Orthotamine derivatives of benzoic acid, the method of production thereof, a method of obtaining a pharmaceutical composition, the pharmaceutical composition

 

(57) Abstract:

Orthotamine derivatives of benzoic acid of formula I, where R1- alkyl, halogen or -- XR4; R2- -SOn,-R6or-SO2, NR4R5; R3- CN or halogen; Q - N= C(NH2)2, OA or HE; R4, R5- H or C1-6-alkyl; R6- C1-6alkyl; X Is O or NR5and n = 2, as well as their physiologically compatible salts and pharmaceutical compositions on their basis with cardiotoxin action, suitable for the preparation of medicines or as intermediate products for the manufacture of other active substances. 6 C. and 1 C.p. f-crystals, 1 PL.

The invention relates to orthotamine derivative of benzoic acid of the formula I

< / BR>
where R1A, Hal, -X-R4;

R2- -SOn-R6or-SO2NR4R5;

R3- CN, Hal;

Q - -N=C(NH2)2, OA, OH;

R4means H, A;

R5- H or A;

R6- A;

A is alkyl with 1-6 C-atoms;

X is O or NR5;

n = 2,

and pharmaceutically compatible salts of these derivatives.

The basis for this invention is the task to find new compounds with valuable properties, in the mswb for the manufacture of other active substances.

It turned out that the compounds of formula I, in particular those in which Q means-N=C(NH2)2and their physiologically compatible salts with good compatibility possess valuable pharmacological properties.

Further, the compounds of formula I are especially suitable as intermediate products, are suitable for use in the synthesis of other, not stated here inhibitors of the cellular Na+/H+antiporta type arylguanidines.

Under these new compounds have in mind inhibitors of this type is that as the active agent inhibit the exchange mechanism of the aforementioned sodium ions and hydrogen in the cells (seeDsinget al., ed. Klin.87, 378-384 (1992)) and thus are good medications arrhythmia, suitable in particular for the treatment of arrhythmias of various kinds, due to the lack of oxygen supply.

The most well-known active substance group acylhalides is amiloride. However, this substance has primarily by the ability to lower blood pressure and diuretic effect, which is undesirable, particularly in the treatment of disorders of heart rhythm, at the same time antiaritmicheskoe action of this substance is expressed only very weak shall I type arylguanidines according to this invention have good cardiostim action and is therefore suitable in particular for the treatment of heart attacks, prevention and treatment of angina. In addition, they are effective against all kinds of pathological hypoxic and ischemic disorders, so they are suitable for the treatment of resulting directly or indirectly diseases. Such active substances are well suited for preventive purposes.

Taking into account the protective effect of these substances in pathological hypoxic or ischemic situations, this is the other possibility of their application in surgical interventions is to protect the organs of the body operated temporarily in a state of low blood flow, organ transplants, for the protection of retrieved organs angioplasticheskih surgical interventions on the heart or blood vessels in the ischemia of the nervous system, in the treatment of shock, and also for preventive prevention of essential hypertension.

In addition, these compounds can be used as therapeutic agents for such diseases caused by cell proliferation, atherosclerosis, late diabetic complications, neoplastic disease, fibrations diseases, particularly lung, liver, and kidney, as well as hypertrophy and hyperplasia of the one antiporta, for example, in erythrocytes, platelets or leukocytes.

The activity of such compounds can be identified by known methods described, for example, in publications such as N. Escobales and J. Figeroa: J. Membrane Biol. 120, 41-49 (1991); L. Counillon, W. Scholz, H. J. Lang and J. Pouyssegur: Mol. Pharmacol. 44, 1041-1045 (1993).

As a suitable experimental animals, for example mice, rats, Guinea pigs, cats, monkeys or pigs.

Therefore, the compounds of formula I, in particular, derivatives arylguanidines, can be used as the active ingredient in drugs in medicine and in veterinary medicine. In addition, they are suitable as intermediate products for the manufacture of other active substances for medicinal products, in particular for those that are inhibitors of sodium-hydrogen cell antiporta.

The subject invention are orthotamine derivatives of benzoic acid of formula I and their physiologically compatible salts.

In the above formulas here A denotes a branched or unbranched alkyl group with 1-6, preferably 1-4 C atoms, or more preferably 1, 2 or 3 carbon atoms, in particular methyl and ethyl, further preferably propyl, isopropyl,hexyl(4-methylpentyl). In this formula, R1means, preferably A, where A has the abovementioned particularly preferred meanings, more preferably OA, CF3, chlorine, bromine, NH2or CN; R2means particularly preferably SO2A, SO2NH2or CN; R3- preferably fluorine, but is particularly preferably bromine or chlorine, and A, especially methyl, CN or CHO; R4and R5means are preferably independently from each other H or A.

If R4and R5together mean alkylen, Allenova group is preferably unbranched, particularly preferably -(CH2)k-, with k = 4 or 5; however, preferably -(CH2)2-O-(CH2)2, -(CH2)2-NH-(CH2)2, -(CH2)2-NA-(CH2)2, -(CH2)-O(CH2)2, -CH2NH-(CH2)2or-CH2-NA-(CH2)2or-CO-(CH2)3, -CO-(CH2)4or-CH2-CO-(CH2)2.

Ph means phenyl, preferably nezametny or substituted by chlorine, bromine, A, OA, NH2, NHA, NA2or CF3;

R6means, preferably A, in particular methyl or unsubstituted phenyl;

R7and R8mean the mean-N=C(NH2)2if we are talking about the active substances with good pharmacological properties.

For the case of particularly suitable intermediates for the synthesis of active substances in the structure of drugs Q means, in addition to guanidine, particularly preferably chlorine, bromine, OH or OA, and-O-CO-A or-O-CO-Ph;

Ac means mainly alkanoyl 1-6 carbon atoms, in particular formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or caproyl, more preferably benzoyl, toluyl or 1 - or 2-naphtol;

n means preferably 2.

As a General rule, all radicals, multiply existing in these compounds, may be the same or different.

In accordance with this object of the present invention are, in particular, such compounds of formula I in which at least one of these radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds may correspond to the following formulae Ia-Ih corresponding to the formula I and in which not mentioned in detail radicals are given in the formula I values, but:

in formula Ia, R1means A and R2mean-S is rum, NH2, OH or OA and R2means SO2CH3;

in formula Ic R1means A chlorine or bromine and R3means CN, CHO, chlorine or bromine;

in the formula Id R means SO2-CH3, -SO2NH2or SO2-NA2and R3means A fluorine, chlorine, bromine or CN;

in the formula Ie R1means A, R2- -SO2-CH3and R3- A, fluorine, chlorine, bromine or CN;

- the formula If R1means A, R2- -SO2-NH2or-SO2N(CH3)2and R3-A fluorine, chlorine or bromine;

in the formula Ig R1means CH3or C2H5, R3- fluorine, chlorine, bromine, CHO or COA and R2-SO2-CH3;

in the formula Ih R1and R3independently from each other mean Hal or CN.

Further preferred are such compounds in which the radicals R1, R2and R3have the preferred values in formulas Ia-Ih, but in which, however, Q may also be-N=C(NH2)2.

The subject of the invention is, furthermore, a method of obtaining orthotamine derivatives of benzoic acid of the above formula I and their salts, characterized in that the compound of formula II

< / BR>
where R1, R2and R3are above the mules I or that

the compound of formula II in which L is CN, by hydrolysis is converted into the compound of formula I or the fact that

the compound of formula II in which R2is hydrogen and L means CO2by chlorosulfonylphenyl subsequent reduction and alkylation is converted into a compound of formula I, or the fact that

the compound of formula I is recovered from one of its functional derivatives by treatment solvolysis or hydrogenolysis means, or the fact that

derivatives of benzoic acid corresponding to the formula I, in which, however, is missing one of the radicals R1, R2and R3by alkylation, acylation, halogenation or nitriding transferred to the compound of formula I, or the fact that

one radical R, R, R and/or Q is converted into another radical R1, R2, R3and/or Q by:

- saponification of ester of the formula I or

- by the esterification of carboxylic acids of formula I and a translation in the anhydride or acid halide or acylhalides, or

by catalytic hydrogenation of the CN-group, or

by the hydrolysis nitrile groups in carbamoyl or acid group, or

- by converting nitrile is Oh, or the ground is transferred into one of its salts.

The compounds of formula I in the rest get by known methods described in the literature (see, for example, such standard publishing, as Houben-Weyl: Methods der organischen Chemie, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York), as well as in the aforementioned patent application. In particular, they receive under such reaction conditions which are known and suitable for the above-mentioned transformations. This includes the possible use and in themselves known, not discussed here in detail options.

The initial substance can be obtained, if desired, and in situ so that they are not isolated from the reaction mixture, and immediately converted into the compound of formula I.

In particular, the compounds of formula I are preferably obtained by oxidation of compounds of formula I with L = CH3CH2OH, CHO or phenyl.

Oxidation methylseleninic derivatives of benzoic acid may, for example nitric acid or margantsevokislogo potassium. Primary alcohols of the formula II can be converted to the corresponding acid, for example, by AgO, KMnO4, CrO3or other known strong oxidizing agents. In addition, it is possible, for example, by conventional oxidizers or, for example, by reaction of Canizzaro periodicline direct conversion of aldehydes of the formula II into the corresponding esters by, for example, Al(OC2H5)3. Then you can translate into the corresponding acid biphenyls with the corresponding sample substitution by oxidation using RUO Li4.

Oxidation always concerns about the known methods described, for example, in the publication of H. March Adv.Org.Chem., 3 ed., Jonh Wiley & Sons (1985).

The compounds of formula I can be obtained, in addition, by electrophilic substitution reactions on aromatic compounds, if can be excluded other adverse reactions. For example, under the reaction conditions of the Friedel-craft can be gloriavale, bronirovat, alkilirovanii or allievate, for which the corresponding halogen or alkylchloride, or allylbromide during the catalysis of Lewis acids, for example AlCl3, FeBr3or Fe or outer alkylchloride in the presence of Lewis acid is subjected to interaction with the compound of the formula I, subject to translation in the derived temperatures in the range of 30-150oC, preferably 50-150oC, in an inert solvent, for example hydrocarbons, THF or carbon tetrachloride.

The compounds of formula I can be obtained by highlighting them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis is ur nitrile group, or such compounds of formula II in which L is CN. Such compounds can hydrolyze to carboxylic acid in a known reaction conditions, for example in sulfuric acid environment, through the appropriate derived amidocarbonyl acid or by heating with strong acids or bases.

Other preferred initial agents for the solvolysis or hydrogenolysis are those which, corresponding to the formula I, do not have, however, one or more free amino and/or hydroxyl groups, in particular such that instead of the hydrogen atom linked to the nitrogen atom, contain a protective amino group, in particular such compounds, which, instead of the group HN contain a group R'-N, where R' means aminosidine group, as well as those in which instead of the hydrogen atom of the hydroxyl group contained hidroxizina group, such as those corresponding to the formula I, instead of the group-COOH contain a group - COOR", where R" means hydroxyamino group.

Molecule of the original substance may also contain the same or different protected amino and/or hydroxy-group. In the case of different protective groups, they may be in many cases selectively derived.

The expression "acyl group" should be understood in conjunction with the method described here in its broadest sense. This expression includes acyl groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxypropanolamine first and foremost alcoxycarbenium group. Examples of such acyl groups are alkanoyl (acetyl, propionyl, butyryl), then arkanoid (for example, phenylacetyl), aroyl (benzoyl or toluyl), aryloxyalkanoic (phenoxyacetyl), alkoxycarbonylmethyl) Uralelectromed (benzyloxycarbonyl, 4-methoxybenzeneboronic, 9-foranimation). Preferred aminosilane groups are tert-butoxycarbonyl, 2,4-dinitrophenyl and benzyloxyethyl, then benzyloxycarbonyl and acetyl.

The expression "hidroxizina group" is also generally known and relates to groups capable of protecting the hydroxy-group of chemical transformations, but which lagoudaki after the desired chemical reaction with another molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl, and alkyl groups. The nature and magnitude of hydroxyamine groups is not critical, so they are after the desired chemical reaction or sequence of reactions can be removed. A preferred group with 1 to 20, especially from 1 to 10, carbon atoms. Examples hydroxyamine groups are, in particular, tert-butyl, benzyl, para-nitrobenzyl, para-toluensulfonyl and acetyl and benzyl and acetyl is particularly preferred.

Used as starting substances, the functional derivatives of compounds of formula I can be obtained by conventional means, for example, described in the above-mentioned standard publications is depending on the used protective group, for example, by reacting with strong acids, expediently with triperoxonane or charnawati acid and other strong inorganic acids, for example hydrochloric or sulphuric, with strong organic carboxylic acids, for example, trichloroacetic or with sulfonic acids (benzene or para-toluensulfonate). Interaction is possible, moreover, in the presence of an additional inert solvent, but it is not always necessary.

As inert solvents are suitable, preferably organic, for example carboxylic acid (acetic), ethers (tetrahydrofuran or dioxane), amides (dimethylformamide), halogenated hydrocarbons such as dichloromethane, then alcohols (methanol, ethanol or isopropanol) and water. Suitable mixtures of the aforementioned solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent; chlorobutyl acid is used in the form of a mixture of acetic acid with 70% charnawati acid in the ratio 9:1. The reaction temperature removal is in the range from approximately 0 to 50oC, preferably 15-30oC, i.e., at room temperature.

Group trelane or 3-5 N. solution of hydrochloric acid in dioxane at a temperature of 15-60oC, group 9-toradoltoradol amenable to removal by 5-20% solution of dimethylamine, diethylamine or piperidine in dimethylformamide when 15-50oC. Cleavage of the group of 2,4-dinitrophenyl possible, for example, and by 3-10% solution of 2-mercaptoethanol in dimethylformamide/water at 15-30oC.

Hydrogenations otsepleniya protective group, for example, benzoyloxymethyl, benzyloxycarbonyl or benzyl, can be split, for example, by treatment with hydrogen in the presence of a catalyst, for example, of the noble metal (palladium, expediently coal carrier). As a suitable solvent mentioned above, for example, alcohols (methanol or ethanol) or amides (dimethylformamide). The hydrogenolysis is carried out, generally at temperatures of approximately 0 and 100oC and pressures in the range of about 1 and 200 bar, preferably at 20-30oC and 1-10 bar. Hydrogenolysis group benzyloxycarbonyl good, for example, on 5-10% catalyst (coal carrier) in methanol at 20-30oC.

In addition, in the compound of the formula I can be converted one of the radicals R1, R2, R3oC, preferably at 10-30oC.

Then you can restore the cyanic group aminomethyl. Such recovery should be performed by catalytic hydrogenation, for example, Nickel Rania at temperatures between 0 and 100oC, preferably at 10-30oC, and at pressures from 1 to 200 bar, mostly at normal pressure, in an inert solvent, for example in a lower alcohol (methanol or ethanol), expediently in the presence of ammonia. When doing process, for example at 20oC and 1 bar, in the source material remains available benzylamine or n-benzyl group. If you wish to split their hydrogenations it is advisable to use a catalyst based on a noble metal, preferably palladium on carbon carrier, and the solution is to add the acid, for example acetic acid, and water.

For the esterification of the acid of formula I can be treated with excess alcohol, preferably in the presence of any of the oC.

You can then interact with the hydrogen sulfide to translate nitrile group in thiocarbamoyl group, preferably at temperatures in the range from -10 to +50oC and the duration of the reaction from a few minutes up to 3 days in the respective solvents or mixtures of solvents with a continuous supply of gaseous hydrogen sulfide.

The solvent is suitable, in particular, alcohols, such as methanol, ethanol, isopropanol, n-butanol or tert-butanol, ethers (diethylether, diisopropylate, tetrahydrofuran or dioxane), glycolether (etilenglikolevye) or monoethylether (methylglycol or ethylglycol), ethylenglykolether (diglyme); ketones (acetone or butanone; NITRILES (acetonitrile); nitro compounds (nitromethane or nitrobenzene); esters such as ethyl acetate or hexamethylene phosphoric acid; sulfoxide (dimethyl sulfoxide); chlorinated hydrocarbons, such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or platetronic; hydrocarbons such as benzene, toluene or xylene. Suitable mixtures of these solvents with each other. Particularly suitable pyridine, triethylamine or dimethylformamide or mixtures thereof.

to be translated into acylhalides.

The interaction of a reactive carboxylic acid derivative of the formula II with guanidine is per se known manner, preferably in eroticheskom or apothecom polar or non-polar inert organic solvent.

Suitable as the solvent, methanol, tetrahydrofuran, dimethoxyethane, dioxane or mixtures thereof, and water. The reaction proceeds at temperatures between 20oC and the boiling point of the respective solvent. The duration of the reaction varies from 5 min to 12 hours, it is Advisable to add the reaction of the acid trap. For this purpose, any suitable types of foundations, which themselves do not violate the reaction. However, particularly suitable organic bases, such as triethylamine or pyridine, or an excess of guanidine.

The basis of the formula I by acid can be translated into the appropriate cyclododecanol salt. This is suitable, in particular, such acids, which give physiologically compatible salts. Can be used, for example, inorganic acids such as sulfuric, nitric, halomonadaceae acid (florodora or bromatologia), phosphoric acid (orthophosphoric), sulfamido the definition or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, for example formic, acetic, triperoxonane, propionic, pavlikova, diethyloxalate, malonic, succinic, Emelyanova, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinoyl, methane - or econsultancy, ethicality, 2-hydroxyethanesulfonic, benzolsulfonat, paratoluenesulfonyl acid, naphthalene-mono - and naphthalenedisulfonic acid, and louisanna acid. Salts with physiologically incompatible with acids, such as the picrate, can be used for isolating and/or purifying compounds of formula I.

Free base of formula I can optionally be the highlight of their salts, for example the processing of strong bases (gerakis sodium or potassium), sodium carbonate or potassium.

The compounds of formula I and their physiologically compatible salts can be used for pharmaceutical preparations, in particular by non-chemical. For this purpose it is necessary to transfer them together with at least one solid, liquid and/or semi-liquid carrier or target additive, and optionally in combination with one or more other active substances in sootvetstvuushuu ticheskie, containing at least one compound of formula I in which Q means guanidine and/or one of its physiologically compatible salts.

Such compositions are applicable as drugs in medicine or in veterinary medicine. As materials carriers suitable organic or inorganic substances suitable for oral administration, for example oral, parenteral or local (topical) receive and do not react with this new compounds, for example water, vegetable oil, benzelstierna, glycols, glyceryltrinitrate, gelatin, carbohydrates (lactose, starch, magnesium stearate, talc, lanolin, petrolatum. For oral administration of such drugs are especially tablets, coated tablets, capsules, syrups, juices or drops; for rectal preparations are candles, and for receiving parenteral solutions are predominantly oily or aqueous solutions, further suspensions, emulsions or implants; for topical application are ointments, creams, pastes, lotions, gels, aerosols, foams, solvents (e.g. alcohols - ethanol or isopropanol, acetonitrile, dimethylformamide, dimethylacetamide, 1,2-propane diol or their mixtures with each other and/or with water), and tarpoline drugs for injection.

In particular, for topical application suitable liposomal composition. These formulations can be sterilized and/or to enter accessories/conservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants, flavoring and/or aromatic additives. They may optionally also contain one or more other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically compatible salts can be entered both people and animals, in particular mammals such as monkeys, dogs, cats, rats or mice, and use in therapeutic treatment for diseases, in particular in the treatment and/or prevention of the violation of the cardiovascular system. For this reason, they are suitable for the treatment of arrhythmias, especially if due to oxygen deficiency, for the treatment of angina, heart attacks, ischemia of the nervous system and for preventive treatment.

Further, these substances can be used as therapeutic drugs for such diseases, which have the value of cell proliferation, Narimanov and hyperplasia of bodies.

Moreover, the substances according to this invention are usually applied, by analogy with the previously known drugs against arrhythmias, for example, aprindine, preferably with doses of approximately from 0.01 to 5 mg, preferably from 0.02 to 0.5 mg per dose. The daily dose is from about 0.0001 to 0.1 mg, preferably from 0.0003 to 0.01 mg per 1 kg body weight of the patient. Special dose for each particular patient depends, however, on various factors, such as the efficiency of the used compound, the age, body weight, General health, sex, particularly of food, time of day and method of making medicines from the rate of release from a combination of medication and the severity of the particular disease to be cured which is the site of this therapy. Preferred oral administration.

In the following examples, the expression "conventional treatment" means the following.

If necessary, adding water, produce extraction with an organic solvent (ethyl acetate), the separation, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by the method of chromatography and/or crystallization.

Example 1. A solution of 200 g of 4-chloro-2-methylbenzoyl the ion mixture on ice. The precipitate is sucked off and portions introduced into the suspension 447 g of sodium sulfate in 1170 ml of water at 10oC, while adding caustic soda, so that is pH = 9. Then continue stirring for 3 h and then produce acidification under ice cooling. The formed precipitate is sucked off again and together with 610 g matilida injected a mixture of 575 ml of methanol, 350 ml of water. Set pH 9 and evaporated in continuation of 36 h before removing the solvent, and then treated in the usual way. Get complex methylether 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid with a melting point of 151oC.

Similarly, interaction with chlorosulfonic acid by reduction and methylation, get:

- 2-ethyl-4-chloro-benzoic acid methyl ester 2-ethyl-4-chloro-5-methylsulphonyl - benzoic acid with a melting point of 98-100oC;

from 2,4-dichloro-benzoic acid: methyl ester of 2,4-dichloro-5-methylsulphonyl-benzoic acid with a melting point 155-156oC;

from 2-methyl-4-bromo-benzoic acid: methyl ester of 2-methyl-4-bromo-5-methylsulphonyl - benzoic acid with a melting point of 150oC;

from 2-bromo-4-methyl-benzoic keys is
from 2-bromo-4-methyl-benzoic acid: methyl ester of 2-bromo-4-methyl-5-methylsulphonyl-benzoic acid with a melting point of 160 - 165oC.

- 2-ethyl-4-bromo-benzoic acid methyl ester 2-ethyl-4-bromo-5-methylsulphonyl - benzoic acid;

- 2-ethyl-4-chloro-benzoic acid methyl ester 2-ethyl-4-chloro-5-methylsulphonyl - benzoic acid;

- 2-ethyl-4-5-fluoro-benzoic acid methyl ester 2-ethyl-4-chloro-5-methylsulphonyl-fluoro-benzoic acid;

from 2-chloro-4-fluoro-benzoic acid methyl ester 2-chloro-4-fluoro-5-methylsulphonyl-benzoic acid with a melting point of 137 to 138oC;

- 2-methoxy-4-chloro-benzoic acid methyl ester 2-methoxy-4-chloro-5-methylsulphonyl-benzoic acid;

- 2-formatosi-4-chloro-benzoic acid methyl ester 2-formatosi-4-chloro-5-methylsulphonyl-benzoic acid;

- 2-deformity-4-chloro-benzoic acid methyl ester 2-deformity-4-chloro-5-methylsulphonyl-benzoic acid;

- 2-ethinyl-4-bromo-benzoic acid methyl ester 2-ethinyl-4-bromo-5-methylsulphonyl-benzoic acid;

- 2-ethinyl-4-methyl-benzoic acid methyl ester 2-these are the Il-2-nitro-4-fluoro-5-methylsulphonyl-benzoic acid;

- 2-methoxy-4-formyl-benzoic acid methyl ester 2-methoxy-4-formyl-5-methylsulphonyl-benzoic acid;

- 2-deformity-4-formyl-benzoic acid methyl ester 2-deformity-4-formyl-5-methylsulphonyl-benzoic acid;

- 2-ethyl-4-chloro-benzoic acid methyl ester 2-ethinyl-4-chloro-5-methylsulphonyl-benzoic acid;

- 2-cyan-4-methyl-benzoic acid methyl ester 2-cyan-4-methyl-5-methylsulphonyl-benzoic acid;

- 2-pentafluoroethyl-4-fluoro-benzoic acid methyl ester 2-pentafluoroethyl-4-fluoro-5-methylsulphonyl-benzoic acid;

from 2-methyl-4-fluoro-benzoic acid: methyl ester of 2-methyl-4-fluoro-5-methylsulphonyl-benzoic acid;

- 2-cyan-4-formyl-benzoic acid methyl ester 2-cyan-4-formyl-5-methylsulphonyl-benzoic acid.

Example 2. 10 g of complex methyl ester of 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid contribute under ice cooling in a mixture of 30 ml of concentrated hydrochloric acid and 200 ml of methanol and stirred for 2 hours the precipitate is sucked off and recrystallized from methanol. Get 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid with visiting th the new ester 2-ethyl-4-chloro-5 - methylsulphonyl-benzoic acid: 2-ethyl-4-chloro-5-methylsulphonyl-benzoic acid with a melting point of 180 183oC;

- from the complicated methyl ester 2,4-dichloro-5 - methylsulphonyl-benzoic acid: 2,4-dichloro-5-methylsulphonyl-benzoic acid with a melting point of 208oC;

- from the complicated methyl ester of 2-methyl-4-bromo-5 - methylsulphonyl-benzoic acid: 2-methyl-4-bromo-methylsulphonyl-benzoic acid with a melting point of 221 - 222oC;

- from the complicated methyl ester of 2-bromo-4-methyl-5 - methylsulphonyl-benzoic acid: 2-bromo-4-methyl-5-methylsulphonyl-benzoic acid with a melting point of 209 - 212oC;

- from the complicated methyl ester 2-chloro-4-fluoro-5 - methylsulphonyl-benzoic acid: 2-chloro-4-fluoro-5-methylsulphonyl-benzoic acid with a melting point of 213 - 215oC;

- from the complicated methyl ester 2-methoxy-4-chloro-5 - methylsulphonyl-benzoic acid: 2-methoxy-4-chloro-5-methylsulphonyl-benzoic acid with a melting point of 236 - 237oC;

- from the complicated methyl ester 2-vermeil-4-chloro-5 - methylsulphonyl-benzoic acid: 2-vermeil-4-chloro-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-ethyl-4-bromo-5 - methylsulphonyl-benzoic acid: 2-ethyl-4-bromo-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester of 2-methyl-4-fluoro-5-methylsulphonyl - benzoic acid is sulfonyl - benzoic acid: 2-ethyl-4-fluoro-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-deformity-4-fluoro-5-methylsulphonyl-benzoic acid: 2-deformity-4-fluoro-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-ethinyl-4-bromo-5-methylsulphonyl-benzoic acid: 2-ethinyl-4-bromo-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-ethinyl-4-methyl-5-methylsulphonyl-benzoic acid: 2-ethinyl-4-methyl-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-nitro-4-fluoro-5-methylsulphonyl-benzoic acid: 2-nitro-4-fluoro-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-methoxy-4-formyl-5-methylsulphonyl-benzoic acid: 2-methoxy-4-formyl-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-deformity-4-formyl-5-methylsulphonyl-benzoic acid: 2-deformity-4-formyl-5-methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-ethinyl-4-chloro-5-methylsulphonyl-benzoic acid: 2-ethinyl-4-chloro-5 - methylsulphonyl-benzoic acid:

- from the complicated methyl ester 2-cyan-4-methyl-5 - methylsulphonyl-benzoic acid: 2-cyan-4-methyl-5 - methylsulphonyl-benzoic acid;

- from the complicated methyl ester 2-pentafluoroethyl-4-fluoro-5 - methylsulfone ether 2-cyan-4-formyl-5 - methylsulphonyl-benzoic acid: 2-cyan-4-formyl-5 - methyl-sulfonyl-benzoic acid.

Example 3. 15 g of complex methyl ester 2-ethyl-4-chloro-5 - methylsulphonyl-benzoic acid is stirred in 100 ml of methanol and 50 ml of sodium hydroxide for 1 h at room temperature.

Then the reaction mixture was concentrated and mixed with 200 ml of ice water. After acidification with concentrated hydrochloric acid, the precipitate is sucked off, washed it with ether and dried. Get 2-ethyl-4-chloro-5-methylsulphonyl-benzoic acid with a melting point of 180 - 183oC.

Example 4. 2 g of 1-chloro-2-methylsulphonyl-4,5-xylene (obtained according to example 1 from 1-chloro-3,4-xylene by reacting with chlorosulfonic acid, sodium sulfite and methyliodide) together with 40 ml of 15% nitric acid are heated in an autoclave in further 5 h at 132oC. Then, this reaction mixture is extracted with telefonom acetic acid and then treated in the usual way. Get 2-methyl-4-chloro-5-methyl-sulfonyl-benzoic acid with a melting point of 217 - 218oC.

Example 5. of 8.3 g of 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid mixed with 70 ml of n-methylpyrrolidone and 7.4 CuCN and stir this mixture into continued for 3 days at 150oC. Then the reaction mixture is poured into 250 ml of water and treated Yes the acid with a melting point of 248 - 249oC.

Similarly, by interaction with CuCN:

with 2-ethyl-4-chloro-5-methylsulphonyl-benzoic acid: 2-ethyl-4-cyan-5-methylsulphonyl-benzoic acid;

with 2,4-dichloro-5-methylsulphonyl-benzoic acid: 2,4 - dicyan-5-methylsulphonyl-benzoic acid;

- with 2-chloro-4-fluoro-5-methylsulphonyl-benzoic acid: 2-chloro-4-cyan-5-methylsulphonyl-benzoic acid;

- with 2-chloro-4-fluoro-5-methylsulphonyl-benzoic acid: 2-chloro-4-cyan-methylsulphonyl-benzoic acid;

- 2-methoxy-4-chloro-5-methylsulphonyl-benzoic acid 2-methoxy-4-cyan-5-methylsulphonyl-benzoic acid;

- 2-vermeil-4-chloro-5-methylsulphonyl-benzoic acid: 2-vermeil-4-cyan-5-methylsulphonyl-benzoic acid;

- 2-deformity-4-chloro-5-methylsulphonyl-benzoic acid: 2-diplomatic-4-chloro-5-methylsulphonyl-benzoic acid: 2-deformity-4-cyan-5-methylsulphonyl-benzoic acid;

- 2-ethinyl-4-chloro-5-methylsulphonyl-benzoic acid: 2-ethinyl-4-chloro-5-methylsulphonyl-benzoic acid;

2-pentafluoroethyl-4-chloro-5-methylsulphonyl-benzoic acid: 2-pentafluoroethyl-4-cyan-5-methylsulphonyl-benzoic acid.

Example 6. 50 g of 2,4-dichloro-5-methylsulphonyl-benzoic acid (her receive the pressure of 30 bar. Then this reaction mixture was poured onto ice, acidified with concentrated hydrochloric acid and boiled with methanol. Get 2-amino-4-chloro-5-methylsulphonyl-benzoic acid with a melting point of 284 - 286oC.

Example 7. 5.8 g of 2-bromo-4-fluoro-5-methylsulphonyl-benzoic acid together with a 3.7 ml methyliodide and 8.3 g of potassium carbonate is stirred in 20 ml of dimethylformamide in further 12 h at room temperature.

Then the reaction mixture was concentrated and mixed with 50 ml of water. The resulting precipitate is sucked off and dried. Get the methyl ester of 2-bromo-4-fluoro-5-methylsulphonyl-benzoic acid with a melting point of 126oC.

Example 8. 74,1 g 2-methyl-4-bromo-5-methylsulphonyl-benzoic acid (obtained by reaction of 2-methyl-4-bromo-benzoic acid with chlorosulfonic acid) is stirred at 10oC for 1.5 h in 170 ml of 32% aqueous ammonia solution, and then stirred at room temperature for 3 h then the reaction mixture was concentrated, mixed with 50 ml of water and acidified with concentrated hydrochloric acid. The resulting precipitate is sucked off and recrystallized from methanol. Get 2-methyl-4-bromo-5-aminosulfonyl-benzoic acid with whom-bromo-5-chlorosulfonyl-benzoic acid: 2-ethyl-4-bromo-5-aminosulfonyl-benzoic acid;

- 2 propyl-4-bromo-5-chlorosulfonyl-benzoic acid: 2-propyl-4-bromo-5-aminosulfonyl-benzoic acid;

- 2-isopropyl-4-chloro-5-chlorosulfonyl-benzoic acid; 2-isopropyl-4-chloro-5-aminosulfonyl-benzoic acid;

- 2-propyl-4-fluoro-5-aminosulfonyl-benzoic acid: 2-propyl-4-fluoro-5-aminosulfonyl-benzoic acid;

- 2-methoxy-4-bromo-5-aminosulfonyl-benzoic acid 2-methoxy-4-bromo-5-aminosulfonyl-benzoic acid;

- 2-cyan-4-chloro-5-aminosulfonyl-benzoic acid: 2-cyan-4-chloro-5-aminosulfonyl-benzoic acid;

- 2-isopropyl-4-fluoro-5-aminosulfonyl-benzoic acid: 2-isopropyl-4-fluoro-5-aminosulfonyl-benzoic acid;

2-butyl-4-fluoro-5-aminosulfonyl-benzoic acid: 2-butyl-4-fluoro-5-aminosulfonyl-benzoic acid: 2-butyl-4-fluoro-5 - aminosulfonyl-benzoic acid;

with 2-ethyl-4-fluoro-5-aminosulfonyl-benzoic acid: 2-ethyl-4-fluoro-5-aminosulfonyl-benzoic acid;

- 2-nitro-4-bromo-5-aminosulfonyl-benzoic acid: 2-nitro-4-bromo-5-aminosulfonyl-benzoic acid;

- with 2 ethinyl-4-chloro-5-aminosulfonyl-benzoic acid: 2-ethinyl-4-chloro-5-aminosulfonyl-benzoic acid;

- 2-trifluoromethyl-4-fluoro-5-aminosulfonyl-Benz who were radioactive-benzoic acid: 2-vermeil-4-bromo-5-aminosulfonyl-benzoic acid;

- 2-vermeil-4-formyl-5-chlorosulfonyl-benzoic acid: 2-vermeil-4-formyl-5-aminosulfonyl-benzoic acid;

- 2-deformity-4-bromo-5-chlorosulfonyl-benzoic acid: 2-deformity-4-bromo-5-aminosulfonyl-benzoic acid;

- 2-pentafluoroethyl-4-chloro-5-chlorosulfonyl-benzoic acid: 2-pentafluoroethyl-4-chloro-5-aminosulfonyl-benzoic acid;

with pentafluoroethyl-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-pentafluoroethyl-4-fluoro-5-aminosulfonyl-benzoic acid.

Example 9. 7 g of 2-methyl-4-bromo-aminosulfonyl-benzoic acid (prepared as in example 8) is boiled in a solution of hydrochloric acid in methanol in further 5 hours and Then the reaction mixture is cooled to room temperature, concentrated and further processed in the usual way. After recrystallization from methanol receive complex methylether 2-methyl-4-bromo-5-aminosulfonyl-benzoic acid with a melting point of 198 - 200oC.

In a similar way by matrifocal compounds of example 8 with methanol receive:

- methyl ester-2-ethyl-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-propyl-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-isopropy what sainoi acid;

- methyl ester 2-methoxy-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-cyan-4-chloro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-isopropyl-4-fluoro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-butyl-4-fluoro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-ethyl-4-fluoro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-nitro-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-ethinyl-4-chloro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-trifluoromethyl-4-fluoro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-vermeil-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-vermeil-4-formyl-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-deformity-4-bromo-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-pentafluoroethyl-4-chloro-5 - aminosulfonyl-benzoic acid;

- methyl ester 2-pentafluoroethyl-4-fluoro-5 - aminosulfonyl-benzoic acid.

Example 10. Analogously to example 8 is obtained by interaction of the amine with the following connection is islote;

- 2-propyl-4-bromo-5-chlorosulfonyl-benzoic acid: 2-propyl-4-bromo-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-isopropyl-4-chloro-5-chlorosulfonyl-benzoic acid: 2-isopropyl-4-chloro-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-propyl-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-propyl-4-chloro-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-methoxy-4-bromo-5-chlorosulfonyl-benzoic acid 2-methoxy-4-bromo-5-N,N-dimethylaminomethyl-benzoic acid;

- c 2-cyan-4-chloro-5-chlorosulfonyl-benzoic acid: 2-cyan-4-chloro-5-N, N-dimethylaminomethyl-benzoic acid;

- 2-isopropyl-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-isopropyl-4-fluoro-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-butyl-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-butyl-4-fluoro-5-N,N-dimethylaminomethyl-benzoic acid;

with 2-ethyl-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-ethyl-4-fluoro-5-N, N-dimethylaminomethyl-benzoic acid;

- 2-nitro-4-bromo-5-chlorosulfonyl-benzoic acid: 2-nitro-4-bromo-5-N,N-dimethylaminomethyl-benzoic acid;

- with 2 ethinyl-4-chloro-5-chlorosulfonyl-benzoic acid: 2-ethinyl-4-chloro-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-the strong acid;

- 2-vermeil-4-bromo-5-chlorosulfonyl-benzoic acid: 2-vermeil-4-bromo-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-vermeil-4-formyl-5-chlorosulfonyl-benzoic acid: 2-vermeil-4-formyl-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-deformity-4-bromo-5-chlorosulfonyl-benzoic acid: 2-vermeil-4-bromo-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-pentafluoroethyl-4-chloro-5-chlorosulfonyl-benzoic acid: 2-pentafluoroethyl-4-chloro-5-N,N-dimethylaminomethyl-benzoic acid;

- 2-pentatration-4-fluoro-5-chlorosulfonyl-benzoic acid: 2-pentafluoroethyl-4-fluoro-5-N,N-dimethylaminomethyl-benzoic acid.

Example 11. Analogously to example 9 is obtained by the esterification of the compound from example 10 with methanol the following connections:

- methyl ester 2-ethyl-4-bromo-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester-2-isopropyl-4-chloro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-propyl-4-fluoro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-methoxy-4-bromo-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-cyan-4-chloro-5-N,N - dimethyl what-benzoic acid;

- methyl ester 2-butyl-4-fluoro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-ethyl-4-fluoro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-ethinyl-4-chloro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-trifluoromethyl-4-fluoro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-vermeil-4-bromo-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-vermeil-4-formyl-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-deformity-4-bromo-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-pentafluoroethyl-4-chloro-5-N,N - dimethylaminomethyl-benzoic acid;

- methyl ester 2-pentafluoroethyl-4-fluoro-5-N,N - dimethylaminomethyl-benzoic acid.

Example 12. 1.0 g of 2-methyl-4-cyan-5-methylsulfanyl-benzoic acid (obtained according to example 5) are dissolved in 15 ml of 1-methyl-pyrrolidone are mixed with 0.67 g of 1-methyl-2-chloropyridinyl and mix when operating the mixer in the sequel to 15 minutes Then added to a mixture of 1 equivalent of guanidine chloride and 2.6 ml of diisopropylethylamine and the mixture is stirred at tempele (flash way the ethyl acetate/10% methanol) and then treated with hydrochloric acid. Get N-diaminomethylene-2-methyl-4-cyan-5-methylsulphonyl-benzamid, hydrochloride with a melting point of 227-228oC.

Similarly obtained by interaction of guanidinylation the following connections:

with 2-ethyl-4-cyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethyl-4-cyan-5-methylsulphonyl-benzamide, hydrochloride;

- with 2.4-dicyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2,4-dicyan-5-methylsulphonyl-benzamide;

- 2-methoxy-4-cyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-methoxy-4-cyan-5-methylsulphonyl-benzamide;

- 2-vermeil-4-cyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-vermeil-4-cyan-5-methylsulphonyl-benzamide;

2-deformity-4-cyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-deformity-4-cyan-5-methylsulphonyl-benzamide;

- 2-pentafluoroethyl-4-cyan-5-methylsulphonyl-benzoic acid; N-diaminophenyl-2-pentafluoroethyl-4-cyan-5-methylsulphonyl-benzamide;

- 2-ethinyl-4-cyan-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethinyl-4-cyan-5-methylsulphonyl-benzamid.

Example 13. A solution of 1.8 g of complex methyl ester (2-prodolzhenie 5 h and then remove the solvent. The residue is treated with water, the remaining crystallized sucked off and treated with concentrated sodium hydroxide, the solid residue is filtered, recrystallized from ethanol. Get N-diaminomethylene-2-methyl-4-bromo-5-methylsulphonyl - benzamide with a melting point of 207-208oC.

In a similar way we obtain by reacting guanidine following connections:

with complex methyl ether 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-methyl-4-chloro-5-methylsulphonyl-benzamide with a melting point 204-205oC;

with complex methyl ether 2-amino-4-chloro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-amino-4-chloro-5-methylsulphonyl-benzamide with a melting point of 245oC;

with complex methyl ether of 2,4-dichloro-5-methylsulphonyl-benzoic acid; N-diaminomethylene-2,4-dichloro-5-methylsulphonyl-benzamide with a melting point 189-190oC;

with complex methyl ester 2-ethyl-4-chloro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethyl-4-chloro-5-methylsulphonyl-benzamide with a melting point of 160-162oC;

with complex methyl ether 2-methyl-4-bromo-5-aminosulfonyl-benzoic acid: N-diaminomethylene-2-methyl-4-bromo-5-aminosulfonyl-benzamid point card: N-diaminomethylene-2-methyl-4-bromo-5-N, N'-dimethylaminomethyl-benzamide with a melting point 222-223oC;

with complex methyl ether 2-chloro-4-fluoro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-chloro-4-fluoro-methylsulphonyl-benzamide;

with complex methyl ether 2-methyl-4-chloro-5-phenylsulfonyl-benzoic acid: N-diaminomethylene-2-methyl-4-chloro-5-phenylsulfonyl-benzamide with a melting point of 185-187oC; 230-232oC (hydrochloride);

with complex methyl ether 2-vermeil-4-chloro-5-methylsulphonyl - benzoic acid: N-diaminomethylene-2-vermeil-4-chloro-5-methylsulphonyl-benzamide;

with complex methyl ester 2-ethyl-4-bromo-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethyl-4-bromo-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethyl-4-bromo-5-metalinsulator benzamide with a melting point 169-171oC;

with complex methyl ether 2-methyl-4-fluoro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-methyl-4-fluoro-5-methylsulphonyl-benzamide with a melting point 208-210oC;

with complex methyl ester 2-ethyl-4-fluoro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethyl-4-fluoro-5-methylsulphonyl-benzamide;

with complex methyl ether 2,4-debtor-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2,4-debtor-5-methylsulphonyl-benzamide with a melting point of 260
with complex methyl ether 2-nitro-4-fluoro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-nitro-4-fluoro-5-methylsulphonyl-benzamide;

with complex methyl ether 2-methoxy-4-formyl-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-methoxy-4-formyl-5-methylsulphonyl-benzamide;

with complex methyl ether 2-deformity-4-formyl-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-detromental-4-formyl-5-methylsulphonyl-benzamide;

with complex methyl ether 2-ethinyl-4-chloro-5 - methylsulphonyl-benzoic acid: N-diaminomethylene-2-ethinyl-4-chloro-5-methylsulphonyl-benzamide;

with complex methyl ether 2-pentafluoroethyl-4-fluoro-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-pentafluoroethyl-4-fluoro-5-methylsulphonyl-benzamide;

with complex methyl ether 2-cyan-4-formyl-5-methylsulphonyl-benzoic acid: N-diaminomethylene-2-cyan-4-formyl-5-methylsulphonyl-benzamid.

The examples below relate to pharmaceutical compositions.

Example A. Ampoules for injection. A solution of 100 g of the active substance of formula 1 and 5 g of disodium phosphate in 2 l of double-distilled water by 2 N. hydrochloric acid set pH = 6,5, sterile filtered, poured into the active substance.

Example B. Candles. A mixture of 20 g of the active substance of the formula I and 100 g of lecithin and 1400 g of cocoa butter is poured into molds and allowed to cool. Each suppository contains 20 mg of active substance.

Example C. A Solution. Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g benzylaniline in 940 ml of double-distilled water. Set pH to 6.8, bring the solution to 1 l and sterilized by irradiation. This solution can be used, such as eye drops.

Example, The Ointment. 500 g of the active substance of the formula I are mixed with 99.5 g of vaseline under aseptic conditions.

Example D. The Pill. A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in the usual way in the tablet so that each tablet contained 10 mg of active substance.

Example E. Bean. Analogously to example D is pressed tablets, which are then the usual way is covered with a film of sucrose, potato starch, talc, dye and tragant.

Example J. Capsules. 2 kg of active substance of the formula I filled in the usual way in capsules of hard gelatin so, codesta of the formula I in 60 l of double-distilled water is sterile filtered, poured into ampoules, lyophilizer sterile and sterile sealed. Each ampoule contains 10 mg of active substance.

Experimental data are shown in table.

These results characterize the compounds claimed in the description as Na+/H+antiportals inhibitors. Compounds according to the invention inhibit the Na+/H+antiport and, therefore, acceptable in order to prevent heart disease and are good cardioprotective effect. The results clearly demonstrate the activity of compounds effective for the treatment of diseases arrhythmia, heart attack and and pathological hypoxic or ischemic damage damage.

1. Orthotamine derivatives of benzoic acid of the formula I

< / BR>
where R1- A Gal or-X-R4;

R2- -SOn- R6or-SO2NR4R5;

R3- CN or Hal;

Q - -N=C(NH2)2, OA or OH;

R4- N or A;

R5- N or A;

R6- A;

And - alkyl with 1 to 6 carbon atoms;

X is O or NR5;

n = 2,

as well as their physiologically compatible salts.

2. Derivatives under item 1, which represents the N-diaminomethylene-2-methyl-4-broan-5-methylsulfonylbenzoyl, N-diaminomethylene-2-ethyl-4-bromo-5-methylsulfonylbenzoyl, N-diaminomethylene-2-ethyl-4-chloro-5-methylsulfonylbenzoyl, N-diaminomethylene-2-methyl-4-fluoro-5-methylsulfonylbenzoyl, N-diaminomethylene-2-ethyl-4-fluoro-5-methylsulfonylbenzoyl, as well as their physiologically compatible salts.

3. The method of obtaining orthotamine derivatives of benzoic acid of formula I on p. 1, where Q is OH, characterized in that the ester of the formula I in which Q means OA and R1, R2and R3matter under item 1, omelet.

4. The method of obtaining orthotamine derivatives of benzoic acid of formula I on p. 1, where Q - OA or-N=C(NH2)2, characterized in that the carboxylic acid of the formula I in which Q is - OH and R1, R2and R3are specified in paragraph 1 values, etherification or transferred to acylhalides.

5. The method of obtaining orthotamine derivatives of benzoic acid of formula I under item 1, characterized in that the compound of formula I is transferred by treatment with acid or base in its physiologically compatible salts.

6. Pharmaceutical composition having cardiostim effect, characterized in that it contains an effective amount of at least one of the compounds forms is 2">

7. A method of obtaining a pharmaceutical composition having cardiostim action, by mixing the active substance with at least one solid, liquid or semi-liquid carrier or auxiliary component, characterized in that the active substance is used as a compound of the formula I on p. 1, where Q is-N=C(NH2)2and/or one of its physiologically compatible salts.

 

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