DE19901061A1 - Treatment of dysfunction of autonomous nervous system, especially vagal system of the heart, with benzenesulfonyl(thio)urea derivatives optionally with beta-receptor blocker - Google Patents

Abstract

Benzenesulfonyl(thio)urea derivatives (I) are used for preparing a medicament for the treatment of a dysfunction of the autonomous nervous system. Benzenesulfonyl(thio)urea derivatives of formula (I) and their salts are used for preparing a medicament for the treatment of a dysfunction of the autonomous nervous system. R<1> = H, Me or CF3; R<2> = H, halo, 1-6C alkyl, 1-6C alkoxy, 1-6C alkoxy-(1-4C alkoxy), 1-6C alkoxy-(1-4C alkoxy)-(1-4C alkoxy), 1-6C alkylthio, 1-6C fluoroalkoxy or 1-6C fluoroalkyl; E = O or S; Y' = -(CR<3>2)n; R<3> = H or 1-2C alkyl; n = 1 to 4; X = H, halo or 1-6C alkyl; Z = halo, NO2, 1-4C alkoxy or 1-4C alkyl. Independent claims are included for a product and a pharmaceutical preparation comprising (I).

Description

Substituted benzenesulfonylureas and thioureas of the formula I,

wherein R ¹ , R ² , E, X, Y and Z have the meanings given below, show effects on the autonomic nervous system. The invention relates to the use of the compounds of the formula I in the treatment and prophylaxis of dysfunctions of the autonomic nervous system, in particular vagal dysfunctions, for example in cardiovascular diseases, and the use for the manufacture of medicaments therefor. Furthermore, it relates to the use of compounds of the formula I in combination with beta-receptor blockers and pharmaceutical preparations which contain at least one compound of the formula I and at least one beta-receptor blocker.

Compounds of formula I are from EP-A-612 724 and EP-A-727 416 known, the content of which is part of the present disclosure. There will described that these compounds in particular ATP-sensitive potassium channels inhibit at heart and have a direct antiarrhythmic effect via a Influencing the action potential duration of the heart by direct Effect on the electrical properties of cardiac muscle cells arises. The Because of this property, compounds of the formula I are suitable, for example for the treatment of ventricular fibrillation and other cardiac arrhythmias. Other The pharmacological effects of the compounds of the formula I have not been so far described. Surprisingly, it has now been found that the compounds of the formula I also have an effect on the peripheral and / or the central autonomous Show nervous system. In particular, they affect the vagal and nervous systems show a stimulating effect on the vagal nervous system.

Ideally, there is an optimal one adapted to the respective situation Interplay between the sympathetic (= stimulating) nervous system and the vagal (or parasympathetic) (= dampening) nervous system. in the However, this interaction can be disrupted and a dysfunction of the autonomous nervous system, i.e. an imbalance between the activity of the vagal nervous system and the activity of the sympathetic Nervous system exist. Sympathovagal imbalance is understood in general an overfunction of the sympathetic (= stimulating) Nervous system and / or an underfunction of the vagal (= damping) Nervous system, whereby the two parts of the nervous system are mutually reciprocal can influence. In particular, it is known that an underactive vagal System can lead to an overfunction of the sympathetic system. To Avoid damage to cells or organs of the body excessive biological or biochemical processes caused by too high a Activity of the sympathetic nervous system is therefore stimulated in such Cases tried to balance a sympathovagic imbalance, for example by treating vagal dysfunction or hypofunction the normal vagal one Restore activity.

Examples of diseases in which an elimination of a harmful sympathovagal imbalance by treating vagal dysfunction Organic heart diseases, for example the coronary, are considered Heart disease, heart failure and cardiomyopathies. Health Damage resulting from an imbalance in the autonomic nervous system if the dysfunction affects the heart, for example, are the weakening cardiac strength and fatal cardiac arrhythmias. The importance of autonomic nervous system for sudden cardiac death in heart disease for example by P. J. Schwartz (The ATRAMI prospective study: implications for risk stratification after myocardia) infarction; Cardiac Electrophysiology Review 1998, 2, 38-40) or T. Kinugawa et al. (Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure; At the. J. Physiol. 1995, 37, R310-316) described. Experimental investigations with electrical stimulation of the Cardiac vagus or stimulant analogues of the vagal transmitter acetylcholine, for example carbachol, prove the protective effect of vagal activation against fatal cardiac arrhythmia (see for example E. Vanoli et al., Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction; Circ. Res. 1991, 68 (5), 1471-81).

A sympathovagic imbalance can also result, for example a metabolic disorder such as diabetes mellitus (see for example A. J. Burger et al., Short and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus; At the. J. Cardiol. 1997, 80, 1198-1202). An underfunction of the vagal system can also occur temporarily, for example in the case of a lack of oxygen, for example, the heart leads to a lower distribution of vagal neurotransmitters, such as acetylcholine.

Because of the surprising ability of the compounds of the formula I to remedy a subfunction of the vagal system or to restore normal vagal activity, these compounds offer an efficient way of reducing dysfunctions of the autonomic nervous system and their consequences, such as the disease states mentioned eliminate or prevent. The present invention therefore relates to the use of benzenesulfonyl (thio) ureas of the formula I,

wherein
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ² for hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents hydrogen, halogen or (C ₁ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios, and / or their physiologically tolerable salts for the manufacture of a medicament for the treatment or prophylaxis of a dysfunction of the autonomic nervous system.

Alkyl stands for straight-chain, branched or cyclic saturated hydrocarbon residues. This also applies if the alkyl radical is substituted, for example in fluoroalkyl radicals, or occurs as a substituent on another radical, for example in alkoxy radicals, alkylthio radicals or fluoroalkoxy radicals. Examples of straight-chain and branched alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl. Examples of cyclic alkyl radicals which must have at least three carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cyclic alkyl radicals can additionally carry one or more, for example 1, 2, 3 or 4, (C ₁ -C ₄ ) alkyl radicals and fluoroalkyl radicals, for example methyl groups or trifluoromethyl groups.

Examples of the radical alkoxy (= alkyloxy) bonded via an oxygen atom are Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n- Pentoxy, neopentoxy, isohexoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy or Cyclohexoxy. Examples of the alkylthio radical bonded via a sulfur atom are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert- Butylthio, n-pentylthio, neopentylthio, isohexylthio, cyclopropylthio, cyclobutylthio, Cyclopentylthio or Cyclohexylthio.

Fluoroalkyl stands for an alkyl radical in which one or more hydrogen atoms of the alkyl radical defined above are replaced by fluorine atoms. It can be a or more fluorine atoms, for example 1, 2, 3, 4, 5, 6 or 7, in one Fluoroalkyl radical may be included. A maximum of all hydrogen atoms can be exchanged be, that is, perfluorine substitution. Examples of fluoroalkyl are trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl. Fluoroalkoxy stands for one as above defined alkoxy radical, in which, as explained above, one or more Hydrogen atoms are replaced by fluorine atoms.

For all alkyl groups in the alkoxy radicals bonded via an oxygen atom The above definitions and explanations apply to alkoxy- and alkoxy-alkoxy-alkoxy independently of each other. In the double-bound contained in these groups Alkyl groups can be the two free bonds through which these groups join the neighboring groups are bound to be in any position, for example in the 1,1-position of an alkyl radical, in the 1,2-position, in the 1,3-position or 1,4-position. Examples of such divalent radicals are methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, 1,4-butylene or 2,2-dimethyl-1,3-propylene. A preferred one such a divalent radical is 1,2-ethylene. Examples of alkoxy-alkoxy radicals are Methoxy-methoxy, 2-methoxy-ethoxy, 3-methoxy-propoxy, 4-methoxy-butoxy, 6- Methoxy-hexoxy, 2-ethoxy-ethoxy, 2-ethoxy-2-methyl-ethoxy, 3-ethoxy-propoxy, 2-  Isobutoxy-ethoxy, 2-tert-butoxy-ethoxy, 2-cyclopropoxy-ethoxy, 2-cyclopentoxy ethoxy. Examples of alkoxy-alkoxy-alkoxy radicals are 2- (2-methoxy-ethoxy) - methoxy, 2- (2-methoxyethoxy) ethoxy, 2- (2-isopropoxyethoxy) ethoxy, 2- (2-n- Butoxy-ethoxy) -ethoxy, 2- (2-cyclopropyloxy-ethoxy) -ethoxy, 3- (2-methoxy-ethoxy) - propoxy, 2- (2-methoxy-2-methyl-ethoxy) -2-methyl-ethoxy.

Examples of halogen are fluorine, chlorine, bromine and iodine, especially fluorine and Chlorine.

The present invention encompasses all stereoisomeric forms of the compounds of formula I. Asymmetry centers contained in the compounds of formula I to Example in group Y, all can independently of one another the S configuration or have the R configuration. All possible belong to the invention Enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or Diastereomers, in all proportions. So enantiomers are in enantiomerically pure form, both as left-handed and right-handed Antipodes, in the form of racemates and in the form of mixtures of the two The invention relates to enantiomers in all ratios. Are diastereomers both in pure form and in the form of mixtures of diastereomers in arbitrary proportions subject of the invention. Are included in the Example also meso compounds. If there is a cis / trans isomerism, both the cis form as well as the trans form and mixtures of these forms in all Conditions object of the invention. The manufacture of individual If desired, stereoisomers can be resolved by separating a mixture usual methods, for example by chromatography or crystallization or by using stereochemically uniform starting substances in the Synthesis. If necessary, a before a separation of stereoisomers Derivatization done. The separation of a mixture of stereoisomers can occur the stage of the compounds of the formula I or at the stage of a Intermediate in the course of the synthesis. The invention also includes all tautomeric forms of the compounds of formula I.

Physiologically acceptable salts of the compounds of the formula I are in particular pharmaceutically usable salts or non-toxic salts. They can contain inorganic or organic salt components (see also Remington's Pharmaceutical Sciences (AR Gennard, Editor, Mack Publishing Co., Easton PA, 17th edition, page 1418 (1985)). Such salts can be obtained, for example, from compounds of the formula I and not produce toxic inorganic or organic bases, for example suitable alkali metal or alkaline earth metal compounds such as sodium hydroxide or potassium hydroxide, or with ammonia or organic amino compounds or ammonium hydroxides. Reactions of compounds of the formula I with bases for the preparation of the salts are generally carried out in a solvent or diluent in accordance with customary procedures Salts which are advantageous on account of the physiological and chemical stability are in many cases sodium, potassium, magnesium or calcium salts or ammonium salts, in particular sodium salts, a salt formation on the nitrogen atom of the urine substituted by the sulfonyl group group of substances leads to compounds of the formula II,

in which R ¹ , R ² , E, X, Y and Z have the meanings given above and the cation M represents, for example, an alkali metal ion or an equivalent of an alkaline earth metal ion, for example the sodium, potassium, magnesium or calcium ion, or stands for the unsubstituted ammonium ion or for an ammonium ion with one or more organic radicals. An ammonium ion standing for M can, for example, also be the cation obtained from an amino acid, in particular a basic amino acid such as lysine or arginine, by protonation.

The present invention also includes all solvates of compounds of the formula I. and their physiologically acceptable salts, for example hydrates or adducts with alcohols, and derivatives of the compounds of formula I and pro-drugs and active metabolites.

In formula I, R ¹ preferably represents hydrogen or methyl, particularly preferably methyl.

If R ² in formula I is halogen, the rest is preferably chlorine or fluorine. If R ² in formula I is (C ₁ -C ₆ ) alkyl, the rest is preferably (C ₁ - C ₄ ) alkyl, in particular methyl. If R ² in formula I represents (C ₁ -C ₆ ) alkoxy, the remainder preferably represents (C ₁ -C ₄ ) alkoxy, in particular methoxy. If R ² in formula I stands for (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy, the rest preferably stands for (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, especially 2 - ((C ₁ -C ₄ ) alkoxy) ethoxy, especially 2-methoxy-ethoxy. If R ² in formula I is (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, the rest is preferably (C ₁ -C ₄ ) -Alkoxy- (C ₁ -C ₄ ) -alkoxy- (C ₁ -C ₄ ) -alkoxy, especially 2- (2- ((C ₁ -C ₄ ) -alkoxy) -ethoxy) -ethoxy, especially 2- (2-methoxy-ethoxy) ethoxy.

The radicals R ³ are preferably independently of one another hydrogen or methyl, particularly preferably hydrogen. n is preferably 2 or 3. The group Y preferably contains up to four carbon atoms. Y particularly preferably represents the group - (CH ₂ ) _n -, in which n represents 2 or 3, or the group -CHR ³ -CH ₂ -, in which R ^{3 represents} methyl or ethyl and the group -CHR ³ - is bound to the NH group. Y very particularly preferably represents the group -CH ₂ -CH ₂ -.

X preferably represents halogen or (C ₃ -C ₆ ) alkyl.

Z preferably represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl, particularly preferably (C ₁ -C ₄ ) alkoxy.

If the group E in the compounds of the formula I which can be used according to the invention is oxygen, the ureas of the formula Ia are present, if E is sulfur the thioureas of the formula Ib are present.

Preferred compounds of formula I for the use according to the invention are Compounds in which one or more of the radicals have preferred meanings have, with all combinations of preferred meanings the subject of present invention.

Thus, preference is given to using compounds of the formula I in which
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ^{2 represents} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) mercaptoalkyl, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

Particular preference is given to the use of compounds of the formula I in which R ^{1 represents} hydrogen or methyl;
R ² for hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) - alkoxy, (C ₁ - C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) mercaptoalkyl, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ - C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

On the one hand, very particular preference is given to the use of compounds of the formula I in which
R ^{1 represents} hydrogen or methyl;
R ^{2 represents} hydrogen or halogen;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

On the other hand, very particular preference is given to the use of compounds of the formula I in which
R ^{1 represents} hydrogen or methyl;
R ^{2 represents} (C ₁ -C ₆ ) mercaptoalkyl, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

Furthermore, the use of compounds of the formula I in which
R ^{1 represents} hydrogen or methyl;
R ² for (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) - Alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

Preference is furthermore given to the use of compounds of the formula I in which
R ^{1 represents} hydrogen or methyl;
R ^{2 represents} methyl, methoxy or 2-methoxyethoxy;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ^{3 are} all independently of one another hydrogen or methyl and n is 2 or 3;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in all their stereoisomeric forms and mixtures thereof in all ratios and / or their physiologically tolerable salts.

The use of compounds of the formula I in which
R ^{1 represents} methyl;
R ^{2 represents} methyl, methoxy or 2-methoxyethoxy;
E represents sulfur;
Y represents a hydrocarbon radical of the formula - (CH ₂ ) _n -, in which n represents 2 or 3;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy;
in their stereoisomeric old forms and mixtures thereof in all proportions and / or their physiologically acceptable salts.

The compounds of the formula I which can be used according to the invention can for example, by the following methods.

(a) Aromatic sulfonamides of the formula III or their salts of the formula IV can be reacted with R ¹ -substituted isocyanates of the formula V to give substituted benzenesulfonylureas of the formula Ia.

Suitable cations M ¹ in the salts of the formula IV are alkali metal ions, alkaline earth metal ions or ammonium ions such as, for example, tetraalkylammonium ions. Equivalent to the R ¹ -substituted isocyanates of the formula V, R ¹ -substituted carbamic acid esters, R ¹ - substituted carbamic acid halides or R ¹ -substituted ureas can be used.

(b) On the urea group unsubstituted benzenesulfonylureas of the formula Ia, in which R ^{1 is} hydrogen, can be prepared by reacting aromatic benzenesulfonamides of the formula III or their salts of the formula IV with trialkylsilyl isocyanates such as trimethylsilyl isocyanate or with silicon tetraisocyanate and hydrolysis of the primary silicon sulfonyl substituted urethanesol. Compounds of the formula Ia in which R ^{1 is} hydrogen can also be obtained from benzenesulfonamides of the formula III or their salts of the formula IV by reaction with cyanogen halides and hydrolysis of the primary N-cyanosulfonamides with mineral acids at temperatures between 0 ° C. and 100 ° C. be preserved.

(c) Benzenesulfonylureas of the formula Ia can be obtained from aromatic benzenesulfonamides of the formula III or their salts of the formula IV with R ¹ - substituted trichloroacetamides of the formula VI in the presence of a base in an inert solvent according to Synthesis 1987, 734-735 at temperatures between 25 ° Produce C and 150 ° C.

Cl ₃ C-CO-NH-R ¹ (VI)

Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or also alcoholates, such as sodium hydroxide, potassium hydroxide, Calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, Potassium amide, sodium methoxide, sodium ethanolate, potassium methoxide or Potassium ethanolate. Suitable inert solvents are ethers such as tetrahydrofuran, Dioxane, ethylene glycol dimethyl ether (DME), ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as Dimethylformamide (DMF) or N-methylpyrrolidone (NMP), Hexamethylphosphoric acid triamide, sulfoxides such as DMSO, sulfones such as sulfolane, Hydrocarbons such as benzene, toluene, xylenes. Also suitable Mixtures of these solvents with each other.

(d) Benzenesulfonylthioureas of the formula Ib can be prepared from benzenesulfonamides of the formula III and their salts of the formula IV and R ¹ = substituted isothioyanates - of the formula VII.

R ¹ -N = C = S (VII)

Unsubstituted benzenesulfonylthioureas of the formula Ib in which R ^{1 is} hydrogen can be prepared on the urea group by reacting aromatic benzenesulfonamides of the formula II or their salts of the formula III with trialkylsilylisothiocyanates such as trimethylsilylisothiocyanate or with silicon tetraisothiocyanate and hydrolysedilylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl and the hydrolysis of the primary resulting. It is also possible, for the preparation of compounds of the formula Ib in which R ^{1 is} hydrogen, to react aromatic benzenesulfonamides of the formula III or their salts of the formula IV with benzoyl isothiocyanate and then to react the intermediate benzoyl-substituted benzenesulfonylthioureas with aqueous mineral acids. Similar methods are described in J. Med. Chem. 1992, 35, 1137-1144.

(e) Substituted benzenesulfonylureas of the formula Ia can be replaced by Conversion reactions prepared from benzenesulfonylthioureas of the formula Ib will. Desulfurization, that is, the replacement of the sulfur atom by a Oxygen atom in the correspondingly substituted benzenesulfonylthioureas, can for example with the help of oxides or salts of heavy metals or by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid. Thioureas can also go through Treatment with phosgene or phosphorus pentachloride can be desulfurized. As Intermediate compounds are chloroformic acid amidines or carbodiimides obtained, for example, by saponification or accumulation of water in the corresponding substituted benzenesulfonylureas are transferred.

(f) Benzenesulfonylureas of the formula Ia can be prepared from benzenesulfonyl halides of the formula VIII with R ¹ -substituted ureas or R ¹ -substituted bis (trialkylsilyl) ureas. The trialkylsilyl protecting group can be removed from the resulting (trialkylsilyl) benzenesulfonylurea by standard methods. Furthermore, the sulfonic acid chlorides of the formula VIII can be reacted with parabanic acids to give benzenesulfonylparabanic acids, the hydrolysis of which gives the corresponding benzenesulfonylureas of the formula Ia with mineral acids.

(g) Benzenesulfonylureas of the formula Ia can be prepared by reacting amines of the formula R ¹ -NH ₂ with benzenesulfonyl isocyanates of the general formula IX. Likewise, amines of the formula R ¹ -NH ₂ can be reacted with benzenesulfonylcarbamates, carbamides, or benzenesulfonylureas of the formula Ia, in which R ^{1 is} hydrogen, to give compounds of the formula Ia.

(h) Benzenesulfonylthioureas of the formula Ib can be prepared by reacting amines of the formula R ¹ -NH ₂ with benzenesulfonyl isothiocyanates of the formula X. Likewise, amines of the formula R ¹ -NH ₂ can be reacted with benzenesulfonylcarbamic acid thioesters or carbamic acid thiohalides to give compounds of the formula Ib.

(i) Correspondingly substituted benzenesulfenyl or sulfinyl ureas can be used Oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid Oxidize benzenesulfonylureas of the formula Ia.

The starting compounds for the synthesis processes of the compounds mentioned of the formula I can be prepared by methods known per se, such as in the literature (for example in the standard works such as Houben-Weyl, methods Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; as well as in the above Patent applications) are described, under reaction conditions that are known and suitable for the above-mentioned implementations. You can also do that use of variants known per se but not mentioned here in more detail do. If desired, the starting materials can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately further implements.

Thus, appropriately substituted amines of the formula XI can be acylated and subjected to halogen sulfonation. In formula XI, R ² and Y have the meanings given above. Suitable acylating agents for acylating the amino group in the compounds of the formula XI are

Alkyl esters, halides (for example chlorides or bromides) or anhydrides of carboxylic acids of the general formula R ⁴ -COB. R ⁴ stands for example for a trihalomethyl radical, a (C ₁ -C ₄ ) alkyl radical or a phenyl radical. If R ^{4 is} a phenyl radical, the compound of the formula R ⁴ -COB is a benzoic acid derivative. The benzoic acid derivative can be unsubstituted or substituted by one or two identical or different X and Z radicals. X and Z are as defined above, so X can represent hydrogen, (C ₁ -C ₆ ) alkyl or halogen, Z represents halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) - Alkoxy or nitro. Group B is a leaving group such as halogen, (C ₁ -C ₄ ) alkoxy, trihaloacetoxy or (C ₁ -C ₄ ) alkylcarbonyloxy. Examples of compounds of the formula R ⁴ -COB are acetic anhydride, Trihalogenacetanhydrid, acetyl halides, Trihalogenacetylhalogenide, propionyl chloride, Isobutyrylbromid and chloride, formic acid / acetic anhydride, benzoyl chloride and substituted benzoic acid derivatives such as 5-chloro-2-methoxybenzoyl chloride or anhydride, or - (C ₁ - C ₄ ) alkyl ester or 2,5-difluorobenzoic acid chloride. The syntheses of the compound of formula XII are preferably carried out with the addition of a tertiary base such as pyridine or a trialkylamine in the presence or absence of an inert solvent, it being possible for a catalyst such as dimethylaminopyridine to be present. The reaction is generally carried out at temperatures between about 0 ° C. and 160 ° C., preferably between 20 ° C. and 150 ° C. The acyl group in the compound of the formula XII can be both a protective group and, in the case of the benzoic acid derivatives, can be part of the compound of the formula I. Examples of suitable inert solvents for the acylation are ethers such as tetrahydrofuran, dioxane, glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (DME), ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as Ethyl acetate, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, sulfoxides such as DMSO, chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, hydrocarbons such as benzene, toluene, xylenes. Mixtures of these solvents with one another are also suitable. The sulfonamides of the formula XIII can be prepared from the compounds of the formula XII by methods known per se, namely under

Reaction conditions known and suitable for such reactions are. You can also use those that are known per se but not mentioned here in detail Make use of variants. If desired, the syntheses can be two or more steps. In particular, are procedures preferred, in which the acylated amine of formula XII by electrophilic Reagents in the presence or absence of inert solvents Temperatures between -10 ° C to 120 ° C, preferably between 0 ° C and 100 ° C, in aromatic sulfonic acids or their derivatives such as, for example Sulfonic acid halides are transferred. For example, sulfonations with Sulfuric acids or oleum, halogen sulfonation with halogen sulfonic acids, Reactions with sulfuryl halides in the presence of anhydrous Metal halides or with thionyl halides in the presence of anhydrous Metal halides with subsequent, carried out in a known manner, Oxidations to aromatic sulfonic acid chlorides are carried out. are Sulfonic acids are the primary reaction products, so they can either be direct or by treatment with tertiary amines such as pyridine or Trialkylaminen or with alkali or alkaline earth metal hydroxides or reagents these form basic compound in situ, in a known manner by acid halides such as for example phosphorus trihalides, phosphorus pentahalides, Phosphorus oxychlorides, thionyl halides, oxalyl halides, in Sulfonic acid halides are transferred. The transfer of the sulfonic acid derivatives in sulfonamides can be carried out in a manner known from the literature. Preferably the Sulfonic acid chlorides in inert solvents at temperatures between 0 ° C to 100 ° C with aqueous ammonia in the absence or presence of an  implemented organic solvent. You can also use aromatic Sulfonamides from the acylated amines of the Formula XII by reaction with organic alkali metal or alkaline earth metal Reagents in inert solvents and under an inert gas atmosphere Temperatures between -100 ° C and 50 ° C, preferably -100 ° C to 30 ° C and with Sulfur dioxide and subsequent thermal treatment with amidosulfonic acid synthesize.

Acts as a protective group for the acyl group in the compound of formula XIII Amino group, this protective group can be introduced after the introduction of Sulfonamide group can be split off with acids or bases. By splitting with aqueous acids or with acids in inert solvents Acid addition salt of the amino compound arise. For this Deprotection come for example sulfuric acid, Hydrohalic acids such as hydrochloric acid or hydrobromic acid, Phosphoric acids such as orthophosphoric acid or organic acids into consideration. The Cleavage of the amino protecting group in the compound of formula XIII with bases can be done in aqueous or inert solvents. As bases are suitable for Example alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, Potassium hydroxide or calcium hydroxide or alcoholates such as sodium methoxide, Sodium ethanolate; Potassium methoxide or potassium ethanolate: From the so produced sulfonamide-substituted amines or their acid addition compounds can as explained above as the acylation of the compounds of formula XI which Benzenesulfonamides of the formula III can be prepared.

The compounds of formula I can have one or more chiral centers. You can therefore in their manufacture as racemates or, if optically active Starting materials are used, can also be obtained in optically active form. If the compounds have two or more chiral centers, they can be at the synthesis as mixtures of racemates, from which the individual Isomers, for example by recrystallization from inert solvents, in can isolate pure form. Racemates obtained can, if desired, according to known methods mechanically or chemically separated into their enantiomers will. So can from the racemate by reaction with an optically active Release agent diastereomers are formed. As a release agent for basic Compounds are suitable, for example, optically active acids, such as the R- or R, R- and S or S, S forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, Camphorsulfonic acids, mandelic acids, malic acid or lactic acid. For separation can also carbinols using chiral acylation reagents, for example R- or S-α-methylbenzyl isocyanate, acylated and then separated. The different forms of the diastereomers can be prepared in a manner known per se, for example by fractional crystallization, separated and the enantiomers can be released from the diastereomers in a manner known per se will. Enantiomer separation is also achieved by chromatography optically active carrier materials.

Depending on the nature of the radicals R ¹ , R ² , R ³ , E, X, Y and Z, one or the other of the processes mentioned will be unsuitable for the preparation of the compounds of the formula I in individual cases or at least precautions to protect active groups make necessary. Such, relatively rarely occurring cases can easily be recognized by the person skilled in the art, and it is not difficult to successfully use another of the described synthetic routes in such cases. With regard to the preparation of the compounds of the formula I to be used according to the invention, reference is also made to EP-A-612 724 and EP-A-727 416.

The compounds of formula I are inadequate because of their ability Function of the vagal nervous system and therefore a vagal dysfunction and / or to reduce or decrease dysfunction of the autonomic nervous system eliminate valuable agents for the therapy and prophylaxis of diseases that with such subfunctions or dysfunctions of the vagal nervous system are connected or caused by such or for their therapy  or prophylaxis an increase or normalization of vagal activity Nervous system is sought. The effect of the compounds of formula I on the For example, vagal nervous system can be described in the below pharmacological model can be demonstrated on the mouse. The effect can for example also rats, guinea pigs, rabbits, dogs, monkeys or Pigs are detected.

Diseases and pathological conditions in which treatment or Prevention of vaginal nervous system dysfunction or dysfunction of the autonomic nervous system have already been mentioned above. Except generally for the treatment or prophylaxis of a dysfunction of the autonomous Nervous system and especially vagal dysfunction are suitable Compounds of formula I and their physiologically tolerable salts specifically for Use for disorders of the cardiovascular system and for heart diseases Treatment and prophylaxis of a sympathovagal imbalance or for Treatment and prophylaxis of vagal heart dysfunction. In consideration upcoming such heart diseases are coronary artery disease, angina pectoris, heart failure, cardiomyopathies, heart transplant or vagal Heart dysfunction in diabetes mellitus. Because the connections Formula I in addition to its known direct cardiac action, that is, the effect on the action potential of the heart muscle cells also an indirect effect on the Nervous system of the heart or the parts of the heart which act on the heart Nervous system, they can be present at the particular one Condition of disease from the nervous system or through the nervous system reduce or prevent mediated undesirable consequences on the heart. This can cause further health damage such as a weakening of the Cardiac strength or sometimes fatal cardiac arrhythmias such as ventricular fibrillation be reduced or avoided. The compounds of formula I and their Physiologically acceptable salts result in the elimination or reduction the dysfunction of the autonomic nervous system that weakens Heart strength returned to normal and the arrhythmia leading to sudden Can cause cardiac death, can no longer arise. Areas of application of the Compounds of formula I and / or their physiologically tolerable salts in The scope of the present invention is therefore in particular the application for heart failure and the prevention of cardiac arrhythmias such as the deadly ventricular fibrillation and the prevention of sudden cardiac death. By Selection of compounds of formula I with a suitable activity profile with regard to the direct heart effect (= direct effect on the action potential of the Cardiac muscle cells and because of its direct effect on the contraction force and direct antiarrhythmic effect) on the one hand and the effect on the Cardiac nerves, on the other hand, are special with the aid of the compounds of the formula I. efficiently possible to influence heart diseases favorably. Depending on present clinical picture, it can also be advantageous to connect the Use Formula I, which have a relatively low direct cardiac output and thus, for example, only a relatively small direct effect on the Have contraction power of the heart or the emergence of arrhythmias, however about the influence of the autonomic nervous system the heart strength or the Can improve or normalize heart rhythm again. As already mentioned a subfunction of the vagal system with its consequences can also be temporary occur, for example in the absence of oxygen to the heart. The compounds of formula I. are therefore particularly suitable for use in angina pectoris or coronary artery disease where oxygen deficiency occurs.

Compounds of the formula I can moreover generally be used in Dysfunction of the autonomic nervous system, especially a vagal one Dysfunction resulting from a metabolic disorder such as diabetes mellitus occur.

The compounds of formula I and their physiologically tolerable salts can thus on animals, preferably on mammals, and especially on humans as Medicines on their own, in mixtures with each other or together with other active ingredients are used, in particular in the form of pharmaceutical preparations. The present invention therefore relates to Use of compounds of formula I and / or their physiological tolerable salts for the manufacture of a medicament for therapy or Prophylaxis of the above clinical pictures, but is also The invention relates to the use of the compounds of the formula I and their physiologically acceptable for therapy or prophylaxis of the above Clinical pictures.

Medicaments which can be used according to the invention and which contain the compounds of the formula I and / or contain their physiologically tolerated salts can enterally, to Example administered orally or rectally, for example in the form of pills, Tablets, film-coated tablets, coated tablets, granules, hard and soft gelatin capsules, Solutions such as aqueous, alcoholic or oily solutions, juices, drops, Syrups, emulsions or suspensions. Administration can also be parenteral take place, for example subcutaneously, intramuscularly or intravenously in the form of Solutions for injection or infusion. More eligible Application forms are, for example, percutaneous or topical application, for Example in the form of ointments, creams, pastes, lotions, gels, sprays, powders, Foams, aerosols or solutions, or use in the form of Implants.

The production of the pharmaceutical preparations that can be used according to the invention can according to the known standard procedures for the production of pharmaceutical Preparations are made. For this, one or more compounds of the formula I and / or their physiologically acceptable salts together with one or more solid or liquid galenic carriers and / or additives or Auxiliaries and, if desired, in combination with others Active pharmaceutical ingredients with a therapeutic or prophylactic effect in one brought appropriate administration form or dosage form, which then as Medicines can be used in human medicine or veterinary medicine. The pharmaceutical preparations contain a therapeutic or prophylactic effective dose of the compounds of formula I and / or their physiological compatible salts, which are usually 0.5 to 90 percent by weight of pharmaceutical preparation.

Organic or inorganic substances are suitable as carrier substances for enteral (e.g. oral) or parenteral (e.g. intravenous) application or topical applications and with the Active substances do not react undesirably, for example water, vegetable oils, alcohols such as ethanol, isopropanol or benzyl alcohols, 1,2- Propanediol, polyethylene glycols, glycerol tricacetate, gelatin, carbohydrates such as Lactose or starch, magnesium stearate, talc, lanolin petroleum jelly, acetonitrile, Dimethylformamide, dimethylacetamide. Mixtures of two or several carriers are used, for example mixtures of two or more solvents, especially mixtures of one or more organic solvents with water. Can be used as additives or auxiliary substances the pharmaceutical preparations, for example stabilizing and / or wetting agents, Emulsifiers, salts for example to influence the osmotic pressure, Lubricants, preservatives, colors and flavors and / or aromas, Buffer substances included. You can also choose one or more if desired contain other active ingredients, for example one or more vitamins. The Compounds of the formula I and / or their physiologically tolerable salts can also lyophilized and the lyophilizates obtained, for example for the production of Injectables are used. Especially for topical use liposomal preparations are also suitable.

The dosage of the active ingredient of formula I and / or one to be administered physiologically acceptable salts thereof in the use according to the invention depends on the individual case and is as usual for an optimal effect adapt to individual circumstances. So it depends on the type and strength the disease to be treated as well as gender, age, weight and individual responsiveness of the person or animal to be treated, by the  Potency and duration of action of the compounds used, whether acute or is treated chronically or prophylaxis is practiced, or whether, besides Compounds of formula I other active ingredients are administered. In general is a dose range for the treatment of autonomic dysfunction Nervous system in humans from about 0.1 mg to about 100 mg per kg per day Administration to an approximately 75 kg adult to achieve the desired effect appropriate. A dose range of 1 to 10 mg is preferred per kg and day (each mg per kg body weight). The daily dose can be as Single dose or multiple, for example one, two, three or four, single doses can be divided. It can also be administered continuously will. Depending on individual behavior, it may be necessary from the specified daily dose upwards or downwards to deviate. Pharmaceutical preparations usually contain 0.2 to 500 mg, preferably 1 to 200 mg of active ingredient of the formula I and / or its physiological tolerable salts.

In addition to the effect on the autonomic nervous system, was used for the connections Formula I also has a synergistic effect with beta-blockers found, particularly in the treatment and prophylaxis of Heart diseases such as heart failure can be used to advantage kannz is known to improve the application-low dose Betaceptor blockers reduce the symptoms of heart failure by dampening the Sympathicus, while compounds of formula I the disturbed balance between vagal and sympathetic nerves primarily via vagal stimulation produce. As shown in the animal experiment described below, one Combination of compounds of formula I and beta receptor blockers superadditive effect in preventing heart disease or Heart damage and is therefore advantageous, for example, for improvement the symptoms of heart failure or to prevent or reduce Cardiac arrhythmias such as ventricular fibrillation or to prevent the sudden cardiac death. In other words, the connections of the  Formula I, for example, the effect of beta-blockers on the heart significantly improve. The compounds of formula I are therefore very suitable for a combination with beta receptor blockers.

The subject of the present invention is therefore also the treatment and Prevention of autonomic nervous system dysfunction, especially one vagal dysfunction, especially vagal dysfunction of the heart, and more generally the treatment of the heart diseases mentioned above, such as the Heart failure due to one or more compounds of formula I and / or physiologically acceptable salts thereof in combination with one or more Beta receptor blockers and / or physiologically acceptable salts thereof, as well the use of the compounds of formula I and / or their physiological compatible salts for the manufacture of medicines for such Combination treatment. Within the scope of the invention Combination treatment or combination prophylaxis can be the representatives of two classes of active ingredients in the form of a pharmaceutical combination preparation administered, but also in separate form, the latter being the Representatives of the two active substance classes simultaneously, one after the other or in time can be administered in stages. All of these types and suitable ones Products are encompassed by the present invention. Depending on the The circumstances of the individual case may be more favorable to the representatives of the two Active substance classes in the form of a pharmaceutical combination preparation administer in a fixed ratio, or they separated in the form of several, in particular two, pharmaceutical single preparations to administer. In the latter case, the individual preparations can be more suitable Primary packaging and possibly together with one on the Invention instructions for use referring to the use in a common Packaging are located, or the individual preparations may be each together with references to the use according to the invention Instructions for use are located in separate packaging. All of these Products and types of preparations are encompassed by the present invention.  

The present invention also relates in particular to the pharmaceutical combination preparations described, that is to say pharmaceutical preparations which contain one or more compounds of the formula I,

wherein
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ² for hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents hydrogen, halogen or (C ₁ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios, and / or a physiologically acceptable salt thereof, one or more beta receptor blockers and / or a physiologically acceptable salt thereof and a physiologically acceptable carrier.

All of the above apply to these pharmaceutical combination preparations Explanations, for example on carriers, auxiliaries, production, possible forms of application, use in human medicine and Veterinary medicine, treatable diseases, etc. The Beta receptor blockers are an example of the other active ingredients to view, which in addition to the compounds of formula I explained in the above pharmaceutical preparations can be present. Also all explanations above the compounds of formula I apply to those in the pharmaceutical Combinations containing compounds of formula I corresponding to Example the explanations for the individual residues and groups for the preferred compounds of formula I or their salts. Are preferred pharmaceutical preparations containing one or more of the compounds 1 - [[5- [2- (5- Chloro-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea, 1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- (2-methoxyethoxy) phenyl] sulfonyl] - 3-methylthiourea and 1 - [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea and / or a physiological compatible salt thereof in combination with one or more beta receptors Blockers included.

As a suitable combination partner for the invention Combination treatment or combination prophylaxis and for the pharmaceutical combination preparations according to the invention come for example, the following beta-blockers: alprenolol, Oxprenolol, penbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutolol, Metipranolol, propranolol, nadolol, pindolol, mepindolol, carteolol, timolol, sotalol, Carvedilol; Bisoprolol, celiprolol, carazolol, talinolol, - mepindolol, carteolol; Tertatolol, bopindolol. Preferred beta-blockers are propanolol and Carvedilol.

When combining the compounds of formula I with beta-receptor blockers are generally lower to achieve the desired effect Dosages of the compounds of formula I and / or the beta receptor blockers required than only one active ingredient class when using the compounds. A preferred dosage of the compounds of formula I when combined with a Beta receptor blockers range from about 0.3 to about 3 mg per kg per day. The dosage of the beta receptor blockers in the combination depends on the  dosage customary for the individual compound. The is preferred lowest usual dosage for the respective substance and the respective Area of application related. All the above explanations for the dosage of the compounds of formula I as individual active ingredients apply to the invention Combination application accordingly, for example for the necessary adjustment the dosage to the circumstances of the individual case and the division into Single doses.

Because of their effect on the autonomic nervous system, the connections of formula I and its salts other than as active pharmaceutical ingredients in human medicine and veterinary medicine as a scientific tool or as an aid for biochemical studies are used in which such an effect is intended, as well as for diagnostic purposes, for example in the in vitro Diagnostics of cell samples or tissue samples.

The present invention also relates to those which have not yet been described Compounds of the formula I as such and their physiologically tolerable salts, in particular the new substances described in the exemplary embodiments, furthermore their use as active pharmaceutical ingredients and pharmaceutical preparations, such substances and physiologically compatible carriers and optionally contain auxiliaries. The same applies here for the carriers and auxiliary substances the above explanations accordingly.

In addition to the compounds described in the exemplary embodiments, the compounds of the formula I listed in the following table can also be used according to the invention.

(1) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) propyl] -2-methoxyphenyl] sulfonyl] - 3-methylthiourea
(2) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) butyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea
(3) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethoxyphenyl] sulfonyl] -3-methylthiourea
(4) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-propoxyphenyl] sulfonyl] -3-methylthiourea
(5) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethylphenyl] sulfonyl] -3-methylthiourea
(6) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methylphenyl] sulfonyl] -3-methylthiourea
(7) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-isopropylphenyl] sulfonyl] - 3-methylthiourea
(8) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-bromophenyl] sulfonyl] -3-methylthiourea
(9) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-fluorophenyl] sulfonyl] -3-methylthiourea
(10) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-trifluoromethoxyphenyl] sulfonyl] -3-methylthiourea
(11) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methylthiophenyl] sulfonyl] - 3-methylthiourea
(12) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethylthiohenyl] sulfonyl] -3-methylthiourea
(13) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-isopropoxyphenyl] sulfonyl] -3-methylthiourea
(14) 1 - [[5 - [(5-tert-butyl-2-methoxybenzamido) methyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea
(15) 1 - [[5- [2- (5- (1,1-Dimethylpropyl) -2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea
(16) 1 - [[5- [2- (5-sec-butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea
(17) 1 - [[5- [2- (5-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea
(18) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) propyl] -2-methoxyphenyl] sulfonyl] - 3-methylurea
(19) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) butyl] -2-methoxyphenyl] sulfonyl] -3-methylurea
(20) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethoxyphenyl] sulfonyl] -3-methylurea
(21) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-propoxyphenyl] sulfonyl] -3-methylurea
(22) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethylphenyl] sulfonyl] -3-methylurea
(23) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methylphenyl] sulfonyl] -3-methylurea
(24) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-isopropylphenyl] sulfonyl] - 3-methylurea
(25) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-bromophenyl] sulfonyl] -3-methylurea
(26) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-fluorophenyl] sulfonyl] -3-methylurea
(27) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-trifluoromethoxyyphenyl] sulfonyl] -3-methylurea
(28) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methylthiophenyl] sulfonyl] - 3-methylurea
(29) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethylthiohenyl] sulfonyl) -3-methylurea
(30) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-isopropoxyphenyl] sulfonyl] -3-methyl urea
(31) 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) methyl] -2-methoxyphenyl] sulfonyl] - 3-methylurea
(32) 1 - [[5- [2- (5- (1,1-Dimethylpropyl) -2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylurea
(33) 1 - [[5- [2- (5-sec-butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylurea
(34) 1 - [[5- [2- (5-n-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylurea

Examples

example 1

1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea

0.286 g (0.68 mmol) 5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- methoxybenzenesulfonamide were dissolved in 7.5 ml of dimethylformamide and after Add 0.1 g of potassium carbonate with 0.68 ml of a 1 M solution of Methyl isothiocyanate in dimethylformamide was added and the mixture was stirred at 80 ° C. for 2 hours. The cooled reaction mixture was poured onto dilute aqueous hydrochloric acid, the precipitate is suctioned off and air-dried. The product had one Melting point of 201-203 ° C.

Preparation of the starting compound

1.51 g (10.0 mmol) of 2- (4-methoxyphenyl) ethylamine were dissolved in 40 ml of pyridine, with a 4-dimethylaminopyridine spatula tip and then with a solution of 2.15 g (10.5 mmol) of 2-methoxy-5-tert-butylbenzoic acid chloride are added. To complete conversion of 2- (4-methoxyphenyl) ethylamine was the Poured reaction mixture on cold dilute hydrochloric acid, the precipitated Aspirated and dried product. The N- (2- (4-methoxyphenyl) ethyl) -2- was obtained. methoxy-5-tert-butylbenzamide as a colorless oil. The benzamide thus obtained was in cold chlorosulfonic acid entered. After complete implementation of the benzamide the reaction mixture was poured onto ice, suction filtered and the precipitate dissolved in Acetone. This solution was concentrated with excess aqueous Ammonia added and after the exothermic reaction has subsided to a third of the the original volume was concentrated and the precipitate was suction filtered. The 5- [2- (5- tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxybenzenesulfonamide fell in the form of colorless crystals with a melting point of 165-168 ° C.

Example 2

1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylurea

0.252 g (0.5 mmol) 1 - [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea were dissolved in 2.5 ml of 2N sodium hydroxide solution dissolved and mixed with ice cooling with 0.25 ml of 30% hydrogen peroxide. It was stirred for 24 h at room temperature and the solution was added to a mixture of Poured ice water and 2N hydrochloric acid. White air was obtained after air drying Crystals melting at 209-212 ° C.

Example 3

1 - ([5- [2- (5-Isopropyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea

The preparation was carried out analogously to Example 1. White crystals of Melting point 177-179 ° C obtained.

Example 4

1 - [[5- [2- (5-Chloro-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] - 3-methylthiourea

The preparation of the substance is described in EP-A-612 724.

Example 5

1 - [[5- [2- (5-Chloro-2-methoxybenzamido) ethyl] -2- (2-methoxy ethoxy) phenyl] sulfonyl] -3-methylthiourea

The preparation of the substance is described in EP-A-727 416.

Example 6

1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- (2-methoxy ethoxy) phenyl] sulfonyl] -3-methylthiourea

The preparation was carried out analogously to Example 1 using 5- [2- (5-tert-butyl- 2-methoxybenzamido) ethyl] -2- (2-methoxy-ethoxy) benzenesulfonamide. Instead of Potassium carbonate was used as the base in the reaction with methyl isothiocyanate Example 5 sodium hydride used. Melting point: 61 ° C.

Examples of pharmaceutical preparations Example A tablet

Tablets were made by (1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea (Example 4), low substituted Hydroxypropyl cellulose (L-HPC), polyvinyl pyrrolidone (Povidone 25) and Croscarmellose sodium (cross-linked sodium carboxymethyl cellulose) with water were wet granulated and the granulate was passed through a 1-1.5 mm sieve, was mixed with croscarmellose sodium and magnesium stearate and to Tablets was pressed.

Amounts per tablet

Substance of Example 4 600 mg L-HPC 95 mg Povidone 25 15 mg Croscarmellose sodium 60 mg Magnesium stearate 20 mg

Example B Aqueous solution for intravenous application

For the preparation of 10 ml solution containing 10 mg active ingredient per ml 100 mg of the sodium salt of 1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] - 2-methoxyphenyl] sulfonyl] -3-methylthiourea (see Example 4) in 10 ml Isotonic (0.9 percent) sodium chloride solution dissolved.

Pharmacological examinations 1. Effect in vagal dysfunction

The substances were found in the model of chloroform-induced ventricular fibrillation mouse (see J. W. Lawson, Antiarrhythmic activity of some isoquinoline derivatives determined by a rapid screening procedure in the mouse; J. Pharmacol. Exp. Ther. 1968, 160, 22-31). The substance was in a mixture from dimethyl sulfoxide (DMSO) and 10 percent sodium hydrogen carbonate solution dissolved and administered intraperitoneally (i.p.). 30 minutes later the mouse was in stunned a beaker with chloroform. As soon as in deep anesthesia, stop breathing had occurred (toxic anesthetic stage), the animal's chest was opened a pair of scissors and visually inspected the heartbeat. This can be done with see at a glance whether the heart is beating, flickering or standing still. The through Chloroform-induced respiratory arrest leads to absolute anoxia (Lack of oxygen) in connection with a direct stimulating effect of Chloroform on the sympathetic nervous system causes a strong arousal of the Sympathetic, which in turn is linked to that due to lack of oxygen caused a lack of energy in the heart to the deadly rhythm disturbance, the Ventricular fibrillation leads. This toxic chloroform anesthesia resulted in 100% of the untreated mice (control) to ventricular fibrillation. The percentage of Mice with ventricular fibrillation in the individual test groups is in Table 1 specified.

Table 1

Chloroform-induced ventricular fibrillation in the mouse

The results show that the compounds of formula I the occurrence of Significantly reduce ventricular fibrillation. A statement about the mechanism of action  allows the observed influence of atropine, the classic blocker of muscarinic (vagal) receptors of the autonomic nervous system, which have the effect of the vagal Transmitter acetylcholine blocked at the receptor level. Atropine decreased or prevents the protective effect of the compounds of formula I. This Cancellation of the protective effect of the substances by atropine clearly shows for a vagal mechanism of action. A similar protective effect could be achieved through vagal arousal with carbachol, a more stable analogue of the natural vagal transmitter acetylcholins, which are protective was also inhibited by atropine. The cholinesterase inhibitor also mimicked Physostigmine, which slows down the breakdown of acetylcholine, the protective effect of Compounds of formula I according to, an effect that is also canceled by atropine has been.

2. Effect of a combination of compounds of the formula I with beta receptors Blockers

In the same animal model as in the Vagale experiment described above Dysfunction has been shown to be combined with treatment Beta-receptor blockers and compounds of formula I at a favorable leads to a synergistic effect. 10 mg / kg 1 - [[5- [2- (5-chloro-2- methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea Sodium salt (see example 4; dissolved in DMSO / 10 percent. Sodium bicarbonate solution) were treated with 0.3 mg / kg propranolol (dissolved in distilled water), a standard beta blocker combined. It turned out that the combined pretreatment of both substances has a synergistic effect results. The flicker rate was statistically significantly lower than with the individual substances. For comparison, a 10-fold higher dose of 3 mg / kg was used Propranolol used. It was found that 0.3 mg / kg of propranolol combined with 10 mg / kg 1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea sodium salt about the same Result, like 3 mg / kg propranolol or even the effect of a propanolol Dose of 3 mg / kg dose was superior (see Table 2).

Table 2

Synergistic effect of compounds of the formula I and beta-receptor blockers

Claims (23)

1. Use of benzenesulfonyl (thio) ureas of the formula I,
wherein
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ² for hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents hydrogen, halogen or (C ₁ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios, and / or their physiologically tolerable salts for the manufacture of a medicament for the treatment or prophylaxis of a dysfunction of the autonomic nervous system. 2. Use of compounds of formula I in all their stereoisomers. Forms and mixtures thereof in all proportions and / or their physiologically tolerable salts according to claim 1, characterized in that in the formula I
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ^{2 represents} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy; (C ₁ -C ₆ ) mercaptoalkyl, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl. 3. Use of compounds of formula I in all their stereoisomeric forms and mixtures thereof in all proportions and / or of their physiologically tolerable salts according to claims 1 and / or 2, characterized in that in formula I.
R ^{1 represents} hydrogen or methyl;
R ^{2 represents} hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) mercaptoalkyl, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ -C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy. 4. Use of compounds of formula I in all their stereoisomeric forms and mixtures thereof in all ratios and / or of their physiologically tolerable salts according to one or more of claims 1 to 3, characterized in that in formula I.
R ^{1 represents} hydrogen or methyl;
R ² for (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) - Alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ are each independently hydrogen or methyl and n is 1, 2, 3 or 4;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy. 5. Use of compounds of formula I in all their stereoisomeric forms and mixtures thereof in all ratios and / or of their physiologically tolerable salts according to one or more of claims 1 to 4, characterized in that in formula I.
R ^{1 represents} hydrogen or methyl;
R ^{2 represents} methyl, methoxy or 2-methoxyethoxy;
E represents oxygen or sulfur;
Y is a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ^{3 are} all independently of one another hydrogen or methyl and n is 2 or 3;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy. 6. Use of compounds of formula I in all their stereoisomeric forms and mixtures thereof in all ratios and / or of their physiologically tolerable salts according to one or more of claims 1 to 5, characterized in that in formula I
R ^{1 represents} methyl;
R ^{2 represents} methyl, methoxy or 2-methoxyethoxy;
E represents sulfur;
Y represents a hydrocarbon radical of the formula - (CH ₂ ) -, in which n represents 2 or 3;
X represents halogen or (C ₃ -C ₆ ) alkyl;
Z represents (C ₁ -C ₄ ) alkoxy. 7. Use of compounds of formula I according to one or more of the Claims 1 to 6, characterized in that one or more of the Compounds 1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea, 1 - [[5- [2- (5-chloro-2- methoxybenzamido) ethyl] -2- (2-methoxyethoxy) phenyl] sulfonyl] -3- methylthiourea and 1 - [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea and / or its physiological compatible salts are used. 8. Use according to one or more of claims 1 to 7, characterized characterized in that the salt of a compound of formula I is a sodium salt is used. 9. Use of compounds of formula I in all their stereoisomers Forms and mixtures thereof in all proportions and / or theirs physiologically acceptable salts according to one or more of claims 1 to 8 for the manufacture of a medicament to treat vagal dysfunction. 10. Use of compounds of formula I in all their stereoisomers Forms and mixtures thereof in all proportions and / or theirs physiologically acceptable salts according to one or more of claims 1 to 9 for the manufacture of a medicament for the treatment of vagal dysfunction of the heart. 11. Use of compounds of formula I in all their stereoisomers Forms and mixtures thereof in all proportions and / or theirs physiologically acceptable salts according to one or more of claims 1 to 10 for the manufacture of a medicament to treat a vagal  Dysfunction of the heart in coronary artery disease, angina pectoris, Heart failure, cardiomyopathies or diabetes mellitus. 12. Use of compounds of formula I in all their stereoisomers Forms and mixtures thereof in all proportions according to one or more of claims 1 to 11, characterized in that one or more Compounds of the formula and / or their physiologically tolerable salts together with one or more beta-blockers and / or their physiologically acceptable salts are used. 13. Use according to claim 12, characterized in that the or Beta-blockers from the series of compounds Alprenolol, Oxprenolol, Penbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutolol, metipranolol, Propranolol, nadolol, pindolol, mepindolol, carteolol, timolol, sotalol, carvedilol, Bisoprolol, Celiprolol, Carazolol, Talinolol, Mepindolol, Carteolol, Tertatolol and Bopindolol are selected. 14. Pharmaceutical preparation containing one or more compounds of the formula I
wherein
R ^{1 represents} hydrogen, methyl or trifluoromethyl;
R ² for hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -Ce) alkoxy- (C ₁ -C ₄ ) alkoxy- (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) fluoroalkoxy or (C ₁ - C ₆ ) fluoroalkyl;
E represents oxygen or sulfur;
Y represents a hydrocarbon radical of the formula - (CR ³ ₂ ) _n -, in which the radicals R ³ all independently of one another represent hydrogen or (C ₁ -C ₂ ) alkyl and n represents 1, 2, 3 or 4;
X represents hydrogen, halogen or (C ₁ -C ₆ ) alkyl;
Z represents halogen, nitro, (C ₁ -C ₄ ) alkoxy or (C ₁ -C ₄ ) alkyl;
in all their stereoisomeric forms and mixtures thereof in all ratios, and / or their physiologically acceptable salts, one or more beta receptor blockers and / or their physiologically acceptable salts and a physiologically acceptable carrier. 15. Pharmaceutical preparation according to claim 14, characterized in that there is one or more of the compounds 1 - [[5- [2- (5-chloro-2- methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3-methylthiourea, 1 - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- (2-methoxy-ethoxy) phenyl] sulfonyl] -3- methylthiourea and 1 - [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- methoxyphenyl] sulfonyl] -3-methylthiourea and / or its physiological contains compatible salts. 16. Pharmaceutical preparation according to claims 14 and / or 15, characterized characterized in that it contains a sodium salt of a compound of formula I. 17. Pharmaceutical preparation according to one or more of claims 14 to 16, characterized in that there is one or more beta-blockers from the series of compounds alprenolol, oxprenolol, penbutolol, bupranolol, Metoprolol, betaxolol, atenolol, acebutolol, metipranolol, propranolol, nadolol, Pindolol, Mepindolol, Carteolol, Timolol, Sotalol, Carvedilol, Bisoprolol, Celiprolol, Contains Carazolol, Talinolol, Mepindolol, Carteolol, Tertatolol and Bopindolol. 18. Product containing one or more compounds of formula I and / or their physiologically tolerable salts and one or more beta receptors  Blockers and / or their physiologically tolerable salts according to one or several of claims 14 to 17 as a combination preparation for simultaneous separate or graduated use in treatment or prophylaxis of heart disease. 19. 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3- methylthiourea and its physiologically acceptable salts. 20. [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3- methyl urea and its physiologically acceptable salts. 21. 1 - [[5- [2- (5-isopropyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] sulfonyl] -3- methylthiourea and its physiologically acceptable salts. 22. 1 - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- (2-methoxy ethoxy) phenyl] sulfonyl] -3-methylthiourea and its physiologically compatible Salts. 23. Pharmaceutical preparation containing one or more compounds of Claims 19 to 22 and / or their physiologically tolerable salts and one physiologically compatible carrier.