Method for synthesis of 3(5)-pyridyl-substituted 5(3)-amino-1,2,4-triazoles

FIELD: chemistry.

SUBSTANCE: described is an improved method for synthesis of 3(5)-pyridyl-substituted 5(3)-amino-1,2,4-triazoles of general formula (I)

, where R denotes 2-pyridyl, 3-pyridyl or 4-pyridyl, involving reaction of pyridine carboxylic acid of general formula (II)

, where R assumes said values, with an aminoguanidine hydrocarbonate in the presence of hydrochloric acid in molar ratio acid (II): aminoguanidine hydrocarbonate: hydrochloric acid = 1.0:1.0:1.3-1.5, while boiling the reaction mixture with gradual distillation of water at atmospheric pressure until temperature of the reaction mixture equals 165-180°C and then holding the reaction mixture at this temperature for 3-5 hours and then adding an alkali solution in water, boiling alkaline solution and extraction of the end product by filtering after neutralisation of the reaction mixture and cooling.

EFFECT: method enables to obtain said compounds from cheaper material, increases output of end products and shortens duration of the synthesis process.

1 cl, 14 ex

 

The invention relates to the field of production of organic substances and can be used in the production of medicines and biologically active substances.

A method of obtaining 5(3)-amino-3(5)-(pyridine-3-yl)-1,2,4-triazole or 5(3)-amino-3(5)-(pyridine-2-yl)-1,2,4-triazole by boiling sulfate solution aminoguanidine and pyridine-3-carboxylic acid or hydrochloride pyridine-2-carboxylic acid in 40%Hydrobromic acid for 40 hours, followed by neutralization of the reaction mixture with sodium carbonate, the process of evaporation and extraction of the target product by ethyl acetate (Atkinson M.R., Komzak A.A., Parkes E.A., Polya J.B. J. Chem. Soc., 1954, P.4508-4510). The disadvantages of this method are the relatively low yields of the target products (42-44%), large amounts of waste inorganic salts and the long duration of the process.

Describes how to obtain 5(3)-amino-3(5)-(pyridine-4-yl)-1,2,4-triazole by fusing the acid chloride pyridine-4-carboxylic acid hydrochloride aminoguanidine at a temperature of 205-210°C, followed by separation and cyclization of the obtained 1-(4-pyridylmethylene) by boiling in a solution of KOH (Grinstein VA, Chipen GI Journal. General chemistry, 1961, T, S-890). The disadvantages of this method are the high cost of the acid chloride pyridine-4-carboxylic acid, costly overruns hydrochloride Aminogen the Dina (the synthesis is carried out in a molar ratio of acid chloride pyridine-4-carboxylic acid hydrochloride aminoguanidine 1:2, in stoichiometry 1:1), the relatively low overall yield (47%).

Describes how to obtain 5(3)-amino-3(5)-(pyridine-2-yl)-1,2,4-triazole or 5(3)-amino-3(5)-(pyridine-3-yl)-1,2,4-triazole interaction hydrazide pyridine-2-carboxylic acid or hydrazide pyridine-3-carboxylic acid sulfate S-methylisothiazoline in the presence of alkali, followed by heating the obtained guanylhydrazone corresponding acid at a temperature of approximately 250°C (S.A. Lipinski J. Med. Chem., 1983, Vol.26, P.1-6). The disadvantages of this method are the high cost of the starting substances (hydrazides pyridineboronic acids and sulphate methylisothiazoline), the formation of by-products from the decomposition of the target triazoles at high temperatures, the release of toxic mercaptan synthesis step of guanylhydrazone and the long duration of the process of obtaining guanylhydrazone (20 hours).

Describes how to obtain 5(3)-amino-3(5)-(pyridine-2-yl)-1,2,4-triazole or 5(3)-amino-3(5)-(pyridine-3-yl)-1,2,4-triazole or 5(3)-amino-3(5)-(pyridine-4-yl)-1,2,4-triazole interaction of the corresponding hydrazides pyridineboronic acid sulphate S-methylisothiazoline in the presence of alkali, followed by separation and cyclization of the obtained guanylhydrazone pyridineboronic acid by boiling in water or in conditions microwave heating (Dolzhenko A.V., Chia H-S., Chui, W.-K. Synthesis of 5-amino-3-(het)aryl-1H-1,2,4-triazoles via cyclization of (het)aroylaminoguanidines in aqueous medium. 9thInternational Electronic Conference on Synthetic Organic Chemistry. ECSOC-9. 1-30 November 2005. A-026.http://www.usc.es/congresos/ecsoc/9/GOS/a026/index.htm; Dolzhenko A.V., G. Pastorin, Dolzhenko A.V., Chui, W.-K. Tetrahedron Letters, 2009, Vol.50, P. 2124-2128). The disadvantages of this method are the high cost of the original hydrazides pyridineboronic acids and sulphate methylisothiazoline, the formation of toxic mercaptan synthesis step of guanylhydrazone.

Describes how to obtain the monohydrate of 5-amino-1,2,4-triazole-3-luxusni acid by reacting malonic acid with bicarbonate aminoguanidine with a ratio of malonic acid : aminoguanidine 1.1-1.3:1.0 at pH 0-1 in the presence of hydrochloric acid at a temperature of 80-100°C. and the distillation of water from the reaction mixture in vacuum with subsequent cyclization of the resulting guanylhydrazone in alkaline medium (RF Patent 2313522. The method of obtaining the monohydrate of 5-amino-1,2,4-triazole-3-luxusni acid. Appl. 06.06.2006. Publ. 27.12.2007. Bull. No. 36. Chernyshev, V. M., Chernyshev A.V., Carnosic VA, Ivashkov A.I.). The disadvantages of this method are the low yield of the target products, since the interaction aminoguanidine with pyridylcarbonyl acids at a temperature of 80-100°C flows very slowly, and the use of vacuum distillation, which requires a lot of energy and complex equipment./p>

The closest in technical essence and the achieved result is a method of obtaining 5(3)-amino-3(5)-(pyridine-4-yl)-1,2,4-triazole-fused pyridine-4-carboxylic acid sulfate aminoguanidine at a temperature of about 210°C, followed by dissolving the melt in water and neutralization with sodium hydroxide (C.A. Lipinski J. Med. Chem. 1983, Vol.26, P.1-6). The disadvantages of this method are costly overruns sulfate aminoguanidine (the synthesis is carried out in a molar ratio piridinkarbonovaya acid sulfate aminoguanidine 1:2.4, the stoichiometry 1:1) and the formation of by-products as a result of decomposition of the desired product at high temperature.

The objective of the invention is to develop a method for the preparation of 3(5)-pyridylamine 5(3)-amino-1,2,4-triazoles of General formula (1),

where R represents 2-pyridyl, 3-pyridyl or 4-pyridyl, cheap and available source of nutrients that can improve the product yield and reduce the synthesis time.

This object is achieved in the inventive method for the preparation of 3(5)-pyridylamine 5(3)-amino-1,2,4-triazoles of General formula (I), namely, that pyridylcarbonyl acid of General formula (II), where R has the above meanings, is subjected to interaction with hydrogen aminoguanidine in the presence of hydrochloric sour the s when boiling the reaction mixture and at a molar ratio of acid (II): hydrogen aminoguanidine: hydrochloric acid =1.0:1.0:1.3-1.5 with the gradual distillation of water at atmospheric pressure until a temperature of the reaction the mixture 165-180°C, the reaction mixture was kept at this temperature for 3-5 hours, then add a solution of alkali in water, boil the obtained alkaline solution, followed by neutralization to pH 7-8 and the selection of the target product.

When mixing reagents leads to the formation of hydrochloride aminoguanidine (reaction 1). The use of bicarbonate aminoguanidine and hydrochloric acid economically feasible than using ready hydrochloride aminoguanidine due to the high commercial value of the latter. The excess hydrochloric acid creates an acidic environment, which is necessary for the catalysis of reactions of formation of guanylhydrazone pyridineboronic acid (reaction 2). The molar ratio of carboxylic acid : hydrogen aminoguanidine : hydrochloric acid = 1:1:1.3-1.5 is optimal. The use of excess hydrogen aminoguanidine or pyridineboronic acid is impractical because it leads to waste of one of the reagents. The decrease in the quantity of hydrochloric acid relative to the other reagents leads to a substantial decrease in the reaction rate, and the use of a larger excess of hydrochloric acid does not lead to a significant increase in the reaction rate, however, causes p is reached alkali in the second stage of the synthesis and the formation of large quantities of sodium chloride, that is not economically feasible. Temperature range 165-180°C at the stage of synthesis of guanylhydrazone (reaction 2) is optimal. At lower temperatures the reaction proceeds too slowly, and at a higher gradual decomposition of the target product, the formation of inseparable impurities and reduce output. The temperature 165-180°C at the stage of synthesis of guanylhydrazone allows not only to provide an acceptable reaction rate, but also to achieve a sufficiently remove water from the reaction mixture to achieve a high equilibrium degree of conversion of the reactants.

Distillation of water at atmospheric pressure is more economically feasible than distillation in a vacuum, because it allows to avoid additional expenditure of energy.

The concentration of hydrochloric acid has no significant effect on the output. However, it is advisable to use concentrated hydrochloric acid (with a concentration of not less than 30%), because in the reaction mixture is paid less water and reduced the duration of the stage of distillation of water until a temperature 165-180°C.

The method is as follows.

Mix the bicarbonate aminoguanidine appropriate pyridylcarbonyl acid (II) and hydrochloric acid, the resulting mixture is heated with stirring to Kip who were gradually distilled water at atmospheric pressure until while the temperature of the reaction mixture reaches the desired value (165-180°C). Then the reaction mixture was kept at this temperature for 3-5 hours, poured a solution of sodium hydroxide and heated with stirring until complete dissolution. The obtained alkaline solution is refluxed for 30 min, then neutralized with hydrochloric acid to a pH of 7-8, cooled to 5-10°C, the precipitation is filtered off, recrystallized from water and dried.

Example 1

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 165°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 5.19 g (79%), TPL226-227 of°C.

An NMR spectrum1H, δ, ppm (DMSO-d6): 6.15 (2H, NH2), 7.41 Shostakovich (1H,3J=7.8 is 4.8 Hz, H-5'), 8.16 dt(1H,3J=8.1 Hz,4J=1.8 Hz, H-4'), 8.53 Shostakovich (1H,3J=5.1 Hz,4J=1.8 Hz, H-6'), 9.03 D. (1H,4J=1.2 Hz, H-6'), 12.28 of user. S. (1H, NH).

Found (%): 52.21; N, 4.42; N 43.37

C7H7N5.

Calculated (%): 52.17; H 4.38; N 43.45

Example 2

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 5.23 g (80%). Properties of the obtained product are identical to those described in example 1.

Example 3

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 4.6 ml (0.0487 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure up until t is mperature the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 4.45 g (68%). Properties of the obtained product are identical to those described in example 1.

Example 4

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 7.6 ml (0.0812 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 6.5 g (0.1624 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 5.23 g (80%). Properties of the obtained product are identical to those described in example 1.

Example 5

Mix 5.53 g (mol) bicarbonate aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 160°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 4.25 g (65%). Properties of the obtained product are identical to those described in example 1.

Example 6

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 145°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid is th to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 2.94 g (45%). Properties of the obtained product are identical to those described in example 1.

Example 7

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 190°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water with the addition of activated charcoal and dried at 110-120°C. the Yield of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole 3.92 g (60%). Properties of the obtained product are identical to those described in example 1.

Example 8

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-3-carboxylic acid and 20 ml of water, the resulting mixture is heated under stirring until complete dissolution of the reagents, and then acidified with concentrated hydrochloric acid to a pH of 0 to 1, and heated at a temperature of 90-100°C for 15 minutes Then from the reaction mixture in a water-jet pump vacuum (15 mm Hg) and distilled water. To the residue is poured a solution of 6.5 g (0.1625 mol) of sodium hydroxide in 30 ml of water and the resulting mixture was refluxed for 30 min, then neutralized 10%hydrochloric acid to pH 7-8 and cool. Precipitated residue is recrystallized and obtain 0.65 g (yield 10%) of 3-(pyridin-3-yl)-5-amino-1,2,4-triazole. Properties of the obtained product are identical to those described in example 1.

Example 9

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-4-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 165°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-4-yl)-5-amino-1,2,4-triazole 4.66 g (71%), TPL271-272°C.

An NMR spectrum1H, δ, ppm (DMSO-d6): 6.22 (2H, NH2), 7.76 Shostakovich (2H,3J=4.5 Hz,4J=1.5 Hz, the -3' and H-5'), 8.57 D. (2H,3J=5.7 Hz, H-4' and H-6'), 12.35 of user. S. (1H, NH).

Found (%): 52.01; N, 4.36; N 43.63

C7H7W5.

Calculated (%): 52.17; H 4.38; N 43.45

Example 10

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-4-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-4-yl)-5-amino-1,2,4-triazole 4.73 g (72%). Properties of the resulting product is identical to that described in example 9.

Example 11

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-4-carboxylic acid and 5.7 ml (0.0609 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 165°C. Then the reaction mixture videri is up at this temperature for 3 h, then add a solution of 4.87 g (0.122 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-4-yl)-5-amino-1,2,4-triazole 4.78 g (73%). Properties of the resulting product is identical to that described in example 9.

Example 12

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-2-carboxylic acid and 5.0 ml (0.0528 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 165°C. Then the reaction mixture was kept at this temperature for 5 hours, then add a solution of 4.22 g (0.106 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-2-yl)-5-amino-1,2,4-triazole 4.91 g (75%), TPL214-216°C. In solution in dimethyl sulfoxide substance is a mixture of two tautomers - 3-(pyridin-2-yl)-5-amino-1,2,4-triazole (tautomer a) and 5-(pyridin-2-yl)-3-Amin is -1,2,4-triazole (tautomer B) in a ratio of 1:0.6.

An NMR spectrum1H, δ, ppm (DMSO-d6: 5.32 (2H, NH2tautomer B), 6.07 (2H, NH2tautomer A), 7.32-7.43 m (1H, H-5'), 7.81-7.90 m (2H, H-3' and H-4'), 8.57 m (1H, H-6'), 12.22 of user. S. (1H, NH tautomer A), 13.44 (1H, NH tautomer B).

Found (%): 52.34; N, 4.20; N 43.46

C7H7N5.

Calculated (%): 52.17; H 4.38; N 43.45

Example 13

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-2-carboxylic acid and 5.7 ml (0.0609 mol) 33.5%hydrochloric acid, the resulting mixture is heated with stirring to a boil and gradually distilled water at atmospheric pressure as long as the temperature of the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.87 g (0.122 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-2-yl)-5-amino-1,2,4-triazole 5.04 g (77%). Properties of the resulting product is identical to that described in example 12.

Example 14

Mix 5.53 g (0.0406 mol) of hydrogen aminoguanidine, 5.01 g (0.0406 mol) pyridine-2-carboxylic acid and 20.1 ml (0.0609 mol) 10.5%hydrochloric acid, the resulting mixture is heated with stirring to boil and gradually distilled water at atmospheric pressure until while the temperature of the reaction mixture reaches 180°C. Then the reaction mixture was kept at this temperature for 3 hours, then add a solution of 4.87 g (0.122 mol) of sodium hydroxide in 10 ml of water. The obtained alkaline solution is refluxed for 30 minutes, neutralized 10%hydrochloric acid to pH 7-8 and cool. The precipitation is filtered off, recrystallized from water and dried at 110-120°C. the Yield of 3-(pyridin-2-yl)-5-amino-1,2,4-triazole 5.11 g (78%). Properties of the resulting product is identical to that described in example 12.

Method for the preparation of 3(5)-pyridylamine 5(3)-amino-1,2,4-triazoles of General formula (I)

where R represents 2-pyridyl, 3-pyridyl or 4-pyridyl, namely, that pyridylcarbonyl acid of General formula (II)

where R has the above meanings, is subjected to interaction with hydrogen aminoguanidine in the presence of hydrochloric acid at boiling of the reaction mixture and at a molar ratio of acid(II): hydrogen aminoguanidine : hydrochloric acid = 1,0:1,0:1,3-1,5, with a gradual distillation of water at atmospheric pressure until a temperature of the reaction mixture 165-180°C, the reaction mixture was kept at this temperature for 3-5 h, and then add a solution of alkali in water, boil the obtained alkaline solution with PEFC is blowing its neutralization to pH 7-8 and the selection of the target product.



 

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SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

Substituted indoles // 2255087

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

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