The method of obtaining pyrazolidinone derivative or its salt

 

(57) Abstract:

Usage: in medicine as substances with a wide pharmaceutical actions. The inventive product total f-ly 1 , where R1- phenyl, R2group f-crystals of 2 - 7, R3- alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, carbamoylethyl or N, N-dialkyl (or together form a pyridine ring; R4- carboxyethyl or alkoxycarbonyl; R5- alkoxycarbonylmethyl; R6- alkyl, carboxylic or alkoxycarbonyl; R7- N, carboxy or cyano, alkoxycarbonyl; R8- carboxyethyl or alkoxycarbonyl; R9- alkyl, carboxylic, alkoxycarbonylmethyl; R10- H or HE, in all cases used the lowest alkali. Reagent 1: product f-ly 1, where instead of R2used group f-l 2 - 7 missing on the corresponding nitrogen groups: R3- R10or a salt of this product. Reagent 2: connection f-ly QY, where Q values of R3- R9Y is the group to delete. The reaction of these reagents obtain the target product of f-crystals 1. If necessary, the resulting compound, where R3- R9and each is (lower)alkoxycarbonyl(lower)alkyl, remove the lower alkiswani or its pharmaceutically suitable salts, which are antagonists of adenosine and have different pharmaceutical activities, such as cognitive enhancing action, analgesic action, locomotor action, the action of the antidepressant, dilates blood vessels brain action, diuretic action, cardiotonic action, the ability to increase the rate of passage of blood in the kidneys, the ability to increase lipolysis and a number of other valuable properties.

New pyrazolidinone connection corresponding to this invention may be represented by the formula I R1where R1is phenyl;

R2group of the formula

< / BR>
or

R3- lower alkyl, hydroxy (lower alkyl), lower alkoxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, carbarnoyl (lower) alkyl or N, N-di (lower) allylcarbamate (lower) alkyl, where two lower alkyl groups at the nitrogen atom can be connected to each other, forming piperidine ring,

R4- carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl; R5lowest alkoxycarbonyl (lower) alkyl; R6- lower alkyl, carboxy (lower) alkyl or lower; alkoxycarbonyl (lower) alkylalkoxysilane (lower) alkyl; R9- lower alkyl, carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl; R10is hydrogen or hydroxy.

Known interaction Akilov with halogen derivatives of (1).

The purpose of the invention is the synthesis of new compounds in a series of pyrazolidine their properties superior structural analog with the same type of activity.

This goal is achieved by the proposed method of obtaining compounds of General formula 1 consists in the fact that the compound of General formula

where R1has the specified values,

R2is a group of the formula

< / BR>
orwhere R7and R10each has the meaning as defined above, or its salt, is subjected to reaction with the compound of the formula

QY where Q has the values of R3, R4, R5, R6, R8and R9Y is the group to delete and, if necessary, the resulting compound, where R3, R4, R5, R6, R8and R9each represents a lower alkoxycarbonyl (lower) alkyl, remove the lower alkyl group with obtaining the compounds of formula I, where R3, R4, R5,R6, R8and R9represents each carboxy (lower) alkyl with the kind of ablaut dropwise with stirring to a solution of 2-phenylpyrazole(1,5 - a )pyridine (2,54 g) and pyridine (5,00 g) in methylene chloride (5.0 ml) at 10aboutC. After stirring at a temperature of 10aboutC for 1 h and then at room temperature for 2 h, the reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The combined extracts washed with saturated aqueous sodium chloride (100 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (150 g) with a mixture of chloroform and n-hexane (1: 1) as eluant. The fractions containing the parent product (compound (A)), are combined and evaporated in vacuo to obtain 3-(1-etoxycarbonyl-1,4-dihydropyridin-4-yl)-2-phenylpyrazole(1,5 - a )pyridine (2,42 g); melting point 173-174aboutC.

IR (Nujol): 1740, 1700, 1670, 1635, 1615 cm-1.

NMR (CDCl3, ): of 1.40 (3H, t, J = 7.0 Hz), 4,43 (2H, q, J = 7.0 Hz), 4,48-4,70 (1H, m), of 5.03 (1H, dt, J = 8,5 Hz and 3.0 Hz), 6,67-of 7.82 (10H, m), and 8.50 (1H, DD, J = 7.0 Hz and 1.0 Hz).

Fractions containing by-product (compound (C)), are combined and evaporated in vacuo to obtain 3-(2-etoxycarbonyl-2,3-dihydro - pyridazin-3-yl)-2-phenylpyrazole(1,5 - a )-pyridine (0.39 g); melting point 150-152aboutC;

IR (Nujol): 1720, 1635 cm-1.

NMR (CDCl3, ): of 1.16 (3H, t, J = 7.0 Hz), 4,18 (2H, q, J = 7.0 Hz), 5,67-7,95 (N, m), 8,48 (1H, DD, J = 7.0 Hz and 1.0 Hz).

and (1.12 g) and tert-butoxide potassium (1.18 g) in tert-butanol (25 ml) at 50aboutC for 10 min.

Tert-butanol evaporated in vacuo and to the residue was added ice water (50 ml). The mixture is extracted with chloroform (30 ml, three times). The combined extracts washed with saturated aqueous sodium chloride (50 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (20 g) with chloroform as eluent. The fractions containing the target compound are pooled and evaporated in vacuo to obtain 3-(pyridazin-4-yl)-2-phenylpyrazole/1,5 /pyridine (0.35 g); melting point 204-205aboutC; IR (Nujol): 1630, 1580, 1515 cm-1.

NMR (DMSO-d6, ): 6,97-8,00 (N, m), cent to 8.85 (1H, d, J = 7,0 Hz), 9,03-9,27 (2H, m).

Calculated, % : C 74,98; N. Of 4.44; N 20,58.

WITH17H12N4.

Found, % : C 75,27; N 4,63; N 20,38.

P R I m e R 3. 3-(Pyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine receive in accordance with the methods of example 1 and example 2; melting point: 166-167aboutC; IR (Nujol): 1630, 1600, 1530 cm-1.

NMR (CDCl3, ): 6,83 (1H, dt, J = 1.5 Hz and 7.0 Hz), 7,20-7,83 (N, m), 8,45-8,83 (3H, m).

Calculated, % : C 79,68, N. A 4.83; N 15,49. WITH18H13N3.

Found, % : C 80,20; N A 4.86; N 15,56.

P R I m e R 4. A mixture of 3-acetyl-2-phenylpyrazole/1,5- /5 o'clock The reaction mixture is dissolved in a mixture of ethyl acetate (220 ml) and aqueous sodium hydroxide (12% , 220 ml). The aqueous layer was washed with 100 ml of chloroform, then acidified with 10% aqueous solution of hydrochloric acid. The mixture is extracted with chloroform (150 ml x 2). The extracts are combined, washed with saturated aqueous sodium chloride. The solvent is evaporated and the residue (39,8 g) is dissolved in aqueous ammonia solution (120 ml), and to the solution was added hydrazine monohydrate (42 g). The mixture is refluxed for 2 hours, the Precipitates are collected by filtration to obtain 3-(3-oxo-2,3-dihydropyridin-6-yl)-2-phenylpyrazole/1,5 /pyridine (accounted for 14.45 g); melting point 212-214aboutC.

IR (Nujol): 1660, 1625, 1580, 1510 cm-1.

NMR (CDCl3, ): 6,87 (1H, d, S = 11 Hz), 7,00 (1H, TD, J = 7 Hz and 1 Hz), was 7.08 (1H, d, J = 11 Hz), 7.23 percent-7,73 (6N, m), 7,83 (1H, d, J = 8 Hz), to 7.77 (1H, d, J = 7 Hz).

Calculated, % : C 70,82; N 4,20; N 19,43. WITH17H12N4O.

Found, % : C 70,75; N. Of 4.83; N 19,24.

P R I m e R 5. A mixture of 3-(3-oxo-2,3-dihydropyridin-6-yl)-2-phenylpyrazole/1,5 /pyridine (0,37 g); melting point: 133-133,5aboutC.

IR (Nujol): 1730, 1660, 1585 cm-1.

NMR (CDCl3, ): 2,90 (2H, t, J = 6 Hz), to 3.67 (3H, s), of 4.57 (2H, t, J = 6 Hz), 6,70 (1H, d, J = 9 Hz), 6.87 in (1N, the tx2">

Calculated, % : C 67,37; N Is 4.85; N 14,96. WITH21H18N4O2< / BR>
Found, % : C 67,31, N 5,35; N 14,94.

P R I m e R 6. A mixture of 3-/2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (1,94 g) and 24% aqueous solution of sodium hydroxide (2 ml) in methanol (8 ml) is heated under reflux for 30 min and then evaporated in vacuum. The residue is dissolved in water (30 ml) and the aqueous solution acidified with hydrochloric acid and extracted with chloroform (25 ml). The extract is dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is recrystallized from a mixture of ethanol and n-hexane to obtain 3-/2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (1.24 g); melting point 155,5-156aboutC.

IR (Nujol): 1835, 1640, 1570, 1520, 1490 cm-1.

NMR (CDCl3, ): of 2.97 (2H, t, J = 7 Hz), 4,60 (2H, t, J = 7 Hz), 6,15-7,00 (1H, Shir. d), 6,75-7,70 (N, m), of 8.00 (1H, d J = 9 Hz), 8,53 (1H, d, J = 7 Hz).

Mass spectrum (M+): 360.

Calculated, % : C 66,66; N 4,47, N 15,55. WITH20H16N4O3.

Found, % : 66,61, N Br4.61, N 15,50.

P R I m e R 7. To a mixture of 3-/2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (10.0 g), ethanol (100 ml) and water (1T under reflux for 2 h to obtain a clear solution, then the solution is cooled. The obtained solid is collected by filtration and washed with 85% ethanol (8 ml) and recrystallized twice from 83% ethanol (48 ml) to give crystals of sodium salt 3-/2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2-phenyl - pyrazolo/ 1,5 /pyridine (5,13 g); melting point: 271-272aboutC.

IR (Nujol): 3400, 1670, 1610, 1580, 1530 cm-1.

NMR (DMSO-d6, ): of 2.45 (2H, t, J = 8 Hz), the 4.29 (2H, t, J = 8 Hz), for 6.81 (1H, d, J = 9 Hz), 7,02 (1H, d, J = 9 Hz), 7,07 (1H, TD, J = 7 Hz and 1 Hz), 7,40-7,63 (6N, m), 8,02 (1H, d, J = 9 Hz), 8,80 (1H, d, J = 7 Hz).

Mass spectrum: 360 (M+).

Calculated, % : C 58,67; N 4,43; N 13,69. WITH20H15N4O3Na 3/2 H2O

Found, % : C 58,49; N 4,27, N 13,96.

P R I m e R 8. To a mixture of 3-chloropyridazine (0.66 g), 2-phenylpyrazole-/1,5/pyridine (1.12 g) and chloroform (6.6 ml) was added ethylchloride (1,38 g) under cooling on ice and stirred for 2 h at room temperature. To the reaction mixture was added methylene chloride (10 ml). The solution was washed with saturated aqueous acidic sodium carbonate (10 ml) and dried in the presence of magnesium sulfate. The organic layer is evaporated in vacuum and recrystallized from a mixture of ethyl acetate and 2-propanol with 3-(3-chloro-1-etox the

IR (Nujol): 1715, 1675, 1630 cm-1.

NMR (DCl3, ): of 1.42 (3H, t, J = 7,1 Hz), 4,42 (2H, q, J = 7,1 Hz), 4,80 (1H, DD, J = 1.6 Hz and 3.6 Hz), 5,00 (1H, DD, J = 3,6 Hz and 8.2 Hz), 6,86 (1H, dt, J = 1.4 Hz and 6.8 Hz), 7,15-of 7.69 (8H, m), 8,51 (1H, DD, J = 1.0 Hz and 7.0 Hz).

Calculated, % : C 63,08; N 4,50; N 14,71. WITH20H17ClN4O2< / BR>
Found, % : C 63,04; N To 4.52; N 14,50.

The following compounds (examples 9 and 10) obtained in accordance with example 8.

P R I m e R 9. 3-(3-Acetyl-1-etoxycarbonyl-1,4-dihydropyridines-4-yl)-2-phenyl - pyrazolo /1,5 /pyridine; the melting point of 151-153aboutC.

IR (Nujol): 1735, 1660, 1610 cm-1.

NMR (CDCl3, ): to 1.32 (3H, t, J = 7.5 Hz), was 2.05 (3H, s), 4,32 (2H, q, J = 7.5 Hz), 4,84 (1H, d, J = 4.0 Hz), 5,15 (1H, DD, J = 8.0 Hz and 4.0 Hz), to 6.75 (1H, d, J = 8.0 Hz), to 6.80 (1H, t, J = 7.5 Hz), to 7.15 (1H, t, J 7.5 Hz), 7,16 to 7.75 (6N, m) of 7.82 (1H, s), 8,58 (1H, d, J = 7.5 Hz); Mass spectrum: 387 (M+): 344, 314, 300, 269, 241.

P R I m e R 10. 3-(3-Cyano-1-etoxycarbonyl-1,4-dihydropyridines-4-yl)-2-phenyl - pyrazolo/ 1,5 /pyridine; melting point: 182-183aboutC.

IR (Nujol): 2215, 1740, 1680, 1620 cm-1.

NMR (CDCl3, ): is 1.31 (3H, t, J = 7.5 Hz), the 4.29 (2H, q, J 7.5 Hz), and 4.75 (1H, m), 5,14 (1H, DD, J = 9.0 Hz), and 3.0 Hz), to 6.80 (1H, d, J = 9.0 Hz), 6,93 (1H, t, J = 7.5 Hz), 7,27 (1H, t, J 7.5 Hz), of 7.36-of 7.70 (7H, m), to 8.70 (1H, d, J = 7.5 Hz).

Mass spectrum: 370 (M+aboutC.

IR Nujol): 1630, 1610 cm-1.

NMR (CDCl3, ): 246 (3H, s), 6,98 (1H, t, J = 7.5 Hz), 7,19-7,58 (7H, m), to $ 7.91 (1H, d, J = 6.0 Hz), 8,58 (1H, d, J = 7.5 Hz), to 9.32 (1H, d, J = 6.0 Hz).

Mass spectrum: 286 (M+), 257, 231, 218.

The following compounds (examples 12 and 13) are obtained in accordance with example 11.

P R I m e R 12. 3-(5-Methylpyridazin-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 158-159,5aboutC.

IR (Nujol): 3080, 1630 cm-1.

NMR (CDCl3, ): 1,90 (3H, s), to 6.80 (1H, t, J = 7.5 Hz), 7,12-to 7.50 (7H, m), 8,51 (1H, d, J = 7.5 Hz), 8,99 (2N, C).

Mass spectrum: 286 (M+), 257, 243, 218.

Calculated, % : C 75,50; N Is 4.93; N 19,57.

WITH18H14N4.

Nienie: 130-131aboutC.

IR Nujol): 1625, 1580 cm-1.

NMR (CDCl3, ): of 6.96-7,06 (2H, m), 7,35-to 7.64 (6N, m), 8,40 (1H, d, J = 5.4 Hz), by 8.22-8,61 (2H, m), which 9.22 (1H, d, J = 1.3 Hz).

Mass spectrum: 271 (M+), 244, 217.

Calculated, % : C 74,98; N. Of 4.44; N 20,57.

WITH17H12N4.

Found, % : C 74,87; N TO 4.62; N 20,33

P R I m e R 14. A mixture of 2-phenylpyrazole/1,5 /pyridine (0.50 g), 2,4-piperidinedione (0,292 g), concentrated sulfuric acid (1 drop) and acetic acid (0.5 ml) is heated at 135aboutWith for 13.5 hours, the reaction mixture was added saturated aqueous solution of acid sodium carbonate (20 ml) and the mixture extracted with chloroform (20 ml x 2). The combined extract was washed with saturated aqueous sodium chloride (20 ml) and dried in the presence of magnesium sulfate. The solvent is evaporated in vacuum. The residue is purified column chromatography on silica gel using a mixture of chloroform and ethyl acetate (9: 1) and recrystallized from ethyl acetate to obtain crystals of 3-(2-oxo-1,2,5,6-tetrahydropyridine-4-yl)-2-Fe - elpirata/1,5 /pyridine; melting point: 188-189aboutC.

IR (Nujol): 1655, 1630, 1605 cm-1.

NMR (CDCl3, ): 2,44 (2H, t, J = 6.5 Hz), 3,44 (2H, t, J = 6.5 Hz), of 6.20 (2H, s) 6,86 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,20 to 7.75 O.

Found, % : C 75,13; N 5,33; N 14,69.

P R I m e R 15. A solution of 3-(3-N, N-dimethylaminoacetyl)-2-phenylpyrazole/1,5 / pyridine (0,63 g) guanidine-hydrochloride (0.31 g), ethylate sodium (0.54 g) and ethanol (9 ml) is heated under reflux for 2 hours To the reaction mixture was added water (30 ml) and the mixture extracted with ethyl acetate (60 ml). The organic layer is evaporated, whereupon the residue is recrystallized from ethanol to obtain 3-(2-aminopyrimidine-4-yl)-2-phenyl-pyrazolo/1,5 /pyridine (0.40 g); melting point: 222,5-223aboutC.

IR (Nujol): 3370, 3320, 3180, 1640, 1560 cm-1.

NMR (CDCl3, ): 6,14 (1H, d, J = 4,8 Hz), of 6.52 (2H, s), 7,05 (1H, TD, J = 7.0 Hz and 1.0 Hz), 8,53 (1H, d, J = 8.0 Hz), 8,76 (1H, d, J = 7,0 Hz).

Mass spectrum: 286.

Calculated, % : C 71,07; N 4,56; N 24,37.

WITH17H13N5.

Found, % : C 70,93; N 4,59; N 23,74.

P R I m e R 16. A mixture of 3-(2-phenylpyrazole/1,5 /pyridine-3-yl)acrylaldehyde (CIS - and TRANS-mixture) (1,15 g) and 1-carbamoylbiphenyl (0,80 g), 50% aqueous dimethylamine (0,44 g) and methanol (10 ml) is heated under reflux for 3 hours, the Reaction mixture was evaporated in vacuum and the residue is heated for 10 minutes at 200aboutC. the resulting mixture chromatographic on silica gel (80 g)IU and recrystallized from ethanol to obtain 3-(2-oxo-1,2-dihydropyridines-4-yl)-2-Fe - elpirata/1,5-pyridine (0.33 g).

IR (Nujol): 1655, 1580 cm-1.

NMR (DMSO-d6, ): 5,72 (1H, DD. J = 1.8 Hz and 6.8 Hz), 6,30 (1H, d, J = 1.2 Hz), 7,40 (1H, dt, J = 1.3 Hz and 6.8 Hz), 7,33 to 7.62 (7H, m), 7,73 (1H, d, J = 9.0 Hz), 8,80 (1H, d, J = 7,0 Hz), to 11.52 (1H, Shir. the singlet).

Mass spectrum: 286 (M+-1), 268.

Calculated, % : C 73,60; N 4,69; N 14,30.

WITH18H13N3O 1/3 H2O

Found, % : C 73,70; N 4,82, N Of 14.28.

P R I m e R 17. A mixture of 4-oxo-4-(2-phenylpyrazole/1,5 /pyridine-3-yl)-butyric acid (1,71 g), hydrazine monohydrate (1,46 g) and ethanol (17 ml) is heated under reflux for 1 h, the Ethanol evaporated in vacuo. To the residue was added water (20 ml), acidified with 5% hydrochloric acid and extracted with chloroform (25 ml x 3). The combined extract was washed with saturated aqueous sodium chloride, dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is recrystallized from ethanol to obtain crystals of 3-(3-oxo-2,3,4,5-tetrahydropyridine-6-yl)-2-Panalpina - gold/1,5 /pyridine (1.19 g); melting point: 187-189aboutC.

IR (Nujol): 3325, 1675, 1630 cm-1.

NMR (DMSO-6, ): 2,29 is 2.51 (4H, m), 7,05 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,37-7,68 (6N, m) of 7.96 (1H, d, J = 9.0 Hz), 8,78 (1H, d, J = 7,0 Hz).

Calculated, % : C 70,33; N A 4.86; N 19,30.

aboutC.

IR (Nujol): 2670, 2570, 1640, 1610 cm-1.

NMR (DMSO-d6, ): 5,43 (1H, s), 6,97 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,21-7,80 (7H, m), 8,73 (1H, d, J = 7,0 Hz).

Calculated, % : C 69,55; N. Of 4.38; N To 20.28.

WITH16H12N4O.

Found, % : C 69,46; N. Of 4.35; N 19,99.

P R I m e R 19. A mixture of 3-(2-bromoacetyl)-2-phenylpyrazole/1,5 /pyridine (1,87 g), 2-amino-5-methyl-1,3,4-thiadiazole (0.68 g) and 1-butanol (19 ml) is heated under reflux for 5 hours and 20 minutes, the Reaction mixture was evaporated in vacuum and the residue taken in methylene chloride (40 ml). A solution of methylene chloride is washed with aqueous potassium carbonate solution and dried in the presence of magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel (25 g) with chloroform as a/a 2.1 /1,3,4-thiadiazole-6-yl-2-phenylpyrazole/1,5 /pyridine (1.06 g), which is recrystallized from acetone to obtain crystals (0,69 g); melting point: 204aboutC.

IR (Nujol): 3130, 3100, 1635, 1590 cm-1.

NMR (CDCl3, ): to 2.65 (3H, s), of 6.75 (1H, t, J = 7.5 Hz), 7,13 (1H, t, J = 7.5 Hz), 7,25 is 7.50 (4H, m), 7,55-7,80 (2H, m) to 8.14 (1H, d, J = 9.0 Hz), 8,40 (1H, d, J = 7.5 Hz).

Mass spectrum: 302 (M+), 261, 221, 193.

Calculated, % : C 62,24; N. Of 3.95; N 21,33.

WITH18H13N3S.

Found, % : C 65,58; N 3,98; N Each Holding 21.25.

P R I m e R 20. A mixture of 3-(N, N-dimethylamino)-2-(2-phenylpyrazole/1,5 /pyridine-3-yl)acrylaldehyde (CIS - and TRANS-mixture) (4,00 g), 2-cyanoacetamide (2,31 g), ethylate sodium (4,67 g) and ethanol (40 ml) is heated under reflux for 2 hours After cooling, the reaction mixture is performed with the addition of acetic anhydride (24 ml) and water (120 ml) and the resulting mixture was stirred at room temperature. The resulting precipitates is collected and recrystallized from a mixture of N, N-dimethylformamide and water to obtain 3-(3-cyano-2-oxo-1,2-dihydropyridines-5-yl)-2-phenylpyrazole/1,5 /pyridine (2,08 g); melting point: 312-314aboutC.

IR (Nujol): 2240, 1670, 1540 cm-1.

NMR (DMSO-d6, ): 6,93 (1H, t, J ) 7.5 Hz), 7,27 (1H, t, J = 7.5 Hz), 7,33-7,72 (8H, m), 8,03 (1H, d, J = 7.5 Hz), 8,71 (1H, d, J = 7.5 Hz).SUB>NO.

Found, % : C 72,96; N 4,19; N 17,83.

P R I m e R 21. A mixture of 3-(N, N-dimethylamino)-2-(2-phenylpyrazole/1,5 /pyridine-3-yl)acrylaldehyde (0,70 g), hydrazine monohydrate (0.18 g) and ethanol (7 ml) is heated under reflux for 4 hours To the reaction mixture was added water (12 ml) and stirred for a certain time while cooling on ice. The precipitates is collected and recrystallized from a mixture of ethanol and water to obtain 3-(4-pyrazolyl)-2-phenylpyrazole/1,5 /pyridine (0.51 g); melting point 188-190aboutC.

IR (Nujol): 3150, 1630 cm-1.

NMR (CDCl3, ): to 6.75 (1H, t, J = 7.5 Hz), 7,10 (1H, t, J = 7.5 Hz), 7,25-7,80 (N, m), to 8.57 (1H, d, J = 7.5 Hz).

Mass spectrum: 260 (M+), 232, 205.

Calculated, % : C 73,83; N 4,65; N 21,52.

WITH16H12N4.

Found, % : C 73,49; N 5,01; N 21,18.

The following compounds (examples 22-25) are obtained in accordance with example 21.

P R I m e R 22. 3-(1-Methylpyrazole-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 100-103aboutC.

IR (Nujol): 1630 cm-1.

NMR (CDCl3, ): 3,90 (3H, s) 6,70 (1H, t, J = 7.5 Hz), 7,07 (1H, t, J = 7.5 Hz), 7,21-7,46 (5H, m), of 7.48 (1H, s), 7,60-7,80 (2H, m), 8,43 (1H, d, J = 7.5 Hz).

Mass spectrum: 274 (M+), 246.

P R I m e R 23. 3-(5-Pyrimidinyl)-2-phenylpyrazole/1,5 /pyridine; melting point: 163-165aboutC.

IR (Nujol): 1625 cm-1.

NMR (CDCl3, ): 6,83 (1H, t, J = 7.5 Hz), 7,18 (1H, t, J = 7.5 Hz), 7,25-7,60 (6N, m), 8,51 (1H, d, J = 7.5 Hz), to 8.70 (2H, s), 9,10 (1H, s).

Mass spectrum: 272 (M+), 244, 218.

Calculated, % : C 74,98; N. Of 4.44; N 20,57.

WITH17H12N4.

Found, % : C 75,14, N 5,04, N 20,42.

P R I m e R 24. 3-(2-Methylpyrimidin-5-yl)-2-phenylpyrazole/1,5 /pyridine, melting point: 152-153aboutC.

IR (Nujol): 3030-3100, 1635 cm-1.

NMR (CDCl3, ): 2,73 (3H, s), to 6.80 (1H, t, J = 7.5 Hz), 7,18 (1H, t, J = 7.5 Hz), 7,20-7,65 (6N, m), and 8.50 (1H, d, J = 7.5 Hz), at 8.60 (2H, s).

Mass spectrum: 286 (M+), 244, 218.

Calculated, % : C 75,51; N Is 4.93; N 19,57.

WITH18H14N4.

Found, % : C 75,38; N 5,14; N 19,16.

P R I m e R 25. 3-(2-Aminopyrimidine-5-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 304-305aboutC.

IR (Nujol): 3400-3050, 1660, 1605 cm-1.

NMR (DMSO-d6, ): to 6.43 (2H, s), of 6.68 (1H, t, J = 7.5 Hz), 7,02 (1H, t, J = 7.5 Hz), 7,07 was 7.45 (6N, m), to 7.93 (2H, s), 8,48 (1H, d, J = 7.5 Hz).

Mass spectrum: 287 (M+), 246, 218.

Calculated, % : C 71,07; N 4,56; N 24,37.

WITH17H13N<-penile - rasalo/1,5 /pyridine (0.47 in), ethyl-4-bromobutyrate (0.32 g). Triton (0.5 ml) and chloroform is stirred for 2 days at room temperature. The reaction mixture is evaporated and the residue is subjected to column chromatography on silica gel (20 g) with chloroform as eluent. The fractions containing the target compound are pooled (20 ml) and concentrate under reduced pressure. The residue is dissolved in ethyl acetate and filtered. Filter evaporated obtaining 3-2-(3-ethoxycarbonylphenyl)-3-oxo-2,3-dihydro - pyridazin-6-yl(-2 - phenylpyrazole/1,5 /pyridine (0,49 g); melting point: 71-75aboutC.

IR (Nujol): 1730, 1660, 1630, 1590, 1525 cm-1.

NMR (CDCl3, ): a 1.25 (3H, t, J = 6 Hz), 2.00 in 2,60 (4H, m), 4,00 is 4.45 (4H, Neh), 6,77 (1H, d, J = 10 Hz), 6,92 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,03 (1H, d, J = 10 Hz), 7,25-7,80 (6N, m), of 8.00 (1H, d, J = 9.0 Hz), charged 8.52 (1H, d, J = 7,0 Hz).

Mass spectrum: 402.

Calculated, % : C 68,64; N 5,51; N 13,92.

WITH23H22N4O3.

Found, % : C 68,79; N 5,78; N 13,72.

The following compounds (examples 27-32) obtained in accordance with example 26.

P R I m e R 27. 3-(2-Methoxycarbonylmethyl-3-oxo-2,3-dihydropyridin-6-yl)-2 - phenylpyrazole/1,5 /pyridine; melting point: 142,5-143aboutC.

IR (Nujol): 1740, 1670, 1630, 1590 cm-1.

Mass spectrum: 360 (M+).

Calculated, % : C 66,66; N To 4.47%; N 15,55.

C20H16N4O3.

Found. % : 66,69; N 4,47; N OF 15.75.

P R I m e R 28. 3-(2-Methyl-3-oxo-2,3-dihydropyridin-6-yl)-2-phenyl-pyrazolo/1,5 /pyridine; melting point: 145-145,5aboutC.

IR (Nujol): 1675, 1585 cm-1.

NMR (CDCl3, ): the 3.89 (3H, s), 6,72 (1H, d, J = 9 Hz), to 6.88 (1H, TD, J = 6 Hz and 1 Hz), 7,00 (1H, d, J = 9.0 Hz), 7,15-7,70 (6N, m) of 7.97 (1H, d, J = 9,0 Hz) and 8.50 (1H, d, J = 8.0 Hz).

Mass spectrum: 302.

Calculated, % : C 71,51; N. Of 4.67; N 18,53.

WITH18H14N4O.

Found, % : C 71,60; N 4,58; N 18,65.

P R I m e R 29. 3-(2-Propyl-3-oxo-2,3-dihydropyridin-6-yl)-2-phenyl-Pirat - lo/1,5 /pyridine; melting point: 110-110,5aboutC.

IR (Nujol): 1660, 1590, 1530 cm-1.

NMR (CDCl3,): of 1.05 (3H, t, J = 7.0 Hz), 1,95 (2H, Neh, J = 7,0 Hz) to 4.23 (2H, t, J = 7.0 Hz), 6,72 (1H, d, J = 10 Hz), 6.87 in (1H, TD, J = 7.0 Hz and 1.0 Hz), 6,97 (1H, d, J = 10 Hz), 7,17-7,70 (6N, m), to 7.93 (1H, d, J = 10 Hz), and 8.50 (1H, d, J Hz).

Mass spectrum: 330.

Calculated, % : C 72,71; N 5,49; N 16,69.

WITH20H18N4O

Found, % : C 72,81; N The 5.65; N 16,98.

P R I m e R 30. 3/2-(2-2-Hydroxyethyl)-3-oxo-2,3-dihydropyrido is 500 cm-1.

NMR (CDCl3, ): of 4.05 (2H, m), 4,30 (2H, d, J = 4.0 Hz), 6,70 (1H, d, J = 10.0 Hz), PC 6.82 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,00 (1H, d, J = 10.0 Hz), 7,15-7,60 (6N, m), 7,87 (1H, d, J = 10.0 Hz), to 8.45 (1H, d, J = 7,0 Hz).

Mass spectrum: 332 (M+).

Calculated, % : C 68,66; N Is 4.85; N 16,86.

WITH19H16N4O2.

Found, % : C 67,29; N. Of 5.05; N 16,42.

P R I m e R 31. 3-/2-(3-Hydroxypropyl)-3-oxo-2,3-dihydropyridin-6-yl/-2-Fe - elpirata /1,5 /pyridine; melting point: 164,5-165aboutC.

IR (Nujol): 1660, 1590, 1540 cm-1.

NMR CDCl3, ): 2,11 (2H, q, J = 6.0 Hz), 3.46 in-3,70 (3H, m), 4,46 (2H, t, J = 6.0 Hz), to 6.80 (1H, d, J = 10.0 Hz), 6,14 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,01 (1H, d, J = 8.0 Hz).

Mass spectrum: 346 (M+).

Calculated, % : C 69,35; N 5,24; N 16,17.

WITH20H18N4O2.

Found, % : From 69.02; H 5,28; N 15,74.

P R I m e R 32. 3-/2-(2-Ethoxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/2-phenyl - pyrazolo /1,5 /pyridine; melting point: 117-118aboutC.

IR (Nujol): 1665, 1630, 1590, 1530 cm-1.

NMR (CDCl3, ): of 1.23 (3H, T. , J = 7,0 Hz) and 3.59 (2H, q, J = 7.0 Hz), to 3.92 (2H, t, J = 6.0 Hz), of 4.49 (2H, t, J = 6.0 Hz), to 6.75 (1H, d, J = 10.0 Hz), 6,94 (1H, TD, J = 6.0 Hz and 1.0 Hz), 7,00 (1H, d, J = 10.0 Hz), 7.24 to 7,76 (6N, m), to 8.12 (1H, d, J = 12.0 Hz), charged 8.52 (1H, d, J = 8.0 Hz).

MAV>.

Found, % : C 70,57; N 5,52; N 15,82.

P R I m e R 33. 3-/1-(2-Methoxycarbonylethyl)-5-hydroxypyrazol-3-yl/-2-phenyl - pyrazolo /1,5 /pyridine receive in accordance with example 5; melting point: 194-196aboutC.

IR (Nujol): 2630, 1730, 1635, 1585 cm-1.

NMR (DMSO-d6, ): 2,49 of $ 2.53 (2H, m) to 3.38 (3H, s), 5,63 (1H, s) to 3.67 (2H, Shir. C), 7,03 (1H, TD, J = 7,0 Hz and 1.5 Hz), 7,31 to 7.62 (7H, m), 8,81 (1H, d, J = 7,0 Hz), 9,84 (1H, s).

Calculated, % : C 64,69; N 5,12; N 15,04.

WITH20H18N4O31/2 H2O.

Found, % : C 64,99; N. Of 5.29; N 14,77.

P R I m e R 34. Sodium hydride (60% , by 43.6 mg) was added to a mixture of 3-(2-oxo-1,2,5,6-tetrahydropyridine-4-yl)-2-phenylpyrazole /1,5 /pyridine (210 mg), methyl acrylate (93,8 mg) and tetrahydrofuran (2.1 ml) under cooling on ice. The reaction mixture was stirred at room temperature for 1.5 hours Then the mixture was added a saturated solution of sodium chloride (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined extract was washed with a saturated solution of sodium chloride (20 ml), dried in the presence of magnesium sulfate and evaporated and vacuum. The residue is purified column chromatography on silica gel using a mixture of chloroform and ethyl acetate as eluent (10: 1) to obtain 3-/-(2-tx2">

IR (film): 1730, 1640, 1600, 1515 cm-1.

NMR (CDCl3, ): to 2.41 (2H, t, J 6.5 Hz), 2,69 (2H, t, J = 6.5 Hz), 3,47 (2H, t, J = 6.5 Hz), of 3.69 (3H, s), and 3.72 (2H, t, J = 6.5 Hz), of 6.20 (1H, s), 6,85 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,19-7,74 (7H, m), 8,48 (1H, d, J = 7,0 Hz).

Mass spectrum: 375 (M+).

P R I m e R 35. 3-/2-(2-Methoxycarbonylethyl)-3-oxo-2,3, 4,5-tetrahydropyrimidin-6-yl/-2 - phenylpyrazole/1,5 / pyridine receive in accordance with the same method of example 34.

IR (film): 1730, 1670 cm-1.

P R I m e R 36. A mixture of 3-/2-(3-ethoxycarbonylphenyl)-3-oxo-2,3-dihydropyrido - Zin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (13,7 g) and sodium hydroxide (2,73 g) in a mixture of water (8.6 ml) and methanol (96 ml) was heated under reflux for 2 hours, then the solvent evaporated in vacuum. The residue is dissolved in water and the aqueous layer was acidified with hydrochloric acid, then extracted with chloroform. The extract is dried in the presence of magnesium and the solvent evaporated in vacuum. The residue is recrystallized from a mixture of ethanol and n-hexane to obtain 3-/2-(3-carboxypropyl)-3-oxo-2,3-dihydropyri - datin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (9,48 g); melting point: 240-240,5aboutC (EtOH).

IR (Nujol): 1710, 1635, 1560, 1530, 1500 cm-1.

NMR (DMSO-d

Mass spectrum (M+): 374.

Calculated, % : C 67,37; N Is 4.85; N 14,96.

WITH21H18N4O3.

Found, % : C 67,10; N 4,91; N 14,94.

P R I m e R 37. Sodium salt of 3-/2-(3-carboxypropyl)-3-oxo-2,3-dihydropyri - datin-6-yl/-2-phenylpyrazole/1,5 /pyridine is obtained from the corresponding free compounds (example 36) in accordance with the traditional way; melting point: 114-116aboutC;

IR (Nujol): 1660, 1585 cm-1.

NMR (DMSO-d6, ): a 2.01 (4H, m), is 4.15 (2H, t), at 6.84 (1H, d, J = 9.0 Hz), 7,00-to 7.09 (2H, m), 7,39-7,62 (6N, m) of 7.97 (1H, J = 8.0 Hz), 8,79 (1H, d, J = 7,0 Hz).

P R I m e R 38. 3-/2-(4-Ethoxycarbonylbutyl)-3-oxo-2,3-dihydropyridin-6-yl/ -2-phenylpyrazole/1,5 /pyridine receive in accordance with the same method of example 26.

IR (film): 1725, 1655, 1590 cm-1.

NMR (CDCl3, ): a 1.25 (3H, t, ) = 7,0 Hz), 1,74-2,02 (4H, m), is 2.41 (2H, t, J = 7.0 Hz), of 4.13 (2H, q, J = 7.0 Hz), 4,32 (2H, t, J = 7.0 Hz), 6.87 in (1H, d, J = 8.0 Hz), 7,02-7,07 (2H, m), 7,40-7,65 (6N, m), with 8.05 (1H, d, J = 9 Hz), total of 8.74 (1H, d, J = 7,0 Hz).

P R I m e R 39. 3-/2-(4-Carboxybutyl)-3-oxo-2,3-dihydropyridin-6-yl/-2-Fe - elpirata /1,5 /pyridine receive in accordance with the method of example 36; melting point: 182-183aboutThe n, t, J = 6.0 Hz), 6,79 (1H, d, J 10.0 Hz), 6,91 (1H, t, J = 6.0 Hz), 7,01 (1H, d, J = 10.0 Hz), 7,26-7,63 (6N, m) of 7.97 (1H, d, J = 9.0 Hz), 8,54 (1H, d, J = 7,0 Hz),

P R I m e R 40. Sodium salt of 3-/2-(4-carboxybutyl)-3-oxo-2,3-dihydropyrido - Zin-6-yl/-2-phenylpyrazole /1,5 /pyridine is obtained from the corresponding free compounds (example 39) in accordance with the traditional way; melting point: 244-245aboutC.

IR (Nujol): 1660, 1650, 1570 cm-1.

NMR (DMSO-d6, ): 1,38-to 1.60 (2H, m), 1,62 of-1.83 (2H, m), with 1.92 (2H, t, J = 7.0 Hz), 4,11 (2H, t, J = 7.0 Hz), 6,85 (1H, d, J = 10.0 Hz),? 7.04 baby mortality-to 7.09 (2H, m), 7,42-to 7.61 (6N, m), 7,95 (1H, d, J = 8.0 Hz), 8,81 (1H, d, J = 7,0 Hz).

P R I m e R 41. A mixture of 3-(3-cyano-2-oxo-1,2-dihydropyridines-5-yl)-2-Fe - Nile-pyrazolo/1,5 /pyridine (0,60 g) and 85% potassium hydroxide (0,38 g) in 67% aqueous solution of ethanol (6 ml) is heated under reflux for 4 hours After cooling, the reaction mixture is poured on ice (12 g) and acidified with 5% hydrochloric acid. The precipitates is collected and recrystallized from a mixture of 11.11-dimethylformamide and water (twice) to give 3-(3-carboxy-2-oxo-1,2-dihydropyridines-5-yl)-2-Panalpina - gold/ 1,5 /pyridine (0.36 g); melting point: 335-336aboutC.

IR (Nujol): 1700, 1630, 1585, 1535 cm-1.

NMR (DMSO-d6, ): 6,98 (1H, t, J = 7.0 Hz), UP>), 287.

Calculated, % : C 68,88; N. Of 3.95; N 12,68.

WITH19H13N3O3< / BR>
Found, % : C 68,58, N 3,99; N 12,63.

P R I m e R 42. A mixture of 3-/1-(2-methoxycarbonylethyl)-2-oxo-1,2,5,6-tetrahydrate - ridin-4-yl/-2-phenylpyrazole/1,5 /pyridine (440 mg), 1 n aqueous solution of sodium hydroxide (3 ml) and methanol (4 ml) is heated under reflux for 1.5 hours, the Methanol is evaporated in vacuo and to the residue was added water (20 ml). The aqueous solution acidified with 5% hydrochloric acid and the precipitates are collected by filtration, washed with water and then with petroleum ether (5 MSL). The precipitates is recrystallized from 95% ethanol to obtain crystals of 3-/1-(2-carboxyethyl)-2-oxo-1,2,5,6-tetrahydropyridine-4 - yl/-2 - phenylpyrazole/1,5 /pyridine (220 mg); melting point: 182-184aboutC.

IR (Nujol): 1735, 1640, 1585 cm-1.

NMR (CDCl3, ): to 2.42 (2H, t, J = 6.5 Hz), is 2.74 (2H, t, J = 6.5 Hz), 3,49 (2H, t, J = 6.5 Hz), to 3.73 (2H, t, J = 6.5 Hz), to 6.22 (1H, s), 7,20-7,74 (8H, m), 8,49 (1H, d, J = 7,0 Hz).

P R I m e R 43. A mixture of 3-/2-(2-methoxycarbonylethyl)-3-oxo-2,3,4,5-tetrahydrate - ridazin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (484 mg), 1 N. aqueous solution of sodium hydroxide (2.1 ml) and methanol (5 ml) was stirred at room temperature for 1 h Methanol upar is tracerout chloroform (20 ml x 2). The combined extracts washed with saturated aqueous sodium chloride (20 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel using a mixture of chloroform and methanol (30: 1) as eluent, obtaining 3-/2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydropyridine-6 - yl/-2-phenylpyrazole-/1,5 /pyridine (198 mg) as oil. This free acid was dissolved in a mixture of 1 N. aqueous solution of sodium hydroxide (0,547 mg) and ethanol (3 ml) and the solvent evaporated in vacuum. The residue is ground to powder using 95% ethanol, collected by filtration, washed with acetone and dried to obtain a powder of sodium salt 3-/2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydropyrido - Zin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (129 mg).

IR (Nujol): 1640, 1560, 1510 cm-1.

NMR (D2O ): 2,04 (4H, in), 2.25 (2H, t, J = 7.5 Hz), 3,71 (2H, t, J = 7.5 Hz), of 6.71 (1H, t, J = 7.0 Hz), was 7.08-7.23 percent (6N, m), 7,63 (1H, d, J = = 9,0 Hz), of 8.06 (1H, d, J = 7,0 Hz).

Calculated, % : C 54,79; N A 5.25; N 12,99.

WITH20H17NaN4O33H2O.

Found, % : C 55,46, N 4,71, N 12,71.

P R I m e R 44. A mixture of 3-/1-(2-methoxycarbonylethyl)-5-hydroxypyrazol-3-yl/-2 - phenylpyrazole /1,5 /pyridine (0.50 g), 1 n aqueous solution of hikooki who headed the remainder of acidified with 5% hydrochloric acid and extracted with chloroform (25 ml x 2). The combined extract was washed with saturated aqueous sodium chloride (25 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel using a mixture of chloroform and methanol (30: 1) as eluent and is recrystallized from ethanol to obtain crystals of 3-/1-(2-carboxyethyl)-5-hydroxypyrazol-3-yl/-2 - phenylpyrazole/1,5 /pyridine (141 mg); melting point: 211-213aboutC.

IR (Nujol): 1705, 1610 cm-1.

NMR (CDCl3, ): 2,11 (2H, Shir. C) to 3.89 (2H, Shir. C) of 5.83 (1H, s) 6,91 (1H, t, J = 6.0 Hz), 7.23 percent-7,71 (7H, m), 8,54 (1H, d, J = 6.0 Hz).

Calculated, % : C 65,51; N 4,63; N 16,08.

WITH19H16N4O3.

Found, % : C 65,10; H 4,60, N 16,16.

P R I m e R 45. 3-(3-carboxy-2-oxo-1,2-dihydropyridines-5-yl)-2-phenyl-pyrazolo/1,5 /pyridine (120 mg) is melted using an electric hot plate at a temperature of 370aboutC. Then, this compound is dissolved in a mixture of chloroform (26 ml) and methanol (13 ml), after which the mixture was added silica gel (1 g) and charcoal (0.2 g) and carry out the filtering mixture. The solvent of the filtrate is removed and implement chromatography on silica gel (3 g) using a mixture of chloroform, methanol izbivaut from ethyl acetate to obtain 3-(2-oxo-1,2-dihydropyridines-5-yl)-2-phenylpyrazole/1,5 /pyridine (30 mg); melting point: 222-224aboutC.

IR (Nujol): 1665, 1630 cm-1.

NMR (DMSO-d6,) grades: 6.39 (1H, d, J = 9,2 Hz), of 6.96 (1H, t, J = 6.0 Hz), 7.23 percent-7,65 (N, m), 8,73 (1H, d, J = 7,0 Hz), 11,75 (1H, Shir. C).

Mass spectrum: 287 (M+), 258, 231.

Calculated, % : C 73,70; N 4,70, N 14,34.

WITH18H13N3O) 1/3 H2O.

Found, % : C 73,88; N A 4.53; N 14,16.

P R I m e R 46. A mixture of 3-(3-chloro-1-etoxycarbonyl-1,4-dihydropyridin-4-yl)-2 - phenylpyrazole/1,5 /pyridine (1.26 g), manganese oxide (IV) (12,6 g) and chloroform (12,6 ml) is heated under reflux for 10 hours After filtration the organic layer is dried in the presence of magnesium sulfate. The solvent is removed and chromatography carried out on silica gel (12,6 g) using a mixture of hexane and ethyl acetate as eluent. The fractions containing the target compound are pooled and evaporated in vacuum and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3-(3-chloropyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine (0,78 g); melting point: 208-210aboutC.

IR (Nujol): 1635, 1570 cm-1.

NMR (CDCl3, ): 6,94 (1H, dt, J = 1.6 Hz and 6.7 Hz), 7,25-7,49 (8H, m), 8,58 (1H, DDD, J = 0,96 Hz, 0,96 Hz and 7.0 Hz), 9,06 (1H, d, J = 4,9 Hz).

Mass spectrum: 306 (M+), : 66,96; N 3,63; N 18,31.

P R I m e R 47. A mixture of 3-(1-etoxycarbonyl-3-acetyl-1,4-dihydropyridines-4-yl)-2-phenylpyrazole/ 1,5 /pyridine (2.20 g), tert-butoxide potassium (3,19 g) and tert-butanol (22 ml) is heated under reflux for 1 hour and 30 minutes the Solvent is removed and the residue extracted with methylene chloride. The combined extract is washed with water and saturated aqueous sodium chloride and dried in the presence of magnesium sulfate. The solvent is evaporated in vacuum. The residue is subjected to chromatography on silica gel (12 g) using a mixture of n-hexane and ethyl acetate (4: 1) as eluent. The fractions containing the target compound are pooled and the solvent evaporated in vacuum. Recrystallization from a mixture of ethyl acetate and n-hexane leads to the production of 3-(3-acetylpyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine (0.52 g); melting point: 159-161aboutC.

IR (Nujol): 1690, 1630 cm-1.

NMR (CDCl3, ): 1,94 (3H, s), 6,83 (1H, t, J = 7.5 Hz), 7,17 (1H, t, J = 7.5 Hz), 7,20-7,53 (7H, m), and 8.50 (1H, d, J = 7.5 Hz), 8,65 (1H, d, J = 5.0 Hz), 8,80 (1H, s).

Mass spectrum: 313 (M+), 298, 242, 210.

Calculated, % : C 76,66; N 4,82; N 13,41.

WITH20H15N3O.

Found, % : C 76,34; N. Of 5.48; N 13,17.

P R I m e R 48. 3-(3-Cyano-4-yl)-2-who.

IR (Nujol): 2220, 1630, 1585 cm-1.

NMR (CDCl3, ): to 6.80 (1H, t, J = 7.5 Hz), 7,07-the 7.43 (8H, m), 8,43 (1H, d, J = 7.5 Hz), 8,53 (1H, d, J = 5.0 Hz), 8,77 (1H, s).

Mass spectrum: 296 (M+), 270.

Calculated, % : C 77,01; N 4,08; N 18,91.

WITH19H12N4.

Found, % : C 77,30; N 4,17; N 19,02.

P R I m e R 49. A mixture of 3-/2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2-phenylpyrazole/ 1,5 /pyridine (0.36 g), methylene chloride (4 ml) and thionyl chloride (0,08 ml) is stirred for 30 min at room temperature, then re-added thionyl chloride (0,08 ml) and stirring is continued for 60 min at room temperature. The reaction mixture is evaporated. The residue is dissolved in acetone (3 ml), slowly added to aqueous ammonia solution (6 ml), stirring at room temperature. After 20 minutes the reaction mixture is evaporated and carry out the addition of water (3 ml). The precipitates are collected by filtration and recrystallized from ethanol to obtain 3-/2-(2-carbarnoyl-ethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine (0.24 g); melting point: 215-215,5aboutC.

IR (Nujol): 3450, 3330, 3210, 1660, 1595, 1535 cm-1.

NMR (CDCl3, ): 2,89 (2H, t, J = 7.0 Hz), 4,58 (2H, t, J = 7.0 Hz), 5,20-the ceiling of 5.60 (1H, s), 6,00-6,50 (1H, s), 6,70 the range: (M+): 359.

Calculated, % : C 66,84; N. Of 4.77; N 19,49.

WITH20H17N5O2.

Found, % : C 67,11; N 5,01; N 19,65.

The following compounds (examples 50 and 51) are obtained in accordance with the same method of example 49.

P R I m e R 50. 3-/2-(2-N, N-Dimethylcarbamoyl)-3-oxo-2,3-dihydropyridin-6-yl /-2-phenylpyrazole/1,5 /pyridine; melting point: 144-145aboutC.

IR (Nujol): 1665, 1640, 1590, 1530 cm-1.

NMR (CDCl3, ): of 2.97 (2H, t, J = 8.0 Hz), 2,98 (3H, s), 3,03 (3H, s), br4.61 (2H, t, J = 8.0 Hz), to 6.75 (1H, d, J = 10.0 Hz), 6,93 (1H, TD, J = 6.0 Hz and 1.0 Hz), 7,02 (1H, d, J = 10 Hz), 7,26-8,64 (6N, m), 8,08 (1H, d, J = 8.0 Hz), charged 8.52 (1H, d, J = 7,0 Hz).

Mass spectrum (M+): 387.

Calculated, % : C 68,20; N 5,46; N 18,08.

WITH22H21N5O2< / BR>
Found, % : C 68,60; N 5,67; N 18,04.

P R I m e R 51. 1-/ -{ 6-(2-Phenylpyrazole/1,5 /pyridine-3-yl)-3-oxo-2,3-dihydropyridin-2-yl} propionyl/piperidine; melting point: 65 to 70aboutC.

IR (Nujol): 1660, 1630, 1585, 1520 cm-1.

NMR (CDCl3, ): 1,58-1,76 (6N, m), 2,96 (2H, t, J = 8.0 Hz), 3,49 (4H, d, J 32 Hz), br4.61 (2H, t, J = 8.0 Hz), to 6.75 (1H, d, J = 10.0 Hz), 6,94 (1H, TD, J = 7.0 Hz and 1.0 Hz), 7,02 (1H, d, J = 10.0 Hz), 7,26-7,63 (6N, m), 7,68 (1H, d, J = 8.0 Hz), 8,53 (1H, d, J = 7,0 Hz).

Mass spectrum: 427 (M+).

P R I m e R 52. To a mixture of 3-(2-aminopyrimidine-5-yl)-2-phenylpyrazole/1,5 /pyridine (0,70 g) and 50% sulfuric acid (5.6 ml) is gradually added an aqueous solution (5.6 ml) of sodium nitrite (1.68 g) at a temperature of from 5 to 10aboutC, and the resulting mixture stirred for 3 h at the same temperature and then for 2 h at room temperature. In the reaction mixture are added water (14 ml). The precipitate is collected by filtration, subjected to column chromatography on silica gel (14 g) using a mixture of chloroform and methanol (10: 1) as eluent. The fractions containing the target compound are pooled, and the solvent evaporated in vacuo to obtain 3-(2-oxo-1,2-dihydropyrimidin-5-yl)-2 - phenylpyrazole/1,5 /pyridine (0,44 g); melting point: 324-326aboutC (decomposition).

IR (Nujol): 3200-2300, 1720, 1700, 1645, 1625 cm-1.

NMR (DMSO-o6, ): 6,93 (1H, t, J = 7.5 Hz), 7,27 (1H, t, J = 7.5 Hz), 7,33-7,70 (6N, m), 8,15 (2H, s), is 8.75 (1H, d, J = 7.5 Hz).

Mass spectrum: 288 (M+), 260, 246, 218.

P R I m e R 53. 3-(2-Oxo-1,2-dihydropyrimidin-4-yl)-2-phenylpyrazole/1,5 / pyridine receive in accordance with the same method of example 52, melting point; 287-289aboutC.

IR (Nujol): 1640, 1610 cm-1.

IR (DMSO-d6, ): 5,91 (1H, d, J = 6.6 Hz), 7.18 in -1), 259, 244.

Calculated, % : C 68,68, N To 4.41; N 18,84.

WITH17H12N4O 1/2 H2O

Found, % : C 68,48; H 4,24; N 18,51.

P R I m e R 54. A mixture of 3-(2-oxo-1,2-dihydropyridines-4-yl)-2-phenylpyrazole/1,5 /pyridine (0.6 g) and the acid chloride phosphoric acid (1.8 ml) is stirred at a temperature of 70aboutC for 6 hours After cooling, the reaction mixture is poured on ice (30 g) and make alkaline with 24% aqueous sodium hydroxide solution (pH 10) and extracted with chloroform (18 ml). The combined extract is washed with water and aqueous sodium chloride solution and dried in the presence of magnesium sulfate. The solvent is removed in vacuo and the residue chromatographic on silica gel (12 g) using chloroform as eluent. The fractions containing the target compound are pooled and evaporated in vacuum and recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 3-(2-chloropyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine (0.21 g); melting point: 167-168aboutC.

IR (Nujol): 1630, 1590, 1530 cm-1.

NMR (CDCl3, ): 6,91 (3H, t, J = 6.8 Hz), to 7.15 (1H, DD, J = 1.5 Hz and 5.2 Hz), 7,25-7,69 (6N, m), 8,32 (1H, DD, J = 0.5 Hz and 5.2 Hz), 8,54 (1H, DD, J = 1.0 and 6.0 Hz).

Mass spectrum: 305 (M+), 270, 243.

Calc

P R I m e R 55. 3-(2-Chloropyrimidine-4-yl)-2-phenylpyrazole/1,5 /pyridine receive in accordance with the same method of example 54; melting point: 181-182aboutC.

IR (Nujol): 1630, 1570, 1530 cm-1.

NMR (DCl3, ): 6,92 (1H, d, J = 5.5 Hz), 7,02 (1H, dt, J = 1.3 Hz and 6.9 Hz), 7,43-7,62 (6N, m) 8,23 (1H, d, J = 5.4 Hz), 8,55 (1H, d, J = 6.9 Hz), 8,64 (1H, d, J = 9.0 Hz).

Mass spectrum: 306 (M+): 271, 244, 217.

Calculated, % : 66,56; N 3,61 N 18,26.

C17H11ClN4.

Found, % : C To 66.30; H 3,52; N 18,59.

P R I m e R 56. A mixture of 3-(3-oxo-2,3-dihydropyridin-6-yl)-2-Panalpina - gold/1,5 /pyridine (2.91 in g) and the acid chloride phosphoric acid (10 ml) is heated under reflux for 1 h acid chloride phosphoric acid evaporated in vacuum. The residue is neutralized with saturated aqueous solution of acid sodium carbonate and extracted with chloroform (30 ml x 3). The combined extract was washed with saturated aqueous sodium chloride (20 ml) and dried in the presence of magnesium sulfate. The solvent is evaporated in vacuum and the residue proscout ethanol, collected by filtration, washed with ethanol and dried to obtain crystals of 3-(3-chloropyridin-6-yl)-2-phenylpyrazole-/1,5 /pyridine (2,42 g); melting point: 208-211aboutC. what C), 7,47-7,60 (6N, m), 7,78 (1H, d, J = 9.0 Hz), 8,16 (1H, d, J = 9.0 Hz), 8,87 (1H, d, J = 7,0 Hz).

Calculated, % : C 63,65; N. Of 3.53; N 17,22.

WITH17H11ClN4.

Found, % : C 63,14; H 3,48; N 17,29.

P R I m e R 57. A mixture of 3-(3-chloropyridin-6-yl)-2-phenylpyrazole/1,5- /-pyridine (1,00 g) and a solution of dimethylamine in methanol (30 ml) is heated under reflux for 8.5 hours, the Methanol is evaporated in vacuum and the residue is dissolved in chloroform (50 ml). A solution of chloroform extracted with 10% hydrochloric acid (50 ml x 2). The aqueous layer was neutralized with potassium carbonate and extracted with chloroform (30 ml x 2). The combined extract was washed with saturated aqueous sodium chloride (30 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is recrystallized from ethanol to obtain crystals of 3-(3-N, N-dimethylaminopyridine-6-yl)-2-Fe - elpirata/1,5 /pyridine (421 mg); melting point 190-194aboutC.

IR (Nujol): 1630, 1605, 1550, 1530 cm-1.

NMR (DMSO-d6, ): 3,13 (6N, (6N, (C), 6,99-7,07 (3H, m), 7,31-to 7.59 (6N, m) of 7.96 (1H, d, J = 9.0 Hz), 8,79 (1H, d, J = 6.0 Hz).

Calculated, % : C 72,36; N 5,43; N 22,21.

WITH19H17N5.

Found, % : C 72,50; N 5,33; N 22,16.

P R I m e R 58. To 28% of the resultant methyl is heated under reflux for 1 h and evaporated in vacuum. The residue is dissolved in chloroform (20 ml). Chloroformyl the solution washed with water (5 ml) and saturated aqueous sodium chloride (5 ml) and dried in the presence of magnesium sulfate. The solvent is removed and implement chromatography on silica gel (10 g) using n-hexane-ethyl acetate as eluent. The fractions containing the target compound are pooled, evaporated in vacuum and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3-(3-methoxypyridine-4-yl)-2-phenylpyrazole/1,5 /piridin (0,30 g); melting point: 180-182aboutC.

IR (Nujol): 1630, 1580, 1510 cm-1.

NMR (CDCl3, ): of 3.97 (3H, s), 6.89 in (1H, dt, J = 1.4 Hz and 6.4 Hz), 7,20-7,52 (8H, m), 8,55 (1H, d, J = 6.9 Hz), 8,79 (1H, d, J = 4,8 Hz).

Mass spectrum: 302 (M+), 279.

Calculated, % : C 71,51; N. Of 4.67; N 18,53.

WITH18H14N4O.

Found, % : C 71,45; N To 4.68; N 18,63.

The following compounds (examples 59 and 60) are obtained in accordance with the same method of example 58.

P R I m e R 59. 3-(2-Methoxypyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 130-132aboutC.

IR (Nujol): 1600, 1530 cm-1.

NMR (CDCl3, ): of 3.96 (3H, s), 6,80-to 6.88 (2H, m), 7,19 (1H, dt, J = 1.0 Hz and 6.8 Hz), 7.36-7,39 (3H, m), EUR 7.57-to 7.67 chileno, % : 75,73; N 5,02; N 13,94.

C19H15N3O.

Found, % : C 75,72; N Equal To 4.97; N 13,78.

P R I m e R 60. 3-(2-Methoxypyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine: melting point: 156,5-157aboutC.

IR (Nujol): 1620, 1570 cm-1.

NMR (CDCl3, ): 4,08 (3H, s) 6,70 (1H, d, J = 5.4 Hz), 6,69 (1H, dt, J = 1.4 Hz and 6.8 Hz), 7,34-to 7.64 (6N, m), by 8.22 (1H, d, J = 5.4 Hz), 8,55 (2H, m).

Mass spectrum: 301 (M+)-+), 271, 243.

Calculated, % : C 71,51; N. Of 4.67; N 18,53.

WITH18H14N4O.

Found, % : C 71,44; N To 4.68; N 18,47.

P R I m e R 61. A solution of sodium methylate in methanol (28% , 411 mg) was added to a mixture of 3-(3-chloropyridin-6-yl)-2-phenylpyrazole-/1,5 /pyridine (436 mg) and methanol (4 ml) at room temperature. The reaction mixture is heated under reflux for 3 hours After evaporation of the solvent in vacuum, to the residue was added a saturated aqueous solution of sodium chloride (20 ml) and extracted with chloroform (20 ml x 3). The combined extract was washed with saturated aqueous sodium chloride (20 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel (10 g) using chloroform as eluent and paracrystalline; 03-205aboutC.

IR (Nujol): 1625, 1600 cm-1.

NMR (CDCl3): 4,18 (3H, s), is 6.78 (1H, d, J = 9.0 Hz), make 6.90 (1H, TD, J = 8.0 Hz and 2.0 Hz), to 7.15 (1H, d, J = 9.0 Hz), 7,25 to 7.62 (6N, m), at 8.36 (1H, DD, J = 9,0 Hz and 1.0 Hz), 8,53 (1H, DD, J = 7.0 Hz and 1.0 Hz).

Calculated, % : C 71,51; N. Of 4.67; N 18,53.

C18H14N4O.

Found, % : C 71,13; N The 5.65; N 18,48.

P R I m e R 62. Concentrated hydrochloric acid (5 ml) was added to 3-(3-methoxypyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine (0.50 g) and heated under reflux for 2 hours and 30 minutes. After cooling, to the reaction mixture was added water (10 ml). The precipitate is collected by filtration to obtain 3-(3-oxo-2,3-dihydropyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine (0,41 g).

IR (Nujol): 1640, 1600, 1530 cm-1.

NMR (DMSO-d6, ): 7,01 (1H, t, J = 6.8 Hz), 7,22 (1H, d, of 4.1 Hz), 7,28-to 7.61 (7H, m), to 7.84 (1H, d, J = 4,1 Hz), 8,78 (1H, d, J = 6.9 Hz), of 13.18 (1H, Shir. C).

Mass spectrum: 288 (M+), 261, 231.

Calculated, % : C 70,82; N 4,20; N 19,43.

WITH17H12N4O.

Found, % : C 70,87; N 4,15; N Fall Of 19.88.

P R I m e R 63. To ethanol (21 ml) solution of 3-(3-methylpyridazin-4-yl)-2-phenylpyrazole/1,5 /pyridine (0,42 g) was added 20% (the ratio of mass to volume) ethanol solution chlorite is teaching 3-(3-methylpyridazin-4-yl)-2-phenylpyrazole/1,5 /pyridinoline (0,23 g); melting point: 197-201aboutC (decomposition).

IR (Nujol): 2700-2150, 2080-1980, 1625, 1605 cm-1.

NMR (DMSO-d6/D2O ): 2,30 (3H, s), 7,10 (1H, t, J = 7.5 Hz), 7,37 (lH, t, J = 7.5 Hz), 7,40-to 7.67 (6N, m), 8,10 (1H, d, J = 5.0 Hz), 8,82 (1H, d, J = 7.5 Hz), of 9.30 (1H, d, J = 5.0 Hz).

Mass spectrum: 286 (M+-HCl), 257, 242, 218.

Calculated, % : C 66,98; N To 4.68; N 17,36.

WITH18H14N4HCl.

Found, % : C 66,26; N 5,09; N 16,82.

P R I m e R 64. A mixture of 3-(3-methylpyridazin-4-yl)-2-phenylpyrazole/1,5 /-pyridine (0.40 g), chloral hydrate (0,70 g) and pyridine (4 ml) is stirred for 20 hours at a temperature of 90-100aboutC. After cooling, to the reaction mixture was added methylene chloride (4 ml) and water (4 ml) at room temperature, then stirred for 3 hours, the Precipitates are collected by filtration to obtain 3-/3-(2-hydroxy-3,3,3-trichloropropane)-pyridazin-4-yl/-2-phenyl-pyrazolo /1,5 /pyridine (0.26 g); melting point: 206-207aboutC.

IR (Nujol): 3400-2900, 1625 cm-1.

NMR (CDCl3, ): 2,70-of 3.60 (2H, m), 4,50-and 5.30 (1H, m), to 6.80 (1H, t, J = 7.5 Hz), 7,13-7,40 (8H, m), 7,45 (1H, d, J = 7.5 Hz), of 9.02 (1H, d, J = 6.0 Hz).

Mass spectrum: 434 (M+), 397, 361, 326, 286.

P R I m e R 65. To an ethanol (12 ml) solution of 3-/3-(2-hydroxy-3,3,3-trichloropropane)pyridazin-4-Óle: 227-229aboutC (decomposition).

IR (Nujol): 3100, 2550, 1930, 1700, 1630 cm-1.

Mass spectrum: 342 (M+), 297, 257, 195.

NMR (DMSO-d6, ): 6,77 (1H, d, J = 16.5 Hz), 7,06 (1H, t, J = 7.5 Hz), 7,22 (1H, d, J = 16.5 Hz), 7,34-of 7.55 (7H, m), of 7.70 (1H, d, J = 6.0 Hz), with 8.33 (1H, d, J = 8.5 Hz), the 9.25 (1H, q, j 6.0 Hz), 11,8-of 12.8 (1H, Shir. C).

The following compounds (examples 66-74) receive, in accordance with the same method of example 1 and example 2.

P R I m e R 66. 3-(3-Chloropyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 208-210aboutC.

IR (Nujol): 1635, 1570 cm-1.

P R I m e R 67. 3-(3-Acetylpyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 159-161aboutC.

IR (Nujol): 1690, 1630 cm-1.

P R I m e R 68. 3-(3-Cyano-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point 208-210aboutC.

IR (Nujol): 2220, 1630, 1585 cm-1.

P R I m e R 69. 3-(2-Chloropyridin-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 167-168aboutC.

IR (Nujol): 1630, 1590, 1530 cm-1.

P R I m e R 70. 3-(3-Chloropyridin-6-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 208-211aboutC.

IR (Nujol): 1630, 1575, 1530 cm-1.

P R I m e R 71. 3-(3-Methoxypyridine-4-yl)-2-phenylpyrazole/1,5 - a /2. 3-(2-Methoxypyridine-4-yl)-2-phenylpyrazole/1,5 /pyridine.

P R I m e R 73. 3-(3-Methoxypyridazine-6-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 203-205aboutC.

IR (Nujol): 1625, 1600 cm-1.

P R I m e R 74. 3-(3-Methylpyridazin-4-yl)-2-phenylpyrazole/1,5 /pyridine hydrochloride; melting point: 197-201aboutC (decomposition).

IR (Nijol): 2700-2150, 2080-1980, 1625, 1605 cm-1.

The following compounds (examples 75-89) receive, in accordance with the same method of example 5.

P R I m e R 75. 3-/2-(2-Carboxyethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2-phenyl - pyrazolo /1,5 /pyridine; melting point: 155,5-156aboutC.

IR (Nujol): 1835, 1640, 1570, 1520, 1490 cm-1.

P R I m e R 76. 3-(1-Methylpyrazole-4-yl)-2-phenylpyrazole/1,5 /pyridine; melting point: 100-103aboutC.

IR (Nujol): 1630 cm-1.

P R I m e R 77. 3-/2-(3-Carboxypropyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine; melting point: 240-240,5aboutC.

IR (Nujol): 1710, 1635, 1560, 1530, 1500 cm-1.

P R I m e R 78. 3-/2-(4-Carboxybutyl)-3-oxo-2,3-dihydropyridin-6-yl/2 - phenylpyrazole/1,5 /pyridine; melting point: 182-183aboutC.

IR (Nijol): 1710, 1640, 1570, 1530, 1500 cm-1the temperature of the melting point: 182-184aboutC.

IR (Nujol): 1735, 1640, 1585 cm-1.

P R I m e R 80. Sodium salt of 3-/2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydrate - ridazin-6-yl/ -2-phenylpyrazole/1,5 /pyridine.

IR (Nujol): 1640, 1560, 1510 cm-1.

P R I m e R 81. 3-/1-(2-Carboxyethyl)-5-hydroxypyrazol-3-yl/-2-phenylpyrazole- /1,5 /pyridine; melting point: 211-213aboutC.

IR (Nujol): 1705, 1610 cm-1.

P R I m e R 82. 3-/2-(2-Carbamoylethyl)-3-oxo-2,3-dihydropyridin-6-yl/-2 - phenylpyrazole/1,5 /pyridine; melting point: 215-215,5aboutC.

IR (Nujol): 3450, 3330, 3210, 1660, 1595, 1535 cm-1.

P R I m e R 83. 3-/2-(2-N, N-Dimethylcarbamoyl)-3-oxo-2,3-dihydropyridin-6-yl/2-penile understand /pyridine; melting point: 144-145aboutC.

IR (Nujol): 1665, 1640, 1590, 1530 cm-1.

P R I m e R 84. 1-/3-{ 6-(2-Phenylpyrazole/1,5 /pyridine-3-yl)-3-oxo-2,3-dihydropyridin-2-yl} propionyl/piperidine; melting point: 65 to 70aboutC.

IR (Nujol): 1660, 1630, 1585, 1520 cm-1.

P R I m e R 85. 3-/2-(2-Methoxycarbonylethyl)-3-oxo-2,3-dihydropyridin-4-yl/- 2 - phenylpyrazole/1,5 /pyridine; melting point: 136-138aboutC.

IR (Nujol): 1730, 1640, 1600 cm-1.

NMR (CDCl3, ): of 2.92 (2H, t, J = 6.0 Hz), and 3.72 (3H, s), of 4.57 (2H,5, 287.

P R I m e R 86. 3-/1-(2-Methoxycarbonylethyl)2-oxo-1,2-dihydropyrimidin-5-yl/-2 - phenylpyrazole/1,5 /pyridine; melting point: 115-118aboutC.

IR (Nujol): 1730, 1660 cm-1.

NMR (CDCl3, ); of 2.97 (2H, t, J = 6.0 Hz), 3,66 (3H, s) to 4.16 (2H, t, J = 6.0 Hz), PC 6.82 (1H, t, J = 7.5 Hz), 7,21 (1H, t, J = 7.5 Hz), 7,33-7,73 (6N, m), to $ 7.91 (1H, d, J = 4.0 Hz), 8,49 (1H, d, J = 4.0 Hz), charged 8.52 (1H, s).

Mass spectrum: 374 (M+), 332, 288, 272.

P R I m e R 87. 3-/1-(2-Methoxycarbonylethyl)-2-oxo-1,2-dihydropyridines-4-yl/-2 - phenylpyrazole/1,5 /pyridine, melting point: 173-174aboutC.

IR (Nujol): 1740, 1660, 1590 cm-1.

NMR (CDCl3, ): only 2.91 (2H, t, J = 6.3 Hz), of 3.69 (3H, s), is 4.21 (2H, t, J = 6.3 Hz), 5,98 (1H, DD, J = 1.9 Hz and 7.1 Hz), 6,72 (1H, d, J = 1,8 Hz), 6,86 (1H, dt, J = 1.4 Hz and 6.9 Hz), 7,2-7,4 (1H, m, J = 7,0 Hz), and 7.6 to 7.7 (2H, m), 7,74 (1H, d, J = 9.0 Hz), 8,51 (1H, d, J = 7,0 Hz).

Mass spectrum: 373 (M+), 314, 286.

P R I m e R 88. 3-1-(2-Methoxycarbonylethyl)-3-carboxy-2-oxo-1,2-dihydropyri - DIN-5-yl/-2 - phenylpyrazole/1,5 /pyridine; melting point: 185-186aboutC.

IR (Nujol): 1725, 1630, 1560 cm-1.

NMR (CDCl3, ): of 2.92 (2H, t, J = 6.0 Hz), 3,68 (3H, s), or 4.31 (2H, t, J = 6.0 Hz), 6.89 in (1H, t, J = 7.5 Hz), and 7.1 to 7.7 (7H, m), 7,80 (1H, d, J = 3.0 Hz), and 8.50 (1H, d, J = 7.5 Hz), to 8.57 (1H, d, J = 3.0 Hz).

Mass spectrum: 373, 314, 287.

P ur melting point: 155-157aboutC.

IR (Nujol): 2225, 1725, 1660, 1620 cm-1.

NMR (CDCl3, ): 2,90 (2H, t, J = 6.0 Hz), 2.63 in (3H, s), 4,20 (2H, t, J = 6.0 Hz), for 6.81 (1H, t, J = 7.5 Hz), 7,20 (1H, t, J = 7.5 Hz), between 7.4 and 7.7 (7H, m), 7,78 (1H, d, J = 3.0 Hz), 7,49 (1H, d, J = 7.5 Hz).

Mass spectrum: 398 (M+), 312.

The following compounds (examples 90-92) receive, in accordance with the same method of example 6.

P R I m e R 90. 3-/2-(2-Carboxyethyl)-3-oxo-2,3-dihydropyridin-4-yl/-2-phenyl - pyrazolo/ 1,5 /pyridine; melting point: 150-152oC.

IR (Nujol): 1710, 1630, 1590 cm-1.

NMR (CDCl3, ): of 2.97 (2H, t, J = 7.0 Hz), 4,58 (2H, t, J = 7.0 Hz), 6.87 (1H, dt, J = 1.3 Hz and 6.9 Hz), to 6.95 (1H, d, J = 4, 2 Hz), of 7.2 to 7.7 (8H, m), 8,53 (1H, d, J = 6,9 Hz).

Mass spectrum: 360 (M+), 288.

P R I m e R 91. 3-/1-(2-Carboxyethyl)-2-oxo-1,2-dihydropyridines-4-yl/-2 - phenylpyrazole/1,5 /pyridine; melting point: 238-241aboutC.

IR (Nujol): 1700, 1640 cm-1.

NMR (DMSO-d6, ): 2,70 (2H, t, 7.5 Hz), 4,06 (2H, t, J = 7.5 Hz), 6,04 (1H, DD, J = 1.9 Hz and 7.0 Hz), 6,37 (1H, d, J = 1.9 Hz),? 7.04 baby mortality (1H, dt, J = 1.3 Hz and 6.9 Hz), and 7.3 to 7.7 (7H, m), 7,74 (1H, d, J = 8,8 Hz), 8,80 (1H, d, J = 6,9) 12,2-of 12.6 (1H, Shir. ).

Mass spectrum: 358 (M+), 314, 286.

P R I m e R 92. 3-/1-(2-Carboxyethyl)-3-carboxy-2-oxo-1,2-digitope - ridin-5-yl/-2 - phenylpyrazole/1,5 /pyridine; : and 2.83 (2H, t, J = 6.0 Hz), 4,35 (2H, t, J = 6.0 Hz), 6,98 (1H, t, J = 7.5 Hz), 7,2-7,8 (7H, m), 8,03 (1H, d, J = 3.0 Hz), 8,44 (1H, d, J = 3.0 Hz), the rate of 8.75 (1H, DD, J = 7.5 Hz).

Mass spectrum: 403 (M+), 331, 287.

P R I m e R 93. A mixture of 3-/1-(2-methoxycarbonylethyl)-3-cyano-2-oxo-1,2-dihydro - pyridine-5-yl/ -2-phenylpyrazole/1,5 /pyridine (0,46 g) and potassium carbonate (0,92 g) in 80% aqueous ethanol (4.6 ml) is stirred for 6 hours at a temperature of 80aboutC. the Mixture is acidified with 5% hydrochloric acid to pH 2). The resulting precipitates are collected by filtration, washed with water (10 ml) and subjected to column chromatography on silica gel (10 g) using a mixture of chloroform, methanol and acetic acid (40: 4: 1). The fractions containing the target compound are pooled and evaporated in vacuo to obtain 3-/1-(2-carboxyethyl)-3-cyano-2-oxo-1,2-dihydro - pyridine-5-yl/ -2-phenylpyrazole/1,5 /pyridine (0.40 g); melting point: 196-200aboutC.

IR (Nujol): 3400, 2230, 1720, 1660, 1600 cm-1.

NMR (DMSO-d6): 2,69 (2H, t, J = 6.0 Hz), 4,18 (2H, t, J = 6.0 Hz) of 6.99 (1H, t, J = 7.8 Hz), 7,31 (1H, t, J = 7.8 Hz), between 7.4 and 7.7 (5H, m), to 7.77 (1H, d, J = 3.0 Hz), and 7.9 (1H, J = 3.0 Hz), 8,30 (1H, d, J = 3.0 Hz), 8,76 (lH, d, J = 7,8 Hz).

Mass spectrum: 384 (M+), 312.

The following compounds (examples 94-97) receive, in accordance with the same method of the example is="ptx2">

IR (Nujol): 1710, 1630, 1590 cm-1.

P R I m e R 95. 3-/1-(2-Carboxyethyl)-2-oxo-1,2-dihydropyridines-4-yl/-2-penile - rasalo/1,5 /pyridine.

IR (Nujol): 1700, 1640 cm-1.

P R I m e R 96. 3-/1-(2-Carboxyethyl)-3-carboxy-2-oxo-1,2-dihydropyridines-5 - yl/-2 - phenylpyrazole/1,5 /pyridine.

IR (Nujol): 1730, 1690, 1630 cm-1.

P R I m e R 97. 3-/1-(2-Carboxyethyl)-3-cyano-2-oxo-1,2-dihydropyridines-5 - yl/-2-phenylpyrazole/1,5 /pyridine.

IR (Nujol): 3400, 2230, 1720, 1660, 1600 cm-1.

P R I m e R 98. To a mixture of 3-(3-carboxy-2-oxo-1,2-dihydropyridines-5-yl)-2-penile - rasalo/1,5 /pyridine (0,92 g) and powdered potassium hydroxide (0.54 g) is 11.11-dimethylformamide (9 ml) was added 93% methyl iodide (0,64 ml) under cooling in an ice bath (temperature 0-5aboutC) the Mixture is stirred for 3 hours under ice-cooling and then at room temperature for 1 h and diluted with water. The resulting precipitates are filtered off and the filtrate is acidified with 5% hydrochloric acid and extracted with ethyl acetate (20 ml). The extract was washed with water (5 ml) and aqueous solution of sodium chloride (5 ml), then dried in the presence of magnesium sulfate. The solvent is removed and the residue chromatographic on silica gel (12 g) using a mixture which exist in vacuum to obtain 3-(1-methyl-3-methoxycarbonyl-2-oxo-1,2-dihydropyridines-5-yl)- 2-phenylpyrazole/1,5 /pyridine (0.34 g); melting point: 268-270aboutC.

IR (Nujol): 1690, 1670, 1620 cm-1.

NMR (CDCl3, ): of 3.54 (3H, s), 3,86 (3H, s), PC 6.82 (1H, t, J ) 2.5 Hz), 7,18 (1H, t, J = 7.5 Hz), 7,2-7,8 (N, m), 8,18 (1H, s), and 8.50 (1H, d, J = 7.5 Hz).

Mass spectrum: 359 (M+).

P R I m e R 99. A mixture of 2-phenylpyrazole/1,5 /pyridine-3-carbaldehyde (1,00 g), methylacetoacetate (1.10 g) and 14% methanol ammonia (18 ml) in a mixture of methanol (20 ml) and chloroform (10 ml) is stirred for 246 hours at room temperature. The solvent is removed in vacuum and the residue is dissolved in methylene chloride (30 ml). The solution was washed with water (10 ml) and aqueous solution of sodium chloride (10 ml), dried in the presence of magnesium sulfate and evaporated in vacuum. The remainder chromatographic on silica gel (15 g) using a mixture of n-hexane and ethyl acetate (2: 1) as eluent. The fractions containing the target compound are pooled and evaporated in vacuo to obtain 3-/2,6-dimethyl-3,5-bis(methoxycarbonyl)-1,4-dihydro - pyridine-4-yl/-2 - phenylpyrazole/1,5 /pyridine. This compound is purified from a mixture of ethyl acetate and n-hexane; melting point: 183-186aboutC.

IR (Nujol): 3330, 3250, 3120, 1690 cm-1.

NMR (CDCl3): 2,13 (6N, C) 3,37 (6N, (C), 5,19 (1H, Shir. ), the 5.51 (1H, s), 6,69 (1H, t, J = 6.8 Hz), 7,06 (1H, t, J = 6.8 Hz),oceanog means (1). Test the connection.

3-/2-(2-Carboxyethyl)-3-oxo-2,3-Digi - dropyridine-6-yl/-2 - phenylpyrazole/1,5-a/pyridine

Test method.

Used rats males of strain JCL: SD at the age of 6 weeks weighing approximately 200 g after 18-hour fast. Immediately after oral input doses of the test compounds suspended in 0.5% methylcellulose (0.5% of MS), in the body of rats was administered orally physiological saline at 20 ml/kg Rats were placed three pieces in the camera for metabolism studies. Collected urine for six hours. Urinary electrolyte (PA+) was analyzed by the system Stat/R (Rechnichon). Tested three groups of rats three pieces in each group.

3. The results of the test.

Data for urinary electrolyte (Na+) (% , control = 100% ) is presented below.

Dose, mg/kg Na+< / BR>
10,0 244

Test for a diuretic effect (2)

Test the connection.

Sodium salt of 3-/2-(3-carboxypropyl)-3-oxo-2,3-dihydropyridin-6-yl/ -2-phenylpyrazole/1,5-a/pyridine.

Test method.

Used rats males JCL strain SD at the age of 6 weeks, weighing approximately 200 g after fasting for 18 hours. Immediately the village who took oral physiological saline at 20 ml/kg Rats were placed three pieces in the camera for metabolism studies. Collected urine for 6 hours. Urinary electrolyte (PA+analyzed through a system Stat/R (Eechnichon). Tested three groups of rats three pieces in each group.

The results of the test

The value of the ED100(mg/kg) had the following

ED1000,31.

For therapeutic input in the body of the claimed compound 1 and pharmaceutically usable salt, corresponding to this invention, was used in the form of conventional pharmaceutical preparation which contains the compound as an active ingredient in a mixture with a pharmaceutically suitable carriers, such as organic or inorganic solid or liquid excipient suitable for oral, parenteral input and outdoor applications.

The toxicity of the compounds of the invention is low.

The data of comparative tests.

Test method.

Typical representatives of compounds of the present application and the representative compounds of the prior art were tested for diuretic activity in accordance with the same method as in the case of tests on the diuretic and the present application were the following:

(1) 3-[2-(3-ethoxycarbonylphenyl)-3-oxo-2,3-dihydropyridin-6-yl] -2-phenylpyrazole/1,5-a/pyridine/compound of example 26).

(2) 3-[2-(3-carboxypropyl)-3-oxo-2,3-dihydropyridin-6-yl] - 2-phenylpyrazole/1,5-a/pyridine (compound of example 36);

(3) 3-(2-propyl-3-oxo-2,3-dihydropyridin-6-yl/-2-phenylpyrazole/1,5-a/ pyridine (compound of example 29);

(4) 3-[2-(3-hydroxypropyl)-3-oxo-2,3-dihydropyridin-6-yl] - -2-phenylpyrazole/1,5-a/pyridine (compound of example 31).

(5) 3-[2-(2-ethoxyethyl)-3-oxo-2,3-dihydropyridin-6-yl] -2 - phenylpyrazole/1,5-a/pyridine (compound of example 32);

(6) 3-[2-(2-N, N-dimethylcarbamoyl)-3-oxo-2,3-dihydropyridin-6 - yl] -2-phenylpyrazole-/1,5-a/pyridine (compound of example 83).

(7) Sodium salt of 3-[2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydropyridine-6 - yl] -2-phenylpyrazole/1,5-a/pyridine (compound of example 43);

(8) 3-[1-(2-methoxycarbonylethyl)-2-oxo-1,2-dihydropyrimidin-5 - yl] -2-phenylpyrazole/1,5-a/pyridine (compound of example 86).

(9) 3-[1-(2-methoxycarbonylethyl-3-cyano-2-oxo-1,2-dihydropyridines-5 - yl] -2-phenylpyrazole/1,5-a/pyridine (compound of example 89).

As known compounds were used the following connection

(A) 2-phenylpyrazole/1,5-a/pyridine-3-carbonitrile (CLASS="ptx2">

The table shows urinary electrolyte (Na+), the control 100% (each test compound) dose: 10.0 mg/kg

The method of obtaining pyrazolidinone derivative of General formula

R1< / BR>
where R1is phenyl;

R2group of General formula

; ;

; ;

or

where R3- lower alkyl, hydroxy(lower alkyl), lower alkoxy(lower alkyl), carboxy (lower)alkyl, lower (alkoxycarbonyl (lower)alkyl, carbarnoyl(lower)alkyl, or N, N-di(lower)allylcarbamate(lower)alkyl, where two lower alkyl groups at the nitrogen atom can be combined with one another, forming piperidine ring,

R4- carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl;

R5lowest alkoxycarbonyl(lower)alkyl;

R6- lower alkyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl);

R7is hydrogen, carboxy, lower alkoxycarbonyl or cyano;

R8- carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl;

R9- lower alkyl, carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl;

R10is hydrogen or hydroxy,

or its salts, characterized in that the compound of General formula<>SUB>orwhere R7and R10has the specified values;

or its salt, is subjected to reaction with a compound of General formula

QY,

where Q has the values of R3- R8and R9;

Y - deleted group and, if necessary, the resulting compound, where R3- R8and R9each represents a lower alkoxycarbonyl(lower)alkyl, remove lower alkyl group,

obtaining the compounds of formula I, where R3- R8, R9are each carboxy(lower)alkyl, with the separation of the target product in free form or in salt form.

 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 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

FIELD: chemistry of heterocyclic compounds, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine hydrochloride (promedol) used extensively as an analgetic medicinal agent. Method involves reaction of 1,2,5-trimethylpiperidone-4 with aromatic compound of alkaline or earth-alkaline metal that is carried out at temperature from -10°C to -100°C and wherein 1-1.15 mol of aromatic compound of alkaline or earth-alkaline metal, in particular, phenyllithium or phenylmagnesium bromide is used per 1 mol of 1,2,5-trimethylpiperidone-4 followed by two-fold treatment with propionyl chloride. Invention provides enhancing yield of promedol.

EFFECT: improved preparing method.

5 cl, 8 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) given in the invention claim wherein substituted are indicated in the description. Method involves interaction of ketone of the formula (II) given in the invention claim with succinic acid anhydride and alkoxide base to yield compound of the formula (III):

. The latter is subjected for interaction with compound of the formula (IV) given in the invention claim to obtain compound of the formula (V):

and interaction of compound of the formula (V) with alcohol to yield the corresponding ester of the formula (VI):

, and interaction of ester with N-methylhydroxylamine. Invention provides enhancing yield, reducing cost as compared to the known methods.

EFFECT: improved preparing method.

9 cl, 6 ex

FIELD: cosmetic chemistry.

SUBSTANCE: invention relates to compositions for dyeing keratin fibers such as human hair. Composition of invention contains, in dyeing appropriate medium, first oxidizable diaminopyrazole-type base, second monobenzenic, dibenzenic, or heterocyclic oxidizable compound with at least one cationic group Z selected from aliphatic chain optionally substituted by saturated or unsaturated cycle, said group Z being directly linked to at least one benzene cycle or heterocycle of indicated oxidizable base or bound to at least one amino group being substituent of said benzene cycle or heterocycle, or one of addition salts, and coupler. Method for dyeing keratin fibers using indicated composition as well as dyeing kit for implementation of the invention are also described.

EFFECT: expanded dyeing possibilities.

31 cl, 2 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, 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, herbicides, agriculture.

SUBSTANCE: invention describes substituted benzoylcyclohexanediones of the general formula (I):

wherein m = 0 or 1; n = 0 or 1; A means a single bond or alkanediyl (alkylene) with 1-4 carbon atoms; R1 means hydrogen atom or unsubstituted alkyl with from 1 to 6 carbon atoms; R2 means methyl; R3 means hydrogen atom, nitro-, cyano-group, halogen atom, alkyl with from 1 to 4 carbon atoms substituted with halogen atom, alkoxy-group with from 1 to 4 carbon atoms or alkyl sulfonyl with from 1 to 4 carbon atoms; R4 means nitro-group, halogen atom, unsubstituted alkyl with from 1 to 4 carbon atoms of that substituted with halogen atom; Z means heterocycle, and herbicide agent based on thereof. Also, invention describes substituted derivatives of benzoic acid of the general formula (III):

wherein values n, A, R3, R4 and Z are given above. These compounds represent the parent substances used for preparing compound of the formula (I). Compounds of the formula (I) elicit high and selective herbicide activity.

EFFECT: valuable properties of compounds.

7 cl, 8 tbl, 7 ex

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