Heterocyclyl-benzoyl-guanidine, methods for their preparation and pharmaceutical composition

C07D279/10 - 1,4-Thiazines; Hydrogenated 1,4-thiazines


(57) Abstract:

Heterocyclyl-benzoyl-guanidine formula I, where R1"AH, CF3CH2F, CHF2C2F5Hal , X-R4; R2- SO2-A; R3= N, R4-N or A; Het is a saturated or unsaturated aromatic single or dual aromatic heterocycle with 1 to 2 nitrogen atoms or oxygen atom linked via a nitrogen or carbon, possibly substituted by alkyl, amino group or hydroxyl group; And - alkyl; X = O, Hal Is F, Cl, Br, I, and their physiologically acceptable salts are inhibitors of Na+/N+- pump antiporta and, thus, represent a good antiarrhythmic agent. 4 S. and 2 C.p. f-crystals.

The invention relates to ortho-substituted heterocyclyl-benzoyl-guanidine formula (I)

< / BR>
where R1denotes A, CF3CH2F, CHF2C2F5, CN, NO2, Gal, CCH or-X-R4;

R2and R3each, independently of one another, denote H, Gal A, -X-R4, CN, NO2, CF3CH2F, CHF2C2F5CH2CF3, -SOn-R6, -SO2NR4R5Ph or OPh;

R4denotes H, a, cycloalkyl with 5-7 C atoms, cycloalkyl the AET H or A, or, however,

R4and R5together also denote alkylene with 4-5 C atoms, and one CH2the group may also be replaced by O, S, NH, N-A or N-CH2-Ph;

R6denotes A or Ph;

Het denotes a dual core, saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, linked via N or C, which is unsubstituted or may be substituted by one, two or three times with Gal, CF3, A, -X-R4, CN, NO2and/or carbonyl oxygen;

A denotes alkyl with 1-6 C-atoms;

X denotes O, S or NR5;

Ph denotes unsubstituted or one-, two - or three-fold substituted with A, OA, NR4R5, Gal or CF3phenyl;

"n" is 1 or 2; and

Gal denotes fluorine, chlorine, bromine or iodine,

and their physiologically acceptable salts.

The basis of the invention is to obtain new compounds with valuable properties, especially those that can be used for the preparation of drugs.

Found that the compound of formula (I) and their physiologically acceptable salts with good compatibility possess valuable pharmacological properties.

In the case of new connections, we are talking about inhibitable the mechanism of Na+/H+-metabolism in cells (Dusing, etc., Med. Klin. 87, 378-384 (1992)), and thus represent a good antiarrhythmic agent, is suitable in particular for the treatment of arrhythmias, which appear as a consequence of lack of oxygen.

The most well-known biologically active substance from the group of acyl-guanidino is Amiloride. This substance, however, in the first place, has lowering blood pressure and salureticheskoe action, which is particularly undesirable in the treatment of heart rhythm disturbances, while antiarrhythmic properties expressed only very weakly.

In addition, similar in structure to the compounds known, for example, from European patent EP-04 16499.

The subject invention are the compounds of formula (I) and their physiologically acceptable salts.

Proposed according to the invention the compounds of the present application have good cardiostim by the action and are therefore suitable in particular for the treatment of myocardial infarction, prophylaxis heart attack and to treat angina. Further, substances counteract any pathological hypoxic and ischemic damage, so you can treat caused due to this primary or secondary disease is x action of these substances in pathological hypoxic or ischemic situations, followed by a further possible use in surgical procedures to protect the temporarily insufficient supply of organs; transplant organs for the protection of the recoverable authorities to protect recoverable bodies; when angioplasticheskih interventions in the vessels and heart; when ischemia of the nervous system; in the treatment of shock and relief prevention of essential hypertension.

Further, the compounds can also be used as therapeutic agents when caused by cell proliferation diseases as arteriosclerosis caused by diabetes later complications, neoplastic disease, fibrations diseases, especially lung, liver, and kidney, as well as hypertrophy and hyperplasia of the bodies. Moreover, substances suitable for diagnosis in order to identify diseases that are accompanied by increased activity of Na+/H+antinomies, for example, in erythrocytes, platelets or leukocytes.

Steps compounds can be identified using in itself known methods, which are listed, for example, N. Escobales, and J. Figueroa and J. Membrane Biol, 120, 41-49 (1991), or L. Counillon, W. Scholz, H. J. Lang and J. Pouyssegur in Mol. Pharmacol., 44, 1041-1045 (1993).

As a suitable experimental animals, e.g. mice, rats, Guinea pigs, dogs, cats, monkeys or pigs.

Connection poterenii. Further, they can be used as intermediate products for other biologically active substances of medicines.

In the above formulas:

A denotes a branched or unbranched alkyl group with 1-6, preferably 1-4, especially 1, 2 or 3 C-atoms, particularly preferably methyl, furthermore, preferably ethyl, propyl, isopropyl, butyl, isobutyl; further, preferably Deut.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methyl-pentyl);

R1means preferably O, OA or Gal, in particular Br or Cl, further, however, also preferably CH2F, CHF2, CF3or C2F5;

R2and R3preferably denote, independently of one another, H, A,-SO2, A, CF3, Cl, Br, CN or OA; particularly preferably one of both residues denotes H3C-SO2-, while the other is preferably hydrogen. One of both residues R2and R3preferably is in position 3 or 5 benzoylpyridine group. If one denotes A residue-SO2-, it is preferably in meta-position. Especially preferred benzoylamino group, preferably methyl or ethyl;

R4means, preferably, as R5, H or A; if R4and R5together denote alkylene, Allenova group preferably neravetla, especially preferably represents -(CH2)k- and "k" denotes a 4 or 5; however, it is also preferably represents -(CH2)2-O-(CH2)2-; -(CH2)2-NH-(CH2)2-; -(CH2)2-NA-(CH2)2-;

-CH2-O-(CH2)2-; -(CH2-NH-(CH2)2- or-CH2-NA-(CH2)2-, respectively,

-CO-(CH2)3; -CO-(CH2)4- or-CH2-CO-(CH2)2-;

Ph preferably denotes unsubstituted or once substituted with Cl, Br, A, OA, NH2, NHA, NA2or CF3phenyl;

R6preferably denotes A, in particular methyl, or, however, also preferably unsubstituted phenyl;

X is preferably O or NH;

Het preferably denotes 2 - or 3-furyl; 2 - or 3-thienyl; 1-, 2 - or 3-pyrrolyl; 1-, 2-, 4 - or 5-imidazolyl; 1-, 3-, 4 - or 5-pyrazolyl; 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl; 2-, 4 - or 5-thiazolyl; 3-, 4 - or 5-isothiazolin; 2-, 3-, or 4 is whether 5-tetrazolyl; 1,2,3-oxadiazol-4 - or-5-yl; 1,2,4-oxadiazol-3 - or-5-yl; 1,3,4-thiadiazole-2 - or 5-yl; 1,2,4-thiadiazole-3 - or-5-yl; 1,2,3-thiadiazole-4 - or-5-yl; 2-, 3-, 4-, 5- or 6-2H-dipiradol; 2-, 3 - or 4-4H-dipiradol; 3 - or 4-pyridazinyl; pyrazinyl; 2-, 3-, 4-, 5-, 6- or 7-benzofuran; 2-, 3-, 4-, 5-, 6- or 7-benzothiazyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl; 1-, 2-, 4 - or 5-benzimidazolyl; 1-, 3-, 4-, 5-, 6- or 7-benzimidazolyl; 2-, 4-, 5-, 6- or 7-benzoxazolyl; 3-, 4-, 5-, 6- or 7-benzisoxazoles; 2-, 4-, 5-, 6- or 7-benzothiazolyl; 2-, 4-, 5-, 6- or 7-benzisothiazolin; 4-, 5-, 6 - or 7-Benz-2,1,3-oxadiazole; 2-, 3-, 4-, 5-, 6-, 7- or 8-chinoline; 1-, 4-, 5-, 6-, 7- or 8-ethenolysis; 1-, 2-, 3-, 4- or 9-carbazolyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridine; 3-, 4-, 5-, 6-, 7- or 8-cinnolin; 2-, 4-, 5-, 6-, 7- or 8-hintline. Heterocyclic residues may also be partially or fully gidrirovanny.

Het, therefore, also, for example, may denote 2,3-dihydro-2-, -3-, -4- or-5-furyl; 2,5-dihydro-2-, -3-, -4- or-5-furyl; tetrahydro-2 - or-3-furyl; 1,3-dioxolane-4-yl; tetrahydro-2 - or-3-thienyl; 2,3-dihydro-1-, -2-, -3-, -4- or-5 - pyrrolyl; 2,5-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl; 1-, 2 - or 3-pyrrolidinyl; tetrahydro-1-, -2 - or-4 - imidazolyl; 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl; tetrahydro-1-, -3 - or-4-pyrazolyl; 1,4-dihydro-1-, -2-, -3- or 4-pyridyl; 1,2,3,4-Tetra-hydro-1-, -2-, -3-, -4-, -5- or-6-PI or-4-pyranyl; 1,4-dioxane; 1,3-dioxane-2-, -4 - or-5-yl; hexahydro-1-, -3 - or-4-pyridazinyl; hexahydro-1-, -2-, -4- or-5-pyridinyl; 1-, 2 - or 3-piperazinil; 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-chinoline; 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8 - ethenolysis.

For the whole of the invention has a value that all residues, which occurs a number of times, may be the same or different, i.e. are independent of one other.

Accordingly, the subject invention particularly are the compounds of formula (I) in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred groups of compounds can be characterized by the following formulas (Ia-(Ih), which correspond to the formula (I) and where more not mentioned residues are given in case of formula (I) value, which, however:

in Ia: R1indicates Gal, or A NH2and R2means-SO2-CH3or-SO2-NH2;

in Ib: R1denotes A or Cl and R2means SO2-CH3;

Ic: R1denotes A and R2means SO2-CH3and R2located in the para - or ortho-position to R1;

I settled on using A imidazol-1-yl;

Ie: Het is preferred, specified in (Id) value, and R2means SO2-A and is in meta-position to the amide group;

If: Het denotes unsubstituted or substituted once with A or OH pyrrol-1-yl, pyrrolidin-1-yl, piperidine-1-yl or piperazine-1-yl, and R2means-SO2-A and is in meta-position to the amide group;

in Ig: Het represents pyridyl, oxopiperidin or benzimidazolyl and is located in the n-position to guanidiniocarbonyl group and R2means SO2-A and R3denotes H;

d Ih: R1indicates Gal and Het has one of these in (Id) to (Ig) preferred values.

The subject invention further is a method of obtaining compounds of formula (I) in claim 1 of the formula of the invention, and their salts, characterized in that the connection forms (II):

< / BR>
where R1, R2and Het have the abovementioned meanings, and

Q denotes Cl, Br, OA, O-CO-A-O-CO-Ph, OH or other reactive, esterified ester to OH-group, respectively, it is easy nucleophile replaced a group to delete, enter into interaction with the guanidine; or benzylguanine formula (III):

< / BR>
where R1, R2and R3have videocase the symbolic connection of the formula (IV):

Het - D, (IV)

where Het has the specified value, and

D denotes H, B(OH)2, trialkylsilyl, cation of an alkali metal or ammonium, or, however, easily substituted organic residue; or otherwise corresponding to formula (I) compound, which, however, instead of one or more hydrogen atoms contains one or more recoverable groups and/or one or more additional C-C and/or C-N - bonds is treated with a reducing agent;

or otherwise corresponding to formula (I) compound, which, however, instead of one or more hydrogen atoms contains one or more solvolysis groups, process solvolysis tool;

and/or received the basis of the formula (I) by treatment with acid is converted into one of its salts.

The compounds of formula (I), however, get itself known in ways that are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thieme, Stuttgart; Organic Reactions, John Wiley and Sons, Inc., New York, as well as in the above patent application), namely under reaction conditions which are known and suitable for the specified interactions. This can also be used by itself, izvestnymi also in situ thus, they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

Preferably, the compounds of formula (I) receive the fact that activated carboxylic acid derivative of the formula (II), and Q is particularly preferably denotes Cl or-O-CH3enter into interaction with guanidine. Particularly suitable options for reactions in which free carboxylic acid of the formula (II)(Q=OH) is in itself known turn in the corresponding activated derivative and then directly, without intermediate isolation, enter into interaction with guanidine. Methods in which the intermediate selection is not necessary to undertake, represent, for example, activating using carbonyldiimidazole, dicyclohexylcarbodiimide or options Mukayama (Angew. Chem. 91, 788-812 (1979)).

Carboxylic acids of formula (II) are obtained, for example, by nucleophilic aromatic substitution on the basis of suitable derivatives of benzoic acid, or by introducing into engagement with the relevant geterotsiklicheskikh acids or esters geterotsiklicheskikh acids of the formula (IV). The interaction is carried out by analogy with reactie who are, for example, 2-, 3 - or 4-hydroxypyridine derivatives, which, if necessary, may contain other substituents; hereinafter, also derivatives of piperidine, piperazine, benzimidazole, imidazole, pyrazine, pyrimidine or pyridazine. In particular trimethylsilyl derivatives, alkali metal salts or derivatives of boric acid, respectively, their esters of the above compounds, as compounds of the formula (IV) are suitable components of the reaction.

The interaction of a reactive carboxylic acid derivative of the formula (II) with guanidine exercise in itself known, preferably in the proton, polar or non-polar, inert organic solvent.

Suitable solvents are given below for the interaction of the compounds of formulas (III) and (IV). Especially preferred solvents are, however, methanol, THF, dimethoxyethane, dioxane or produced from these mixtures, and water. As the reaction temperature is suitable, for example, temperature of 20oC to the boiling point of the solvent. The reaction time is from 5 minutes to 12 hours. Appropriate response to use the acid acceptor. For this purpose, any suitable types of is Avani, as carbon potassium, or organic bases like triethylamine or pyridine, or, however, an excess of guanidine.

Compounds according to formula (I) under item 1, then you can get that benzylguanine formula (III) enter into interaction with the compound of the formula (IV). Educt of the formula (III) can be obtained in simple manner by reacting correspondingly substituted benzoic acids or received from them reactive acids, as for example, galodamadruga acids, esters or anhydrides, with guanidine, at reaction conditions, which is in itself known and commonly used for obtaining amides. Particularly suitable again, such reactions described above for the interaction of the compounds of formula (II) with guanidine.

The compounds of formula (IV) as well as methods for their production are known. If they are known, they can get itself known methods.

Obtaining the compounds of formula (II), and the interaction of the compounds of formula (III) with the compound of the formula (IV) conduct itself in a known manner, preferably in a proton or aprotic polar inert organic solvent.

The preferred option, however, the situation of the ug with each other.

Upon receipt of the compounds of formula (II) or in the interaction of the compounds of formula (III) with the compound of the formula (IV) is also advisable to work in the presence of base or with an excess of the basic components. As the bases are preferably usable, for example, hydroxides, carbonates, alkaline alcoholate or alkaline earth metals, or organic bases like triethylamine or pyridine, which can also be used in excess, and then at the same time they can serve as a solvent.

As inert solvents particularly suitable alcohols as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, as etilenglikolevye or monotropy simple ether (methylglycol or ethylglycol), etilenglikolevye simple ether (diglyme); ketones, such as acetone or butanol; NITRILES like acetonitrile; nitro compounds, as nitromethane or nitrobenzene; esters as ethyl acetate; amides, as hexamethylene phosphoric acid; sulfoxidov as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons like dichloromethane, chloroform, trichloroethylene, 1,these solvents with each other.

Further, the compounds of formula (I) can be obtained by the fact that their release from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis, respectively, hydrogenolysis are those which otherwise correspond to formula (I), however, instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably such that instead of the H atom, which is connected with the N-atom, contain protective for amino functions of the group that instead of HN-groups contain R' -N-group, where R' denotes a protective for the amino function group, and/or such which, instead of the H atom of the hydroxyl group containing protective for hydroxyl function group, for example, those that correspond to the formula (I), however, instead of the OH-groups contain OR 'group, where R' denotes a hydroxyl protective for the function group.

In the molecule of the original substance can also be several of the same or different protected amino and/or hydroxyl groups. If the existing protective groups differ from each other, they can in many cases to split select is suitable for protecting (blocking) amino group from chemical influences, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are especially unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl (DNP)), arelaxation (for example, benzoyloxymethyl (BOM) or kalkilya group (for example, benzyl, 4-nitrobenzyl, triphenylmethyl). As for protective amino group functions after the desired reaction (or sequence of reactions) are removed, they were kind and magnitude, however, is not critical; however, a preferred group with 1-20, in particular 1-8 C-atoms. The expression "acyl group" in connection with the present method should be understood in its broadest sense. It covers produced from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids acyl group, and in particular alkoxycarbonyl, aryloxyalkyl and primarily aradoxically group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichloracetic cocciantericcardo, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protective for amino function groups are BOC, DNP and PTO, then, CBZ, benzyl and acetyl.

The expression "hydroxyl protective for function group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical interactions, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are the abovementioned unsubstituted or substituted aryl or acetyl group, hereinafter, also alkyl groups. The nature and magnitude protective for hydroxyl group functionality is not critical, because after the desired chemical reaction or sequence of reactions again remove; preferred group with 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective for function groups are, inter alia, tert.-butyl, benzyl, n-nitrobenzoyl, n-toluensulfonyl and acetyl, and especially preferred benzyl and acetyl.

Used as starting substances, the functional derivatives of compounds of formula (I) can be obtained by conventional means, for example, that described in the above reference publications, sawako, at least one of these compounds instead of H-atom contains a protective group.

The release of the compounds of formula I from their functional derivatives is carried out depending on the protective group, for example using strong acids, expediently using triperoxonane acid or perchloric acid, but also using other strong inorganic acids as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid, or sulfonic acids, as benzene or n-toluensulfonate. The presence of an additional inert solvent may, however, not always necessary.

As the inert solvent is preferably suitable organic, for example carboxylic acids, as acetic acid; ethers, like tetrahydrofuran (THF) or dioxane; amides, as dimethylformamid (DMF); halogenated hydrocarbons like dichloromethane; hereinafter, also alcohols as methanol, ethanol or isopropanol; and water. Further, taking into consideration the mixture of the above solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent; perchloric acid is used in the form of a mixture of the order of about 0-50oC; preferably operate at 15-30oC (room temperature).

The BOC group can be split, for example, preferably using 40% triperoxonane acid in dichloromethane or using approximately 3 to 5N. HCl in dioxane at 15-60oC; FMOC group can be split with approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Removal of DNP-groups are, for example, also by means of approximately 3-10% solution of 2-mercaptoethanol in a mixture of DMF with water at 15-30oC.

Hydrogenations removable protective group (e.g., CMV, CBZ or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, expediently on the media, as coal). As solvents if this is suitable to the above, in particular, for example, alcohols, like methanol or ethanol, or amides, as DMF. Hydrogenolysis, as a rule, carried out at temperatures of about 0-100oC and pressures of about 1-200 bar, preferably at 20-30oC and a pressure of 1-10 bar. Hydrogenolysis of CBZ-group flows well, for example, in the presence of 5-10% palladium-on-coal in methanol at 20-30oC. of the acid. For this transformation is applied acid, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid; sulfamic acid; further, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2 - or 3-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, n-toluensulfonate, naphthalene-mono - and-disulfonate, louisanna acid.

The compounds of formula (I) and their fisiologicas the m way. While their together with at least one liquid, semi-liquid and/or solid carrier or auxiliary substance and, if necessary, in combination with one or more other biologically active substances can be brought to a suitable dosage forms.

The subject of the invention, then, are tools, in particular pharmaceutical compositions containing at least one compound of formula (I) and/or one of its physiologically acceptable salts.

These compositions can be used as drugs in medicine or veterinary medicine. As carriers take into account organic or inorganic substances which are suitable for intestinal (e.g. oral), parenteral or topical administration and do not react with the new compounds, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. For oral administration are, in particular tablets, coated tablets, capsules, syrups, juices or drops; for rectal use candles; for parenteral administration are solutions, preferably m and, creams, pastes, lotions, gels, spray preparations, foams, aerosols, solutions (e.g. solutions in alcohols as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propane diol or their mixtures with each other and/or with water) or powders (powder). The new compounds can also be liofilizirovanny and received lyophilizate to apply, for example, for the preparation of drugs for injection.

In particular for topical application take into consideration liposomal composition. These compositions can be sterilized and/or may contain auxiliary substances, as giving skolzkosti (tablets) agents, preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, dyes, improves the taste of substances and/or flavouring substances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

The compounds of formula (I) and their physiologically acceptable salts can enter humans and animals, particularly mammals like monkeys, dogs, cats, rats or mice, and used in the treatment of the human or animal body, the AI system. They are therefore suitable for the treatment of arrhythmias, in particular when they appear due to lack of oxygen, angina, heart attacks, ischemia of the nervous system, such as stroke or brain edema, shock and prevention.

Substance, then, can be used as therapeutic agents for diseases in which play the role of cell proliferation as arteriosclerosis, later complications due to diabetes, neoplastic diseases, fibrosis, and hypertrophy and hyperplasia of bodies.

This proposed according to the invention substances, usually administered by analogy with the known means of complications, such as aprindine, preferably in doses of about 0.01 to 5 mg, in particular 0,02-0, mg per dosing unit. The daily dose is preferably about of 0.0001 to 0.1, in particular 0,0003-0.01 mg/kg of body weight. Special dose for each particular patient, however, depends on various factors, for example, the effectiveness of used special connections, age, body weight, General health, sex, cost, time and route of administration, rate of excretion, combination of drugs and the severity of the>/P>In the following examples, the expression "conventional treatment" means Add, if necessary, water, extracted with an organic solvent like ethyl acetate; separated; the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography and/or crystallization.

Example 1.

A solution of 2.54 g of guanidine and 2.41 g of methyl ester of 2-methyl-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid (obtained by interaction of 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid with imidazole in the presence of NaH in N-organic and subsequent esterification to complex ether) in 20 ml of methanol is stirred for 3 hours at 50oC. Then the reaction mixture is mixed with water, sucked off usageprice this crude product and recrystallized from methanol. Get N-diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methylsulphonyl-benzamid. So pl.=236oC.

Similarly, by reacting guanidine with methyl ether of 2-chloro-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(1-imidazolyl)-5-methylsulphonyl-benzamid, so pl. 220oC;

with methyl ester 2-ethyl-4-(1-piperidinyl)-5-methylsulphonyl-benzoic acid get N-yl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1-piperidinyl)-5-methylsulphonyl-benzamide; so pl. 224oC;

with methyl ester of 2-methyl-4-(4-amino-piperidino)-5-methyl-sulfonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(4-amino-piperidino)-5-methylsulphonyl - benzamid; so pl. 305-310oC (dihydrochloride);

with methyl ether of 2-chloro-4-(4-amino-piperidino)-5-methyl-sulfonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(4-amino-piperidino)-5-methylsulphonyl - benzamid, so pl. 302-305oC (dihydrochloride);

with methyl ether of 2-chloro-4-(5-pyrimidinyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-chloro-4- (5-pyrimidinyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(2 - pyridazinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(2 - pyridazinyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(3-pyridazinyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-chloro-4-(3 - pyridazinyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(4-pyridazinyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-chloro-4-(4-pyridazinyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-methyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(1,6-dihydro-6)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-chloro-4-(1,6-dihydro-6-oxo-3-pyridazinyl)-5 - methylsulphonyl-benzamide;

with methyl ester 3-ethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl)-5-methyl-sulfonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl)- 5-methylsulphonyl-benzamide;

with methyl ether 2-amino-4-(1,6-dihydro-6-oxo-4-pyridazinyl)-5-methyl-sulfonyl - benzoic acid get N-diaminomethylene-2-amino-4-(1,6-dihydro-6-oxo-3-pyridazinyl)-5 - methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methyl-sulfonyl-benzoic acid get N-diaminomethylene-2 - fluoro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(2-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-chloro-4-(2-pyridyl)- 5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(4-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(4-pyridyl)-5-methylsulphonyl-benzamide;

with methyl ether of 2-chloro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

tilen-2-chloro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

with methyl ester 2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

with methyl ether 2-amino-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-amino-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

with methyl ether 2-propyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-propyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

Example 2

4 g of N-diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methylsulphonyl-benzamide (produced according to example 1) for 1 hour, treated with 1 m aqueous HCl solution and then subjected to drying by freezing. Get N-diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methylsulphonyl-benzamid - dihydrochloride.

Similarly, by treatment with aqueous HCl and subsequent freeze-drying:

N-diaminomethylene-2-chloro-4-(1-imidazolyl)-5-methylsulphonyl-benzamide get dihydrochloride:

N-diaminomethylene-2-methyl-4-(1-piperidinyl)-5-methylsulphonyl-benzamide receive hydrochloride, T. pl. 247oC;

from N-d is C.

Example 3

A solution of 4.2 g of methyl ester of 2-methyl-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl-benzoic acid (obtained by interaction of 3-hydroxy-piperidine and 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid and subsequent esterification to complex ether) and the 3.89 g of guanidine in 20 ml of methanol is stirred for 3 hours at 50oC. After cooling, water is added, additionally stirred for hours and separating the precipitate. After recrystallization from a mixture of acetone with methanol receive N-diaminomethylene-2-methyl-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl - benzamid. So pl. 194-196oC.

Similarly, by reacting guanidine with methyl ether of 2-chloro-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-chloro-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl-benzamid, so pl. 170oC;

with methyl ether 2-amino-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-amino-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl - benzamid, so pl. 232-233oC.

with methyl ester 2-ethyl-4-(3-hydroxy-1-piperidinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-those who EN-2-ethyl-4-chloro-5-methylsulphonyl-benzamide (obtained by interaction of the methyl ester of 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid with guanidine) together with 30 ml of 4-trimethylsilylacetamide in the presence of 3 g K2CO3in a sealed tube heated at 135oC for 5 hours. After cooling, the excess siliporite removed by decantation and the residue triturated with ether and sucked off. Then the solid residue is dissolved in methanol and chromatographic through silica gel (ethyl acetate/methanol). After recrystallization from isopropanol and ethanol N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl - benzamid. So pl. 261-263oC.

Example 5

2.1 g of N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide (produced according to example 4) for 1 hour, treated with 1M aqueous HCl solution and then subjected to drying by freezing. Get N-diaminomethylene-2-ethyl-4- (1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzamide hydrochloride, T. pl. > 270oC.

Example 6

Analogously to example 1, by reacting guanidine with methyl ether of 2,3-dimethyl-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid (obtained by interaction of 2-methyl-4-chloro-methyl-sulfonyl-benzoni acid with 1-trimethyl-2-methyl-imidazole and subsequent esterification to complex ether) receive N - diaminomethylene-2,3-dimethyl-4-(1-imidazolyl)-5-methylsulphonyl-benzamid, so the l-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2,3,4-trimethyl-5-(1-pyrrolyl)-benzoic acid get N-diaminomethylene-2,3,4-trimethyl-5-(1-pyrrolyl)-benzamid, so pl. 218oC; methanesulfonate, so pl. 205-206oC;

with methyl ester of 2-methyl-4-(2-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(2-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide; so pl. 251oC;

with methyl ester 2-ethyl-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-(1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-methyl-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulphonyl-benzamid, so pl. 210-211oC;

with methyl ester of 2-methyl-4-(1-benzimidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester 2-ethyl-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester 2-ethyl-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzamide-2-amino-4-(1-piperidinyl)-5-methylsulphonyl-benzamide; so pl. 240-241oC; hydrochloride, T. pl. 305-310oC;

with methyl ester of 2-methyl-4-(1-pyrrolidinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1-pyrrolidinyl)-5-methylsulphonyl-benzamide; so pl. 222-224oC;

with methyl ester of 2-methyl-5-(1-methyl-2-benzimidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-5-(1-methyl-2-benzimidazolyl)-5-methylsulphonyl - benzamid, so pl. 210oC;

with methyl ester of 2-methyl-4-(2-furanyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(2-furanyl)-5-methylsulphonyl-benzamide; so pl. 185-186oC; methanesulfonate, so pl. 280-281oC;

with methyl ether 2-amino-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-amino-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl - benzamide;

with methyl ester of 2-methyl-4-(1-pyrazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(1-pyrazolyl)-5-methylsulphonyl-benzamide; so pl. 225-226oC;

with methyl ester of 2-methyl-3-(1-pyrrolyl)-5-methylsulphonyl-betinol acid get N-diaminomethylene-2-methyl-3-(1-pyrrolyl)-5-methylsulphonyl-benzamide; so pl. 216oC;

with methyl ether 2-amino-4-(1-benzimidazolyl)-5-the MFA;

with methyl ester of 2-methyl-4-(1-imidazolyl)-5-nitro-benzoic acid get N - diaminomethylene-2-methyl-4-(1-imidazolyl)-5-nitro-benzamide; so pl. 244oC;

with methyl ester of 2-methyl-3-(1-pyrrolyl)-4-chloro-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-methyl-3-(1-pyrrolyl)-4-chloro-5-methylsulphonyl-benzamide; so pl. 250oC;

with methyl ester of 2-nitro-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-nitro-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-nitro-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-nitro-4-(1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-nitro-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-nitro-4-(1-pyrrolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-nitro-4-(1-benzimidazolyl)-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-nitro-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-vermeil-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N - diaminomethylene-2-vermeil-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-fluoro shall imethyl-1-imidazolyl)-5-methylsulphonyl - benzamide;

with methyl ether 2-vermeil-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-vermeil-4-(1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-vermeil-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-vermeil-4-(1-pyrrolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-vermeil-4-(1-benzimidazole-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-vermeil-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-deformity-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl - benzamide;

with methyl ether 2-deformity-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl - benzamide;

with methyl ether 2-deformity-4-(1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-deformity-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(1-pyrrolyl)-5-methylsulphonyl-the Ute N-diaminomethylene-2-deformity-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-trifluoromethyl-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene- -2-trifluoromethyl-4-(4-methyl-1-imidazole)-5-methylsulphonyl-benzamide;

with methyl ester of 2-trifluoromethyl-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(2,4-dimethyl-1-imidazolyl)-5 - methylsulfonylbenzoyl;

with methyl ester of 2-trifluoromethyl-4-(1-imidazolyl)-5 - methylsulphonyl-benzoic acid N-diaminomethylene-2-trifluoromethyl-4- (1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-trifluoromethyl-4-(1-pyrrolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(1-pyrrolyl)-5-methylsulphonyl-benzamide;

with methyl ester of 2-trifluoromethyl-4-(1-benzimidazolyl)-5-methyl - sulfonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(1-benzimidazole)-5-methylsulphonyl - benzamide;

with methyl ether 2-cyan-4-(4-methyl-1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-cyan-4- (4-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-cyan-4-(2,4-dimethyl-1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-cyan - 4-(2,4-dimethyl-1 the acid get N-diaminomethylene-2-cyan-4- (1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-cyan-4-(1-pyrrolyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-cyan-4-(1-pyrrolyl)- 5-methylsulphonyl-benzamide;

with methyl ether 2-cyan-4-(1-benzimidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-cyan-4-(1 - benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-methoxy-4-(4-methyl-1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2 - methoxy-4-(4-methyl-1-imidazolyl)-5-methyl-sulfonyl-benzamide;

with methyl ether 2-methoxy-4-(2,4-dimethyl-1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2 - methoxy-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-methoxy-4-(1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-methoxy-4-(1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-methoxy-4-(1-pyrrolyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methoxy-4-(1-pyrrolyl - 5-methylsulphonyl-benzamide;

with methyl ether 2-methoxy-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2 - methoxy-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-ethinyl-4-()-5-methylsulphonyl - benzamide;

with methyl ether 2-ethinyl-4-(2,4-dimethyl-1-imidazolyl)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene-2 - ethinyl-4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-ethinyl-4-(1-imidazolyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethinyl-4-(1 - imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-ethinyl-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethinyl-4-(1-pyrrolyl)-5-methyl-sulfonyl-benzamide;

with methyl ether 2-ethinyl-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethinyl - 4-(1-benzimidazolyl)-5-methylsulphonyl-benzamid.

Example 7

1.0 g of methyl ester of 2-amino-4-(3-pyridyl)-5-methylsulphonyl - benzoic acid (produced by interaction of the methyl ester 2-amino-4-bromo-5-methylsulphonyl-benzoic acid and pyridine-3-boronic acid) dissolved in 15 ml of 1-methyl-pyrrolidone and stirred in 15 ml of 1-methyl-pyrrolidone and stirred for 15 minutes. Then add 0.9 g guanidinylation and 2,6 ml diisopropylethylamine and stirred for 1 hour at room temperature. After normal processing of receive N-diaminomethylene-2-amino-4-(3 - pyridyl)-5-METI delovogo ether 2-amino-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-amino-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-cyan-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-cyan-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester 2-methoxy-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methoxy-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-ethinyl-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethinyl-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-vermeil-4-(3-pyridyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-vermeil-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-deformity-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(3-pyridyl)-5-Meinel-benzamide;

of the methyl ester of 2-trifluoromethyl-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester 2-amino-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-amino-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

of the methyl ester 2-methoxy-4-(4-aminopiperidine)-5-methylsulphonyl-the P>oC (dihydrochloride);

of the methyl ester of 2-cyan-4-(1,4-dihydro-4-oxo-1-pyridyl)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-cyan - 4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzamide;

of the methyl ester 2-methoxy-4-(1,4-dihydro-4-oxo-1 - pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methoxy-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

of the methyl ester of 2-ethinyl-4-(1,4-dihydro-4-oxo-1-pyridyl)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene-2 - ethinyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulfone-benzamide;

of the methyl ester of 2-vermeil-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-vermeil-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl - benzamide;

of the methyl ester of 2-deformity-4-(1,4-dihydro-4-oxo - 1-pyridyl)-5-methylsulphonyl-benzoic acid N-diaminomethylene-2 - deformity-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulfonyl - benzamide;

of the methyl ester of 2-trifluoromethyl-4-(1,4-dihydro-4-oxo-1 - pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5 - methylsulphonyl-benzamide;

of the methyl ester 2-amino-4-ethylsulfonyl-benzamide;

of the methyl ester of 2-cyan-4-(1-benzimidazolyl)-5 - methylsulphonyl benzoic acid get N-diaminomethylene-2-cyan-4- (1-benzimidazolyl)-5-methylsulphonyl-benzamide;

of the methyl ester 2-methoxy-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-methoxy - 4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-ethinyl-4-(1-benzimidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethinyl-4-(1-benzimidazolyl)- 5-methylsulphonyl-benzamide;

of the methyl ester of 2-vermeil-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2 - vermeil-4-(1-benzimidazolyl)-5-methylsulphonyl-benzamide;

of the methyl ester of 2-deformity-4-(1-benzimidazolyl)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-deformity-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzamide;

of the methyl ester of 2-trifluoromethyl-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-trifluoromethyl-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzamide;

of the methyl ester of 2-methyl-4-piperidino-5-nitro-benzoic acid get N-diamino-2-methyl-4-piperidino-5-nitro-benzamide, so pl. 174oC.

zolyl)-5-methylsulphonyl-benzoic acid (obtained by interaction of 2-fluoro-4-chloro-5-methylsulphonyl-benzoic acid with 2-methyl-imidazole and subsequent esterification to complex ether) receive N-diaminomethylene-2-fluoro-4-(2-methyl-1-imidazolyl)-5-methylsulphonyl - benzamid.

Similarly, by reacting guanidine with methyl ether 2-fluoro-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(4-methyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(2,4-dimethyl-1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro - 4-(2,4-dimethyl-1-imidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(1-imidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(1-imidazolyl)-5-methylsulphonyl-benzamide; methyl ether 2-fluoro-4-(1-pyrrolyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(1-imidazolyl)-5 - methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(1-benzimidazolyl)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(1 - benzimidazolyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(1-piperidinyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(1-piperidinyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-fluoro-4-(3-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

with methyl ether 2-forenamed;

with methyl ether 2-fluoro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-fluoro-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methyl-sulfonyl - benzamide);

with methyl ester of 2-methyl-3-methylsulphonyl-4-(4-methyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-methyl-4-(4-methyl-1-imidazolyl)-3-methylsulphonyl-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(2-methyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-methyl-4-(2-methyl-1-imidazolyl)-3-methylsulphonyl-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(2,4-dimethyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(2,4-dimethyl-1-imidazolyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(1-imidazolyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(1-imidazolyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(1-pyrrolyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(1-piroli)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(1-benzimidazolyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(1-benzimidazolyl)-benzamide;

with methyl avirom-(1-piperidinyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(3-hydroxy-1-piperidinyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(3-hydroxy-1-piperidinyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(3-pyridyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(3-pyridyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(2-pyridyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(2-pyridyl)-benzamide;

with methyl ester of 2-methyl-3-methylsulphonyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-benzoic acid get N-diaminomethylene-2-methyl-3-methylsulphonyl-4-(1,4-dihydro-4-oxo-1 - pyridyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(4-methyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-ethyl-4-(4-methyl-1-imidazolyl)-3-methylsulphonyl-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(2-methyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-ethyl-4-(2-methyl-1-imidazolyl)-3-methylsulphonyl-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(2,4-dimethyl-1-imidazolyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(2,4-dimethyl-1-imidazolyl)-benzamide;

with methyl ether-imidazolyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(1-pyrrolyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(1-pyrrolyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(1-benzimidazolyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(1-benzimidazolyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(1-piperidinyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(1-piperidinyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(3-hydroxy-1-piperidinyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(3-hydroxy-1-piperidinyl)- benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(3-pyridyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(3-pyridyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(2-pyridyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(2-pyridyl)-benzamide;

with methyl ester 2-ethyl-3-methylsulphonyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-benzoic acid get N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(1,4-dihydro-4-oxo-1 - pyridyl)-benzamide.

The following examples relate to pharmaceutical competitative substances of the formula (I) and 5 g of dinitrigenoxide in 3 l of double-distilled water using 2 N. hydrochloric acid to establish a pH of 6.5, the solution is sterile filtered, filled them with glass bubbles for drugs for injection, lyophilizers and sterile closed. Each glass bottle of medicine for injection contains 5 mg of biologically active substances.

Example B: Candles

Melted mixture of 20 mg of biologically active substances of the formula (I) with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically active substances.

Example: Solution

Prepare a solution of 1 g of biologically active substances of the formula (I), 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH to 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

Mix 500 mg of biologically active substances of the formula (I) with 99.5 g of vaseline under aseptic conditions.

Example D: Tablets

A mixture of 1 kg of biologically active substances of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablets this is Similar to example D is pressed tablets, which are then applied in the usual manner a coating of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of biologically active substances of the formula (I) in the usual way making capsules of hard gelatin, so that each capsule contains 20 mg of biologically active substances.

Example 3: Ampoules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is introduced into the ampoule, lyophilizer under aseptic sterile conditions and closed (sealed). Each ampoule contains 10 mg of biologically active substances.

1. Heterocyclyl-benzoyl-guanidine formula I

< / BR>
where R1- A, CF3CH2F, CHF2C2F5C2F5Hal or X-R4;

R2- SO2-A;

R3denotes H;

R4- N or A;

Het is a saturated or unsaturated aromatic single or dual aromatic heterocycle with 1 to 2 nitrogen atoms or oxygen atom linked via a nitrogen or carbon, unsubstituted or once substituted C1-6-alkyl, amino group or hydroxyl group;

And - alkyl with 1 to 6 C-atoms;

X - ON;

Hal is F, Cl, Br or I,

and their f is R> (a) N-diaminomethylene-2-ethyl-4-(1-imidazolyl)-5-methyl-sulfonylmethane;

(b) N-diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methylsulfonylbenzoyl;

(C) N-diaminomethylene-2-ethyl-4-(3-pyridyl)-5-methylsulphonyl-benzamide;

(g) N-diaminomethylene-2-ethyl-4-(2-pyridyl)-5-methylsulphonyl-benzamide;

(d) N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulphonyl-benzamide;

(e) N-diaminomethylene-2-ethyl-3-methylsulphonyl-4-(3-pyridyl)-benzamid, as well as their physiologically acceptable salts.

3. Heterocyclyl-benzoyl-guanidine under item 1 as an inhibitor of hepatocellular Na+/H+antinomies.

4. The method of obtaining heterocyclyl-benzoylpyridine formula I under item 1, characterized in that the compound of formula II

< / BR>
where R1, R2, R3, Het have the meanings specified in paragraph 1;

Q represents Cl, Br, OA, OH or another reactive esterified ester to the Oh-group, respectively, it is easy nucleolonema group

enter into interaction with the guanidine and/or received base of formula I is treated with acid to obtain its salts.

5. The method of obtaining heterocyclyl-benzoylpyridine formula I under item 1, characterized in that the connection is Br,

enter into an interaction with a heterocyclic compound of the formula IV

Het - D,

where Het takes the values specified in paragraph 1;

D - H, B(OH)2or trialkylsilyl,

and/or the received base of formula I is treated with acid to obtain its salts.

6. Pharmaceutical composition having the ability to inhibit hepatocellular Na+/H+-antisocial, characterized in that it contains at least one compound of General formula I under item 1 and/or one of its physiologically acceptable salt in an effective amount.


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The invention relates to medicine, namely to addiction

FIELD: medicine, toxicology.

SUBSTANCE: invention proposes applying 15% aqueous solution of 1-methyl-5-[2'-(benzyldimethylammonio)ethyl]carbamoyl pyridinium-2-aldoxime dichloride that exceeds the 15% solution of dipiroxime (TMB-4, trimedoxime bromide) used in native medicinal practice by the curative effectiveness. Invention can be used in urgent treatment of acute poisoning with organophosphorus poisonous substances eliciting neuroparalytic effect.

EFFECT: enhanced effectiveness, valuable medicinal properties of agent.

3 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.

EFFECT: valuable medicinal properties of compound.

1 cl, 7 tbl, 3 ex

FIELD: medicine, oncology.

SUBSTANCE: method involves carrying out chemotherapy. Firstly, dose of nicotinic acid is administrated that is sufficient to initiate hyperemia of skin integuments and in appearance of first symptoms of hyperemia cytostatics are administrated by parenteral route. Method provides increasing duration of contact of cytostatics with tumor cells and micrometastasis due to inclusion of blood volumes depots in the parent state in vascular skin networks to volume of circulating blood. Invention can be used in treatment of malignant neoplasms with cutaneous and subcutaneous localization.

EFFECT: improved treatment method.

2 ex

FIELD: medicine, dermatology.

SUBSTANCE: the present innovation deals with treating different forms of localized sclerodermia: plaque, linear, scleroatrophic lichen, idiopathic atrophodermia. The method deals with introducing delagyl, xanthinol nicotinate, claritine, application of "Elocom" ointment. At the background mentioned one should alternate 8-10 procedures of intravenous injection of ozonized physiological solution at ozone concentration being 1.5 mg/l at the volume of 200 ml and 5-7 procedures of subcutaneous puncturing in lesion foci with oxygen-ozone gaseous mixture at ozone concentration of 2 mg/l. This mixture should be introduced along focal periphery at the volume of 10-30 ml. Intravenous injections should be carried out twice or thrice weekly, and subcutaneous puncturing - once or twice weekly. The innovation enables to decrease sickness rate due to increased velocity and full-value absorption of the ointment used, immunomodulating, antiphlogistic, collagen-formation and microcirculation normalizing effect of complex therapy, liquidation of tissue hypoxia and reflexogenic stimulation of body vascular system.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.

EFFECT: improved preparing method, improved pharmaceutical properties of composition.

30 cl, 12 tbl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-phenylpyridine of the general formula: (I) wherein R means halogen or halogen atom; R1 means -(C≡C)mR1' or -(CR'=CR'')mR1'; X means -C(O)N(R8)-, -N(R8)C(O)- or -N(R8)-(CH2)p- wherein m = 0-4 and p = 1-2; values of radicals R1', R2, R3', R3, R4, R4', R8, R' and R'' are given above, and to their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. New compounds are neurokinine-1 antagonists and can be used as medicinal agents in treatment of diseases mediated by neurokinine-1 receptors.

EFFECT: valuable medicinal properties of derivatives.

13 cl, 119 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to creation of therapeutical and prophylactic balsams, which can be used as generally restorative and tonic agents to increase resistance of organism to reduced levels of atmosphere oxygen (increase of hypoxia resistance) as well as to prevention and correction of functional disorders associated with stress and exhausting environmental factors affecting organism. Invention proposes two variants of therapeutical-prophylactic balsam producing generally restorative and tonic effects, each containing vegetable oils, vitamins, amino acids, hepatic implant cells (Hepatosan), adaptogen (Astragerm), antioxidant, odorant, and thickener.

EFFECT: achieved normalization of vitality in exhausted organism.

6 cl

FIELD: medicine.

SUBSTANCE: about 10 min before occlusion of carotid arteries into total carotid artery at the side of reconstruction it is necessary to introduce nicotinamide solution at 2.0 mg/kg body weight. The innovation provides cerebral protection against ischemic lesion in case of reconstructive operations upon carotid arteries under local anesthesia, at keeping patient's consciousness, in particular, in case of contraindications for total anesthesia and at necessity for verbal contact between a doctor and a patient under operation.

EFFECT: higher efficiency.

4 dwg, 1 ex, 1 tbl