A method of obtaining a hydrazone derivatives or their salts of inorganic acids


(57) Abstract:

The essence of the invention: method of obtaining derivatives, hydrazone, product hydrazone derivative of the formula given in the text of the description, or their salts of inorganic acids. Reagent 1: derived amidino-1-indanone, reagent 2 derivative of 2'-amidinophenoxy. 1 C.p. f-crystals

The invention relates to methods for new compounds that have the properties of an inhibitor of the enzyme S-adenosylmethionine (SAMDC) and can find application in the pharmaceutical industry.

Previously, B. L. Freedlander and French F. A. "Cancer Res." 18, 360-363 described hydrazone derivative of methylglyoxal of biguanidine exhibiting the property of SAMDC inhibitor.

According to the present invention offers a method of obtaining a previously unknown hydrazone derivatives of General formula I

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or their salts of inorganic acids, where R1hydrogen or lower alkyl; R2hydrogen or hydroxy, And a direct link or -(CH2)-. The method consists in the fact that the compound of formula II

where the values of R1above, is subjected to the interaction with the compound of the formula III

H2N R2where a value of R2defined above, amidino-1-indanone-2l-amidinohydrolase or its pharmaceutically applicable inorganic salts as the starting compound of formula II using 4-amidino-1-indanone, as well as the compounds of formula III using 2-amidinohydrolase.

Used the concepts of the present application are mainly the following values.

"Lower" denotes a radical containing up to 7, especially up to 4 C-atoms.

"Lower alkyl", for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl, and above all methyl.

"Halogen" is, in particular, chlorine or bromine, but may also be fluorine or iodine.

Salt proposed in the invention compounds are primarily used in the pharmaceutical industry non-toxic salts with inorganic acids such as hydrochloric, sulfuric and phosphoric acid. In the presence of several major groups can be mono - or polysol.

For isolation or purification of compounds can be used also unsuitable for pharmaceutical salts such as perchlorates. For use as drugs are only used in pharmaceutical p. the shadow of the compounds can exist in the form of mixtures of isomers or pure isomers. If, for example, R1means the lower alkyl, the corresponding compounds of formula I can be in the form of racemates or pure enantiomers.

Proposed in the invention compounds have valuable, especially in regard to pharmacological properties. In particular, they find strong specific inhibitory effect on the enzyme S-adenosylmethionine (SAMDC). It is known that SAMDC as a key enzyme plays an important role in the synthesis of polyamines, is typical for almost all mammals, including humans. Under the action of SAMDC is regulated by the concentration of polyamine in the cells. Inhibition of SAMDC enzyme leads to a decrease in the concentration of polyamines. The lower the concentration of the enzyme causes inhibition of cell growth, Prem preparations containing inhibiting SAMDC-substances that can "freeze" the growth of eukaryotic and prokaryotic cells or even kill cells or inhibit the mechanism of cell division.

Inhibition of SAMDC enzyme can be determined, for example, by the method of Williams-Ashman and Schenone, Biochem. Biophys. Res. Commun. 46, 288 (1972). Thus by measuring at different concentrations of inhibitory substances determine JC50-value, i.e. the concentration ingibiruyah sravnitelnim connection served as methylglyoxal bis-guanylhydrazone (MGBG), known from the prior techniques. The obtained data are given in the table. Proposed in the invention compounds have the minimum value JC50-0,005 mm.

From these examples it is seen that all these compounds have the best results of inhibition than the comparative compound MGBG. From this we can conclude that, in General, all the compounds obtained according to the invention, have the best results of inhibition than the comparative compound. Thus, the method of obtaining new compounds according to the invention represents technical progress.

Studied so far, the compounds of formula I in experiments on animals have value toxicity from low to medium. This classification also confirmed still in cell cultures.

Another advantage of the invention compounds is that they possess a strong inhibitory effect on the SAMDC, partially inhibit diaminooctane and compatible with it. Inhibition of diaminooctane according to J. Jaenne and D. R. Morris, Biochem. 218, 974 (1984), is an unfavorable phenomenon, as it can lead to the accumulation of putrescine and indirect activation of SAMDC. Therefore, the compounds of formula I are used, for example, for leenie process of cell multiplication and growth of cells micrometastases. In addition, they can be used, for example, for the treatment of prototipami, such as trypanosomes, malaria and pneumonia caused by Pneumocystis carinii.

As selective inhibitors of SAMDC can be used the compounds of formula I alone or in combination with other pharmacologically active substances. You can keep in mind, for example, a combination with (a) inhibitors of other enzymes in the biosynthesis of polyamines, for example, inhibitors of ornithine-decarboxylase, (b) inhibitors of protein kinase C, (C) inhibitors tyrosylprotein, (g) tsitokinazy, (d) negative growth regulators, (e) aromatase inhibitors, (W) antiestrogens or (C) classical cytotoxic substances.

In the following more detailed description of the method (a) the symbols A, R1and R2have the meanings indicated in formula I, if no other value is not given.

Method (a).

The condensation reaction proceeds at already known conditions with the formation of hydrazones. The reaction is catalyzed by acid.

Intermediate products of the formula II are obtained by treatment of compounds of formula IV

< / BR>
hydrogen sulfide conversion into the corresponding thiocarboxamide [-C by reaction with a reagent Lawessoud [2,4-bis-(4-methoxyphenyl)-2,4-dicicco-1,3,2,4-dithia - diphosphate]

Thiocarboxamide in the interaction, for example, with the lowest alkylation or three lowest alkylchloroformates are S-alkilirovanny and become hydroiodic imino-lower-alkylthiophene [C(= NH)-S-alkyl-HJ] or tetrafluoroborate this aminothiophene, which when reacted with ammonia easily converted into the desired carboxamide formula II (cf. S. Patai (ed.) Chemistry amidino and imidates, Wiley, London, 1975, pp. 303-304).

Another option for obtaining compounds of formula II is that the compounds of formula IV is treated with, for example, ethanol and hydrochloric acid in chloroform or diethyl ether with the formation of the corresponding hydrochloride aminoethylamide ether. The last in the interaction, for example, methanol can be converted into the desired carboxamide formula II. However, in some cases, this method could not be implemented due to the steric hindrance caused by the presence of groups a and R1.

The initial compounds of the formula IV in themselves well known and are obtained similarly to the previously described compounds.

The compounds of formula IV can, for example, be obtained through intramolecular acylation w-phenyl-lower alkanovykh acids of formula V

OH g the method of Friedel -. As catalysts, in the case of free acids can be used, for example, polyphosphoric acid, and acid chlorides and anhydrides of acids, for example, AlCl3.

In this reaction it is preferable to use the compounds of formula V where w4not cyano, and its predecessor, for example, halogen, in particular bromine, or a protected amino group, for example, acetylamino. Then after the cyclization stage predecessor of ceanography known method can be converted into cyano, for example, if it is a bromine by reaction with copper cyanide (I), or, if acetylamino the removal of the protective acetyl group, diazotization and interaction with copper cyanide (I).

The compounds of formula IV can be obtained, for example, in the oxidation process, for example, chromium trioxide (CrO3), from the corresponding decarbonising compounds of the formula VI:

where w4cyano group or its predecessor, with the specified value. In the case of the group's predecessor, the latest in the oxidation process is converted into a cyano group by the described method.

Getting aminoguanidine formula III are well known. Aminomethane (procarbazine) Polui, can also be obtained in the form of hydrates. Their crystals can include used for crystallization, solvent.

These reactions may be carried out under known conditions in the presence or absence of solvents and diluents, mainly those which are inert under the reaction conditions and dissolve the original reagents, in the presence or absence of catalysts, condensation funds or neutralizing agents, depending on the type of reaction and/or reaction components at high, normal and low temperatures, for example, in a temperature range from -70 to 190aboutWith, mainly from -20 to 150aboutWith, for example, at the boiling point of the employed solvent under atmospheric pressure or in a closed vessel under pressure and/or in the atmosphere of inert gas, for example, in nitrogen atmosphere.

It is possible to use compounds of the formula I in the pharmaceutical preparations containing them as active substances. Especially important enteral drugs, particularly oral and parenteral use. The preparations can contain one active ingredient, or even the media, which is preferable. The dosage of the active substance depends on with who to medications.

The pharmaceutical preparations contain from 0.1 to 95% of active substance, and single dose contains predominantly from 1 to 90% and niedozywienie forms respectively from 0.1% to 20% of Dosage forms such as pills, tablets or capsules, contain from 1 to 500 mg of active substance.

Pharmaceutical preparations obtained by such known techniques as, for example, mixing, granulating, drazhirovanie, dissolution. Thus it is possible to obtain pharmaceutical compositions for oral administration, by combining the active compounds with one or more solids-carriers. The resulting mixture is granulated, and the granules, after adding auxiliary substances are processed into tablets and coated tablets.

As matter-carriers can be used fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium, in addition, binding agents such as starches of different origin (maize, wheat, rice or potato), methyl cellulose, hypromellose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone acid sludge its salt, for example, sodium alginate.

Added excipients is, first and foremost, means regulating the flow and lubrication, for example, silicic acid, talc, stearic acid or its salts, such as magnesium stearate and calcium, and/or polyethylene glycol and its derivatives.

The bean seeds enclosed in suitable, resistant to gastric juice, coating, using for this purpose, concentrated sugar solutions containing gum Arabic, talc, polyvinylpyrrolidone, polyethylenglycol and/or titanium dioxide, solutions varnish in suitable organic solvents or solvent mixtures, and to obtain resistant to gastric juice coating solutions of the corresponding cellulose preparations, such as cellulose acetate phthalate and phthalate of hydroxypropylmethylcellulose. In pill or grain pills with coatings can be added dyes or pigments, for example, for identification or marking of different doses of active substance.

Applied oral pharmaceutical compositions are soft, closed capsules using a softener, such as glycerol or sorbitol. Capsules may contain the active substance in the form of greathearted magnesium, as well as stabilizers. In soft capsules the active substance is dissolved or suspendered, mainly in suitable liquid auxiliary substances, such as fatty oils, paraffin oil or liquid polyethylene glycols, also with the addition of stablization.

Other, used in the mouth, the dosage form is prepared in the usual way syrups containing the active substance, for example, in suspended form in a concentration of from 0.1 to 10% preferably about 1% or within these limits, which entered as a single dose when measuring 5-10 ml of syrup. In addition, widely used powdered or liquid concentrates in different environments, for example, in milk. Such concentrates can rasfasovyvaetsya in the form of single doses.

Pharmaceutical preparations for rectal application are candles, made from a combination of active substances with suppozitornyj basis. As a candlestick (suppozitornyj) masses are used, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration are primarily aqueous solutions and the de, containing substances of high viscosity, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran, and sometimes stabilizers.

When this active substance together with auxiliary means may also exist in the form of a lyophilisate and before parenteral introduction to dissolve with the addition of suitable solvents.

Solutions for parenteral administration may be similar to the solutions for intravenous administration.

Pharmaceuticals for the treatment, including as applicable the beginning of the compounds of formula I can have a therapeutic and prophylactic use. When the body mass of 70 kg, a daily dose ranges from 1 to 1000 mg, preferably from 25 to 100 mg for oral and from 2 to 50 mg of parenteral application.

The following examples illustrate the invention; temperatures are given in degrees Celsius. Abbreviations: DMF=N,N-dimethylformamide, ether-diethyl ether, MS (FAB)=mass spectrum ("the bombardment of heavy atoms").

P R I m e R 1. 4-Amidino-1-indanone-2l-amidinohydrolase hydrochloride.

A solution of 3.8 g (27.9 mmol) of bicarbonate aminoguanidine in 200 ml of water and 14.7 ml of 2 N. hydrochloric acid heated to 60she in 200 ml of methanol. The reaction mixture is boiled for 24 h before phlegmy and after cooling, evaporated to dryness. The residue is suspended in 50 ml of ethanol, filtered, washed with ethanol and ether. Get listed in the title compound, containing 1 mol of crystal water, so pl. > 330aboutWith; up to 330aboutSince there was no decomposition. MS (FAB):(M+H)+=231;1H NMR (D2O) =8,08 (d, 1H); of 7.75 (d, 1H); 7,58 (t, 1H); to 3.35 (m, 2H); 2,96 (m, 2H).

The parent compound was obtained as follows.

a) 4-Thiocarbamoyl-1-indanone.

A solution of 12.1 g (77 mmol) of 4-cyano-1-indanone [Coll.Czechoslov. Chem. Commun. 43, 3227 (1978)] in 200 ml of pyridine and 10.6 ml (77 mmol) of triethylamine saturate at 40aboutC for 3 h hydrogen sulfide and stirred at the same temperature for another 16 hours After cooling, the reaction mixture is evaporated to dryness, and the residue is diluted with 300 ml of water. Vykristalizovyvalsya the yellow product is sucked off, washed with water, dried and recrystallized from ether acetic acid. Get a connection (a) with a melting point of 197aboutC (decomposition).

b) 4-Amidino-1-indanone hydrochloride.

A solution of 9.8 g (51,3 mmole) 4-thiocarbamoyl-1-indanone in 500 ml of absolute methylene chloride is diluted at room temperature in atmosphericcurrent potassium and 4.2 g of water. The mixture is then short time, stirred, filtered and the filtrate washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. Thus obtained crude ethylthiomethyl dissolved in 160 ml of absolute atenolo, diluted with 3.3 g (60 mmol) of ammonium chloride and heated for 20 h before phlegmy. After cooling, the reaction mixture is evaporated to dryness. Connection b) purify by chromatography on 1000 ml of Amberlite (resin R180) using water as wymiwyg tools and recrystallized from a mixture of ethanol/ether. The melting point of the product 215-218aboutC (decomposition).

P R I m m e R 2. 4-Amidino-1-indanone-2l-(N-hydroxyamino)-hydrazone - dihydrochloride.

A solution of 316 mg (1.5 mmole) 4-amidino-1-indanone-hydrochloride (example 1B) in 7 ml of methanol diluted with a solution of 394 mg (1.5 mmole) of 1-amino-3-hydroxyguanidine-4-toluensulfonate in 6 ml of water and 0.75 ml (1.5 mmole) of 2n.of hydrochloric acid. Then the mixture is heated for 2 h before phlegmy, stirred for 16 h at room temperature, evaporated and the residue purified by chromatography (column pharmaceutical SR-28-100) on kieselgel OPTY-UPC12(use water as eluent, 5-ml fractions, speed run of 27.5 ml/h). Faction 56-78 with the IDA waxy crystals. MS (FAB): (M+N)+=247;1H NMR (D2O): =of 8.06 (d, 1H); 7,73 (d, 1H); 7,58 (t, 1H); to 3.36 (m, 2H); 2,98 (m, 2H).

P R I m e R 3. 5-Amidino-1-tetralone-2l-amidinohydrolase-dihydrochloride.

A solution of 0.41 (3 mmole) of bicarbonate aminoguanidine in 31.5 ml of 0.1 G. of hydrochloric acid diluted 0,675 g (3 mmole) of the hydrochloride of 5-amidino-1-tetralone and within 72 h boil until phlegmy. After cooling, evaporated to dryness and recrystallized from methanol/ether specified in the title compound with a melting point of > 330aboutWith; up to 330aboutWith the decomposition occurred. MS (FAB): (M+H)+= 245;1H NMR (DMSO-d6): =11,3 (s, 1H); 9,5 (m, 4H); 8,65 (d, 1H); 7,92 (m, 3H); 7,52 (d, 1H); 7,46 (t, 1H); 2,7-to 2.85 (m, 4H); 1,9 (m, 4H).

The original connection was obtained as follows.

a) 5-Cyano-1-tetralone.

A solution of 1.0 g (4.4 mmole) of 5-bromo-1-tetralone [J.Org. Chem. 49 - 4226 (1984)] in 1.3 ml DMF is diluted 0,41 g (4.5 mmole) of copper cyanide (I) and stirred for 6 h at 160aboutC. After that the reaction mixture is cooled to 80aboutAnd add a solution of 1.6 g of uranyl chloride iron (III) in 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid. Stirred for further 45 min, cooled, diluted with a mixture of water and extracted with toluene. The organic phase is washed with water, dried on the. THE K (CH2WITH2): 2220, 1690 cm-1;1H NMR (CDCl3): = compared to 8.26 (q, 1H); to $ 7.91 (q, 1H); the 7.43 (t, 1H); is 3.21 (t, 2H); of 2.72 (t, 2H); of 2.23 (m, 2H).

b) 5-Thiocarbamoyl-1-tetralone.

analogously to example 1A, 10.6 g (62 mmole) of 5-cyano-1-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine is treated with hydrogen sulfide. The result is a compound b) in the form of yellow crystals. The melting point of the substance 200-205aboutC.

C) 5-Amidino-1-tetralone hydrochloride.

Analogously to example 1B, 8.6 g (42 mmole) of 5-thiocarbamoyl-1-tetralone treated with 8.8 g (44 mmole) of triethylorthoformate and 2.6 g (49 mmol) of ammonium chloride. Get listed at the beginning of the connection), which looks slightly pinkish crystals. MS (FAB):(M+H)+=189.

P R I m e R 4. 4-Amidino-2-methyl-1-indanone-2l-amidinohydrolase - dihydrochloride.

A solution of 1.0 g (5.0 mmol) 4-amidino-2-methyl-1-indanone hydrochloride mixed with 0.68 g (5,0 by mmol) of bicarbonate amidinopropane in 10 ml of 0.5 N. hydrochloric acid for 120 h at 25aboutC. Vegascasinoonline the product is sucked off, washed with a small amount of water and dried. Get listed in the title compound with a melting point > 330aboutWith; up to 330aboutWith the decomposition occurred. MS (the unity gain as described below.

a) 4-Thiocarbamoyl-2-methyl-1-indanone.

By analogy with example 1A, 11.1 g (65 mmol) of 4-cyano-2-methyl-1-indanone (see U.S. patent 3956363) in 200 ml of pyridine and 9.7 ml of triethylamine is treated with hydrogen sulfide. After processing the receive connection in the form of yellow crystals with a melting point 195-198about(Razlog.); 1H NMR (DMSO-d6): =9,81 (d, 1H); 7,71 (m, 2H); of 7.48 (m, 1H); of 3.48 (m, 1H); of 2.81 (m, 2H); of 1.23 (s, 3H); 1,19 (s, 3H).

b) 4-Amidino-2-methyl-1-indanone hydrochloride.

By analogy with example 1B, 10.2 g (50 mmol) of starting compound (a) is treated 11,0 (55 mmol) of tetrafluoroborate triethyloxonium and 3.2 g (60 mmol) of ammonium chloride. Get connection b) as pink crystals. The compound is administered in a further reaction.

P R I m e R 5. 4-Amidino-3-methyl-1-indanone-2-amidinohydrolase - dihydrochloride.

A solution of 300 mg (1.3 mmole) 4-amidino-3-methyl-1-indanone-hydrochloride in 6 ml of water diluted with 300 mg (2.3 mmole) of bicarbonate aminoguanidine in 4 ml of 0.5 N. hydrochloric acid and stirred for 24 h at 80aboutC. the Reaction mixture is cooled, evaporated and the residue purified by chromatography on 180 ml Amberlite (resin ER180when using water as eluent. Specified in the header connection precrystallization the(kieselgel), methylene chloride/methanol/concentrated ammonia 5:3:1; MS (FAB):(M+N)+=245;1H NMR (D2O): =of 7.97 (d, 1H); to 7.64 (d, 1H); 7,49 (t, 1H); 3,86 (m, 1H); 3,17 (q, 1H); 2.49 USD (d, 1H); to 1.24 (d, 3H).

The parent compound was obtained as follows.

a) 4-Cyano-3-methylindene.

A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org.Chem. 22, 1019 (1957)] and 1.14 g (12.7 mmol) of copper cyanide (I) in 2.5 ml DMF is stirred for 6 h at 170aboutC. After that the reaction mixture is cooled to 100aboutWith and serially diluted with 50 ml of toluene and a solution of 4.5 g (16.5 mmol) of uranyl ferric chloride in 7 ml of water and 1.7 ml of concentrated hydrochloric acid. Stirred for 20 min at 70about, Then cooled and diluted with a mixture of toluene and water. The organic phase is separated, washed with water, polysystem solution of acid sodium carbonate and again with water, dried and evaporated. The residue is distilled at 100-120about/0,05 mbar in the tube with the steam expansion. Get the product corresponding to the original (a) with a melting point 109-111aboutC; IR (CH2CL2): 2220, 1710 cm-1,1H NMR (CDCl3d6): =a 7.92 (m, 2H); 7,52 (t, 1H); to 3.73 (m, 1H); 3,03 (q, 1H); 2.40 a (q, 1H); of 1.55 (d, 3H).

b) 4-Thiocarbamoyl-3-methylindene.

On annalovedream. Get connection b) in the form of pale yellow crystals with a melting point of 198-200about;1H NMR (DMSO-d6): =9,78 (s, 1H); the 7.65 (m, 2H); 7,46 (m, 1H); 3,98 (m, 1H); 2.95 and (q, 1H); of 1.25 (d, 3H).

d) 4-Amidino-3-methyl-1-indanone hydrochloride.

By analogy with example 1B, 0.96 g (4,68 mmole) of starting compound b) is treated with 1.0 g (is 4.93 mmole) of tetrafluoroborate triethyloxonium and 0.3 (6 mmol) of ammonium chloride. Get a connection in the form of beige crystals. 1H NMR 9DMSO-d6): = 9,59 (s, 4H); the 7.65 (m, 2H); 7,46 (m, 1H); 3,98 (m, 1H); 2.95 and (q, 1H); 2.26 and (q, 1H); of 1.25 (d, 3H).

P R I m e R 6. 4-Amidino-2-ethyl-1-indanone-2"-amidinohydrolase-dihydrochloride.

3-(2-Bromophenyl)-2-ethylpropane acid (German patent 2733868) is subjected to cyclization with polyphosphoric acid with the formation of the corresponding 1-indanone and, by analogy with example 3, in turn specified in the header connection. So pl. > 250about;1H NMR (D2O): =of 7.95 (d, 1H); to 7.68 (d, 1H); of 7.48 (t, 1H); to 3.34 (m, 2H); 2,98 (d, 1H); 1,25-1,75 (bm, 2H); from 0.84 (t, 3H).

P R I m e R 7. 4-Amidino-2-n-butyl-1-indanone-2l-amidinohydrolase-dihydroiso - Reid.

3-(2-Bromophenyl)-2-n-butylamino - new acid (German patent 2733868) is subjected to cyclization by heating with polyphosphoric acid with the appropriate education );1H NMR (DMSO/D2O): = 8,19 (d, 1H); 7,63 (d, 1H); 7,52 (t, 1H); to 3.38 (m, 2H); 2,90 (d, 1H); 1,08-1,65 (bm, 2H); from 0.76 (t, 3H).

P R I m e R 8. Pharmaceutical drugs.

a) Capsules containing 0.25 g of active substance, for example, one of the compounds of examples 1-22 obtained as follows. Composition (550 capsules), g Active substance 1250 Talc 180 Wheat starch 120 magnesium Stearate 80 Lactose 20

Powder is sifted through a sieve with openings of 0.6 mm and mixed. Portion mixture of 0.33 g using a special machine for encapsulation enclosed in gelatin capsules.

b) Produce 10,000 tablets containing 5 mg of active substance, for example, compounds obtained in accordance with examples 1-8. The composition g of the Active substance 50,000 Milk sugar 2535,00 Maize starch 125,00 polyethylene Glycol 150,00 magnesium Stearate 40,00 Sterile water consumption-

activity q/s

Method of preparation tablets.

All powdered ingredients sifted through a sieve with openings of 0.6 mm, Then the active substance, lactose, magnesium stearate and half the quantity of starch are mixed in a mixer. The second half of the starch is suspended in 65 ml of water and the resulting suspension is added to boiling restorelayout. The granulate is dried overnight at 35aboutWith, pass through a sieve with openings of 1.2 mm and pressed into tablets coated with grooves to separate into two halves.

1. A method of obtaining a hydrazone derivatives of General formula I

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where a is a direct bond or CH2-;

R1hydrogen, lower alkyl;

R2hydrogen, hydroxy;

or their salts neorganicheskoi acids, characterized in that the compound of General formula II

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where R1and have the specified values,

subjected to interaction with the compound of General formula III

< / BR>
where R2has the specified value

and the process is conducted in the presence of inorganic acids.

2. The method according to p. 1, characterized in that to obtain 4-amidino-1-indanone-2-amidinopropane or its pharmaceutically acceptable salt of an inorganic acid as a starting compounds of General formula II using 4-amidino-1-indanone, and as a source of compounds of General formula III used 2-amidinopropane.


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10 cl, 14 tbl, 164 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of 1H-imidazole-4-carboxamide of the formula (I): wherein R represents phenyl, 2-pyridinyl, 3-pyridinyl that can be substituted; R1 means phenyl, 5-membered aromatic heterocyclic ring comprising one nitrogen atom (N) as a heteroatom that can be substituted; R2 means hydrogen atom (H), (C1-C8)-alkyl; R3 represents (C2-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, benzyl group, aromatic ring that can be substituted; R4 means hydrogen or halogen atom, cyano-group, sulfamoyl, methanesulfonyl, methylsulfanyl or (C1-C4)-alkyl. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions. Derivatives of 1H-imidazole-4-carboxamide are effective agonists, partial agonists or antagonists of cannabinoid CB1-receptors that can be useful in treatment of psychic and neurological diseases and other diseases with involving cannabinoid neurotransmission.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

11 cl, 1 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N'-benzoyl-N-substituted amidines of 3-phenoxy benzoic acid or derivatives thereof, having formula , where X=(C2H5)2N-; ; ; ; ; where Y - is a single bond. If ; then Y= , ,

. The method involves reacting N'-benzoyl-substituted ethylimiate of 3-phenoxy benzoic acid or derivatives thereof with amines from the group: diethylamine, aniline, p-nitroaniline, p-chloroaniline, p-bromoaniline in a medium of absolute benzene or chloroform in molar ratio of 1:1.2-1.26, at temperature 55-76C for 1-3 hours.

EFFECT: obtaining novel N'-benzoyl- N'-substituted amidines of 3-phenoxy benzoic acid or derivatives thereof with high output.

1 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula

and/or to all isomer forms of a compound of formula I, and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula 1, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents amino group, aminomethylene or amidino group, and wherein aryl is unsubstituted, 2) Het-Z, wherein Z represents amino group, aminomethylene or amidino group, and wherein Het is selected from benzimidazolyl and isoquinolinyl, and Het is unsubstituted or monosubstituted by group T, R2 and R4 are identical, and each represents hydrogen atom, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 2) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryls are unsubstituted, 3) -(C0-C4)-alkylene-(C6-C14)-aryl-p-Het, wherein aryl and Het in each case are unsubstituted, and Het represents piperidinyl, Q represents a covalent bond or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl wherein alkyl is unsubstituted, 3) -(C3-C8)-cycloalkyl or 4) -NO2, R5 and R6 are identical, and each represents hydrogen atom. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds effective as blood coagulation factor IXA inhibitors.

6 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a novel method of producing N-4-nitrophenylbenzamidine I, which is used in synthesis of biologically active heterocyclic compounds, by reacting benzonitrile with 4-nitroaniline in the presence of anhydrous aluminium chloride as a catalyst, while heating to temperature 150-200C and in molar ratio benzonitrile:4-nitroaniline:anhydrous aluminium chloride of 1:1:1.

EFFECT: obtaining a product with higher output of product, increase in affordability of the method.

2 cl, 1 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where R1 is hydrogen or C1-C6alkyl; R2 is hydrogen and R3 is hydroxy(C1-C6)alkyl; or pharmaceutically acceptable salts thereof. The invention also relates to methods of producing compounds of formula (I), intermediate compounds given in paragraphs 14-19 of the claim, and a method of producing an intermediate compound according to paragraph 17 of the claim.

EFFECT: obtaining compounds of formula as PGD2 synthase inhibitors and intermediate compounds for production thereof.

20 cl, 3 ex