Method for synthesis of benzo[7,8]azonino[5,4-b]indole, 7,9-etheno-azecino [5,4-b]indole and 7,9-ethano-azecino[5,4-b]indole derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

 

The invention relates to a new method of obtaining compounds with the General formulas I-III IV-VI and VII-IX:

I, IV, VII, X=H, Y=CO2Me

II, V, VIII, X=H, Y=COMe

III, VI, IX, X=Y=CO2Me

The synthesis of similar structure to the compounds described in the following works (.Magnus, M.Giles, R.Bonnert, G.Jonhson and other Sintesis of strychnine and Wieland-Gumlich aldehide. Journal of the American Chemicale Society, 1993, 115(18), 8116-8129):

and in the work (B.Hoefgen, M.Decker, P.Mohr, A.M.Schramm, S.A.F.Rostom and other Dopamin / Serotonin Receptor Ligands.1: SAR Studies on Azecine-type Dopamin Receptor Ligands by Functional Screening at Human Cloned D1D2L, and D5Receptor with a Microplate Reader Based Calcium Assay Lead to a Novel Potent D1/D5Selective Antagonist. Journal Medical Chemistry, 2006, 49, 760-769):

Structural analogues of the obtained compounds are currently used in medicine anti-cancer (cytotoxic) drugs vinblastine and vincristine (Register of medicines of Russia, 2002, 9 s.204-205).

The technical result for the solution of which the invention is directed, is to develop a new method for the synthesis of derivatives of benzo[7,8]asinine[5,4-b]indoles, 7,9-ethenoadenine[5,4-b]indoles and 7.9-ethenoadenine[5,4-b]indoles, which at initial screening showed himself as cytostatic and cytotoxic compounds.

The technical result is achieved at the, the method of obtaining derivatives of benzo[7,8]asinine[5,4-b]indoles, 7,9-ethenoadenine[5,4-b]indoles and 7.9-ethenoadenine[5,4-b]indoles with General structural formulas:

I, IV, VII, X=H, Y=CO2Me

II, V, VIII, X=H, Y=COMe

III, VI, IX, X=Y=CO2Me

is that 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole, the ethyl Bornemann-14-carboxylate (semi-synthetic Vinca alkaloid - Vinpocetine) and methyl (3-α,14-β,16α)-14-hydroxy-14,15-dihydroartemisinin-14-carboxylate (Vinca alkaloid - vincamine) is dissolved in methanol and subjected to interaction with excess methylpropionate, acetylacetone or diethylazodicarboxylate at temperatures from +40 to +50°C, the residue obtained after the reaction and removal of the solvent, crystallized from hexane or a mixture of hexane with ethyl acetate or ether or purified by column chromatography on aluminium oxide.

Thus, the proposed method allows the effect of different alkynes, under mild conditions and without the use of chemically aggressive trichlorethylphosphate and sodium amide to obtain the derivatives of benzo[7,8]asinine[5,4-b]indoles (I-III, 7,9-ethenoadenine[5,4-b]indoles IV-VI and 7.9-ethenoadenine[5,4-b]indoles VII-IX.

The method is as follows. To a solution of 3,8,13,13b-tetrahydro-5H-benzo,2]indolizino[8,7-b]indole or ethyl Bornemann-14-carboxylate or methyl (3-α,14-β,16α)-14-hydroxy-14,15-dihydrohelenalin-14-carboxylate (1 mmol) in methanol add activated alkyne (diethylazodicarboxylate (ADCA) or methylpropionate, or acetylacetone) (1,2-2 mmol) and stirred at 40-50°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil. The reaction time ranges from 20 minutes to 4 hours depending on the type of reagent and the original connection. After the reaction, the solvent is evaporated to dryness, the resulting residue is triturated in cold hexane or mixture of hexane with ethyl acetate (ester) prior to crystallization for I, IV, VII-IX. All other reaction products produce by using column chromatography on silica gel or aluminium oxide, elentari are a mixture of ethyl acetate with hexane different composition. Thus, derivatives of benzo[7,8]asinine[5,4-b]indoles (I-III, 7,9-ethenoadenine[5,4-b]indoles IV-VI and 7.9-ethenoadenine[5,4-b]indoles VII-IX are obtained from 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole, the ethyl Bornemann-14-carboxylate and methyl 14-hydroxy-14,15-dihydrohelenalin-14-carboxylate interaction with alkynes and activated electron-withdrawing substituents, under mild conditions at a temperature of 40-50°C in methanol:

The outputs of the compounds I-IX range from 24 to 82% and depend on the nature of the initial connection and allocation method.

The structure of the obtained compounds was confirmed by mass-SP is chromefree, IR spectroscopy and spectroscopy of the PMR. For compounds III and IV structure further confirmed by x-ray method.

Example 1

To a solution of 0.400 g (1.54 mmol) 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole in 20 ml of methanol was added 0,194 g (2,31 mmol) methylpropionate and stirred at 40°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 1 hour. After the reaction, the solvent is evaporated to dryness, the residue triturated in a mixture of ethyl acetate with hexane, thus there is spontaneous crystallization of compound I in the amount 0,19,

Methyl (E)-3-(14-methoxy-5,6,7,8,13,14-hexahydrobenzo[7,8]asinine[5,4-b]indol-6-yl)-2-propenoate (I): yield 50%, colorless crystals with TPL 215-217°C, IR spectrum (in KBr): 1613, 1681 cm-1. NMR1H (CDCl3, 400 MHz):δ=2.96-3.03 (m, 1H, 5-H), 3.13-3.22 (m, 2H, 8-H), 3.36 (s, 3H, OCH3,), 3.60 (s, 3H, CO2CH3), 3.73-3.82 (m, 2H, 7-CH2), 4.31 (d, 1H, J=15.8 Hz, 5-CH2), 4.92 (USS, 1H, HC=CH-CO2CH3), 5.54 (s, 1H, 14-H), 7.11-7.34 (m, 5H, 1-H, 2-H, 3-H, 4-H, 11-H), 7.36 (d, 1H, J=13.1 Hz,HC=CH-CO2CH3), 7.44 (t, 3H, J=7.9 Hz, 10-H), 7.57 (d, 1H, J=1.9 Hz, 12-H), 7.89 (s, 1H, NH), 7.96 (d, 1H, J=7.9 Hz, 9-H). Mass spectrum m/z: 376 (M+). C23H24N2O3. Calculated: N, 7.44%, found: N, 7.47%.

Example # 2

To a solution 0,500 g (1.92 mmol) 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole in 20 ml of methane is La add 0,196 g (2,88 mmol) acetylacetone and stirred at 40°C. The progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 45 minutes After the end of the reaction the solvent is evaporated to dryness, the residue is placed on a column of aluminum oxide, a mixture of ethyl acetate with hexane 1:5 wash to 0.19 g of compound (II).

(E)-4-(14-methoxy-5,6,7,8,13,14-hexahydrobenzo[7,8]asinine[5,4-b]indol-6-yl)-3-butene-2-he (II): yield 28%, colorless crystals with TPL 125-128°C, IR spectrum (in KBr): 1561, 1652 cm-1.NMR1H (CDCl3, 400 MHz): δ=2.98-3.26 (m, 2H, 8-H), 3.92 (d, 1H, J=14.9 Hz, 5-H), 3.29-3.68 (m, 2H, 7-CH2), 3.35 (c, 3H, COCH3), 4.53 (d, 1H, J=14.9 Hz, 5-CH2), 4.78 (c, 3H, OCH3), 5.00 (d, 1H, J=13.7 Hz, HC=CH-COCH3), 5.59 (c, 1H, 14-H), 7.00-7.32 (m, 6H, 1-H, 2-H, 3-H, 4-H, 11-H andHC=CH-COCH3), 7.47 (t, 3H, J=7.5 Hz, 10-H), 7.57-7.55 (m, 1H, 12-H), 7.84 (c, 1H, NH), 7.95-7.97 (m, 1H, 9-H). Mass spectrum m/z: 360 (M+). C23H24N2O2. Calculated: N 7.77%, found: N 7.79%.

Example # 3

To a solution of 0.400 g (1.54 mmol) 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole in 20 ml of methanol was added 0,327 g (2,31 mmol) of diethylazodicarboxylate (ADCA) and stirred at 40°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 20 minutes After the end of the reaction the solvent is evaporated to dryness, the residue is placed on a column with silica, a mixture of methanol with chlorof ROM 1:50 wash 0.16 g of compound III.

Dimethyl (E)-2-(14-methoxy-5,6,7,8,13,14-hexahydrobenzo [7,8] asinine [5,4-b] indol-6-yl)-2-butenedioate (III): exit 24%, colorless crystals with TPL 210-212°C, IR spectrum (in KBr): 1577, 1692, 1737 cm-1. NMR1H (CDCl3, 400 MHz): δ=3.02 (d, 1H, J=15.8 Hz, 5-H), 3.09-3.29 (m, 2H, 8-H), 3.42 (c, 3H, OCH3,), 3.55 (c, 3H, CO2CH3), 3.68 (c, 3H, CO2CH3), 3.73-3.82 (m, 2H, 7-CH2), 4.43 (d, 1H, J=15.8 Hz, 5-CH2), 4.68 (c, 1H, C(CO2CH3)=CH-CO2CH3), 5.92 (c, 1H, 14-H), 7.25-7.07 (m, 5H, 1-H, 2-H, 3-H, 4-H, 11-H), 7.42 (t, 3H, J=7.9 Hz, 10-H), 7.55 (d, 1H, J=7.9 Hz, 12-H), 7.81 (c, 1H, NH), 7.97 (d, 1H, J=7.9 Hz, 9-H). Mass spectrum m/z: 434 (M+). C25H26N2O5. Calculated: N, 6.45%, found: N 6.52%.

Example No. 4

To a solution 0,500 g (1,400 mmol) of ethyl Bornemann-14-carboxylate in 20 ml of methanol was added 0,235 g (2,80 mmol) methylpropionate and stirred at 40°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 1.5 hours. After the reaction, the solvent is evaporated to dryness, the residue triturated in hexane, thus there is spontaneous crystallization of compound IV in the amount of 0.59,

Ethyl 7-ethyl-8-methoxy-3[(1E)-3-methoxy-3-oxoprop-1-EN-1-yl]-1,2,3,4,5,6,7,8-octahydro-7,9-ethenoadenine[5,4-b] indole-14-carboxylate (IV): yield 82%, colorless crystals with TPL 157-159°C, IR spectrum (in KBr): 1611, 1693, 1721 cm-1. NMR1H (CDCl3, 400 MHz): δ=0.98 (t, 3H, J=7.4 Hz, CH2-CH3), 1-40 (t, 4H, J=7.2 Hz, OCH2-CH3and CH2), 1.73-1.82 (m, 3H,CH2-CH3and CH2), 2.50 (DD, 1H, J=4.9, 14.2 Hz, CH2), 2.93-a 3.01 (m, 2H, CH2), 3.23 (c, 4H, OCH3and CH2), 3.23-3.39 (m, N, CH2), 3.35-3.81 (m, 1H, CH2), 3.72 (c, 3H, CO2CH3), 3.76-3.81 (m, 2H, CH2), 4.09 (c, 1H,CH-OCH3), 4.44 (q, 2H, J=7.2 Hz, OCH2CH3), 4.80 (d, 1H, J=13.1 Hz, HC=CH-CO2CH3), 6.23 (c, 2H, 15-H), 7.23 (DDD, 2H, J=6.9, J=8.3 Hz, CH-Ar), 7.32 (d, 1H, J=8.3 Hz, CH-Ar), 7.52 (d, 1H, J=6.9 Hz, CH-Ar), 7.54 (d, 1H, J=13.1 Hz,HC=CH-CO2CH3). Mass spectrum m/z: 467 (M++1). C27H34N2O5. Calculated: N 6.00%, found: N 6.12%.

Example No. 5

To a solution of 0.400 g (1,14 mmol) of ethyl Bornemann-14-carboxylate in 20 ml of methanol was added 0,233 g (3,42 mmol) acetylacetone and stirred at 40°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 2.5 hours. After the reaction, the solvent is evaporated to dryness, the residue is placed on a column of aluminum oxide, a mixture of ethyl acetate with hexane 1:3 wash 0,22 g of compound V.

Ethyl 7-ethyl-8-methoxy-3[(1E)-3-exabot-1-EN-1-yl]-1,2,3,4,5,6,7,8-octahydro 7,9-ethenoadenine[5,4-b]indole-14-carboxylate (V): yield 45%, colorless crystals with TPL 156-158°C, IR spectrum (in KBr): 1566, 1622, 1722 cm-1.NMR1H (CDCl3, 400 MHz): δ=0.97 (t, 3H, J=7.4 Hz, H 2-CH3), 1.40 (t, 3H, J=7.1 Hz, OCH2-CH3), 1-60-1 .90 (m, 3H,CH2-CH3and CH2), 2.18 (c, 3H, CH3CO), 2.50-2.65 (m, 2H, CH2), 3.22 (c, 4H, OCH3and CH2), 3.22-3.34 (m, 2H, CH2), 3.75-3.85 (m, 1H, CH2), 4.05 (USS, 1H,CH-OCH3), 4.44 (q, 2H, J=7.1 Hz,OCH2CH3), 5.31 (ush. s, 1H, HC=CH-COCH3), 6.22 (c, 1H, 15-H), 7.18-7.27 (m, 3H, CH-Ar), 7.33 (d, 1H, J=7.9 Hz, CH-Ar), 7.52 (d, 1H, J=6.9 Hz, CH-Ar), 7.55 (d, 1H, J=13.1 Hz,HC=CH-COCH3). Mass spectrum m/z: 467 (M++1). C27H34N2O4. Calculated: N, 6.17%, found: N, 6.22%.

Example No. 6

To a solution of 0.400 g (1,14 mmol) of ethyl Bornemann-14-carboxylate in 20 ml of methanol was added 0,486 g (4.20 mmol) of ADCA and stirred at 40°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate : hexane, 1:1. The reaction time is 4 hours. After the reaction, the solvent is evaporated to dryness, the residue is placed on a column of aluminum oxide, a mixture of ethyl acetate with hexane 1:10 wash of 0.25 g of compound VI.

Dimethyl (2E)-2[14-etoxycarbonyl-7-ethyl-8-methoxy-1,2,3,4,5,6,7,8-octahydro-7,9-ethenoadenine[5,4-b]Indo-3(2H)yl]-but-2-entiat(VI): yield 42%, colorless crystals with TPL 154-156°C, IR spectrum (in KBr): 1573, 1701, 1725, 1738 cm-1NMR1H (CDCl3, 600 MHz): δ=0.98 (t, 3H, J=7.4 Hz, CH2-CH3), 1.09-1.32 (m, 1H, CH2), 1.40 (t, 3H, J=7.1 Hz, OCH2-CH3), 1.45-1.70 (m, 3H,CH2 -CH3and CH2), 1.71-1.85 (m, 1H, CH2), 1.85-2.00 (m, 1H, CH2), 2.31-2.45 (m, 1H, CH2), 2.95-3.07 (m, 1H, CH2), 3.33 (c, 3H, OCH3), 3.49-3.58 (m, 1H, CH2), 3.69 (c, 3H, CO2CH3), 3.82-3.93 (m, 1H, CH2), 3.94 (c, 3H, CO2CH3), 4.37-of 4.44 (m, 3H, OCH2CH3+CH-OCH3), 4.65 (c, 1H, C(CO2CH3)=CH-CO2CH3), 6.35 (c, 1H, 15-H), 7.15-7.25 (m, 2H, CH-Ar), 7.32 (d, 1H, J=8.1 Hz, CH-Ar), 7.56 (d, 1H, J=7.6 Hz, CH-Ar). Mass spectrum m/z: 524 (M+). C29H36N2O7. Calculated: N, 5.28%, found: N, 5.34%.

Example No. 7

To a solution of 0.250 g (0,706 mmol) of methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydroartemisinin-14-carboxylate in 60 ml of methanol are added 0,089 g (1.06 mmol) methylpropionate and stirred at 50°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate : hexane, 1:1. The reaction time is 17 hours. After the reaction, the solvent is evaporated to dryness, the residue triturated in a mixture of ether and hexane, thus there is spontaneous crystallization of compound VII in the amount of 0.26 g

Ethyl 7-ethyl-8-methoxy-3[(1E)-3-methoxy-3-oxoprop-1-EN-1-yl]-1,2,3,4,5,6,7,8-octahydro-7,9-ethenoadenine[5,4-b]indole-14-carboxylate (VII): yield 78%, colorless crystals with TPL 205-206°C, IR spectrum (in KBr): 1612, 1668, 1741 cm-1. NMR1H (CDCl3, 600 MHz): δ=0.89 (t, 3H, J=7.5 Hz, CH2-CH3), 1.25-1.30 (m, 1H, CH2), 1.59-1.62 (m, 2H,CH2-H 3), 1.72-1.80 (m, 1H, CH2), 1.80-1.85 (m, 1H, CH2), 1.87-1.93 (m, CH2-3H, 15-H and 1-H from CH2), 2.32-2.35 (m, 1H, CH2), 2.76 (d, 1H, J=13.8 Hz, 15-H), 2.88-2.96 (m, 2H, CH2), 3.24 (c, 3H, OCH3), 3.50-3.65 (m, 1H, CH2), 3.75 (c, 3H, CO2CH3), 4.22 (c, 1H, OH), 4.65 (c, 1H,CH-OCH3), 4.87 (USS, 1H, HC=CH-CO2CH3), 7.22-7.24 (m, 3H, 10-H, 11-H, 12-H), 7.55 (d, 1H, J=7.5 Hz, 13-H), 7.61 (d, 1H, J=13.4 Hz,HC=CH-CO2CH3). Mass spectrum m/z: 470 (M+). C26H34N2O6. Calculated: N, 5.95%, found: N 6.00%.

Example No. 8

To a solution of 0.400 g (1.13 mmol) of methyl (3-α,14-β,16α)-14-hydroxy-14,15-dihydroartemisinin-14-carboxylate in 50 ml of methanol was added 0,115 g (1.70 mmol) of acetylacetone and stirred at 50°C. Progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 20 hours. After the reaction, the solvent is evaporated to dryness, the residue is recrystallized from hexane with ethyl acetate. Obtain 0.32 g of compound VIII.

Ethyl 7-ethyl-8-methoxy-3[(1E)-3-exabot-1-EN-1-yl]-1,2,3,4,5,6,7,8-octahydro 7,9-ethenoadenine[5,4-b]indole-14-carboxylate (VIII): yield 63%, colorless crystals with TPL 221-222°C, IR spectrum (in KBr): 1559, 1651, 1745 cm-1NMR1H (CDCl3, 400 MHz): δ=0.86 (t, 3H, J=7.5 Hz, CH2-CH3), 1.26-1.29 (m, 1H, CH2), 1.53-1.62 (m, 2H,CH2-CH3), 1.67-1.91 (m, 3H, CH2), 1.85 (d, 1H, J=13.4 Hz, 15-H), 2.17 (c, 3H, CH3CO), 2.35 (the d, 1H, J=8.7, 13.1 Hz, CH2), 2.74 (d, 1H, J=13.4 Hz, 15-H), 2.90-2.97 (m, 2H, CH2), 3.19-3.26 (m, 1H, CH2), 3.21 (c, 3H, OCH3), 3.57-3.64 (m, 1H, CH2), 3.73-3.76 (m, 1H, CH2), 3.83 (s, 3H, CO2CH3), 4.16 (c, 1H, OH), 4.64 (c, 1H,CH-OCH3), 5.33 (USS, 1H, HC=CH-COCH3), 7.13-7.23 (m, 3H, 10-H, 11-H, 12-H), 7.53 (d, 1H, J=6.8 Hz, 13-H), 7.60 (d, 1H, J=13.7 Hz,HC=CH-COCH3). Mass spectrum m/z: 454 (M+). C26H34N2O5. Calculated: N 6.16%, found: N, 6.20%.

Example No. 9

To a solution 0,500 g (1,41 mmol) of methyl (3-α,14-β,16α)-14-hydroxy-14,15-dihydroartemisinin-14-carboxylate in 60 ml of methanol are added 0,301 g (2,12 mmol) ADCA and stirred in boiling methanol. The progress of the reaction is controlled by thin layer chromatography on sorbfil, eluent - ethyl acetate. The reaction time is 18 hours After the end of the reaction the solvent is evaporated to dryness, the residue triturated in a mixture of ether and hexane, thus there is spontaneous crystallization of compound IX in the amount of 0.54 g

Dimethyl (2E)-2[14-etoxycarbonyl-7-ethyl-8-methoxy-1,2,3,4,5,6,7,8-octahydro-7,9-ethenoadenine[5,4-b]Indo-3(2H)yl]-but-2-entiat(1X):

the yield was 73%, colorless crystals with TPL 201-203°C, IR spectrum (in KBr): 1573, 1667, 1732, 1748 cm-1. NMR1H (CDCl3, 400 MHz):): δ=0.83 (t, 3H, J=7.5 Hz, CH2-CH3), 1.18-1.24 (m, 1H, CH2), 1.53-1.60 (m, 2H,CH2-CH3), 1.62-1.70 (m, 1H, CH2), 1.78-1.83 (m, 2H, CH2), 1.87 (d, 1H, J=13.7 Hz, 15-H), 2.25-2.29 (m, 1H, CH22), 2.98 (DDD, 1H, J=1.5, 4.4, 14.9 Hz, CH2), 3.20 (DDD, 1H, J=1.5, 11.8, 14.3 Hz, CH2), 3.32 (c, 3H, OCH3), 3.50-3.65 (m, 1H, CH2), 3.68 (c, 3H, CO2CH3), 3.78-3.82 (m, 1H, CH2), 3.82 (c, 3H, CO2H3), 3.97 (c, 3H, CO2CH3), 4.48 (c, 1H,CH-OCH3), 4.57 (s, 1H, OH), 4.69 (USS, 1H, C(CO2CH3)=CH-CO2CH3), 7.13-7.19 (m, 3H, 10-H, 11-H, 12-H), 7.48 (d, 1H, J=8.1 Hz, 13-H). Mass spectrum m/z: 528 (M+). C28H36N2O8. Calculated: N 5.30%, found: N, 5.38%.

The method of obtaining derivatives of benzo[7,8]asinine[5,4-b]indoles, 7,9-ethenoadenine[5,4-b]indoles and 7.9-ethenoadenine[5,4-b]indoles with General structural formula:

I, IV, VII, X=H, Y=CO2Me;
II, V, VIII, X=H, Y=COMe;
III, VI, IX, X=Y=CO2Me,
characterized in that 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indole, the ethyl Bornemann-14-carboxylate or methyl (3-α,14-β,16-α)-14-hydroxy-14,15-dihydroartemisinin-14-carboxylate is dissolved in methanol and subjected to interaction with an excess of diethylazodicarboxylate (ADCA) or methylpropionate or acetylacetone, stirring at a temperature of 40-50°C. the residue obtained after the reaction and removal of the solvent, triturated in hexane or in a mixture of hexane with ethyl acetate (ether) or purified by column chromatography on aluminium oxide is Oia.



 

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SUBSTANCE: described are novel imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives of formula , where R1 is hydrogen, halogen, lower alkyl or lower alkoxy, possibly substituted with a halogen, nitro group, C3-6cycloalkyl, -O(CH2)mO(CH2)mOH or -C≡C-R'; R2 is hydrogen or methyl; R3 is lower alkyl, lower alkenyl, lower alkynyl, possibly substituted with a halogen, -(CH2)n-C3-6cycloalkyl, -(CR'R'')m-CH3, phenyl, possibly substituted with a halogen, pyridinyl substituted with a lower alkyl, -(CH2)n- NH-C3-6cycloalkyl, lower alkenyl-C3-6cycloalkyl, lower alkynyl- (CR'R")m-OH, lower alkynyl-phenyl, where the phenyl ring is possibly substituted with a halogen, CF3, lower alkyl or lower alkoxy; R' is hydrogen or lower alkyl; R" is hydrogen, hydroxy or lower alkyl; n is equal to 0, 1, or 2, m is equal to 1, 2 or 3, o is equal to 1 or 2, or their pharmaceutically acceptable acid addition salts.

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22 cl, 60 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) and their pharmaceutically acceptable salts with antagonistic properties towards adenosine A2A receptor, which can be used for treating central nervous system diseases such as Parkinson's disease. In general formula (I) , R is ,, R1, R2, R3, R4 and R5 is independently selected from a group which consists of hydrogen; R6 is hydrogen, (C1-C6)alkyl or -CH2F; R7, R8 and R9 are independently selected from a group which consists of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, haloid and -CF3; Z is R10-phenyl, R10-5-6-member heteroaryl, which contains 1 or 2 hetwroatoms, selected from nitrogen or from nitrogen and oxygen, possibly condensed with a benzene ring, or ; R10 represents 1 to 3 substitutes, independently selected from a group which consists of hydrogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkoxy, hydroxy-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (di-(C1-C6)-alkoxy)-(C1-C6)-alkyl, (hydroxy)-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C6)-cycloalkyloxy, (C3-C6)-cycloalkyl-O-(C3-C6)-alkoxy, (C1-C6)-alkyl-SO2-, (C1-C6)-alkyl-SO-, haloid, -CN, cyano-(C1-C6)-alkyl, -CHF2, -CF3, -C(O)R13, -C(O)O-(C1-C6)-alkyl, -N(R11)(R12), N(R11)(R12)- (C1-C6)-alkyl, - C(O)N(R13)(R16), R11-5-6-member nitrogen-containing heteroaryl, possibly condensed with a benzene ring, R15-5-6-member heterocycoalkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkoxy, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-oxy, with 1 or 2 heteroatoms in a heterocyclic ring selected from nitrogen and oxygen, CF3-(C1-C4)alkylene-O-(C1-C6)alkyl, CF3-hydroxy(C1-C6)alkyl, cyano-(C1-C6)-alkoxy, (C1-C4)alkylene-C(O)-O-(C1-C6)alkyl, -SO2-N((C1-C4)alkyl)2, ((C3-C4)cycloalkyl)hydroxy(C1-C6)alkyl, (hydroxy(C1-C6)alkyl)-(C1-C4)alkoxy, (dihydroxy)-(C1-C6)-alkyl, (dihydroxy)(C1-C6)alkoxy, -C(=NOR17)- (C1-C6)alkyl and -C(=NOR17)-CF3; or two R10 groups, on neighbouring carbon atoms of the ring, together form -O-CH2-O-, -O-(CH2)2-O-, -CH2-O(CH2)2-O-, -O-(CH2)2-, -(CH2)3-O-, -O-(CH2)3-O, -(CH2)3-, where the ring, formed by two R10 substitutes and ring carbon atoms with which they are bonded, is substituted with R16; or two R10 groups on neighbouring ring carbon atoms, together form -O(CH2)3CH((OR18)-, each R11 is independently selected from a group which consists of hydrogen and (C1-C6)alkyl; each R12 is independently selected from a group which consists of (C1-C6)alkyl, hydroxy(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, ((C1-C6)alkoxy)hydroxy(C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkyl-C(O)-, -SO2(C1-C6)alkyl; R13 is hydrogen, (C1-C6)alkyl or -CF3; R14 is (C1-C6)alkoxy-C(O)-; R15 represents 1 to 3 substitutes, independently selected from a group which consists of (C1-C6)alkoxy, hydroxy-(C1-C6)alkyl; or two R15 substitutes, taken together with the carbon atom with which they are bonded, form a -C(=O)- group; R16 is (C1-C6)alkoxy(C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl; R17 is hydrogen or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: increased effectiveness of composition and method of treatment.

17 cl, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 5-aminopyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine of the general formula: wherein R means furanyl, possibly substituted pyrrolyl, possibly substituted pyridyl, possibly substituted phenyl or (C4-C6)-cycloalkenyl; X means (C2-C6)-alkylene or -C(O)CH2-; Y means the following groups: -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)- wherein R2 and R3 mean hydrogen atom or (C1-C6)-alkyl, -O-, -S-, -CH2S-, -(CH2)2-NH- or compound of the formula: wherein Q means or R4 means hydrogen atom or (C1-C6)-alkyl, or two R at one carbon atom form group =O; Z means phenyl comprising from 1 to 5 of different substitutes, phenylalkyl or heteroaryl, diphenylmethyl and other values; or Z and Y in common can form substituted piperidinyl or substituted phenyl also possessing activity of antagonist of A2a adenosine receptors. Also, invention relates to a pharmaceutical composition based on these compounds, using novel compounds for preparing medicinal agents in treatment, for example, Parkinson's disease, and two methods for synthesis of intermediate compounds of formulae (II) and (IIIa) .

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

17 cl, 17 tbl, 29 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel imidazo-condensed compounds of the general formula (I): wherein Z represents nitrogen atom (N); Z1 represents N whein a bond between C5 and Z1 represents a simple bond, and Z1 represents carbon atom (C) when a bond between C5 and Z1 represents a double bond; R1 represents hydrogen atom; R2 represents (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, phenyl-(C1-C4)-alkyl substituted with halogen atom, ((C1-C4)-alkyl)-SO2, (C1-C6)-alkyl, (C5-C6)-cycloalkyl possibly substituted with hydroxy-group, phenyl substituted with halogen atom, heterocyclyl possibly substituted and chosen from group consisting of tetrahydropyranyl, (N-methylsulfonyl)piperidinyl or tetrahydro-1,1-dioxide-2H-thiopyranyl; A is absent or represents -O-; a bond between C5 and Z1 is a simple or double bond; a bond between C8 and C9 is a simple or double bond; Y represents phenyl substituted with halogen atom, or their pharmaceutically acceptable salts possessing inhibitory activity with respect to p38 MAP kinase, and pharmaceutical composition containing thereof. Proposed compounds can be used, for example, in treatment/or prophylaxis of such diseases as rheumatic arthritis, fever and reduced bone resorption.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine of the formula (I): , wherein R1 means halogen atom or (lower)alkyl; R2 means hydrogen atom, (lower)alkyl, (C3-C7)-cycloalkyl, -(CH2)m-phenyl wherein phenyl ring can be substituted with (lower)alkoxy-group or it means -(CH2)m-indolyl; R3 means -C(O)O-(lower)alkyl, -C(O)OH or five-membered heteroaromatic group comprising nitrogen and oxygen atoms as heteroatoms and wherein rings can be substituted with (lower)alkyl or (C3-C7)-cycloalkyl; n means 0, 1 or 2; m means 0, 1 or 2, and their pharmaceutically acceptable acid-additive salts. Compounds of this class elicit the high degree and selectivity to binding sites of GABA A α5-receptor and can be used in treatment of the conception enhancer or disorders of cognitive ability similar with Alzheimer's disease.

EFFECT: valuable medicinal properties of derivatives.

10 cl, 6 sch, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I): wherein R1 represents hydrogen, halogen atom, (C1-C7)-alkyl, hydroxy- or (C1-C7)-alkylthio-group; R2 represents -C(O)O-(C1-C7)-alkyl, 1,2,4-oxadiazole-3-yl or 1,2,4-oxadiazole-5-yl wherein their cyclic fragments are substituted with (C3-C7)-cycloalkyl; R3 represents hydrogen atom (C1-C7)-alkyl, -(CH2)n-(C3-C7)-cycloalkyl, -(CH2)n-halogen, -(CH2)n-pyridine-4-yl or -(CH2)n-phenyl wherein phenyl ring can be substituted with one or some substitutes chosen from the group comprising (C1-C7)-alkoxy-group, halogen atom, -SO2CH3, phenyl, -OCF3, nitro-group, -CF3, -NR2, or it means -(CH)n-indolyl optionally substituted with (C1-C7)-alkyl or (C1-C7)-alkoxy-group, or means pyrrolidinyl-5-oxo-group, -C(O)-NR2, -(CH2)n-OH, -(CH2)n-NR2 or -(CH2)n-benzo[1,3]dioxol; R represents hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3, and its pharmaceutically acceptable acid-additive salts with exception for the following compounds: 9H-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester. 10-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine, 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d]benzodiazepine-10-carboxylic acid ethyl ester, 10-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine, 3-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester, 3-chloro-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine and 3-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester. Also, invention relates to pharmaceutical composition comprising both new and above enumerated and excluded compounds. New compounds possess ability for selective binding with α5-subunit of gamma-aminobutyric acid receptor A and can be used in treatment, for example, Alzheimer's diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 1 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, where X is CH; R1 is phenyl or a 6-member heteroaryl which contains 1 or 2 nitrogen atoms as heteroatoms, independently and optionally substituted with up to five groups J; R2 and R3 each independently represents hydrogen, halogen, -V-R or -V-Ra; R5 is R; R is H or an optionally substituted C1-6aliphatic group, where the substitutes are selected from -OR0, phenyl, substituted R0, -N(R0)2; where each independent R0 is selected from hydrogen, halogen, C1-6aliphatic group; Ra is morpholine, V is a bond or Q; Q is -NR5-; each J group independently represents a halogen, -N(R5)2. The invention also relates to a pharmaceutical composition with protein kinase inhibiting properties, and to methods of inhibiting Aurora A protein kinase using the said compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which can be used in medicine to treat or alleviating a proliferative disorder, such as cancer, in a patient.

25 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to pyrido[1,2-a]benzimidazole derivatives of general formula I, where R=alkyl; R1=alkyl, aryl; R2=alkyl. The invention also relates to a method of producing formula I compounds.

EFFECT: novel to pyrido[1,2-a]benzimidazole derivatives with antibacterial activity are obtained.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention discloses pharmaceutical compositions based on telozolomide-8-carboxylate compounds of general formula I, as well as a method of preparing the said compositions. The disclosed composition has anti-tumour activity and can be especially useful during transdermal application.

EFFECT: obtaining compositions which, along with conventional pharmaceutical carriers, contain a component of acidic nature which gives the pharmaceutical composition high resistance to pH fluctuation.

16 cl, 2 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 1-(3-morpholinopropyl)-2-phenylimidazo[1,2-a]benzimidazole dihydrochloride of formula I:

having purine P2Y1-receptor antagonist properties, antiaggregant and antithrombotic activity.

EFFECT: obtaining a new compound which can be used in medicine for making a medicinal drug for therapy of diseases accompanied by increase in thrombogenic potential of the blood: atherosclerosis, ischemic heart disease, diabetic angiopathy.

1 cl, 5 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 7H-pyrrol[2,3-d]pyrimidine derivatives of formula I. In compounds of formula R1 is phenyl which is optionally substituted with a halogen, phenylalkyl, where the alkyl contains 1-4 carbon atoms, morpholinoalkyl, where the alkyl contains 1-4 carbon atoms, dialkylaminoalkyl, where the alkyl contains 1-4 carbon atoms, or pyridyl which is optionally substituted with alkyl which contains 1-4 carbon atoms, R2, R3 optionally represent methyl, or R2 and R3 together form a tetramethylene group, R4 is or or where R5 is phenyl which is optionally substituted with 1-3 groups selected from nitro, trifluoromethyl, benzyloxy, hydroxy, alkoxy, alkyl, where the alkyl contains 1-4 carbon atoms, cyano, dialkylamino, where the alkyl contains 1-4 carbon atoms, either a thiophene or naphthyl ring; R6, R7, R8 and R9 independently represent hydrogen, halogen, trifluoromethoxy, sulphonyl or alkyl containing 1-4 carbon atoms, R10 is hydrogen, a nitrile group, or an alkyl containing 1-4 carbon atoms, R11 is tert-butyl or phenyl, or together with X form a tetramethylene ring, or; R12 is phenyl which is possibly substituted with nitro, halogen, alkoxy, or phenyl-alkyl, where the alkyl contains 1-4 carbon atoms, X is carbon, or R11 together with X form a tetramethylene ring, otherwise X denotes nitrogen, methine, methylmethine, ethylmethine, propylmethine, isopropylmethine, tert-butylmethine or phenylmethine. The invention also relates to a pharmaceutical composition and a method of preparation.

EFFECT: obtaining compounds and pharmaceutically acceptable salts which have anti-inflammatory and anaesthetic effect.

10 cl, 3 tbl, 96 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

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