or one triple bond. Examples of alkenyl and alkynyl are vinyl, prop-2-enyl (allyl), prop-1-enyl, but-2-enyl, but-3-enyl, 3-methyl-but-2-enyl, pent-2,4-dienyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl and but-3- ynyl. In substituted alkenyl residues and alkynyl residues the substituents can be situated in any desired positions. Halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine. In substituted phenyl residues the substituents can be situated in any desired positions. In monosubstituted phenyl residues the substituent can be situated in the 2-position, the 3-position or the 4-position. In disubstituted phenyl residues the substituents can be situated in 2,3-position, 2,4-position, 2, 5-position, 2,6-position, 3,4-position or 3, 5-position. If a phenyl residue carries a further phenyl residue as a substituent, then this second phenyl residue can also be unsubstituted or can be substituted by the substituents which are indicated for the first phenyl residue, apart from by a phenyl residue. The heteroaryl residues which are derived from monocyclic 5-membered or 6- membered aromatic ring systems can be also be regarded as residues derived from cyclopentadienyl or phenyl by replacement of one or two CH groups and/or CH 2 groups by S, O, N, NH (or N carrying a substituent such as, for example, N-CH 3 ), the aromatic ring system being retained or an aromatic ring system being formed. In addition to the one or two ring heteroatoms, they contain three to five ring carbon atoms. Examples of heteroaryl are in particular furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1 ,3-oxazolyl, 1 ,2-oxazolyl, 1 ,3-thiazolyl, 1 ,2-thiazolyl, pyridyl, pyrazinyl, pyrimidyl or pyridazinyl. A heteroaryl residue can be bonded via any ring carbon atom. For example, a thienyl residue can be present as a 2-thienyl residue or 3- thienyl residue, a furyl residue as a 2-furyl residue or 3-furyl residue, a pyridyl residue as a 2-pyridyl residue, 3-pyridyl residue or 4-pyridyl residue. A residue which is derived from 1 ,3-thiazole or from imidazole can be bonded via the 2-position, the 4- position or the 5-position. Suitable nitrogen heterocycles can also be present as N- oxides or as quaternary salts with an anion derived from a physiologically tolerable acid as counter ion. Pyridine rings can thus also be present, for example, as pyridine N-oxides. In substituted heteroaryl residues the substituents can be situated in any desired positions and can occur in any desired combinations, provided the corresponding heteroaromatic is stable and its properties are suitable for the intended use. If the compounds of the formula I contain nitro groups, then preferably in total not more than two nitro groups are present in the molecule. For example, a monosubstituted 2- thienyl residue, 2-furyl residue or 2-pyrrolyl residue can be substituted in the 3- position, the 4-position or the 5-position, a monosubstituted 3-thienyl residue, 3-furyl residue or 3-pyrroIyl residue in the 2-position, 4-position or 5-position. A disubstituted 2-thienyl residue, 2-furyl residue or 2-pyrrolyl residue can be substituted in 3,4- position, 3,5-position or 4,5-position, a disubstituted 3-thienyl residue, 3-furyl residue or 3-pyrrolyl residue in 2,4-position, 2, 5-position or 4,5-position. A monosubstituted 2- pyridyl residue can be substituted in the 3-position, 4-position, 5-position or 6- position, a monosubstituted 3-pyridyl residue in the 2-position, 4-position, 5-position or 6-position, and a monosubstituted 4-pyridyl residue in the 2-position or the 3- position. A disubstituted 2-pyridyl residue, for example, can be substituted in 3,4- position, 3,5-position, 3, 6-position, 4,5-position, 4, 6-position or 5,6-position. A tetrahydrofuranyl residue can be bonded via the 2-position or the 3-position, a tetrahydropyranyl residue via the 2-position, the 3-position or the 4-position. Preferred tetrahydrofuranyl and tetrahydropyranyl residues are tetrahydrofuran-2-yl and tetrahydropyran-2-yl. The present invention comprises all stereoisomeric forms of the compounds of the formula I. Asymmetric centers present in the compounds of the formula I can all independently of one another have the S configuration or the R configuration. The invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers, for example, thus are a subject of the invention in enantiomerically pure form, as levorotatory as well as dextrorotatory antipode, in the form of the racemate and in the form of mixtures of the two enantiomeric forms in all ratios. In the presence of cis/trans isomerism or E/Z isomerism, the cis form, the trans form, the E form, the Z form and mixtures of these forms in all ratios are a subject of the invention. Individual stereoisomers can be prepared, if desired, by resolution of a mixture according to customary methods, for example by chromatography or crystallization, or by use of stereochemically uniform starting substances in the synthesis, or by stereoselective reactions. If appropriate, a derivatization can be carried out before separation of stereoisomers. The separation of a stereoisomer mixture can be carried out at the stage of the compounds of the formula I or at the stage of an intermediate in the course of the synthesis. The invention also comprises all tautomeric forms of the compounds of the formula I. Physiologically tolerable salts of the compounds of the formula I are, in particular, nontoxic salts or pharmaceutically utilizable salts. They can contain inorganic or organic salt components. Such salts can be prepared, for example, from compounds of the formula I which contain one or more acidic groups, and nontoxic inorganic or organic bases. Possible bases are, for example, suitable alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide or potassium hydroxide, or ammonia or organic amino compounds or quaternary ammonium hydroxides. Reactions of compounds of the formula I with bases for the preparation of the salts are in genera! carried out according to customary procedures in a solvent or diluent. On account of the physiological and chemical stability, advantageous salts in the presence of acidic groups are in many cases sodium, potassium, magnesium or calcium salts or ammonium salts which can carry one or more organic residues on the nitrogen. Salt formation on the nitrogen atom of the benzenesulfonamide group in this case leads to compounds of the formula II, in which R(1), R(2), R(3), R(4), Het, X, Y and Z have the meanings indicated above and the cation M, for example, is an alkali metal ion or an equivalent of an alkaline earth metal ion, for example the sodium, potassium, magnesium or calcium ion, or the unsubstituted ammonium ion or an ammonium ion having one or more organic residues. An ammonium ion representing M can, for example, also be the cation which is obtained from an amino acid, in particular a basic amino acid such as, for example, lysine or arginine, by protonation. Compounds of the formula I which contain one or more basic, i.e. protonatable, groups, can be present and can be used according to the invention in the form of their acid addition salts with physiologically tolerable inorganic or organic acids, for example as salts with hydrogen chloride, phosphoric acid, sulfuric acid or organic carboxylic acids or sulfonic acids such as, for example, p-toluenesulfonic acid, acetic acid, tartaric acid, benzoic acid, fumaric acid, maleic acid, citric acid etc. Acid addition salts can also be obtained from the compounds of the formula I according to customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid in a solvent or diluent. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, the present invention also comprises internal salts or betaines (zwitterions), in addition to the salt forms described. The present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use in pharmaceuticals but can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically tolerable salts, for example by anion exchange or cation exchange. The present invention furthermore comprises all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I such as, for example, esters and amides of acid groups, and prodrugs and active metabolites of compounds of the formula I. In compounds of the formula I in which Z is oxygen, X is preferably oxygen. Y is preferably the residue -(CR(5) 2 ) n - in which the residues R(5) are hydrogen or methyl, particularly preferably hydrogen, n is preferably 2 or 3, particularly preferably 2. An especially preferred group Y is the group -CH 2 -CH 2 -. Z is preferably NH, i.e. preferred compounds of the formula I are the benzenesulfonamide derivatives of the formula la, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A subgroup of these compounds is formed by the benzenesulfonylthiourea derivatives of the formula lb, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, another subgroup by the benzenesulfonylurea derivatives of the formula lc, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. In the formulae la, lb and lc the residues R(1), R(2), R(3), R(4), Het, X and Y have the meanings indicated above. A special subgroup of the compounds according to the invention is formed by compounds of the formula I in which X is oxygen, Z is NH and R(2) is methyl. A (CrC 4 )-alkyl residue representing R(1) is preferably one of the residues methyl, ethyl and isopropyl. An unsubstituted -0-(Ci-C 4 )-alkyl residue representing R(1) is preferably one of the residues methoxy, ethoxy and propoxy, in particular methoxy or ethoxy. The alkyl group in a substituted -0-(Cι-C )-alkyl residue representing R(1 ) is preferably a methyl group or an ethyl group which is substituted in the 2-position. A fluorine- substituted -O-(C-ι-C )-aIkyl residue representing R(1 ) is preferably one of the residues trifluoromethoxy, 2-fluoroethoxy and 2,2,2-trifluoroethoxy, in particular trifluoromethoxy. A substituted -O-(Cι-C )~alkyl residue representing R(1), which carries a substituent other than fluorine atoms, preferably carries one of the substituents ((Cι-C 4 )-alkyl)carbonylamino, (Cι-C )-alkylamino, di((Cι-C 4 )-alkyl)amino, piperidin-1-yl, morpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenoxy and phenyl, particularly preferably one of the substituents morpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenoxy and phenyl, very particularly preferably one of the substituents tetrahydrofuranyl, tetrahydropyranyl and phenyl, where the phenyl group and the phenoxy group can in each case be unsubstituted or substituted as indicated and are preferably unsubstituted. Especially preferred -O-(Cι-C 4 )-alkyl residues which carry a substituent other than fluorine atoms are tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy. 2-(morpholin-4-yl)ethoxy, 2-phenoxyethoxy and benzyloxy, very especially preferred residues are tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy and benzyloxy. In the residue -O-(Cι-C 4 )-alkyl-E(1 )-(CrC )-alkyl-D(1 ) representing R(1), the groups E(1 ), E(2) and E(3) which can be present therein are preferably oxygen. D(1 ) is preferably hydrogen. If D(1) has a meaning other than hydrogen, D(2) is preferably hydrogen. Preferred meanings of the residue -O-(C C )-alkyl-E(1)-(Cι-C 4 )-alkyl-D(1) are -O-(C 1 -C )-alkyl-O-(C 1 -C 4 )-alkyl and -O-(Cι-C 4 )-alkyl-0-(Cι-C 4 )-alkyl-O-(Cι-C 4 )- alkyl, a particularly preferred meaning is -O-(CrC 4 )-alkyl-0-(Cι-C 4 )-alkyl. Especially preferred meanings of the residue -O-(CrC )-alkyl-E(1)-(Cι-C )-alkyl-D(1) are 2-methoxyethoxy, 2-ethoxyethoxy and 2-(2-methoxyethoxy)ethoxy, in particular 2-methoxyethoxy and 2-ethoxyethoxy. In a fluorine-substituted -O-(Ci-C 4 )-alkyl-O-(C-i-C 4 >-alkyl residue representing R(1 ), preferably the terminal alkoxy group, i.e. the alkoxy group which is not directly bonded to the benzene ring in the formula I, is substituted by fluorine. Preferably, such a terminal fluorine-substituted alkoxy group is trifluoromethoxy. Preferably, a fluorine-substituted -O-(Cι-C 4 )-alkyl-O-(Cι-C )-alkyl residue representing R(1) is -O-(C 1 -C 4 )-alkyl-0-CF 3 , particularly preferably 2-(trifluoromethoxy)ethoxy. A residue -O-(C 2 -C 4 )-aIkenyl representing R(1 ) is preferably allyloxy. A residue -O-phenyl representing R(1) is preferably unsubstituted or monosubstituted phenoxy, particularly preferably phenoxy which is unsubstituted or substituted in the 4-position, in particular unsubstituted phenoxy, 4-methylphenoxy, 4- methoxyphenoxy, 4-fIuorophenoxy or4-trifluoromethy!phenoxy. Halogen representing R(1 ) is preferably bromine or iodine. A phenyl residue representing R(1) is preferably unsubstituted or monosubstituted phenyl, particularly preferably phenyl which is unsubstituted or substituted in the 4- position, in particular unsubstituted phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-trifluoromethylphenyl, especially unsubstituted phenyl. A residue (C 2 -Cs)-alkenyl representing R(1) is preferably allyl. A residue (C 2 -C 5 )-alkynyl representing R(1 ) is preferably ethynyl. A heteroaryl residue representing R(1 ) preferably contains one ring heteroatom and is particularly preferably a pyridyl residue, thienyl residue or furyl residue, in particular one of the residues 2-pyridyl, 3-pyridyl, 2-thienyl and 2-furyl. A residue -S(O) m -phenyl representing R(1 ) is preferably unsubstituted or monosubstituted -S(0) m -phenyl, particularly preferably unsubstituted -S(O) m -phenyl, especially preferably the unsubstituted residue -S-phenyl. m is preferably 0 or 2, particularly preferably 0. R(1) is preferably 1 ) methyl, ethyl or isopropyl; or 2) methoxy, ethoxy, propoxy, trifluoromethoxy, 2-fluoroethoxy or 2,2,2-trifluoroethoxy; or 3) tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, 2-(morpholin-4- yl)ethoxy, 2-phenoxyethoxy or benzyloxy; or 4) 2-methoxyethoxy or 2-ethoxyethoxy; or 5) 2-(trifluoromethoxy)ethoxy; or 6) allyloxy; or 7) phenoxy, 4-fluorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy or 4-trifluoromethylphenoxy; or 8) bromine or iodine; or 9) phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-trifluoromethylphenyl; or 10) allyl; or 11) ethynyl; or 12) furyl, thienyl or pyridyl; or 13) -S-phenyl. Particularly preferably, R(1) is one of the residues mentioned in the general or in a preferred definition of R(1 ) which are bonded via an oxygen atom to the benzene ring carrying the group R(1 ), or is an optionally substituted phenyl residue or heteroaryl residue. Very particularly preferably, R(1 ) is one of the residues methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy and benzyloxy. The heteroaryl residue representing Het preferably contains one ring heteroatom. Particularly preferably the ring heteroatom is selected from the group consisting of nitrogen and sulfur. Especially preferably, Het is a thienyl residue or a pyridyl residue. If Z is NH, R(2) is preferably hydrogen or (C-ι-C 4 )-alkyl, particularly preferably hydrogen, methyl, ethyl or isopropyl. A group of very particularly preferred compounds of the formula I, in which Z is NH, is formed by compounds in which R(2) is hydrogen or methyl, another group is formed by compounds in which R(2) is (C C 4 )-alkyl, in particular methyl, ethyl or isopropyl. If Z is oxygen, R(2) is preferably (C-i- C 4 )-alkyl. An especially preferred meaning of R(2) is methyl. R(3) and R(4) are preferably independently of one another hydrogen or methyl, particularly preferably hydrogen. Preferred compounds of the formula I are those in which one or more of the residues present therein have preferred meanings, where all combinations of preferred substituent definitions are a subject of the present invention. Also with respect to all preferred compounds of the formula I the present invention comprises all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Thus, for example, a group of preferred compounds is formed by those compounds of the formula I in which Z is NH, X is sulfur and R(2) is methyl, and the other residues have the general or preferred meanings indicated above, in al! their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A group of preferred compounds is also formed by those compounds of the formula I in which Y is -CH 2 -CH 2 -; R(2) is methyl, ethyl or isopropyl; R(3) and R(4) are hydrogen; and R(1 ), Het, X and Z have the general or preferred meanings indicated above, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly preferred subgroups of these compounds are formed by compounds of the formula I in which Z is NH and/or X is sulfur. A very particularly preferred subgroup is formed by compounds of the formula I in which R(2) is methyl. A group of particularly preferred compounds is formed, for example, by compounds of the formula Id, in which X is oxygen or sulfur; Y is -(CR(5) 2 ) n -, R(5) is hydrogen or methyl and n is 1 , 2, 3 or 4; R(1 ) is methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2- ylmethoxy or benzyloxy; R(2) is methyl, ethyl or isopropyl; and the thienyl residue is bonded in the 2-position or the 3-position, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A preferred meaning of R(2) in the compounds of the formula Id is methyl. X in the compounds of the formula Id preferably is sulfur. The thienyl residue is preferably bonded in the 2-position. A group of very particularly preferred compounds is formed by compounds of the formula le, in which X is sulfur or oxygen; R(1 ) is methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2- ylmethoxy or benzyloxy; R(2) is methyl, ethyl or isopropyl; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, where in these compounds R(2) preferably is methyl and X preferably is sulfur. A further group of particularly preferred compounds is formed, for example, by compounds of the formula If, in which X is oxygen or sulfur; Y is -(CR(5) 2 )n-, R(5) is hydrogen or methyl and n is 1 , 2, 3 or 4; R(1) is methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2- ylmethoxy or benzyloxy; R(2) is methyl, ethyl or isopropyl; and the pyridyl residue is bonded in the 2-position, the 3-position or the 4-position, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A preferred meaning of R(2) in the compounds of the formula If is methyl. X in the compounds of the formula If preferably is sulfur. The pyridyl residue is preferably bonded in the 2-position. A group of very particularly preferred compounds is formed by compounds of the formula Ig, in which X is sulfur or oxygen; R(1 ) is methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(trifluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2- ylmethoxy or benzyloxy; R(2) is methyl, ethyl or isopropyl; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, where in these compounds R(2) preferably is methyl and X preferably is sulfur. The present invention also relates to processes for the preparation of the compounds of the formula I which are illustrated below and according to which the compounds of the invention are obtainable. Compounds of the formula I in which X is sulfur and Z is NH, i.e. benzenesulfonylthioureas of the formula lb, in which R(1), R(2), R(3), R(4), Het and Y have the abovementioned meanings, can be prepared, for example, by reacting benzenesulfonamides of the formula III, in which R(1), R(3), R(4), Het and Y have the abovementioned meanings, in an inert solvent or diluent with a base and with an R(2)-substituted isothiocyanate of the formula IV R(2)-N=C=S IV in which R(2) has the meanings indicated above. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or quaternary ammonium hydroxides. The reaction of the compound of the formula III with the base can initially be carried out in a separate step and the resulting salt of the formula V, in which R(1), R(3), R(4), Het and Y have the abovementioned meanings and the cation M 1 is an alkali metal ion, for example a sodium ion or potassium ion, or an equivalent of an alkaline earth metal ion, for example of a magnesium ion or calcium ion, or an ammonium ion which is inert under the reaction conditions, for example a quaternary ammonium ion, can also be intermediately isolated, if desired. The salt of the formula V, however, can particularly advantageously also be produced in situ from the compound of the formula III and reacted directly with the isothiocyanate of the formula IV. Suitable inert solvents for the reaction are, for example, ethers such as tetrahydrofuran (THF), dioxane, ethylene glycol dimethyl ether (DME) or diethylene glycol dimethyl ether (diglyme), ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoric triamide (HMPT), sulfoxides such as dimethylsulfoxide (DMSO) or hydrocarbons such as benzene, toluene or xylenes. Furthermore, mixtures of these solvents with one another are also suitable. The reaction of the compound of the formula III or V with the compound of the formula IV is in general carried out at temperatures from room temperature to about 150°C, in particular from room temperature to about 100°C. Compounds of the formula I in which X is oxygen and Z is NH, i.e. benzenesulfonylureas of the formula lc, in which R(1 ), R(2), R(3), R(4), Het and Y have the abovementioned meanings, can be prepared, for example, by reacting, analogously to the synthesis of the thiourea derivatives of the formula lb described above, benzenesulfonamides of the formula III or their salts of the formula V in an inert solvent or diluent with a base and with an R(2)-substituted isocyanate of the formula VI R(2)-N=C=O VI in which R(2) has the meanings indicated above. The above illustrations of the reaction with isothiocyanates correspondingly apply to the reaction with the isocyanates. Benzenesulfonylureas of the formula lc can also be prepared from the benzenesulfonamides of the formula III or their salts of the formula V by reaction with R(2)-substituted 2,2,2-trichloroacetamides of the formula VII, CI 3 C-CO-NH-R(2) VII in which R(2) has the meanings indicated above, in the presence of a base in an inert, high-boiling solvent such as, for example, DMSO. Benzenesulfonylureas of the formula lc can also be prepared by means of a conversion reaction (desulfurization) from the corresponding benzenesulfonylthioureas of the formula lb. The replacement of the sulfur atom in the thiourea group of the compounds of the formula lb by an oxygen atom can be carried out, for example, with the aid of oxides or salts of heavy metals or by use of oxidants such as hydrogen peroxide, sodium peroxide or nitrous acid. Benzenesulfonylureas and -thioureas of the formulae lc and lb can also be prepared by reaction of amines of the formula R(2)-NH 2 in which R(2) has the abovementioned meanings, with benzenesulfonyl isocyanates and isothiocyanates of the formula VIII, in which R(1 ), R(3), R(4), Het, X and Y have the abovementioned meanings. The sulfonyl isocyanates of the formula VIII (X = oxygen) can be obtained from the benzenesulfonamides of the formula III according to customary methods, for example using phosgene. The sulfonyl isothiocyanates of the formula VIII (X = sulfur) can be prepared by reaction of the sulfonamide of the formula III with alkali metal hydroxides and carbon disulfide in an organic solvent, such as DMF, DMSO or NMP. The di- alkali metal salt of the sulfonyldithiocarbamic acid obtained here can be reacted in an inert solvent using a slight excess of phosgene or of a phosgene substitute such as triphosgene or using a chloroformic acid ester (2 equivalents) or using thionyl chloride. The solution of the sulfonyl iso(thio)cyanate of the formula VIII obtained can be reacted directly with the appropriately substituted amine of the formula R(2)-NH 2 or, if compounds of the formula I are to be prepared in which R(2) is hydrogen, can be reacted with ammonia. Correspondingly, starting from benzenesulfonyl iso(thio)cyanates of the formula VIII, by addition of alcohols of the formula R(2)-OH in which R(2) has the abovementioned meanings with the exception of hydrogen, compounds of the formula I can be prepared in which Z is oxygen, i.e. the benzenesulfonylurethane derivatives of the formula Ih, in which R(1), R(2), R(3), R(4), Het, X and Y have the abovementioned meanings, but R(2), as mentioned, is not hydrogen. Compounds of the formula Ih can also be prepared, for example, by reacting, analogously to the syntheses described above, benzenesulfonamides of the formula III or their salts of the formula V in an inert solvent, for example a high-boiling ether, with reactive carbonic acid derivatives, for example with chloroformic acid esters of the formula CI-CO-OR(2) or pyrocarbonic acid diesters of the formula (R(2)0-C(=0)) 2 O in which R(2) has the abovementioned meanings with the exception of hydrogen. Starting from the compounds of the formula Ih in which X is oxygen, compounds of the formula lc are in turn obtainable by reaction with the appropriate amine of the formula R(2)-NH 2 in an inert, high- boiling solvent, for example toluene, at temperatures up to the boiling point of the respective solvent. The benzenesulfonamides of the formula III as the starting compounds for the processes for the synthesis of the benzenesulfonamide derivatives of the formula I can be prepared according to or analogously to known methods such as are described in the literature, for example in standard works like Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart, and Organic Reactions, John Wiley & Sons, Inc., New York, and in the patent documents indicated above, if necessary with appropriate adjustment of the reaction conditions as is familiar to the person skilled in the art. Use can also be made in this case of variants which are known per se but not illustrated here in greater detail. In the synthesis, it may also be appropriate to temporarily block functional groups which would react in an undesired manner or give rise to side reactions by protective groups, or to employ them in the form of precursor groups which are only later converted into the desired groups. Strategies of this type are known to the person skilled in the art. Starting substances can, if desired, also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further. Thus it is possible, for example, to react p-substituted benzene derivatives of the formula IX, in which Y has the abovementioned meanings and R(0) is, for example, (Cι-C 4 )-a!kyl, (Cι-C 4 )-aIkoxy or bromine or nitro, with trifluoroacetic anhydride in the presence of pyridine in an inert solvent such as, for example, THF to give compounds of the formula X, in which Y and R(0) have the meanings indicated above. Starting from the compounds of the formula X in which R(0) is nitro, it is possible by means of reduction of the nitro group using a reductant such as, for example, SnCI 2 x 2 H 2 0 in an inert solvent such as ethyl acetate, diazotization of the resulting amino group and subsequent reaction of the intermediate diazonium compound according to processes known per se, such as are described, for example, in Larock, Comprehensive Organic Transformations, VCH, 1989, for example by reaction with potassium iodide for the preparation of the iodo compounds, to obtain the corresponding p-halogen-substituted compounds of the formula XI, in which Y has the meanings indicated above and Hal is halogen. The compounds of the formula XI and the compounds of the formula X in which R(0) is (Cι-C4)-alkyl, (C C 4 )-alkoxy or bromine, which are collectively designated as compounds of the formula XII, in which Y has the meanings indicated above and R(1a) is (Cι-C 4 )-aIkyl, (C C 4 )- alkoxy or halogen, can be converted in a known manner into the benzene sulfonamides of the formula XIII, in which Y and R(1a) have the meanings mentioned. The preparation of the sulfonamides of the formula XIII from the compounds of the formula XII can be carried out in one, two or more steps. In particular, processes are preferred in which the acylamines of the formula XII are first converted by means of electrophilic reagents in the presence or absence of inert solvents or diluents at temperatures from about -20°C to about 120°C, preferably from about 0°C to about 100°C, into the 2,5-substituted benzenesulfonic acids or their derivatives such as, for example, the sulfonic acid halides. For this, it is possible, for example, to carry out sulfonations using sulfuric acids or oleum, or halosulfonations using halosulfonic acids such as chlorosulfonic acid, or reactions with sulfuryl halides in the presence of anhydrous metal halides, or reactions with thionyl halides in the presence of anhydrous metal halides with subsequent oxidations, carried out in a known manner, to give sulfonyl chlorides. If sulfonic acids are the primary reaction products, these can be converted into sulfonic acid halides either directly or after treatment with amines such as, for example, triethylamine or pyridine, or with alkali metal or alkaline earth metal hydroxides or with other suitable bases, in a manner known per se by means of acid halides such as, for example, phosphorus trihalides, phosphorus pentahalides, thionyl halides or oxalyl halides. The conversion of the sulfonic acid derivatives into the sulfonamides of the formula XIII is carried out in a manner known from the literature. Preferably, sulfonyl chlorides are reacted with aqueous ammonia in an inert solvent such as, for example, acetone at temperatures from about 0°C to about 100°C. For the preparation of compounds of the formula I in which R(1 ) is (Cι-C 4 )-alkyl, (d- C 4 )-alkoxy or halogen, the compounds of the formula XIII can be converted by treatment with an acid such as, for example, hydrochloric acid or sulfuric acid, if appropriate with addition of a polar organic solvent such as methanol or ethanol, at temperatures from about 0°C up to the boiling point of the solvent, into the compounds of the formula XIV, in which R(1a) is (Cι-C 4 )-alkyl, (C-ι-C 4 )-alkoxy or halogen and Y has the meaning indicated above. For the preparation of compounds of the formula I in which R(1) is the other residues mentioned above, initially the sulfonamide group in suitable compounds of the formula XIII can be temporarily protected by conversion into the N-(N,N- dimethylaminomethylene)suIfonamide group. For example, starting from compounds of the formula XIII the dimethylaminomethylene compounds of the formula XV, in which Y has the meanings mentioned and R(1 b) is (Cι-C 4 )-aIkoxy, bromine or iodine, can be prepared by reacting the compounds of the formula XIII, for example, with N,N-dimethyIformamide dimethyl acetal or reacting them with N,N-dimethyI- formamide in the presence of dehydrating agents such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride. The compounds of the formula XV in which R(1 b) is (C-ι-C 4 )-alkoxy can then be converted by ether cleavage into the phenols of the formula XVI in which Y is as defined above. This ether cleavage is carried out, for example, by treatment of the compounds of the formula XV in which R(1b) is methoxy with acids or with Lewis acids such as boron trifluoride, boron trichloride, boron tribromide or aluminum trichloride or their etherates, preferably with boron tribromide in an inert solvent such as, for example, dichloromethane. The phenols of the formula XVI obtained can be converted into the compounds of the formula XVII in which Y has the abovementioned meanings and R(1c) is one of the residues -O-(d-C 4 )-alkyl-E(1 )-(C C 4 )-alkyl-D(1 ), fluorine-substituted -0-(d-C 4 )-alkyl-O-(Cι- C 4 )-alkyl, substituted -O-(C 1 -C 4 )-alkyl, -O-(C 2 -C 4 )-alkenyl, or -O-phenyl. This conversion is carried out by means of an O-alkylation of the phenols of the formula XVI using appropriately substituted halogen compounds such as iodides or bromides or sulfonic acid esters such as methanesulfonic acid esters, p-toluenesulfonic acid esters or trifluoromethanesulfonic acid esters. The sulfonic acid esters are obtainable from the correspondingly substituted alcohols of the formula R(1c)-H according to standard processes, for example by using methanesulfonyl chloride in an inert solvent in the presence of a base such as potassium carbonate or cesium carbonate in the case of the methanesulfonic acid esters. For example, with (2-bromoethyl) methyl ether or benzyl bromide the compounds of the formula XVII and thus the final compounds of the formula I are obtained in which R(1c) and R(1), respectively, is 2-methoxyethoxy or benzyloxy. The O-alkylation is in general carried out in the presence of a base in an inert solvent at temperatures from about 0°C up to the boiling point of the solvent according to processes known per se. The preparation of compounds of the formula XVII in which R(1c) is -O-phenyl can be carried out by means of an O-arylation of the phenols of the formula XVI with phenylboronic acids, for example with phenylboronic acid or with substituted phenylboronic acids such as 4-methoxyphenylboronic acid, in the presence of copper catalysts, for example copper(ll) acetate. Analogous reactions are described, for example, in Tetrahedron Lett. 39 (1998), 2937. Starting from the compounds of the formula XV in which R(1 b) is bromine or iodine, the compounds of the formula XVIII XVIII can be obtained in which Y has the indicated meanings and R(1d) is one of the residues (Cι-C 4 )-alkyl, phenyl, (C 2 -C 5 )-alkenyl, (C 2 -C 5 )-alkynyl, heteroaryl or -S(O) m -phenyl. The conversion into the compounds of the formula XVIII can be carried out by means of palladium-catalyzed Suzuki coupling using arylboronic acids, for example phenylboronic acid, 4-methoxyphenylboronic acid or 4- methylthiophenylboronic acid, or heteroarylboronic acids, for example thienylboronic acid, or by means of Stille coupling using trialkylstannanes, for example tributylstannylfuran, trimethylstannylpyridine or ethinyltributylstannane. The Suzuki coupling is carried out in the presence of palladium(ll) acetate and triphenylphosphine or tetrakis(triphenylphosphine)palladium and a base such as, for example, cesium carbonate or potassium carbonate. Corresponding reactions are described in the literature. The Stille coupling is carried out analogously to literature procedures using bis(triphenylphosphine)palladium(ll) chloride as catalyst. The preparation of suitable stannanes is described, for example, in Tetrahedron 49 (1993) 3325. The preparation of compounds of the formula XVIII in which R(1d) is alkyl can be carried out by means of Pd(0)-catalyzed Nikishi-Kumada coupling of the compounds of the formula XV in which R(1 b) is iodine with an appropriate organozinc derivative in the presence of 1 ,1'-bis(diphenylphosphino)ferrocene, palladium(ll) acetate and copper(l) iodide as catalysts in an inert solvent. Corresponding couplings are described, for example, in Synlett 1996, 473. Compounds of the formula XVIII in which R(1d) is -S-phenyl can be prepared, analogously to literature procedures, from the compounds of the formula XV in which R(1 b) is iodine by means of a copper(l) iodide-catalyzed nucleophilic substitution reaction, using the sodium salt of the appropriate thiophenol. The thioether group introduced in this way, and just so thioether groups in other positions of the molecule of the formula I or of a synthetic intermediate, can be oxidized by standard processes to the sulfoxide group or to the sulfone group, for example by using a peracid such as m-chloroperbenzoic acid. The subsequent removal of the dimethylaminomethylene group and of the trifluoroacetyl group functioning as a sulfonamide protective group and amino protective group, respectively, from the compounds of the formulae XVII and XVIII then leads to the corresponding compounds having a H 2 N-Y group and H 2 N-SO 2 group which, together with the compounds of the formula XIV, are represented by the formula XIX, in which Y and R(1 ) have the meanings indicated above for the formula I. This removal of the protective groups can be carried out either under basic or under acidic conditions. Preferably, it is carried out by treatment of the compounds of the formulae XVII and XVIII in an inert solvent, for example an alcohol, with acids such as, for example, hydrochloric acid. The benzenesulfonamides of the formula XIX are then acylated using heteroarylacrylic acid derivatives to give the heteroarylacryloylaminoalkyl-substituted benzenesulfonamides of he formula III. The heteroarylacrylic acids are commercially obtainable or are prepared according to or analogously to literature procedures, for example starting from the corresponding heteroaromatic aldehydes. The acylation is in generally carried out by converting the heteroarylacrylic acid firstly into a reactive derivative, for example by reaction with N,N'-carbonyldiimidazole in an inert solvent such as, for example, THF, dioxane or DMF, and subsequent reaction with the amine of the formula XIX, if appropriate in the presence of a base such as triethylamine or pyridine. As reactive derivatives of the heteroarylacrylic acids also the acid halides or the acid anhydrides, for example, can be used. The reactions are in this case preferably carried out at temperatures from about 0°C up to the boiling point of the chosen solvent or diluent, particularly advantageously at room temperature. The acylation of the amines of the formula XIX using the heteroarylacrylic acids can also be carried out, for example, in the presence of condensing agents such as, for example, N,N'-dicyclohexylcarbodiimide, O-((cyano(ethoxycarbonyI)methylene)- amino)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TOTU) or 1 -benzotriazolyloxy- tripyrrolidinophosphonium hexafluorophosphate (PyBOP). The steps described for the preparation of the compounds of the formula I can also be carried out in another sequence. Depending on the substituents to be introduced in the individual steps, one or another variant may be more advantageous. Thus, for example, the preparation of the compounds of the formula III in which R(1 ) is one of the residues (Cι-C 4 )-alkyl, phenyl, (C 2 -C 5 )-alkenyl, (C 2 -C 5 )-alkynyl, heteroaryl or -S(0)m-phenyl, can also be carried out in such a way that firstly a compound of the formula XIV in which R(1a) is iodine or bromine is converted by coupling with a heteroarylacrylic acid derivative and temporary protection of the sulfonamide group, as described above, into a compound of the formula XX, in which R(3), R(4), Het and Y are as defined for formula I and Hal 1 is iodine or bromine. From the compound of the formula XX, it is then possible by means of the Suzuki, Stille or Nikishi-Kumada couplings described above using the appropriate abovementioned coupling components, to obtain the compounds of the formula XXI, in which R(1d), R(3), R(4), Het and Y have the meanings indicated above. The compounds of the formula XXI can then be converted into the compounds of the formula III by removal of the sulfonamide protective group according to the process described above. The compounds of the formula I inhibit ATP-sensitive potassium channels and influence the action potential of cells, in particular of cardiac muscle cells. In particular, they have a normalizing action on a disturbed action potential, such as is present, for example, in the case of ischemia, and are suitable, for example, for the treatment and prophylaxis of disorders of the cardiovascular system, in particular of arrhythmias and their sequelae, for example of ventricular fibrillation or of sudden cardiac death. The activity of the compounds of the formula I can be demonstrated, for example, in the model described below, in which the action potential duration on the papillary muscle of the guinea pig is determined. In addition to their action on ATP-sensitive potassium channels in the cardiac muscle cell, the compounds of the formula I also have an action on the peripheral and/or the central autonomic nervous system. In particular, they influence ATP-sensitive potassium channels of the vagal nervous system and have a stimulating action on the vagal nervous system, in particular a stimulating action on the vagal nervous system of the heart due to inhibition of ATP-sensitive potassium channels in the cardiac nerve. In the ideal case, an optimum interaction, adapted to the particular situation, exists between the vagal (or parasympathetic) nervous system (= depressing nervous system) and the sympathetic nervous system (= stimulating nervous system). In the case of disease, however, this interaction may be disturbed and a dysfunction of the autonomic nervous system may be present, i.e. an inequilibrium may exist between the activity of the vagal nervous system and the activity of the sympathetic nervous system. Sympathovagal inequilibrium is understood in general as meaning a hyperactivity of the sympathetic (= stimulating) nervous system and/or a hypoactivity of the vagal (= depressing) nervous system, where the two parts of the nervous system can reciprocally influence one another. In particular, it is known that a hypoactivity of the vagal system can result in a hyperactivity of the sympathetic system. To avoid damage to cells or organs of the body due to overshooting biological or biochemical processes which are stimulated by an excessively high activity of the sympathetic nervous system, it is therefore attempted in such cases to compensate for a sympathovagal inequilibrium, for example to restore the normal vagal activity by eliminating a vagal dysfunction or hypoactivity. Examples of diseases which can be treated by eliminating a vagal dysfunction and thus compensating for a harmful sympathovagal inequilibrium, are organic heart diseases such as coronary heart disease, cardiac insufficiency and cardiomyopathies. Damages to health which result from an inequilibrium of the autonomic nervous system when the dysfunction affects the heart are, for example, weakening of the myocardial contractile force and fatal cardiac arrhythmias. The importance of the autonomic nervous system for sudden cardiac death in heart diseases was described, for example, by P. J. Schwartz (The ATRAM1 prospective study: implications for risk stratification after myocardial infarction; Cardiac Electrophysiology Review 2 (1998) 38) or T. Kinugawa et al. (Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure; Am. J. Physiol. 37 (1995) R310). Experimental investigations with electrical stimulation of the cardiac vagus or stimulating analogs of the vagal transmitter acetylcholine, for example carbachol, confirm the protective action of a vagal activation against fatal cardiac arrhythmias (see, for example, E. Vanoli et al., Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction; Circ. Res. 68 (1991) 1471). A sympathovagal inequilibrium, however, can also occur, for example, as a result of a metabolic disorder, for example of diabetes mellitus (see, for example, A. J. Burger et al., Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus; Am. J. Cardiol. 80 (1997) 1198). A hypoactivity of the vagal system can also temporarily occur, for example in the case of oxygen deficiency, for example oxygen deficiency of the heart, which leads to a reduced secretion of vagal neurotransmitters, for example of acetylcholine. On account of the surprising ability of the compounds of the formula I to abolish a hypoactivity of the vagal system or to restore the normal vagal activity, these compounds offer an efficient possibility of reducing, eliminating or preventing dysfunctions of the autonomic nervous system, in particular in the heart, and their sequelae such as, for example, the disease conditions mentioned. The efficacy of the compounds of the formula I in the abolition of dysfunctions of the autonomic nervous system, in particular of a vagal dysfunction of the heart, can be demonstrated in the model of chloroform-induced ventricular fibrillation in mice described below. The compounds of the formula I and their physiologically tolerable salts can be used in animals, preferably in mammals, and in particular in humans as pharmaceuticals on their own, in mixtures with one another or in the form of pharmaceutical preparations. Mammals in which the compounds of the formula I can be used or tested are, for example, monkeys, dogs, mice, rats, rabbits, guinea pigs, cats and larger farm animals such as, for example, cattle and pigs. The invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts and their prodrugs for use as pharmaceuticals, and pharmaceutical preparations (or pharmaceutical compositions) which contain an efficacious dose of at least one compound of the formula I and/or of a physiologically tolerable salt thereof and/or of a prodrug thereof as active constituent and a pharmaceutically tolerable carrier, i.e. one or more pharmaceutically acceptable vehicles and/or excipients (additives). The invention furthermore relates to the use of the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs for the treatment, including the therapy and prophylaxis, of the syndromes mentioned above or below, to their use for the production of pharmaceuticals for the treatment, including therapy and prophylaxis, of the syndromes mentioned above or below, and to methods for the treatment, including the therapy and prophylaxis, of the syndromes mentioned above or below which comprise administering an efficacious amount of at least one compound of the formula I and/or a physiologically tolerable salt and/or a prodrug thereof. The pharmaceutical preparations can be intended for enteral or parenteral use and normally contain 0.5 to 90 percent by weight of at least one compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs. The amount of active compound of the formula I and/or its physiologically tolerable salts and/or its prodrugs in the pharmaceutical preparations is in general about 0.2 to about 1000 mg, preferably about 0.2 to about 500 mg, particularly preferably about 1 to about 300 mg, per dose unit. The pharmaceutical preparations can be prepared in a manner known per se. For this, the compounds of the formula I and/or their physiologically tolerable salts and/or their prodrugs are mixed with one or more solid or liquid vehicles and/or excipients and, if desired, with other pharmaceutical active compounds, for example pharmaceutical active compounds having cardiovascular activity such as, for example, calcium antagonists, ACE inhibitors or β-b!ockers, and brought into a suitable dose form and administration form which can then be used as pharmaceuticals in human medicine or veterinary medicine. Possible vehicles are organic and inorganic substances which are suitable, for example, for enteral, for example oral or rectal, administration, or for parenteral administration, for example by intravenous, intramuscular or subcutaneous injection or infusion, or for topical or percutaneous administration, and do not react in an undesired manner with the compounds of the formula I. Examples which may be mentioned are water, vegetable oils, waxes, alcohols such as ethanol, propanediol or benzyl alcohols, glycerol, polyols, polyethylene glycols, polypropylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures of two or more vehicles, for example mixtures of water with one or more organic solvents such as mixtures of water with alcohols. For oral and rectal administration, in particular, pharmaceutical forms such as tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, preferably oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or emulsions, are used. For topical application, in particular, ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders are used. As solvents for solutions including injection and infusion solutions, for example water or alcohols such as ethanol, isopropanol or 1 ,2-propanediol or their mixtures with one another or with water can be used. Further possible pharmaceutical forms are, for example, implants. The compounds of the formula I and their physiologically tolerable salts can also be Iyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. Liposomal preparations are also suitable, in particular for topical application. As examples of excipients (or additives) which can be present in the pharmaceutical preparations, glidants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving depot effect, emulsifiers, salts (for example for influencing the osmotic pressure), buffer substances, colorants, flavorings and aromatizers may be mentioned. If desired, pharmaceutical preparations can also contain one or more further active compounds and/or, for example, one or more vitamins. On account of their ability to inhibit ATP-sensitive potassium channels, in particular in the heart, and/or to decrease or to eliminate an inadequate function of the vagal nervous system and thereby a vagal dysfunction or a dysfunction of the autonomic nervous system, in particular in the heart, the compounds of the formula I and their physiologically tolerable salts and prodrugs are valuable pharmaceutical active compounds which are suitable not only as antiarrhythmics and for the control and prevention of the sequelae of arrhythmias, but also for treatment and prophylaxis in other heart diseases or disorders of the cardiovascular system. Examples of such diseases which may be mentioned are cardiac insufficiency, cardiomyopathies, cardiac hypertrophy, coronary heart disease, angina pectoris, ischemia, vagal dysfunction of the heart or, for example, vagal dysfunction of the heart in diabetes mellitus. The compounds of the formula I can generally be employed in the treatment of diseases which are associated with a dysfunction of the autonomic nervous system or a hypoactivity or dysfunction of the vagal nervous system, in particular in the heart, or are caused by such a dysfunction or in whose treatment an increase in or normalization of the activity of the vagal nervous system is desired. The compounds of the formula I can also be generally employed in diseases which are characterized by oxygen deficiency conditions, in cerebral vascular disorders, and in dysfunctions of the autonomic nervous system, in particular of a vagal dysfunction in the heart, which occur as a result of a metabolic disorder such as, for example, of diabetes mellitus. The compounds of the formula I are especially used as antiarrhythmics for the treatment of cardiac arrhythmias of very different origin and especially for the prevention of sudden cardiac death due to arrhythmia. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias such as, for example, atrial tachycardia, atrial flutters or paroxysomal supraventricular arrhythmias, or ventricular arrhythmias such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardia or the particularly dangerous fatal ventricular fibrillation. They are suitable, in particular, in those cases where arrhythmias are the result of constriction of a coronary vessel such as occur, for example, in angina pectoris or during acute cardiac infarcts or as a chronic result of a cardiac infarct. They are therefore in particular suitable for the prevention of sudden cardiac death in post- infarct patients. Further syndromes in which arrhythmias of this type and/or sudden cardiac death due to arrhythmia play a part are, for example, cardiac insufficiency or cardiac hypertrophy as a result of chronically raised blood pressure. Moreover, the compounds of the formula I are able to positively influence decreased contractility of the heart and a weakened myocardial contractile force. This can be a disease-related decline in cardiac contractility, such as, for example, in cardiac insufficiency, but also acute cases such as heart failure in the case of shock. Generally, the compounds of the formula I and their physiologically tolerable salts are suitable for improving cardiac function. Specifically in a heart transplantation, under the influence of the compounds of the formula I the heart can resume its capability faster and more reliably after the operation has taken place. The same applies to operations on the heart which necessitate temporarily stopping cardiac activity by means of cardioplegic solutions. Owing to the fact that the compounds of the formula I, in addition to their direct cardiac action, i.e. the effect on the action potential of the cardiac muscle cells, also have an indirect action on the nervous system of the heart or on the parts of the nervous system acting on the heart, they can decrease or prevent undesirable sequelae emanating from the nervous system or mediated by the nervous system in the respective syndrome present. On account of this, further damage to health such as a weakening of the myocardial contractile force or in some cases fatal cardiac arrhythmias such as ventricular fibrillation can be reduced or avoided. Owing to the elimination or reduction of the dysfunction of the autonomic nervous system, the compounds of the formula I have the effect that the weakened myocardial contractile force is normalized again and that the cardiac arrhythmias which can lead to sudden cardiac death do no longer develop. By selecting compounds of the formula I having a suitable profile of action with respect to direct cardiac action (= direct effect on the action potential of the cardiac muscle cells and on account of this a direct effect on the contractile force and a direct antiarrhythmic effect) on the one hand and the action on the cardiac nerves on the other hand, it is particularly efficiently possible with the aid of the compounds of the formula I to favorably influence heart diseases. Depending on the syndrome present, it can also be advantageous in this case to employ compounds of the formula I which have only a relatively slight direct cardiac effect and, on account of this, for example, have only a relatively slight direct effect on the contractile force of the heart or the formation of arrhythmias, but can improve or normalize the myocardial contractile force or the cardiac rhythm by means of the effect on the autonomic nervous system. The dose of the compounds of the formula I or their physiologically tolerable salts depends, as usual, on the circumstances of the particular individual case and is adjusted by the person skilled in the art according to the usual rules and procedures. It depends, for example, on the specific compound of the formula I administered, its potency and duration of action, on the nature and severity of the individual syndrome, on the sex, age, weight and on the individual responsiveness of the human or animal to be treated, on whether treatment is to be acute or prophylactic or on whether further active compounds are administered in addition to compounds of the formula I. Normally, in the case of administration to an adult weighing about 75 kg it is possible to manage with a dose which is about 0.1 mg to about 100 mg per kg per day, preferably about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight). The daily dose can be administered in the form of a single oral or parenteral dose or divided into a number of individual doses, for example two, three or four doses. The administration can also be carried out continuously. In particular, if acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration, for example by injection or by intravenous continuous infusion, can be advantageous. A preferred dose range in critical situations then is about 1 to about 100 mg per kg of body weight per day. Depending on individual behavior, it may be necessary to deviate upward or downward from the doses indicated. Apart from as a pharmaceutical active compounds in human medicine and veterinary medicine, the compounds of the formula I can also be employed, for example, as auxiliaries for biochemical investigations or as a scientific tool when a respective effect on ion channels is intended, or for the isolation or characterization of potassium channels. They can also be used for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples. The compounds of the formula I and their salts can furthermore be used as chemical intermediates for the production of further pharmaceutical active compounds. The invention is illustrated by the examples below, without being restricted to these. Abbrevi; ations DCI Desorption chemical ionization DCM Dichloromethane DMF Dimethylformamide EA Ethyl acetate ESI Electron spray ionization FAB Fast atom bombardment M.p. Melting point h Hour(s) MeOH Methanol min Minute(s) MS Mass spectrum RT Room temperature THF Tetrahydrofuran Example 1 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- thiourea a) 2,2,2-Trifluoro-N-(2-(4-methoxyphenyl)ethyl)acetamide 32.2 ml (0.23 mol) of trifluoroacetic acid were added dropwise to a solution of 22.3 ml (0.15 mol) of 2-(4-methoxyphenyl)ethylamine and 24.7 ml (0.23 mol) of pyridine in 125 ml of absolute THF cooled to 5°C, and the resulting solution was stirred at RT for 3 h. The reaction solution was then poured onto 750 ml of ice, and the deposited precipitate was filtered off with suction and dried at 40°C in a high vacuum. 36.3 g of the title compound were obtained as a beige solid. M.p.: 74 - 77°C R f (SiO 2 , EA/toluene 1 :4) = 0.62 MS (ESI): m/z = 248 [M+H] + b) 2-Methoxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)benzenesulfonamide 36.3 g (0.15 mol) of the compound of example 1a) were added in portions to 200 ml of chlorosulfonic acid and the resulting mixture was stirred at RT for 2 h. The reaction solution was then added dropwise to about 1.5 I of ice and the deposited precipitate was filtered off with suction. The precipitate was dissolved in 100 ml of acetone, the solution was treated with 250 ml of concentrated ammonia solution with ice-cooling, and the mixture was stirred for 45 min. The reaction solution was then poured onto about 800 ml of ice, and the deposited precipitate was filtered off with suction and dried in a high vacuum. 30.4 g of the title compound were obtained as a pale yellow solid. M.p.: 160 - 161 °C R f (SiO 2 , EA/heptane 4:1 ) = 0.51 MS (DCI): m/z = 327 [M+H] + c) 5-(2-Aminoethyl)-2-methoxybenzenesulfonamide A solution of 30.3 g (93.0 mmol) of the compound of example 1 b) in 130 ml of 2N hydrochloric acid was heated to reflux for 12 h. The deposited precipitate was filtered off with suction, dissolved in 70 ml of water and the pH of the resulting solution was adjusted to about 10 by addition of 2N sodium hydroxide solution. The mixture was briefly warmed to 100°C and then cooled in an ice bath. The deposited precipitate was filtered off with suction and dried in a high vacuum. 13.7 g of the title compound were obtained as a beige solid. M.p.: 180 - 181 °C R f (SiO 2 , EA/heptane 4:1 ) = 0.02 MS (ESI): m/z = 231 [M+H] + d) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxybenzenesulfonamide A solution of 300.0 mg (1.95 mmol) of trans-3-(2-thienyl)acrylic acid in 14 ml of absolute THF was treated under an argon atmosphere with 243.0 mg (1.5 mmol) of N.N'-carbonyldiimidazoIe, and the mixture was stirred at RT for 3 h. The resulting solution was treated successively with 946 μl of triethylamine and 400 mg (1.5 mmol) of the compound of example 1c) and stirred at RT for 22 h. The reaction solution was then poured onto 70 ml of 1 N hydrochloric acid. The deposited precipitate was filtered off, washed with a little water and dried in a high vacuum. 270 mg of the title compound were obtained as a white solid. M.p.: 218-221 °C R f (SiO 2 , EA) = 0.72 MS (ESI): m/z = 367 [M+H] + e) 1 -[5-(2-(trans-3-(2-Thienyl)acryIoylamino)ethyl)-2-methoxyphenylsulfonyl]-3- methyl-thiourea A solution of 180 mg (0.49 mmol) of the compound of example 1d) and 66.2 mg (0.59 mmol) of potassium tert-butoxide in 4 ml of absolute DMF was stirred at RT for 15 min. 542 μl (0.54 mmol) of a 1 M solution of methyl isothiocyanate in absolute DMF were added and the resulting solution was stirred at 80°C for 1 h. The reaction solution was then poured onto 50 ml of 1 N hydrochloric acid, and the deposited precipitate was filtered off with suction and washed several times with water. Drying of the precipitate in a high vacuum yielded 214 mg of the title compound as a pale yellow solid. M.p.: 215°C R f (SiO 2 , EA) = 0.60 MS (ESI): m/z = 440 [M+H] + Example 2 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- thiourea sodium salt 200 mg (0.46 mmol) of the compound of example 1 e) were added in portions to a solution of 19.1 mg (0.48 mmol) of sodium hydroxide in 15 ml of ethanol. The resulting solution was stirred at RT for 2 days, and the deposited precipitate was filtered off, washed with a little cold ethanol and dried in a high vacuum. 191 mg of the title compound were obtained as a white solid. M.p.: 242°C MS (FAB): m/z = 462 [M+H] + Example 3 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- urea 90.0 mg (0.20 mmol) of the compound of example 1e) were dissolved in 1.8 ml of 1 N sodium hydroxide solution. 92 μl of a 35% strength aqueous hydrogen peroxide solution were added and the resulting solution was heated on the water bath for 30 min. The pH of the solution was then adjusted to 2 by addition of 2N hydrochloric acid, and the deposited precipitate was filtered off with suction, washed with a little water and dried in a high vacuum. 52 mg of the title compound were obtained as a white solid. M.p.: 120°C R f (SiO 2 , EA) = 0.39 MS (ESI): m/z = 424 [M+H] + Example 4 1 -[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- urea sodium salt According to the process described in example 2), starting from 64 mg (0.15 mmol) of the compound of example 3), 31 mg of the title compound were obtained as a slightly beige solid. M.p.: 180°C MS (FAB): m/z = 445 [M+H] + Example 5 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3- isopropyl-thiourea According to the process described in example 1e), starting from 100 mg (0.27 mmol) of the compound of example 1d) and 32 μl (0.29 mmol) of isopropyl isothiocyanate, 106 mg of the title compound were obtained as a slightly beige solid. M.p.: 96°C R f (SiO 2 , EA) = 0.55 MS (ESI): m/z = 468 [M+H] + Example 6 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]- 3-methyl-thiourea a) N-Dimethylaminomethylene-2-methoxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide 30.2 g (92.6 mmol) of the compound of example 1b) were dissolved in 70 ml of absolute DMF, 14.0 ml (105.4 mmol) of dimethylformamide dimethyl acetal were added and the resulting solution was stirred at RT for 3 h. The reaction mixture was concentrated to dryness and the residue obtained was stirred in 100 ml of water and 100 ml of 5% strength sodium hydrogensulfate solution. The residual crystalline precipitate was washed several times with water and then dried in a high vacuum. 29.6 g of the title compound were obtained as a white solid. M.p.: 143 - 144°C R f (SiO 2 , EA) = 0.25 MS (DCI): m/z = 382 [M+H] + b) N-Dimethylaminomethylene-2-hydroxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide hydrobromide 100 ml of a 1 M boron tribromide solution in DCM were added dropwise at RT in the course of 40 min to a solution of 29.5 g (77.2 mmol) of the compound of example 6a) in 450 ml of DCM. After stirring at RT for 5 h, the reaction mixture was treated with 150 ml of methanol and then with about 2 I of diisopropyl ether. The deposited precipitate was filtered off with suction and dried in a high vacuum. 32.7 g of the title compound were obtained as a white solid. M.p.: 160 - 161 °C R f (SiO 2 , EA) = 0.52 MS (DCI): m/z = 368 [M+H] + c) N-Dimethylaminomethylene-2-(2-methoxyethoxy)-5-(2-(2,2,2-trifluoroacetamido)- ethyl)benzenesulfonamide A mixture of 9.1 g (20.3 mmol) of the compound of example 6b) and 7.1 g (50.8 mmol) of potassium carbonate in 50 ml of absolute DMF was treated with 6.7 ml (71.7 mmol) of 2-bromoethyl methyl ether and stirred at 70°C for 3 h. After adding a further 6.7 ml of 2-bromoethyl methyl ether and stirring at 70°C for 2 h, the reaction solution was treated with about 300 ml of EA. It was washed with water and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and concentrated to dryness. The residual light yellow oil was purified by chromatography on silica gel using EA. Concentration of the product-containing fractions and drying in a high vacuum yielded 7.25 g of the title compound as a pale yellow solid. M.p.: 134 - 136°C R f (SiO 2 , EA) = 0.35 MS (DCI): m/z = 426 [M+H] + d) 5-(2-Aminoethyl)-2-(2-methoxyethoxy)benzenesulfonamide hydrochloride A solution of 7.24 g (17.0 mmol) of the compound of example 6c) in 100 ml of methanol and 100 ml of half-concentrated hydrochloric acid was heated to reflux for 8 h. About 40 ml of ethanol were then added to the reaction solution and the deposited precipitate was filtered off with suction. Washing the precipitate with cold ethanol and drying in a high vacuum yielded 4.0 g of the title compound as a white solid. M.p.: 230 - 233°C MS (DCI): m/z = 275 [M+H] + e) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)benzene- sulfonamide According to the process described in example 1d), starting from 300 mg (1.04 mmol) of the compound of example 6d) and 207 mg (1.35 mmol) of trans-3-(2- thienyl)acrylic acid, 325 mg of the title compound were obtained as a white solid. M.p.: 140°C R f (SiO 2 , DCM/MeOH 20:1 ) = 0.28 MS (ESI): m/z = 411 [M+H] + f) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenyl- sulfonyl]-3-methyl-thiourea According to the process described in example 1 e), starting from 190.0 mg (0.46 mmol) of the compound of example 6e) and 511 μl (0.51 mmol) of a 1 M solution of methyl isothiocyanate in absolute DMF, 194 mg of the title compound were obtained as a slightly beige solid after drying in a high vacuum. M.p.: 152°C R f (Si0 2 , DCM/MeOH 18:2) = 0.18 MS (ESI): m/z = 484 [M+H] + Example 7 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]- 3-methyl-urea According to the process described in example 3), starting from 90 mg (0.19 mmol) of the compound of example 6f), with hydrogen peroxide 65 mg of the title compound were obtained as a white solid. M.p.: 99°C R f (Si0 2l EA) = 0.32 MS (ESI): m/z = 468 [M+Hj + Example 8 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]- 3-isopropyl-thiourea According to the process described in example 1e), starting from 100 mg (0.24 mmol) of the compound of example 6e), with isopropyl isothiocyanate 109 mg of the title compound were obtained as a slightly beige solid. M.p.: 101°C R f (Si0 2 , DCM/MeOH 19:1 ) = 0.15 MS (ESI): m/z = 512 [M+H] + Example 9 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-ethoxyphenylsulfonyl]-3-methyl- thiourea a) N-Dimethylaminomethylene-2-ethoxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide A mixture of 2.0 g (5.44 mmol) of the compound of example 6b) and 1.88 g (13.6 mmol) of potassium carbonate in 10 ml of absolute DMF was treated with 1.42 ml (19.0 mmol) of ethyl bromide and stirred at 70°C for 1.5 h. The reaction solution was then treated with about 10 ml of EA. It was washed with water and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and concentrated to dryness. The residual colorless oil was purified by chromatography on silica gel using EA/heptane (8:1). Concentration of the product- containing fractions and drying in a high vacuum yielded 1.01 g of the title compound as a white solid. M.p.: 145°C R f (Si0 2 , EA) = 0.48 MS (ESI): m/z = 396 [M+H] + b) 5-(2-Aminoethyl)-2-ethoxybenzenesulfonamide According to the process described in example 1c), starting from 1.0 g (2.55 mmol) of the compound of example 9a), with hydrochloric acid 604 mg of the title compound were obtained as a white solid. M.p.: 237-241 °C R f (SiO 2 , EA) = 0.03 MS (DCI): m/z = 281 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-ethoxybenzenesulfonamide According to the process described in example 1d), starting from 205 mg (0.73 mmol) of the compound of example 9b), with trans-3-(2-thienyl)acrylic acid 96 mg of the title compound were obtained as a pale yellow solid. M.p.: 55°C R f (Si0 2 , EA) = 0.59 MS (ESI): m/z = 381 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-ethoxyphenylsulfonyl]-3-methyl- thiourea According to the process described in example 1e), starting from 91 mg (0.24 mmol) of the compound of example 9c), with methyl isothiocyanate 51 mg of the title compound were obtained as a slightly yellow solid. M.p.: 74°C Rf (SiO 2 , EA) = 0.69 MS (ESI): m/z = 454 [M+H] + Example 10 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-ethoxyethoxy)phenylsulfonyl]-3- methyl-thiourea a) N-Dimethylaminomethylene-2-(2-ethoxyethoxy)-5-(2-(2,2,2-trifluoroacetamido)- ethyl)benzenesulfonamide A mixture of 1.0 g (2.72 mmol) of the compound of example 6b) and 940 mg (6.80 mmol) of potassium carbonate in 5 ml of absolute DMF was treated with 1.07 ml (9.53 mmol) of 2-bromoethyl ethyl ether and stirred at 70°C for 1.5 h. The reaction solution was then treated with about 5 ml of EA. It was washed with water and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and concentrated to dryness. The residual colorless oil was purified by chromatography on silica gel using EA heptane (8:1). Concentration of the product-containing fractions and drying in a high vacuum yielded 663 mg of the title compound as an amorphous white solid. R f (Si0 2 , EA) = 0.40 MS (ESI): m/z = 440 [M+H] + b) 5-(2-Aminoethyl)-2-(2-ethoxyethoxy)benzenesulfonamide According to the process described in example 1c), starting from 659 mg (1.50 mmol) of the compound of example 10a), with hydrochloric acid 405 mg of the title compound were obtained as a white solid. M.p.: 191 °C R f (SiO 2 , EA) = 0.04 MS (ESI): m/z = 289 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-ethoxyethoxy)benzene- sulfonamide According to the process described in example 1d), starting from 200 mg (0.61 mmol) of the compound of example 10b), with trans-3-(2-thienyl)acrylic acid 173 mg of the title compound were obtained as a white solid. M.p.: 52°C R f (Si0 2 , EA) = 0.49 MS (ESI): m/z = 425 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-ethoxyethoxy)phenylsulfonyl]- 3-methyl-thiourea According to the process described in example 1e), starting from 169 mg (0.40 mmol) of the compound of example 10c), with methyl isothiocyanate 134 mg of the title compound were obtained as a slightly yellow solid. M.p.: 51 °C R f (Si0 2 , EA) = 0.66 MS (ESI): m/z = 498 [M+H] + Example 11 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-ethoxyethoxy)phenylsulfonyl]-3- methyl-urea According to the process described in example 3), starting from 50 mg (0.10 mmol) of the compound of example 10d), with hydrogen peroxide 44 mg of the title compound were obtained as a white solid. M.p.: 65°C R f (SiO 2 , EA) = 0.81 MS (ESI): m/z = 482 [M+H] + Example 12 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-benzyloxyphenylsulfonyl]-3-methyl- thiourea a) N-Dimethylaminomethylene-2-benzyloxy-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide According to the process described in example 9a), starting from 1.5 g (4.01 mmol) of the compound of example 6b), with benzyl bromide 1.16 g of the title compound were obtained as a white solid. M.p.: 103°C R f (Si0 2 , EA) = 0.62 MS (ESI): m/z = 458 [M+H] + b) 5-(2-Aminoethyl)-2-benzyloxybenzenesulfonamide According to the process described in example 1 c), starting from 1.15 g (2.51 mmol) of the compound of example 12a), with hydrochloric acid 485 mg of the title compound were obtained as a white solid. M.p.: 250-255°C R f (SiO 2 , EA) = 0.03 MS (ESI): m/z = 307 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-benzyloxybenzenesulfonamide According to the process described in example 1d), starting from 240 mg (0.70 mmol) of the compound of example 12b), with trans-3-(2-thienyl)acrylic acid 134 mg of the title compound were obtained as a white solid. M.p.: 177°C R f (SiO 2 , EA) = 0.69 MS (ESI): m/z = 443 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-benzyloxyphenylsulfonyl]-3- methyl-thiourea According to the process described in example 1e), starting from 164 mg (0.38 mmol) of the compound of example 12c), with methyl isothiocyanate 116 mg of the title compound were obtained as a slightly gray solid. M.p.: 94°C R f (Si0 2 , EA) = 0.84 MS (FAB): m/z = 510 [M+H] + Example 13 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-phenylethoxy)phenylsulfonyl]-3- methyl-thiourea a) N-Dimethylaminomethylene-2-(2-phenylethoxy)-5-(2-(2,2,2-trifluoracetamido)- ethyl)benzenesulfonamide According to the process described in example 9a), starting from 1.5 g (4.01 mmol) of the compound of example 6b), with 2-phenylethyl bromide 1.21 g of the title compound were obtained as a white solid. M.p.: 48°C R f (SiO 2 , EA) = 0.67 MS (ESI): m/z = 472 [M+H] + b) 5-(2-Aminoethyl)-2-(2-phenylethoxy)benzenesulfonamide According to the process described in example 1c), starting from 1.2 g (2.54 mmol) of the compound of example 13a), with hydrochloric acid 880 mg of the title compound were obtained as a white solid. M.p.: 207-212°C R f (SiO 2 , EA) = 0.73 MS (ESI): m/z = 321 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-phenylethoxy)benzene- sulfonamide According to the process described in example 1d), starting from 350 mg (0.70 mmol) of the compound of example 13b), with trans-3-(2-thienyI)acrylic acid 298 mg of the title compound were obtained as a white solid. M.p.: 170-174°C R f (SiO 2 , EA) = 0.74 MS (ESI): m/z = 457 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-phenylethoxy)phenylsulfonyl]- 3-methyl-thiourea According to the process described in example 1e), starting from 95 mg (0.21 mmol) of the compound of example 13c), with methyl isothiocyanate 89 mg of the title compound were obtained as a white solid. M.p.: 74°C R f (SiO 2 , EA) = 0.90 MS (FAB): m/z = 524 [M+H] + Example 14 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(tetrahydrofuran-2-ylmethoxy)- phenylsu!fonyl]-3-methyl-thiourea a) N-Dimethylaminomethylene-2-(tetrahydrofuran-2-ylmethoxy)-5-(2-(2,2,2- trifIuoroacetoamido)ethyl)benzenesulfonamide According to the process described in example 9a), starting from 1.0 g (2.72 mmol) of the compound of example 6b), with 2-bromomethyltetrahydrofuran 661 mg of the title compound were obtained as a pale yellow solid. M.p.: 138-140°C R f (SiO 2 , EA) = 0.25 MS (ESI): m/z = 452 [M+H] + b) 5-(2-Aminoethyl)-2-(tetrahydrofuran-2-ylmethoxy)benzenesulfonamide According to the process described in example 1c), starting from 655 mg (1.45 mmol) of the compound of example 14a), with hydrochloric acid 250 mg of the title compound were obtained as a white solid. M.p.: 135-140°C R f (Si0 2) EA) = 0.04 MS (ESI): m/z = 301 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloyiamino)ethyl)-2-(tetrahydrofuran-2-ylmethoxy)- benzenesulfonamide According to the process described in example 1d), starting from 246 mg (0.73 mmol) of the compound of example 14b), with trans-3-(2-thienyl)acrylic acid 151 mg of the title compound were obtained as a white solid. M.p.: 180-185°C R f (SiO 2 , EA) = 0.49 MS (ESI): m/z = 437 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(tetrahydrofuran-2-ylmethoxy)- phenylsulfonyl]-3-methyl-thiourea According to the process described in example 1e), starting from 146 mg (0.33 mmol) of the compound of example 14c), with methyl isothiocyanate 135 mg of the title compound were obtained as a slightly yellow solid. M.p.: 78°C R f (Si0 2 , EA) = 0.68 MS (ESI): m/z = 510 [M+H] + Example 15 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(tetrahydropyran-2-ylmethoxy)- phenyisulfonyl]-3-methyl-thiourea a) N-Dimethylaminomethylene-2-(tetrahydropyran-2-ylmethoxy)-5-(2-(2,2,2- trifluoroacetamido)ethyl)benzenesulfonamide According to the process described in example 9a), starting from 1.0 g (2.72 mmol) of the compound of example 6b), with 2-bromomethyltetrahydro-2H-pyran 661 mg of the title compound were obtained as a white solid. R f (Si0 2 , EA) = 0.40 MS (ESI): m/z = 466 [M+H] + b) 5-(2-Aminoethyl)-2-(tetrahydropyran-2-ylmethoxy)benzenesulfonamide According to the process described in example 1c), starting from 685 mg (1.47 mmol) of the compound of example 15a), with hydrochloric acid 295 mg of the title compound were obtained as a white solid. M.p.: 204-208°C R f (SiO 2 , EA) = 0.02 MS (ESI): m/z = 315 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(tetrahydropyran-2-ylmethoxy)- benzenesulfonamide According to the process described in example 1d), starting from 290 mg (0.83 mmol) of the compound of example 15b), with trans-3-(2-thienyl)acrylic acid 204 mg of the title compound were obtained as a white solid. M.p.: 106°C R f (SiO 2 , EA) = 0.62 MS (ESI): m/z = 451 [M+H] + d) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(tetrahydropyran-2-ylmethoxy)- benzenesulfonyl-3-methyl-thiourea According to the process described in example 1e), starting from 99 mg (0.22 mmol) of the compound of example 15c), with methyl isothiocyanate 101 mg of the title compound were obtained as a slightly yellow solid. M.p.: 8Q°C R f (Si0 2 , EA) = 0.76 MS (ESI): m/z = 524 [M+H] + Example 16 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-(trifluoromethoxy)ethoxy)- phenylsulfonyl]-3-methyl-thiourea a) N-Dimethylaminomethylene-2-(2-(trifluoromethoxy)ethoxy)-5-(2-(2,2,2- trifIuoroacetamido)ethyl)benzenesulfonamide A solution of 13.8 g (37.5 mmol) of the compound of example 6b) and 28 g of potassium carbonate in 150 ml of N-methyl-2-pyrrolidone was treated with 5.6 g (37.5 mmol) of 2-chloroethyl trifluoromethyl ether (prepared according to G. Siegemund and W. Schwertfeger, J. Fluorine Chem. 21 (1982) 133), and the mixture was stirred at 100°C for 1 h. After aqueous work-up, 7.1 g of the title compound were obtained as a white solid. M.p.: 111-114°C MS (ESI): m/z = 480 [M+H] + b) 5-(2-Aminoethyl)-2-(2-(trifluoromethoxy)ethoxy)benzenesulfonamide A solution of 3.3 g of the compound of example 16a) in 20 ml of ethanol was treated with 12.5 ml of 2N sodium hydroxide solution and heated to reflux for 1 h. After addition of some glacial acetic acid, the reaction solution was concentrated to dryness and residual water was removed by repeated concentration in a rotary evaporator with THF and toluene. Drying in a high vacuum yielded 1.7 g of the title compound. MS (ESI): m/z = 329 [M+H] + c) 5-(2-(trans-3-(2-Thienyl)acryloyIamino)ethyl)-2-(2-(trifluoromethoxy)ethoxy)- benzenesulfonamide 1.5 g of trans-3-(2-thienyl)acrylic acid were activated by stirring with 1.6 g of N,N'- carbonyldiimidazole for 15 minutes in 30 ml of THF, and the solution obtained was stirred overnight with 1.5 g of the compound of example 16b). The reaction mixture was concentrated to dryness and the residue was taken up in a DCM/water mixture. The organic phase was separated off, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel using toluene/EA/ethanol (19:1 :1 ) and recrystallization of the residue resulting after concentration of the product-containing fractions from diethyl ether yielded 0.85 g of the title compound as a white solid. M.p.: 203-205°C MS (ESI): m/z = 480 [M+H] + d) 1 -[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-(trifluoromethoxy)ethoxy)- phenylsulfonyl]-3-methyl-thiourea According to the process described in example 1e), starting from 220 mg of the compound of example 16c), with methyl isothiocyanate 112 mg of the title compound were obtained as a white solid. M.p.: 161-163°C MS (ESI): m/z = 538 [M+H] + Example 17 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-furyl)phenylsulfonyl]-3-methyl- thiourea a) 2,2,2-Trifluoro-N-(2-(4-nitrophenyl)ethyl)acetamide According to the process described in example 1a), starting from 29.8 g (0.15 mol) of 2-(4-nitrophenyl)ethylamine hydrochloride, with trifluoroacetic anhydride 34.7 g of the title compound were obtained as a beige solid. M.p.: 96 - 97°C R f (SiO 2 , EA/heptane 1 :1 ) = 0.52 MS (ESI): m/z = 263 [M+H] + b) 2,2,2-Trifluoro-N-(2-(4-aminophenyl)ethyl)acetamide A mixture of 34.6 g (0.13 mol) of the compound of example 17a) and 197 g (0.87 mol) of SnCI 2 x 2H 2 0 in 1 I of EA was stirred at 80°C for 3.5 h. The reaction mixture was then treated with 2 I of 10% strength sodium hydrogencarbonate solution and the precipitate was filtered off. The organic phase was separated, dried over sodium sulfate and concentrated to dryness in vacuo. 26.9 g of the title compound resulted as a pale brown solid. M.p.: 81 - 85°C R f (SiO 2 , EA/heptane 1 :1 ) = 0.35 MS (ESI): m/z = 233 [M+H] + c) 2,2,2-Trifluoro-N-(2-(4-iodophenyl)ethyl)acetamide A solution of 8.3 g (0.12 mol) of sodium nitrite in 28 ml of water was added dropwise at 0°C to a suspension of 26.8 g (0.11 mol) of the compound of example 17b) in 125 ml of dilute hydrochloric acid. After stirring at 0°C for 15 min, a solution of 19.9 g (0.12 mol) of potassium iodide in 28 ml of water was added dropwise and the resulting solution was stirred at RT for 3 h. It was extracted with DCM, and the organic phase was separated off, washed with 10% strength sodium hydrogensulfite solution and water and dried over sodium sulfate. After concentration and chromatographic purification of the residue on silica gel using DCM/EA (80:1), 17.1 g of the title compound were obtained as a pale yellow solid. M.p.: 136 - 138°C R f (SiO 2 , EA/heptane 1 :1 ) = 0.67 MS (DCI): m/z = 344 [M+H] + d) 2-lodo-5-(2-(2,2,2-trifluoroacetamido)ethyl)benzenesulfonamide 10 g (29.1 mmol) of the compound of example 17c) were added in portions at 0°C to 95 ml of chlorosulfonic acid. After stirring at RT for 3.5 h, the solution was added dropwise to 400 ml of ice. The deposited precipitate was filtered off with suction, dissolved in 200 ml of acetone, and 56 ml of concentrated ammonia solution were added dropwise to the solution with ice-cooling. After stirring at RT for 45 min, the deposited precipitate was filtered off with suction and the acetone was stripped from the filtrate on a rotary evaporator. The residual solution was extracted with EA, the EA phase was separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatographic purification of the residue on silica gel using EA/heptane (1 :2), 4.5 g of the title compound were obtained. M.p.: softening from 100°C R f (SiO 2 , EA/heptane 1 :1 ) = 0.32 MS (ESI): m/z = 423 [M+H] + e) N-Dimethylaminomethylene-2-iodo-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide A solution of 2.9 g (6.87 mmol) of the compound of Example 17d) and 1.26 ml (8.26 mmol) of N,N-dimethylformamide dimethyl acetal in 16 ml of absolute DMF was stirred at RT for 1 h. The reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in 5 ml of DMF. 70 ml of a 5% strength sodium hydrogensulfate solution was then added dropwise to this solution at 0°C, and the deposited precipitate was filtered off with suction, washed with water and dried in a high vacuum. 3.2 g of the title compound were obtained as a slightly yellow solid. M.p.: 155-156°C Rf (Si0 2 , EA/heptane 1 :1 ) = 0.10 MS (ESI): m/z = 478 [M+H] + f) N-Dimethylaminomethylene-2-(2-furyl)-5-(2-(2,2,2-trifluoroacetamido)ethyl)- benzenesulfonamide 26.6 mg (0.03 mmol) of bis(triphenylphosphine)palladium(ll) chloride and 2.9 ml (9.28 mmol) of 2-(tri-n-butylstannyl)furan were added under an argon atmosphere to a solution of 3.1 g (6J0 mmol) of the compound of example 17e) in 30 ml of DMF. The resulting reaction solution was heated under reflux for 8 h. It was then diluted with EA, and the solution was washed with water and dried over sodium sulfate. Chromatographic purification of the residue, remaining after removal of the solvent, on silica gel using EA/n-heptane (1 :1 ) afforded 2.6 g of the title compound as a pale yellow solid. M.p.: 150°C R f (Si0 2 , EA/heptane 1 :1 ) = 0.06 MS (ESI): m/z = 418 [M+H] + g) 5-(2-Aminoethyl)-2-(2-fup l)benzenesuIfonamide A solution of 2.6 g (6.23 mmol) of the compound of example 17f) and 9 ml of 2N sodium hydroxide solution in 46 ml of ethanol was stirred at 80°C for 2 h. After cooling to RT, the pH of the solution was adjusted to 7 by addition of concentrated acetic acid and the solution was concentrated to dryness. Drying of the residue in a high vacuum yielded 1.6 g of the title compound as a colorless oil. R f (SiO 2 , EA) = 0.10 MS (ESI): m/z = 267 [M+H] + h) 5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-furyl)benzenesulfonamide According to the process described in example 1d), starting from 500 mg (1.88 mmol) of the compound of example 17g), with trans-3-(2-thienyl)acrylic acid 316 mg of the title compound were obtained as a beige solid. M.p.: 165-166°C R f (Si0 2 , EA heptane 4:1) = 0.30 MS (ESI): m/z = 403 [M+H] + i) 1-[5-(2-(trans-3-(2-Thienyl)acryloylamino)ethyl)-2-(2-furyl)phenylsulfonyl]-3-methyl- thiourea According to the process described in example 1 e), starting from 310 g (077 mmol) of the compound of example 17h), with methyl isothiocyanate 345 mg of the title compound were obtained as a pale beige solid. M.p.: 175-176°C R f (SiO 2 , EA/heptane 2:1 ) = 0.24 MS (ESI): m/z = 476 [M+H] + Example 18 1-[5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- thiourea a) 5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-methoxybenzenesulfoπamide According to the process described in example 1d), starting from 250 mg (1.09 mmol) of the compound of example 1c), with trans-3-(2-pyridyl)acrylic acid 120 mg of the title compound were obtained as an amorphous solid. R f (SiO 2 , DCM/MeOH 20:1) = 0.24 MS (ESI): m/z = 362 [M+H] + b) 1-[5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-methoxyphenylsulfonyl]-3-methyl- thiourea According to the process described in example 1 e), starting from 118 mg (0.33 mmol) of the compound of example 18a), with methyl isothiocyanate 71 mg of the title compound were obtained as a slightly yellow solid. M.p.: 188°C R f (SiO 2 , DCM/MeOH 20:1) = 0.11 MS (ESI): m/z = 435 [M+H] + Example 19 1-[5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]- 3-methyl-thiourea a) 5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)benzene- sulfonamide According to the process described in example 1d), starting from 300 mg (1.04 mmol) of the compound of example 6d), with trans-3-(2-pyridyl)acrylic acid 291 mg of the title compound were obtained as an amorphous solid. R f (SiO 2 , DCM/MeOH 20:1) = 0.25 MS (ESI): m/z = 406 [M+H] + b) 1-[5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenyl- sulfonyl]-3-methyl-thiourea According to the process described in example 1e), starting from 190 mg (0.22 mmol) of the compound of example 19a), with methyl isothiocyanate 150 mg of the title compound were obtained as an amorphous solid. R f (SiO 2 , DCM/MeOH 18:2) = 0.44 MS (ESI): m/z = 479 [M+H] + Example 20 1-[5-(2-(trans-3-(2-Pyridyl)acryloylamino)ethyl)-2-(2-methoxyethoxy)phenylsulfonyl]- 3-isopropyl-thiourea According to the process described in example 1e), starting from 90 mg (0.22 mmol) of the compound of example 19a), with isopropyl isothiocyanate 60 mg of the title compound were obtained as an amorphous solid. R f (SiO 2 , DCM/MeOH 18:2) = 0.49 MS (ESI): m/z = 507 [M+H] + Pharmacological investigations 1 ) Action potential duration on the papillary muscle of the guinea pig ATP deficiency states, as are observed during ischemia in the cardiac muscle cell, lead to a shortening of the action potential duration (ATP = adenosine triphosphate). They are regarded as one of the causes of so-called reentry arrhythmias which can cause sudden cardiac death. The opening of ATP-sensitive potassium channels by the lowering of the ATP level is regarded as causal for this. For the measurement of the action potential on the papillary muscle of the guinea pig a standard microelectrode technique was employed. Guinea pigs of both sexes were killed by a blow to the head, the hearts were removed, and the papillary muscles were separated out and suspended in an organ bath. The organ bath was rinsed with Ringer's solution (136 mmol/l of NaCl, 3.3 mmol/l of KCI, 2.5 mmol/l of CaCI 2 , 1.2 mmol/l of KH 2 P0 4 , 1.1 mmol/l of MgS0 4 , 5.0 mmol/l of glucose, 10.0 mmol/l of 1-(2-hydroxyethyl)piperazine-4-(2-ethanesulfonic acid) (HEPES), pH adjusted to 7.4 with NaOH) and aerated with 100% oxygen at a temperature of 37°C. The muscle was stimulated with square-wave pulses of 1 V and 1 ms duration and a frequency of 1 Hz by means of an electrode. The action potential was derived and recorded by means of a glass microelectrode inserted intracellularly, which is filled with 3 mol/l of KCI solution. The compound to be tested was added to the Ringer's solution in a concentration of 2 μmol/l. The action potential was amplified using an amplifier from Hugo Sachs (March-Hugstetten, Germany) and stored and analyzed by means of a computer. The duration of the action potential was determined at a degree of repolarization of 90 % (APDgo). After an equilibration time of 30 min, the action potential shortening was produced by rinsing the papillary muscle with a hypoxic NaCl solution. The glucose was removed here, the HEPES buffer replaced by PIPES buffer (piperazine-1 ,4-bis(2-ethanesulfonic acid)), the pH was adjusted to 6.5 and the aeration was carried out using 100% nitrogen. After a time of 60 min, this led to a marked shortening of the APDgo. After this time, the test compound was added and the relengthening of the action potential recorded after a further 60 min. The compound-caused relengthening of the APDgo was calculated in percent in relation to the shortening caused by hypoxia. The test compounds were added to the bath solution as stock solution in propanediol. The following relengthenings of the APDgo values were observed. Compound Concentration Relengthening of the APDgo shortened by hypoxia Example 1 2 μM 33% Example 7 2 μM 39% Example 10 2 μM 50% Example 20 2 μM 26% The observed values confirm the normalizing action of the compounds according to the invention on a hypoxically shortened action potential duration. 2) Chloroform-induced ventricular fibrillation in the mouse (action in the case of vagal dysfunction) Hypoactivity of the vagal nervous system leads to hyperactivity of the sympathetic nervous system. Damages to health which result from an inequilibrium of the autonomic nervous system when the dysfunction affects the heart include the weakening of the myocardial contractile force and fatal cardiac arrhythmias such as ventricular fibrillation. The action of the test compounds was investigated in the model of chloroform-induced ventricular fibrillation in the mouse (see J. W. Lawson, Antiarrhythmic activity of some isoquinoline derivatives determined by a rapid screening procedure in the mouse; J. Pharmacol. Exp. Ther. 160 (1968) 22). The test compound was dissolved in a mixture of dimethyl sulfoxide (DMSO) and 10 percent sodium hydrogencarbonate solution and administered intraperitoneally (i.p.). The dose was 3 mg/kg. 30 min later, the mouse was anesthetized with chloroform in a beaker. As soon as respiratory arrest had occurred under deep anesthesia (toxic stage of anesthesia), the thorax of the animal was opened using a pair of scissors and the heartbeat was visually inspected. It can be determined here at a glance whether the heart is beating, fibrillating or has stopped. The respiratory arrest induced by chloroform leads via an absolute anoxia (oxygen deficiency) in combination with a direct stimulating action of chloroform on the sympathetic nervous system to a strong stimulation of the sympathetic nervous system, which for its part, in combination with the energy deficiency caused by oxygen deficiency, leads in the heart to the fatal arrhythmia, ventricular fibrillation. This toxic chloroform anesthesia led to ventricular fibrillation in 100 % of the untreated mice (control). The percentage proportion of the mice with ventricular fibrillation in the individual test groups (consisting of n animals) is indicated as the fibrillation ratio. The following fibrillation ratios were observed. Compound Fibrillation ratio (in %) Untreated control (n = 300) 100% Example 3 (n = 10) 65% Example 7 (n = 10) 80% Example 20 (n = 10) 80% 0 The reduction of the percentage proportion of mice having ventricular fibrillation in comparison with the control (with a 100% fibrillation ratio) confirms that the compounds of the formula I significantly prevent the occurrence of ventricular fibrillation. 3) Action on hSUR1/hKir6.2-transfected CHO cells (hypoglycemic action) The mechanism of action of hypoglycemic sulfonylureas such as, for example, glibenclamide has been roughly elucidated. The target organ of these compounds is the β cell of the pancreas where they block ATP-sensitive potassium channels and produce a release of the hypoglycemic hormone insulin by influencing the electrical potential of the cell membrane. In molecular biology terms, pancreatic ATP-sensitive potassium channels are composed of the sulfonylurea receptor SUR1 and the inwardly rectifying potassium channel Kir6.2 (Inagaki et al., Science 270 (1995) 1166; Inagaki et al., Neuron 16 (1996) 1011 ). A hypoglycemic compound such as, for example, glibenclamide brings about, by binding to the sulfonylurea receptor, a depolarization of the cell membrane which leads to an increased influx of calcium ions and as a consequence thereof to a release of insulin. The extent of this depolarization of the cell membrane which is caused by the compounds according to the invention was investigated on CHO cells which were transfected with the cloned components of human pancreatic ATP- sensitive potassium channels, hSUR1 and hKir6.2, and activated by pretreatment with diaxozide, an opener of ATP-sensitive potassium channels. The potency of a compound with respect to the membrane potential of these transfected and activated CHO cells is a measure of the hypoglycemic potential of this compound. The CHO cells which showed a stable expression of human SUR1 and Kir6.2 were inoculated into 96-well microtiter plates on the day before measurement. On the day of measurement, the microtiter plates were washed three times with PBS (physiological buffer solution). In the last washing step, 90 μl remained in each well. The cells were then loaded with the fluorescent dye DlBAC (Molecular Probes, Portland, OR, USA) by addition of 90 μl of a 10 micromolar solution of DIBAC 4 in PBS and of 90 μl of a 400 micromolar solution of diaxozide in PBS to each well. After an incubation time of 30 min at 37°C, the microtiter plates were then transferred to a fluorescent microtiter plate reader (FLIPR; Molecular Devices, Sunnyvale, CA, USA). The cells were stimulated by means of an argon laser (Innova 90; Coherent, Santa Clara, CA, USA) at a wavelength of 488 nm and the fluorescence emission was measured by means of a CCD camera. The measurement of the membrane potential began after 4 min by addition of 20 μl of a solution of the test compound or of the control solution to each well, the resulting fluorescence emission being measured every 20 seconds for a period of 20 min. The data shown are mean values of at least 4 experiments. The following results were obtained. Compound Concentration Blockade hSUR1/hKir6.2 Glibenclamide (hypoglycemic 0.01 μM 92.7 % comparison su ibstance) Example 1 10 μM 30.7 % Example 3 10 μM 1.7 % Example 7 10 μM 8.1 % Example 20 10 μM 5.9 % The obtained results confirm that the compounds according to the invention have no or an only very slight hypoglycemic action.

Claims: Patent claims 1. A compound of the formula I, in which R(1) is 1 ) (d-C 4 )-alkyl; or 2) -O-(Cι-C )-alkyl which is unsubstituted or is substituted by 1 , 2 or 3 fluorine atoms; or 3) -O-(C-i-C 4 )-alkyl which is substituted by a substituent selected from the group consisting of nitro, ((Cι-C 4 )-alkyl)carbonylamino, (C C 4 )-alkylamino, di((d-C 4 )- alkyl)amino, hydroxycarbonyl, ((Cι-C 4 )-alkoxy)carbonyl, piperidin-1-yl, morpholin- 4-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl and phenoxy, where the phenyl group and the phenoxy group are unsubstituted or are substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C 4 )-alkyl, (Cι-C 4 )-alkoxy and trifluoromethyl; or 4) -O-(Cι-C 4 )-alkyl-E(1 )-(d-C 4 )-alkyl-D(1 ), in which D(1 ) is hydrogen or -E(2)-(d-C 4 )-alkyl-D(2), in which D(2) is hydrogen or -E(3)-(d-C 4 )-alkyl, where E(1 ), E(2) and E(3), which are independent of one another and can be identical or different, are O, S or NH; or 5) -O-(Cι-C 4 )-alkyl-0-(C 1 -C 4 )-alkyl which is substituted by 1 , 2 or 3 fluorine atoms; or 6) -O-(C 2 -C 4 )-alkenyl; or 7) -O-phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C )-alkyl, (Cι-C 4 )-alkoxy and trifluoromethyl; or 8) halogen; or 9) phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C 4 )-alkyi, (d-d)- alkoxy, -S(O) m -(Cι-C )-alkyl, phenyl, amino, hydroxyl, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, ((Cι-C 4 )-alkoxy)carbonyl and formyl; or 10) (C 2 -C 5 )-alkenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of phenyl, cyano, hydroxycarbonyl and ((Cι-C )- a!koxy)carbonyl; or 11 ) (C 2 -C 5 )-alkynyl which is unsubstituted or is substituted by a substituent selected from the group consisting of phenyl and (d-C 4 )-alkoxy; or 12) 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or 13) -S(O) m -phenyl which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, (Cι-C 4 )-alkyl, (CrC 4 )-alkoxy and trifluoromethyl; R(2) is hydrogen or (Cι-C 6 )-alkyl, but is not hydrogen if Z is oxygen; the residues R(3) and R(4), which are independent of one another and can be identical or different, are hydrogen or (Cι-C 4 )-alkyI; the residues R(5), which are all independent of one another and can be identical or different, are hydrogen or (CrC 3 )-aIkyl; Het is 5-membered or 6-membered monocyclic heteroaryl having one or two identical or different ring heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which is unsubstituted or is substituted by one or two identical or different substituents selected from the group consisting of halogen, nitro, (CrC 4 )-alkyl, (d- C 4 )-alkoxy and trifluoromethyl; X is oxygen or sulfur; Y is -(CR(5) 2 ) n -; Z is NH or oxygen; m is 0, 1 or 2; n is 1 , 2, 3 or 4; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 2. A compound of the formula I as claimed in claim 1 , in which Het is 5-membered or 6-membered monocyclic heteroaryl having one ring heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 3. A compound of the formula I as claimed in claims 1 and/or 2, in which Z is NH, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which R(1) is 1) methyl, ethyl or isopropyl; or 2) methoxy, ethoxy, propoxy, trifluoromethoxy, 2-fluoroethoxy or 2,2,2-trifluoroethoxy; or 3) tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy, 2-(morpholin-4- yl)ethoxy, 2-phenoxyethoxy or benzyloxy; or 4) 2-methoxyethoxy or 2-ethoxyethoxy; or 5) 2-(trifluoromethoxy)ethoxy; or 6) allyloxy; or 7) phenoxy, 4-fluorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy or 4-trifluoromethylphenoxy; or 8) bromine or iodine; or 9) phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-trifluoromethylphenyl; or 10) allyl; or 11) ethynyl; or 12) furyl, thienyl or pyridyl; or 13) -S-phenyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which R(1 ) is methoxy, ethoxy, trifluoromethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(tri- fluoromethoxy)ethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydropyran-2-ylmethoxy or benzyloxy, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 6. A compound of the formula I as claimed in one or more of claims 1 to 5, in which R(2) is (Cι-C 4 )-alkyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 7. A compound of the formula I as claimed in one or more of claims 1 to 6, in which R(2) is methyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 8. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 to 7, which comprises converting a benzenesulfonamide of the formula 111 into a benzenesulfonyl iso(thio)cyanate of the formula VIII and reacting this with an amine of the formula R(2)-NH 2 or an alcohol of the formula R(2)-OH, or, for the preparation of a compound of the formula I in which Z is NH, reacting a benzenesulfonamide of the formula 111 or a salt thereof with an iso(thio)cyanate of the formula R(2)-N=C=X, or, for the preparation of a compound of the formula I in which Z is NH and X is oxygen, reacting a benzenesulfonamide of the formula III or a salt thereof with a trichloroacetamide of the formula CI 3 C-CO-NH-R(2), or, for the preparation of a compound of the formula I in which Z is NH and X is oxygen, desulfurizing the corresponding compound of the formula I in which Z is NH and X is sulfur on the thiourea group, where R(1), R(2), R(3), R(4), Het, X and Y are as defined in claims 1 to 7. 9. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts for use as a pharmaceutical. 10. A pharmaceutical preparation which comprises at least one compound of the formula I as claimed in one or more of claims 1 to 7 and/or a physiologically tolerable salt thereof and a pharmaceutically tolerable carrier. 11. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts for the inhibition of ATP-sensitive potassium channels or for the stimulation of the vagal nervous system. 12. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts for the treatment of a dysfunction of the autonomic nervous system of the heart. 13. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts for use in the treatment of cardiovascular diseases, ischemic conditions of the heart, coronary heart disease, weakened myocardial contractile force, cardiac insufficiency, cardiomyopathies or cardiac arrhythmias or for the prevention of sudden cardiac death or for the improvement of cardiac function.

Inventors: ENGLERT HEINRICH CHRISTIAN, HEITSCH HOLGER, ENGLERT, HEINRICH, CHRISTIAN, HEITSCH, HOLGER
Applicants: AVENTIS PHARMA GMBH, AVENTIS PHARMA DEUTSCHLAND GMBH
Application year: 2001
Main classification: C07D213
IPC codes: A61K31, A61P9, A61P25, A61P43, C07D213, C07D333, C07D409