Applying benzenesulfonyl(thio)ureas for treatment and prophylaxis of disturbances in vegetative nervous system and applying benzenesulfonyl(thio)ureas in combination with beta-receptor blocking agents

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying substituted benzenesulfonylureas and -thioureas of the formula (I) for preparing a medicinal agent used for treatment and prophylaxis of disturbances in vegetative nervous system. In particular, invention relates to treatment and prophylaxis of disturbances associated with vagus nerve, for example, in cardiovascular diseases, and to applying compounds of the formula (I) in combination with beta-receptor blocking agents. Also, invention relates to products and pharmaceutical compositions that comprise at least one substance among compounds of the formula (I) and at least one beta-receptor blocking agent, and to new compounds also. Invention provides enhancing effectiveness in treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

22 cl, 2 tbl, 6 ex

 

Substituted benzosulfimide and-thiourea of the formula I

where R1, R2, E, X, Y, and Z are defined below, have effect on the autonomic nervous system. This invention relates to the use of compounds of formula I for the treatment and prevention of disorders of the autonomic nervous system, particularly disorders associated with the vagus nerve, for example, in the case of cardiovascular diseases, and to their use as drugs for such treatment and prevention. In addition, the invention relates to the use of compounds of formula I in combination with blockers beta-receptors and to the products and pharmaceutical compositions that include at least one of the compounds of formula I and at least one blocker beta-receptors, and new connections.

The compounds of formula I are known from US-A-5574069 (EP-A-612724) and US-A-5652268 (EP-A-727416), which are included in this invention as a reference and the content of which represents a part of the present description. In these publications described that the compounds of formula I inhibit ATP-sensitive potassium channels, in particular, in heart, and that they have a direct antiarrhythmic effect due to the effect on the duration of the cardiac action potential, that is PE is the query result of direct influence on the electrical properties of the cells of the heart muscle. Due to this property of the compounds of formula I can be used, for example, for treatment of ventricular fibrillation and other cardiac arrhythmias. Other pharmacological actions of the compounds of formula I are still described were not. Unexpectedly, at the present time, it was found that the compounds of formula I also have an effect on the peripheral and/or Central nervous system. In particular, they affect the autonomic nervous system and have a stimulating effect on vagusnye nervous system.

In the ideal case, there exists an optimal interaction, adapted to a specific situation, between the sympathetic (= stimulus) nervous system and vagusnye (or parasympathetic) (= the majority) of the nervous system. However, in case this interaction can be disrupted and may be a violation of the autonomic nervous system, there is an imbalance between the activity vagusnye nervous system and sympathetic nervous system activity. Sympathovagal imbalance is usually understood as an overactive sympathetic (= stimulus) nervous system and/or reduced functioning vagusnye (= the majority) of the nervous system, where two parts of the nervous system can have a reciprocal influence on each other. In particular, it is known that reduced functioning of vagus the th system can lead to over-activity of the sympathetic system. Therefore, to prevent damage to cells or organs of the body by going beyond the limits of biological or biochemical processes that are stimulated by excessive activity of the sympathetic nervous system, in such cases, attempts to balance sympathovagal imbalance, for example, to re-establish vagusnye activity by treatment vagusnye disorders or impaired functioning.

Examples of diseases where the inhibition invalid sympathovagal imbalance by treating vagusnye violations appears to be suitable are organic heart disease, such as coronary heart disease, heart failure and cardiomyopathy. Disabilities resulting from imbalance of the autonomic nervous system, in which violation adversely affects the heart, are, for example, weakening of the heart activity or sometimes heart arrhythmia fatal. The importance of the autonomic nervous system in sudden cardiac arrest in cases of heart disease has been described, for example, in P.J.Schwartz The ATRAMI prospective study: implications for t op risk after myocardial infarction; Cardiac Electrophysiology Review, 1998, 2, 38-40) or T.Kinugawa et al. (Altered vagal and sympathetic control of heart rate in left ventricular disfunction and heart failure; Am. J.Physiol., 1995, 37, R310-316). Experimental the studies using electrical stimulation of vagal cardiac nerve or during stimulation analogues vagusnye transmitter acetylcholine, for example carbachol confirm a protective effect vagusnye activation for heart arrhythmia, fatal (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 sympathovagal imbalance may also occur, for example, as a consequence of metabolic diseases such as diabetes (see, for example, A.J. Burger et al., Short - and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus; Am. J. Cardiol., 1997, 80, 1198-1202). Impaired functioning vagusnye system may also be temporary, such as in the case of oxygen deficiency, for example, of the heart, which causes reduced secretion vagusnye neurotransmitters, such as acetylcholine.

Due to the unexpected ability of compounds of the formula I to restore the reduced functioning vagusnye system or re-restore normal vagusnye activity of these compounds have an effective opportunity to reduce, eliminate or prevent violations of the autonomic nervous system and their consequences, such as, for example, the above-mentioned diseases. Thus, an object of the present invention is the use of benzazolyl(thio)ureas of the formula I

where R1represents hydrogen, methyl or triptime is l;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3, each independently, represent hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C6)-alkyl;

in any of its stereoisomeric forms and/or mixtures thereof in all ratios, and/or their physiologically acceptable salts for obtaining a medicinal product for the treatment or prevention of disorders of the autonomic nervous system.

Alkyl represents a linear, branched or cyclic saturated uglevodorodnyi balance. This term is also used if the alkyl residue is substituted, as, for example, in the case of alkyl fluoride residues, or if present in image quality is as a Deputy in another residue, for example in the CNS remains, alkylthiols residues or peralkaline residues. Examples of the linear or branched alkyl residues 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 residues, which are in accordance with his nature must have at least three carbon atoms, are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cyclic alkyl residues may optionally be associated with one or more, e.g. 1, 2, 3, or 4 (C1-C4)-alkyl residues, or (C1-C4)-alkyl fluoride residues, for example, methyl groups or triptoreline groups.

Examples of alkoxygroup (= alkyloxy), which is linked via an oxygen atom groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentox, neopentane, isohexane, cyclopropane, CYCLOBUTANE, cyclopentane or cyclohexane. Examples of allylthiourea, which is linked via a sulfur atom, groups are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, tert-butylthio, n-pentylthio, neopentyl, isohexyl, cyclopropylethyl, cyclobutyl, cyclopentyl or cyclohexylthio.

Foralkyl present is employed, an alkyl residue, in which one or more hydrogen atoms in a higher alkyl residue are replaced with fluorine atoms. Alkyl fluoride residue may contain one or more fluorine atoms, for example 1, 2, 3, 4, 5, 6 or 7. As a maximum, can be replaced by all of the hydrogen atoms, that is perversione. Examples of foralkyl are vermeil, 2,2,2-triptorelin or pentafluoroethyl. Feralcode represents a higher CNS residue, in which, as illustrated above, one or more hydrogen atoms replaced with fluorine atoms.

For all alkyl groups in the residues alkoxy-alkoxy, alkoxy-alkoxy-alkoxy, which are connected via an oxygen atom, the above definitions and illustrations apply independently of each other. In divalent alkyl groups contained in these fragments, two free groups, through which these groups are linked with neighboring groups may be in any position, for example, 1,1-position alkyl residue in 1,2-position of the 1,3-position or 1,4-position. 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. Preferred divalent residue of this type is 1,2-ethylene. Examples of alkoxy-alkoxy residues are methoxyethoxy, 2-methoxyethoxy, 3-meth is ciprodex, 4 methoxybutyl, 6-methoxyphenoxy, 2-ethoxyethoxy, 2-ethoxy-2-methylethoxy, 3 ethoxypropane, 2-isobutoxide, 2-tert-butoxyethoxy, 2-cyclopropylmethoxy, 2-cyclopentanedione. Examples of alkoxy-alkoxy-alkoxy residues are (2 methoxyethoxy)methoxy, 2-(2-methoxyethoxy)ethoxy, 2-(2-isopropoxyphenoxy)ethoxy, 2-(n-butoxyethoxy)ethoxy, 2-(2-cyclopropylmethoxy)ethoxy, 3-(2-methoxyethoxy)propoxy, 2-(2-methoxy-2-methylethoxy)-2-methylethoxy.

Examples of halogen are fluorine, chlorine, bromine and iodine, in particular fluorine and chlorine.

The present invention includes all stereoisomeric forms of the compounds of formula I. Each of the asymmetric centers contained in the compounds of the formula I, for example, in the group Y may, independently, have the S-configuration or R-configuration. The invention includes all possible enantiomers and diastereoisomers, and also mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers or diastereomers. Therefore, the invention includes enantiomers in enantiomerically pure form, both as levogyrate, and programalso antipodes, in the form of racemates and in the form of a mixture of two enantiomers in any ratio. The invention includes diastereomers in pure form and in the form of a mixture of two or more diastereomers in all proportions. Also included, for example, meso -, with the organisations. If you have a CIS/TRANS isomerism, the invention includes both the CIS-form and TRANS-form, and mixtures of these forms in all ratios. Individual stereoisomers can be obtained, if desired, by separation of the mixture in accordance with conventional ways, for example by chromatography or crystallization, or by using the stereochemical synthesis of homogeneous materials. If it is convenient, before separation of the stereoisomers can be carried out obtaining derivatives. The mixture of stereoisomers may be separated at the stage of preparing compounds of the formula I or at the stage of obtaining the intermediate products in the synthesis process. The invention also includes all tautomeric forms of compounds of formula I.

Physiologically acceptable salts of the compounds of formula I are, in particular, used pharmaceutically salt or non-toxic salts. They may contain inorganic or organic salts (see also Remington's Pharmaceutical Sciences (A.R.Gennaro (editor). Mark Publishing Co., Easton PA, 17th edition, str (1985)). Such salts, for example, can be obtained from compounds of formula I and a suitable inorganic or organic bases, for example compounds of alkali metals or alkaline earth metals such as sodium hydroxide or potassium hydroxide, or ammonia, or organic aminos is dinani, or ammonium hydroxides. The reaction of compounds of formula I with bases to obtain the salts are usually carried out according to conventional methods in the solvent or diluent. Salts, which are preferred due to their physiological and chemical stability, in many cases, are salts of sodium, potassium, magnesium or calcium or ammonium salts, in particular sodium salts. The salt formation on the nitrogen atom of the group (thio)urea-related sulfonyloxy group, gives compounds of formula II

where R1, R2, E, X, Y and Z have the above values, and the cation M is, for example, alkali metal ion or an equivalent of an alkali earth metal ion such as sodium ion, potassium, magnesium or calcium, or ion unsubstituted ammonium, or ammonium ion having one or more organic substituents. Ion ammonium representing M, can also be, for example, cation obtained by protonation of amino acids, in particular basic amino acids such as lysine or arginine.

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

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

If R2in the formula I is halogen, the remainder preferably represents chlorine or fluorine. If R2in the formula I represents a C1-C6)-alkyl, the remainder is preferably (C1-C4)-alkyl, in particular the stands. If R2in the formula I represents a C1-C6)-alkoxy, the residue is preferably (C1-C4)-alkoxy, in particular methoxy. If R2in the formula I represents a C1-C6)-alkoxy-(C1-C4)-alkoxy, the residue is preferably (C1-C4)-alkoxy-(C1-C4)-alkoxy, in particular 2-((C1-C4)alkoxy)ethoxy-especially 2-methoxyethoxy. If R2in the formula I represents a C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, the residue is preferably (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, in particular 2-(2-((C1-C4)-alkoxy)ethoxy)ethoxy-especially 2-(2-methoxyethoxy)ethoxy. A group of preferred residues R2founded residues (C1-C6)-alkyl, (C1-C6)-alkoxy and (C1-C6)-alkoxy-(C1-C4)-alkoxy, in particular residues of the (C 1-C6)-alkoxy and (C1-C6)-alkoxy-(C1-C4)-alkoxy, especially the remnants of methoxy and 2-methoxyethoxy-.

The remains of R3independently preferably represent hydrogen or methyl, particularly preferably hydrogen, n is preferably 2 or 3. The group Y preferably contains up to four carbon atoms. Particularly preferably, Y represents a group -(CH2)n-where n is 2 or 3, or a group-CHR3-CH2-, in which R3represents methyl or ethyl, and the group CHR3linked with the NH group. Particularly preferably, when Y represents a group-CH2-CH2-.

X preferably represents halogen or (C3-C6)-alkyl, for example fluorine, chlorine, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl or 1,1-dimethylpropyl, in particular chlorine or tert-butyl. Z preferably represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl, particularly preferably (C1-C4)-alkoxy, for example methoxy. Residues X and Z can be in any position of the phenyl residue, to which they are attached. Preferably X is attached in the 5-position, and Z in the 2-position of the phenyl residue, in each case in relation to the group C(=O)-NH located in the 1-position.

If in the compounds of the formula I according to the invention GRU is PA E represents oxygen, the compounds are urea of the formula Ia. If E is sulfur, the compounds are thiourea of formula Ib. Preferably E is sulfur.

Preferred compounds of formula I for use according to the invention are compounds in which one or more residues are preferred values, all combinations of preferred values represent the object of the present invention.

For example, preference is given to using compounds of the formula I, in which R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently of one another represent hydrogen or (C1-C2)-alkyl, AP is 1, 2, 3, or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

Special preference is given to using compounds of the formula I, in which R1represents hydrogen or methyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently of one another, represent hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

Preference also gives the I to the use of compounds of the formula I, in which

R1represents hydrogen or methyl;

R2represents hydrogen or halogen;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently of one another, represent hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

In particular, preference is also given to the use of compounds of the formula I, in which

R1represents hydrogen or methyl;

R2is (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)nin which the residues R3each independently of one another, represent hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-al the sludge;

Z represents a C1-C4)-alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

More specifically, preference is also given to the use of compounds of the formula I, in which

R1represents hydrogen or methyl;

R2is (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy or (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy,

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)nin which the residues R3each independently of one another, represent hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4) -alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

Special preference is given to using compounds of the formula I, in which

R1represents hydrogen or methyl;

R2represents methyl, methoxy or 2-methoxyethoxy-;

E represents oxygen or sulfur;

Y present is employed, the hydrocarbon residue of the formula -(CR

3
2
)nin which the residues R3each independently of one another, represent hydrogen or methyl, and n is 2 or 3;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

Particular preference is given to using compounds of the formula I, in which

R1is methyl;

R2represents methyl, methoxy or 2-methoxyethoxy-;

S is sulfur;

Y is a hydrocarbon residue of the formula -(CH2)nin which n is 2 or 3;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy;

in all their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts.

The compounds of formula I according to the invention can be obtained, for example, the methods described below.

(a) Aromatic sulfonamides of the formula III or their salts of the formula IV may interact with R1-substituted isocyanates of the formula V, to obtain the substituted benzosulfimide formula Ia:

Suitable cations M1the salts of formula IV are alkali metal ions or alkaline earth metal ions, such as sodium ions or potassium ions, or ammonium ions, such as, for example, tetraalkylammonium ions. Equivalent to R1-substituted the isocyanates of the formula V, it is also possible to use R1-substituted esters karbinovykh acids, R1-substituted carbamoylated or R1-substituted urea.

(b) Benzosulfimide formula Ia, which are unsubstituted on the urea group and in which R1represents hydrogen, can be obtained by interaction of aromatic benzosulfimide formula III or their salts of the formula IV with triallylisocyanurate, such as trimethylsilyltriflate, or territorialisation silicon and hydrolysis of the initially formed silicon-substituted benzosulfimide. In addition, the compounds of formula Ia, in which R1represents hydrogen, can be obtained from benzosulfimide formula III or their salts of the formula IV interaction with halogenand and hydrolysis of the initially formed N-cyanocarbonimidate mineral acids at temperatures from 0°to 100°C.

(c) Benzosulfimide formula Ia can be obtained from aromatic benzosulfimide formula III or their salts fo the mules IV using R 1-substituted trichloroacetamido formula VI in the presence of a base in an inert solvent in accordance with the method described in the publication Synthesis 1987, 734-735 at a temperature of from 25°to 150°C.

Suitable bases are, for example, hydroxides, hydrides, amides or alkoxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, ethoxide sodium, potassium methoxide or ethoxide potassium. Suitable inert solvents are ethers, such as tetrahydrofuran, dioxane or 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-organic (NMP), hexamethylphosphorotriamide, sulfoxidov, such as dimethylsulfoxide (DMSO), sulfones such as sulfolane, hydrocarbons, such as benzene, toluene, xylenes. Moreover, mixtures of these solvents are also suitable.

(d) Benzosulfimide formula Ib can be obtained from benzosulfimide formula III or their salts of the formula IV and R1-substituted isothioscyanates formula VII

Benzosulfimide formula Ib, which have no substituents from the group of thiourea, and in which R1represents hydrogen, can be obtained by interaction of aromatic benzosulfimide formula III or their salts of the formula IV with triallylisocyanurate, such as trimethylsilyldiazomethane, or territorialisation silicon and hydrolysis of the initially formed silicon-substituted benzosulfimide. In addition, the compounds of formula Ib, in which R1represents hydrogen, can be obtained by interaction of aromatic benzosulfimide formula III or their salts of the formula IV with benzoylisothiocyanate and the subsequent interaction of the intermediate compounds benzoyl-substituted benzosulfimide with aqueous mineral acids. Similar methods are described in J.Med.Chem., 1992, 35, 1137-1144.

(e) Substituted benzosulfimide formula Ia can be obtained by the reactions of transformation of benzosulfimide formula Ib. Desulfurization, i.e. the substitution of the sulfur atom in the corresponding benzosulfimide on the oxygen atom, can be carried out, for example, the addition of oxides or salts of heavy metals or using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid. Timoci the ins can also be desulfuromonas treatment with phosgene or pentachloride phosphorus. As intermediates get amidine Harborview acid or carbodiimide that can be converted into the corresponding substituted benzosulfimide, for example, by hydrolysis or by the addition of water.

(f) Benzosulfimide formula Ia can be obtained from benzosulphochloride formula VIII using R1-substituted ureas or R1-substituted bis(trialkylsilyl)ureas. Trialkylsilyl protective group can be removed from the received (trialkylsilyl)benzosulfimide in accordance with standard methods. In addition, sulphonylchloride formula VIII can interact with paranavai acid, giving benzolsulfonate acid, the hydrolysis of which mineral acids gives the corresponding benzosulfimide formula Ia.

(g) Benzosulfimide formula 1A can be prepared by the interaction of amines of the formula R1-NH2with benzolsulphonate formula IX. Similarly, amines of the formula R1-NH2can interact with esters benzensulphochloramide acid, with carbamoylation or benzosulfimide formula Ia, in which R1represents hydrogen, giving the compounds of formula Ia.

(h) Benzo is sulfanilimide formula Ib can be obtained by the interaction of amines of the formula R 1-NH2with benzolsulphonate formula X. Similarly, amines of the formula R1-NH2can interact with thioethers benzensulphochloramide acid or-carbamoylation, giving the compounds of formula Ib.

(i) appropriately substituted benzazolyl or sulfonylation can be oxidized oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid, giving benzosulfimide formula Ia.

Source materials for the above-mentioned methods of synthesis of compounds of formula I can be obtained by known methods, such as described in the literature (for example, in standard methods, for example, Houben-Weyl, Methods der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; or in the above patent references), and known or suitable for the specified reaction conditions. Options ways that are known in themselves, but which are not mentioned in more detail in this description can also be used for these reactions. If desired, the starting materials can also be obtained in situ, i.e. they are not separated from the reaction mixture, and immediately subjected to further interaction.

Thus, the appropriately substituted amines of formula XI can be proanimirovany and subjected to what halogencontaining. In the formula XI, R2and Y have the above values.

Suitable alleluya agents for acylation of the amino group in compounds of formula XI are basically alkalemia esters, halides (e.g. acid chlorides or bromohydrin) or anhydrides of carboxylic acids of formula R4-COB. Here R4for example, is trihalomethyl residue, (C1-C4)-alkyl residue or a phenyl residue. If R4represents phenyl residue, the compound of formula R4COB is a derivative of benzoic acid. A derivative of benzoic acid may be unsubstituted or substituted by one or two identical or different groups X and Z. Here X and Z are as defined above, that is, X may be hydrogen, (C1-C6)-alkyl or halogen, and Z may be a halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy or nitro-group. The group represents a leaving group such as, for example, halogen, (C1-C4)-alkoxy, trichloracetate or (C1-C4)-alkylcarboxylic. Examples of compounds of the formula R4-COB are acetic anhydride, trigalogenmetany anhydride, acetic acid halides, halides of trialgebras the Oh of the acid, propionate, isobutyrate and isobutylene, the anhydride of formic acid/acetic acid, benzoyl chloride and substituted derivatives of benzoic acid such as 5-chloro-2-methoxybenzoate or anhydride 5-chloro-2-methoxybenzoic acid or (C1-C4)-alkyl-5-chloro-2-methoxybenzoate, 5-tert-butyl-2-methoxybenzoate or 2.5-differentiald. The synthesis of compounds of the formula XII is preferably carried out with addition as the basis of a tertiary amine, such as pyridine or trialkylamine, in the presence or absence of an inert solvent, it is also possible presence of a catalyst, such as, for example, dimethylaminopyridine. The reaction is preferably carried out at a temperature in the range from approximately 0°and up to 160°C, preferably at temperatures from 20°150°C. Acyl group in compounds of formula XII may represent a protective group, or in the case of derivatives of benzoic acid can be a part of the compounds of formula I. Suitable inert solvents for the acylation are, for example, ethers such as tetrahydrofuran, dioxane, or ethers of glycol, such as onomatology ether of ethylene glycol or monotropy ether of ethylene glycol (methylglycol or ethylglycol) or dimethyl ether of ethylene glycol, ketones, such is as acetone or butanone, NITRILES, such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides, such as DMF or NMP, hexamethylphosphorotriamide, sulfoxidov, such as DMSO, chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride, or hydrocarbons such as benzene, toluene or xylenes. Also suitable are mixtures of these solvents with each other.

Sulfonamides of formula XIII can be obtained from compounds of formula XII by known methods using suitable and well-known reaction condition.

Can also be used in known ways such reactions, which are not mentioned in more detail in this description. If desired, the synthesis can be carried out in one, two or several stages. Especially preferred are the ways in which the acylated amines of the formula XII is transformed into aromatic sulfonic acids or their derivatives, such as halides sulfonic acid (sulphonylchloride), under the action of electrophilic reagents in the presence or in the absence of inert solvents at temperatures between -10°to 120°C, preferably from 0°to 100°C. Can be performed, for example, sulfonation using servicesat or oleum, halogencontaining using halogencontaining acids, reactions with sulfurylchloride in the presence of anhydrous metal halides or reaction with thionylchloride in the presence of anhydrous metal halides with subsequent oxidation carried out by known methods of obtaining aromatic sulphonylchloride. If the primary products of the reactions are a sulfonic acid, they can be converted into halides sulfonic acids, either directly or in the processing of tertiary amines, such as, for example, pyridine or trialkylamine, or hydroxides of alkaline or alkaline earth metals, or compounds which form these key compounds in situ, in a known manner using acid halides, such as, for example, trihalogen phosphorus, pentachloride phosphorus, oxychloride phosphorus, thionylchloride or oxaliplatin. The transformation of the derivatives of sulfonic acid sulfonamides can be made by the method known from the literature. Preference is given to the interaction of sulphonylchloride in inert solvents at temperatures from 0°to 100°With aqueous ammonia in the absence or in the presence of an organic solvent. In addition, aromatic sulfonamides can be synthesized in accordance with the written literature of the acylated amines of the formula XII interaction with (alkaline or alkaline earth) metal-organic reagents in an inert solvent in the atmosphere of inert gas at a temperature from -100°C to 50°C, preferably from -100°With 30°and sulfur dioxide and subsequent processing by heating amidosulfonic acid.

If the acyl group in the compound of formula XIII acts as a protective group of amino group, the protective group can be removed by treatment with acids or bases after the introduction sulfonamidnuyu group. The splitting of water by the acid or acids in inert solvents can lead to the formation of acid additive salts of amino compounds. Removal of such protective groups are suitable, for example, sulfuric acid, halogen acids such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid or organic acid. Removing the amino-protective group in the compound of formula XIII using bases can be carried out in water or inernej solvents. Suitable bases are, for example, hydroxides of alkali or alkaline earth metals such as sodium hydroxide, potassium hydroxide or calcium hydroxide or alkoxides of alkali or alkaline earth metals, such as sodium methoxide, ethoxide sodium, potassium methoxide or ethoxide potassium. From the thus obtained sulfadimethoxine amines or acid-additive compounds can in order to alocate benzosulfimide formula III by acylation of substituted benzoic acids or derivatives of benzoic acid, as illustrated above for the acylation of compounds of formula XI.

The compounds of formula I may have one or more chiral centers. Therefore, upon receipt they can be obtained in the form of a racemate or in addition, when using optically active starting materials in optically active form. If the compounds have two or more chiral center in the synthesis they can be obtained as mixtures of racemates, from which in its pure form can be allocated to the individual isomers, for example, by recrystallization from inert solvents. If desired, the resulting racemates can be separated by known methods, mechanically or chemically, to the enantiomers. So, when interacting with the optically active separating agent from the racemate can be obtained diastereomers. Suitable separation agents for basic compounds, for example, are optically active acids, such as R - or R,R - or S or S,S-forms of tartaric acid, dibenzoyltartaric acid, diatsetilvinny acid, camphorsulfonic acids, almond acid, malic acid or lactic acid. In addition to separation can be allievate carbinol using chiral alleluya agents, for example, R - or S-α-methylbenzenesulfonate, with further separation. Various forms of the diastereomers can be separated famous the mi way for example by fractional crystallization, and the enantiomers can be liberated from the diastereomers in a known manner. Separation of enantiomers, it is also possible using chromatography on optically active stationary phases.

Depending on the nature of the residues R1, R2, R3, E, X, Y and Z in some cases, one or another of the above methods of producing compounds of the formula I is unsuitable or at least will require measures to protect the active groups. Such cases are relatively rare, easily recognized by a person skilled in the art, and will not make any difficulty successfully used in such cases other described methods of synthesis. As to obtain the compounds of formula I used according to this invention, U.S. patent US-A-5574069 (EP-A-612724) and US-A-5652268 (EP-A-727416) specifically included in this invention as a reference.

Due to its ability to reduce or eliminate the lack of functioning vagusnye nervous system and, therefore, vagusnye disorders and/or disorders of the autonomic nervous system, the compounds of formula I are agents useful for the treatment and prevention of diseases that are associated with reduced features or violations vagusnye nervous system or caused by them, or for the treatment or care what those diseases, where the purpose is to increase or normalization of activity vagusnye nervous system. The effect of the compounds of formula I on vagusnye nervous system can be demonstrated, for example, the following pharmacological model in mice. The effect can also be demonstrated, for example, rats, Guinea pigs, rabbits, dogs, monkeys or pigs.

Diseases and pathological painful condition, which shows the treatment or prevention of a reduced function vagusnye nervous system or disorders of the autonomic nervous system, mentioned above. In addition to the General suitability for the treatment or prevention of disorders of the autonomic nervous system and, in particular, vagusnye violations of the compounds of formula I and their physiologically acceptable salts are particularly suitable for use in diseases of the cardiovascular system and heart diseases for the treatment or prevention sympathovagal imbalance or for the treatment and prevention of vagusnye dysfunction of the heart. Examples of heart diseases and painful conditions of this type are coronary heart disease, angina, heart attack, postmyocardial heart attack, heart failure, cardiomyopathy, heart transplantation or vagusnye disorders of the heart in the case of diabetes. As with the unity of the formula I in addition to their known direct action on the heart, that is in addition to the effect on the action potential of cells of the heart muscle, also have an indirect effect on the nervous system or heart on the part of the nervous system that affect the heart, they can reduce or prevent undesirable consequences for the heart, caused or mediated by when considering diseases of the nervous system. So, you can reduce or eliminate further injury, as, for example, the weakening of the activity of the heart or, sometimes, heart arrhythmia, which may be fatal, such as ventricular fibrillation. By eliminating or reducing disturbances of the autonomic nervous system, the compounds of formula I and their physiologically acceptable salts lead to the normalization of the weak activity of the heart and prevent the development of cardiac arrhythmias, which can lead to sudden cardiac arrest. Fields of application of compounds of the formula I and/or their physiologically acceptable salts in the context of the present invention, therefore, are, in particular, used in cases of heart failure and prevention of cardiac arrhythmias, such as ventricular fibrillation, fatal, and for the prevention of sudden cardiac death. The choice of compounds of formula I, having, on the one hand, a suitable profile activity against neposredstvennoj the action on the heart (= direct effect on the potential activity of the cells of the heart muscle and, accordingly, a direct effect on the force of heart contractions and direct antiarrhythmic effect), and on the other hand, affecting the nerves of the heart, may be a particularly effective way favorable effect on heart disease using compounds of formula I. depending on the specific symptoms may also be advantageous to use compounds of formula I having only a relatively weak direct effect on the heart and, respectively, with, for example, only a relatively weak direct impact on the strength of cardiac contractions or the development of arrhythmias, but which can improve or normalize the activity of the heart or heart rhythm due to the effect on the autonomic nervous system. As already noted, the reduced function vagusnye system and its consequences can also occur temporarily, for example, in the case of oxygen deficiency of the heart. Therefore, the compounds of formula I are particularly suitable for use in angina or coronary heart disease, where there is an oxygen deficiency. In addition, the compounds of formula I can generally be used for disorders of the autonomic nervous system, in particular, vagusnye violations that occur in the metabolic for the is of Alemania, such as, for example, diabetes.

The compounds of formula I and their physiologically acceptable salts thus can be used as a medicine for animals, preferably mammals, and particularly humans, in mixtures with one another or with other active compounds, in particular in the form of pharmaceutical preparations (or pharmaceutical compositions). Thus, an object of the present invention is the use of compounds of the formula I and/or their physiologically acceptable salts for getting medicines for the treatment or prophylaxis of the abovementioned syndromes. The object of the present invention is also the use of compounds of the formula I and/or their physiologically acceptable salts for the treatment or prophylaxis of the abovementioned syndromes, and an object of the present invention are methods of treatment or prophylaxis of the abovementioned 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 of such treatment.

Used according to the invention of drugs which contain compounds of the formula I and/or their physiologically acceptable salts, you can enter enterline, for example, orally or rectally, for example in the form of pill is, tablets, film-coated tablets coated with sugar tablets, granules, hard or soft gelatin capsules, suppositories, solutions, such as aqueous, alcoholic or oily solutions, juices, drops, syrups, emulsions or suspensions. Medicines can also be entered parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or solution for infusion. Other suitable forms of introduction are, for example, percutaneous or local injection, for example, in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols or solutions, or use in the form of implants.

Pharmaceutical formulation that can be used in accordance with this invention, can be obtained by known standard methods of obtaining pharmaceutical preparative forms. To this end one or more compounds of the formula I and/or their physiologically acceptable salts are mixed together with one or more solid or liquid pharmaceutical excipients and/or auxiliary additives or excipients and, if desired combined preparative form, together with the additional pharmaceutically active compounds that have medicinal or preventative action, and transferred to the right of the entry form or dosage form, which can then be used as a drug in medicine or veterinary medicine. Pharmaceutical formulation include a therapeutically or prophylactically effective dose of the compounds of the formula I and/or their physiologically acceptable salts, which typically ranges from 0.5 to 90% by weight of the pharmaceutical formulation. The number of active compound of the formula I and/or physiologically acceptable salts in the pharmaceutical formulation is usually from 0.2 to 1000 mg, preferably from 0.2 mg to 500 mg, particularly preferably from 1 mg to 500 mg per unit dosage preparative form, but it can also exceed this amount, depending on the nature of the pharmaceutical drug.

Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral (e.g. intravenous) administration, or topical administration and which do not interact in undesirable ways with the active compounds, such as, for example, water, vegetable oils, alcohols, such as ethanol, isopropanol or benzyl alcohols, 1,2-propandiol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petrolatum, acetonitrile, dim telharmonic, dimethylacetamide. Is also possible to use mixtures of two or more fillers, for example, mixtures of two or more solvents, in particular mixtures of one or more organic solvents with water. As auxiliary additives or excipients of the pharmaceutical formulation may contain, for example, stabilizers, wetting agents, emulsifiers, soljubilizatory, thickeners, salts, for example, for influencing the osmotic pressure, lubricants, preservatives, colorants, flavoring agents, flavoring agents and/or buffer substances. If necessary, they can also include one or more additional active compounds/ for example, one or more vitamins. Also the compounds of formula I and/or their pharmaceutically acceptable salts can be subjected to lyophilization and use the resulting lyophilizate, for example, to obtain compositions for injection. Also suitable are liposomal formulation, in particular for local injection.

The dose for administration of the active compounds of formula I and/or physiologically acceptable salts, when used according to the invention depends on the individual case and, as usual, it must be adapted to the individual circumstances to achieve an optimum effect. Therefore, it C is dependent on the nature and severity of the disease, being treated, as well as gender, age, weight and individual responsiveness of the human or animal being treated, the effectiveness and duration of action of the compounds used, whether the treatment of acute or chronic treatment or used for prevention, or on whether other active compounds in addition to the compounds of formula I. Typically, the interval of the dose for treating disorders of the autonomic nervous system for people of about 0.1 mg to about 100 mg per kg per day with the introduction of an adult weighing about 75 kg is adequate to achieve the desired effect. The preferred dose range from about 1 mg to about 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 may be divided into a greater number of individual doses, for example two, three or four. It is also possible to perform the continuous introduction. Depending on individual behaviour may need to increase or decrease the initial daily dose.

In addition to the action on the autonomic nervous system, it has also been found that the compounds of formula I possess a synergistic effect together with blockers beta-receptors, which can mainly be used for treatment and the pros who ACTICE heart disease, such as, for example, heart failure. As is known, the use of blockers of beta-receptors at low doses improves symptoms in cases of heart failure due to suppression of the sympathetic part of the autonomic nervous system, whereas the compounds of formula I restore the balance between the vagus and sympathetic nerves, primarily by stimulation of the vagus nerve. As demonstrated in the following experiments on animals, the combination of compounds of formula I and blockers beta-receptors showed superadditive or synergistic effect in the prevention of heart disease or cardiac activity, and therefore this combination is particularly suitable, for example, to improve symptoms in cases of heart failure or to prevent or reduce cardiac arrhythmia, such as ventricular fibrillation, or to prevent sudden cardiac death. In other words, the compounds of formula I significantly improve the effect of blockers of beta-receptors, for example, on the heart. Thus, the compounds of formula I are particularly suitable for combining with receptors beta-blockers.

Therefore, an object of the present invention is the treatment and prevention of the above-mentioned heart disease, such as, e.g. the measures heart failure, angina, heart attack, postmyocardial infarction or cardiac arrhythmia, such as ventricular fibrillation, or the prevention of sudden cardiac death, and the treatment and prevention of disorders of the autonomic nervous system, in particular vagusnye violations, especially vagusnye disorders of the heart using one or more compounds of the formula I and/or their physiologically acceptable salts in combination with one or more blockers beta-receptors and/or their physiologically acceptable salts. The object of the present invention is also the use of compounds of the formula I and/or their physiologically acceptable salts to obtain drugs for such combined treatment or combination prevention, and the object of the invention are methods of such a combined treatment or combination prevention. In addition, the object of the invention is a combination of one or more compounds of the formula I and/or their physiologically acceptable salts and one or more blockers beta-receptors and/or their physiologically acceptable salts for simultaneous, separate or sequential use in the above mentioned conditions.

In the combined treatment or combination prevention according to the invention the representatives of the two classes of active compounds can be administered as pharmaceutical compositions where both included in the same pharmaceutical unit dosage form, for example in a tablet, that is in the form of a combination pharmaceutical composition. But just the same they can be entered separately, for example in the form of pharmaceutical compositions, each of which includes representatives of only one of the two classes of active compounds, in this case, the representatives of the two classes of active compounds can be introduced simultaneously, consecutively or sequentially, including, for example, after introduction of the relatively large period of time. All data types introduction included in the scope of the present invention. Depending on the characteristics of the individual case, may be more successful introduction of representatives of the two classes of active compounds in the form of a combination pharmaceutical compositions in which they are present together in a fixed ratio in the same pharmaceutical preparative form, or introducing them separately in the form of more than one, for example two separate pharmaceutical compositions, each of which contains, for example, only one active connection. In the latter case, separate pharmaceutical compositions, forming a set of parts, may be Packed together in a suitable primary packaging, in which adaweya in a common outer packaging optionally together with instructions for use, related to the combined use according to the invention, or separate pharmaceutical compositions can be in a separate outer packaging, if desired, together with instructions in each pack, for use, indicating that the combined use according to the invention. All such products and release forms suitable for use according to the invention, included in the scope of the present invention.

Accordingly, an object of the present invention are also products that includes one or more compounds of formula I

in which R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independent is about represents hydrogen or (C 1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C6)-alkyl;

in any of their stereoisomeric forms and their mixtures in all proportions; and/or their physiologically acceptable salts in combination with or as a combined preparation with one or more blockers beta-receptors and/or their physiologically acceptable salts, for simultaneous, separate or sequential use for the treatment or prevention of disorders of the autonomic nervous system, vagusnye violations, vagusnye heart disorders or for the treatment or prevention of the above diseases, particularly heart disease, such as heart failure, angina, heart attack, postmyocardial infarction or cardiac arrhythmia, such as ventricular fibrillation, or to prevent sudden cardiac arrest.

The object of the present invention, in particular, are these pharmaceutical combination formulation, in which the representatives of the two classes of active compounds are present together in the same pharmaceutical compositions, that is, a pharmaceutical formulation that includes one or more connections fo the mules I

in which R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C6)-alkyl;

in any stereoisomeric form or their mixtures in all proportions; and/or their physiologically acceptable salts, one or more blockers beta-receptors and/or their physiologically acceptable salts and physiologically acceptable carrier, i.e. one or more physiologically acceptable excipients and/or auxiliary additives or auxiliary substances.

All of beseitigen the I information for example, regarding fillers, excipients and auxiliary additives for pharmaceutical forms such as tablets, coated sugar tablets, capsules or solutions, and their reception, the possible forms of administration, such as oral or intravenous maintenance, use in human or veterinary medicine, or related diseases that can be treated, etc. that apply respectively for the above products and pharmaceutical compositions. In this context blockers beta-receptors should be considered as an example of the additional pharmaceutically active compounds which, in addition to the compounds of formula I may be present in the above-described pharmaceutical compositions. All the data given above for the compounds of formula I also apply, respectively, for compounds of formula I contained in the pharmaceutical compositions, such as descriptions of individual residues and groups, preferred compounds of the formula I or their salts. Pharmaceutical compositions containing the compounds of formula I together with blockers beta-receptors in the same pharmaceutical preparative form, may also be present in salt, which is formed by compounds of these classes to each other, i.e. salts which contain blocker beta-receptors (liblocation beta-receptors), representing organic amino compounds, in protonated form as the cation of the compound (or compounds) of formula I in deprotonated form as anion. The ratio by weight of compounds of the formula I and blockers beta-receptors in the pharmaceutical compositions in which both the active compounds are present in the same pharmaceutical preparative form usually ranges from 500 to 0.02, preferably from 100 to 0.1 parts by weight of the compound (or compounds) of formula I to a part by weight of blocators beta-receptors (or blockers beta-receptors). For example, the ratio by weight may be about 35 parts by weight of the compounds of formula I on part by weight of the blocker beta-receptor, or it may be approximately 1 part by weight of compounds of formula I on part by weight of the blocker beta-receptors.

As pharmaceutical compositions for use in accordance with the invention that do not contain any blocker beta-receptors, and products and pharmaceutical compositions according to the invention, which contain blockers beta-receptors, as compounds of the formula I preferably contain one or more compounds selected from the group including

1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthio-urea,

1-[[5-[2-(5-chloro-2-IU is oxybenzone)ethyl]-2-

(2 methoxyethoxy)-phenyl]sulfonyl]-3-methylthymidine and

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine and/or their physiologically acceptable salts, preferably salts of these compounds, which are salts of sodium.

Suitable blockers beta-receptors for combinational treatment and Raman prevention according to the invention and for products and pharmaceutical compositions according to the invention are, for example, the following connections: alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutolol, metoprolol, propranolol, nadolol, pindolol, timolol, sotalol, carvedilol, bisoprolol, celiprolol, carazolol, talinolol, mepindolol, carteolol, tertatolol, bopindolol. The preferred blockers beta-receptors are propanolol, atenolol, bisoprolol, and carvedilol.

When combinations of compounds of the formula I with blockers beta-receptors usually to achieve the desired action requires a smaller dose of the compounds of the formula I and/or blockers of beta-receptors than in the case when the compounds are applied only one class of active compounds. The preferred dose of the compounds of formula I in combination with a beta blocker receptor is from about 0.3 mg to about 15 mg, predpochtitelno about 1 mg to about 10 mg per kg of body weight per day. The dose of the blocker beta-receptors in combination depends on the dose, usual to separate the compounds being considered. Preference is given to using the lowest regular dose of the compounds being considered and pending applications. The above data concerning the dose of the compounds of formula I used as individual active compounds, applicable, respectively, for the combined use according to the invention, for example, in relation to the necessary adaptation of the dose to the circumstances of the individual case or to divide the dose individual dose.

Due to their effects on the autonomic nervous system, the compounds of formula I and their salts can be used as pharmaceutically active compounds in medicine and veterinary medicine but also as a research tool or as excipients for biochemical studies, which assume such action, and also for diagnostic purposes, for example, for in vitro diagnostic sample of cells or tissue samples.

The present invention also includes undescribed until now the compounds of formula I per se and their physiologically acceptable salts. In particular, the invention includes new substances per se is described in the working examples, for example, 1-[[5-[2-(5-tert-butyl-2-methox is benzamido)propyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine and its physiologically acceptable salts, including sodium salt, the use of new compounds as pharmaceutically active compounds and pharmaceutical compositions that include one or more of these compounds and physiologically acceptable carrier, i.e. one or more physiologically acceptable excipients and/or additives or auxiliary substances. The above information applies, respectively, to pharmaceutical compositions, fillers and auxiliaries.

In addition to the compounds described in the working examples in accordance with this invention can also, for example, be used the following compounds of formula I.

(1) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)propyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine

(2) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)butyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine

(3) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-ethoxyphenyl]sulfonyl]-3-methylthymidine

(4) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-propoxyphenyl]sulfonyl]-3-methylthymidine

(5) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-ethylphenyl]sulfonyl]-3-methylthymidine

(6) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-were]sulfonyl]-3-methylthymidine

(7) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-isopropylphenyl]sulfonyl]-3-meth is tiomochevina

(8) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-bromophenyl]sulfonyl]-3-methylthymidine

(9) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-forfinal]sulfonyl]-3-methylthymidine

(10) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-trifloromethyl]sulfonyl]-3-methylthymidine

(11) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido) ethyl] -

2-methylthiophenyl]sulfonyl]-3-methylthymidine

(12) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-ethylthiophene]sulfonyl]-3-methylthymidine

(13) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-isopropoxyphenyl]sulfonyl]-3-methylthymidine

(14) 1-[[5-[(5-tert-butyl-2-methoxybenzamido)methyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine

(15) 1-[[5-[2-(5-(1,1-dimethylpropyl)-2-methoxybenzamido)

ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine

(16) 1-[[5-[2-(5-sec-butyl-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine

(17) 1-[[5-[2-(5-n-butyl-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine

(18) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)propyl]-

2-methoxyphenyl]sulfonyl]-3-metalmachine

(19) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)butyl]-2-

methoxyphenyl]sulfonyl]-3-metalmachine

(20) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

ethoxyphenyl]sulfonyl]-3-metalmachine

(21) 1-[[5-[2-(5-tert-butyl-methoxybenzamido)ethyl]-2-

propoxyphenyl]sulfonyl]-3-metalmachine

(22) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

ethylphenyl]sulfonyl]-3-metalmachine

(23) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-were]sulfonyl]-3-metalmachine

(24) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

isopropylphenyl]sulfonyl]-3-methylthymidine

(25) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-bromophenyl]sulfonyl]-3-metalmachine

(26) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-forfinal]sulfonyl]-3-metalmachine

(27) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-trifloromethyl]sulfonyl]-3-metalmachine

(28) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-methylthiophenyl]sulfonyl]-3-metalmachine

(29) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-ethylthiophene]sulfonyl]-3-metalmachine

(30) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-isopropoxyphenyl]sulfonyl]-3-metalmachine

(31) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-methoxyphenyl]sulfonyl]-3-metalmachine

(32) 1-[[5-[2-(5-(1,1-dimethylpropyl)-2-methoxybenzamido)

ethyl]-2-methoxyphenyl]sulfonyl]-3-metalmachine

(33) 1-[[5-[2-(5-sec-butyl-2-methoxybenzamido)ethyl]

-2-methoxyphenyl]sulfonyl]-3-metalmachine

(34) 1-[[5-[2-(5-n-butyl-2-methoxybenzamido)ethyl]-

2-methoxyphenyl]sulfonyl]-3-metalmachine

(35) 1-[[5-[2-(5-what isopropyl-2-methoxybenzamido)ethyl]

-2-methoxyphenyl]sulfonyl]-3-metalmachine

Examples

Example 1. 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]

-2-methoxyphenyl]sulfonyl]-3-methylthymidine

0,286 g (of 0.68 mmol) 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxybenzenesulfonamide was dissolved in 7.5 ml of dimethylformamide and, after addition of 0.1 g of potassium carbonate, were mixed with 0.68 ml of a 1M solution methylisothiocyanate 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 under vacuum and dried in the air. The product has a melting point 201-203°C.

Obtaining source materials

1.51 g (10.0 mmol) of 2-(4-methoxyphenyl)ethylamine was dissolved in 40 ml of pyridine and mixed with taken on the tip of a spatula 4-dimethylaminopyridine and then with a solution of 2.15 g(10.5 mmol) of 5-tert-butyl-2-methoxybenzonitrile. After complete conversion of 2-(4-methoxyphenyl)ethylamine, the reaction mixture was poured into cold diluted hydrochloric acid and precipitated precipitated product was filtered under vacuum and dried, obtaining 5-tert-butyl-2-methoxy-N-[2-(4-methoxyphenyl)ethyl]benzamide in the form of a colorless solid. Benzamide was injected into the cold chlorosulfonic acid. After full conversion of benzamide reaction mixture was poured into Les and filtered under vacuum and the residue was dissolved in acetone. This solution was mixed with an excess of concentrated aqueous ammonia. After the weakening of the exothermic reaction the mixture was concentrated to one third its original volume and the precipitate was filtered under vacuum. Received 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxy-benzosulfimide in the form of colorless crystals with a melting point 165-168°C.

Example 2.

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-metalmachine

0,252 g (0.5 mmol) 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine (example 1) was dissolved in 2.5 ml of 2n aqueous sodium hydroxide solution and mixed under ice cooling with 0.25 ml of 30%hydrogen peroxide. The solution was stirred at room temperature for 24 hours and poured into a mixture of ice-water and 2n hydrochloric acid. Air drying gave white crystals with a melting point 209-212°C.

Example 3. 1-[[5-[2-(5-Isopropyl-2-methoxybenzamido)ethyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine

The product was obtained according to the method of example 1. The obtained white crystals with a melting point 177-179°C.

Example 4. 1-[[5-[2-(5-Chloro-2-methoxybenzamido)ethyl]-

2-methoxyphenyl]sulfonyl]-3-methylthymidine

On the doctrine of the substance described in the patent US-A-5574069 (EP-A-612724), included in this description as a reference and the contents of which relating to the receipt of this substance, is part of the present description.

Example 5. 1-[[5-[2-(5-Chloro-2-methoxybenzamido)ethyl]-2-

(2 methoxyethoxy)phenyl]sulfonyl]-3-methylthymidine

This matter is described in the patent US-A-5652268 (EP-A-727416), which is included in this description as a reference and the contents of which relating to the receipt of this substance, is part of the present description.

Example 6. 1-[[5-[2-(5-tert-Butyl-2-methoxybenzamido)ethyl]-

2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthymidine

The product was obtained according to the method of example 1, using 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)-benzosulfimide. Instead of potassium carbonate as a base in the reaction with methylisothiocyanate used sodium hydride 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-methoxy-benzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine

is 4.93 g of 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine (example 1) were introduced in 32 ml of methanol, in which you have previously dissolved 0,425 g t is ejogo sodium hydroxide. After 15 minutes of mixing to the transparent solution was added 125 ml tert-butyl methyl ether. Sodium salt was allowed to crystallize with stirring and then was filtered in vacuum, washed with a small amount of cold methyl tert-butyl ether and dried. Output 5,09, melting point: 235-250°C (decomposition). IR spectrum (Nujol): 1646,1 cm-1.

Examples of pharmaceutical preparative forms.

Example: Tablet

To obtain tablets 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine (example 4), nitrosamino hydroxypropylcellulose (H-MPC), polyvinylpyrrolidone (Povidone 25) and cross carmellose sodium (cross-stitched sodium carboxymethyl cellulose) was grained, moistening with water. The granules were passed through 1-1,5 mm sieve, mixed with the cross carmelose sodium and magnesium stearate and pressed into tablets.

Amount per tablet:

The compound of example 4 600 mg

H-MPC 95 mg

Povidone 25 15 mg

Cross-carmellose sodium 60 mg

Magnesium stearate 20 mg

Example C. an Aqueous solution for intravenous injection

To obtain 10 ml of a solution containing 10 mg of active compound per ml, 100 mg of sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine (see example 4) was dissolved in 10 ml of isotonic (0.9% to ncentrate) solution of sodium chloride.

Pharmacological studies 1. Action to violations associated with the vagus nerve

Substances investigated using the model of ventricular fibrillation in mice induced by chloroform (see J.W. Lawson, Antiarrthmic activity of some isoquinoline derivatives determined by a rapid screening procedure in the mouse; J. Pharmacol. Exp. Ther., 1968, 160, 22-31). The test substance was dissolved in a mixture of dimethyl sulfoxide (DMSO) and 10%aqueous sodium bicarbonate solution and was injected intraperitoneally (I.P. Pavlova.). After 30 minutes the mouse was anestesiologi chloroform in the beaker. Once during deep anesthesia was observed to stop breathing (stage toxic anesthesia), the chest of the animal was cut open using a pair of scissors and examined visually heartbeat. Here, at first glance, to define does your heart beats, fibrillary or stopped. Caused by chloroform stop breathing, leads, through absolute anoxia (lack of oxygen), in combination with a direct stimulating effect of chloroform on the sympathetic nervous system to the powerful stimulation of the sympathetic part of the autonomic nervous system, which, in turn, combined with the lack of energy in the heart, caused by lack of oxygen leads to arrhythmia, fatal, i.e. to ventricular fibrillation. Such toxic anesthesia with chloroform resulted in ventricular fibrillation in 100% with ucaev mice, not subjected to the treatment (control). The percentage of mice with ventricular fibrillation in individual study groups are presented in table 1.

Table 1

Induced by chloroform of fibrillatio ventricles in mice
Substance (dose)Share fibrillyatsy (%)
without atropinewith atropine (1 mg/kg intravenously)
The control without treatment100%100%
Example 1 (3 mg/kg, intraperitoneally)30%#90%*
Example 2 (1 mg/kg, intraperitoneally)60%#100%*
Example 3 (3 mg/kg, intraperitoneally)60%#
Sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (example 4) (10 mg/kg, intraperitoneally)50%#90%*
Example 5 (10 mg/kg, intraperitoneally)60%#100%*
Carbachol (60 mg/kg intravenously)60%#100%*
Physostigmine (1 mg/kg subcutaneously)70%#100%*
# significant inhibition of prophetic is Tami fibrillyatsy poly (n=10) compared with control animals (n=300), p<0,005

* significantly reduced the protective action of substances by using atropine (n=10), p<0,05

The results show that the compounds of formula I reduce the appearance of fibrillyatsy ventricles. The observed influence of atropine, classical muscarinic blocker (vagusnye) receptors of the autonomic nervous system, which blocks the action vagusnye transmitter acetylcholine at the receptor level, indicates that the mechanism of action. Atropine reduces or prevents the protective effect of the compounds of formula I. Such neutralization atropine protective action of substances clearly indicates vagusnye mechanism of action. A similar protective effect may be caused by vagusnye stimulation using carbachol, a more stable analogue of natural vagusnye transmitter acetylcholine, where the protective effect can also be inhibited by atropine. In addition, the cholinesterase inhibitor physostigmine, which reduces the decomposition of acetylcholine mimics the protective effect of the compounds of formula I, the effect of which is also kind of balanced out by atropine.

2. The effect of combinations of compounds of the formula I with blockers beta-receptors

On the same animal model, which is described earlier in the experiment “Effect on vagusnye violations”, it was demonstrated that combined the automated processing blockers beta-receptors and compounds of the formula I leads to a favourable synergistic effect. Active compounds were injected i.v. (intravenously) or I.P. Pavlova. (intraperitoneally). In one experiment, 10 mg/kg of sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (example 4; dissolved in DMSO/10%sodium bicarbonate solution) was combined with 0.3 mg/kg propanolol (dissolved in distilled water), which is the usual beta-blocker. It was found that the combined pre-treatment of animals two substances gave a synergistic effect. Statistically significant, the percentage of fibrillyatsy could be further reduced in comparison with the individual substances. For comparison used 10 times higher dose of propanolol, component 3 mg/kg). It is shown that 0.3 mg/kg propanolol in combination with 10 mg/kg of sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine has about the same effect as 3 mg/kg propanolol or even exceed the dose of propanolol 3 mg/kg In another experiment similarly combined 3 mg/kg 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (example 1) and 3 mg/kg of atenolol. The results of the combined treatment are presented in table 2.

Table 2

Sin is ergicheskoe action of the compounds of formula I and blockers beta-receptors
Substance (dose)The share of atrial %
The control without treatment (n=100)100%
Sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (see example 4) (10 mg/kg, intravenously)50%*
propranolol (0.3 mg/kg, intravenously)37%*
propranolol (3 mg/kg, intravenously)17%*
Sodium salt of 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (10 mg/kg, intravenously) plus propranolol (0.3 mg/kg, intravenously)10%*#
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine (example 1) (3 mg/kg, intraperitoneally)53%*
atenolol (3 mg/kg, intravenously)48%*
1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-

methoxyphenyl]sulfonyl]-3-methylthymidine (example 1) (3 mg/kg, intraperitoneally) plus atenolol (3 mg/kg, intravenously)
25%*#
* p<0.001 in comparison with control without treatment; # P<0,05 in comparison with blocker beta-receptor or a compound of formula I; n=30 for all treated groups.

1. Application benzazolyl(thio)urea of the formula I

where R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each, independently, represents hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl;

in any of its stereoisomeric forms and/or their mixtures in any ratio, and/or its physiologically acceptable salts, provided that the compound of formula I is not

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiophenol;

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-metallocenes is th;

1-[[5-[2-(5-isopropyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiophenol;

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthiophenol and their physiologically acceptable salt, to obtain drugs for treatment or prevention of disorders of the autonomic nervous system.

2. The use of the compounds of formula I in any of its stereoisomeric forms and mixtures thereof in any ratio and/or its physiologically acceptable salts according to claim 1, where in formula I

R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)nin which the residues R3each independently represents hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3 -C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl.

3. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, and/or its physiologically acceptable salts according to any one of claims 1,2, where in formula I

R1represents hydrogen or methyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy.

4. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, and/or its physiologically acceptable salts according to any one of claims 1 to 3, where in formula I

R1represents hydrogen or methyl;

R2is (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkoxy or (C1-C4)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents hydrogen or methyl, and n is 1, 2, 3 or 4;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy.

5. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio and/or its physiologically acceptable salts according to any one of claims 1 to 4, wherein in the formula I

R1represents hydrogen or methyl;

R2represents methyl, methoxy or 2-methoxyethoxy-;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents ogorodili methyl, and n is 2 or 3;

X represents halogen or (C3-C6) -alkyl;

Z represents a C1-C4)-alkoxy.

6. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio and/or its physiologically acceptable salts according to any one of claims 1 to 5, where in formula I

R1is methyl;

R2represents methyl, methoxy or 2-methoxyethoxy-;

S is sulfur;

Y is a hydrocarbon residue of the formula -(CH2)nwhere n is 2 or 3;

X represents halogen or (C3-C6)-alkyl;

Z represents a C1-C4)-alkoxy.

7. The use according to any one of claims 1 to 6, using at least one of the compounds 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthio-urea and 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-(2-methoxy-ethoxy)phenyl]sulfonyl]-3-methylthymidine and/or their physiologically acceptable salts.

8. The use according to any one of claims 1 to 7, where the compound of formula I is used in the form of its sodium salt.

9. The use according to any one of claims 1 to 8, where receiving the drug for treatment or prevention of disorders associated with the vagus nerve.

10. The use according to any one of claims 1 to 9, where receiving the drug for treatment or prevention and disruption of the heart, associated with the vagus nerve.

11. The use according to any one of claims 1 to 10, where receiving the drug for treatment or prevention of dysfunction of the heart, associated with the vagus nerve, in the case of coronary heart disease, angina, heart attack, postmyocardial heart attack, heart failure, cardiomyopathy or diabetes.

12. The use according to any one of claims 1 to 11, where one or more compounds of the formula I and/or their physiologically acceptable salts are used simultaneously, separately or sequentially in combination with one or more blockers beta-receptors and/or their physiologically acceptable salts.

13. The application indicated in paragraph 12, where the blocker beta-receptor used by one or more compounds selected from a range, including alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutolol, metoprolol, propranolol, nadolol, pindolol, mepindolol, carteolol, timolol, sotalol, carvedilol, bisoprolol, celiprolol, carazolol, talinolol, tertatolol and bopindolol.

14. Product comprising one or more compounds of formula I

where R1represents hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C 6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl;

in any of their stereoisomeric forms and/or their mixtures in any ratio, and/or their physiologically acceptable salts in combination with one or more blockers beta-receptors and/or their physiologically acceptable salts for simultaneous, separate or sequential use for the treatment or prophylaxis of cardiac diseases or disorders of the autonomic nervous system.

15. Pharmaceutical composition comprising one or more compounds of formula I

where R1before the hat hydrogen, methyl or trifluoromethyl;

R2represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkoxy-(C1-C4)-alkoxy-(C1-C4)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-feralcode or (C1-C6-foralkyl;

E represents oxygen or sulfur;

Y is a hydrocarbon residue of the formula -(CR

3
2
)n-in which the residues R3each independently represents hydrogen or (C1-C2)-alkyl, and n is 1, 2, 3 or 4;

X represents hydrogen, halogen or (C1-C6)-alkyl;

Z represents halogen, nitro, (C1-C4)-alkoxy or (C1-C4)-alkyl;

in any of their stereoisomeric forms and/or their mixtures in any ratio, and/or their physiologically acceptable salts, one or more blockers beta-receptors and/or their physiologically acceptable salts and physiologically acceptable medium.

16. Product or pharmaceutical composition according to 14 or 15, comprising one or more compounds of formula I, selected from a range that includes 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-methoxy who enyl]sulfonyl]-3-methylthymidine, 1-[[5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)-phenyl]sulfonyl]-3-methylthymidine and 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine and/or their physiologically acceptable salts.

17. Product or pharmaceutical composition according to any one of p-16 that includes one or more sodium salts of compounds of formula I.

18. Product or pharmaceutical composition according to any one of p-17 containing one or more blockers beta-receptors, selected from a range that includes alprenolol, oxprenolol, penbutolol, bupranolol, metoprolol, betaxolol, atenolol, acebutolol, metoprolol, propranolol, nadolol, pindolol, mepindolol, carteolol, timolol, sotalol, carvedilol, bisoprolol, celiprolol, carazolol, talinolol, tertatolol and bopindolol and/or their physiologically acceptable salts.

19. The compound of the formula

chosen from:

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine;

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-metallocene;

1-[[5-[2-(5-isopropyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine;

1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthymidine and the physical is logically acceptable salt.

20. The connection according to claim 19, which is a sodium salt of 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthymidine.

21. The connection according to claim 19 or 20 as the active agent for the treatment or prevention of disorders of the autonomic nervous system.

22. Pharmaceutical composition for treatment or prevention of disorders of the autonomic nervous system, which includes one or more compounds according to any one of p and 20 and/or their physiologically acceptable salts and physiologically acceptable medium.

Priority items:

10.09.1998 - claims 1 to 18 and claim 19 in part of the first three joints; PP and 22;

14.01.1999 - PP in part 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-(2-methoxyethoxy)phenyl]sulfonyl]-3-methylthymidine and paragraph 20.



 

Same patents:

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

The invention relates to new substituted benzosulfimide or timesaving formula I and their pharmaceutically acceptable salts, method of production thereof, containing pharmaceutical composition and method of reception

The invention relates to new substituted benzosulfimide or-thiourea of the formula I and their pharmaceutically acceptable salts, possess antiarrhythmic activity and activity to prevent sudden, caused by arrhythmia death from cardiac arrest, the way they are received, containing pharmaceutical composition and method of reception

The invention relates to substituted benzosulfimide formula I

< / BR>
where mean:

R(1) - alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

R(2) - alkoxy with 1, 2, 3, 4, 5 or 6 C-atoms;

R(3) - hydrogen;

R(4), R(5) R(6) - independently from each other hydrogen, aryl or alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

E - sulfur;

X is oxygen;

Y - CH2group,

and their pharmaceutically tolerable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; R2 and R3 mean independently of one another F, Cl, Br, J, CO-R(6) or O-R(7); R(6) means hydrogen atom; R(7) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R4 means S(O)p-R(16); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also. Also, invention relates to pharmaceutical composition used for inhibition of cellular Na+-dependent bicarbonate/chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; or R2 and R3 mean independently of one another CO-R(6), O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17) wherein R(17) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(6) means hydrogen atom; R4 and R5 mean independently of one another hydrogen atom, F, Cl, Br, J, S(O)p-R(16) or O-(alkylene with 2, 3 or 4 carbon atoms)-OR(33); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(33) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also under condition that at least one of residues R2 or R3 means O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17). Also, invention relates to pharmaceutical composition used for inhibition of Na+-dependent bicarbonate-chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: before applying substitute hormonal therapy (SHT) on should evaluate antithrombogenic activity of vascular wall in women. For this purpose one should determine quantitative values of ADP-induced aggregation of thrombocytes, activity of antithrombin III in blood and fibrinolytic blood activity both before and after "cuff"-test. Then one should detect the indices calculated as the ratio of mentioned values both before and after carrying out the mentioned test. If mentioned indices are decreased against the norm by 20-40% women should be prescribed to undergo SHT at additional introduction of aspirin and supradin. The method provides prophylaxis of cardio-vascular diseases in this category of female patients due to correcting affected functional activity of vascular endothelium.

EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: medicine, pediatrics.

SUBSTANCE: the present innovation deals with treating motor-autonomic disorders in children associated with affected function of central nervous system. For this purpose one should puncture perineural areas in the region of the main nervous trunks with alfetin dissolved in cerebrolysine. Additionally, one should puncture in projection area of cervical and lumbar spinal thickenings and areas that correspond to segmentary innervation of organs with affected function and, also, in scalp areas depending upon the character of patient's disorders. The method suggested provides improved autonomic-trophic impact of nervous system.

EFFECT: higher efficiency of therapy.

2 ex

The invention relates to medicine, in particular to endocrinology, and for the treatment of complications of diabetes - neuropathy

The invention relates to medicine, in particular for orthopedics and neurosurgery, vertebrology, and can be used in the intervertebral disc

The invention relates to medicine and can be used in the treatment of musculoskeletal disorders of the larynx caused by damage to the recurrent nerve
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