EMPLOYMENT OF BENCENSULFQN1L (TIQ) UREAS FOR THETREATMENT AND PROPHYLAXIS OF SYSTEM DYSFUNCTIONSAUTONOMOUS NERVOUS AND THE EMPLOYMENT OFBENCENSULFONILGGIO.UREAS IN COMBINATION WITH BETA-RECEPTORS BLOCKERSBenzenesulfonylureas and substituted benzenesulfonylthioureas, of the formula I:in which R1, R2, E, XY 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 of vagal dysfunctions, for example in the case of cardiovascular diseases, and their use in preparing medicaments for such treatment and prophylaxis. Also, the invention relates to the use of compounds of formula I, in combination with beta-receptor blockers and pharmaceutical products and preparations comprising at least one compound of formula I and at least one beta-receptor blocker, and novel compounds. The compounds of formula I are known from US-A-5 574 069 (EP-A-612 724) and US-A-5 652 268 (EP-A-727 416), which are incorporated herein by reference and whose contents are part of the present description. In these publications, it is described that the compounds of formula I inhibit ATP-sensitive potassium channels, in particular in the heart, and that they have a direct antiarrhythmic action by influencing the potential duration of action of the heart, which it is the result of the direct effect on the electrical properties of the muscle cells of the heart. Due to this property, the compounds of the formula I are suitable, for example, in treating ventricular fibrillation and other cardiac arrhythmias. Other pharmacological effects of the compounds of formula I have not been described so far. Surprisingly, it has been found that the compounds of the formula I also have an effect on the central peripheral and / or autonomic nervous system. In particular, they have an influence on the vagal nervous system and have a stimulating effect on this vagal nervous system.
In an ideal case, an optimal cooperation, adapted to the particular situation, exists between the sympathetic nervous system (= stimulant) and the vagal (or parasympathetic) nervous system (= depressive). In the case of a disease, however, this cooperation may be disturbed and a dysfunction of the autonomic nervous system may be present, for example an imbalance between the activity of the vagal nervous system and the activity of the sympathetic nervous system. This sympathetic-vagal imbalance is generally understood as an overactivity of the sympathetic nervous system (= stimulant) and / or an irregular function of the vagal (= depressive) nervous system, when the two parts of the nervous system can influence each other mutually. In particular, it is known that an irregular function of the vagal system can result in overactivity of the sympathetic system. To avoid damage to the cells or organs of the body by exceeding biological or biochemical processes, which are stimulated by excessive activity of the sympathetic nervous system, therefore, it is attempted in such cases to balance the sympathetic-vagal imbalance, for example, to re-establish normal vagal activity, treating vagal dysfunction or impaired function. Examples of diseases where the elimination of a sympathetic-vagal imbalance detrimental to the treatment of a vagal dysfunction is appropriate, are the organic diseases of the heart, for example, coronary heart disease, heart failure and cadiomyopathies. Damage to the heart resulting from an imbalance of the autonomic nervous system, when the dysfunction affects the heart, are, for example, weakening of the heart's strength or, sometimes, fatal cardiac arrhythmias. The importance of the autonomic nervous system in sudden cardiac deaths, in cases of heart disease, has been described, for example, by P. J. Schwartz (The prospective ATRAMI study: implications for the risk of stratification after myocardial infarction; Cardiac Electrophysilogy 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, Am. J. Physiol. 1995, 37, R310-316). Experimental investigations with the electrical stimulation of the heart vagus or analogous stimuli of vagal transmitting acetylcholine, for example, carbachol, support the protective effect of vagal activation against fatal cardiac arrhythmias (see, for example, E. Vanoli et al. , Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction, Circ Res. 1991, 68 (5), 1471-81).
However, the sympathetic-vagal imbalance can also occur, for example, as a consequence of a metabolic disorder, for example diabetes mellitus (see, for example, AJ Burger et al., Reproducibility for short and long period of variability of the heart rate in patients with type I diabetes mellitus, for a long time, AM J. Cardiol. 1997, 80, 1198-1202). The disturbed function of the vagal system can also be temporary, for example in cases of oxygen deficit, for example, in the heart, which results in a reduced secretion of vagal neurotransmitters, for example acetylcholine. Due to the surprising ability of the compounds of formula I to correct the impaired function of the vagal system, or to restore normal vagal activity, these compounds offer an efficient possibility of reducing, eliminating or preventing the dysfunctions of the autonomic nervous system and its consequences, such as, for example, the aforementioned diseases. Thus, an object of the present invention is the use of benzenesulfonyl (thio) ureas, of formula I:wherein: R1 is hydrogen, methyl or trifluoromethyl; R 2 is hydrogen, halogen, alkyl- (C 6 -C 6), alkoxy- (Ci- Ce), alkoxy- (C 6 -C 6) -alkoxy- (C 1 -C 4) -, alkoxy- (C 6 -C 6) alkoxy- (C 1 -C 4) -alkoxy- (C 1 -C 4) -, alkyl- (C 6 -C 6) -thio, fluoroalkoxy- (Cx-Cß) or fluoroalkyl- (dC 6); E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or alkyl- (C? ~ C2), and is 1, 2, 3 or 4; X is hydrogen, halogen or alkyl- (Cx-Ce); Z is halogen, nitro, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl; in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable salts, to prepare a medicament for the treatment or prophylaxis of autonomic nervous system dysfunction.
The alkyl is a saturated, straight-chain or branched or cyclic hydrocarbon residue. This also applies if the alkyl residue is substituted, such as, for example, in fluoroalkyl residues, or is present as a substituent in another residue, for example in alkoxy residues, alkylthio residues or fluoroalkoxy residues. Examples of straight or branched chain alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl. Examples of cyclic alkyl residues which, according to their nature, must have at least three carbon atoms, are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cyclic alkyl residues can additionally carry one or more, for example, 1, 2, 3 or 4, (C1-C4) alkyl residues or fluoroalkyl- (Ci-C) residues, for example methyl groups or trifluoromethyl groups. Examples of alkoxy residues (= alkyloxy), which are attached by means of an oxygen atom, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary butoxy, n-pentoxy, neopentoxy, isohexoxy, cyclopropoxy , cyclobutoxy, cyclopentoxy or cyclohexoxi. Examples of alkylthio residues, which are attached by a sulfur atom, are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tertiary butylthio, n-pentylthio, neopentylthio, isohexylthio, chloropropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. Fluoroalkyl is an alkyl residue in which one or more hydrogen atoms of an alkyl residue, which is as defined above, are replaced by fluorine atoms. A fluoroalkyl residue may contain one or more fluorine atoms, for example 1, 2, 3, 4, 5, 6 or 7. At most, all the hydrogen atoms may have been exchanged, ie the perfluoro is present -substitution. Examples of fluoroalkyls are trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl. Fluoroalkoxy is an alkoxy residue, as defined above, in which, as illustrated above, one or more hydrogen atoms are replaced by fluorine atoms. For all the alkyl groups in the alkoxy-alkoxy- and alkoxy-alkoxy-alkoxy- residues, which are linked by means of an oxygen atom, the above definitions and illustrations apply independently of each other. In the divalent alkyl groups contained in these groups, the two free bonds by means of which these groups are bound to the neighboring groups, can be in any position, for example in the 1,1-position of an alkyl residue, in position 1,2, in position 1,3 or in position 1,4. Examples of such divalent residues are methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, 1,4-butylene or 2,2-dimethyl-1,3-propylene. A preferred divalent residue of this type is 1,2-ethylene. Examples of alkoxy alkoxy residues are methoxymethoxy, 2-methoxyethoxy, 3-ethoxypropoxy, 4-methoxybutoxy, 6-ethoxyhexoxy, 2-ethoxyethoxy, 2-ethoxy-2-methylethoxy, 3-ethoxypropoxy, 2-isobutoxyethoxy, -tert-butoxyethoxy, 2-cyclopropoxyethoxy, 2-cyclopentoxyethoxy. Examples of alkoxy alkoxy alkoxy residues are (2-methoxyethoxy) ethoxy, 2- (2-methoxyethoxy) ethoxy, 2- (2-isopropoxyethoxy) ethoxy, 2- (2-n-butoxyethoxy) ethoxy, 2- (2-cyclopropoxyethoxy) ethoxy, 3- (2-methoxyethoxy) propoxy, 2- (2-methoxy-2-methylethoxy) -2-methylethoxy. Examples of halogen are fluorine, chlorine, bromine iodine, in particular fluorine and chlorine. The present invention encompasses all the stereosomeric forms of the compounds of the formula I. The asymmetric centers contained in the compounds of the formula I, for example in the group Y, can each, independently of each other, have the configuration of S or the R configuration. The invention includes all possible enantiomers and diastereomers, and also mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereomers, in all ratios. The invention provides the enantiomers, therefore, in pure enantiomeric form, both levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of two enantiomers in all ratios. The invention supplies the distereomers, both in the pure form and in the form of mixtures of two or more diastereomers, in all ratios in quantity. Meso compounds, for example, are also included if cis / trans isomerism is present, the invention provides both cis and trans forms and mixtures of these forms in all ratios. The individual stereoisomers can be prepared, if desired, by separation of a mixture according to customary methods, for example by chromatography or crystallization, or by the use of stereochemically uniform starting materials in the syntheses. If appropriate, the derivatization can be carried out before the separation of the stereoisomers. A mixture of stereoisomers can be separated in the step of the compounds of the formula I or in the step of an intermediate in the course of the synthesis. The invention also includes all tautomeric forms of the compounds of the formula I. The physiologically acceptable salts of the compounds of the formula I are, in particular, salts that can be used pharmaceutically or non-toxic salts. They may contain components of inorganic or organic salts(see also Remington's Pharmaceutical Sciences (AR Gennaro (Editor), Mack Publishing CO., Easton PA 17th edition, page 1418 (1985).) These salts can be prepared, for example, from compounds of formula I with inorganic or organic bases. suitable, for example, with alkali metal or alkaline earth metal compounds, cutting such as sodium hydroxide or potassium hydroxide, or with ammonium or organic amino compounds or ammonium hydroxides Reactions of the compounds of formula I with bases, for preparing the salts, it is generally carried out according to the customary procedures in a solvent or diluent.The salts which are advantageous due to their physiological and chemical stability are, in many cases, sodium, potassium, magnesium salts or of calcium of the group (thio) urea, which bind to the sulfonyl group, and lead to the compounds of the formula II:wherein, R1, R2, E, X, Y and Z have the meanings given above, and the cation M is, for example, an alkali metal ion or an equivalent of an alkaline earth metal ion, for example, sodium, potassium, magnesium or calcium ions, or is an unsubstituted ammonium ion or an ammonium ion having one or more organic residues. An ammonium ion, which represents M, can be, for example, also the cation obtained by the protonation of an amino acid, in particular a basic amino acid, such as, for example, lysine or arginine. The present invention also includes all the solvates of the compounds of the formula I and their physiologically acceptable salts, for example the hydrates or adducts with alcohols, and also the derivatives of the compounds of the formula I and the active prodrugs and metabolites. In the formula I, R1 is preferably hydrogen or methyl, particularly preferred is methyl. If R2, in formula I, is halogen, the residue is preferably chlorine or fluorine. If R2, in formula I, is alkyl- (C? -C6), the residue is preferably alkyl- (C?C), in particular methyl. If R2, in formula I is alkoxy- (C? -C6), the residue is preferably alkoxy- (C? -C4), in particular methoxy. If R2, in formula I, is alkoxy- (C? C6) -alkoxy- (C1-C4) -, the residue is preferably (C1-C4) alkoxy- (C1-C4) alkoxy-, in particular - ((C 1 -C 4) alkoxy) ethoxy, specifically 2-methoxyethoxy. If R2, in formula I, is alkoxy- (C? -C6) -alkoxy- (C1-C4) -alkoxy- (C1-C4) -, the residue is preferably alkoxy- (C? -C4) -alkoxy- (C1-C4) -alkoxy- (C1-C4) -, in particular 2- (2- ((C1-C4) alkoxy) ethoxy) ethoxy-, specifically 2- (2-methoxyethoxy) ethoxy-. A group of preferred residues R2 is formed by the residues alkyl- (C? -C6), alkoxy- (C? -C6) and alkoxy- (C? -C6) -alkoxy- (C1-C4) -, in particular the alkoxy- (C? -C6) and alkoxy- (C? -C6) -alkoxy- (C1-C4) - residues, specifically methoxy and 2-methoxyethoxy- residues. The residues R3, independently of one another, are preferably hydrogen or methyl, particularly preferred is hydrogen, n is preferably 2 or 3. The group Y preferably contains up to four carbon atoms. Particularly preferred Y is the group - (CH2) n-, where n is 2 or 3, or the group -CHR3-CH2-, where R3 is methyl or ethyl and the group -CHR3, joins the NH group. Very particularly preferred, Y is the group -CH2-CH2-. X is preferably halogen or (C3-C6) alkyl, for example fluorine, chlorine, n-propyl, isopropyl, n-butyl, isobutyl, sec. -butyl, tere. -butyl, tere. -amyl or 1,1-dimethylpropyl, in particular chlorine or tere. -butyl. Z is preferably halogen, nitro, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl, particularly preferred is (C 1 -C 4) alkoxy, for example methoxy. The X and Z residues can be in any position of the phenyl residue to which they are bound. Preferably, X is attached in the 5-position and Z in the 2-position of the phenyl residue, in each case relative to the group C (= 0) -NH in the 1-position.
If, in the compounds of the formula I, according to the invention, the group E is oxygen, the ureas of the formula are present. If E is sulfur, the thioureas of the formula Ib are present. E is preferably sulfur:Preferred compounds of the formula I, for use according to the invention, are the compounds in which one or more of the residues have the preferred meanings, all combinations of the preferred meanings represent an object of the present invention. For example, preference is given to the use of the compounds of formula I, in which: R 1 is hydrogen, methyl or trifluoromethyl;R2 is hydrogen, halogen, alkyl- (C? -C6), alkoxy- (d.-C6) alkoxy- (C? -C6) -alkoxy- (C1-C4) -, alkoxy- (d-C6) -alkoxy - (C1-C4) -alkoxy- (C1-C4) -, alkyl- (C? -C6) -thio, fluoroalkoxy- (C? -C6) or fluoroalkyl- (d-C6); E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or alkyl- (C? ~ C2), and n is 1, 2, 3 or 4; X is halogen or (C3-C6) alkyl; Z is halogen, nitro, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl; in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable salts.
Particular preference is given to the use of the compounds of the formula I, in which: R1 is hydrogen or methyl; R2 is hydrogen, halogen, (C? -C6) alkyl, alkoxy- (d- C6), (C1-C4) alkoxy- (C1-C4) alkoxy-, (C1-C4) alkoxy- alkoxy- (C1-C4) -alkoxy- (C1-C4) -, alkyl- (C? -C6) -thio, fluoroalkoxy- (C? -C6) or fluoroalkyl- (C? -C6); E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or methyl, and n is1, 2, 3 or 4;X is halogen or (C3-C6) alkyl; Z is alkoxy- (C1-C4); in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable saltsMore particular preference is given to the use of the compounds of formula I, wherein: R 1 is hydrogen or methyl; R2 is hydrogen or halogen; JE is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or methyl, and n is1, 2, 3 or 4; X is halogen or (C3-C6) alkyl; Z is alkoxy- (C1-C4); in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable saltsMore particular preference is also given to the use of compounds of the formula I, wherein: R 1 is hydrogen or methyl; R2 is alkyl- (C? -C6) -thio, fluoroalkoxy- (d-C6) or fluoroalkyl- (d-C6); E is oxygen or sulfur;Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or methyl, and n is 1, 2, 3 or 4; X is halogen or (C3-C6) alkyl / Z is alkoxy- (C? -C4); in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable saltsMore particular preference is likewise given to the use of compounds of the formula I, wherein: R 1 is hydrogen or methyl; R2 is alkyl- (d.-C6), alkoxy- (C? -C6), alkoxy- (d.-C4) -alkoxy- (C1-C4) -, alkoxy- (C1-C4) -alkoxy- (C1 -C4) - alkoxy- (C1-C4) -; E is oxygen or sulfur; ? is a hydrocarbon radical of the formula - (CR32) wherein R3 residues, independently of one another, are each hydrogen or methyl, and n is 1, 2, 3 or 4; X is halogen or (C3-C6) alkyl; Z is alkoxy- (C1-C4); in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable salts.
Particular preference is given to the use of compounds of the formula I, in which: R1 is hydrogen or methyl; R 2 is methyl, methoxy or 2-methoxyethoxy; E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n_ in which the residues R3, independently of each other, are each hydrogen or methyl, and n is 2 or 3; X is halogen or (C3-C6) alkyl; Z is alkoxy- (C? -C); in all its stereoisomeric forms and their mixtures in all ratios, and / or their physiologically acceptable saltsSpecific preference is given to the use of compounds of the formula I, in which: R1 is methyl; R 2 is methyl, methoxy or 2-methoxyethoxy; E is sulfur; Y is a hydrocarbon radical of the formula - (CH2) "- in which n is 2 or 3; X is halogen or (C3-C6) alkyl; Z is alkoxy- (C? -C4); in all its stereoisomeric forms and mixtures thereof in all ratios, and / or its physiologically acceptable salts The compounds of the formula I, according to the invention, can be prepared, for example, by the following processes: (a) The aromatic sulfonamides, of the formula III, or their salts of the formula IV, can react with R1-substituted isocyanates, of the formula V, to give the substituted benzenesulfonylureas, of the formula la:1 _ N = C = O VSuitable cations M1 in the salts of the formula IV are the alkali metal ions or alkaline earth metal ions, such as, for example, sodium ions or potassium ions or ammonium ions, for example the tetraalkylammonium ions. Equivalent to the R1-substituted isocyanates of the formula V, it is possible to use the R1-substituted carbamic acid esters, R1-substituted carbamoyl halides or R1-substituted ureas. (b) The benzenesulfonylureas, of the formula la, which are not substituted in the urea group and in which R1 is hydrogen, can be prepared by the reaction of the aromatic benzenesulfonylamides 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 silicon-substituted benzenesulfonylureas, which are formed primarily. Also, compounds of the formula la, in which R1 is hydrogen, can be obtained from the benzenesulfonamides of the formula III, or their salts of the formula IV, by the reaction with halogen cyanides and the hydrolysis of the N-cyanosulfonamides, which They are formed primarily with mineral acids, at temperatures between 0 and 100 ° C. (c) The benzenesulfonylureas, of the formula la, can be prepared from aromatic benzenesulfonamides, of the formula III, or their salts of the formula IV, using R 1 -substituted trichloroacetes, of the formula VI, in the presence of a base, in an inert solvent, according to Synthesis 1987, 734-735, at temperatures between 25 and 150 ° C.
CI3C-CO-NH-R1 VISuitable bases are, for example, the alkali metal or alkaline earth metal hydroxides, hydrides, amides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, amide sodium, potassium amide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Suitable inert solvents are ethers, such as tetrahydrofuran, dioxane or 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 dimethylsulfoxide (DMSO), sulfones, such as sulfolane, hydrocarbons, such as benzene, toluene, xylenes. Also, mixtures of these solvents with each other are also suitable. (d) The benzenesulfonylureas, of the formula Ib, can be prepared from the benzenesulfonamides, of the formula III, or their salts of the formula IV, and the R1-substituted isocyanates, of the formula VII:R1 - N = C = S VilThe benzenesulfonylthioureas, of the formula Ib, which are unsubstituted in the thiourea group, and in which R 1 is hydrogen, can be prepared by the reaction of the aromatic benzenesulfonylamides of the formula III, or their salts of the formula IV, with the trialkylsilyl isothiocyanates, such as trimethylsilyl isothiocyanate, or with silicon tetraisothiocyanate, and hydrolysis of the silicon-substituted benzenesulfonylthioureas, which are formed primarily. In addition, it is possible to prepare compounds of the formula Ib, in which R.sup.1 is hydrogen, by the reaction of the aromatic benzenesulfone amines of the formula III, or their salts of the formula IV, with the benzoyl isothiocyanate, and subsequently to react the intermediates Benzene-substituted benzenesulfonylthiourea with aqueous mineral acids. Similar processes are described in J. Med. Chem. 1992, 35, 1137-1144. (e) The substituted benzenesulfonylureas of the formula la can be prepared by conversion reactions of the benzenesulfonylthioureas of the formula Ib. The desulfurization, ie the replacement of the sulfur atom, in the corresponding benzenesulfonylurea, by an oxygen atom, can be carried out, for example, with the aid of oxides or heavy metal salts or by using the oxidizing agents, such as hydrogen peroxide, sodium peroxide or nitrous acid. Thioureas can also be desulfurized by treatment with phosgene or phosphorus pentachloride. The amidines or carbodiimides of chloroformic acid are obtained as intermediates and can be converted into the corresponding substituted benzenesulfonylureas, for example, by hydrolysis or by adding water. (f) The benzenesulfonylureas of the formula la can be prepared from the benzenesulfonyl halides of the formula VIII, using the R-substituted ureas the R 1 -substituted bis (trialkylsilyl) ureas. The trialkylsilyl protecting group can be removed from the(trialkylsilyl) benzenesulfonylurea resulting, according to standard methods. Similarly, the sulfonyl chlorides of the formula VIII can be reacted with the parabanic acid to give the benzenesulfonyl parabanic acids, whose hydrolysis with mineral acids, supplies the corresponding benzenesulfonylureas of the formula la.(g) Benzenesulfonylureas of the formula la can be prepared by the reaction of amines of the formula R1-NH2 with the benzenesulfonyl isocyanates of the formula IX. Similarly, amines of the formula R1-Nh2 can react with esters of benzenesulfonylcarbamic acid. with carbamoyl halides or with benzenesulfonylureas, of the formula la, in which R1 is hydrogen, to give compounds of the formula la.(h) The benzenesulfonylureas, of the formula Ib, can be prepared by reacting the amines, of the formula R1-NH2, with the benzenesulfonyl isothiocyanates, of the formula X. Similarly, the amines of the formula R1-NH2, can react with thioesters or carbamoyl trihalides of benzenesulfonylcarbamic acid, to give the compounds of the formula Ib:(i) The benzenesulfenyl- or -sulfinylureas, appropriately substituted, can be oxidized with oxidizing agents, such as hydrogen peroxide, sodium peroxide or nitrous acid, to give the benzenesulfonylureas, of the formula la. The starting materials for the aforementioned synthesis processes of the compounds of the formula I can be prepared by methods known per se, as described in the literature (for example in standard works, such as Houben's) -Weyl, Methoden der Organischen CEIME [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart, Organic Reactions, John Wiley &Sons, Inc., New York: or in the patent references, mentioned above), and under conditions of reaction that are known and suitable for the reactions mentioned. Variants that are known per se, which are not mentioned here in greater detail, can also be used for these reactions. If desired, the starting materials can also be formed in themselves, so they are not isolated from the reaction mixture and are then reacted immediately. Thus, the amines, appropriately substituted,• Formula XI can be acylated and subjected to halosulfonation. In the formula XI, R2 and Y have the meanings given above. Acylation agents suitable for acylating the amino group in the compounds of theXI XIIformula XI are advantageously alkyl esters, halides (for example, chlorides or bromides) or anhydrides of carboxylic acids, of the formula R 4 -COB. Here, R 4 is, for example, a trihalomethyl residue, an alkyl residue (C 1 -C 4) or a phenyl residue. If R4 is a phenyl residue, the compound of the formula R4-COB is a benzoic acid derivative. This benzoic acid derivative can be unsubstituted or substituted by one or two residues, identical or different, X and Z. Here X and Z are as defined above, that is, X can be hydrogen, alkyl- (d.-C6) or halogen and Z may be halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or nitro. Group B is a starting group, such as, for example,. halogen, (C 1 -C 4) alkoxy, trihaloacetoxy or alkyl- (dC 4) -carbonyloxy. Examples of compounds of the formula R 4 -COB are the derivatives of acetic anhydride, trihaloacetic anhydride, acetyl halides, trihaloacetyl halides, propionyl chloride, isobutyryl bromide and isobutyryl chloride, formic acid / acetic anhydride, benzoyl chloride and substituted benzoic acid, such as 5-chloro-2-methoxybenzoyl chloride or 5-chloro-2-methoxybenzoic anhydride or (C 1 -C 4) -alkyl 5-chloro-2-methoxybenzoate, 5-tert. .butyl-2-methoxybenzoyl or 2,5-difluorobenzoyl chloride. The synthesis of the compounds of the formula XII is preferably carried out with the addition of a tertiary amine base, such as, for example, pyridine or a trialkylamine, in the presence or absence of an inert solvent, the presence of a catalyst, such as, for example, dimethylaminopyridine is also possible. The reaction is generally carried out at temperatures between about 0 and 150 ° C, preferably between 20 and 150 ° C,. The acyl group in the compounds of the formula XII can be a protecting group or, in the case of the benzoic acid derivatives, also part of the compounds of the formula I. Inert solvents suitable for acylation are, for example, the ethers , such as tetrahydrofuran, dioxane or glycol ethers, such as ethylene. glycol monomethyl ether or ethylene glycol monoethyl ether (methylglycyl or ethyl glycol) or ethylene glycol dimethyl ether, ketones, such as acetone or butanone, nitriles, such as acetonitrile, nitro compounds, such such as nitromethane, esters, such as ethyl acetate, amides, such as DMF or NMP, hexamethylphosphoric triamide, sulfoxides, such as DMSO, chlorinated hydrocarbons, such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, or hydrocarbons, such as benzene, toluene or xylenes, and mixtures of these solvents with each other are also suitable.From the compounds of formula XII, the sulfonamides of formula XIII can be prepared according to methods of yes known, under reaction conditions are suitable and known for such reactions.
XII XIII Variants that are known per se, but are not mentioned in more detail here, can also be used for these reactions. If desired, the syntheses can be carried out in one, two or several stages. Particular preference is given to processes in which the acylated amine of formula XII is converted by electrophilic reagents, in the presence or absence of inert solvents, at temperatures between -10 and 10 ° C, preferably between 0 and 100 ° C, aromatic sulfonic acids or their derivatives, such as, for example, sulfonyl halides. It is possible to carry out, for example, sulphonations using sulfuric acids or oil, halosulfonations using halosulfonic acids, reactions with sulfuryl halides, in the presence of anhydrous metal halides, or reactions with thionyl halides, in the presence of anhydrous metal halides, with subsequent oxidation, carried out in a manner known per se, to give aromatic sulfonyl chlorides. If the primary reaction products are sulfonic acids, they can be converted to sulfonyl halides either directly or by treatment with tertiary amines, such as, for example, pyridine or trialkylas, or with alkali metal or alkaline earth metal hydroxides, or reagents that form these basic compounds, in itself in a known manner, using acid halides, such as, for example, phosphorus trihalides, phosphorus pentahalides, phosphorus oxychlorides, thionyl halides or oxalyl halides. The conversion of the sulfonic acid derivatives into sulfonamides can be carried out in a manner known per se in the literature. Preference is given to the reaction of sulfonyl chlorides in inert solvents, at temperatures between 0 and 100 ° C, with aqueous ammonia, in the absence or presence of an organic solvent. Likewise, the aromatic sulfonamides can be synthesized according to the processes described in the literature from the acylated amines, of the formula XII, by the reaction with organometallic reagents (alkaline or alkaline earth) in inert solvents and under an atmosphere of inert gas , at temperatures from -100 to 50 ° C, preferably from -100 to 30 ° C and with sulfur dioxide and the subsequent thermal treatment with amidosulfonic acid. If the acyl group in the compound of the formula XIII acts as a protecting group for the amino group, this protecting group can be removed by the treatment with acids or bases, after the introduction of the sulfonamide group. The splitting with aqueous acids or acids in inert solvents can supply the acid addition salt of the amino compound. Suitable for this removal of the protective group are, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or organic acids. The removal of the "amino protecting group in the compound of the formula XIII, with bases, can be carried out in aqueous or inert solvents Suitable bases are, for example, the hydroxides of alkali metals or alkaline earth metals, such as Sodium hydroxide, potassium hydroxide or calcium hydroxide, or the alkali metal or alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide, of the amines substituted with sulfonamide or its addition compounds with acids, prepared in this manner, it is possible to prepare the benzenesulfonamides of the formula III by acylation with the substituted benzoic acids or benzoic acid derivatives, as illustrated above for the acylation of the compounds of the formula XI. of formula I may have one or more chiral centers, consequently, they may be obtained in their preparation as racemates or others, if used n Optically active starting materials. in optically active form. If the compounds have two or more chiral centers, they can be obtained in the syntheses as mixtures of racemates of which the individual isomers can be isolated in pure form, for example by the recrystallization of inert solvents. If desired, the racemates obtained can be separated by methods known per se, mechanically or chemically, into their enantiomers. Thus, diastereomers can be formed from the racemate by reaction with an optically active resolving agent. Suitable resolving agents for the basic compounds are, for example, optically active acids, such as the R- or R-, R- and S- or S-, S- forms of tartaric acid, dibenzoyltatartaric acid, diacetyltartaric acid, camphoric acids, sulfonic acids, mandelic acids, malic acid or lactic acid. For the separation, it is also possible to acylate the carbonols with the aid of chiral acylating agents, for example, the isocyanate of R- or S-α-methylbenzyl, followed by separation. The different forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers can be released from the diastereomers in a manner known per se. The separation of the enantiomers is also possible by chromatography on optically active stationary phases. Depending on the nature of the residues R1, R2, E, X, Y and Z, in individual cases, one or the other of the processes, mentioned above, for the preparation of the compounds of the formula I, will be inadequate, or at least they will require measures of protection of the active groups.
Such cases, which are relatively rare, will be easily recognized by a person skilled in the art and will not cause difficulties using other synthetic routes successfully described in such cases. With respect to the preparation of the compounds of the formula I, patents US-A-5 574 069 (EP-A-612 724) and US-A-5 652 268 (EP-) will be used according to the invention. A-727 416), which are expressly incorporated herein by reference. Due to their ability to reduce or eliminate insufficient function of the vagal nervous system and thus vagal dysfunctions and / or autonomic nervous system dysfunction, the compounds of formula I are useful agents for the treatment and prophylaxis of diseases, which are associated with such impaired functions or dysfunctions of the vagal nervous system or that are caused by them, or for treatment or prophylaxis where an increase or normalization of vagal nervous system activity is sought. The effect of the compounds of formula I on the vagal nervous system can be demonstrated, for example, in the mouse model, described below. The effect can also be demonstrated, for example, in rats, guinea pigs, rabbits, dogs, monkeys or pigs. Diseases and pathological conditions where the treatment or prophylaxis of a damaged function of the vagal nervous system or a dysfunction of the autonomic nervous system, is indicated, has already been mentioned before. In addition to being generally suitable for the treatment or prophylaxis of autonomic nervous system dysfunction and, in particular, a vagal dysfunction, the compounds of the formula I and their physiologically acceptable salts are suitable specifically for use in disorders of the cardiovascular system and in heart disease, for the treatment or prophylaxis of sympathetic-vagal imbalance or for the treatment and prophylaxis of a vagal dysfunction of the heart. Examples of heart diseases and conditions of this type are coronary heart disease, agina pectoris, cardiac infarction, postmyocardial infarction, heart failure, cardiomyopathies, heart transplants, or vagal dysfunctions of the heart in cases of diabetes mellitus. Since the compounds of the formula I have, in addition to their known direct effect on the heart, that is to say in addition to the effect on the potential action of the heart muscle cells, also an indirect effect on the nervous system of the heart or on the parts of the nervous system that act on the heart, they can reduce or prevent the unwanted consequences for the heart, which are, in the state of the disease in- question, caused or mediated by the nervous system. Thus, it is possible to reduce or avoid further damage to the balance, such as a weakening of heart resistance or sometimes fatal heart arrhythmias, such as ventricular fibrillation. By eliminating or reducing the dysfunction of the autonomic nervous system, the compounds of the formula I and their physiologically acceptable salts, lead to a normalization of the weakened resistance of the heart and to the prevention of the development of cardiac arrhythmias which can lead to sudden cardiac death. Areas of use of the compounds of the formula I and / or their physiologically acceptable salts, in the context of the present invention, are, therefore, in particular, also the use in cases of heart failure and the prevention of cardiac arrhythmias, such as fatal ventricular fibrillation and the prevention of sudden cardiac death. By the selection of the compounds of the formula I, which have an adequate activity profile with respect to the direct effect on the heart (= direct effect on the action potential of the heart muscle cells and the corresponding direct effect on the force contractile and the direct antiarrhythmic effect) on the one hand, and the effect on the nerves of the heart, on the other hand, it is possible, in a particularly efficient manner, to have influence on heart diseases favorably, with the help of the compounds of formula I. Depending on the particular symptoms, it may also be advantageous to use compounds of formula I which have only one direct effect, relatively low, in the heart and, therefore, only, for example, have a relatively low direct effect on the contractile force of the heart or the generation of arrhythmias, whereby they can improve or normalize the resistance of the heart or the rhythm of the heart because of its influence on the autonomic nervous system. As already mentioned, a deteriorated function of the vagal system and its consequences can also occur temporarily, for example in the case of oxygen deficiency of the heart. The compounds of the formula I are, therefore, also particularly suitable for use in angina pectoris or coronary heart disease, where oxygen deficiency states occur. Likewise, the compounds of the formula I can be used generally in cases of dysfunctions of the autonomic nervous system, in particular in vagal dysfunction, which occurs as a result of a metabolic disorder, such as, for example, diabetes mellitus. The compounds of the formula I and their physiologically acceptable salts can therefore be used in animals, preferably in mammals and, in particular, humans, as a medicinal product per se, in mutual mixtures or together with other active compounds , in particular in the form of pharmaceutical preparations (or pharmaceutical compositions). An object of the present invention is thus the use of the compounds of the formula I and / or their physiologically acceptable salts for preparing the medicaments for the therapy or prophylaxis of the aforementioned syndromes. Another object of the invention is also the use of the compounds of the formula I and / or their physiologically acceptable salts, for the therapy or prophylaxis of the aforementioned syndromes, and another object of the invention are the methods for therapy or prophylaxis. of the aforementioned syndromes, in which an effective amount of one or more compounds of the formula I and / or their physiologically acceptable salts is administered to a human or animal patient in need thereof. Medicines, . which can be used, according to the invention, comprise the compounds of the formula and / or their physiologically acceptable salts and can be administered in enteral form, for example oral or rectal, such as in the form of pills, tablets, coated tablets , tablets coated with sugar, granules, hard and soft gelatine capsules, suppositories, solutions, as well as aqueous, alcoholic or oily solutions, juices, drops, syrups, emulsions or suspensions. The medicaments can also be administered parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions for injections or solutions for infusions. Other suitable administration 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 pharmaceutical preparations,. which can be used, according to the invention, can be prepared by known standard processes to obtain these pharmaceutical preparations. For this purpose, one or more of the compounds of the formula I and / or their physiologically acceptable salts are mixed together with one or more excipients and / or solid or liquid pharmaceutical additives or auxiliaries and, if a combined preparation is desired, compounds pharmaceutically active agents having a therapeutic or prophylactic effect and then carrying a suitable dosage or administration form, which can be used as a medicine in human medicine or veterinary medicine. The pharmaceutical preparations comprise a therapeutically or prophylactically effective dose of the compounds of the formula I and / or their physiologically acceptable salts, which is usually 0.5 to 90% by weight of the pharmaceutical preparation. The amount of the active compound of the formula I and / or its physiologically acceptable salts in the pharmaceutical preparations is generally from 0.2 mg to 1000 mg, preferably from 0.2 mg to 500 mg, particularly preferred from 1 mg to 500 mg per unit, but may also be greater, depending on the nature of the pharmaceutical preparation. Suitable excipients are organic or inorganic substances, which are suitable, for example, for enteral (for example oral) or parenteral (for example intravenous) administration or topical administrations and which do not react with the active compounds in an undesired manner, for example. example water, vegetable oils, alcohols, such as ethanol, isopropanol or benzyl alcohols, 1,2-propanediol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile, dimethylformamide, dimethylacetamide. It is also possible to use mixtures of two or more excipients, for example mixtures of two or more solvents, in particular also mixtures of one or more organic solvents in water. As additives or auxiliaries, the pharmaceutical preparations may contain, for example, stabilizers, wetting agents, emulsifiers, solubilizers, thickeners, salts, for example for the influence on osmotic pressure, glidants, preservatives, dyes, flavoring agents, flavors and / or regulatory substances. If desired, they may also comprise one or more other active compounds, for example, one or more vitamins. It is also possible to lyophilize the compounds of the formula I and / or their physiologically acceptable salts and to use the resulting lyophilizates for the preparation of preparations for injection, for example. Also suitable are liposomal preparations, in particular for topical administration. The dose of the active compound of the formula I, can be administered and / or its physiologically acceptable salt, when used, according to the invention, depends on the individual case and has to be adapted to individual circumstances to obtain an optimal effect, such as it's usual. Therefore, it depends on the nature and seriousness of the disease to be treated and also on the sex, age, weight and individual sensitivity of the human or animal to be treated, on the effectiveness and duration of the treatment. action of the compounds used, whether the treatment is an acute or chronic therapy or prophylaxis, or whether other active compounds are administered, in addition to the compounds of the formula I. In general, a dose range for the treatment of a dysfunction of the autonomic nervous system in humans is from about 0.1 mg to about 100 mg per kg per day, when administered to an adult weighing about 75 kg, it is adequate to achieve the desired effect. Preference is given to a dose range of about 1 to 10 mg per kg per day (in each case mg per kg of body weight). The daily dose can be administered as a single dose or divided into more than one, for example, two, three or four individual doses. It can also be administered continuously. Depending on the individual behavior, it may be necessary to exceed reducing the daily doses indicated. In addition to the effect on the autonomic nervous system, it has also been found that the compounds of the formula I have a synergistic effect with the beta-receptor blockers, which can be used advantageously, in particular, in the treatment and prophylaxis of heart diseases , such as, for example, heart failure. As is known, the use of β-receptor blockers, at low doses, improves the symptoms in the case of heart failure due to the depression of the sympathetic nervous system, while the compounds of the formula I re-establish the disturbed equilibrium between the vague and sympathetic nerves, primarily by vagal stimulation. As demonstrated in the animal experiment, described below, a combination of the compounds of formula I and beta-receptor blockers showed a superadditive or synergistic effect in the prevention of heart disease or heart damage, and, therefore, thus, it is particularly advantageous, for example, to improve symptoms in cases of heart failure or to prevent or reduce cardiac arrhythmias, such as ventricular fibrillation, or to prevent sudden cardiac death. Expressed in a different way, the compounds of formula I significantly improve the effect of beta-receptor blockers, for example in the heart. Thus, the compounds of formula I are highly suitable for combinations with beta-receptor blockers. An object of the present invention, therefore, is also the treatment and prophylaxis of the aforementioned heart diseases, such as, for example, heart failure, angina pectoris, cardiac infarction, post-iocardial infarction or cardiac arrhythmias, such such as ventricular fibrillation, or the prevention of sudden cardiac death, and the treatment and prophylaxis of autonomic nervous system dysfunctions, in particular vagal dysfunction, specifically vagal dysfunction of the heart, by one or more compounds of formula I and / or their physiologically acceptable salts, in combination with one or more beta-receptor blockers and / or their physiologically acceptable salts. Another object of the invention is also the use of the compounds of the formula I, and / or their physiologically acceptable salts, to prepare medicaments for such treatment or prophylaxis in combination, and an object are the methods for such combination therapy or prophylaxis in combination. Another object of the invention are combinations of one or more compounds of the formula I and / or their physiologically acceptable salts and one or more blockers of the beta-receptors and / or their physiologically acceptable salts for simultaneous, separate or sequential use in the conditions mentioned. In the context of the treatment or prophylaxis in combination, according to the invention, the representatives of the two classes of active compounds can be administered in the form of a pharmaceutical preparation, where both of them are contained together in the same pharmaceutical formulation, by example, in a tablet, ie in the form of a combined pharmaceutical preparation, but also they can be administered separately, for example in the form of pharmaceutical preparations, each containing the representatives of only one of the two classes of the compounds active agents, where, in this case, the representatives of the two classes of active compounds can be administered simultaneously directly, one after another or in sequence, including, for example, after a relatively large interval. All these types are encompassed by the present invention. Depending on the circumstances of the individual case, it may be more favorable to administer the representatives of the two classes of active compounds in the form of a pharmaceutical combination preparation, in which they are present together in a fixed ratio in the same pharmaceutical formulation, or administer them separately in the form of more than one, for example two, individual pharmaceutical preparations, in each of which, for example, only one active compound is contained. In the latter case, the individual pharmaceutical preparations, which then form a set of parts, which can, in suitable primary packages, be present together in a common external package, if desired, together with the instructions for use concerning the use of the combination, according to the invention, or the individual pharmaceutical preparations can be present in separate external packages, if desired, in each case together with the instructions for use relating to the use of the combination, according to the invention. All these suitable products and forms of presentation, for use according to the invention, are within the scope of the present invention."An object of the present invention, therefore, also refers to the products or articles, which comprise one or more compounds of the formula I:wherein: R1 is hydrogen, methyl or trifluoromethyl; R2 is hydrogen, halogen, alkyl- (d-Cß), alkoxy- (d.-C6), alkoxy- (Ci-Ce) -alkoxy- (C1-C4) -, alkoxy- (C? -C6) -alkoxy - (C1-C4) -alkoxy- (C1-C4) -, alkyl- (C? -C6) -thio, fluoroalkoxy- (C? -C6) or fluoroalkyl- (C? -C6); E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or alkyl- (C? -C2), and n is 1, 2, 3, 6, 4; X is hydrogen, halogen or alkyl- (d-C6); Z is halogen, nitro, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl; in all its stereoisomeric forms and mixtures thereof in all ratios, and / or its physiologically acceptable salts, in combination or as a combination preparation, with one or more blockers of the beta-receptors and / or their physiologically acceptable salts, for the use simultaneous, separate or in sequence in the treatment or prophylaxis of autonomic nervous system dysfunctions, a vagal dysfunction, a vagal dysfunction of the heart or in the treatment or prophylaxis of the aforementioned diseases, in particular heart diseases, such as for example, heart failure, angina pectoris, cardiac infarction, postmyocardial infarction or cardiac arrhythmias, such as ventricular fibrillation, or in the prevention of sudden cardiac death. In particular, an object of the present invention relates to the aforementioned preparations of pharmaceutical combinations, in which the representatives of two classes of active compounds are present together in the same pharmaceutical formulation, ie pharmaceutical preparations comprising one or more of the compounds of the formula I:wherein: R1 is hydrogen, methyl or trifluoromethyl; R2 is hydrogen, halogen, alkyl- (C? -Cb), alkoxy- (Cr. C6), alkoxy- (d-Ce) -alkoxy- (C1-C4) -, alkoxy- (C? -C6) -alkoxy - (C1-C4) -alkoxy- (C? -C4) -, alkyl- (C? -C6) -thio, fluoroalkoxy- (C? -C6) or fluoroalkyl- (C? -C6) E is oxygen or sulfur; Y is a hydrocarbon radical of the formula - (CR32) n- in which the residues R3, independently of each other, are each hydrogen or alkyl- (C? -C2), and n is 1, 2, 3, 6, 4; X is hydrogen, halogen or alkyl- (C? -C6); Z is halogen, nitro, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl; in all its stereoisomeric forms and mixtures thereof in all ratios, and / or its physiologically acceptable salts, one or more beta-receptor blockers and / or their physiologically acceptable salts and a physiologically acceptable carrier, i.e., one or more excipients and / or additive or auxiliaries, physiologically acceptable. All the above illustrations, for example with respect to excipients, auxiliaries or additives, to pharmaceutical forms, such as tablets, sugar coated tablets, capsules or solutions, and their preparation, to the possible administration forms, such as oral or intravenous , to the use in human medicine and in veterinary medicine, or to the diseases that are treated, etc., are applied, correspondingly, to the pharmaceutical products and preparations described above. In this context, beta-receptor blockers will be considered as an example of more pharmaceutically active compounds which, in addition to the compounds of Formula I, may be present in the aforementioned pharmaceutical preparations. All the illustrations given above for the compounds of the formula I, by themselves, also apply, correspondingly, to the compounds of the formula I, contained in the products and the pharmaceutical preparations, for example the illustrations with respect to the residues and "individual" groups, to the preferred compounds of the formula I or to their salts In the pharmaceutical preparations containing the compounds of the formula I, together with the beta-receptor blockers in the same pharmaceutical formulation, also their salts, may be present, which are formed by the compounds of these classes with each other, ie salts containing the beta-receptor blocker (or beta-blockers). receptors) which are organic amino compounds, in protonated form as cation, and the compound (or compounds) of formula I in the deprotonated form as an anion. The weight ratio of the compounds of the formula I to the beta-receptor blockers in the pharmaceutical preparations in which both active compounds are present in the same pharmaceutical formulation is generally from 500 to 0.02, preferably from 100 to 0.2, parts by weight of the compound (or compounds) of formula I per part by weight of the beta-receptor blocker (or beta-receptor blockers). For example, the weight ratio may be about 35 parts by weight of the compound of formula I per part by weight of the beta-receptor blocker, or may be 1 part by weight of the compound of formula I per part by weight of the beta-receptor blocker. As the compounds of the formula I, both pharmaceutical preparations will be used, according to the invention, which does not contain any beta-receptor blocker and the pharmaceutical preparations and products, according to the invention, which do not contain beta-receptor blockers, they preferably comprise one or more of the compounds selected from the group consisting of l - [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2- (2-methoxyethoxy) phenyl] -sulfonyl] -3 -methythiourea and 1- [[5- [2- (5-tert-butyl-2-methoxy-benzamido) ethyl] -2- (2-methoxyethoxy) phenyl] -sulfonyl] -3-methylthiourea and / or its physiologically acceptable salts, preferred salts of these compounds are the sodium salts. Suitable beta-receptor blockers for combination treatment and prophylaxis in combination, according to the invention, and for the pharmaceutical products and preparations, according to the invention, are, for example, the following compounds: alprenolol, oxprenolol , pentbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutalol, metipranolo, propranolol, nadol, pindolo, timolol, sotalol, carvedilol, bisprolol, celiprolil, carazolol, talinolol, mepinodolol, cateolol, tertatolol, bopindolol. Preferred beta-receptor blockers are propranolol, atenolol, bioprolol and carvedilol. When combining compounds of formula I with beta-receptor blockers, in general lower doses of the compounds of formula I and / or beta-receptor blockers are required to achieve the desired effect than when compounds of only one Class of active compounds is used. A preferred dose of the compounds of the formula I, in combination with a beta-receptor blocker, is in the range of about 0.3 mg to about 15 mg, preferably about 1 to 20 mg, per kg of body weight per day. The dose of beta-receptor blockers in the combination depends on the dose customary for the individual compound in question. Preference is given to the use of the lowest customary doses for the substance in question and the area of use in question. The above illustrations with respect to the doses and compounds of the formula I, as individual active compounds, are applied, correspondingly, to the use of the combination, according to the invention, for example with respect to the necessary adaptation of the dose to the circumstances of the individual case or a division of the dose into individual doses. Due to their effect on the autonomic nervous system, the compounds of the formula I and their salts can be used not only as pharmaceutically active compounds in human or veterinary medicine, but also as a scientific tool or as an aid for biochemical investigations, in which such effect is attempted, and also for diagnostic purposes, for example, in the diagnosis of cell or tissue samples. The present invention also provides the compounds of the formula I by themselves that not been described so far, and their physiologically acceptable salts. In particular, the invention provides the novel substances per se, described in the working examples, for example 1- [[5- [2- (5-tert.-butyl-2-methoxybenzamido) -ethyl] -2- (2-methoxyethoxy) phenyl] -sulfonyl] -3-methylthiourea and its physiologically acceptable salts, including its sodium salt, the use of the novel compounds as pharmaceutically active compounds, and the pharmaceutical preparations comprising one or more of these compounds and a physiologically acceptable carrier, that is, one or more excipients and / or additives or auxiliaries, physiologically acceptable. The above illustrations apply correspondingly to these pharmaceutical preparations, excipients and auxiliaries. In addition to the compounds described in the working examples, it is also possible to use, for example, the compounds of the formula I, compiled below, 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-Buty-1-2-methoxybenzamido) ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylthiourea; (4) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- propoxy-phenyl] -sulfonyl] -3-methylthiourea; (5) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethyl-phenyl] -sulfonyl] -3-methylthiourea; (6) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethyl-phenyl] -sulfonyl] -3-methylthiourea; (7) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- isopropyl-phenyl] -sulfonyl] -3-methylthiourea; (8) 1- [[5- [2- (5-tert.-butyl-2-methoxybenzamido) ethyl] -2-bromo-phenyl] -sulfonyl] -3-methylthiourea; (9) 1- [[5- [2- (5-tert-Buty-1-2-methoxybenzamido) ethyl] -2-fluoro-phenyl] -sulfonyl] -3-methylthiourea;(10) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- trifluoro-methoxyphenyl] -sulfonyl] -3-methylthiourea;(11) 1- [[5- [2- (5-tert.-butyl-2-methoxybenzamido) ethyl] -2-methylthio-phenyl] -sulfonyl] -3-methylthiourea; (12) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethylthio-phenyl] -sulfonyl] -3-methylthiourea; (13) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- isopropoxyphenyl] -sulfonyl] -3-methylthiourea; (14) l - [[5- [2- (5-tert-Butyl-2-methoxybenzamido) methyl] -2-methoxy-phenyl] -sulfonyl] -3-methylthiourea; (15) 1- [[5- [2- (5- (1,1-dimethylpropyl) -2-methoxy-benzamido) ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylthiourea; (16) l - [[5- [2- (5-sec. -butyl-2-methoxybenzamido) ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylthiourea; (17) 1- [[5- [2- (5-n-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylthiourea; (18) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) propyl] -2-methoxy-phenyl] -sulfonyl] -3-methylurea; (19) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) butyl] -2-methoxy-phenyl] -sulfonyl] -3-methylurea; (20) l- [[5- [2- (5-tert-Buty-1-2-methoxybenzamido) ethyl] -2-ethoxy-phenyl] -sulfonyl] -3-methylurea; (21) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- propoxy-phenyl] -sulfonyl] -3-methylurea;(22) 1- [[5- [2- (5-tert.-butyl-2-methoxybenzamido) ethyl] -2-ethyl-phenyl] -sulfonyl] -3-methylurea; (23) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethyl-phenyl] -sulfonyl] -3-methylurea; (24) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- isopropyl-phenyl] -sulfonyl] -3-methylurea; (25) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-bromo-phenyl] -sulfonyl] -3-methylurea; (26) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-fluoro-phenyl] -sulfonyl] -3-methylurea; (27) 1- [[5- [2- (5-tert-Buty-1-2-methoxybenzamido) ethyl] -2- trifluoro-methoxy-phenyl] -sulfonyl] -3-methylurea; (28) l- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methyl-thiophenyl] -sulfonyl] -3-methylurea; (29) 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-ethyl-thiophenyl] -sulfonyl] -3-methylurea; (30) 1- [[5- [2- (5-tert-Buty-1-2-methoxybenzamido) ethyl] -2- isopropoxy-phenyl] -sulfonyl] -3-methylurea; (31) l - [[5- [2- (5-tere. -buty1-2-methoxybenzamido) ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylurea; (32) 1- [[5- [2- (5-1, 1-dimethylpropyl) -2-methoxybenzamido] ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylurea; (33) 1- [[5- [2- (5-sec. -buty1-2-methoxybenzamido) ethyl] -2-methoxy-phenyl] -sulfonyl] -3-methylurea;(34) 1- [[5- [2- (5-n-butyl-2-methoxybenzamido) ethyl] -2- ethoxyphenyl] -sulfonyl] -3-methylurea; (35) 1- [[5- [2- (5-isopropyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylurea.
EXAMPLESExample 1: 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] 2-methoxy-phenyl] -sulfonyl] -3-methylthiourea0. 286 g (0.68 mmol) of 5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2-, methoxybenzenesulfonamide were dissolved in 7.5 ml of dimethylformamide and, after the addition of 0.1 g of carbonate of potassium, was mixed with 0.68 ml of a 1M solution of methyl isothiocyanate in dimethylformamide and stirred at 80 ° C for 2 hours. The cooled reaction mixture was poured into dilute aqueous hydrochloric acid, and the precipitate was filtered off with suction and dried in air. The product had a melting point of 20l-203 ° C.
Preparation of the starting material 1.51 g (10.0 mmol) of 2- (4-methoxyphenyl) ethylamine, they were dissolved in 40 ml of pyridine and mixed with a spatula pinch of the 4-dimethylaminopyridine and then with a solution of 2.15 g (10.5 mmol) of 5-tert. Chloride. -butyl-2-methoxybenzoyl. After the 2- (4-methoxyphenyl) ethylamine had been completely converted, the reaction mixture was poured into dilute, cold hydrochloric acid, and the precipitated product was filtered off with suction and dried to give 5-tert. -butyl-2-methoxy-N- [2- (4-methoxyphenyl) ethyl] benzamide, as a colorless solid. The benzamide was introduced into cold chlorosulfonic acid. After the benzamide had completely turned, the reaction mixture was emptied on ice and filtered off with suction, and the precipitate was dissolved in acetone. This solution was mixed with an excess of aqueous ammonia and concentrated. After the exothermic reaction had subsided, the mixture was concentrated to one third of its original volume and the precipitate was filtered off with suction. 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxy-benzenesulfonamide was obtained, in the form of colorless crystals, with melting point of 165-168 ° C .
Example 2: 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylurea0. 252 g (0.5 mmol) of the 1- [[5- [2- (5-tert-butyl-2-m-toxibenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylthio-urea (Example 1) were dissolved in 2.5 ml of a 2N aqueous solution of sodium hydroxide and mixed, with ice cooling, with 0.25 ml of 30% hydrogen peroxide. The solution was stirred at room temperature for 24 hours and was poured into a mixture of ice and water and 2N hydrochloric acid. Air drying gave white crystals with a melting point of 209-212 ° C.
Example 3: 1- [[5- [2- (5-isopropyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylthioureaThe preparation was carried out analogously to Example 1. White crystals with a melting point of 177-179 ° C were obtained.
Example 4 1- [[5- [2- (5-Chloro-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylthioureaThe preparation of this substance is described in the patent US-A-5 574 069 (EP-A-612 724), which is incorporated herein by reference and the contents thereof with respect to the preparation of the substance are part of the present description.
Example 5: 1- [[5- [2- (5-Chloro-2-methoxybenzamido) ethyl] -2- (2-methoxyethoxy) phenyl] -sulfonyl] -3-methylthioureaThe preparation of this substance is described in the patent US-A-5 652 268 (EP-A-612 724), which is incorporated herein by reference and the contents thereof with respect to the preparation of the substance are part of the present description.
Example 6: 1- [[5- [2- (5-tert-Butyl-2-methoxybenzamido) ethyl] -2- (2-methoxyethoxy) phenyl] -sulfonyl] -3-methylthioureaThe preparation was carried out analogously to Example 1, using 5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2- (2-methoxyethoxybenzenesulfonamide.) Instead of potassium carbonate, the sodium hydride as a base in the reaction with methyl isothiocyanate, analogously to Example 5. The product had a melting point of 61 ° C.
Example 7: Sodium salt of 1- [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2-methoxyethoxyphenyl] -sulfonyl] -3-methylthiourea4. 93 g of the 1- [[5- [2- (5-tert-butyl-2-methoxybenzamido) ethyl] -2-methoxyphenyl] -sulfonyl] -3-methylthio-urea (Example 1) were introduced in 32 ml of methanol, in which 0.425 g of solid sodium hydroxide had previously been dissolved. After stirring for 15 minutes, 125 ml of methyl-tert.-ether was added. -butyl to the clear solution.
With stirring, the sodium salt was allowed to crystallize and then separated by filtration, with suction, washed with a little cold ether of methyl-tert. -butyl and dried. Yield of 5.09 g. Melting point of 235-250 ° C (decomposition). Infrared spectrum (IR) (Nujol): 1646.1 cm-1.
Examples of pharmaceutical preparationsExample A: Tablets To prepare tablets, 1- [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2-methoxyethoxyphenyl] -sulfonyl] -3-methylthiourea (Example 4), low substituted hydroxypropylcellulose ( L-HPC), polyvinylpyrrolidone (Povidone 25) and the interlaced sodium carboxymethyl cellulose, were granulated by moistening with water. The granules were passed through a sieve of 1 to 1.5 mm, mixed with the sodium carboxymethylcellulose and the magnesium stearate and compacted into tablets.
Amounts per tablet: Compound of Example 4 600 mg L-HPC 95 mg Povidone 25 15 mg Sodium carboxymethyl cellulose 60 mg Magnesium stearate 20 mgExample B: Aqueous solution for intravenous administration To prepare 10 ml of solution, comprising 10 mg of the active compound per ml, 100 mg of the sodium salt of the 1- [[5- [2- (5-chloro-2 -methoxybenzamido) ethyl] -2-methoxyethoxyphenyl] -sulfonyl] -3-methylthiourea (see Example 4) were dissolved in 10 ml of an isotonic sodium chloride solution (0.9% strength).
Pharmacological investigations 1. Effect on vagal dysfunction Substances were investigated using the model of ventricular fibrillation induced by chloroform in the mouse (see J. W. Lawson, Antiarrhythmic activity of some isoquinoline derivatives, determined by the procedure of rapid classification in the mouse; J. Pharmacol. Exp. Ther, 1968, 160, 22-31). The test substance was dissolved in a mixture of dimethyl sulfoxide (DMSO) and a 10% sodium bicarbonate solution, and administered intraperitoneally (i.p.). After 30 minutes, the mouse was anesthetized with chloroform in a laboratory beaker. As soon as, in the deep anesthesia, the respiratory arrest (stage of toxic anesthesia) has occurred, the animal's chest was opened using a pair of scissors and the heart beats were visually inspected. Here, it is possible to determine at first glance if the heart is beating, fibrillating or stopped. Respiratory arrest produced by chloroform leads, by means of absolute anoxia (lack of oxygen) in combination with a direct stimulant effect of chloroform in the sympathetic nervous system, to a powerful stimulation of the sympathetic, which, in turn, in combination with the deficit of energy in the heart, caused by the lack of oxygen, results in fatal arrhythmia, that is, ventricular fibrillation. This toxic chloroform anesthesia led to ventricular fibrillation in 100% of the untreated mice(control) . The percentage of mice with ventricular fibrillation in the individual test groups is shown in Table 1.
Table Fibrillation ventricular, induced by chloroform, in the mouse# significant inhibition of ventricular fibrillation by substances (n = 10), compared to control animals (n = 300), p < 0.005. * Significant reduction of the protective effect of the substances by atropine (n = 10), p < 0.05.
The results show that the compounds of the formula I significantly reduce the occurrence of ventricular fibrillation. The observed influence of atropine, the classic blocker of the muscarinic (vagal) receptors of the autonomic nervous system, which blocks the effect of vagal transmitting acetylcholine at the receptor level, gives an indication of the mechanism of action. Atropine reduces or prevents the protective effect of the compounds of formula I. This neutralization of the protective effect of substances by atropine unambiguously indicates the vagal mechanism of action. A similar protective effect can be generated by vagal stimulation with carbacol, a more stable analogue of acetylcholine from the natural vagal transmitter, where the protective effect can similarly be inhibited by atropine. Likewise, physostigmine, inhibitor of cholinesterase, which decreases the degradation of acetylcholine, simulates the protective effect of the compounds of formula I, an effect that was similarly neutralized by atropine.2. Effect of combinations of the compounds of formula I with beta-receptor blockers In the same animal model as in the experiment "effect on vagal dysfunction", described above, it was shown that a combination treatment with beta-receptor blockers and The compounds of the formula I result in a favorable synergistic effect. The active compounds were administered i.v. (intravenously) or i.-p. (intraperitoneally). In one experiment, 10 mg / kg of the sodium salt of 1- [[5- [2- (5-chloro-2-methoxybenzamido) -ethyl] -2-methoxyethoxyphenyl] -sulfonyl] -3-methylthiourea (cf. Example 4, dissolved in DMSO / 10% sodium bicarbonate solution) were combined with 0.3 mg / kg of propranolol (dissolved in distilled water), a standard beta-blocker. It was found that the combined pretreatment of the animals with the two substances had a synergistic effect. The proportion of fibrillation could be decreased more than with the individual substances, in a statistically significant manner. For comparison, a 10-fold higher dose of 3 mg / kg of propranolol was used. It was found that 0.3 mg / kg of propranolol in combination with 10 mg / kg of the sodium salt of 1- [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2-methoxyethoxyphenyl] -sulfonyl ] -3-methylthiourea gave approximately the same result as 3 mg / kg of proanolol, or was even higher than the effect of a propranolol dose of 3 mg / kg. In another experiment, 3 mg / kg of 1- [[5- [2- (5-chloro-2-methoxybenzamido) ethyl] -2-methoxyethoxyphenyl] -sulfonyl] -3-methylthiourea (Example 1) and 3 mg / kg of atenolol were combined in an analogous manner. The results of the combination treatments are shown in Table 2.
Table 2: Synergistic effect of the compounds of the formula I and the beta-receptor blockers* p < 0 .001 vs untreated control; # p < 0. 05 vs. beta-receptor blocker or compound of formula I; n 0 30 for all treated groups.