Title of Invention	SUBSTITUTED BENZENESULFONYLUREAS AND -THIOUREAS, PROCESSES FOR THEIR PREPARATION AND USE OF PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, AND MEDICAMENTS CONTAINING THEM
Abstract	ABSTRACT 214/MAS/96 "SUBSTITUTED BENZENESULFONYLUREAS AND -THIOUREAS, PROCESSES THEIR PREPARATION AND USE OF PHARMACEUTICAL PREPARATIONS BASED THESE COMPOUNDS, AND MEDICAMENTS CONTAINING THEM" Substituted benzenesulfonylureas and -thioureas of the formula I in which R(l), R(2), R(3), R(4), E, X and Y which have the meanings indicated in the patent claims, exhibit effects on the cardiovascular system. in which R(l), R(2), R(3), R(4), E, X and Y which have the meanings indicated in the patent claims, exhibit effects on the cardiovascular system.

Title of Invention

SUBSTITUTED BENZENESULFONYLUREAS AND -THIOUREAS, PROCESSES FOR THEIR PREPARATION AND USE OF PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, AND MEDICAMENTS CONTAINING THEM

Abstract

ABSTRACT 214/MAS/96 "SUBSTITUTED BENZENESULFONYLUREAS AND -THIOUREAS, PROCESSES THEIR PREPARATION AND USE OF PHARMACEUTICAL PREPARATIONS BASED THESE COMPOUNDS, AND MEDICAMENTS CONTAINING THEM" Substituted benzenesulfonylureas and -thioureas of the formula I in which R(l), R(2), R(3), R(4), E, X and Y which have the meanings indicated in the patent claims, exhibit effects on the cardiovascular system. in which R(l), R(2), R(3), R(4), E, X and Y which have the meanings indicated in the patent claims, exhibit effects on the cardiovascular system.

Full Text	Substituted benzenesulfonylureas and -thioureas, pro¬cesses for their preparation and use of pharmaceutical preparations based on these compounds, and medicaments containing them The invention relates to substituted benzenesulfonylureas and -thioureas I R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, additionally (C1-Cg) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S, (where n = 1-4), F or CI; R(3) is H, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S (n = 1, 2, 3 or 4); R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S (n = 1, 2, 3 or 4); or R(3) and R(4) together form a (CH2)2.8 ring, in which one or more of the CH2 groups can be replaced by heteroatoms; R(3) and R(4) can be identical or different; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R(5')]; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts. The term alkyl describes, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. The cycloalkyl radical can additionally carry an alkyl substituent. Halogen substituents which can be employed are the elements fluorine, chlorine, bromine and iodine. Furthermore, compounds having centers of chirality in the alkyl chains Y, R(3) and R(4) can occur. In this case, the invention includes both the individual antipodes per se, and a mixture of the two enantiomers in different proportions, and also the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers. Similar sulfonylureas are disclosed in German Offen-legungsschrift 1 198 354. The hypoglycemic actions of the sulfonylureas are described therein. A prototype of such hypoglycemic sulfonylureas is glibenclaunide.. which is used therapeutically as an agent for the treatment of diabetes mellitus and serves in research o.s a much-esteemed tool for the study of so-called ATP-sensitive potassium channels. In addition to its hypoglycemic action, glibenclamide has still other actions, which up to now can still not be employed therapeutically, but which all are attributed to blockade of exactly these ATP-sensitive potassium channels. This includes, in particular, an antifibrillatory action on the heart. In the treatments of ventricular fibrillation or its preliminary stages, however, a simultaneous blood sugar fall would be undesirable or even dangerous, as it can further aggravate the condition of the patient. It was therefore the object of the present invention to synthesize compounds which have a cardiac action which is equally as good as glibenclamide but do not affect the blood sugar or affect it distinctly less in cardioactive doses or concentrations than glibenclamide. Suitable experimental animals for the detection of such actions are, for example, mice, rats, guinea-pigs, rabbits, dogs, monkeys or pigs. The compounds I are used as pharmaceutical active com¬pounds in human and veterinary medicine. They can further be used as intermediates for the production of further pharmaceutical active compounds. Preferred compounds I are those in which: R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is hydrogen, F, C1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoroalkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, a (CH2)2.7 chain in which one or more of the CH2 groups can be replaced by heteroatoms O, NH or S; R(3) and R(4) are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or a (C1--C10) chain in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) together are (CH2)2-8' which one of the CHj groups can be replaced by a heteroatom 0, S or NH; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R(5')]i; m is 1, 2, 3 or 4; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; and their pharmaceutically tolerable salts. Particularly preferred compounds of the formula I are those in which: R(l) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or a (CH2)2.7 chain, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH; R(3) and R(4) are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, or (CH2)i.j0' which one or more CHj groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) are together (€112)2.7/ in which one of the CHj groups can be replaced by heteroatoms 0, S or NH; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R(5')]j„; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts. Very particularly preferred are those compounds I in which: R(l) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3 or 4 carbon atoms; R(2) is methoxy or ethoxy; R(3) and R(4) are identical or different and are hydrogen, alkyl having 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or a (C3.8H7_;i7) group, in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) together are the (0112)2.8 gjoup, in which one of the CH2 groups can be replaced by heteroatoms O, S or NH; E is sulfur or oxygen; X is oxygen; Y is [CR(5)R(5')]jn; R(5) and R (5')' independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1 or 2; and their pharmaceutically tolerable salts. Likewise very particularly preferred compounds I are those in which: R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms; R(2) is methoxy or ethoxy; R(3) and R(4) are identical or different and are hydrogen, alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a [Cg.gH-.) group, in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH; or R(3) and R{4) together are (CH2)5.g, in which one of the CHj groups can be replaced by heteroatoms O, S or NH; E is oxgyen or sulfur; X is oxygen; Y is [CR(5)R(5')]i„; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1 or 2; and their pharmaceutically tolerable salts. Additionally very particularly preferred compounds I are those in which: R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms; R(2) is methoxy or ethoxy; R(3) is hydrogen; R(4) is alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a (Cg.gH-L-L.-L) group, in which one or more of the CHj groups can be replaced by heteroatoms 0, S or NH; E is sulfur or oxygen; X is oxygen; Y is [CR(5)R{5')]in; R(5) and R(5') independently of one another are hydrogen or methyl; where the members [CR(5)R(5')] are identical or different; m is 1 or 2; and their pharmaceutically tolerable salts. The compounds I of the present invention are useful pharmaceuticals for the treatment of cardiac arrhythmias of all types of origin and for the prevention of sudden heart death due to arrhythmia and can therefore be used as antiarrhythmics. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias, such as atrial tachycardias, atrial flutters or paroxysmal supraventricular arrhythmias or ventricular arrhythmias, such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardias or the particu¬larly dangerous ventricular fibrillation. They are suitable, in particular, for those cases where arrhythmias are the consequence of a constriction of a coronary vessel, such as occur in angina pectoris or during an acute cardiac infarct or as a chronic con¬sequence of a cardiac infarct. They are therefore particularly suitable in postinfarct patients for the prevention of sudden heart death. Further syndromes where arrhythmias of this type and/or sudden heart death due to arrhythmia play a part are, for example, cardiac insuffi¬ciency or cardiac hypertrophy as a consequence of a chronically increased blood pressure. Moreover, the compounds I can positively affect a decreased contractility of the heart. This can include a disease-related fall in cardiac contractility, for example in cardiac insufficiency, but also acute cases such as heart failure in the case of the effects of shock. Likewise, in the case of a heart transplantation, after operation has taken place the heart can resume its operational capacity more rapidly and reliably. The same applies to operations on the heart, which necessitate a temporary stopping of cardiac activity by means of cardioplegic solutions, it being possible to use the compounds both for the protection of the organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the recipient body. The invention furthermore relates to processes for the preparation of the compounds I. A procedure can thus be used which comprises (a) reacting a sulfonamide of the formula II in which R(l), R(2), R(3), R(4), X, Y and M have the meanings indicated in claim 1, to give the substituted benzenesulfonylurea I a. Suitable cations M in the salts of the formula III are alkali metal and alkaline earth metal ions. Equivalently to the R(l)-substituted isocyanates IV, R(1)-substituted carbamic acid esters, R(1)-substituted carbamoyl halides or R(l)-substituted ureas can be employed. can be prepared from an aromatic benzenesulfonamide of the formula II or its salt III with an R(1)-substituted trichloroacetcunide of the formula V in the presence of a base in an inert solvent according to Synthesis 1987, 734-735 at temperatures from 25°C to 150°C. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, or alternatively alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodivun methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (diglyme), nitriles such as aceto-nitrile, amides such as dimethyIformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoramide, sul¬foxides such as DMSO, sulfones such as sulfolane, hydro¬carbons such as benzene, toluene, xylenes. Furthermore, mixtures of these solvents with one another are also suitable. (d) A benzenesulfonylurea of the formula I a can be prepared by a conversion reaction of a benzenesulfonyl- thiourea of the formula I b. The replacement of the sulfur atom by an oxygen atom in the appropriately substituted benzenesulfonylthiourea lb can be carried out, for example, with the aid of oxides or salts of heavy metals or also by use of oxidants such as hydrogen peroxide, sodium peroxide or nitrous acid. Thioureas can also be desulfurized by treatment with phosgene or phosphorus pentachloride. The intermediate compounds obtained are chloroformamidines or carbodiimides, which are converted into the corresponding substituted benzene- sulfonylureas la, for example by hydrolysis or addition of water. During desulfurization, isothioureas behave like thioureas and can accordingly also be used as starting substances for these reactions. (e) A benzenesulfonylurea I a can be prepared by reaction of an amine of the formula R(1)-NH2 with a benzenesul- fonyl isocyanate of the formula VII Likewise, an amine RCD-NHj can be reacted with a benzenesulfonylcarbeunic acid ester, a -carbamoyl halide or a benzenesulfonylurea I a [where R(l) = H] to give a compound I a. (f) A benzenesulfonyl thiourea I b can be prepared by reaction of an amine of the formula R(1)-NH2 with a benz¬enesulfonyl isothiocyanate of the formula VIII and R(3)R(4)NH by means of dehydrating agents or activ¬ation by means of carbonyl halides or formation of mixed anhydrides. The dehydrating agents employed can be all compounds suitable for the preparation of amide bonds, such as dicyclohexylcarbodiimide, carbonyldiimidazole or propanephosphoric anhydride. The solvents used are inert nonprotic solvents such as THF, DMF, diethyl ether, dichloromethane, as well as mixtures of these solvents. (h) A benzenesulfonylthiourea I b can be prepared from a benzenesulfonylthiourea of the formula X and R(3)R(4)NH by means of dehydrating agents or activa¬tion by means of carbonyl halides or formation of mixed anhydrides. The dehydrating agents employed can be all compounds suitable for the preparation of amide bonds, such as dicyclohexylcarbodiimide, carbonyldiimidazole or propanephosphoric anhydride. The solvents used are inert nonprotic solvents such as THF, DMF, diethyl ether, dichloromethane, as well as mixtures of these solvents. The compounds I and their physiologically acceptable salts are useful therapeutics which are suitable not only as antiarrhythmics, but as prophylactics in disorders of the cardiovascular system, cardiac insufficiency, heart transplantation or cerebral vascular disorders in hiomans or mammals (for example monkeys, dogs, mice, rats, rabbits, guinea-pigs and cats). Physiologically acceptable salts of the compounds I are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14-18 as meaning compounds of the formula XI, which can be prepared from nontoxic organic and inorganic bases and benzenesulfonylureas I. Salts are preferred in this context in which M in the formula XI is a sodium, potassiiom, rubidium, calcium or magnesium ion, and also the acid addition products of basic amino acids, such as lysine or arginine. The starting compounds for the mentioned synthesis processes of the benzenesulfonylureas I are prepared by methods known per se, 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., New York; and also in the patent applications indicated above) , ncimely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but not mentioned here in more detail. If desired, the starting substances can also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further. A suitably substituted carboxylic acid of the formula XII can thus be subjected to a halosulfonation according to Scheme 1 and the sulfonamide XIII obtained by subsequent ammonolysis can be reacted with an appropriate amine R(3)R(4)NH after activation of the carboxylic acid group to give the carboxamide of the formula II. Suitable activation methods are the preparation of the carbonyl chloride or mixed carboxylic anhydrides using formyl halides. In addition, the reagents known for amide bond preparation, such as carbonyldiimidazole, dicyclo-hexylcarbodiimide and propanephosphoric anhydride, can be used. to give the benzenesulfonylureacarboxylic acids of the formula XIV The compounds I can have one or more chiral centers. In their preparation they can therefore be obtained as racemates or, if optically active starting substances are used, alternatively in optically active form. If the compounds have two or more chiral centers, they can be obtained in the synthesis as mixtures of racemates from which the individual isomers can be isolated in pure form, for example by recrystallizing from inert solvents. If desired, racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. Diastereomers can thus be formed from the racemates by reaction with an optically active resolving agent. Suitable resolving agents for basic compounds are, for example, optically active acids, such as the R- or R,R- and S- or S,S-forms of tartaric acid, dibenzoyl-tartaric acid, diacetyltartaric acid, camphorsulfonic acids, mandelic acids, malic acid or lactic acid. Carbinols can further be amidated with the aid of chiral acylating reagents, for example R- or S-a-methylbenzyl isocyanates, and then separated. The various forms of the diastereomers can be separated in a known manner, for excunple by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a known manner. Resolution of enantiomers is further carried out by chromatography on optically active support materials. The compounds I according to the invention and their physiologically acceptable salts can be used for the production of pharmaceutical preparations. In this I context, they can be brought into a suitable dose form together with at least one solid or liquid excipient or auxiliary on their own or in combination with other pharmaceuticals having cardiovascular activity, such as calcium antagonists, NO donors or ACE inhibitors. These preparations can be used as pharmaceuticals in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration, for excunple intravenous administration, or topical applications and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin and petroleiom jelly. In particular, tablets, coated tablets, capsules, syrups, juices or drops are used for oral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, are used for rectal administration, and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols such as ethanol or isopropanol, acetonitrile, 1,2-propanediol or their mixtures with one another or with water) or powders are used for topical application. The compounds I can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. In particular for topical application, liposomal prepara¬tions are also suitable, which contain stabilizers and/or wetting agents, emulsifiers, salts and/or auxiliaries such as lubricants, preservatives, salts for affecting the osmotic pressure, buffer substances, colorants and flavorings and/or aromatic substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins. The doses which are necessary for the treatment of cardiac arrhythmias with the compounds I depend on whether the therapy is acute or prophylactic. Normally, a dose range of approximately at least 0.1 mg, preferably at least 1 mg, up to at most 100 mg, preferably up to at most 10 mg, per kg per day is adequate if prophylaxis is conducted. The dose can in this case be divided as an oral or parenteral individual dose or else in up to four individual doses. If acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration can be advantageous. A preferred dose range in critical situations can then be 10 to 100 mg and be administered, for example, as an intravenous continuous infusion. According to the invention, in addition to the compounds described in the working examples, the compounds I compiled in the following Table can also be obtained: (1) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-methylacetamide (2) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-ethylacetamide (3) 3 - Sulf onylamino-N-methyl aminocarbonyl-4-me thoxy-phenyl-N-1-propylacetamide (4) 3 -Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-2-propylacetamide (5) 3 - Sul f onylamino -N-me thy 1 aminocarbonyl - 4 -me thoxy-phenyl-N-1-butylacetamide (6) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl -N- 2 -butylace taunide (7) 3-Sulf onylamino-N-me thy laminocarbonyl-4-me thoxy-phenyl-N-1-pentylacetamide (8) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-2-pentylacetamide (9) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-3-pentylacetcunide (10) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-pheny1-N-1-butyl-2-methylacetamide (11) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-phenyl -N-1 -butyl - 3 -me thylacetsunide (12) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-phenyl-N-1-hexylacetamide (13) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-2 -hexylacetcimide (14) 3 -Sulf onylamino-N-methylaminocarbonyl-4-methoxy- phenyl-N-3-hexylacet amide (15) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-heptylacetamide (16) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-heptylacetamide (17) 3-Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-3-heptylacetamide (18) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-oc tylacetamide (19) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-2 -octylacetcunide (2 0) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl -N-1 - adcunantylacet amide (21) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 -methoxy-phenyl-N-2 -adamantylacetamide (22) 3 -Sulf onylamino-N-methylaminocarbonyl-4-me thoxy-phenyl-N-dimethylacetamide (23 ) 3 -Sulf onylamino-N-me thyl aminocarbonyl-4 -methoxy-phenyl-N-methyl-N'-ethylacetamide (24) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-methyl-N'-1-propylacetamide (2 5) 3-Sulf onylamino-N-me thyl aminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-2-propylacetamide (26) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-1-butylacetamide (27) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-2-butylacetamide (2 8) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-diethylacetamide (2 9) 3-Sulfonylamino-N-methylaminocarbonyl-4 -me thoxy-phenyl-N-ethyl-N'-1-propylacetamide (3 0) 3-Sulf onylamino-N-me thylaminocarbonyl-4 -me thoxy-phenyl-N-ethyl-N' -2-propylacetcunide (31) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 - me thoxy-phenylpyrrolidinylacetamide (32) 3-Sulfonylamino-N-methylaminocarbonyl-4 -me thoxy-phenylpiperidylacetamide (33 ) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenylmorpholinoacetamide (34) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-methylpiperazinylacetamide (35) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-4-thiomorpholinylaceteunide (36) 3 -Sulf onylamino-N-methylaininothiocarbonyl-4-inethoxy-phenyl -N-methylacetcunide (37) 3 -Sulfonylcunino-N-methylaminothiocarbonyl-4-inethoxy-phenyl -N- e thylace taunide (38) 3 - Sul f onylamino-N-me thyletminothiocarbonyl - 4 -methoxy-phenyl-N-1-propylacetamide (39) 3 -Sulf onylamino-N-inethylaminothiocarbonyl-4-methoxy-phenyl-N-2-propylacetamide (40) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-butylacetamide (41) 3 -Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-butylacetamide (42) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-pentylacetamide (43) 3 - Sul fony lamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-2-pentylacetamide (44) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-3-pentylacetamide (45) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-butyl-2-methylacetamide (46) 3 - Sul fony lamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-butyl-3-methylacetamide (47) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-pheny1-N-1-hexylace tamide (48) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-2-hexylacetamide (49) 3 - Sul f onylamino-N-methyleuninothiocarbonyl - 4 -methoxy-phenyl-N-3-hexylacetamide (50) 3 - Sulf onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-1-heptylacetamide (51) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-2-heptylacetamide (52) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl -N- 3 -heptylaceteunide (53) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-octylacetamide (54) 3 - Sul f onylamino-N-methylaminothiocarbonyl -4 -methoxy-phenyl-N-2-octylacetainide (55) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -methoxy-pheny1-N-1-adamantylacetamide (56) 3 -Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2 -adamantylacetamide (57) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -methoxy-phenyl-N-dimethylacetamide (58) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-ethylacetamide (59) 3-Sulf onylamino-N-me thylaminothiocarbonyl-4-me thoxy-phenyl-N-methyl-N'-1-propylacetamide (60) 3-Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl -N-me thyl -N'-2-propylacetamide (61) 3 - Sul f onylamino-N-methyleiminothiocarbonyl -4 -methoxy-phenyl-N-methyl-N'-1-butylacetamide (62) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylacetamide (63) 3 - Sul fonylamino -N-methylaminothiocarbonyl - 4 -me thoxy-phenyl-N-diethylacetamide (64) 3 - Sul fonylamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-ethyl-N'-1-propylacetamide (65) 3 - Sul fonylamino -N-me thylaminothiocarbonyl -4 -me thoxy-phenyl-N-ethyl-N'-2-propylacetamide (66) 3 - Sul fonylamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenylpyrrolidinylacetamide (67) 3 - Sul f onylamino-N-methylaminothiocarbonyl -4 -me thoxy-phenylpiperidylacetamide (68) 3 - Sul f onylcutiino -N-methylaminothiocarbonyl -4 -me thoxy-phenylmorpholinoacetamide (69) 3 - Sul f onylamino-N-me thylaminothiocarbonyl -4 -me thoxy-phenyl-N-methyIpiperazinylacetamide (70) 3 - Sulf onylamino-N-methylaminothiocarbonyl -4 -methoxy-phenyl- 4 -thiomorpholinylacetamide (71) 3-Sul fonylamino-N-me thy laminocarbonyl-4-me thoxy- phenyl-N-methyIpropionamide (72) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-N-ethylpropionamide (73) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-1-propylpropionamide (74) 3-Sulf onylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-2-propylpropionamide (75) 3 -Sulf onylamino-N-me thy laminocarbonyl-4-methoxy-phenyl-N-1-butylpropionamide (76) 3 -Sulf onylamino-N-me thylaminocarbonyl-4-methoxy-phenyl-N-2-butylpropionamide (77) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-pentylpropionamide (78) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-pentylpropionamide (79) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl-N-3-pentylpropionamide (80) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 - methoxy-phenyl-N-1-butyl-2-methylpropionamide (81) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl-N-1-butyl-3-methylpropionamide (82) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl -N-1 -hexylpropioneunide (83) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-hexylpropionamide (84) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-3-hexylpropionamide (85) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-heptylpropionamide (86) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 - methoxy-phenyl -N- 2 -heptylpropioncunide (87) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl -N- 3 -heptylpropioncunide (88) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-octylpropionamide (89) 3-Sulf onylamino-N-me thylaminocarbonyl-4-methoxy-phenyl-N-2-octylpropionamide (90) 3-Sulfonylamino-N-methylaminocarbonyl-4 - methoxy-phenyl -N-1 -adamantylpropionsunide (91) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-N-2-adamantylpropionamide (92) 3-Sulf onylamino-N-methylaIninocarbonyl-4-methoxy-phenyl-N-ciimethylpropionamide (93) 3-Sulfonylamino-N-niethylaininocarbonyl-4-methoxy-phenyl-N-methyl-N'-ethylpropionamide (94) 3-Sulfonylainino-N-methylaininocarbonyl-4-inethoxy-phenyl-N-methyl-N'-1-propylpropionamide (95) 3-Sulfonylamino-N-inethylaininocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-propylpropionamide (96) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-methyl-N'-1-butylpropionamide (97) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylpropionamide (98) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-diethylpropionamide (99) 3 -Sulf onylamino-N-me thyl aminocarbonyl-4 -methoxy-phenyl-N-ethyl-N'-1-propylpropionamide (10 0) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-ethyl-N'-2-propylpropionamide (101) 3 -Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylpyrrolidinylpropionamide (102) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylpiperidylpropionamide (103) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylmorpholinopropionamide (104) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy- phenyl-N-methyIpiperazinylpropionamide (10 5) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-4-thiomorpholinylpropionamide (106) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methylpropionamide (107) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-ethylpropionamide (108) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-propylpropionamide (109) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-propylpropionamide (110) 3-Sulfonylamino-N-methylaininothiocarbonyl-4-methoxy-phenyl-N-1-butylpropionamide (111) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-butylpropionamide (112) 3-Sulf onylaInino-N-methylaIninothiocarbonyl-4-me thoxy-phenyl -N-1-pentylpropionamide (113) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-pentylpropionamide (114) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N- 3 -pentylpropioneunide (115) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N-1-butyl-2-methylpropionamide (116) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-butyl-3-methylpropionamide (117 ) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-1-hexylpropionamide (118) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-2-hexylpropioneunide (119) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N- 3 -hexylpropioneunide (12 0) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-1-heptylpropionamide (121) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-heptylpropionamide (12 2) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-3-heptylpropionamide (123) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-octylpropionamide (12 4) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-octylpropionamide (125) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-adamantylpropionamide (12 6 ) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-2-adamantylpropionamide (12 7) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-dimethyIpropionamide (12 8) 3 -Sulfonylamino-N-methylaminothiocarbonyl- 4 -methoxy-phenyl-N-methyl-N'-ethyIpropionamide (129) 3-Sulfonylamino-N-methylaininothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-1-propylpropionamide (13 0) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-methyl-N' -2-propylpropioncunide (131) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-1-butylpropionamide (132) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylpropionamide (13 3) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-diethylpropionamide (13 4) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-ethyl-N'-1-propylpropionamide (13 5) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-ethy1-N'-2-propylpropionamide (13 6) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenylpyrrolidinylpropionsunide (13 7) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenylpiperidylpropionamide (13 8) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenylmorpholinopropionamide (139) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methylpiperazinylpropionamide (140) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-4-thiomorpholinylpropionamide (141) 3 - Sulf onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-methylacetamide (142) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethylacetamide (143) 3-Sulf onylamino-N-me thylaminothiocarbonyl-4-methyl-phenyl-N-1-propylacetamide (144) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-2-propylacetamide (145) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-butylacetamide (146) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N- 2 -butylaceteunide (147) 3 - Sulf onylamino-N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-pentylacetamide (lb) 3-Sulfonylainino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-pentylacetamide (149) 3-Sulfonylainino-N-inethylaininothiocarbonyl-4-inethyl-phenyl-N-3-pentylacetamide (150) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-inethyl-phenyl-N-1-butyl-2-methylacetamide (151) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-butyl-3-methylacetamide (152) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-hexylacetamide (153) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-hexylacetamide (154) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-3-hexylacetamide (155) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-heptylacetamide (156) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-heptylacetamide (157) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-3-heptylacetamide (158) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-1 -oc tylaceteunide (159) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-octylacetamide (160) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-1 - adeunantylace tamide (161) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2 -adamantylacetamide (162) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-dimethylacetamide (163) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-ethylacetamide (164) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-propylacetamide (165) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-2-propylacetamide (166) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-butylacetamide (167) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methy1-N'-2-butylacetamide (16 8) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methyl-phenyl-N-diethylacetamide (169) 3-Sulfonylamino-N-methylaininothiQcarbonyl-4-niethyl-phenyl-N-ethyl-N' -1-propylaceteunide (17 0) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-2-propylacetamide (171) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenylpyrrolidinylacetamide (172) 3-Sul f onylamino-N-me thylcuninothiocarbonyl-4-methyl-phenylpiperidylacetamide (173) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenylmorpholinoacetamide (174) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-me thyIpiperazinylacetcunide (175) 3 - Sulf onylamino-N-me thylaminothiocarbonyl - 4 -methyl -phenyl-4-thiomorpholinylacetamide (176) 3 - Sul f onylamino -N-me thylcunino thiocarbonyl - 4 -methyl -phenyl-N-methylpropionamide (177) 3-Sulf onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-ethylpropionamide (178) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-propylpropionamide (179) 3 - Sulf onylamino-N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-2-propylpropionamide (180) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N- 1-butylpropionamide (181) 3-Sulfonylcunino-N-methylcUiiinothiocarbonyl-4-methyl-phenyl-N-2-butylpropionamide (182) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-pentylpropionamide (183) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-pentylpropionamide (184) 3-Sulf onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-3-pentylpropionamide (185) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-butyl-2-methylpropionamide (186) 3-Sulfonylainino-N-inethylaininothiocarbonyl-4-methyl-phenyl-N-1-butyl- 3-methylpropionamide (187) 3-Sulfonylcimino-N-inethylaminothiocarbonyl-4-methyl-phenyl-N-1-hexylpropionamide (188) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-2-hexylpropioneunide (189) 3-Sul fonyleimino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-3-hexylpropionsunide (190) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-heptylpropionamide (191) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-heptylpropionamide (192) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl -N- 3 -heptylpropioncimide (193) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-oc tyIpropionamide (194) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-2-octyIpropionamide (195) 3-Sul fonylcunino-N-me thylcimino thiocarbonyl-4-methyl-phenyl-N-1-adamantylpropionamide (196) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-adamantylpropionamide (197) 3-Sul fonylcunino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-dimethylpropionamide (198) 3-Sul fonylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-methyl-N' -ethylpropioncunide (199) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-methyl -N' -1 -propylpropionaunide (200) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-methyl-N'-2-propyIpropionamide (201) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-butylpropionamide (202) 3 - Sul fonylamino-N-me thylcunino thiocarbonyl - 4 -methyl -phenyl-N-methyl-N'-2-butyIpropionamide (203) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-diethylpropionamide (204) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-1-propylpropionamide (205) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-2-propylpropionamide (206) 3-Sul fonylcunino-N-me thylamino thiocarbonyl-4-methyl-phenylpyrrolidinylpropionamide (207) 3-Sulfonylamino-N-methylcuninothiocarbonyl-4-methyl-phenylpiperidylpropionamide (208) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyImorpho1inopropi onami de (209) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyIpiperazinylpropionamide (210) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-4 -thiomorpholinylpropionamide Preparation of the starting materials Preparation of 3-sulfonylaminophenylcarboxylic acids The 4-substituted phenylcarboxylic acids are added in portions with stirring to an excess of chlorosulfonic acid. The mixture is stirred for 30 minutes at room temperature, then poured onto ice and the resulting sulfonyl chloride is filtered off with suction. The latter is dissolved in ammonia solution, stirred at room temperature for 3 0 minutes, and the solution is neutralized using 2N hydrochloric acid. The product obtained is filtered off with suction. Prepared according to this method: 3-Sulfonylamino-4-methoxyphenylacetic acid M.p. 164°C 3 -Sulfonylamino- 4-methoxyphenyl-3-propionic acid M.p. 172-176°C r 5 g of 3-sulfonyleunino-4-methoxyphenylacetic acid are dissolved in 3 ml of DMF and stirred at 40°C for 30 minutes with 245 mg of sodixom hydroxide. 328 mg of methyl isothiocyanate are added thereto and the mixture is stirred for a further 2 h at 70°C. 2N hydrochloric acid is added to the cooled solution and the product is filtered off with suction. M.p. 174°C. The following was prepared by an analogous procedure: 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 - ethoxyphenyl -acetic acid M.p. 152-154°C 500 mg of 3-sulfonylainino-4-methoxyphenyl-N-cyclohexyl-propionamide are dissolved in 10 ml of DMF, treated with 88 mg of NaOH and stirred at 40'C for 30 min. 107 mg of methyl isothiocyanate are then added and the mixture is stirred at 70°C for a further 2 h. After cooling and neutralizing with 2N hydrochloric acid, the product is filtered off with suction and dried. M.p. 163°C. Analogously, 360 mg of 3-sulfonylamino-N-methylamino-thiocarbonyl-4-methoxyphenyl-N-cyclohexylacetamide are prepared from 500 mg of 3-sulfonylamino-4-methoxyphenyl-N-cyclohexylacetamide. M.p. 185°C. 400 mg of 3-sulfonylamino-N-inethylaininothiocarbonyl-4-methoxypheny lace tic acid are dissolved in 5 ml of THF and treated with 224 mg of carbonyldiimidazole. The mixture is stirred at room temperature for 2 h. After the addition of 120 mg of 3-aminopentane, it is stirred overnight at room temperature. The amount of solvent is reduced in vacuo and the residue is added to 2N HCl. The solid is filtered off with suction. M.p. 169°C. Analogously to Exsunple 3, 3-sulfonylamino-N-methylamino-thiocarbonyl-4-methoxyphenyl-N-(R)-1-cyclohexyl-l-ethyl-acetamide is obtained from 300 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenylacetic acid and 144 mg of (R)-1-cyclohexyl-l-ethylamine. M.p. 84°C. Example 5: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-(S)-1-cyclohexyl-l-ethylacetamide Analogously to Example 3, 3-sulfonylamino-N-methylcunino-thiocarbonyl-4-methoxyphenyl-N-(S)-1-cyclohexyl-l-ethyl-acetamide is obtained from 3 00 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenylacetic acid and 144 mg of (S)-1-cyclohexyl-l-ethylamine. M.p. 84°C. Example 6: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-l-butylacetamide Analogously to Excunple 3, the product is obtained from 300 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxypheny lace tic acid and 83 mg of butyleunine. M.p. 136°C. Example 7: 3-Sulf onylamino-N-methylciminothiocarbonyl-4-methoxyphenyl-N-isopropylpropionamide Example 8: 3-Sulfonylainino-N-methylaniinothiocarbonyl-4-methoxyphenyl-N-isopropylpropionamide Example 9: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-pentylacetamide Example 10: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-isopropylacetamide Example 11: 3-Sulfonylamino-N-methylciminothiocarbonyl-4-methoxyphenyl-N-2-(R)-butylacetamide Example 12: 3-Sulfonylamino-N-inethylaniinothiocarbonyl-4-methoxyphenyl-N-2-(S)-butylacetamide Example 13: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-4-heptylacetamide Example 14: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-6-methyl-2 -heptylacetamide Example 15: 3-Sulfonylamino-N-niethylaminothiocarbonyl-4-methoxyphenyl-N-2-undecylacetamide Example 16: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-hexylacetamide Example 17: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3 , 3-dimethyl-2-butylacetcunide Example 18: 3-Sulfonyl£unino-N-methylaininothiocarbonyl-4-methoxyphenyl-N-2- (S) -heptylaceteunide Example 19: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-(R)-heptylacetamide Example 20: 3-Sulfonylcunino-N-methylaminothiocarboIlyl-4-methoxyphenyl-N-2-octylacetamide Example 21: 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methoxyphenyl-N-6-2-methylheptan-2-ole-acetamide Example 22: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-(S)-pentylacetamide Example 23: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-4-heptylacetamide Excunple 24: 3-Sulfonylainino-N-methylajninothiocarbonyl-4-ethoxyphenyl-N-(S)-1-cyclohexylethylacetamide Example 25: 3-Sulfonylamino-N-Inethylaminothiocarbonyl-4-e thoxyphenyl -N- 6-methyl-2-heptylacetamide Example 26: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-2 - (S)-heptylacetamide Example 27: 3-Sulfonylaniino-N-methylcUiiinocarbonyl-4-ethoxyphenyl-N-2-(S)-heptylacetamide Excimple 28: 3-SulfonylaInino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-2 -octylacetamide Example 29: 3-Sulfonylamino-N-methylaminothiocarboiiyl-4-ethoxyphenyl-N-1-adamantylacetamide Example 30: 3-Sulfonylainino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-n-heptylacetamide Excunple 31: 3-Sulfonylcimino-N-methyleuiiinothiocarbonyl-4-methoxyphenyl-N-n-octylacetcunide Example 32: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-n-nonylacetamide Example 33: 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxyphenyl-N-2-(S)-heptylacetamide Example 34: 3-Sulfonylamino-N-methylaminocarbonyl-4-me thoxyphenyl -N- 2 -oc tylacetamide Example 35: 1-[3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxyphenyl] -l-cyclopropane-N-2-(S)-heptylcyclo-propane-1-carboxamide Example 36: 3-Sulfonylamino-N-ethylaininothiocarbonyl-4-methoxyphenyl-N-2-octylacetaniide Example 37: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2-octylacetamide Example 38: 3-Sulfonylamino-N-cyclopropylaminothio-carbonyl-4-methoxyphenyl-N-2-octylacetamide Example 39: 3 -Sulfonylamino-N-cyclohexylaminothio-carbonyl-4-methoxyphenyl-N-2-octylacetamide Example 40: 3-Sulfonylamino-N-isopropylaminocarbonyl-4-methoxyphenyl-N-2-octylacetamide Example 41: 3-Sulfonylamino-N-cyclopropylaminocarbonyl-4-methoxyphenyl-N-2-octylacetamide Example 42: 3-Sulf onylaInino-N-ethylaIninocarbonyl-4- methoxyphenyl-N-2 -octylacetamide Example 43: 3-Sulfonylamino-N-methylaminocarbonyl-4-e thoxyphenyl -N- 2 -oc tylacetamide Excimple 44: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2-octylacetamide Example 45: 3-Sulfonylainino-N-inethylaminothiocarbonyl-4-methoxyphenyl-N-4-nonylacetamide Example 46: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3-heptylacetamide Example 47: 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxyphenyl-N-2-nonylacetamide Example 48: 3-Sulfonylaniino-N-ethylaminothiocarbonyl-4-methoxyphenyl-N-2-(S)-heptylacetamide Example 49: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2- (S)-heptylacetamide Example 50: 3 -Sulfonylamino-N-tert-butylaminothio-carbonyl-4-inethoxyphenyl-N-2-octylacetainide M.p.: 126°C Example 51: 3-Sulfonylamino-N-methylaminothiocarbonyl-4- methoxyphenyl-N-2-decylacetamide M.p.: 112°C Example 52: 3-Sulfonylamino-N-cyclopropylaminothio-carbonyl-4-methoxyphenyl-N-2(s)-heptylacetamide Example 53: 3-Sulf onylamino-N-inethylaminothiocarbonyl-4-propoxyphenyl-N-2-(s)-heptylacetamide Example 54: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl -N-4 -nonylacetamide Example 55: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-4-nonyl-2-methylacetamide Example 56: 3-SulfonylaInino-N-methylaminothiocarbonyl-4-methoxyphenyl -N-4 -nonyl - 3 -methylacetaitiide Example 57: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3-octyl-2,2-dimethylacetamide Example 58: 3-Sulfonylcumino-N-methylcuninothiocarbonyl-4-methoxyphenyl-N-3 -octyl-2-methylacetamide Pharmacological data: The therapeutic properties of the compounds I can be revealed using the following models: (1) Action potential duration on the papillary muscle of the guinea-pig: (a) Introduction ATP deficiency states, as are observed during ischemia in the cardiac muscle cell, lead to a reduction of the action potential duration. They count as one of the causes of so-called reentry arrhythmias, which can cause sudden heart death. The opening of ATP-sensitive K channels as a result of the fall of ATP counts as causal here. (b) Method To measure the action potential, a standard micro-electrode technique is employed. For this, guinea-pigs of both sexes are killed 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 irrigated with Ringer solution (0.9% NaCl, 0.048% KCl, 0.024% CaClj, 0.02% NaHC03 and 0.1% glucose) and aerated with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36°C. The muscle is stimulated by means of an electrode using square-wave impulses of 1 V and 1 ms duration and a freqaency of 2 Hz. The action potential is derived and recorded by means of a glass microelectrode inserted intracellularly, which is filled with 3 mM KCl solution. The substances to be tested were added to the Ringer solution in a concentration of 2.2-10' mol per liter. The action potential is amplified using an amplifier from Hugo Sachs and shown on an oscilloscope. The duration of the action potential is determined at a degree of repolarization of 95% (APD95). Action potential reductions are produced either by-addition of a 1 uM-strength solution of the potassium channel opener Hoe 234 (J. Kaiser, H. Gogelein, Naunyn-Schmiedebergs Arch. Pharm. 1991, 343, R 59) or by addi¬tion of 2-deoxyglucose. The action potential-reducing effect of these substances was prevented or reduced by the simultaneous addition of the test substances. Test substances were added to the bath solution as stock solutions in propanediol. The values indicated relate to measurements 30 minutes after addition. Glibenclamide was used in these measurements as a standard. The test concentration in all cases is 2 x 10' M. WE CLAIM: A substituted benzenesulfonylurea or -thiourea of the formula I in which: R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, additionally (C1-C8) chains in which n carbon atoms can be replaced by heteroatoms, e.g. O, N and S (where n = 1-4), F or C1; R(3) is H, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoro-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms 0, NH or S (n = 1, 2, 3 or 4); R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms 0, NH or S (n = 1, 2, 3 or 4); or R(3) and R(4) together form a (CH2)2-8 ring, in which one or more of the CH2 groups can be replaced by hetero-atoms 0, NH, S; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R{5')]; R(5) and R{5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members (CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts. The compound of the formula I as claimed in claim 1, wherein: R{1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is hydrogen, F, C1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoroalkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, a (CH2)2-7 chain in which one or more of the CH2 groups can be replaced by heteroatoms O, NH or S; R(3) and R(4) are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoro-cycloalkyl having 3, 4, 5 or 6 carbon atoms, or a (C1-C10) chain in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) together are (0112)2-8' which one of the CH2 groups can be replaced by a heteroatom O, S or NH; E is oxygen or sulfur; X is oxygen or sulfur; Y is tCR(5)R(5')]; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4 The compound of the formula I as claimed in at least one of claims 1 and 2, wherein: E(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloaklyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is F, C1, alkyl having 1, 2, 3 or 4 carbon-atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or a {CH2)2-7 chain, in which one or more of the CH2 groups can be replaced by heteroatoms 0, S or NH; R(3) and R(4) are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 5, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3,. 4, 5 or 6 carbon atoms, or (CHg)1-10, in which one or more CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) are together {CH2)2-7' in which one of the CH2 groups can be replaced by heteroatoms 0, S or NH; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R(5')]„; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m isl,2,3or4. The compound of the formula I as claimed in at least one of claims 1 to 3, wherein: R{1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3 or 4 carbon atoms; R(2) is methoxy or ethoxy; R(3) and R(4) are identical or different and are hydrogen, alkyl having 4, 5, 6, 7 or 8 carbon atoms, cyclo¬alkyl having 3, 4, 5 or 6 carbon atoms or a (C3-8H7.]7) group, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) together are the (0112)2-8 group, in which one of the CH2 groups can be replaced by heteroatoms O, S or NH; E is sulfur or oxygen; X is oxygen; y is [CR(5)R(5')]n; R(5) and R{5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR{5)R(5')] are identical or different; m is 1 or 2. The compound of the formula I as claimed in at least one of claims 1 to 4, wherein: R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms; R(2) is methoxy or ethoxy; R(3) and R(4) are identical or different and are hydrogen, alkyl having 5, 6, 7 or 8 carbon atoms, cyclo-alkyl having 5 or 6 carbon atoms or a [C5-8H11-.17) group, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4) together are (CH2)5-8, in which one of the CH2 groups can be replaced by heteroatoms 0, S or NH; E is oxygen or sulfur; X is oxygen; Y is [CR{5)R(5')]„; R(5) and R(5') independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR{5)R(5')] are identical or different; m is 1 or 2. The compound of the formula I as claimed in at least one of claims 1 to 5, wherein: R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms; R(2) is methoxy or ethoxy; R(3) is hydrogen; R{4) is alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a 5-811-17 group, in which one or more of the CH2 groups can be replaced by heteroatoms 0, S or NH; E is sulfur or oxygen; X is oxygen; Y is [CR{5)R(5')]n; R(5) and R(5') independently of one another are hydrogen or methyl; where the members [CR(5)R{5')] are identical or different; m is 1 or 2. 57 A process for the preparation of a benzenesulfonylthiourea ib and R(3)R(4)NH by means of a dehydrating agent wherein the dehydrating agent is selected from dicyclohexylcarbodiimide, carbonyldiimidazole and propanephosphoric acid. A medicament comprising an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 6.

Full Text

Substituted benzenesulfonylureas and -thioureas, pro¬cesses for their preparation and use of pharmaceutical preparations based on these compounds, and medicaments containing them
The invention relates to substituted benzenesulfonylureas and -thioureas I

R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, additionally (C1-Cg) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S, (where n = 1-4), F or CI;
R(3) is H, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S (n = 1, 2, 3 or 4);
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4,

5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms, e.g. O, N or S (n = 1, 2, 3 or 4); or R(3) and R(4)
together form a (CH2)2.8 ring, in which one or more of the CH2 groups can be replaced by heteroatoms; R(3) and R(4) can be identical or different; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R(5')]; R(5) and R(5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts.
The term alkyl describes, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. The cycloalkyl radical can additionally carry an alkyl substituent. Halogen substituents which can be employed are the elements fluorine, chlorine, bromine and iodine. Furthermore, compounds having centers of chirality in the alkyl chains Y, R(3) and R(4) can occur. In this case, the invention includes both the individual antipodes per se, and a mixture of the two enantiomers in different proportions, and also the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers.
Similar sulfonylureas are disclosed in German Offen-legungsschrift 1 198 354. The hypoglycemic actions of the sulfonylureas are described therein. A prototype of such hypoglycemic sulfonylureas is glibenclaunide.. which is used therapeutically as an agent for the treatment of

diabetes mellitus and serves in research o.s a much-esteemed tool for the study of so-called ATP-sensitive potassium channels. In addition to its hypoglycemic action, glibenclamide has still other actions, which up to now can still not be employed therapeutically, but which all are attributed to blockade of exactly these ATP-sensitive potassium channels. This includes, in particular, an antifibrillatory action on the heart. In the treatments of ventricular fibrillation or its preliminary stages, however, a simultaneous blood sugar fall would be undesirable or even dangerous, as it can further aggravate the condition of the patient.
It was therefore the object of the present invention to synthesize compounds which have a cardiac action which is equally as good as glibenclamide but do not affect the blood sugar or affect it distinctly less in cardioactive doses or concentrations than glibenclamide.
Suitable experimental animals for the detection of such actions are, for example, mice, rats, guinea-pigs, rabbits, dogs, monkeys or pigs.
The compounds I are used as pharmaceutical active com¬pounds in human and veterinary medicine. They can further be used as intermediates for the production of further pharmaceutical active compounds.
Preferred compounds I are those in which:
R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(2) is hydrogen, F, C1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoroalkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, a (CH2)2.7 chain in which one or more of the CH2 groups can be replaced by heteroatoms O,

NH or S;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or a (C1--C10) chain in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH;
or
R(3) and R(4)
together are (CH2)2-8' which one of the CHj groups can be replaced by a heteroatom 0, S or NH;
E is oxygen or sulfur;
X is oxygen or sulfur;
Y is [CR(5)R(5')]i;
m is 1, 2, 3 or 4; R(5) and R(5')
independently of one another are hydrogen or
alkyl having 1 or 2 carbon atoms;
where the members [CR(5)R(5')] are identical or
different;
and their pharmaceutically tolerable salts.
Particularly preferred compounds of the formula I are
those in which:
R(l) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(2) is F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or a (CH2)2.7 chain, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, or (CH2)i.j0' which one or more CHj groups can be replaced by heteroatoms O, S or NH;

or
R(3) and R(4)
are together (€112)2.7/ in which one of the CHj groups can be replaced by heteroatoms 0, S or NH;
E is oxygen or sulfur;
X is oxygen or sulfur;
Y is [CR(5)R(5')]j„;
R(5) and R(5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts.
Very particularly preferred are those compounds I in
which:
R(l) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3 or 4 carbon atoms;
R(2) is methoxy or ethoxy;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms or a (C3.8H7_;i7) group, in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH;
or
R(3) and R(4)
together are the (0112)2.8 gjoup, in which one of the CH2 groups can be replaced by heteroatoms O, S or NH;
E is sulfur or oxygen;
X is oxygen;
Y is [CR(5)R(5')]jn;
R(5) and R (5')'
independently of one another are hydrogen or
alkyl having 1 or 2 carbon atoms;
where the members [CR(5)R(5')] are identical or
different;

m is 1 or 2; and their pharmaceutically tolerable salts.
Likewise very particularly preferred compounds I are those in which:
R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms;
R(2) is methoxy or ethoxy;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a [Cg.gH-.) group, in which one or more of the CHj groups can be replaced by heteroatoms O, S or NH;
or
R(3) and R{4)
together are (CH2)5.g, in which one of the CHj groups can be replaced by heteroatoms O, S or NH;
E is oxgyen or sulfur;
X is oxygen;
Y is [CR(5)R(5')]i„; R(5) and R(5')
independently of one another are hydrogen or
alkyl having 1 or 2 carbon atoms;
where the members [CR(5)R(5')] are identical or
different;
m is 1 or 2;
and their pharmaceutically tolerable salts.
Additionally very particularly preferred compounds I are
those in which:
R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms;
R(2) is methoxy or ethoxy;
R(3) is hydrogen;
R(4) is alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a (Cg.gH-L-L.-L) group, in which one or more of the CHj

groups can be replaced by heteroatoms 0, S or NH; E is sulfur or oxygen; X is oxygen; Y is [CR(5)R{5')]in; R(5) and R(5')
independently of one another are hydrogen or methyl;
where the members [CR(5)R(5')] are identical or different; m is 1 or 2; and their pharmaceutically tolerable salts.
The compounds I of the present invention are useful pharmaceuticals for the treatment of cardiac arrhythmias of all types of origin and for the prevention of sudden heart death due to arrhythmia and can therefore be used as antiarrhythmics. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias, such as atrial tachycardias, atrial flutters or paroxysmal supraventricular arrhythmias or ventricular arrhythmias, such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardias or the particu¬larly dangerous ventricular fibrillation. They are suitable, in particular, for those cases where arrhythmias are the consequence of a constriction of a coronary vessel, such as occur in angina pectoris or during an acute cardiac infarct or as a chronic con¬sequence of a cardiac infarct. They are therefore particularly suitable in postinfarct patients for the prevention of sudden heart death. Further syndromes where arrhythmias of this type and/or sudden heart death due to arrhythmia play a part are, for example, cardiac insuffi¬ciency or cardiac hypertrophy as a consequence of a chronically increased blood pressure.
Moreover, the compounds I can positively affect a decreased contractility of the heart. This can include a disease-related fall in cardiac contractility, for example in cardiac insufficiency, but also acute cases

such as heart failure in the case of the effects of shock. Likewise, in the case of a heart transplantation, after operation has taken place the heart can resume its operational capacity more rapidly and reliably. The same applies to operations on the heart, which necessitate a temporary stopping of cardiac activity by means of cardioplegic solutions, it being possible to use the compounds both for the protection of the organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the recipient body.
The invention furthermore relates to processes for the preparation of the compounds I. A procedure can thus be used which comprises (a) reacting a sulfonamide of the formula II

in which R(l), R(2), R(3), R(4), X, Y and M have the
meanings indicated in claim 1,
to give the substituted benzenesulfonylurea I a.

Suitable cations M in the salts of the formula III are alkali metal and alkaline earth metal ions. Equivalently to the R(l)-substituted isocyanates IV, R(1)-substituted carbamic acid esters, R(1)-substituted carbamoyl halides or R(l)-substituted ureas can be employed.

can be prepared from an aromatic benzenesulfonamide of the formula II or its salt III with an R(1)-substituted trichloroacetcunide of the formula V

in the presence of a base in an inert solvent according to Synthesis 1987, 734-735 at temperatures from 25°C to 150°C.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, or alternatively alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodivun methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (diglyme), nitriles such as aceto-nitrile, amides such as dimethyIformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoramide, sul¬foxides such as DMSO, sulfones such as sulfolane, hydro¬carbons such as benzene, toluene, xylenes. Furthermore, mixtures of these solvents with one another are also suitable.

(d) A benzenesulfonylurea of the formula I a can be
prepared by a conversion reaction of a benzenesulfonyl-
thiourea of the formula I b. The replacement of the
sulfur atom by an oxygen atom in the appropriately
substituted benzenesulfonylthiourea lb can be carried
out, for example, with the aid of oxides or salts of
heavy metals or also by use of oxidants such as hydrogen
peroxide, sodium peroxide or nitrous acid. Thioureas can
also be desulfurized by treatment with phosgene or
phosphorus pentachloride. The intermediate compounds
obtained are chloroformamidines or carbodiimides, which
are converted into the corresponding substituted benzene-
sulfonylureas la, for example by hydrolysis or addition
of water. During desulfurization, isothioureas behave
like thioureas and can accordingly also be used as
starting substances for these reactions.
(e) A benzenesulfonylurea I a can be prepared by reaction
of an amine of the formula R(1)-NH2 with a benzenesul-
fonyl isocyanate of the formula VII

Likewise, an amine RCD-NHj can be reacted with a benzenesulfonylcarbeunic acid ester, a -carbamoyl halide or a benzenesulfonylurea I a [where R(l) = H] to give a compound I a.
(f) A benzenesulfonyl thiourea I b can be prepared by reaction of an amine of the formula R(1)-NH2 with a benz¬enesulfonyl isothiocyanate of the formula VIII

and R(3)R(4)NH by means of dehydrating agents or activ¬ation by means of carbonyl halides or formation of mixed anhydrides. The dehydrating agents employed can be all compounds suitable for the preparation of amide bonds, such as dicyclohexylcarbodiimide, carbonyldiimidazole or propanephosphoric anhydride. The solvents used are inert

nonprotic solvents such as THF, DMF, diethyl ether, dichloromethane, as well as mixtures of these solvents.
(h) A benzenesulfonylthiourea I b can be prepared from a benzenesulfonylthiourea of the formula X

and R(3)R(4)NH by means of dehydrating agents or activa¬tion by means of carbonyl halides or formation of mixed anhydrides. The dehydrating agents employed can be all compounds suitable for the preparation of amide bonds, such as dicyclohexylcarbodiimide, carbonyldiimidazole or propanephosphoric anhydride. The solvents used are inert nonprotic solvents such as THF, DMF, diethyl ether, dichloromethane, as well as mixtures of these solvents.
The compounds I and their physiologically acceptable salts are useful therapeutics which are suitable not only as antiarrhythmics, but as prophylactics in disorders of the cardiovascular system, cardiac insufficiency, heart transplantation or cerebral vascular disorders in hiomans or mammals (for example monkeys, dogs, mice, rats, rabbits, guinea-pigs and cats).
Physiologically acceptable salts of the compounds I are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14-18 as meaning compounds of the formula XI,

which can be prepared from nontoxic organic and inorganic bases and benzenesulfonylureas I.
Salts are preferred in this context in which M in the formula XI is a sodium, potassiiom, rubidium, calcium or magnesium ion, and also the acid addition products of basic amino acids, such as lysine or arginine.
The starting compounds for the mentioned synthesis processes of the benzenesulfonylureas I are prepared by methods known per se, 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., New York; and also in the patent applications indicated above) , ncimely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but not mentioned here in more detail. If desired, the starting substances can also be formed in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further.
A suitably substituted carboxylic acid of the formula XII can thus be subjected to a halosulfonation according to Scheme 1 and the sulfonamide XIII obtained by subsequent ammonolysis can be reacted with an appropriate amine R(3)R(4)NH after activation of the carboxylic acid group to give the carboxamide of the formula II.

Suitable activation methods are the preparation of the carbonyl chloride or mixed carboxylic anhydrides using formyl halides. In addition, the reagents known for amide bond preparation, such as carbonyldiimidazole, dicyclo-hexylcarbodiimide and propanephosphoric anhydride, can be used.

to give the benzenesulfonylureacarboxylic acids of the formula XIV

The compounds I can have one or more chiral centers. In their preparation they can therefore be obtained as racemates or, if optically active starting substances are used, alternatively in optically active form. If the compounds have two or more chiral centers, they can be obtained in the synthesis as mixtures of racemates from which the individual isomers can be isolated in pure form, for example by recrystallizing from inert solvents. If desired, racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. Diastereomers can thus be formed from the racemates by reaction with an optically active resolving agent. Suitable resolving agents for basic compounds are, for example, optically active acids, such as the R- or R,R- and S- or S,S-forms of tartaric acid, dibenzoyl-tartaric acid, diacetyltartaric acid, camphorsulfonic acids, mandelic acids, malic acid or lactic acid. Carbinols can further be amidated with the aid of chiral acylating reagents, for example R- or S-a-methylbenzyl isocyanates, and then separated. The various forms of the diastereomers can be separated in a known manner, for excunple by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a known manner.
Resolution of enantiomers is further carried out by chromatography on optically active support materials.
The compounds I according to the invention and their physiologically acceptable salts can be used for the production of pharmaceutical preparations. In this I context, they can be brought into a suitable dose form together with at least one solid or liquid excipient or auxiliary on their own or in combination with other

pharmaceuticals having cardiovascular activity, such as calcium antagonists, NO donors or ACE inhibitors. These preparations can be used as pharmaceuticals in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration, for excunple intravenous administration, or topical applications and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin and petroleiom jelly. In particular, tablets, coated tablets, capsules, syrups, juices or drops are used for oral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, are used for rectal administration, and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols such as ethanol or isopropanol, acetonitrile, 1,2-propanediol or their mixtures with one another or with water) or powders are used for topical application. The compounds I can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. In particular for topical application, liposomal prepara¬tions are also suitable, which contain stabilizers and/or wetting agents, emulsifiers, salts and/or auxiliaries such as lubricants, preservatives, salts for affecting the osmotic pressure, buffer substances, colorants and flavorings and/or aromatic substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.
The doses which are necessary for the treatment of cardiac arrhythmias with the compounds I depend on whether the therapy is acute or prophylactic. Normally, a dose range of approximately at least 0.1 mg, preferably at least 1 mg, up to at most 100 mg, preferably up to at most 10 mg, per kg per day is adequate if prophylaxis is conducted. The dose can in this case be divided as an

oral or parenteral individual dose or else in up to four individual doses. If acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration can be advantageous. A preferred dose range in critical situations can then be 10 to 100 mg and be administered, for example, as an intravenous continuous infusion.
According to the invention, in addition to the compounds described in the working examples, the compounds I compiled in the following Table can also be obtained:
(1) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-methylacetamide
(2) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-ethylacetamide
(3) 3 - Sulf onylamino-N-methyl aminocarbonyl-4-me thoxy-phenyl-N-1-propylacetamide
(4) 3 -Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-2-propylacetamide
(5) 3 - Sul f onylamino -N-me thy 1 aminocarbonyl - 4 -me thoxy-phenyl-N-1-butylacetamide
(6) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl -N- 2 -butylace taunide
(7) 3-Sulf onylamino-N-me thy laminocarbonyl-4-me thoxy-phenyl-N-1-pentylacetamide
(8) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-2-pentylacetamide
(9) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-3-pentylacetcunide
(10) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-pheny1-N-1-butyl-2-methylacetamide
(11) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-phenyl -N-1 -butyl - 3 -me thylacetsunide
(12) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 -methoxy-phenyl-N-1-hexylacetamide
(13) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-2 -hexylacetcimide
(14) 3 -Sulf onylamino-N-methylaminocarbonyl-4-methoxy-

phenyl-N-3-hexylacet amide
(15) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-heptylacetamide
(16) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-heptylacetamide
(17) 3-Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-3-heptylacetamide
(18) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-oc tylacetamide
(19) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-2 -octylacetcunide
(2 0) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl -N-1 - adcunantylacet amide
(21) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 -methoxy-phenyl-N-2 -adamantylacetamide
(22) 3 -Sulf onylamino-N-methylaminocarbonyl-4-me thoxy-phenyl-N-dimethylacetamide
(23 ) 3 -Sulf onylamino-N-me thyl aminocarbonyl-4 -methoxy-phenyl-N-methyl-N'-ethylacetamide
(24) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-methyl-N'-1-propylacetamide
(2 5) 3-Sulf onylamino-N-me thyl aminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-2-propylacetamide
(26) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-1-butylacetamide
(27) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-methyl-N'-2-butylacetamide
(2 8) 3-Sulf onylamino-N-me thylaminocarbonyl-4-me thoxy-phenyl-N-diethylacetamide
(2 9) 3-Sulfonylamino-N-methylaminocarbonyl-4 -me thoxy-phenyl-N-ethyl-N'-1-propylacetamide
(3 0) 3-Sulf onylamino-N-me thylaminocarbonyl-4 -me thoxy-phenyl-N-ethyl-N' -2-propylacetcunide
(31) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 - me thoxy-phenylpyrrolidinylacetamide
(32) 3-Sulfonylamino-N-methylaminocarbonyl-4 -me thoxy-phenylpiperidylacetamide
(33 ) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenylmorpholinoacetamide

(34) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-methylpiperazinylacetamide
(35) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-4-thiomorpholinylaceteunide
(36) 3 -Sulf onylamino-N-methylaininothiocarbonyl-4-inethoxy-phenyl -N-methylacetcunide
(37) 3 -Sulfonylcunino-N-methylaminothiocarbonyl-4-inethoxy-phenyl -N- e thylace taunide
(38) 3 - Sul f onylamino-N-me thyletminothiocarbonyl - 4 -methoxy-phenyl-N-1-propylacetamide
(39) 3 -Sulf onylamino-N-inethylaminothiocarbonyl-4-methoxy-phenyl-N-2-propylacetamide
(40) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-butylacetamide
(41) 3 -Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-butylacetamide
(42) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-pentylacetamide
(43) 3 - Sul fony lamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-2-pentylacetamide
(44) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-3-pentylacetamide
(45) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-butyl-2-methylacetamide
(46) 3 - Sul fony lamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-butyl-3-methylacetamide
(47) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-pheny1-N-1-hexylace tamide
(48) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-2-hexylacetamide
(49) 3 - Sul f onylamino-N-methyleuninothiocarbonyl - 4 -methoxy-phenyl-N-3-hexylacetamide
(50) 3 - Sulf onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-1-heptylacetamide
(51) 3 - Sul f onylamino-N-methylaminothiocarbonyl - 4 -methoxy-phenyl-N-2-heptylacetamide
(52) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl -N- 3 -heptylaceteunide

(53) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-1-octylacetamide
(54) 3 - Sul f onylamino-N-methylaminothiocarbonyl -4 -methoxy-phenyl-N-2-octylacetainide
(55) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -methoxy-pheny1-N-1-adamantylacetamide
(56) 3 -Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2 -adamantylacetamide
(57) 3 - Sul f onylamino-N-me thylaminothiocarbonyl - 4 -methoxy-phenyl-N-dimethylacetamide
(58) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-ethylacetamide
(59) 3-Sulf onylamino-N-me thylaminothiocarbonyl-4-me thoxy-phenyl-N-methyl-N'-1-propylacetamide
(60) 3-Sulf onylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl -N-me thyl -N'-2-propylacetamide
(61) 3 - Sul f onylamino-N-methyleiminothiocarbonyl -4 -methoxy-phenyl-N-methyl-N'-1-butylacetamide
(62) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylacetamide
(63) 3 - Sul fonylamino -N-methylaminothiocarbonyl - 4 -me thoxy-phenyl-N-diethylacetamide
(64) 3 - Sul fonylamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenyl-N-ethyl-N'-1-propylacetamide
(65) 3 - Sul fonylamino -N-me thylaminothiocarbonyl -4 -me thoxy-phenyl-N-ethyl-N'-2-propylacetamide
(66) 3 - Sul fonylamino -N-me thylaminothiocarbonyl - 4 -me thoxy-phenylpyrrolidinylacetamide
(67) 3 - Sul f onylamino-N-methylaminothiocarbonyl -4 -me thoxy-phenylpiperidylacetamide
(68) 3 - Sul f onylcutiino -N-methylaminothiocarbonyl -4 -me thoxy-phenylmorpholinoacetamide
(69) 3 - Sul f onylamino-N-me thylaminothiocarbonyl -4 -me thoxy-phenyl-N-methyIpiperazinylacetamide
(70) 3 - Sulf onylamino-N-methylaminothiocarbonyl -4 -methoxy-phenyl- 4 -thiomorpholinylacetamide
(71) 3-Sul fonylamino-N-me thy laminocarbonyl-4-me thoxy-
phenyl-N-methyIpropionamide

(72) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-N-ethylpropionamide
(73) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-1-propylpropionamide
(74) 3-Sulf onylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-2-propylpropionamide
(75) 3 -Sulf onylamino-N-me thy laminocarbonyl-4-methoxy-phenyl-N-1-butylpropionamide
(76) 3 -Sulf onylamino-N-me thylaminocarbonyl-4-methoxy-phenyl-N-2-butylpropionamide
(77) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-pentylpropionamide
(78) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-pentylpropionamide
(79) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl-N-3-pentylpropionamide
(80) 3 -Sulf onylamino-N-me thylaminocarbonyl-4 - methoxy-phenyl-N-1-butyl-2-methylpropionamide
(81) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl-N-1-butyl-3-methylpropionamide
(82) 3 -Sulf onylamino-N-me thy laminocarbonyl-4 - methoxy-phenyl -N-1 -hexylpropioneunide
(83) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-2-hexylpropionamide

(84) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-3-hexylpropionamide
(85) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-heptylpropionamide
(86) 3 -Sulf onylamino-N-methyl aminocarbonyl-4 - methoxy-phenyl -N- 2 -heptylpropioncunide

(87) 3-Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl -N- 3 -heptylpropioncunide
(88) 3 -Sulf onylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-1-octylpropionamide
(89) 3-Sulf onylamino-N-me thylaminocarbonyl-4-methoxy-phenyl-N-2-octylpropionamide
(90) 3-Sulfonylamino-N-methylaminocarbonyl-4 - methoxy-phenyl -N-1 -adamantylpropionsunide

(91) 3-Sulfonylainino-N-methylaininocarbonyl-4-methoxy-phenyl-N-2-adamantylpropionamide
(92) 3-Sulf onylamino-N-methylaIninocarbonyl-4-methoxy-phenyl-N-ciimethylpropionamide
(93) 3-Sulfonylamino-N-niethylaininocarbonyl-4-methoxy-phenyl-N-methyl-N'-ethylpropionamide
(94) 3-Sulfonylainino-N-methylaininocarbonyl-4-inethoxy-phenyl-N-methyl-N'-1-propylpropionamide
(95) 3-Sulfonylamino-N-inethylaininocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-propylpropionamide
(96) 3 -Sulf onylamino-N-methylaminocarbonyl -4 -methoxy-phenyl-N-methyl-N'-1-butylpropionamide
(97) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylpropionamide
(98) 3 -Sulfonylamino-N-methylaminocarbonyl-4 -methoxy-phenyl-N-diethylpropionamide
(99) 3 -Sulf onylamino-N-me thyl aminocarbonyl-4 -methoxy-phenyl-N-ethyl-N'-1-propylpropionamide
(10 0) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-N-ethyl-N'-2-propylpropionamide
(101) 3 -Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylpyrrolidinylpropionamide
(102) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylpiperidylpropionamide
(103) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenylmorpholinopropionamide
(104) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-
phenyl-N-methyIpiperazinylpropionamide
(10 5) 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxy-phenyl-4-thiomorpholinylpropionamide
(106) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methylpropionamide
(107) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-ethylpropionamide
(108) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-propylpropionamide
(109) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-propylpropionamide

(110) 3-Sulfonylamino-N-methylaininothiocarbonyl-4-methoxy-phenyl-N-1-butylpropionamide
(111) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-butylpropionamide
(112) 3-Sulf onylaInino-N-methylaIninothiocarbonyl-4-me thoxy-phenyl -N-1-pentylpropionamide
(113) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-pentylpropionamide
(114) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N- 3 -pentylpropioneunide
(115) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N-1-butyl-2-methylpropionamide
(116) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-butyl-3-methylpropionamide
(117 ) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-1-hexylpropionamide
(118) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-2-hexylpropioneunide
(119) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenyl -N- 3 -hexylpropioneunide
(12 0) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-1-heptylpropionamide
(121) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-heptylpropionamide
(12 2) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-3-heptylpropionamide
(123) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-octylpropionamide
(12 4) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-2-octylpropionamide
(125) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-1-adamantylpropionamide
(12 6 ) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-2-adamantylpropionamide
(12 7) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-dimethyIpropionamide
(12 8) 3 -Sulfonylamino-N-methylaminothiocarbonyl- 4 -methoxy-phenyl-N-methyl-N'-ethyIpropionamide

(129) 3-Sulfonylamino-N-methylaininothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-1-propylpropionamide
(13 0) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-methyl-N' -2-propylpropioncunide
(131) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-1-butylpropionamide
(132) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methyl-N'-2-butylpropionamide
(13 3) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-diethylpropionamide
(13 4) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-ethyl-N'-1-propylpropionamide
(13 5) 3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxy-phenyl-N-ethy1-N'-2-propylpropionamide
(13 6) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-me thoxy-phenylpyrrolidinylpropionsunide
(13 7) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenylpiperidylpropionamide
(13 8) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenylmorpholinopropionamide
(139) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-N-methylpiperazinylpropionamide
(140) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxy-phenyl-4-thiomorpholinylpropionamide

(141) 3 - Sulf onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-methylacetamide
(142) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethylacetamide
(143) 3-Sulf onylamino-N-me thylaminothiocarbonyl-4-methyl-phenyl-N-1-propylacetamide

(144) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-2-propylacetamide
(145) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-butylacetamide
(146) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N- 2 -butylaceteunide
(147) 3 - Sulf onylamino-N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-pentylacetamide

(lb) 3-Sulfonylainino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-pentylacetamide
(149) 3-Sulfonylainino-N-inethylaininothiocarbonyl-4-inethyl-phenyl-N-3-pentylacetamide
(150) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-inethyl-phenyl-N-1-butyl-2-methylacetamide
(151) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-butyl-3-methylacetamide
(152) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-hexylacetamide
(153) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-hexylacetamide
(154) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-3-hexylacetamide
(155) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-heptylacetamide
(156) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-heptylacetamide
(157) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-3-heptylacetamide
(158) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-1 -oc tylaceteunide
(159) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-octylacetamide
(160) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-1 - adeunantylace tamide
(161) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2 -adamantylacetamide
(162) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-dimethylacetamide
(163) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-ethylacetamide
(164) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-propylacetamide
(165) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-2-propylacetamide
(166) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-butylacetamide

(167) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methy1-N'-2-butylacetamide
(16 8) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methyl-phenyl-N-diethylacetamide
(169) 3-Sulfonylamino-N-methylaininothiQcarbonyl-4-niethyl-phenyl-N-ethyl-N' -1-propylaceteunide
(17 0) 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-2-propylacetamide
(171) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenylpyrrolidinylacetamide
(172) 3-Sul f onylamino-N-me thylcuninothiocarbonyl-4-methyl-phenylpiperidylacetamide
(173) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenylmorpholinoacetamide
(174) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-me thyIpiperazinylacetcunide
(175) 3 - Sulf onylamino-N-me thylaminothiocarbonyl - 4 -methyl -phenyl-4-thiomorpholinylacetamide
(176) 3 - Sul f onylamino -N-me thylcunino thiocarbonyl - 4 -methyl -phenyl-N-methylpropionamide
(177) 3-Sulf onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-ethylpropionamide
(178) 3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 -methyl -phenyl-N-1-propylpropionamide
(179) 3 - Sulf onylamino-N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-2-propylpropionamide
(180) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N- 1-butylpropionamide
(181) 3-Sulfonylcunino-N-methylcUiiinothiocarbonyl-4-methyl-phenyl-N-2-butylpropionamide
(182) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-pentylpropionamide
(183) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-pentylpropionamide
(184) 3-Sulf onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-3-pentylpropionamide
(185) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-butyl-2-methylpropionamide

(186) 3-Sulfonylainino-N-inethylaininothiocarbonyl-4-methyl-phenyl-N-1-butyl- 3-methylpropionamide
(187) 3-Sulfonylcimino-N-inethylaminothiocarbonyl-4-methyl-phenyl-N-1-hexylpropionamide
(188) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-2-hexylpropioneunide
(189) 3-Sul fonyleimino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-3-hexylpropionsunide
(190) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-heptylpropionamide
(191) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-heptylpropionamide
(192) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl -N- 3 -heptylpropioncimide
(193) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-1-oc tyIpropionamide
(194) 3-Sul f onylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-2-octyIpropionamide
(195) 3-Sul fonylcunino-N-me thylcimino thiocarbonyl-4-methyl-phenyl-N-1-adamantylpropionamide
(196) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-2-adamantylpropionamide
(197) 3-Sul fonylcunino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-dimethylpropionamide
(198) 3-Sul fonylamino-N-me thylamino thiocarbonyl-4-methyl-phenyl-N-methyl-N' -ethylpropioncunide
(199) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl -N-methyl -N' -1 -propylpropionaunide
(200) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyl-N-methyl-N'-2-propyIpropionamide
(201) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyl-N'-1-butylpropionamide
(202) 3 - Sul fonylamino-N-me thylcunino thiocarbonyl - 4 -methyl -phenyl-N-methyl-N'-2-butyIpropionamide
(203) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-diethylpropionamide
(204) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-1-propylpropionamide

(205) 3 -Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-ethyl-N'-2-propylpropionamide
(206) 3-Sul fonylcunino-N-me thylamino thiocarbonyl-4-methyl-phenylpyrrolidinylpropionamide
(207) 3-Sulfonylamino-N-methylcuninothiocarbonyl-4-methyl-phenylpiperidylpropionamide
(208) 3 - Sul f onylamino -N-me thylamino thiocarbonyl - 4 -methyl -phenyImorpho1inopropi onami de
(209) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-N-methyIpiperazinylpropionamide
(210) 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methyl-phenyl-4 -thiomorpholinylpropionamide
Preparation of the starting materials
Preparation of 3-sulfonylaminophenylcarboxylic acids
The 4-substituted phenylcarboxylic acids are added in portions with stirring to an excess of chlorosulfonic acid. The mixture is stirred for 30 minutes at room temperature, then poured onto ice and the resulting sulfonyl chloride is filtered off with suction. The latter is dissolved in ammonia solution, stirred at room temperature for 3 0 minutes, and the solution is neutralized using 2N hydrochloric acid. The product obtained is filtered off with suction. Prepared according to this method:
3-Sulfonylamino-4-methoxyphenylacetic acid M.p. 164°C
3 -Sulfonylamino- 4-methoxyphenyl-3-propionic acid M.p. 172-176°C

r

5 g of 3-sulfonyleunino-4-methoxyphenylacetic acid are dissolved in 3 ml of DMF and stirred at 40°C for 30 minutes with 245 mg of sodixom hydroxide. 328 mg of methyl isothiocyanate are added thereto and the mixture is stirred for a further 2 h at 70°C. 2N hydrochloric acid is added to the cooled solution and the product is filtered off with suction. M.p. 174°C.
The following was prepared by an analogous procedure:
3 - Sul f onylamino -N-me thylaminothiocarbonyl - 4 - ethoxyphenyl -acetic acid M.p. 152-154°C

500 mg of 3-sulfonylainino-4-methoxyphenyl-N-cyclohexyl-propionamide are dissolved in 10 ml of DMF, treated with 88 mg of NaOH and stirred at 40'C for 30 min. 107 mg of methyl isothiocyanate are then added and the mixture is stirred at 70°C for a further 2 h. After cooling and neutralizing with 2N hydrochloric acid, the product is filtered off with suction and dried. M.p. 163°C.

Analogously, 360 mg of 3-sulfonylamino-N-methylamino-thiocarbonyl-4-methoxyphenyl-N-cyclohexylacetamide are prepared from 500 mg of 3-sulfonylamino-4-methoxyphenyl-N-cyclohexylacetamide. M.p. 185°C.

400 mg of 3-sulfonylamino-N-inethylaininothiocarbonyl-4-methoxypheny lace tic acid are dissolved in 5 ml of THF and treated with 224 mg of carbonyldiimidazole. The mixture is stirred at room temperature for 2 h. After the addition of 120 mg of 3-aminopentane, it is stirred overnight at room temperature. The amount of solvent is reduced in vacuo and the residue is added to 2N HCl. The solid is filtered off with suction. M.p. 169°C.

Analogously to Exsunple 3, 3-sulfonylamino-N-methylamino-thiocarbonyl-4-methoxyphenyl-N-(R)-1-cyclohexyl-l-ethyl-acetamide is obtained from 300 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenylacetic acid and 144 mg of (R)-1-cyclohexyl-l-ethylamine. M.p. 84°C.
Example 5: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-(S)-1-cyclohexyl-l-ethylacetamide

Analogously to Example 3, 3-sulfonylamino-N-methylcunino-thiocarbonyl-4-methoxyphenyl-N-(S)-1-cyclohexyl-l-ethyl-acetamide is obtained from 3 00 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenylacetic acid and 144 mg of (S)-1-cyclohexyl-l-ethylamine. M.p. 84°C.
Example 6: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-l-butylacetamide

Analogously to Excunple 3, the product is obtained from 300 mg of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxypheny lace tic acid and 83 mg of butyleunine. M.p. 136°C.
Example 7: 3-Sulf onylamino-N-methylciminothiocarbonyl-4-methoxyphenyl-N-isopropylpropionamide

Example 8: 3-Sulfonylainino-N-methylaniinothiocarbonyl-4-methoxyphenyl-N-isopropylpropionamide

Example 9: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-pentylacetamide

Example 10: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-isopropylacetamide

Example 11: 3-Sulfonylamino-N-methylciminothiocarbonyl-4-methoxyphenyl-N-2-(R)-butylacetamide

Example 12: 3-Sulfonylamino-N-inethylaniinothiocarbonyl-4-methoxyphenyl-N-2-(S)-butylacetamide

Example 13: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-4-heptylacetamide

Example 14: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-6-methyl-2 -heptylacetamide

Example 15: 3-Sulfonylamino-N-niethylaminothiocarbonyl-4-methoxyphenyl-N-2-undecylacetamide

Example 16: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-hexylacetamide

Example 17: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3 , 3-dimethyl-2-butylacetcunide

Example 18: 3-Sulfonyl£unino-N-methylaininothiocarbonyl-4-methoxyphenyl-N-2- (S) -heptylaceteunide

Example 19: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-(R)-heptylacetamide

Example 20: 3-Sulfonylcunino-N-methylaminothiocarboIlyl-4-methoxyphenyl-N-2-octylacetamide

Example 21: 3-Sulfonylainino-N-methylaininothiocarbonyl-4-methoxyphenyl-N-6-2-methylheptan-2-ole-acetamide

Example 22: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-2-(S)-pentylacetamide

Example 23: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-4-heptylacetamide

Excunple 24: 3-Sulfonylainino-N-methylajninothiocarbonyl-4-ethoxyphenyl-N-(S)-1-cyclohexylethylacetamide

Example 25: 3-Sulfonylamino-N-Inethylaminothiocarbonyl-4-e thoxyphenyl -N- 6-methyl-2-heptylacetamide

Example 26: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-2 - (S)-heptylacetamide

Example 27: 3-Sulfonylaniino-N-methylcUiiinocarbonyl-4-ethoxyphenyl-N-2-(S)-heptylacetamide

Excimple 28: 3-SulfonylaInino-N-methylaminothiocarbonyl-4-ethoxyphenyl-N-2 -octylacetamide

Example 29: 3-Sulfonylamino-N-methylaminothiocarboiiyl-4-ethoxyphenyl-N-1-adamantylacetamide

Example 30: 3-Sulfonylainino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-n-heptylacetamide

Excunple 31: 3-Sulfonylcimino-N-methyleuiiinothiocarbonyl-4-methoxyphenyl-N-n-octylacetcunide

Example 32: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-n-nonylacetamide

Example 33: 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxyphenyl-N-2-(S)-heptylacetamide

Example 34: 3-Sulfonylamino-N-methylaminocarbonyl-4-me thoxyphenyl -N- 2 -oc tylacetamide

Example 35: 1-[3-Sulfonylamino-N-methylaminothiocarbonyl-4 -methoxyphenyl] -l-cyclopropane-N-2-(S)-heptylcyclo-propane-1-carboxamide

Example 36: 3-Sulfonylamino-N-ethylaininothiocarbonyl-4-methoxyphenyl-N-2-octylacetaniide

Example 37: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 38: 3-Sulfonylamino-N-cyclopropylaminothio-carbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 39: 3 -Sulfonylamino-N-cyclohexylaminothio-carbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 40: 3-Sulfonylamino-N-isopropylaminocarbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 41: 3-Sulfonylamino-N-cyclopropylaminocarbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 42: 3-Sulf onylaInino-N-ethylaIninocarbonyl-4-
methoxyphenyl-N-2 -octylacetamide

Example 43: 3-Sulfonylamino-N-methylaminocarbonyl-4-e thoxyphenyl -N- 2 -oc tylacetamide

Excimple 44: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2-octylacetamide

Example 45: 3-Sulfonylainino-N-inethylaminothiocarbonyl-4-methoxyphenyl-N-4-nonylacetamide

Example 46: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3-heptylacetamide

Example 47: 3-Sulfonylamino-N-methylaminocarbonyl-4-methoxyphenyl-N-2-nonylacetamide

Example 48: 3-Sulfonylaniino-N-ethylaminothiocarbonyl-4-methoxyphenyl-N-2-(S)-heptylacetamide

Example 49: 3-Sulfonylamino-N-isopropylaminothiocarbonyl-4-methoxyphenyl-N-2- (S)-heptylacetamide

Example 50: 3 -Sulfonylamino-N-tert-butylaminothio-carbonyl-4-inethoxyphenyl-N-2-octylacetainide

M.p.: 126°C
Example 51: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-
methoxyphenyl-N-2-decylacetamide

M.p.: 112°C
Example 52: 3-Sulfonylamino-N-cyclopropylaminothio-carbonyl-4-methoxyphenyl-N-2(s)-heptylacetamide

Example 53: 3-Sulf onylamino-N-inethylaminothiocarbonyl-4-propoxyphenyl-N-2-(s)-heptylacetamide

Example 54: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl -N-4 -nonylacetamide

Example 55: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-4-nonyl-2-methylacetamide

Example 56: 3-SulfonylaInino-N-methylaminothiocarbonyl-4-methoxyphenyl -N-4 -nonyl - 3 -methylacetaitiide

Example 57: 3-Sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenyl-N-3-octyl-2,2-dimethylacetamide

Example 58: 3-Sulfonylcumino-N-methylcuninothiocarbonyl-4-methoxyphenyl-N-3 -octyl-2-methylacetamide

Pharmacological data:
The therapeutic properties of the compounds I can be revealed using the following models:
(1) Action potential duration on the papillary muscle of the guinea-pig:
(a) Introduction
ATP deficiency states, as are observed during ischemia in the cardiac muscle cell, lead to a reduction of the action potential duration. They count as one of the causes of so-called reentry arrhythmias, which can cause sudden heart death. The opening of ATP-sensitive K channels as a result of the fall of ATP counts as causal here.
(b) Method
To measure the action potential, a standard micro-electrode technique is employed. For this, guinea-pigs of both sexes are killed 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 irrigated with Ringer solution (0.9% NaCl, 0.048% KCl, 0.024% CaClj, 0.02% NaHC03 and 0.1% glucose) and aerated with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36°C. The muscle is stimulated by means of an electrode using square-wave impulses of 1 V and 1 ms duration and a freqaency of 2 Hz. The action potential is derived and recorded by means of a glass microelectrode inserted intracellularly, which is filled with 3 mM KCl solution. The substances to be tested were added to the Ringer solution in a concentration of 2.2-10' mol per liter. The action potential is amplified using an amplifier from Hugo Sachs and shown on an oscilloscope. The duration of the action potential is determined at a degree of repolarization of 95% (APD95).

Action potential reductions are produced either by-addition of a 1 uM-strength solution of the potassium channel opener Hoe 234 (J. Kaiser, H. Gogelein, Naunyn-Schmiedebergs Arch. Pharm. 1991, 343, R 59) or by addi¬tion of 2-deoxyglucose. The action potential-reducing effect of these substances was prevented or reduced by the simultaneous addition of the test substances. Test substances were added to the bath solution as stock solutions in propanediol. The values indicated relate to measurements 30 minutes after addition. Glibenclamide was used in these measurements as a standard. The test concentration in all cases is 2 x 10' M.

WE CLAIM:
A substituted benzenesulfonylurea or -thiourea of the formula I

in which:
R(l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, additionally (C1-C8) chains in which n carbon atoms can be replaced by heteroatoms, e.g. O, N and S (where n = 1-4), F or C1;
R(3) is H, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoro-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms 0, NH or S (n = 1, 2, 3 or 4);
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorocycloalkyl having 3, 4, 5 or 6 carbon atoms, or (C1-C10) chains in which n carbon atoms are replaced by heteroatoms

0, NH or S (n = 1, 2, 3 or 4); or R(3) and R(4)
together form a (CH2)2-8 ring, in which one or more of the CH2 groups can be replaced by hetero-atoms 0, NH, S; E is oxygen or sulfur; X is oxygen or sulfur; Y is [CR(5)R{5')]; R(5) and R{5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members (CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4; and their pharmaceutically tolerable salts.
The compound of the formula I as claimed in claim 1,
wherein:
R{1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(2) is hydrogen, F, C1, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoroalkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1,
2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having
3, 4, 5 or 6 carbon atoms, a (CH2)2-7 chain in which one or more of the CH2 groups can be replaced by heteroatoms O, NH or S;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, fluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluoro-cycloalkyl having 3, 4, 5 or 6 carbon atoms, or a (C1-C10) chain in which one or more of the CH2 groups can be replaced by heteroatoms O, S

or NH; or R(3) and R(4)
together are (0112)2-8' which one of the CH2 groups can be replaced by a heteroatom O, S or NH; E is oxygen or sulfur; X is oxygen or sulfur; Y is tCR(5)R(5')]; R(5) and R(5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m is 1, 2, 3 or 4
The compound of the formula I as claimed in at least one of claims 1 and 2, wherein:
E(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloaklyl having 3, 4, 5, 6 or 7 carbon atoms; R(2) is F, C1, alkyl having 1, 2, 3 or 4 carbon-atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or a {CH2)2-7 chain, in which one or more of the CH2 groups can be replaced by heteroatoms 0, S or NH; R(3) and R(4)
are identical or different and are hydrogen, alkyl having 1, 2, 3, 4, 5, 5, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3,. 4, 5 or 6 carbon atoms, or (CHg)1-10, in which one or more CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4)
are together {CH2)2-7' in which one of the CH2 groups can be replaced by heteroatoms 0, S or NH; E is oxygen or sulfur; X is oxygen or sulfur;

Y is [CR(5)R(5')]„; R(5) and R(5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR(5)R(5')] are identical or different; m isl,2,3or4.
The compound of the formula I as claimed in at least one of claims 1 to 3, wherein:
R{1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cycloalkyl having 3 or 4 carbon atoms; R(2) is methoxy or ethoxy; R(3) and R(4)
are identical or different and are hydrogen, alkyl having 4, 5, 6, 7 or 8 carbon atoms, cyclo¬alkyl having 3, 4, 5 or 6 carbon atoms or a (C3-8H7.]7) group, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH; or R(3) and R(4)
together are the (0112)2-8 group, in which one of the CH2 groups can be replaced by heteroatoms O, S or NH; E is sulfur or oxygen; X is oxygen; y is [CR(5)R(5')]n; R(5) and R{5')
independently of one another are hydrogen or
alkyl having 1 or 2 carbon atoms;
where the members [CR{5)R(5')] are identical or
different;
m is 1 or 2.
The compound of the formula I as claimed in at least one of claims 1 to 4, wherein:
R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms;

R(2) is methoxy or ethoxy;
R(3) and R(4)
are identical or different and are hydrogen, alkyl having 5, 6, 7 or 8 carbon atoms, cyclo-alkyl having 5 or 6 carbon atoms or a [C5-8H11-.17) group, in which one or more of the CH2 groups can be replaced by heteroatoms O, S or NH;
or
R(3) and R(4)
together are (CH2)5-8, in which one of the CH2 groups can be replaced by heteroatoms 0, S or NH;
E is oxygen or sulfur;
X is oxygen;
Y is [CR{5)R(5')]„;
R(5) and R(5')
independently of one another are hydrogen or alkyl having 1 or 2 carbon atoms; where the members [CR{5)R(5')] are identical or different; m is 1 or 2.
The compound of the formula I as claimed in at least
one of claims 1 to 5, wherein:
R(l) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or cycloalkyl having 3 carbon atoms;
R(2) is methoxy or ethoxy;
R(3) is hydrogen;
R{4) is alkyl having 5, 6, 7 or 8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or a 5-811-17 group, in which one or more of the CH2 groups can be replaced by heteroatoms 0, S or NH;
E is sulfur or oxygen;
X is oxygen;
Y is [CR{5)R(5')]n;
R(5) and R(5')
independently of one another are hydrogen or
methyl;
where the members [CR(5)R{5')] are identical or
different;
m is 1 or 2.
57

A process for the preparation of a benzenesulfonylthiourea ib

and R(3)R(4)NH by means of a dehydrating agent wherein the dehydrating agent is selected from dicyclohexylcarbodiimide, carbonyldiimidazole and propanephosphoric acid.
A medicament comprising an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 6.

Documents:

214-mas-1996 abstract duplicate.pdf

214-mas-1996 abstract.pdf

214-mas-1996 claims duplicate.pdf

214-mas-1996 claims.pdf

214-mas-1996 correspondence others.pdf

214-mas-1996 correspondence po.pdf

214-mas-1996 description (complete) duplicate.pdf

214-mas-1996 description (complete).pdf

214-mas-1996 form-19.pdf

214-mas-1996 form-2.pdf

214-mas-1996 form-26.pdf

214-mas-1996 form-4.pdf

214-mas-1996 form-6.pdf

214-mas-1996 others.pdf

214-mas-1996 petition.pdf

214-mas-1996.rtf

« Previous Patent

Next Patent »

Patent Number

224649

Indian Patent Application Number

214/MAS/1996

PG Journal Number

49/2008

Publication Date

05-Dec-2008

Grant Date

21-Oct-2008

Date of Filing

09-Feb-1996

Name of Patentee

HOECHST AKTIENGESELLSCHAFT

Applicant Address

D-65926 FRANKFURT AM MAIN,

Inventors:

#	Inventor's Name	Inventor's Address
1	UWE GERLACH	HEIDECK 30, D-65795 HATTERSHEIM,
2	DIETER MANIA	GOETHESTRASSE 43, D-61462 KONIGSTEIN,
3	HEINRICH ENGLERT	STORMSTRASSE 13, D-65719 HOFHEIM,
4	HEINZ GOGELEIN	ZUM EISKELLER 7, D-60259 FRANKFURT,
5	JOACHIM KAISER	WOOGSTRASSE 29B, D-60431 FRANKFURT,

PCT International Classification Number

CO7C273/02

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	19505398.2	1995-02-17	Germany
2	19522920.7	1995-06-23	Germany