Substituted ω-azolylalkane anilides, method for their preparing and using as anti-aggregating agent

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

EFFECT: valuable properties of compounds, improved method of synthesis.

8 tbl, 11 ex

 

The invention relates to the chemistry of heterocyclic compounds, namely, substituted ω-italiancanadian (ω-(1H-azole-1-yl)-N-phenylalkylamines) of General formula I:

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring; n means an integer from 1 to 3; R is identical or different denote hydrogen atom, halogen, alkyl group with carbon atoms of 1 to 4, alkoxygroup with the number of carbon atoms from 1 to 4, alkylenedioxy, benzyloxy, performanceline group with the number of carbon atoms from 1 to 4, a nitrogroup, alkoxycarbonyl group, carboxyl group, halogenerator, halogenating, m means an integer number of atoms, from 0 to 5; their salts with acids having antiaggregatory activity.

Compounds of General formula I can be used as medical, veterinary and phytotherapeutic drugs in the first place antiplatelet agents.

The invention relates also to methods of preparing compounds of General formula I and the use of these compounds as antiplatelet agents.

Known to many products with azole cycles, in particular N-phenyl-N-benzyl 2-gamerelated with bactericidal activity, used in agriculture and gardens is the rotary, General formula II, where X and Y atom denote a hydrogen atom, lower alkyl or halogen atom; Het means piperidino, methylpiperidino, dimethylpiperidino, hexamethylenimine, pyrazolyl, imidazolyl or 1,2,4-triazolyl [Japan patent No. 4145067, MKI C07D 249/08. - Appl. - 04.10.1990].

Known 2-(azole-1-yl)-N-phenylacetamide with anticancer activity of General formula III, where R means a hydrogen atom, a methyl group or a nitro-group; R1means a hydrogen atom or methyl group [S. Kasai, H. Nagasawa, M. Yamashita New Antimetastatic Hypoxic Cell Radiosensitizers: design, Synthesis, and Biological Activities of 2-Nitroimidazole-acetamide, TX-1877, and its Analogues. // Bioorg. Med. Chem. - 2001. - No.9. - P.453-64].

Known 2-azolyl-N,N-diphenylacetamide General formula IV, where Z denotes a nitrogen atom or CH groupS.Dalkara,A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim. - Forsch. / Drug Res. - 1994. - Vol.44 (II). No. 8. - P.920-924], which possess anticonvulsant activity.

Closest to the claimed substituted ω-(1H-azole-1-yl)-N-phenylalkylamines structure and method for producing N-phenyl-2-(azole-1-yl)-2-alkanity General formula V, where R1means alkyl group with carbon atoms of 1 to 10, phenyl or fenoxaprop; R2means the volume of hydrogen, alkyl group with carbon atoms of 1 to 5, allyl group; R3means alkyl group with carbon atoms of 1 to 8, allyl group, cycloalkyl group, the phenyl group; R4means a hydrogen atom, a lower alkyl group or halogen atom [Japan patent No. 58052256, MKI C07D 249/10. - Appl. - 24.09.1981]used as bactericides in industrial or agricultural purposes, herbicides or fungicides. Compounds of General formula V get in two stages, first by the interaction of 2-bromatological with amines in an inert solvent, for example benzene, toluene or tetrahydrofuran in the presence of an aqueous solution of carbonate or sodium hydroxide at a temperature of -10 to +10°C will receive 2-bromoacetamide, which alkylate azoles in dimethyl sulfoxide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when heated to 60°C within 24 hours.

The first place among the causes of death is occupied by diseases of the cardiovascular system. The purpose of antiplatelet drugs (antiplatelet agents) prevents the development of severe vascular complications, reduces the risk of severe vascular outcomes: myocardial infarction, stroke. This group of drugs is an important part of treatment and prevention of angina, atherosclerosis, periperi the definition of arteries and manifestations of atherothrombosis.

Antiplatelet agents inhibit platelet aggregation, reduce their ability to bonding and adhesion (adhesion) to the endothelium of blood vessels. Antiplatelet agents are not only able to prevent aggregation, but also to cause disaggregation already aggregated blood platelets. Use them to prevent post-operative thrombosis, with thrombophlebitis, thrombosis of vessels of the retina, cerebral circulation, and to prevent thromboembolic complications of ischemic heart disease, including myocardial infarction [Kharkevich, D.A. Pharmacology. - M.: GEOTAR Medicine, 2000. - 664 S.].

An important place among antiplatelet agents take derivatives of azoles, especially imidazole, are inhibitors of thrombogenicity [Demin OV, Hodonou A.A., Shvets V.I., Varfolomeev S.D. Aggregation of human platelets: a molecular-kinetic mechanisms and ways of regulation. // The biologist. the membranes. - 2002. - T, No. 2. - S-152].

After stimulation, cells arachidonic acid is released from membrane phospholipids and turns into a series of enzymatic reactions (arachidonic acid cascade) in many different derivatives of metabolites in two main ways - lipoxygenase and cyclooxygenase. Products cyclooxygenase pathways are most widely is by prostaglandins, of the stable prostacyclin PGH2formed as prostacyclin (PGI2)formed in the vascular endothelium, and thromboxane (tha2), which is synthesized in platelets. In some diseases there is an imbalance between these two eicosanoids, the overproduction of thromboxane A2found in many pathological conditions. Inhibitors thrombogenicity, for example dazoxiben block the biosynthesis of thromboxane, while there has been conversion of platelet endoperekisey (PGH2in prostacyclin PGI2that promotes thrombogenic properties of the vascular wall, the inhibition of adhesion of platelet aggregation and coagulation, and may be accompanied by a pressure decrease [Garsia-Szabo R.R., M.B. Peterson, W.D. Watkins et. al. Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lang Huid balance. // Circ. Res. - 1983. - Vol.53, N2. - P.214-222].

Many antiplatelet agents - inhibitors thrombogenicity used as vasodilators, antihypertensive drugs, antianginal agents, cerebrovasculature, coronary vasodilators, means the treatment of asthma and rhinitis.

Closest to the claimed substituted ω-(1H-azole-1-yl)-N-phenylalkylamines for use as an antiplatelet agents are phenoxyacetamide General formula IV, where R is hydrogen or alkyl; with the number of methyl the new groups of n from 1 to 9; m from 0 to 8; Z means the atom O, S or NH group [U.S. Patent No. 4632934. - Appl. - 21.08.1979], which inhibit thromboxanes and are used as antihypertensive anti-inflammatory, protivodiabeticheskie tools [Cross P.E., Dickinson R.P., M.J. Parry, M.J. Randall Selective tromboxane synthetase Inhibitors. I. 1-[(Aryloxy)alkyl]-1H-imidazoles. // J. Med. Chem. - 1985. - Vol.28. - P.1427-32]

The technical problem of this invention is to increase the efficiency of antiaggregatory medicines and range expansion of hepatotropic drugs.

The problem is solved by obtaining the compounds of General formula I, with antiaggregatory activity. According to the present invention ω-azollaceae (ω-(1H-azole-1-yl)-N-phenylalaninamide) of the formula I get one of two ways. On the first way interaction ω-halogenosilanes, such as chloracetamide substituted with aniline (VII) in organic solvents, for example methylene chloride, chloroform, toluene, etc. in the presence of an aqueous solution of hydroxides or carbonates of alkaline or alkaline-earth metals at a temperature of from 0 to 20°by the reaction of the Schotten's-Bauman received ω-halogenosilanes (VIII), which alkilirovanie isolate alkali metals in the environment of the polar aprotic solvent, for example as is lonitrile, of dimethylformamide, dimethyl sulfoxide, etc. at a temperature of from 40 to 150°C.

For the second method are compounds of General formula I-interaction ω-azollaceae acid (IX) with gloriously agents, such as chloride, phosphorus (V)chloride, phosphorus (III), thionyl chloride, oxalicacid, in an inert solvent, such as dioxane, tetrahydrofuran, methylene chloride, etc. at a temperature of from 20 to 50°received hydrochloride acid chlorides ω-azole-1-illinova acids (X), which are then introduced into reaction with substituted aniline (VII) in a polar aprotic solvent such as acetonitrile, dimethylformamide, dimethyl sulfoxide or methylene chloride, dioxane in the presence of bases, such as triethylamine, diazabicyclo, DBU, etc. at a temperature of from 20 to 60°C.

In the above scheme, R, n, m, Z and Y have the same meanings as in formula I, X represents chlorine, bromine; M stands for an alkali metal such as sodium, potassium and the like; :means In the base, such as triethylamine, DBU, hydroxide or carbonate of alkali or alkaline-earth metals.

Alkylation of azoles, in particular imidazole and 1,2,4-triazole, devoted many articles. Originally receive 1,2,4-triazolin alkali metal, for example, collaboration is receiving with sodium hydride in DMF or with sodium ethylate in alcohol, to which is then added alkylhalogenide and receive a 1-alkyl-1,2,4-triazole [Bergtrap M., Larsen P. Alkylation, acylation and silylation of azoles. // Acta Chem. Scand. - 1990. - Vol.44, No. 10. - R-1057].

2-(Imidazol-1-yl)-N,N-diphenylacetamide produced by interaction of 2-bromo-N,N-diphenylacetamide with imidazolate sodium in boiling DMF for 48 h [fÖzkanIi, S.Dalkara, Ü.Çaliş, A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim.-Forsch. / Drug Res. - 1994. - Vol.44 (II). No. 8. - P.920-924].

Substituted 2-halogenated (VIII), for example bromoacetamide, produced by interaction of anilines (VII) with brazilbrazil in ether in the presence of an aqueous solution of sodium hydroxide.S.Dalkara,A.Willke. Synthesis of Some N-Arylazole Acetamide Derivatives and Their Anticonvulsant and Antimicrobial Activities. // Arzneim.-Forsch. / Drug Res. - 1994. - Vol.44 (II). No. 8. - P.920-924].

The technical result of the invention are new substances - substituted ω-(1H-azole-1-yl)-N-phenylalkylamine General formula I and the way they are received. In the mentioned patent [Japan patent No. 58052256, - Appl. - 24.09.1981] propose to obtain the target 1-substituted azoles in stubborn solvents, e.g. dimethyl sulfoxide in a long time cooperation. We offer to carry out the alkylation in easily removable solvent, for example acetonitrile, at a substantially smaller time interaction. Us Pres is a false alternative way to obtain the target compounds from azollaceae acids in two stages. First interaction with gloriously agents with high yield received the anhydrides of the acids, which then was etilirovany anilines.

The technical result of the invention is also the use of ω-(1H-azole-1-yl)-N-phenylalkylamine formula I as antiplatelet agents, which are superior in activity known antiaggregatory drug dazoxiben (hydrochloride 4-[2-(imidazol-1-yl)ethoxy]benzoic acid) [J. Med. Chem. - 1985. - Vol.28. - P.1427-32], which allows to increase the efficiency of the antiaggregatory of medicines and to expand the range hepatotropic drugs. Effect ω-(1H-azole-1-yl)-N-phenylacetamido formula I in vitro experiments were manifested in the range of pharmacologically acceptable concentration of 10-4-10-6M, while the optical density of the plasma was decreased to 7.7-42,6%. The compounds, for example, 30, 45, 47 surpassed the benchmark dazoxiben as in aggregation caused by ADP and collagen.

Comparing the degree of influence of junction 30 on ADP-induced platelet aggregation in vivo at concentrations of 11, 16, 21 mg/kg, determined that it is in all studied concentrations in different degrees showed antiaggregatory effect, with the maximum effect occurred through 7, 9 and 11 hours depending on dose. The degree of suppression of aggregation was also dose dependent, and the values of protected areas is achieved density was 26.5% (11 mg/kg), 18,8% (16 mg/kg) and 16.9% (21 mg/kg), respectively. The duration of effect of compound 30 at a concentration of 11 mg/kg was observed in the interval from 1 to 13 hours, and under the influence of the concentrations of 16 and 21 mg/kg no significant inhibition of ADP-induced platelet aggregation was observed 24 hours after injection. While a comparative study of the effect dazoxiben on ADP-induced platelet aggregation in vivo at concentrations of 11, 16, 21 mg/kg has allowed to establish that the maximum effect in the study all concentrations occurred within 1 hour after drug administration, with an optical density of plasma was 31% in the study of concentration of 11 mg/kg 29,4% if the concentration of 16 mg/kg and 29.3 per cent in the study of concentration of 21 mg/kg, respectively.

Comparison of data obtained from the study of the influence of the connection 30 concentration 11, 16, 21 mg/kg on plasma coagulation factors in vivo, revealed that the studied compound in all concentrations increased during the formation of a clot. The maximum effect of the connection 30 at concentrations of 16 and 21 mg/kg (28,9, 29,2) showed approximately equal results, and at a concentration of 11 mg/kg (22,7) were somewhat inferior to them. Thus, all studied concentrations (11, 16, 21 mg/kg) compounds increased the time of the formation of a clot when studying the effect on plasma facto is s blood coagulation. At the maximum of the connection 30 at concentrations of 16 and 21 mg/kg (28,9, 29,2 with equally increased the formation of the clot, and at a concentration of 11 mg/kg (22,7) was slightly less than the higher concentrations. The effect when using concentrations of 16 and 21 mg/kg lasted more than 12 hours, and under the influence of the concentration of 11 mg/kg to 8 hours. While a comparative study of the effect dazoxiben in concentrations of 11, 16, 21 mg/kg on plasma coagulation factors in vivo, revealed that the studied compound in all concentrations increased APTT values. If this is not dependent on the concentration of a significant increase in the time of the formation of a clot was observed 3 hours after injection. Thus, all studied concentrations (11, 16, 21 mg/kg) dazoxiben increased the time of the formation of a clot when studying the effect on plasma coagulation factors. At the maximum of the activity of all concentrations was approximately equal, but the maximum duration of effect increased with increasing concentration of the studied compounds (1 hour at a concentration of 11 mg/kg, 2 hours at a concentration of 16 mg/kg and 4 hours at a concentration of 21 mg/kg). The effect when using concentrations of 11 and 16 mg/kg lasted between 1 and 7 hours, and under the influence of the concentration of 21 mg/kg for 2 hours longer (is between 1 and 9 hours).

The invention can be illustrated by the following examples.

Example 1. 2-Chloro-N-phenylacetamide (1).

To a mixture of 19.7 ml of 20%sodium hydroxide solution, 9.3 g (0.1 mol) of aniline and 100 ml of methylene chloride, cooled in a bath of ice and salt to 5°C, under stirring is added dropwise of 13.56 g, 9.6 ml (0.12 mol) of 2-chloroacetanilide so that the temperature of the mixture did not exceed 10°C, and then stirred at room temperature for another 2 hours. The precipitation is filtered and washed with water, the filtrate is washed with a saturated solution of sodium bicarbonate (2×15 ml), water (3×20 ml), brine (15 ml) and dried over magnesium sulfate. After removal of the solvent in a water jet vacuum pump resulting residue is recrystallized from a mixture of hexane:toluene (2:1) and get 19,64 g (86%) of 2-chloro-N-phenylacetamide (1) with TPL 129-131°C.

Similarly, the obtained substituted 2-chloro-N-phenylacetamide. Table 1.

Table 1
The melting temperature and the output of the synthesized 2-chloro-N-phenylacetamide (n=1)
ConnectionRmOutput %TPL, °C
1N086129-131
24-Cl 185170-172
34-OBn154139-140
43,4-Cl2292111-113
53-CF318460-62
64-CF3198161-162
74-i-Pr190130-132
84-NO2197159-162
94-CO2Et8491-93

Example 2. 2-(1,2,4-Triazole-1-yl)-N-phenylacetamide (10).

To a suspension 2,73 g (0.03 mol) of 1,2,4-triazoline sodium in 30 ml of acetonitrile was added with stirring 5 g (0.03 mol) of 2-chloro-N-phenylacetamide (1), boil the reaction mass within 10 hours, the precipitation is filtered off and washed with 5 ml of distilled water and dried. Get 5,628 g technical product is a mixture of the isomers 1 - and 4-alkylation of a triazole, which method dry flash chromatography, using as eluent a mixture of methanol:chloroform 1:10, allocate 3,20 g (57%) of 2-(1,2,4-triazole-1-yl)-N-phenylacetamide (10) with TPL 146-148°C.

Example 3. 2-(1,2,4-Triazole-1-yl)-N-(4-three is timeteller)ndimethylacetamide (17).

To 1,61 g (0.01 mol) 4-1,1,1-triptorelin in 20 ml of absolute acetonitrile was added with stirring to 1.82 g (0.01 mol) of the hydrochloride of the acid chloride 1,2,4-triazole-1-yl acetic acid and 2.02 g (0.02 mol) of triethylamine. Stirred for two hours. The precipitation is filtered off, washed with 2 ml water and 2 ml of acetonitrile. The residue is recrystallized from isopropyl alcohol. Obtain 2.16 g (41%) of 2-(1,2,4-Triazole-1-yl)-N-(4-1,1,1-triptoreline)ndimethylacetamide (17) with TPL 187-188°C.

Similarly, the obtained substituted 2-(1,2,4-triazole-1-yl)-N-phenylacetamide (table 2).

Example 4. 2-(Imidazol-1-yl)-N-phenylacetamide (11).

To a suspension of 2.70 g (0.03 mol) imidazolate sodium in 25 ml of acetonitrile was added with stirring 5 g (0.03 mol) of 2-chloro-M-phenylacetamide (1), boiled for 10 hours, the precipitation is filtered off and washed with 5 ml of distilled water, dried and recrystallized from isopropyl alcohol, to obtain 2.64 g (64%) of 2-(imidazol-1-yl)-N-phenylacetamide (2) with TPL 138-140°C.

Similarly, the obtained substituted 2-(imidazol-1-yl)-N-phenylacetamide (table 2).

Example 5. Ethyl 4[(1H-benzimidazole-1-yl acetyl)amino]benzoate (43).

To 1.65 g (0.01 mol) of ethyl 4-aminobenzoate in 10 ml of absolute acetonitrile was added with stirring portions 2.37 g (0.01 mol) of the hydrochloride of the acid chloride (benzimidazole-1-yl)acetic acid and 2.02 g (0.02 mol) of triethyl is in. Heated to 40°C and maintained at this temperature with stirring for eighteen hours. The precipitation is filtered off, washed with water (2×3 ml), recrystallized from methyl alcohol. Gain of 1.03 g (32%) of ethyl 4-[(1H-benzimidazole-1-yl acetyl)amino]benzoate (43)with TPL 222-223°C.

Similarly, the obtained substituted 2-(1H-benzimidazole-1-yl acetyl)-N-phenylacetamide (table 3).

Example 6. 4-(1H-imidazol-1-yl)-N-(3-nitrophenyl)butanamide (26).

To to 1.38 g (0.01 mol) of 3-nitroaniline in 10 ml of absolute dimethylformamide was added with stirring portions 1,725 g (0.01 mol) of the hydrochloride of the acid chloride of 4-(imidazol-1-yl)butane acid and 2.02 g (0.02 mol) of triethylamine. The reaction mass is heated to 40°With during the day. The precipitation is filtered off, washed with 5 ml water and 1 ml of isopropyl alcohol, the filtrate is evaporated in a water jet vacuum pump. To the obtained residue, add 10 ml of water and filtered. The precipitate is recrystallized from isopropyl alcohol. Obtain 0.56 g (26%). 4-(1H-imidazol-1-yl)-N-(3-nitrophenyl)butanamide (26) with TPL 145-7°C.

Example 7. Ethyl 3-([4-(1H-imidazol-1-yl)butanoyl]amino)benzoate (30).

a) Hydrochloride of the acid chloride of 4-(imidazol-1-yl)butane acid. To 1,16 g (0,0075 mol) of 4-(imidazol-1-yl)butane acid in 5 ml of absolute dioxane is added in portions with stirring, 1.56 g (0,0075 supposedly is) petaluridae phosphorus. The reaction mass is heated to 40°C for six hours until complete dissolution petaluridae phosphorus, cooled to room temperature and stirred for another ten hours. The reaction mass is evaporated in a water jet vacuum pump. Obtain 1.56 g (99%) of the hydrochloride of the acid chloride of 4-(imidazol-1-yl)butane acid in the form of oil. According to the results of potentiometric argentometric titration to determine the chlorine content. Found: Cl 34,35%; With7H10Cl2N2O; calculated: Cl 33,97%. Further the product is used without further purification.

b) To 1,25 g (0,0075 mol) 3-ethoxycarbonylmethylene in 10 ml of absolute dioxane is added with stirring in portions of 1.56 g (0,0075 mol) of the hydrochloride of the acid chloride 1H-imidazol-1-yl butane acid and 1,515 g (0,0075 mol) of triethylamine. The reaction mass is heated for forty-eight hours. The precipitation is filtered off, washed with 10 ml of water, recrystallized from isopropyl alcohol. Obtain 0.56 g (26%) of ethyl 3-{[4-(1H-imidazol-1-yl)butanoyl]amino}benzoate (30) with TPL 146-148°C.

Similarly, the obtained substituted ω-(azole-1-yl)-N-phenylalaninamide.

NMR1N-spectra were recorded on the instrument Bruker AC-200" (operating frequency 200 MHz), shifts measured relative to tetramethylsilane, the solvent used d6-DMSO. IR spectra were registered with the Mami NaCl in a thin film in vaseline oil on the spectrometer Specord M80".

Table 2
The melting temperature and the output of the synthesized ω-(1,2,4-triazole-1-yl)-N-phenylalaninamide and ω-(imidazol-1-yl)-N-phenylalaninamide
ConnectionZnRmOutput %TPL, °C
1234567
10N1N057146-148
11SN1N064138-140
12N14-Cl160198-199
13SN14-Cl198191-192
14N14-Br1 74210-211
15SN14-Br164207-208
16N13,4-Cl2263207-208
17N13-CF3267146-147
18SN13-CF3160162 to 165
19N23-CF3138200-201
20N14-CF3141187-188
21SN14-CF3127191-192
22N14-i-Pr143193195
23SN14-i-Pr148188-190
24N14-NO2168230-232
25SN14-NO2162140-144
26SN33-NO2126145-147
27N14-CO2Et157170-172
28SN14-CO2Et151171-173
29SN23-CO2Et152120-121
30SN33-CO2Et126146-147
31N13,4-(och2CH2O)269205-207
32SN13,4-(och2CH2O)246190-193
33N14-OCH2Ph175184-186
34SN14-OCH2Ph183180-183
35N13-NO2, 5-(4-FPhS)256180-183
36SN13-NO2, 5-(4-FPhS)251204-206
37SN12-(2-ClBz), 4-Br258310-312
Table 3
The melting temperature and the output of the synthesized 2-(b shall Intimidator-1-yl)-N-phenylacetamide (n=1, m=1)
ConnectionROutput %TPL, °
384-Cl11247-248
394-Br25260-261
404-CF338207-209
414-NO233272-273
424-och331200-201
434-CO2Et15222-223
443-CF318197-199

Example 8. Hydrochloride of 2-(imidazol-1-yl)-N-(4-course)ndimethylacetamide (45).

To a solution of 0,326 g (1.38 mmol) of 2-(them the azole-1-yl)-N-(4-course)ndimethylacetamide (13) in 5 ml of methyl alcohol was added with stirring to 1.41 ml (2,08 mmol) 1,47M solution of hydrogen chloride in methanol. The solvent is distilled off in a water jet vacuum pump dry. Get 0,373 g (98%) of the hydrochloride of 2-(imidazol-1-yl)-N-(4-course)ndimethylacetamide (45) with TPL 216-217°C.

Similarly, the received hydrochloride substituted 2-(azole-1-yl)-N-phenylalaninamide: ethyl 4-[2-(1H-imidazol-1-yl)acetylamino]benzoate (28) of the hydrochloride of ethyl 4-[2-(1H-imidazol-1-yl)acetylamino]benzoate (46) with TPL 105-106°from ethyl 4-[2-(1H-1,2,4-triazole-1-yl)acetylamino]benzoate (27) of the hydrochloride of 4-[2-(1H-1,2,4-triazole-1-yl)acetylamino]benzoate (47) with TPL 144-146°C.

Example 9. Testing ω-azole-1-allcan of anilides the presence of antiaggregatory activity in vitro.

The experimental technique. Platelet-rich plasma (average 3×1081 cm3platelets) was obtained by centrifugation their blood of healthy donors (stabilizer - 3.8%sodium citrate, the ratio of blood and solution of citrate 9:1) for 10 minutes at 1000 rpm at room temperature. Prior to the experiment and at the end of it in each sample was counted the number of platelets. In that case, if the plasma contained a greater number of blood platelets, it was diluted to the required number estramboticos plasma, obtained by centrifugation citrate blood for 10 minutes at 3000 rpm as aggregation inductor used ADP, collagen (NP the "RENA", Russia). Platelet aggregation was studied using light scattering by the method of Born [Born J.V.R. Aggregation of blood platelets by adenosine diphosphate and its reversal. // Nature - 1962. - V.194, N5. - P.927-929. Born J.V.R. Quantitative investigation into the aggregation of blood platelets. // J. Physiol. - 1962. - V.162, N4. - P.487-511] aggregometry firm "CHRONO-LOG" (USA).

The conditions of the experiment: 37°C, the volume of platelet rich plasma 450 ál, the volume of the analyzed sample solution 50 ál, preincubation with the drug is an inhibitor of 5 minutes with stirring, the amount of aggregation inductor 50 ál, final concentration for ADP 1×10-5M, collagen - 0.2 mg/ml (as control was used platelet-rich plasma in the volume 450 ml). Quantitative characterization of the degree of aggregation was a relative drop in optical density at the maximum amplitude of agregatogramme. The recording process was observed by the change in optical density of the plasma in the range of 100% (platelet rich plasma) to 0% (estrambotica plasma) (wavelength probed luminous flux 660 nm). The result was expressed in percent drop in optical density at the maximum amplitude agriturismi.

Experiments were carried out comparing the antiaggregatory properties of substances and of the standard, known drug dazoxiben.

Table 5
Impact ω-(1H-azole-1-yl)-N-phenylalkylamines and dazoxiben on ADP-induced platelet aggregation in vitro
Connection% drop optical density plasma
ControlThe concentration of the compounds of the antiplatelet agent, mol/l
10-3M10-4M10-5M10-6M10-7M
3059,1±1,316,9±1,518,3±1,226,4±1,730,7±2,246,6±2,6
4559,2±1,214,0±1,822,2±2,142,9±1,343,0±2,048,0±2,5
4756,3±2,318,0±1,718,6±1,624,5±2,328,4±2,846,1±2,3
Dazoxiben57,9±1,740,9±1,340,1±1,741,0±1,846,1±1,954,0±2,8
Table 6
Impact ω-(1H-azole-1-yl)-N-phenylalkylamines and dazoxiben on collagen-induced platelet aggregation in vitro
Connection% drop optical density plasma
ControlThe concentration of the compounds of the antiplatelet agent, mol/l
10-3M10-4M10-5M10-6M10-7M
3058,3±1,711,4±1,915,1±1,615,4±1,828,1±1,349,3±1,7
Dazoxiben58,7±1,427,1±1,730,2±1,337,8±1,246,1±1,656,9±2,2

Example 10. Conducting biological tests ω-azole-1-allcan of anilides the presence of antiaggregatory activity in vivo.

Selected compounds were administered to rabbits of the Chinchilla breed intravenously in the marginal ear vein at doses of 11, 16, 21 mg/kg of the First blood sampling for the study was carried out 30 min after injection, then after 1 hour, 3, 5, 7, 9, 11 and 24 hours. If the optical density of the plasma within 11 hours after administration of the compounds differed significantly from control values, blood sampling was done at 13 and 15 hours after administration. As the inductor used ADP in the threshold concentration (1×10-5M).

Recip is installed, the results are summarized and presented in table 7.

Example 11. A comparative study of the new derivatives azollaceae acids and dazoxiben on plasma coagulation factors in vivo.

Compounds were administered to rabbits of the Chinchilla breed intravenously in the marginal vein of the ear, in doses 11,16, 21 mg/kg of the Obtained results are summarized and presented in table 8. The first blood sampling for the study was carried out before the introduction of the studied compounds (control). Then after 30 min after injection, after 1 hour, 3, 5, 7, 9, 11 and 24 hours. If the results differed significantly from control values after 11 hours after administration of the compounds, blood sampling was done at 13 and 15 hours after injection.

Table 7
The influence of the connections 30 and dazoxiben on the maximum amplitude of agregators in vivo
Substancemg/kg% drop optical density
ControlTime after injection
30 min1 h3 hours5 h7 h9 h11 h13 h15 h24 hours
3011 60,1±1,350,9±1,539±1,933,2±2,127,4±1,426,5±1,729,5±1,638,7±2,549±1,959,8±2,260,6±2,9
1661,1±1,649,1±1,836,8±1,336±1,934,6±2,221,5±2,118,8±1,122,1±1,330,1±1,535,1±2,656,2±2,5
2159,7±1,247,2±1,432,7±1,125,8±1,622±2,120±1,918,1±1,716,9±2,319,1±1,325,2±2,354±3,4
Dazoxiben1159,7±1,145,7±2,331±1,433,5±1,844,2±2,457,5±1,159,1±1,559,5±2,5--61,2±2,8
1662,3±2,146,3±1,329,4±1,130,2±1,433,2±2,251,7±1,858,1±1,759,2±2,1-60,9±2,5
2160,6±1,648,1±1,430±1,729,3±1,130,3±1,240,9±1,654,7±2,358,7±1,9--59±1,8
Note: * - significantly compared to control at p<0,05
Table 8
The influence of the connections 30 and dazoxiben on indicators APTT rabbits with intravenous (M±t).
Substancemg/kgThe values of APTT
controlTime after injection
30 min1 h3 hours5 h7 h9 h11 h13 h15 h24 hours
301115,7±1,315,2±1,515,9±1,116,4±1,618±1,421,3±2,322,7±2,220,3±1,218,2±1,916,8±2,415,4±2,1
1615,3±1,615,7±1,815,9±1,1 19,5±2,123,5±1,426±1,828,1±1,328,9±1,226,1±2,324,1±2,515,2±1,9
2116,1±1,116,7±1,617±2,119±1,322,9±1,126,5±1,829,1±1,629,2±2,329±1,927,4±1,516,3±2,4
Dazoxiben1114,8±1,415,3±1,616,6±1,223,3±1,921,4±1,317,5±2,115,5±1,215,4±1,7--15,1±2,3
1615,1±1,115,2±1,416±1,724,8±1,324±1,917±1,215,3±2,415,4±2,2--15,3±1,8
2115,5±1,715,9±1,316,6±1,224,3±1,923,5±1,523,1±2,118,3±1,816,3±1,6--15,6±2,1

Application ω-(1H-azole-1-yl)-N-phenylacetamido formula is I as antiplatelet agents in medicine increases the efficiency of antiaggregatory medicines and to expand the range hepatotropic drugs. According to their effect as in the experiments in vitro and in vivo, some of the compounds exceeded the benchmark dazoxiben as in aggregation caused by ADP and collagen, had dozozavisimoe effect on plasma clotting factors blood. Thus, these compounds can expand the Arsenal of drugs? used in diseases of the cardiovascular system.

1. Substituted ω-italiancanadian General formula I

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer from 1 to 3, R is identical or different denote hydrogen atom, halogen, alkyl group with carbon atoms of 1 to 4, alkoxygroup, alkylenedioxy, benzyloxy, performanceline group with the number of carbon atoms from 1 to 4, a nitrogroup, alkoxycarbonyl group, carboxyl group, halogenerator, halogenating, m means an integer number of atoms, from 0 to 5, and their salts with acids.

2. The method of obtaining substituted ω-italiancanadian General formula I,

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component along an aerovane ring, n means an integer from 1 to 3, R is identical or different denote hydrogen atom, halogen, alkyl group with carbon atoms of 1 to 4, alkoxygroup, alkylenedioxy, benzyloxy, performanceline group with the number of carbon atoms from 1 to 4, a nitrogroup, alkoxycarbonyl group, carboxyl group, halogenerator, halogenating, m means an integer number of atoms, from 0 to 5, namely, that ω-galogenirovannami acelerou substituted anilines in organic solvents, in the presence of an aqueous solution of hydroxides or carbonates of alkali or alkaline earth metals at a temperature of from 0 to 20°obtaining ω-halogenoacetyl formula II, where R, m, n have the same meanings as in formula I, X is halogen, which are subjected to interaction with isolate alkali metals in the environment of the polar aprotic solvent at a temperature of from 40 to 150°C.

3. The method of obtaining substituted ω-italiancanadian General formula I,

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer from 1 to 3, R is identical or different denote hydrogen atom, halogen, alkylen the th group with the number of carbon atoms from 1 to 4, alkoxygroup, alkylenedioxy, benzyloxy, performanceline group with the number of carbon atoms from 1 to 4, a nitrogroup, alkoxycarbonyl group, carboxyl group, halogenerator, halogenating, m means an integer number of atoms, from 0 to 5, namely, that ω-azollaceae acid of the formula III, where n, Z and Y have the same meanings as in formula I, is administered in cooperation with gloriously agents in an inert solvent at a temperature of from 20 to 50°obtaining hydrochloride acid chlorides ω-azole-1-illinova acids of the formula IV, where n, Z and Y have the same meanings as in formula I, which acelerou substituted anilines in the environment of the polar aprotic solvent, in the presence of bases at a temperature of from 20 to 60°

4. The use of substituted ω-italiancanadian General formula I

where Z and Y denote a nitrogen atom or CH group, or both are chain-CH=CH-CH=CH-C component together annulirovano ring, n means an integer from 1 to 3, R is identical or different denote hydrogen atom, halogen, alkyl group with carbon atoms of 1 to 4, alkoxygroup, alkylenedioxy, benzyloxy, performanceline group number and the Ohm carbon 1 to 4, the nitrogroup, alkoxycarbonyl group, carboxyl group, halogenerator, halogenating, m means an integer number of atoms, from 0 to 5, and their salts with acids as antiaggregatory agents.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(azol-1-yl)ethaneamines that are used as the parent compounds in preparing biologically active compounds of medicinal and agriculture designation. Method for synthesis of 2-(azol-1-yl)ethaneamines of the general formula (I): wherein R1 means hydrogen atom or alkyl group comprising from 1 to 6 carbon atoms; each Z and X means independently -CH or nitrogen atom (N); or Z and X mean in common group -C-CH=CH-CH=CH-C that forms a system anellated with azole cycle involves the alkylation reaction of azole compounds wherein R1, Z and Y have the same values as in the formula (I) with oxazolines of the formula (II): wherein R2 means alkyl group comprising from 1 to 6 carbon atoms, phenyl, halogenphenyl group in the presence of Lewis acid or protonic acid to yield N-[2-(azol-1-yl)ethyl]alkaneamides of the formula (III): wherein R1, R2, Z and X have above given values followed by their hydrolysis in the presence of acids or bases in polar solvent medium at temperature 60-120°C.

EFFECT: improved method of synthesis.

5 cl, 17 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes substituted 1-(pyridinyl-2)-2-azolylethanols of the general formula (I): wherein R means hydrogen atom, direct or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with from 3 to 8 carbon atoms; X means nitrogen atom or CH-group. Also, invention relates to a method for synthesis of these compounds and a fungicide composition that contains compound of the formula (I). Invention provides expanding assortment of fungicides for carrying out the effective control of harmful fungi.

EFFECT: valuable fungicide properties of compounds and composition.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

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

4 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes a method for synthesis of fluconazole monohydrate of the formula (I): . Method involves hydrolysis of silyl ester derivative of the formula (II): wherein R2 means hydrogen atom, (C1-C10)-alkyl or phenyl group; R3 and R4 mean independently of one another (C1-C10)-alkyl or phenyl group at pH value below 3 or above 8 in an aqueous solution followed by cooling the prepared reaction mixture and isolation of the precipitated fluconazole monohydrate. Also, invention describes methods for synthesis of crystalline modification II of fluconazole of the formula (I). These methods involve dissolving anhydrous fluconazole or its monohydrate in (C1-C4)-alcohol of the linear or branched chain at the boiling point and cooling this solution at the rate 5-15°C/h, or fluconazole monohydrate is dried at 30-70°C. Except for, invention describes a method for synthesis of crystalline modification I of fluconazole of the formula (I) wherein fluconazole monohydrate is dried at 80°C. This invention provides preparing pure or easily purifying fluconazole in crystalline modifications allowing easy preparing the suitable medicinal formulations from them.

EFFECT: improved synthesis method.

16 cl, 1 tbl, 7 dwg, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes the improved method for preparing 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl-methyl)-4,4-dimethylpentane-3-ol. Method involves interaction of 1,2,4-triazole with 2-(4-chlorophenylethyl)-2-tert.-butyloxirane in the presence of potassium hydroxide in n-butanol medium. Process is carried out in reaction mixture directly containing 2-(4-chlorophenylethyl)-2-tert.-butyloxirane prepared by interaction of 4,4-dimethyl-1-(4-chlorophenyl)-pentane-3-one with trimethylsulfonium methylsulfate in n-butanol medium at 50-55°C without preliminary isolation of oxirane and its purification. Method provides reducing number of operations, time for carrying out the process and to retain high yield of product.

EFFECT: improved method for preparing.

4 cl, 3 ex

FIELD: new lubricant oiliness addend.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-1,2,4-triazol and O-(n-butyl)-O-(2-ethyl-n-hexyl)-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product with yield of 94-100 %.

EFFECT: addend compatible with base oil with improved antiscoring properties.

1 cl, 1 ex, 2 tbl

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, veterinary science, cosmetology.

SUBSTANCE: invention relates to agents used for accelerating processes for tissues regeneration and especially in presence of inflammatory processes accompanied with infection with pathogenic microflora. Invention describes 1,3-dialkylbenzimidazolium halides of the general formula: wherein R1 and R2 mean Alk; X- means F-, Cl-, Br-, J- that possess regenerating, anti-inflammatory and antibacterial activity. Invention provides preparing group of compounds of 1,3-dialkylbenzimidazolium monohalides possessing valuable biological properties. Invention can be used in pharmaceutical industry and cosmetology.

EFFECT: valuable properties of compounds.

5 tbl, 1 dwg, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-(azol-1-yl)ethaneamines that are used as the parent compounds in preparing biologically active compounds of medicinal and agriculture designation. Method for synthesis of 2-(azol-1-yl)ethaneamines of the general formula (I): wherein R1 means hydrogen atom or alkyl group comprising from 1 to 6 carbon atoms; each Z and X means independently -CH or nitrogen atom (N); or Z and X mean in common group -C-CH=CH-CH=CH-C that forms a system anellated with azole cycle involves the alkylation reaction of azole compounds wherein R1, Z and Y have the same values as in the formula (I) with oxazolines of the formula (II): wherein R2 means alkyl group comprising from 1 to 6 carbon atoms, phenyl, halogenphenyl group in the presence of Lewis acid or protonic acid to yield N-[2-(azol-1-yl)ethyl]alkaneamides of the formula (III): wherein R1, R2, Z and X have above given values followed by their hydrolysis in the presence of acids or bases in polar solvent medium at temperature 60-120°C.

EFFECT: improved method of synthesis.

5 cl, 17 ex

The invention relates to the field of organic chemistry and medicine and relates to a derivative of imidazo-[1,2-a]-benzimidazole, specifically: 9-diethylaminoethyl-2-(3,4-dioksifenil)-imidazo-[1,2-a]-benzimidazole of dihydrobromide formula (I) providing cerebroprotective effect in radiation damage

The invention relates to compounds, which are Aza-derivatives, such as Aza-indiani, Aza-tinalley or Aza-valley, to pharmaceutical compositions and to a method of treatment of pathological conditions such as cancer, bacterial and viral infection

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to new chemical compounds, namely bis-Quaternary salts of benzimidazole formula

< / BR>
where In= N, CH3R= alkyl, IN1=N, CH3, Cl, co3m=0-8, n=0-2, X=residue of formula

< / BR>
where Y= NH, O, B=H, H, CL, which may find application as antivalent-stabilizer for silver halide photographic emulsions sensitized carbocyanine dyes, as well as to methods of sensitizing silver halide emulsions and their use

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel 2-(2,6-dichlorophenyl)diarylimidazoles of the general formula (I): possessing inhibitory effect on activity of protein-tyrosine kinase and first of all c-met kinase, and can be used in treatment of oncological diseases. In the compound of the general formula (I) X means hydrogen atom, -OR1, -SR2, -(SO2)R2 or group A1-Q wherein A1 means (C1-C3)-alkylene group; Q means -OR1, -NR3R4, -NHCH2CH2NR3R4; R1 is chosen from group comprising hydrogen atom, (C1-C)-alkyl, dimethylphosphonylmethyl, (R)-2,3-dihydroxy-1-propyl, (S)-2,3-dihydroxy-1-propyl, 1,3-dihydroxy-2-propyl, 3-hydroxy-2-hydroxymethyl-1-propyl, 2-methoxyethoxymethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or group A1-Q1 wherein Q1 means (C1-C2)-alkoxy, cyano group, carboxyl, (C1-C6)-alkoxycarbonyl, and if A1 means 1,2-ethylene- or 1,3-propylene group then Q1 means hydroxy group; R2 means (C1-C6)-alkyl or A1-Q; R3 and R4 are chosen independently from group comprising hydrogen atom, (C1-C6)-alkyl, or form in common 6-membered saturated cycle comprising two heteroatoms chosen from nitrogen (N) or oxygen (O) atoms; Y means hydrogen atom or group A2-R wherein A2 means (C1-C5)-alkylene optionally substituted with (C1-C6)-alkyl, phenyl or hydroxy group; R means hydroxy group, linear or branched (C1-C6)-alkoxy, amino, dimethylamino, diethylamino, tert.-butyloxycarbonylamino group, carboxyl, (C1-C6)-alkoxycarbonyl, triazolyl, 1-pyrrolidinyl, morpholino group, 4-methylpiperazin-1-yl, O-A1-NR3R4, S-A1-NR3R4, 4-carboxyphenyl, furan-3-yl, thiophen-2-yl or 3-methylthiophen-2-yl; Z means one or two substitutes chosen independently from group comprising halogen atom, hydroxy, allyloxy group, methyl, (C1-C5)-alkoxy, methoxymethoxy, (2-methoxyethocy)methyloxy, methylthio, ethoxymethoxy group, ethynyl and benzyloxy group optionally substituted with halogen atom, methoxy, cyano, ethoxy group, and its pharmaceutically acceptable salts. Also, invention elates to novel intermediate compounds and synthesis of compounds, and to their using for preparing drugs and pharmaceutical composition.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 97 ex

Up!