Derivatives of 4-mercapto-benzoylpyridine, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

The invention relates to 4-mercapto-benzoylpyridine formula (I), where R1denotes A; R2means And, unsubstituted or substituted by F, Cl, Br, phenyl, pyridyl; And - alkyl with 1-6 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them. The proposed compounds and pharmaceutical composition inhibit Na+/N+-antiport and thereby prevent heart disease and are cardiotoxin action. They can be used for the treatment and prevention of arrhythmia, angina, heart attack and pathological hypoxic and ischemic damage. 3 S. and 1 C.p. f-crystals, 1 PL.

The invention relates to ortho-substituted derivatives of 4-mercapto-benzoylpyridine formula (I)

< / BR>
where R1denotes A, CF3CH2F, CHF2or C2F5;

R2denotes H, a, cycloalkyl with 3-7 C-atoms, Ph or Het;

Het denotes a single or dual core, saturated, unsaturated or aromatic heterocycle with 1 to 4 atoms of nitrogen, oxygen and/or sulphur, linked via N or C, which is unsubstituted or may be once, twice or three times
A denotes alkyl with 1-6 C-atoms;

Gal denotes F, Cl, Br or J; and

Ph denotes unsubstituted or once-, twice -, or trehkanatnoy using A, OA, NH2, NHA, NA2, F, Cl, Br and/or CF3phenyl;

and their physiologically acceptable salts.

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

It was found that the compounds 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 the inhibitors hepatocellular Na+/H+-antiporters, i.e. biologically active substances that inhibit 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 that occur as a result of lack of oxygen.

The most well-known biologically active substance group acylhalides is amiloride. This substance, however, has primarily reduce croviana, while antiarrhythmic properties expressed only very weakly.

In addition, structurally similar compounds are known, for example, from European patent N 0416499.

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

Proposed according to the invention the substance of this application have 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 all pathological hypoxic and ischemic damage, so you can treat caused as a consequence, primary or secondary disease. Biologically active substances are also well suited for prevention.

Based on the protective action of these substances in pathological hypoxic or ischemic situations, hence suitability for further use in surgical interventions to protect temporarily provide enough blood to the organs, transplant organs for the protection of retrieved organs angioplasticheskih interventions in the vessels and heart, when, ischemia of the nervous system, in the treatment of shock and be used as therapeutic agents in the case due to cell proliferation diseases, as arteriosclerosis, diabetic late 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+-bipartite, for example, in erythrocytes, platelets or leukocytes.

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

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

Therefore, the compounds can be used as biologically active substances of medicines in medicine and veterinary medicine. Then they can be used as intermediate products for other biologically active substances of medicines.

In the above formula denotes A branched or unbranched (linear) alkyl group with 1-6, preferably 1-4, especially 1, 2 or 3 C-atoms, in particular, before the p-butyl, tert. -butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).

R1preferably denotes A, in particular methyl or ethyl.

R2denotes A; phenyl; 2-, 3 - or 4-chlorophenyl; 2-, 3 - or 4-forfinal or Gets. Particularly preferably, along with the following values, Het represents pyridyl, pyrimidyl, triazolyl, thiazolyl or partially or fully hydrogenated derivatives of these residues, which can also be substituted as indicated.

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

Gal preferably denotes F, Cl or Br.

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-pyridyl; 2-, 4-, 5 - or 6-pyrimidinyl; further preferably 1,2,3-triazolyl-1-, -4 - or-5-yl; 1,2,4-triazole-1-, -3 - or-5-yl; 1 - or 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; 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-benzo-2,1,3-oxadiazole; 2-, 3-, 4-, 5-, 6-, 7- or 8-chinoline; 1-, 3-, 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-cinnoline; 2-, 4-, 5-, 6-, 7- or 8-hintline. Heterocyclic residues may also be partially or fully gidrirovanny.

Gets, therefore, may also include, for example, 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-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl; 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl; 1-, 2-, 3 - or 4-piperidinyl; 2-, 3 - or 4-morpholinyl, tetrahydro-2-, -3 - 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-pyrimidinyl; 1-, 2 - or 3-piperazinil; 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-� then, all residues such as A, which can repeatedly be contained in the molecule may be the same or different, i.e., can be independent from each other.

Accordingly, the subject invention are in particular those 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 expressed by the following formulas (Ia) to(Ih), which correspond to the formula (I) and where more not mentioned residues are specified in the case of the formula (I) is, however, where:

in Ia: R1denotes methyl or ethyl;

in Ib: R1denotes methyl or ethyl and R2denotes A;

Ic: R1denotes methyl or ethyl and R2denotes 2-thiazolyl, 4,5-dihydro-thiazol-2-yl; 1,2,4-triazole-3-yl or 1,2,4-(4-methylthiazole-3-yl);

in Id: R1denotes methyl or ethyl and R2indicates imidazolyl, pyridyl or pyrimidinyl;

Ie: R1denotes methyl or ethyl and R2denotes pyridyl or pyrimidinyl;

If: R1denotes methyl or ethyl and R2denotes phenyl, forfinal or chlorophenyl;

in Ig: R1denotes methyl or ethyl and R2

Further particularly preferred are those compounds, which are listed in (Ia)-(Ih) preferred values, in which case, however, additionally, - SO2A represents methylsulphonyl.

The subject invention further is a method of obtaining compounds of formula (I) under item 1 of the claims, as well as their salts, characterized in that the compound of formula (II)

< / BR>
where R1, R2and A have the above meanings, and Q denotes Cl, Br, OA, O-CO-A, O-CO-Ph, OH or other reactive, esterified to ester, an OH group, respectively, it is easy nucleophile replaced the deleted group,

enter into interaction with the guanidine; or benzylguanine formula (III)

< / BR>
where R1and A have the above meanings, and

R3denotes F, Cl, Br, J, or other suitable removable group,

enter into interaction with the compound of the formula (IV)

R2- S - H, (IV)

where R2have the above values,

or derived from it saltlike connection, tialata;

or generally corresponding to the formula (I) compound, which, however, instead of one or more hydrogen atoms contains one or more recoverable groups and/or one yea the formula (I) compound, which, however, instead of one or more hydrogen atoms contains one or more solvolysis groups treated with solvolysis tools;

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

The compound of formula (I), however, get itself known in ways that are described in the literature (for example, in Houben-Weil, Methods of organic chemistry, ed. Georg Thieme, Stuttgart; Organic reactions, John Wiley and Sons, int. New York, as well as in the aforementioned patent application), namely under reaction conditions which are known and suitable for the specified interactions. You can also use themselves known here more not mentioned options.

The initial substance in the desirable case can also be obtained in situ, so that they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

Preferably the compound of formula (I) receive the fact that activated carboxylic acid derivative of the formula (II), particularly preferably denotes C1 or-O-CH3enter into interaction with guanidine. Especially suitable that the t in the corresponding activated derivative and then it directly, without intermediate selection enter into interaction with guanidine. Ways in which unnecessary intermediate selection are, for example, activating using carbonyldiimidazole, dicyclohexylcarbodiimide or option 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 using the appropriate thiol, respectively thiophenols. The interaction is carried out by analogy with the reaction of compounds of formulas (III) and (IV). She is described below.

The interaction of a reactive carboxylic acid derivative of the formula (II) with guanidine exercise in itself known, preferably in proton or aprotic, 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, water or prepared mixture of them. As the reaction temperature is suitable, for example, temperature of 20oC to the boiling point of the solvent. BP is s. For this purpose, any suitable types of foundations that do not interfere with the reaction. Especially suitable, however, the use of inorganic bases like potassium carbonate, or organic bases like triethylamine or pyridine, or, however, an excess of guanidine.

The compound of 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 produced from them reactive derivatives of acids, such as galodamadruga, esters or anhydrides, with guanidine, under reaction conditions which are in themselves known and generally normal to obtain amides. Particularly suitable again these possible actions, which are specified above for the interaction of the compounds of formula (II) with guanidine.

Thiols or thiophenol, respectively thiolate, formula (IV), the same as how they get themselves known. If they are unknown, they can get itself known methods.

Obtaining the compounds of formula (II), and the interaction of the compounds of formula (II) with soy is, alarna inert organic solvent.

The preferred option, of course, is that the components of the reaction directly without the addition of solvent, enter into interaction 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 component. As the bases are preferably usable, for example, hydroxides, carbonates, alkaline alcoholate or alkaline earth metals, or organic bases like triethylamine or pyridine, which are also used in excess, and then at the same time they can serve as solvents.

As inert solvents particularly suitable alcohols as methanol, ethanol, isopropanol, n-butanol or tert.-butanol, ethers like diethyl ether, THF or dioxane; a simple glycol ethers as simple etilenglikolevye or monotropy ether (methylglycol or ethylglycol), etilenglikolevye simple ether (diglyme); ketones, such as acetone or butanone; NITRILES like acetonitrile; nitro-compounds as nitromethane or nitrobenzene; the difficulty is(DMSO); chlorinated hydrocarbons like dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons as benzene, toluene or xylene. Further, suitable mixtures of 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.

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

In a mole of hydroxyl groups. If the existing protective group different from each other, but in many cases they can be selectively split.

The expression "protection for the amino function group" is well known and relates to groups which are suitable for protecting (blocking) amino group from chemical interactions, 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 (for example, benzyl, 4-nitrobenzyl, triphenylmethyl) group. As for protective amino group functions after the desired reaction (or sequence of reactions) are removed, their kind and magnitude, however, is not critical; however, preferably those 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 before in the of IMT, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluoyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.-butoxycarbonyl (SIDE), 2-iodoxybenzoic; arelaxation as benzyloxycarbonyl (CBZ), 4-methoxybenzeneboronic, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protective for amino function groups are the SIDE DNF and BOM, 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 above-mentioned, unsubstituted or substituted, aryl, kalkilya or acyl group, further, also alkyl groups. The nature and magnitude protective for hydroxyl group functionality is not critical, as they again removed after the desired chemical reaction or sequence of reactions; preferred group with 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective for Funke preferred benzyl and acetyl.

Used as starting substances, the functional derivatives of compounds of formula (I) can be obtained by conventional means, which are described, for example, specified in the standard works and patent applications, for example, by reacting compounds which correspond to formula (II) and (III), whereby, however, 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, depending on the protective group is carried out, for example using strong acids, expediently using triperoxonane acid or perchloric acid, but also using other strong inorganic acids as hydrochloric or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid, or sulfonic acids, as benzene - or p-toluensulfonate. The presence of an additional inert solvent may, however, not always required.

As the inert solvent is preferably suitable organic, for example carboxylic acids, as acetic acid; ethers, like tetrahydrofuran (THF) or dioxane; amides as dimethylformamide (DMF); halogenated pivot 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 acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperature off appropriate amount from about 0 to about 50oC, preferably operate at 15-30oC (room temperature).

SIDE-group can be split, for example, preferably using 40% triperoxonane acid in dichloromethane or using approximately 3 to 5 N. HCl in dioxane at 15-60oC;

MOS-group can be split with approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Cleavage DNF-groups are, for example, also by means of approximately 3-10% solution of 2-mercapto-ethanol in a mixture of DMF with water at 15-30oC.

Hydrogenations removable protective group (for example, BOM, 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 this is awliyah 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.

The basis of the formula (I), then, can be translated using acid to the corresponding salt accession acid. For this transformation take into account 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, such as ortho-phosphoric acid, sulfamic acid; further, organic acids, especially aliphatic, acyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as 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, Ocelot, 2-hydroxy-econsultation, benzosulfimide, p-toluensulfonate, naphthalene-mono - or di-sulfonic acids, louisanna acid.

The compounds of formula (I) and their physiologically acceptable salts can be used to prepare pharmaceutical compositions, in particular by non-chemical. While their together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance, and, if necessary, in combination with one or more other biologically active substances, can be reduced to suitable dosage forms.

The subject of the invention, then, are the tools, features 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 application (introduction) and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, oral administration in particular are pills, tablets, capsules, syrups, juices or drops; for rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore, suspensions, emulsions or implants; for topical application are ointments, creams, pastes, lotions, gels, pulverizate drugs, 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, such as lubricants, preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and/or aromatic substances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

Connect them, as monkeys, dogs, cats, rats or mice, and used for therapeutic treatment of the human or animal, and also in combating diseases, in particular in the treatment and/or prevention of disorders of the cardiovascular system. They are therefore suitable for the treatment of arrhythmias, particularly when they are caused by lack of oxygen; angina; stroke; ischemia of the nervous system, such as stroke or swelling of the brain; shock and prevention.

Further substances can be used as therapeutic agents for diseases in which play the role of cell proliferation, as arteriosclerosis, diabetic late complications, neoplastic diseases, fibrosis, and hypertrophy and hyperplasia of bodies, particularly in diseases of the prostate.

This proposed according to the invention substances, usually administered by analogy with the known means of complications, such as aplidin, preferably in dosages of about 0.01 to 5 mg, in particular between 0.02 and 0.5 mg, 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 depends,sresta, body weight, General health, sex, on cost, time and route of administration, rate of excretion, combination of drugs and the severity of the respective disease, which has implications for therapy. Preferably oral administration.

In the following examples, the expression "conventional treatment" means add, if necessary, water is extracted using 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.

To a solution of 1.5 g of guanidine dissolved in 20 ml simple etilenpropilendienovogo ether at room temperature was added dropwise 1.8 g of acid chloride of 2-methyl-4-(4-pyridylthio)-5-methylsulphonyl-benzoic acid [obtained by interaction of 2-methyl-4-chloro-5-methylsulphonyl-benzoic acid 4-mercaptopyridine in the presence of NaOCH3if 180oC and subsequent chlorination with SOCl2] dissolved in 20 ml simple etilenpropilendienovogo ether, and the reaction mixture is stirred for 3 hours at 25oC. Then treated as usual and purified by chromatography on CD in the form of a viscous oil; M++1 (FAB) = 365.

Similarly, by reacting guanidine with the acid chloride of 2-methyl-4-(4-chlorophenylthio)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(4-chlorophenylthio)-5-methylsulphonyl-benzamide; so pl. 245-247oC; (methanesulfonate with so pl. above 250oC);

with the acid chloride of 2-methyl-4-(3-chlorophenylthio)-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-(3-chlorophenylthio)-5 - methylsulphonyl-benzamide; so pl. 198-202oC; methanesulfonate, so pl. 213-215oC;

with the acid chloride of 2-methyl-4-(2-chlorophenylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(2 - chlorophenylthio)-5-methylsulphonyl-benzamid, so pl. 184-187oC (methanesulfonate with so pl. above 250oC);

with the acid chloride of 2-methyl-4-phenylthio-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4-phenylthio-5 - methylsulphonyl-benzamid, so pl. 125-139oC;

with the acid chloride of 2-methyl-4-(4-forfinally)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(4 - forfinally)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-methyl-4-(3-forfinally)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(3 - forfinally)-5-methylsulfone iminomethylene-2-methyl-4-(2 - forfinally)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-methyl-4-(3-pyridylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(3 - pyridylthio)-5-methylsulphonyl-benzamide;

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

with the acid chloride of 2-methyl-4-(2-pyridylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-methyl-4-(2 - pyridylthio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-methyl-4-2-(1,4,5,6-tetrahydropyrimidine)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl - 4-2-(1,4,5,6-tetrahydropyrimidine)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-methyl-4-(4,5-dihydrothiazolo-2-yl-thio)-5 - methylsulphonyl-benzoic acid get N-diaminomethylene-2-methyl-4- (4,5-dihydrothiazolo-2-yl-thio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-methyl-4-[2-(4-N-methyl-1,2,4-triazole-3-yl - thio)]-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2 - methyl-4-[2-(4-N-methyl-1,2,4-triazole-3-yl-thio)]-5-methylsulphonyl - benzamid.

Example 2.

0.9 g N-diaminomethylene-2-methyl-4-(4-pyridylthio)-5 - methylsulfonylbenzoyl (produced according to example 1) are suspended in 100 ml of water, is deltio)-5 - methylsulphonyl-benzamid-dihydrochloride, so pl.>250oC.

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

N-diaminomethylene-2-methyl-4-phenylthio-5-methylsulphonyl - benzamide get N-diaminomethylene-2-methyl-4-phenylthio-5 - methylsulphonyl-benzamide hydrochloride, T. pl. > 260oC;

N-diaminomethylene-2-methyl-4-(2-pyridylthio)-5-methylsulphonyl benzamide get N-diaminomethylene-2-methyl-4-(2-pyridylthio)- 5-methylsulphonyl-benzamid-dihydrochloride;

N-diaminomethylene-2-methyl-4-(3-forfinally)-5-methylsulphonyl - benzamide get N-diaminomethylene-2-methyl-4-(3-forfinally)-5 - methylsulphonyl-benzamide hydrochloride;

N-diaminomethylene-2-methyl-4-(4-forfinally-5-methylsulphonyl - benzamide get N-diaminomethylene-2-methyl-4-(4-forfinally)-5 - methylsulphonyl-benzamide hydrochloride;

N-diaminomethylene-2-methyl-4-(4-chlorinity)-5-methylsulphonyl - benzamide get N-diaminomethylene-2-methyl-4-(4-chlorophenylthio)-5 - methylsulphonyl-benzamide hydrochloride;

N-diaminomethylene-2-methyl-4-methylthio-5-methylsulphonyl - benzamide get N-diaminomethylene-2-methyl-4-methylthio-5 - methylsulphonyl-benzamide hydrochloride, T. pl. > 260oC;

N-diaminomethylene-2-methyl-4-(2-chlorophenylthio)-5-methylsulfone the>

Example 3.

2.9 g of N-diaminomethylene-2-methyl-4-chloro-5-methylsulphonyl-benzamide [produced by interaction of the acid chloride of 2-methyl-4-chloro-5 - methylsulphonyl-benzoic acid with guanidine according to example 1] and 700 mg of timedelta of sodium in 30 ml of DMF is stirred for 2 hours at 90oC. Then add 30 ml of ice water and the reaction mixture is acidified with 20 ml of 1 N. HCl. The formed precipitate is sucked off and the crude product is purified by chromatography on silica gel (ethyl acetate +10% methanol). Get N-diaminomethylene-2-methyl-4-methylthio-5-methylsulphonyl-benzamid, so pl. 220-222oC.

Similarly, by reacting N-diaminomethylene-2 - methyl-4-chloro-5-methylsulphonyl-benzamide

with Tiotropium sodium get N-diaminomethylene-2-methyl-4 - propylthio-5-methylsulphonyl-benzamid, so pl. 215-218oC; methanesulfonate, so pl. 195-197oC;

with Tiotropium sodium get N-diaminomethylene-2-methyl-4 - isopropylthio-5-methylsulphonyl-benzamid, so square (methanesulfonate) 185-186oC;

with titillator sodium get N-diaminomethylene-2-methyl-4 - ethylthio-5-methylsulphonyl-benzamid, so pl. 238-240oC; methanesulfonate, so pl. 152-154oC;

with thio-tert.-the butyl sodium get N-deaminated the
with cyclohexyldiamine sodium get N-diaminomethylene-2-methyl - 4-cyclohexylthio-5-methylsulphonyl-benzamide;

with cyclopentolate sodium get N-diaminomethylene-2-methyl - 4-cyclopentyl-5-methylsulphonyl-benzamid.

Similarly, by reacting N-diaminomethylene-2 - ethyl-4-chloro-5-methylsulphonyl-benzamide

with timedelta sodium get N-diaminomethylene-2-ethyl-4 - methylthio-5-methylsulphonyl-benzamide;

with Tiotropium sodium get N-diaminomethylene-2-ethyl-4 - propylthio-5-methylsulphonyl-benzamide;

with diisopropylate sodium get N-diaminomethylene-2-ethyl-4 - isopropylthio-5-methylsulphonyl-benzamide;

with titillator sodium get N-diaminomethylene-2-ethyl-4-ethylthio - 5-methylsulphonyl-benzamide;

with cyclohexyldiamine sodium get N-diaminomethylene-2-ethyl - 4-cyclohexylthio-5-methylsulphonyl-benzamide;

with cyclopentolate sodium get N-diaminomethylene-2-ethyl - 4-cyclopentyl-5-methylsulphonyl-benzamid.

Example 4.

Analogously to example 1, by reacting guanidine with the acid chloride of 2-ethyl-4-(4-pyridylthio)-5-methylsulphonyl-benzoic acid [obtained by interaction of 2-ethyl-4-chloro-5 - methylsulphonyl-benzoic acid to obtain N-diaminomethylene-2-ethyl-4-(4-pyridylthio)-5 - methylsulphonyl-benzamid.

Similarly, by reacting guanidine

with the acid chloride of 2-ethyl-4-(4-chlorophenylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(4 - chlorophenylthio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(3-chlorophenylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(3 - chlorophenylthio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(2-chlorophenylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(2 - chlorophenylthio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-phenylthio-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-phenylthio-5 - methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(4-forfinally)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(4 - forfinally)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(3-forfinally)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(3 - forfinally)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(2-forfinally)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(2 - forfinally)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(3-pyridylthio)-5-is R>
with the acid chloride of 2-ethyl-4-(2-pyrimidinyl)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(2 - pyrimidinyl)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(2-pyridylthio)-5-methylsulphonyl - benzoic acid get N-diaminomethylene-2-ethyl-4-(2 - pyridylthio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-[2-(1,4,5,6 - tetrahydropyrimidine)]-5-methylsulphonyl-benzoic acid get N-diaminomethylene-2-ethyl-4-[2-(1,4,5,6 - tetrahydropyrimidine)]-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-(4,5-dihydro-thiazol-2-yl-thio)- 5-methylsulphonyl-benzoic acid get N-diaminomethylene - 2-ethyl-4-(4,5-dihydro-thiazol-2-yl-thio)-5-methylsulphonyl-benzamide;

with the acid chloride of 2-ethyl-4-[2-(4-N-methyl-1,2,4-triazole-3-yl - thio)]-5-methylsulphonyl-benzoic acid get N-diaminomethylene - 2-ethyl-4-[2-(4-N-methyl-1,2,4-triazole-3-yl-thio)]-5-methylsulphonyl - benzamid.

The following examples relate to pharmaceutical compositions.

Example A. Glass vials of medicine for injection

In a solution of 100 g of biologically active 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, Rast is lnyh sterile conditions and closed. Each glass bottle of medicine for injection contains 5 mg of biologically active substances.

Example B. Candles

Melt a mixture of 20 g of biologically active substances of the formula (I) together 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 C. a 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 a total volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example, 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 such that each tablet contains 10 mg of biologically active substances.

Example E. Bean

Analogously to example D is pressed tab is a and dye.

Example J. Capsules

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

Example z Capsules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules, lyophilizer in sterile sterile conditions and closed. Each ampoule contains 10 mg of biologically active substances.

Pharmacological data

Defined biological (inhibitory) activity of the compounds of General formula (I)

< / BR>
Inhibition of Na+-exchange was determined on rabbit erythrocytes according to the method described Duesing with al., Med. Clin. 87, 378-384 (1992), the activity expressed by the value of the IC50corresponding to 50% of the resultant inhibition of Na+/H+-antiporta (Na+-exchange) on rabbit erythrocytes. The results are shown in table 1.

The results obtained demonstrate significant inhibition of Na+/H+-dependent Na+-exchange compounds of formula (I) in comparison with the known compound, which used a 3-methylsulphonyl-4-(4-pyridylthio) benzylguanine,but the invention the compounds of formula (I) as inhibitors of Na+/H+-antiporta. The proposed compounds inhibit Na+/H+-antiport, thereby preventing heart disease and are cardiotoxin action, therefore suitable for the treatment and prevention of arrhythmia, angina, heart attack, pathological hypoxic and ischemic damage.

1. 4-mercapto-benzoylpyridine formula I

< / BR>
where R1means AND;

R2means And, unsubstituted or substituted by F, Cl, Br, phenyl, pyridyl;

And means alkyl with 1 to 6 C-atoms,

and their physiologically acceptable salts.

2. 4-mercapto-benzoylpyridine formula I on p. 1 representing:

a) N-diaminomethylene-2-methyl-4-(4-pyridylthio)-5-methylsulphonyl-benzamid,

b) N-diaminomethylene-2-methyl-4-methylthio-5-methylsulphonyl-benzamid,

in) N-diaminomethylene-2-methyl-4-isopropylthio-5-methylsulphonyl-benzamid,

g) N-diaminomethylene-2-methyl-4-phenylthio-5-methylsulphonyl-benzamid,

d) N-diaminomethylene-2-methyl-4-(3-chlorophenylthio)-5-methylsulphonyl-benzamid,

and their physiologically acceptable salts.

3. The method of obtaining 4-mercapto-benzoylpyridine formula I and their salts, characterized in that the compound of formula II


enter into interaction with guanidine.

4. The pharmaceutical composition inhibiting Na+/H+-antiport containing the active substance and a pharmaceutically acceptable carrier, characterized in that the active substance it contains at least one 4-mercaptobenzothiazole formula I under item 1 and/or one of its physiologically acceptable salt in an effective amount and at least one solid, liquid or semi-liquid carrier or excipient.

 

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< / BR>
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E - sulfur;

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