NZ270265A

NZ270265A - 3-(azaheterocyclylcarbonylaminoalkyl)benzene sulphonyl(thio)urea derivatives and pharmaceutical compositions

Info

Publication number: NZ270265A
Application number: NZ270265A
Authority: NZ
Inventors: Heinrich Englert; Dieter Mania; Jens Hartung; Heinz Gogelein; Joachim Kaiser; Uwe Gerlach
Original assignee: Hoechst Ag
Priority date: 1993-12-30
Filing date: 1994-12-22
Publication date: 1995-10-26
Also published as: CA2138930C; KR100370307B1; PT661264E; CA2138930A1; NO945083L; HU217122B; FI946136A; ATE194594T1; HUT70830A; DE59409440D1; IL112172A; KR950017939A; DE4344957A1; GR3034513T3; IL112172A0; AU8178994A; FI946136A0; HU9403803D0; NO302750B1; CN1052976C

Abstract

There are described substituted benzenesulphonylureas and -thioureas of the formula I <IMAGE> where R(1) is H, (cyclo)(CH2)a(fluoro)alk(en)yl, R(2) is H, Hal, (fluoro)(mercapto)(CH2)e(cyclo)alk(oxy)(yl), NR(4)R(5) where R(4) and R(5) together are a (CH2)2-7 chain, or R(4), R(5), R(6) are H, (alkyl)(cyclo)(fluoro)alk(en)yl, E is O, S; Y is -[CR(7)2]n-R(3) <IMAGE> B is (C3-C6)-alkenyl, or R(3) is <IMAGE> X is H, Hal, alkyl; Z is Hal, (cyclo)alk(yl)(oxy). Compounds I are used for the treatment of cardiac arrhythmias and for the prevention of sudden heart death caused by arrhythmia and can therefore be used as antiarrhythmics. They are particularly suitable in those cases in which arrhythmias are the result of constriction of a coronary vessel, such as in angina pectoris or in acute cardiac infarct.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £70265 *5 n ^h\ "Patents'Form 5 Priority ,'J.'P.:.)2r..\S3* Compete Specification Filed: Ciass: (S)...C<srl.Q^prib.^...Csd.Q^^l!^oi Publication Dais: ?..^...P..CJ...J995 P.O. Journal No: !3?.^7A N.Z. No. r%U x NEW ZEALAND 11 r:; ir Patents Act 1953 COMPLETE SPECIFICATION ■'C4 r 22 DEC iaS4 "]! V. K1^ L ■: ...A- f k J ..-VrR.t4.*' ^ SUBSTITUTED BENZENESULFONYLIJREAS AND -THIOUREAS. PREPARATION PROCESSES AND POSSIBLE USES OF PHARMACEUTIC AT, PREPARATIONS BASED ON THESE COMPOUNDS We, HOECHST AKTIENGESELLSCHAFT, a Joint Stock Company existing under the laws of the Federal Republic of Germany, of D-65926 Frankfurt am Main, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- -1- (Followed by 1 A) 10 15 20 25 i i — 'A - Description 270265 Substituted benzenesulfonylureas and -thioureas, preparation processes and possible uses of pharmaceutical preparations based on these compounds The invention relates to substituted benzenesulfonylureas and -thioureas of the formula H H H .i.i R(1) - N v /N - S0r - - ^Y-NW*(3) v-Br r R(2) w (I) in which R(l) is hydrogen, (C^Cg) -alkyl, (C3-C6)-cycloalkyl, CaH2ll- (C3-C5) -cycloalkyl, (C3-C6)-alkenyl or CcH2c- CdF2d+l'" a is 0, 1, 2 or 3; c is 0, 1, 2 or 3; d is 1, 2, 3, 4, 5 or 6; R(2) is hydrogen, F, CI, Br, I, (C^-Cg)-alkyl, (C^-Cg) -alkoxy, (C^-Cg)-mercaptoalkyl, (C^-Cg)-f luoroalkoxy, °-c.H2.-cfP2f+i' (Ci-CgJ-fluoroalkyl, CgH2g-ChF2+1, (C3-C,s)-cycloalkyl or NR(4)R(5); e is 0, 1, 2 or 3; f is 1, 2, 3, 4, 5 or 6; g is 0, 1, 2 or 3; h is 1, 2, 3, 4, 5 or 6; R(4) and R(5) together are a (CH2)2_7 chain in which one of the CH2 groups can be replaced by oxygen, sulfur or NR(6), where at least one CH2 group must stand between the N atom of the NR(4)R(5) and the oxygen, sulfur or NR(6); where R(6) is hydrogen, (C^-Cg-alkyl, CteH2k-CBF2B+1, (C,-C«)-cycloalkyl, (Cj^-Cj)-alkyl-(C3-C5)-cycloalkyl alkenyl; k is 0, 1, 2 or 3; f m is 1, 2, 3, 4, S or 6; \ ^ MJO ^/ / or Xfcix' R(4) and R(5) independently of one another are ( 10 I I 2 270265 hydrogen, (C^Cg-allcyl, CJCH2k-ClaF2m+1# (C3-C6)-cycloalkyl, (C-l-C^) -alkyl-(C3-C5)-cycloalkyl or (C3-C6)-alkenyl; k is 0, 1, 2 or 3; m is 1, 2, 3, 4, 5 or 6; E is oxygen or sulfur; Y is a hydrocarbon chain -[CR(7)2]n ; each R(7) is independently H or (C,-C2)-alkyl; n is 1, 2, 3 or 4; R(3) is a substituted heterocyclic radical of the formula N B Y B is (C3-C6) - alkenylene, which is unsubstituted or substituted by up to 3 (C^-C^)-alkyl groups or by a phenyl radical; 15 or R(3) is a bicyclic system of the formula • X ' N— or N— 0 20 is hydrogen, CqF2q+l; p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, S or 6; and CI, Br, I, (C^Cg)-alkyl or C„Ha„- • 270265 Z is F, CI, Br, I, j(C1-C4)-alkoxy, (Cj-C^) -alkyl, (c3~cg) -cycloalkyl or (C3-C6)-cycloalkoxy. Preferred compounds of the formula I are those in which: R(l) is hydrogen, (C1-C4)-alkyl, (C3-Cs)-cycloalkyl, (C3-C5)-alkenyl or CcH2c-CdF2d+1; c is 0, 1, 2 or 3; d is 1, 2, 3, 4, 5 or 6; R(2) is hydrogen, F, CI, (C^Cg) -alkyl, (C^Cg) -alkoxy, (Cj^-Cg) -mercaptoalkyl, (C^Cg)-fluoroalkoxy, (C^Cg) -fluoroalkyl, (C3-C6)-cycloalkyl or NR(4)R(5); R(4) and R(5) together are a (CH2)2_7 chain, in which one of the CH2 groups can be replaced by oxygen, sulfur or NR(6), where at least one CH2 group must stand between the N atom of the NR(4)R(5) and the oxygen, Bulfur or NR (6); where R(6) is hydrogen, (C^Cg)-alkyl, <C3-CS) -cyclo alkyl, (C1-C2) -alkyl- (C3-C5) -cycloalkyl or (C3-C6)-alkenyl; k is 0, 1 or 2; m is 1, 2, 3, 4, 5 or 6; or R(4) and R(5) independently of one another are hydrogen, (G^Cg)-alkyl, C^-CaF2a+1, (C3-C6)-cycloalkyl, (q-Cj)-alkyl-(C3-C5)-cycloalkyl or (C3-Cs)-alkenyl; k is 0, 1 or 2; m is 1, 2, 3, 4, 5 or 6; E is oxygen or sulfur; Y is a hydrocarbon chain -[CR(7) each R(7) is independently H or (C,-C2)-alkyl: n is 1, 2, 3 or 4; R(3) is a substituted heterocyclic radical of the formula -N B Y 0 B is (C3-Cfi) - alkenylene, which is unsubstituted or substituted by up to 3 (C1-C4)-alkyl groups or by a phenyl radical; or R(3) ia a bicyclic system of the formula X Z 0 0 X z N or 0 0 X is hydrogen, F, CI, Br, I or (Cj^-Cg) -alkyl; and Z ia F, CI, Br, I, (C1-C4)-alkoxy, (02-04)-alkyl, (C3-C6)-cycloalkyl or (C3-C6)-cycloalkoxy. Particularly preferred compounds of the formula 1 are those in which: R(l) is hydrogen, (02-04)-alkyl, (C3-C4)-cycloalkyl, (C3-C4)-alkenyl or (02-04)-fluoroalkyl; R(2) ia hydrogen, F, 01, (02-04)-alkyl, (C2-C4)-fluoro- alkyl or (C3-C6) -cycloalkyl; E ia oxygen or aulfur; Y ia a hydrocarbon chain -[OR (7)2]n-; each R (7) is independently H or (C|-Ca)-alkyl; n ia 2 or 3; R(3) ia a substituted heterocyclic radical of the formula B ia (C3-C6) - alkenylene, which ia unaubatituted or aubatitutei 3 (C2-C4)-alkyl groupa or by a phenyl radical; 5 '- 270265 or R(3) is a bicyclic system of the formula X Z 0 0 X z N— or N— 0 0 X is hydrogen, F, CI or (C^C^)-alkyl; and Z is F, CI or (C^C^) -alkoxy. 5 Compounds of the formula X which are likewise particularly preferred are those in which: R(1) is hydrogen, (C^C^ -alkyl, (C3-C4)-cycloalkyl, (C3-C4) -alkenyl or (C^C^)-fluoroalkyl; R(2) ia (C^-C^) -alkoxy, (C^C^) -mercaptoalkyl or (C^C^ -10 fluoroalkoxy; E is oxygen or sulfur; Y is a hydrocarbon chain -[CR(7)2]n-; each R (7) is independently H or (Q-C^-alkyl; 15 R(3) is a substituted heterocyclic radical of the formula n is 2 or 3 N 0 B B is (C3-C4) - alkenylene, which is unsubstituted or substituted by one to three (Cj-C^ -alkyl groups or by a phenyl radical; t - 6 <- or 27026" R(3) is a bicyclic system of the formula X N— or N— X is hydrogen, F, CI or (C^C^ -alkyl? and Z is P, CI or (Cj^-C^) -alkoxy. 5 Compounds of the formula I which are likewise especially preferred are those in which R(l) is hydrogen, (Ci-C*) -alkyl, (C3-C4)-alkenyl or (C^'C^) -fluoroalkyl; R(2) is NR(4)R(5); 10 R(4) and R(5) together are a (CH2)4_S chain, in which one of the CH2 groups can be replaced by oxygen, sulfur or MR(6), where at least one CH2 group must stand between the N atom of the MR(4)R(5) 15 and the oxygen, sulfur or MR(6); or where R(6) is H, CH3 or C2H5; R(4) and R(5) independently of one another are CH3, C2Hs, n-C3H7, iso-C3H7 or cyclo-C3H5;/ 20 E is oxygen or sulfur; Y is a hydrocarbon chain - [CR(7)2]n-; each R(7) is independently H or (C1-C2)-alkyl; n is 2 or 3; R(3) is a substituted heterocyclic radical of the formula y' - 7 - i i -N B Y 270265 B is (C3-C4) - alkenylene, which is unsubstituted or substituted by up to 3 (Cx-C4)-alkyl groups or by a phenyl radical; or R(3) is a bicyclic system of the formulae X C9- o 10 N— or N— X is hydrogen, F, CI or (C^C^-alkyl; and Z is F, CI or (Cx-C4) -alkoxy. Unless stated otherwise, the term alkyl describes straight-chain or branched saturated hydrocarbon radicals. The cycloalkyl radical can additionally carry an alkyl substituent. 15 Unless expressly stated otherwise, fluoroalkyl and fluoroalkoxy are a straight-chain or branched saturated alkyl or alkoxy radical having 1 to 6 carbon atoms, in which at least one or not more than all the hydrogens are replaced by fluorine. Compounds having centers of chirality in the alkyl side chain Y furthermore may occur. In this case, both the individual antipodes in themselves and a mixture of the - 8 - two enantiomers in various ratios, as well as the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers, belong to the invention. Similar sulfonylureas are known from German Offenlegungs-5 schrift 2 413 514, German Patent 1 518 874 and European Patent 0,031,058. DE-OS 2 413 514 and EP 0,031,058 describe exclusively blood sugar-conditioning substances with p-substitution in the central phenyl group. There are no references to m-substitution. 10 The hypoglycemic effects of sulfonylureas are described in the patent publications. The prototype of such hypoglycemic sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus and is used in science as a much-regarded tool 15 for researching so-called ATP-sensitive potassium channels. In addition to its hypoglycemic action, glibenclamide also has other actions which it has so far not yet been possible to employ therapeutically but which are all attributed to blockade precisely of these ATP-sensi-20 tive potassium channels. These include, in particular, an antifibrillatory action on the heart. However, simultaneous lowering of blood sugar would be undesirable or even dangerous during treatment of ventricular fibrillation or its preliminary stages, since it may deteriorate 25 the condition of the patient further. The object of the present invention was therefore to synthesize compounds which have a cardiac action which is equally as good as that of glibenclamide, but do not influence, or influence to a significantly lesser degree 30 than glibenclamide, the blood sugar in cardioactive doses or concentrations. Suitable test animals for detection of such actions are, for example, mice, rats, guineapigs, rabbits, dogs, monkeys or pigs. ' - 9 270265 The compounds I are used as medicament active compounds in human and veterinary medicine. They can furthermore be used as intermediate products for the preparation of other medicament active compounds. 5 The compounds of the formula I of the present invention are useful medicaments for the treatment of disturbances in cardiac rhythm of widely varying origin and for prevention of sudden cardiac death caused by arrhythmia, and cam therefore be used as antiarrhythmics. Examples of 10 arrhythmic disturbances of the heart are supraventricular disturbances in rhythm, such as, for example, auricular tachycardia, auricular flutter or paroxysmal supraventricular disturbances in rhythm, or ventricular disturbances in rhythm, such as ventricular extrasystoles, but in 15 particular life-threatening ventricular tachycardias or the particularly dangerous ventricular fibrillation. They are particularly suitable for those cases where arrhythmias are a consequence of a narrowing of a coronary vessel, such as occur, for example, with angina 20 pectoris or during an acute cardiac infarction or as a chronic consequence of a cardiac infarction. They are therefore particularly suitable for prevention of sudden cardiac death in post-infarction patients. Other syndromes in which such disturbances in rhythm and/or 25 sudden cardiac death caused by arrhythmia play a role are, for example, cardiac insufficiency or cardiac hypertrophy as a consequence of a chronically increased blood pressure. The compounds of the formula I furthermore can positively influence a 30 reduced contractility of the heart. This can be a disease-related decrease in cardiac contractility, for example in cases of cardiac insufficiency, or acute cases, such as cardiac failure under the effects of shock. In cases of a heart transplant, the heart likewise 35 can resume its efficiency faster and more reliably aftert ^ r the operation has been performed. The same applies —w , ff operations on the heart which necessitate temporary m £ \ it MO 1935 10'- 270265 stopping of cardiac activity by cardioplegic solutions, it being possible for the cosipounds to be used both for protection of the organs, for example during treatment with or storage thereof in physiological bath liquids, 5 and during transfer into the recipient organism. The invention furthermore relates to a process for the preparation of the compounds of the formula I, which comprises (a) reacting sulfonamides of the formula II or salts thereof of the formula III with R(l) -substituted 10 isocyanates of the formula IV H H H "-N-S02Xv^/Y-Nx/R(3) Jj Y XJ « nir o «(ar^ 0 (H) <■") R(l) - N ■ C « 0 IV to give substituted benzenesulfonylureas of the formula Ia, below Possible cations M in the salts of the formula III are alkali metal and alkaline earth metal ions, in particular 15 Na+, K+, Ca++ and Mg++. As equivalent to the R(l) -substituted isocyanates IV, R(1)-substituted carbamic acid esters, R(l)-substituted carbamic acid halides or R(l)-substituted ureas can be employed. (b) Benzenesulfonylureas of the formula Ia K I (I.) - Vin 1395 i i - 270265 can be prepared from aromatic benzenesulfonamides of the formula II or their salts of the formula III and R(l)-substituted trichloro- acetamides of the formula V NH - R(1) 0 (V) in the presence of a base in an inert solvent according 5 to Synthesis 1987, 734 - 735 at temperatures of 25eC to Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, or also alcoholates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, 10 sodium methylate, sodium ethanolate, potassium methylate or potassium ethanolate. Suitable inert solvents are ethers, such as tetrahydrofuran, dioxane and ethylene glycol dimethyl ether (diglyme), nitriles, such as acetonitrile, amides, such as dime thy 1 f orm amide (DMF) or 15 N-methylpyrrolidone (NMP), phosphoric acid hexamethyltri-amide, sulfoxides, such as dimethyl sulfoxide, sulfones, such as sulfolane, and hydrocarbons, such as benzene, toluene and xylenes. Furthermore, mixtures of these solvents with one another are also suitable. 20 (c) Benzenesulfonylthioureas of the formula lb 150 °C. H H MO - " H R(3) (Ik) are prepared from benzenesulfonamides of the formula II and their salt R(l)-substituted thioisocyanates of the formula VI / , - 12, - R (1) - N = C - S VI 270265 (d) Substituted benzenesulfonylureas of the formula Ia can be prepared by conversion reactions of benzenesulfonylthloureas of the formula lb. The replacement of 5 the sulfur atom by an oxygen atom in the correspondingly substituted benzenesulfonylthloureas of the formula lb can be carried out, for example, with the aid of oxides or salts of heavy metals or also by using oxidizing agents, such as hydrogen peroxide, sodium peroxide or nitric acid. 10 Thioureas can also be desulfurized by treatment with phosgene or phosphorus pentachloride. Chloroformic acid amidines or carbodiimides are obtained as intermediate compounds, which can be converted into the corresponding substituted benzenesulfonylureas of the formula Ia, for example, by 15 hydrolysis or adding on of water. During desulfurization, isothioureas behave like thioureas and cam accordingly likewise be used as starting substances for these reactions. (e) Benzenesulfonylureas of the formula Ia can be prepared by reactions • 20 of amines of the formula R(1)-NH2 with benzenesulfonyl isocyanates of the formula VII H 0 - C - N (VM) Amines R(1)-NH2 can likewise be reacted with benzene-sulfonylcarbamic acid esters or -carbamic acid 1 benzenesulfonylureas la (where R(l) - H) to 25 compounds la. (f) Benzenesulfonylthloureas of the formula lb can be prepared by reactions of amines of the formula R(1)-NH2 with befrgjfecfi sulfonylisothiocyanates of the formula VIII - 13 - H 270265 S * C ■ N Amines R(1)-NH2 likewise can be reacted with benzene-sulfonylcarbamic acid thioesters or -carbamic acid thiohalides to give the compounds of the formula lb. The compounds of the formula I and physiologically acceptable salts thereof are useful therapeutics which are suitable not only as antiarrhythmics but also as prophylactics for disturbances of the cardiovascular system, cardiac insufficiency, heart transplant or cerebral vascular diseases in humans or mammals (for example monkeys, dogs, mice, rats, rabbits, guineapigs and cats). Physiologically acceptable salts of the compounds of the formula I are understood as meaning, in accordance with Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14 -18, compounds of the formula XX which can be prepared from non-toxic organic and inorganic bases and benzenesulfonylureas of the formula I, Preferred salts here are those in which M(l) in the formula XX is sodium, potassium, rubidium, calcium or magnesium ions, and the acid addition products are basic amino acids, such as, for example, lysine or arginine. H M(1) _ 5 .f.i R(1) - N The starting compounds for the synthesis processes mentioned for the benzenesulfonylureas of the formula I are prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., Mew York; and in the abovementioned patent applications) , and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also possible to use variants which are known per se but are not mentioned in more detail here. If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture but are immediately reacted further. The amine X is first converted into an isocyanate or a reactive carbonic acid derivative (equation 1) . The conversion of the amine X into an isocyanate is carried out in a known manner by reaction of X with carbonic acid halides, such as phosgene or triphosgene, in the presence of tertiary alkylamines or pyridine and inert solvents. Suitable inert solvents are ethers, such as tetrahydro-furan, dioxane or ethyleneglycoldimethyl 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 dimethyl-formamide (DMF) or N-methylpyrrolidone (NMP), phosphoric acid hexamethyltriamide, sulfoxides, such as dimethyl-sulfoxide, sulfones, such as sulfolane, and hydrocarbons, such as benzene, toluene and xylenes. Mixtures of these solvents with one another furthermore are suitable. Suitable reactiva carbonic acid derivatives are carbonic acid esters such as can be synthesized from chloroformic acid alkyl esters and X and suitable tertiary alkylamines or pyridine. N,M-carbonyldiimidazole and analogous reactive derivatives furthermore can be employed as isocyanate equivalents (Staab, H.A.: Synthesen mit heterocyclischen Amiden (Azoliden) [Syntheses with heterocyclic amides (azolides)]. In: Angewandte Chemie 74 (1962), No. 12, pages 407-423). - 15 - Equation 1 The isocyanate XI or corresponding urethanes are linked to the second molecular component (Justis Liebigs Ann. chem. 1955, 598, page 203) in the presence or absence of inert solvents at temperatures of 100-170°C and give the acylurea derivatives XII (equation 2) JX — jCr"T" *U) *(2) (XI) <*"> Equation 2 The compounds XII synthesized according to equation 2 can be converted into the sulfonamides II in a known marker in accordance with equation 3. The sulfonamides II are prepared by methods which are known per se, and in particular under reaction conditions which are known and suitable for the reactions mentioned. In this context, use can also be made of variants which are known per se but are not mentioned in more detail here. If desired, the syntheses can be completed in one, two or mora steps. Processes in which the acylurea derivative XII is converted into aromatic sulfonic acids and derivatives thereof, such as, for example, sulfonic acid halides, by electrophilic reagents in the presence or absence of inert solvents at temperatures between -10°C and 120°C, preferably between 0°C and 100°C, are particularly 16 preferred. For example, halogenosulfonations can be carried out with halogenosulfonic acids. Ortho and meta isomers can be formed in this reaction, and can be separated from one another at the next sulfonamide 5 reaction stage by standard processes (for example column chromatography on inert support materials or crystallization from inert solvents). The conversion of the sulfonic acid derivatives into sulfonamides II is carried out in a manner known from the literature, sulfonic acid 10 chlorides preferably being reacted with aqueous ammonia in inert solvents at temperatures of 0°C to 100°C. Equation 3 The benzenesulfonylureas of the formula I are prepared as mentioned above from the sulfonamide-substituted acylurea 15 derivatives II thus prepared or acid addition compounds thereof. Depending on the nature of the members R(l), R(2), R(3), E, B, X, Y and Z, one or other of the processes mentioned will be unsuitable for the preparation of compounds I, or at least necessitate measures for 20 protection of active groups, in individual cases. Such cases, which occur relatively rarely, can be recognized easily by the expert, and there are no difficulties in successfully using one of the other synthesis routes described in such cases. 25 The compounds I can possess one or more chiral centers. They can therefore be obtained in their preparation as racemates or, if optically active starting substances are used, also in optically active form. If the compounds contain two or more chiral centers, they can be obtained Y-N \s .(I) (X"l) (,,) I I - 17 - 270265 in the synthesis as mixtures of racemates, from which the individual isomers can be isolated in the pure form, for example by recrystallization from inert solvents. If desired, resulting racemates cam be separated mechani-5 cally or chemically into their enantiomers by methods which are known per se. Thus, diastereomers can be formed from the racemate by reaction with an optically active separating agent. Suitable separating agents for basic compounds are, for example, optically active acids, such 10 as the R or R,R and S or S,S forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphor-sulfonic acid, mandelic acid, malic acid or lactic acid. Carbinols furthermore can be amidated with the aid of chiral acylating reagents, for example R- or S-a-methyl-15 benzyl isocyanate, and then separated. The various forms of diastereomers can be separated in a known manner, for example by fractional crystallization, and the enantiomers of the formula I cam be liberated in a manner which is known per se from the diastereomers. Enantiomer 20 separations are also achieved by chromatography over optically active support materials. The compounds of the formula I according to the invention and their physiologically acceptable salts can be used for the preparation of pharmaceutical formulations. In this 25 context, they can be brought into a suitable dosage form together with at least one solid or liquid excipient or auxiliary, by themselves or in combination with other cardiovascular medicaments, such as, for example, calcium antagonists, NO donors or ACE inhibitors. These formula-30 tions can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, such as, for exaunple, intravenous, administration or topical applications and with which the 35 novel compounds do not react, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, s/T lactose or starch, magnesium stearate, talc, lamplln and 0 t: "v m I 1 I) A.liG ® \ 7 n ^ & r / ii' £';' V • • . - 18 - vaseline. Tablets, coated tablets, capsules, syrups, juices or drops are suitable in particular for oral use, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants are 5 suitable for rectal use, and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols, such as ethanol or isopropanol, 1,2-propanediol or mixtures thereof with one another or with water) or powders are suitable for topical use. The novel 10 compounds can also be lyophilized and the resulting lyophilizates can be used, for example, for the preparation of injection preparations. Liposomal preparations are also possible, in particular, for topical use. The [lacuna] comprise stabilizers and/or wetting agents, 15 emulsifiers, salts and/or auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs and flavor and/or aroma substances. If desired, they can also comprise one 2 0 or more other active compounds, for example one or more vitamins. The dosages which are necessary for treatment of disturbances in cardiac rhythm using the compounds I depend on whether therapy is acute or prophylactic. A dose range of at least about 0.001 mg, preferably about 0.01 mg, in particular about 0.1 mg to not more than about 100 mg, preferably about 10 mg, in particular about 1 mg per kg per day is usually adequate if prophylaxis is carried out. A dose range of 1 to 10 mg per kg and day is preferred. The dose here can be an oral or parenteral individual dose or divided into up to four individual doses. If acute cases of disturbances in cardiac rhythm are treated, for example in an intensive care ward, parenteral administration may be advantageous. A preferred dose range in critical situations cam then be 10 to 100 mg, and can be administered, for example, as a continuous intravenous infusion. 25 30 35 19 - 270265 In addition to the examples described in the embodiment examples, the compounds of the formula I summarized in the following table can be obtained according to the invention: 3 -Ethyl-4-methyl-2 -oxo-3-pyrrolinyl-1-carboxamides: 5 (1) 1 - {2-Methoxy-5 -[2 -(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] - phenyl sulfonyl-}3-ethylurea, (2) l-{2-Methoxy-5-[2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 10 (1-propyl)-urea, (3) 1-{2-Methoxy-5-[2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido)-ethyl] - phenyl sulfonyl-}3-(2-propyl)-urea, (4) l-{2-Methoxy-5-[2-(3 - ethyl-4-methyl-2-oxo-3 -15 pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- (cyclopropyl) -urea (5) 1-{2-Ethoxy-5 - [2 -(3-ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-ethylurea, 20 (6) 1-{2-Ethoxy-5- [2 -(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido)-ethyl] -phenylsul£onyl-}3-(1-propyl)-urea, (7) 1-{2-Ethoxy-5- [2 -(3 7 ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 25 (2-propyl)-urea, (8) I-{2-Ethoxy-5- [2- (3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsul£onyl-}3-(cyclopropyl) -urea, (9) 1-{2-(2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methyl-30 2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl- sulfonyl-}3-ethylurea, (10) 1-{2 - (2,2,2-Trifluoroethoxy) -5- [2- (3 - e thyl - 4 -me thyl -2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl] -phenyl-sulfonyl-}3-(1-propyl)-urea, 35 (11) l-{2- (2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-me if % ' 2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl] -phenyl- sulfonyl-}3-(2-propyl)-urea, K - ^ Iv W10 W I /Q? H ^ - 20 - (12) l-{2- (2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methy1-2-oxo-3-pyrrolinyl-l-carboxaxnido) -ethyl] -phenyl-sulfonyl-}3-(cyclopropyl)-urea, (13) 1-{2-Thiomethyl-5-[2-(3-ethyl-4-methyl-2-oxo-3-5 pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}3- ethylurea, (14) l-{2-Thiomethyl-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(1-propyl)-urea, 10 (15) 1-{2-Thiomethyl-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}3-(2-propyl)-urea, (16) l-{2-Thiomethyl-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 15 (cyclopropyl)-urea, (17) l-{2- (N,N-Dimethylamino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-sul£onyl-}3-ethylurea, (18) l-{2-(N,N-Dimethylamino)-5-[2-(3-ethyl-4-methyl-2- 20 oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl- sulfonyl-}3-(1-propyl)-urea, (19) 1 - { 2 - (N, N - D ime thyl amino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-sulfonyl-}3-(2-propyl)-urea, 25 (20) l-{2- (N,N-Dimethylamino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-sul£onyl-}3-(cyclopropyl)-urea, (21) l-{2- (4-Morpholino) -5- [2- (3-ethyl-4-methyl-2-oxo-S-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 30 ethylurea, (22) l-{2- (4-Morpholino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenylsul£onyl-}3-(1-propyl)-urea, (23) l-{2-(4-Morpholino) -5- [2-(3-ethyl-4-methyl-2-oxo-3- 35 pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- (2-propyl)-urea, (24) 1-{2- (4-Morpholino) -5 - [2 - (3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl)-urea. / i y / - 21 (25) 1-{2-Methyl- 5 - [2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-ethylurea, (26) 1-{2-Methyl-5 -[2 -(3 -ethy1-4-methyl- 2 -oxo-3 -5 pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- (1-propyl)-urea, (27) 1-{2-Methyl -5 -[2 -(3-ethyl-4-methyl-2-oxo -3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(2-propyl)-urea, 10 (28) 1-{2-Methyl-5 -[2 -(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl) -urea (29) 1-{2-Pluoro-5 -[2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 15 ethylurea, (30) 1-{2-Pluoro-5 -[2-(3 -e thyl-4-me thyl- 2 -oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(1-propyl)-urea, (31) 1-{2-Pluoro-5 - [2-(3-ethyl-4-methyl-2-oxo-3- 20 pyrrolinyl-l-carboxamido)-ethyl] -phenylsulfonyl-}3- (2-propyl)-urea, (32) 1-{2-Fluoro- 5 - [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl)-urea, 25 (33) 1-{2-Methoxy-5-[2 - (3 - ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-ethylthiourea, (34) 1-{ 2-Methoxy-5- [2- (3 - ethyl - 4-me thyl - 2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 30 (1-propyl)-thiourea, (35) 1-{2-Methoxy-5- [2- (3 - ethyl-4-methyl-2-oxo-3-pyrr olinyl -1 - carboxamido) - e thyl ] - phenyl sul f ony 1 -} 3 -(1-propyl)-thiourea, (36) 1-{2-Methoxy-5- [2 - (3 - ethyl-4-methyl-2-oxo-3 - 35 pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}3- (2-propyl)-thiourea, (37) l-{2-Methoxy-5- [2- (3 - ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl] -phenylsulfonyl-}3-(cyclopropyl)-thiourea. 270 - 22 - (38) 1-{2-Ethoxy-5- [2-(3-ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-e thyl thiourea, (39) 1-{2-Ethoxy-5- [2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(1-propyl)-thiourea, (40) 1-{2-Ethoxy-5 - [2-(3 -e thyl-4-me thy1-2-cxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(2-propyl)-thiourea, (41) 1-{2-Ethoxy-5- [2 -(3 - ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl)-thiourea, (42) 1-{2-(2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-sulfonyl-}3-ethylthiourea, (43) l-{2- (2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-sulfonyl-}3-(1-propyl)-thiourea, (44) 1-{2-(2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-sulfonyl-}3-(2-propyl)-thiourea, (45) 1-{2-(2,2,2-Trifluoroethoxy) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-sulfonyl-}3-(cyclopropyl)-thiourea, (46) l-{2-Thiomethyl-5- [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-ethylthiourea, (47) l-{2-Thiomethyl-5- [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(1-propyl)-thiourea, (48) 1-{2-Thiomethyl-5- [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(2-propyl)-thiourea, (49) 1-{2-Thiomethyl-5- [2-(3 - ethyl-4-methyl-2 -oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl)-thiourea, (50) l-{2 - (N,N-dimethylamino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-sulfonyl-}3-ethylthiourea, I - 23 2 o 5 (51) l-{2- (N,N~dimethylamino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-aulfonyl-}3-(1-propyl)-thiourea, (52) l-{2- (N,N-dimethylamino) -5- [2- (3-ethyl-4-methyl-2-5 oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl- sulfonyl-}3-(2-propyl)-thiourea, (53) l-{2- (N,N-dimethylamino) -5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenyl-sulfonyl-}3-(cyclopropyl)-thiourea, 10 (54) l-{2-(4-Morpholino)-5- [2-(3-ethyl-4-methyl-2~oxo-3-pyrrolinyl-1 -carboxami do) -ethyl] -phenylsulfonyl-}-3-ethylthiourea, (55) 1-{2-(4-Morpholino)-5-[2- (3-ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}-3- 15 (1-propyl)-thiourea, (56) l-{2-(4-Morpholino)-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}-3-(2-propyl)-thiourea, (57) l-{2-(4-Morpholino)-5-[2- (3-ethyl-4-methyl-2-oxo-3- 20 pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}-3- (cyclopropyl)-thiourea, (58) 1-{2-Methyl-5 -[2-(3-ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-ethylthiourea, 25 (59) 1-{2-Methyl-5 -[2 -(3-ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(1-propyl)-thiourea, (60) 1-{2-Methyl-5 -[2-(3 - ethyl-4-methyl-2-oxo-3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3- 30 (2-propyl)-thiourea, (61) 1-{2-Methyl-5 - [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] - phenyl sul fonyl-}3-(cyclopropyl)-thiourea, (62) 1-{2-Pluoro-5 - [2-(3 - ethyl-4-methyl-2-oxo-3 -35 pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}3- ethylthiourea, (63) 1-{2-Fluoro-5 - [2 -(3 - ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl] - phenyl sul fonyl-}3-(1-propyl)-thiourea, - 24 - (64) l-{2-Fluoro-5- [2-(3 -e thyl-4-me thyl-2 -oxo- 3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(2-propyl)-thiourea, (65) l-{2-Fluoro-5- [2-(3 -ethyl-4-me thyl-2-oxo- 3 -pyrrolinyl-l-carboxamido) -ethyl] -phenylsulfonyl-}3-(cyclopropyl)-thiourea, 1-Oxo-3,4-dihydroisoquino1inyl-2-carboxamides (66) N-{5-[Sulfonylamino-N-(methylaminocarbonyl)-2-methoxyphenyl]- ethyl}-1-oxo-3,4 -dihydroiso-quinolinyl-2-carboxamide, (67) N-{5- [Sulfonylamino-N- (methylaminothiocarbonyl) -2-methoxyphenyl]- ethyl}-1-oxo-3,4-dihydroiso-quinolinyl-2-carboxamide, (68) N-{5-[Sulfonylamino-N-(methylaminocarbonyl)-2-methoxyphenyl]-ethyl}-l-oxo-3,4-dihydroiso-quinolinyl -2 -carboxaunide, (69) N-{5- [Sulfonylamino-N- (methylaminothiocarbonyl) -2-methylphenyl] -ethyl}-l-oxo-3,4-dihydroisoquinolinyl-2-carboxamide, 1-Oxo-3H-isoindolinyl-2-carboxamides (70) N-{5-[Sulfonylamino-N-(methylaminocarbonyl)-2 methoxyphenyl] -ethyl}-l-oxo-3H-isoindolinyl-2-car boxamide, (71) N-{5- [Sulfonylamino-N- (methylaminothiocarbonyl) -2 me thoxypheny 1 ] - e thy 1} -1 - oxo - 3 H - i s o indo 1 iny 1 - 2 - car boxamide, (72) N-{5-[Sulfonylamino-N-(methylaminocarbonyl)-2 methylphenyl]-ethyl}-1-oxo-3H-isoindolinyl-2-car boxamide, (73) N-{5- [Sulfonylamino-N- (methylaminothiocarbonyl) -2 methylpheny1]-ethy1}-1-oxo-3H-isoindoliny1-2-car boxamide. 702 n 5 - 25 - Example 1: 1-{2-Methoxy-5- [2- (3-athyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl]-phenylsulfonyl-}3-methylthiourea H H H " N\/N " S02 Xtx^|/CH2CH2'N T ^Cr i 0.22 g (0.58 mmol) of 2-methoxy-5- [2- (3-ethyl-4-methyl-2-5 oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -benzenesulfonamide are dissolved in 10 ml of acetone, and 25 mg of NaOH and 50 fil of water are added. 45 mg (0.6 mmol) of methyliso-thiocyanate are added to the well-stirred reaction mixture, while cooling in ice, the mixture is 10 subsequently stirred at room temperature for one hour and the solvent is then removed under reduced pressure. The residue which remains is purified by column chromatography over silica gel 60 with the aid of the mobile phase ethyl acetate (R; ■ 0.4) and gives 0.18 g of the 15 desired product as colorless crystals which melt at 65 to 70°C. Preparation of the starting compound 4.53 g (30 mmol) of 4-methoxy-/3-phenylethylamine are added dropwise to a solution of 2.96 g (10.0 mmol) of 20 triphosgene in 30 ml of dry tet^ahydrofuran and the mixture is heated at the boiling point for 2 hours. The solution is cooled to room temperature and filtered and the filtrate is concentrated in vacuo. The colorless oil which remains is purified by bulb tube distillation under 25 a pressure of 2 mmHg at a bath temperature of 220°C to give 1.1 g of 4-methoxy-0-phenylethyl isocyanate. 0.7 g (4.0 mmol) of 4-methoxy-£-phenylethyl isocyanate and 0.4 g (3.5 mmol) of 3-ethyl-4-methylr2-oxo-3- 2esp /a / w - 26 - pyrroline are stirred with one another and the mixture is heated at 150°C for one hour. The cooled reaction mixture is dissolved in a minimum of ethyl acetate and purified by column chromatography over silica gel 60 with the aid 5 of the mobile phase ethyl acetate (Rp =» 0.5). After the eluent has been evaporated off under reduced pressure, 0.25 g of methoxy-4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -benzene is obtained, and is introduced in portions into chlorosulfonic acid cooled 10 to 0°C. After being stirred at 0°C for one hour, this reaction mixture is poured onto ice. The sulfonic acid chloride which has precipitated is taken up in ethyl acetate. The organic phase is dried with sodium sulfate and concentrated in vacuo to give the sulfonic acid 15 chloride as a crude product, which is dissolved in acetone and converted into 2-methoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -benzene-sulfonamide with aqueous ammonia solution. The sulfonamide has a melting point of 204-205°C. 20 Example 2 1-{2-Methoxy-5- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl]-phenylsulfonyl-}3-methylurea 0.25 g (0.55 mmol) of 1-{2-methoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-25 sulfonyl}3-methylthiourea is suspended in aqueous sodium hydroxide solution (45 mg of NaOH and 0.5 ml of water), 35% strength aqueous hydrogen peroxide is added at 40°C and the mixture is subsequently stirred at 80 °C for 30 minutes. Methylene chloride is added to the reaction 30 mixture at room temperature and the mixture is acidified - 27 - with a little 2 normal aqueous hydrochloric acid (pE a 2-3) and dried with sodium sulfate. The organic phase Is concentrated in vacuo to give 0.22 g of l-{2-methoxy-5- [2- (3-et.hyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}3-methylurea as colorless crystals of melting point 184-187°C. Example 3 l-{2-Fluoro-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl-}-3-methylthiourea u H S F In accordance with Exmaple 1, l-{2-fluoro-5- [2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -phenyl-sulfonyl-}3-methylthiourea (melting point: 90°C, with decomposition) can be synthesized starting from 4-fluoro-/5-phenylethylamine via fluoro-4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-benzene (melting point: 141°C), 2-fluoro-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-benzenesulfonyl chloride (melting point: 147°C) auad 2-fluoro-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl] -benzene-sulfonamide (melting point: 136°C). Example 4 1- [2-Ethoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido)-ethyl]-phenylsulfonyl]-3-methylthiourea Melting point 176-178°C Analogously to Example 1 i y 3at» - 28 - t- / '' c* (' 0 : v y n Example 5 1- [2-Ethoxy-5-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinyl-l-carboxamido) -ethyl]-phenylsulfonyl]-3-methylurea Melting point: 160-165°C 5 Analogously to Example 2 Pharmacological data: The therapeutic properties of the compounds I can be demonstrated using the following models: (1) Action potential duration on the papillary muscle of 10 the guineapig: (a) Introduction ATP deficiency states such as are observed during ischemia in the cardiac muscle cell lead to a shortening of the duration of action potential. They are one of the 15 causes of so-called reentry arrhythmias, which can cause sudden cardiac death. Opening of ATP-sensitive K channels by the reduction in ATP is a cause of this. (b) Method A standard microelectrode technique is used for measure-20 ment of the action potential. For this, guineapigs of both sexes are sacrificed by a blow to the head, the hearts are removed and the papillary muscles are separated out and suspended in an organ bath. The organ bath is flushed with Ringer solution (0.9% NaCl, 0.048% KC1, 25 0.024% CaCl2, 0.02% NaHC03 and 0.1% glucose) and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36°C. The muscle is stimulated via an electrode with rectangular pulses of 1 V and 1 ms duration and a frequency of 2 Hz. The action potential is 1 O 7 A Hi L: r* C $ y £ L-- Li - 29 - conducted and recorded through a glass microelectrode, which is punctured intracellularly and filled with 3 mmol KC1 solution. The substances to be tested were added to the Ringer solution in a concentration of 2.2 x 10"5 mol 5 per liter. The action potential is shown in amplified form on an oscilloscope using a Hugo Sachs amplifier. The duration of the action potential is determined at a repolarization degree of 95% (APD95) . Shortenings in action potential are caused either by addition of a 1 /xM 10 strength solution of the potassium channel opener rilmakalim (Hoe 234) [W. Linz, E. Klaus, U. Albus, R.H.A. Becker, D. Mania, H.C. Englert, B.A. Scholkens Arzneimittelforschung/ Drug Research, Volume 42 (II) , 1992, pages 1180 - 1185] or by addition of 2-deoxyglucose 15 (DEO). ATP deficiency states are caused in experimental physiology by 2-deoxyglucose by blockade of glucose metabolism. The action potential-shortening effect of these sxibstances was prevented or reduced by the simultaneous dose of the test substances. The test substances were 20 added to the bath solution as stock solutions in propanediol. The values stated relate to measurements 30 minutes after the addition. The APD95 in the presence of DEO or HOE 234 and in the absence of the test substance serves as a control. 25 (c) Results: The following values were measured: Measurement APD95-DEOa) [ms] APDg5-HOE 234a) [ms] Control <40 < 40 Example 1 60 ± 22 (162 ± 7) n i 3 119 ± 16 (162 ± 16) n = 3 Example 2 110 (155) n « 1 125 (185) n = 1 - 30 - a) The measurement values from n experiments are followed by the corresponding blank values in parentheses. The blank values are the APD95 values at the start of the experiment without DEO, HOE 234 or test 5 substance in the Ringer solution. (2) Membrane potential on isolated £ cells: (a) Introduction The action mechanism of hypoglycemic sulfonylureas is clarified in rough outlines. The /3 cells of the pancreas 10 are the target organ, where increased secretion of the hypoglycemic hormone insulin occurs. The release of insulin is controlled by the cell membrane potential. Glibenclamide causes depolarization of the cell membrane, which promotes insulin release via an increased in-flow 15 of calcium ions. The extent of this depolarization of the cell membrane AXJ was determined on RINm5F cells, a pancreas tumor cell line, for some of the compounds according to the invention. The action strength of a compound in this model predicts the extent of the hypo-20 glycemic potential of this compound. (b) Method Cell culture of RINm5F cells RINm5F cells were cultured at 37°C in RPMI 1640 culture medium (flow) , to which 11 mmol of glucose, 10% 25 (volume/volume) of fetal calf serum, 2 mmol of glutamine and 50 fig/ml of gentamycin were added. For the studies, the cells were isolated by incubation (about 3 minutes) in a Ca^+-free medium containing 0.25% of trypsin and stored on ice. 30 Measurement method Isolated RINmSF cells were introduced into a Plexiglas chamber on an inverse microscope fitted with a differential interference contrast lens. A fire-polished / 0 2 c:r 2/up - 31 - micropipette pipette with an opening diameter of about 1 fan was placed on the cell with the aid of a micromanipulator under optical control (400-fold magnification) . By applying a slight reduced pressure in the patch 5 pipette, a high electrical seal was first produced between the glass and cell membrane, and was then broken open by increasing the reduced pressure of the membrane spot under the measurement pipette. The cell potential was recorded in this whole cell configuration with the 10 aid of a patch clamp amplifier (L/M EPC 7) and was measured by applying a potential ramp to the whole cell current. Solutions: The patch pipette was filled with KC1 solution (in mmol): 140 KC1, 10 NaCl, 1.1 MgCl2, 0.5 EGTA, 1 Mg-15 ATP, 10 HEPES, pE - 7.2, and the bath contained NaCl solution (in mmol): 140 NaCl, 4.7 KC1, 1.1 MgCl2, 2 CaCl2, 10 HEPES, pE b 7.4. Stock sol utions of the test substances (concentration 100 mmol) in dimethyl sulfoxide (DMSO) and corresponding dilutions in NaCl solution were 20 prepared. DMSO by itself had no effect on the cell potential. In order to stabilize the cell potential under control conditions, the opener for ATP-sensitive K+ channels diazoxide (100 junol) was added to the bath solution in all the experiments. All the experiments were 25 carried out at 34 ± 1°C. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> / ■» - 32 - (c) Results (The concentrations of the compounds according to the invention in the experiments are 10~5 mol per liter) Measurement Example 1 Example 2 ATJ (mV)m) 2 (-80) n 12 (-71) n 10 The measurement values from n experiments are followed by the corresponding blank values in parentheses. The blank values are the cell potentials under a dose of diazoxide. WHAT WE CLAIM IS: " 33 " »

1. Substituted benzenesulfonylurea or -thiourea of the formula 1 *(1) - N Y":;;pa'-:Y E "(2) R(3) (D in which R(l) is hydrogen, (Cx-Cg) -alkyl, (C3-C6)-cycloalkyl, CaH24- (C3-C5) - cycloalkyl, (C3-C6)-alkenyl or CcH2e- 5 CdF2d+l' a is 0, 1, 2 or 3; c is 0, 1, 2 or 3; d is 1, 2,3, 4, 5 or 6; R(2) is hydrogen, F, CI, Br, I, (C1-C6)-alkyl, (C^Cg) -10 alkoxy, (C^-Cg)-mereaptoalkyl, (C^Cg)-fluoroalkoxy, °-c«H2«-cfF2C+i' (Ci-Cg)-fluoroalkyl, C^2g-ChF2h+1, (C3- C6)-cycloalkyl °r NR(4)R(5); e is 0, 1, 2 or 3; f is 1, 2, 3, 4, 5 or 6; 15 g is 0, 1/2 or 3; h is 1, 2, 3, 4, 5 or 6; R(4) and R(5) together are a (CH2}2.7 chain in which one of the CH2 groups can be replaced by oxygen, 20 sulfur or NR(6) , where at least one CH2 group must stand between the N atom of the NR(4)R(5) and the oxygen, sulfur or NR(6); where R(6) is hydrogen, (^-Cg)-alkyl, CkH2k-CnF2a+1, (C3-Cg)-cycloalkyl, (C1-C2)-alkyl-(C3-C5)-cycloalkyl or (C3-C6)-25 alkenyl; k is 0, 1, 2 or 3; m is 1, 2, 3, 4, 5 or 6; or R(4) and R(5) independently of one another are 30 hydrog«, (Cj-C,)C]tH,k-C.FJ„l, (c,^ (C3-C5) -cycloalJqj alkenyl; k is 0, 1, 2 or 3; ~ m is 1, 2, 3, 4, 5 or 6; E is oxygen or sulfur; c 34 ♦. 270265 Y is a hydrocarbon chain -[CR(7)2]n- ; each R (7) is independently H or (Q-C^-alkyl; n is 1, 2, 3 or 4; R(3) is a substituted heterocyclic radical of the formula -N B is (C3-C5) - alkenylene, which is unsubstituted or substituted by up to 3 (Cj^-C^) - alley 1 groups or by a phenyl radical; or R(3) is a bicyclic system of the formula X N— or N— 0 10 15 is hydrogen, CI, Br, I, (C^Cg)-alkyl or CpH2p-CqP2q+l; p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6; and is F, CI, Br, I, (C^C^) -alkoxy, (C1-C4)-alkyl, (C3-C6) -cycloalkyl or (C3-C6)-cycloalkoxy. 20

2. A compound of the formula X as claimed in claim 1, in which: R(l) is hydrogen, (C1-C4) -alkyl, (C3-C5)-cycloa (C3-C5)-alkenyl or CcH2c-CdF2d+1; c is 0, 1, 2 or 3; '- 35; 270265 d is 1, 2, 3, 4, 5 or Sj R(2) is hydrogen, F, CI, (Cj^Cg)-alkyl, (C^Cg) -alkoxy, (Ci-Cg) -mercaptoalkyl, (Cj^Cg)-fluoroalkoxy, (C1-C6)-fluoroalkyl, (C3-C6) -cycloalkyl or NR(4)R(5); 5 R(4) and R(5) together are a (CH2)2_7 chain, in which one of the CH2 groups can be replaced by oxygen, sulfur or MR(6), where at least one CH2 group must stand between the M atom of the NR(4)R(5) 10 and the oxygen, sulfur or NR(S) ; where R(6) is hydrogen, (C^Cg) -alkyl, C^H^-C^^, (C3-Cs)-cycloalkyl, (Cj-Cj) -alkyl-(C3-C5) -cycloalkyl or (C3-Cs)-alkenyl; k is 0, 1 or 2; 15 m is 1, 2, 3, 4, 5 or 6; or R(4) and R(5) independently of one smother are hydrogen, (Cx-Cg)-alkyl, C^H^-C^^, (C3-C6)-cycloalkyl, {C2"C2) -alkyl- (C3-Cg) -cycloalkyl or (C3-C6)-alkenyl; k is 0, 1 or 2; m is 1, 2, 3, 4, 5 or 6; E is oxygen or sulfur; Y is a hydrocarbon chain -tCR(7)2]a-; each R (7) is independently H or (C,-C2)-alkyl; n is 1, 2, 3 or 4; R(3) is a substituted heterocyclic radical of the formula 20 25 -N Y B is (C3-C6)-alkenylene, which is unsubstituted or substituted by up to 3 (C1-C4) -alkyl groups or phenyl radical; or R(3) is a bicyclic system of the formula / / • " * f- 3$ - 270265 X z N— or 0 is hydrogen, F, CI, Br, I or (C^Cg)-alkyl; and is F, CI, Br, I, (C^C^) -alkoxy, (C1-C4)-alley 1, (C3-C6)-cycloalkyl or (C3-C6)-cycloalkoxy. 10

3. A compound of the formula I as claimed in claim 1, in which: R(l) is hydrogen, (C1-C4)-alkyl, (C3-C4)-cycloalkyl, (C3-C4) -alkenyl or (C1-C4) - fluoroalkyl ; R(2) is hydrogen, F, CI, (C1-C4)-alkyl, (C1-C4)-fluoroalkyl or (C3-C6)-cycloalkyl; E is oxygen or sulfur; Y is a hydrocarbon chain -[CR(7)2]n-; each R (7) is independently H or (C,-C2)-alky.l; n is 2 or 3; R(3) is a substituted heterocyclic radical of the formula -N 15 20 B is (C3-C5) - alkenylene, which is unsubstituted or substituted by up to 3 (C1-C4) -alkyl groups or bjr phenyl radical; or >1 T R(3) is a bicyclic system of the formula .'.MO $95 <- 37i - X 1 0 0 X z N or N— 0 0 X is hydrogen, F, CI or (C1-C3) -alkyl; and Z is F, CI or (C1-C4)-alkoxy.

4. A compound of the formula I as claimed in claim 2, in which: R(l) is hydrogen, (C^^-C^) -alkyl, . (C3-C4)-cycloalkyl, (C3-C4) -alkenyl or (C^-C^-fluoroalkyl; R(2) is (C1-C4)-alkoxy, (C1-C4) -mercaptoalkyl or (C^C^- fluoroalkoxy; E is oxygen or sulfur; Y is a hydrocarbon chain -[CR(7)2]n-; each R(7) is independently H or (Q-Cy-alkyl; n is 2 or 3; R(3) is a substituted heterocyclic radical of the formula B 0 B ia (C3-C4) - alkenylene, which is unsubstituted or substituted by one to three (C1-C4) -alkyl groups or by a phenyl radical; or R(3) is a bicyclic system of the formula V \ •- 38l 270265 cq. 0 N— N— or X is hydrogen, F, CI or (Cj^-Cj)-alkyl; and Z is F, CI or (C^C^) -alkoxy.

5. A compound o£ the formula I as claimed in claim 2, in which 5 R(l) is hydrogen, (C1-C4)-alkyl, (C3-C4)-alkenyl or (C1-C4)-fluoroalkyl; R(2) is NR(4)R(5) ; R(4) and R(5) together are a (CH2)4_6 chain, in which 10 one of the CH2 groups can be replaced by oxygen, sulfur or NR(6), where at least one CH2 group must stand between the N atom of the NR(4)R(5) and the oxygen, sulfur or NR(6) ; where R(6) is H, CH3 or C2H5; 15 or R(4) and R(5) independently of one another are CH3, C2H5, n-C3H7, iso-C3H7 or cyclo-C3H5; E is oxygen or sulfur; 20 Y is .a hydrocarbon chain -[CR(7)2]n-; each R (7) is independently H or (C,-C2)-alkyl; n is 2 or 3; R(3) is a sxibstituted heterocyclic radical of the formuli <■' u I - 39 H B Y B is (C3-C4) - alkenylene, which is unsubstituted or substituted by up to 3 (C^C^ -alkyl groups or by a phenyl radical; or R(3) is a bicyclic system of the formula X N— or 10 X is hydrogen, F, CI or (C1-C3)-alkyl; and Z is F, CI or (C^C^ -alkoxy.

6. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises (a) reacting a sulfonamide of the formula II or a salt thereof of the formula III h2h-so2 *(2) Y-Nx /"(J) xr Y JJ Y-Nv / R(S) Y R(2) (M) (III) 1395 J CSV • - 40 - 270265 in which M is the cation of an alkali metal or alkaline earth metal, and R(l), R(2), R(3) and Y have the definitions given in claim 1, with an R(1)-substituted isocyanate of the formula IV R(l) - N = C = 0 IV to give a substituted benzenesulfonylurea of the formula la below, or (b) preparing a benzenesulfonylurea of the formula la H H H r - n \ /*(5) R ( 1 ) — - SO, «(2) XX T (la) from an aromatic benzenesulfonamide of the formula II above, or a saltof the formula III thereof, above, and from an R(l)-substituted trichloroacetamide of the formula V NH - R(1) C,JC 0 (V) or (c) preparing a benzenesulfonylthiourea of the formula lb xr v R(2) (lb) from a benzenesulfonamide of the formula II above, or a salt of the formulaJII thereof, above, and an R(l)-substituted thioisocyanate of the formula VI R(l) - N - C - S VI 270265 or (d) preparing a. substituted benzenesulfonylurea of the formula Ia, above, by a conversion reaction of a benzenesulfonyl-thiourea of the formula lb, above, or (e) preparing a benzenesulfonylurea of the formula lb, above, by reaction of an amine of the formula R(1)-NH2 with a benzenesulfonylisocyanate of the formula VII or (f) preparing a benzene sul fonyl thiourea of the formula lb, above, by reaction of an amine of the formula R(1)-NH2 with a benzenesulfonylisothiocyanate of the formula VIII H (VII) H VIII

7. The use of a compound of the formula I as claimed in claim 1 for the preparation of a medicament for the treatment of disturbances in cardiac rhythm.

8. The use of a compound of the formula I as claimed in claim 1 for the preparation of a medicament for prevention of sudden cardiac death.

9. The use of a compound of the formula I as claimed in claim 1 the preparation of a medicament for the treatm< ischemic conditions of the heart.

10. The use of a compound of the formula I as claimed in claim I for the preparation of a scientific tool for inhibition of ATP-sensitive potassium channels.

11. The use of a compound of the formula I for the preparation of a medicament for the treatment of weakened cardiac force.

12. The use of a compound of the formula I for the preparation of a medicament for improving cardiac function following a heart transplant.

13. A medicine comprising an active amount of a compound of the formula I as claimed in claim 1.

14. A compound according to claim 1 substantially as herein described or exemplified.

15. A process according to claim 6 substantially as herein described or exemplified.

16. The use according to any one of claims 7, 8, 9, 10, 11 and 12 substantially as herein described or exemplified.

17. A medicine according to claim 13 substantially as herein described or exemplified. V HOECHST AKTIENGESELLSCHAFT By Their Attorneys </div>