Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:

, , , , ,

R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.

EFFECT: obtaining novel compounds with anticancer activity.

37 cl, 3 dwg, 10 ex, 2 tbl

 

The scope of the invention

The present invention relates to novel phosphate derivatives of 2-aryl-4-quinolones and new intermediate compounds, 2-selenophene-4-quinolones and N,N-dialkylaminoalkyl derivative of 2-phenyl-4-quinolones and in particular to their use for the treatment of cancer in humans.

Background of invention

Originally quinolone derivatives were used as agents affecting bacterial DNA girazu and thus was used as antibacterial agents. Recently, DNA topoisomerase II is a pharmacological target for this class of quinolone compounds. We synthesized a series of substituted 2-phenyl-4-quinolone (A), which are new antimitoticheskoy agents. [Kuo, S., Lee, H.Z., Juang, J.P., Lin, WT, Wu, .S., Chang, J.J., Lednicer, D., Paul, K.D., Lin, C.M., Hamel, E. Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinoloncs and related compounds: identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993, 36,1146-56; Li, L., Wang, H.K., Kuo, S.C, Wu, T.S., Mauger, A., Lin. C.M., Hamel, E. Lee, K.H. Antitumor agents. 155. Synthesis and biological evaluation of 3',6,7-substituted 2-phenyl-4-quinolones as antimicrotubule agents. J. Med. Chem. 1994, 37, 3400-7]. Later we continued the synthesis of many analogues, type 2-phenylnaphthalene-4-ones () [Chen, K., Kuo, S., Hsieh, M., Mauger, SA., Lin, S.M., Hamel, E., Lee, K.H. Antitumor agents. 174. 2',3',4',5',6',7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1997, 40, 2266-75], 2-phenyl-4-hinatasou () [Xia, Y., Yang, Z.Y., Hour, M.J., Kuo, SC, Xia, P., Bastow, K.F., Nakanishi, Y., Namrpoothiri, P., Hackl, T., Hamel, E., Lee, K.N. Antitumor Agents. Part 204: Synthesis and Biological Evaluation of Substituted 2-Aryl Quinazolinones, Bioorg. Med. Cem. Lett. 2001, 11, 1193-6; Hour, M.J., Huang, L.J., Kuo, S.C, Xia, Y., Bastow, K.F., Nakanishi, Y., Hamel, E., Lee, K.N. 6-Alkylamino - and 2,3-dihydro-3'-methoxy-2-phenyl-4-quinazolinones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 2000, 43, 4479-87] and tetrahydro-2-phenyl-4-quinolones (D) [Xia, Y, Yang, Z.Y., Xia, P., Bastow, .F., Tachibana, Y., Kuo, S., Hamel, E., Hackl. So, Lee, K.N. Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'-substituted-1,2,3,4- - tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents. J. Med. Chem. 1998, 41. 1155-62], which allow us to establish communication patterns with activity. Among these analogues, we found quite a lot of compounds with potent cytotoxicity, type 3',6-disubstituted 2-phenyl-4-quinolone (a-1) and so on [Li, L., Wang, H.K., Kuo, S., Wu, T.S., Lednicer, D., Lin, C.M., Hamel, E., Lee, K.N. Antitumor agents. 150. 2',3',4',5',5,6,7,-substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity and inhibition of tubulin polymerization. J. Med. Chem. 1994, 37, 1126-35]. However, most compounds with potent cytotoxicity was lipophilic, and therefore they are not suitable for use in vivo and clinical studies. We have attempted to synthesize hydrophilinae derivatives of 2-aryl-4-quinolones to improve their pharmacokinetic properties and make them suitable for use in vivo and clinical studies.

Summary of the invention

The preferred embodiment of the present invention include (but are not limited to) the following items:

1. Phosphate derivatives of 2-aryl-4-quinolone of the formula Ia, Ib or Ic:

where

R2', R3', R4', R5' and R6' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,

where n is an integer from 0 to 4, Y represents O or S, X is F, Cl or Br and R8and R9independently represent (CH2)nCH3where n is an integer 0-4;

R2, R3, R4and R5independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,

or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9defined above; and

R1and R1' independently represent H, Li+, Na+, K+N+R8R9R10Rnor benzyl, where R10and R11independently represent H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, n, R8and R9defined as above and m is an integer 0-4.

2. F. spatnou derived under paragraph 1, which has the formula Ia.

3. The phosphate derivative according to paragraph 2, where R2', R3', R4', R5' and R6' all are H; or one of R2', R3', R4', R5' and R6' is F, och3or (CH2)nNR8R9and the others are H, R8and R9independently represent (CH2)nCH3where n is an integer 0-4.

4. The phosphate derivative according to paragraph 2, where R2, R3, R4and R5all represent H; or one of R2, R3, R4and R5represent F, och3, Y(CH2)nCH3or (CH2)nNR8R9and the others are H; or R2and R5represent N and R3and R4together form-O(CH2)nO-, where R8and R9independently represent (CH2)nCH3where n is an integer 0-4.

5. The phosphate derivative according to paragraph 2, where R1and R1' both represent H or Na+.

6. The phosphate derivative according to item 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2', R3', R4' and R5' all are H; and R6' is F.

7. The phosphate derivative according to item 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2/sub> ', R3', R4' and R6' all are H, and R5' is F.

8. The phosphate derivative according to item 5, where R4is F, and R2, R3and R5are H; and R2', R3', R4', R5' and R6' all represent N.

9. The phosphate derivative according to item 5, where R2, R3, R4and R5all are H; and R2', R3', R4', R5' and R6' all represent N.

10. The phosphate derivative according to item 5, where R4is the co3and R2, R3and R5are H; and R5' is F, and R2', R3', R4' and R5' represent N.

11. The phosphate derivative according to item 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2', R3', R4' and R6' all are H, and R5' is och3.

12. The phosphate derivative according to item 5, where R4is CH2N(C2H5)2and R2, R3and R5are H; and R6' is F, and R2', R3', R4' and R5' represent N.

13. The phosphate derivative according to item 5, where R4is CH2N(C2H5)2and R2, R3and R5are H; and R2', R3', R4', R5' and R6' all p is establet N.

14. The phosphate derivative according to item 5, where R4is the co3and R2, R3and R5are H; and R5' is CH2N(C2H5)2and R2', R3', R4' and R6' represent N.

15. The phosphate derivative according to item 1, which have the formula Ib.

16. The phosphate derivative according to item 15, where R2, R3, R4and R5all represent H; or one of R2, R3, R4and R5is F or co3and the others are H; or R2and R5are H, and R3and R4together form-O(CH2)nO-, where n is an integer 0-4.

17. The phosphate derivative according to item 15, where R2', R3' and R4' all are H; or one of R2', R3' and R4' is F or co3while others represent N.

18. The phosphate derivative according to item 15, where R1and R1' are benzyl.

19. The phosphate derivative according to item 18, where R2', R3', R4', R2and R5all represent H, and R3and R4together form-O(CH2)O-.

20. Pharmaceutical composition for cell lysis, a solid cancer, which comprises as an active ingredient a therapeutically effective amount of a phosphate derivative of 2-aryl-4-quinolone according to any one of paragraphs 1-19, or the th pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leukemia.

21. The pharmaceutical composition according to paragraph 20, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, kidney cancer, hepatoma, or leukemia.

22. The pharmaceutical composition according to paragraph 21, where the solid cancer is breast cancer in humans or colon cancer.

23. Connection 2-selenophene 4-hinolan the following formula IIb or IIc:

where

R2', R3' and R4' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9where n is an integer 0-4, X is F, Cl or Br, and R8and R9independently represent (CH2)nCH3where n is an integer 0-4;

R2, R3, R4and R5independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,

or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9as specified above.

24. The connection point 23, where R2, R3, R4The R 5all represent H; or one of R2, R3, R4and R5is F or co3and the others are H; or R2and R5are H, and R3and R4together form-O(CH2)nO-, where n is an integer 0-4.

25. The connection point 24, where R2', R3' and R4' all are H; or one of R2', R3' and R4' is F or co3while others represent N.

26. The connection point 23 having the formula IIb.

27. The connection point 26, where R2', R3', R4', R2and R5all represent H, and R3and R4together form-O(CH2)O-.

28. Pharmaceutical composition for cell lysis, a solid cancer, which includes as a component of exploring therapeutically effective amount of 2-selenophene 4-quinolone according to any one of paragraphs 23 to 27 or its pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leukemia.

29. The pharmaceutical composition according to paragraph 28, where the solid cancer is breast cancer in humans, cancer is Tolstoy ulcer, lung cancer, kidney cancer, hepatoma, or leukemia.

30. The compound 2-phenyl 4-hinolan the following formula IIA:

where

R2', R3', R4', R5' and R6' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,

where n is an integer 0-4, Y is O or S, X is F, Cl or Br and R8and R9independently represent (CH2)nCH3where n is an integer 0-4;

R2, R3, R4and R5independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,

or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9defined above;

provided that one of R2, R3, R4and R5represents (CH2)qNR8R9or one of R2', R3', R4', R5' and R6' represents (CH2)qNR8R9where q is an integer of 1-4, and R8and R9defined above.

31. Connection unkt 30, where R4represents (CH2)qNgR8R9and R2, R3and R5represent H, where q is an integer of 1-4, and R8and R9independently represent (CH2)nCH3where n is an integer 0-4.

32. The connection point 30, where R5' represents (CH )qNR8R9and R2', R3', R4' and R6' represent H, where q is an integer of 0-4, R8and R9represent (CH2)nCH3where n is an integer 0-4.

33. The connection point 31, where R4is CH2N(C2H5)2, R6' is F, and R2', R3', R4' and R5' represent N.

34. The connection point 31, where R4is CH2N(C2H5)2, R2', R3', R4', R5' and R6' all represent N.

35. The connection point 32, where R4is the co3and R2, R3and R5are H; and R5' is CH2N(C2H5)2and R2', R3', R4' and R6' represent N.

36. Pharmaceutical composition for cell lysis, a solid cancer, which includes as a component of exploring therapeutically effective amount of 2-phenyl 4-quinolone according to any one of paragraphs 30-35 or its pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leikam is she.

37. The pharmaceutical composition according to paragraph 36, where the solid cancer is leukemia.

Brief description of drawings

Figure 1 shows the effect of compound I-1 and compound I-1-b, MCF7 tumor growth in a murine model of xenograft. Mouse SCID female received injections of MCF7 transfectants in order to induce tumor xenografts. Mice were divided into five groups. Group from the second to the fifth received V.B. compounds I-1 (15 mg/kg)I-1 (30 mg/kg), I-1-b (22,5 mg/kg) and (I-1-b (45 mg/kg), respectively, three times per week. Data were expressed as the average weight of tumor (g) ± S... *p<0.05 compared to control.

Figure 2 shows the effect of compound 1-1-b on the survival of animals. Before beginning treatment with compound 1-1-b mice BALB/c mice intraperitoneally injected tumor cells CT-26 in 7 days daily (5 mg/kg/day and 10 mg/kg/day, QD×7).

Figure 3 shows the effect of quinolone derivatives on the viability of breast cancer cells human. The MCF7 cells were treated with dimethyl sulfoxide (DMSO) (Control) or various concentrations (from 0.125 to 10 microns) derived quinolone within 48 hours and was determined subsequent cell viability using the MTT-assay. The results of three separate experiments were averaged and presented as mean ± standard deviation.

A detailed description of the invention

As shown in the following Examples 1-6, when the interaction of 2-phenyl-4-quinolones (1-1 through I-6) with tetraethylpyrophosphate in the presence of alkali are formed corresponding esters of phosphoric acid (1-1-a through I-6-a). Catalytic hydrogenation of the compounds (1-1-a through I-6-a) in alcoholic medium leads to obtaining appropriate monoamino phosphoric acid (I-1-b I-6-b), which can be converted into water-soluble salt (1-1-I-6-C).

Example 1

Dibenzyl 2-(2'-forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-1-a)

To a stirred solution of compound I-1 (64,5 mg, 0.23 mmol) in dry tetrahydrofuran (10 ml) is added at 0°C. sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 mg, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-1-a (69,1 mg, 67%), So pl. 101-104°C.

MS (m/z 544 (ES+)

Calculated for C30H25FNO6P: C, 66.30; H, 4.27; N, 2.58. Found: C, 66.28; H, 4.35; N, 2.55.

2-(2'-Forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-1-b)

A suspension of compound I-1-a (97,7 mg, 0.18 mmol) in anhydrous Meon (10 ml) is subjected to hydrogenation in presets is under 10%Pd/C (50 mg) at room temperature for 10 minutes The catalyst and the precipitate is collected and dissolved in a 10%solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-1-b (63.5 mg, 97.2 per cent).

TPL >300°C

1H-NMR (DMSO-d6, 300 MHz): δ 7.93-7.98 (m, 1H, H-5'), 7.74 (s, 14, H-5), 7.49-7.54 (m, 1H, H-4'), 7.32-7.41 (m, 4H, H-3, H-8, H-3', H-6') 6.22 (s, 2H. OCH2O).

MS (m/z 362 (ES-)

Analysis:

Calculated for C16H13FNO6P: C, 52.91; H, 3.05; N, 3.86.

Found: C, 52.73; H, 3.10; N, 3.81.

Sodium 2-(2'-forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-1-C)

Compound I-1-b is added to a mixture of 20 ml of Amberlite IR-120 (Na+form) and 20 ml of water and then stirred for 6 hours at room temperature. The mixture is filtered to remove Amberlite and then lyophilized obtaining I-1-C (49,1 mg, 69%).

1H-NMR (D2O, 200 MHz): δ 7.48-7.66 (m, 2H, H-4', H-6'), 7.40 (s, 1H, H-8), 7.31-7.35 (m, 1H, H-5), 7.11-7.19 (m, 2H, H-3', H-5'), 7.03 (s, 1H, H-3), 5.92 (s, 2H, OCH2O).

Example 2

Dibenzyl 2-(3'-forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-2)

To a stirred solution of compound I-2 (64,5 mg, 0.23 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 mg, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the STATCOM is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-2-a (for 85.6 mg, 83%).

TPL 94-96°C

MP 94-96°C

MS (m/z 544 (ES+)

Analysis:

Calculated for C30H25FNO6P: C, 66.30; H, 4.27; N, 2.58.

Found: C, 66.25; H, 4.34; N, 2.55.

2-(3'-Forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-2-b)

A suspension of compound I-2 (97,7 mg, 0.18 mmol) in anhydrous MeOH (10 ml) is subjected to hydrogenation in the presence of 10%Pd/C (50 mg) at room temperature for 10 minutes, the Catalyst and the precipitate is collected and dissolved in a 10%solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-2-b (of 60.8 mg, 93.1%of).

TPL >300°C

MP>300°C

1H-NMR (DMSO-d6, 200 MHz): δ 7.91 (s, 1H, H-2'), 7.87 (s, 1H, H-4'), 7.83 (s, 1H, H-5'), 7.50-7.62 (m, 2H, H-5, H-8), 7.25-7.36 (m, 2H, H-5', H-6'), 6.24 (s, 2H, OCH2O).

MS (m/z 362 (ES-)

Analysis: Calculated for C16H13FNO6P: C, 52.91; H, 3.05; N, 3.86.

Found: C, 52.86; H, 3.12; N, 3.79.

Sodium 2-(3'-forfinal)-6,7-methylenedioxyaniline-4-yl-phosphate (I-2)

Compound I-2-b is added to a mixture of 20 ml of Amberlite IR-120 (Na+form) and 20 ml of water and then stirred for 6 hours at room temperature. The mixture is filtered to remove Amberlite and then lyophilized obtaining I-2-C (68,2 mg, 7%).

1H-NMR (D2O, 200 MHz): δ 7.26-7.78 (m, 5H, H-5, H-8, H-2', H-5', H-6'), 6.90-6.96 (m, 2H, H-3, H-4'), 6.03 (s, 2H, OCH2O).

Example 3

Dibenzyl 6-fluoro-2-phenylindolin-4-yl-phosphate (I-3-a)

To a stirred solution of compound I-3 (66,0 mg, 0.23 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 mg, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-3-a as a colorless oil (84,4 mg, 89%).

Analysis: Calculated for C29H23FNO6P: With, at 69.74; H, 4.64; N, 2.80.

Found: C, 69.75; H, 4.6; N, 2.81.

6-fluoro-2-phenylindolin-4-yl-phosphate (I-3-b)

A suspension of compound I-3-a (89,8 mg, 0.18 mmol) in anhydrous MeOH (10 ml) is subjected to hydrogenation in the presence of 10%Pd/C (50 mg) at room temperature for 10 minutes, the Catalyst and the precipitate is collected and dissolved in 10%-th solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-3-b (50.5 mg, 88%).

TPL >300°C

1H-NMR (DMSO-d6, 200 MHz): δ 8.07-8.14 (m, 3 is, H-8, H-2', H-6'), 7.95 (s, 1H, H-5), 7.70-7.74 (m, 2H, H-3', H-5'), 7.50-7.56 (s, 3H, H-3, H-7, H-4')

MS (m/z 318 (ES-)

Analysis: Calculated for C15H11FNO4P: With, at 56.44; H, 3.47; N, 4.39.

Found: C, 56.42; H, 3.49; N, 4.30.

Sodium 6-fluoro-2-phenylindolin-4-yl-phosphate (I-3-C)

Compound I-3-b is added to a mixture of 20 ml of Amberlite IR-120 (Na+form) and 20 ml of water and then stirred for 6 hours at room temperature. The mixture is filtered to remove Amberlite and then lyophilized obtaining I-3-C (41,9 mg, 73%).

1H-NMR (D2O, 200 MHz): δ 7.20-7.83 (m, 5H, H-5, H-7, H-8, H-2', H-6') 7.25-7.31 (m, 4H, H-3, H-3', H-4', H-5').

Example 4

Dibenzyl 2-phenylindolin-4-yl-phosphate (I-4-a)

To a stirred solution of compound I-4 (50,8 mg, 0.23 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 mg, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-4-a as a colorless oil (from 71.3 mg, 78%).

Analysis: Calculated for C29H24NO6P: C, 72.34; H, 5.02; N, 2.90.

Found: C, 71.89; H, 5.13; N, 2.88.

2-Phenylindolin-4-yl-f the SFAT (I-4-b)

A suspension of compound I-4-a (86,6 mg, 0.18 mmol) in anhydrous Meon (10 ml) is subjected to hydrogenation in the presence of 10%Pd/C (50 mg) at room temperature for 10 minutes, the Catalyst and the precipitate is collected and dissolved in a 10%solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-4-b (48,9 mg, 90.3 per cent).

TPL >300°C

1H-NMR (DMSO-d6, 200 MHz): δ 7.80-8.12 (m, 4H, H-5, H-8, H-2', H-6'), 7.49-7.78 (m, 6N, H-3, H-6, H-7, H-3', H-4', H-5'), 7.78 (s, 1H, H-7), 7.66 (t, J=8.0 Hz), 7.42-7.50 (m, 4H, H-3, H-3', H-4', H-5')

MS (m/z) 300 (ES-)

Analysis: Calculated for C15H12NO6P: C, 59.81; H, 4.02; N, 4.65.

Found: C, at 59.52; H, 4.13; N, 4.72.

Sodium 6-fluoro-2-phenylindolin-4-yl-phosphate (I-4-C)

Compound I-4-b is added to a mixture of 20 ml of Amberlite IR-120 (Na+form) and 20 ml of water and then stirred for 6 hours at room temperature. The mixture is filtered to remove Amberlite and then lyophilized obtaining I-4-C (41,2 mg, 74%).

1H-NMR (D2O, 200 MHz): δ 8.21 (d, J=8.2 Hz, 1H, H-5), 7.80-7.89 (m, 3H, H-8, H-2', H-6'), 7.78 (s, 1H, H-7), 7.66 (t, J=8.0 Hz), 7.42-7.50 (m, 4H, H-3, H-3', H-4', H-6')

Example 5

Dibenzyl 6-methoxy-2(3'-forfinal)-quinoline-4-yl-phosphate (I-5-a)

To a stirred solution of compound I-5 (61,9 mg, 0.23 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 m is, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-5-a as a colorless oil (85,4 mg, 85%).

Analysis: Calculated for C30H25FNO5P: C, 68.05; H, 4.76; N, 2.65.

Found: C, 67.32; H, 4.33; N, 2.78.

6-Methoxy-2(3'-forfinal)-quinoline-4-yl-phosphate (I-5-b)

A suspension of compound I-5 (for 95.2 mg, 0.18 mmol) in anhydrous Meon (10 ml) is subjected to hydrogenation in the presence of 10%Pd/C (50 mg) at room temperature for 10 minutes, the Catalyst and the precipitate is collected and dissolved in a 10%solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-5-b (56,5 mg, 89.9 percent).

TPL >300°C

1H-NMR (DMSO-d6, 200 MHz): δ 7.93-7.89 (m, 4H, H-5, H-7, H-8, H-5'), 7.45-7.58 (m, 1H, H-6'), 7.35-7.41 (m, 2H, H-2', H-4'), 7.20-7.32 (m, 1H, H-3), 3.81 (s, 3H, och3)

MS (m/z) 348 (ES-)

Analysis: Calculated for C16H13FNO5P: C, 55.02; H, 3.75; N, 4.01.

Found: C, 54.90; H, 3.89; N, 4.35.

Example 6

Dibenzyl 2-(3'-methoxyphenyl)-6,7-methylenedioxyaniline-4-yl-phosphate (I-6-a)

To a stirred solution of compound I-6 (67,9 the g 0.23 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (13,7 mg, or 0.57 mmol). After 1 hour, add tetraethylpyrophosphate (100 mg, 0,19 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain compound I-6-a as a colorless oil (88,6 mg, 84%)

Analysis: Calculated for C31H26NO7P: C, 67.02; H, 4.72; N, 2.52.

Found: C, 68.15; H, 4.68; N, 2.61.

2-(3'-Methoxyphenyl)-6,7-methylenedioxyaniline-4-yl-phosphate (I-6-b)

A suspension of compound I-6-a (97,74 mg, 0.18 mmol) in anhydrous Meon (10 ml) is subjected to hydrogenation in the presence of 10%Pd/C (50 mg) at room temperature for 10 minutes, the Catalyst and the precipitate is collected and dissolved in a 10%solution of NaHCO3and then filtered. The filtrate is acidified with HCl, the solid precipitate is collected by filtration and washed with acetone to obtain compound I-6-b (63.5 mg, 94%).

TPL >300°C

MS (m/z) 374 (ES-)

Analysis: Calculated for C17H14NO7P: C, 54.41; H, 3.76; N, 3.73.

Found: C, 53.86; H, 3.66; N, 3.81.

Sodium 2-(3'-methoxyphenyl)-6,7-methylenedioxyaniline-4-yl-phosphate (I-6-C)

Compound I-6-b is added to a mixture of 20 ml of Amberlite IR-120 (Na+

1H-NMR (D2O, 200 MHz): δ 7.56 (s, 1H, H-6'), 7.25-7.42 (m, 4H, H-5, H-8, H-2', H-5'), 7.12 (s, 1H, H-4'), 6.95 (s, 1H, H-3), 6.00 (s, 2H, och2Oh), 3.62 (s, 3H, och3)

In the following Example 7 was synthesized new intermediate compound, 2-selenophene-4-chinolin (I-7-d). 2-Selenophene-4-chinolin (I-7-d) were subjected to interaction with tetraethylpyrophosphate in the presence of alkali with the receipt of dimensional ether phosphoric acid (I-7-e).

Example 7

Selenophene-2-carboxylic acid (I-7-a)

To a solution of selenophene (20 g, 152,7 mmol) of (Et)2O (150 ml) was added TMEDA (25,5 ml, 170,0 mmol) and n-utility (66,1 ml of 2.5m solution in hexane, 152,8 mmol). The resulting solution was heated under reflux (reflux) for 1.5 hours and then cooled in a bath of acetone/CO2, then add the crushed solid carbon dioxide (40 g, 909.1 mmol). The reaction mixture is allowed to cool to room temperature and quenched by adding 10%aqueous solution of KOH. The aqueous layer was acidified to pH 3 with 8M HCl, extracted (Et)2O, washed with brine, dried over MgSO4filter and concentrate under vacuum to obtain compound I-7-a (24.6 g, 92.1 per cent).

TPL 122-124°C

MP 122-124°C

1H-NMR (CDCl3-d1, 200 MHz): δ 8.92 (s, 1H, -COON), 8.37 (dd, J=1.0 Hz, 5.6 Hz, 1, H-3), 8.13 (dd, J=0.8 Hz, 3.8 Hz, 1H, H-5), 7.37 (dd, J=3.8 Hz, 5.6 Hz, 1H, H-4).

MS (m/z) 175.0 (EI+)

Analysis: Calculated for C5H4O2Se: C, 34.31; N, 2.30

Found: C, 34.33; N, 2.28.

N-(5-Acetylbenzo[d][1,3]dioxo-6-yl)selenophene-2-carboxamide (I-7-c)

I-7-a (2 g, 11,40 mmol) is subjected to sequential chlorination thionyl chloride (4,1 ml, 56,18 mmol) is heated under reflux for 20 hours to obtain I-7-b, which without further purification process 2-amino-(4,5-methylendioxy)-acetophenone (1.63 g, 9,12 mmol) and triethylamine (2 ml, 14,80 mmol) in 100 ml of toluene at reflux for 3 hours. The reaction mixture is concentrated under vacuum and the solid residue washed sequentially with ethanol, dried at 80°C for 2 hours to obtain a crude compound I-7-(2.7 g, 74%).

TPL 198,5-198,8°C

MP 198.5-198.8°C

1H-NMR (DMSO-d6, 200 MHz): δ 12.85 (s, 1H, NHCO), 8.52 (d, J=5.1 Hz, 1H, H-3'), 8.16 (s, 1H, H-4), 7.93 (d, J=3.8 Hz, 1H, H-5'), 7.61 (1H, H-7), 7.49-7.46 (m, 1H, H-4'), 6.13 (s, 2H, OCH2O), 2.58 (s, 3H, CH3).

MS (m/z 336.2 (EI+)

Analysis: Calculated for C14H11NO4Se: C, 50.01; H, 3.30; N, 4.17.

Found: C, 50.11; H, 3.32; N, 4.15.

2-(2'-Selenophene)-6,7-(methylendioxy)-4-chinolin (I-7-d)

I-7-(2.7 g, 8.0 mmol) is suspended in 100 ml of t-BuOH. Add t-butyl potassium (4,49 g, 40 mmol) and the mixture heated under reflux for 24 hours. The mixture is then cooled to room temperature and poured into 100 ml aqueous NH4 Cl. Collect yellow-brown solid residue and washed with distilled water to obtainI-7-d(3.1 g, 85%).

MP >300°C.

1H-NMR (DMSO-d6, 200 MHz): δ 8.27 (s, 1H, H-3'), 7.83 (5, 1H, H-5'), 7.39 (t, J=4.5 Hz, 1H, H-4'), 7.31 (s, 1H, H-5), 7.14 (s, 1H, H-8), 6.11 (s, 3H, H-3, OCH2O).

MS (m/z 318.2 (EI+)

Analysis: Calculated for C14H9NO3Se: C, 52.85; H, 2.85; N, 4.40.

Found: C, at 52.87; H, 2.82; N, 4.45.

Dibenzyl 2-(2'-selenophene)-6,7-methylenedioxyaniline-4-yl-phosphate (I-7-e)

To a stirred solution of compoundI-7-d(100.0 mg, 0.32 mmol) in dry tetrahydrofuran (10 ml) at 0°C. add sodium hydride (30 mg, 1.25 mmol). After 1 hour, add tetraethylpyrophosphate (204,6 mg, 0.38 mmol) and continue stirring for 20 minutes

The mixture is filtered and the filtrate concentrated under vacuum at a temperature below 35°C. the Residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate solution, dried over MgSO4and concentrate under vacuum to obtain a solid residue, which was subjected to column chromatography on silica gel. In the elution with CH2Cl2get I-7-e (to 151.8 mg, 82%) as a yellowish connection.

So 110.5-110.8°C.

Analysis: Calculated for C28H22NO6PSe: C, 58.14; H, 3.83; N, 2.42.

Found: C, 57.28; H, 3.56; N, 2.59.

Example 8

6-Methyl-2-FeNi is a quinoline-4(1H)-it (I-8-a)

A mixture of p-toluidine (2.14 g, of 0.02 mol), ethylbenzylamine (4.9 g, of 0.025 mole) and polyphosphoric acid (PFC) is heated with stirring at 130°C. After the reaction mixture cooled to room temperature and neutralized 4M NaOH. The yellow solid residue is filtered off, washed with water, dried and recrystallized from ethanol to obtain compound I-8-a as a white residue (2.9 g, 48.9 per cent).

TPL 290,2-291,5°C

Mr 290.2-291.5°C

1H-NMR (DMSO-d6, 200 MHz): δ 11.55 (1H, s, H-1), 7.88 (1H, s, H-5) 7.79-7.82 (2H, m, H-2', H-3'), 7.66 (1H, d, J=8.5 Hz, H-8), 7.54-7.57 (3H, m, H-3', H-4', H-5'), 7.48 (1H, d, J=8.5 Hz, H-7), 6.31 (1H, s, H-3), 2.40 (3H, s, CH3)

MS (m/z 235 (EI+)

Analysis: Calculated for C16H13NO: C, 81.68; H, 5.57; N, 5.95.

Found: C, 81.60; H, 5.63; N, 5.88.

4-(Benzyloxy)-6-methyl-2-phenylphenol (I-8-b)

I-8-a (700 mg, 3 mmol) dissolved in dry DFA (30 ml) and add portions NaH (360 mg, 15 mmol) under stirring for 30 minutes at room temperature. Add dropwise benzylchloride (750 mg, 6 mmol) and mix at room temperature over night. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent n-hexane-EtOAc (3:1)and recrystallized from n-hexane-CH2Cl2obtaining I-8-b in the form of white crystals (536 mg, 54,%).

TPL 138,6-to 139.3°C

Analysis: Calculated for C23H19NO: C.84.89; H, 5.89; N, 4.30.

Found: C, 84.93; H, 5.85; N, 4.33.

N-{[4-(Benzyloxy)-2-phenylphenol-6-yl]methyl}-N-tiletamine (I-8-d)

I-8-b (650 mg, 2 mmol) and N-bromo-succinimide (NBS, 360 mg, 2 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg, 0.19 mmol) was placed in a dry round bottom flask, purged with argon. In an argon atmosphere with stirring 50 ml of dry benzene at room temperature for 30 minutes and then heated under reflux (reflux) at 80°C for 1 hour and then cooled to room temperature to obtain I-8-c, which without further purification process diethylamine (3.0 ml, 29,0 mmol) and then heated under reflux for 1 hour. After removal of the solvent by evaporation, the mixture separated EtOAc and 50 ml of 10%HCl, then the acid layer is neutralized to pH 7-8, 10%NaHCO3, extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent CH2Cl2-methanol (3:1)and recrystallized from n-hexane-EtOAc to obtain I-8-d as a pale yellow solid residue (120 mg, 15.1 per cent).

TPL to 107.7-108,6°C

Analysis: Calculated for C27H28N2O: S; H, 7.12; N, 7.06.

Found: C, 81.68; N, 703; N, 7.15.

6-[(Diethylamino)methyl]-2-phenylindolin-4(1H)-it (I-8-e)

I-8-d (120 mg, 0.3 mmol) was dissolved in glacial acetic acid (5 ml). Add HBr (3 ml) by heating the solution to 60°C., then the mixture is heated to 90°C for 3 hours. After completion of the reaction the mixture is poured into water and extracted with EtOAc. The acid layer is neutralized to pH 7-8 by adding 10%NaHCO3and extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is recrystallized from n-hexane-EtOAc to obtain I-8-d as a gray solid residue (55 mg, 59.9 per cent).

TPL 227,9-229,7°C

Analysis: Calculated for C20H22N2O: C, 78.40; H, 7.24; N, 9.14.

Found: C, 78.43; H, 7.35; N, 9.08.

Example 9

2-(2-Forfinal)-6-methylinosine-4(1H)-it (I-9-a)

A mixture of p-toluidine (2.14 g, of 0.02 mol), 2-fluoro-ethylbenzylamine (5,25 g of 0.025 mole) and polyphosphoric acid (PFC) is heated with stirring at 130°C. After the reaction mixture cooled to room temperature and neutralized 4M NaOH. The yellow solid residue is filtered off, washed with water, dried and recrystallized from ethanol to obtain compound I-9-a as a white residue (2.6 g, 51,3%).

TPL 259,1-259,9°C

1H-NMR (DMSO-d6, 200 MHz): δ 7.86 (1H, s, H-5), 7.64 (1H, td, J=7.58, H-4'), 7.47-7.57 (3H, m, H-7, H-8, H-6'), 7.30-7.43 (2H, d, J=7.02, dd, J=7.36, H-3', 5'), 6.12 (1H, s, H-3), 2.36 (3H, s, CH3 )

MS (m/z 253 (EI+)

Analysis: Calculated for C16H22FNO: C, 75.88; H, 4.78; N, 5.53.

Found: C, 75.94; H, 4.70; N, 5.46.

4-(Benzyloxy)-2-(2-forfinal)-6-methylinosine (I-9-b)

I-9-a (750 mg, 3 mmol) dissolved in dry DFA (30 ml) and add portions NaH (360 mg, 15 mmol) under stirring for 30 minutes at room temperature. Add dropwise benzylchloride (750 mg, 6 mmol) and mix at room temperature over night. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent n-hexane-EtOAc (3:1)and recrystallized from n-hexane-CH2Cl2obtaining I-9-b in the form of white crystals (515 mg, 50,0%).

TPL 91,5-92,8°C

Analysis: Calculated for C23H18FNO: C, 80.45; H, 5.28; N, 4.08.

Found: C, 80.51; H, 5.29; N, 4.17.

N-{[4-(Benzyloxy)-2-(2-forfinal)quinoline-6-yl]methyl}-N-tiletamine (I-9-d)

I-9-b (680 mg, 2 mmol) andN-bromo-succinimide (NBS, 360 mg, 2 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg, 0.19 mmol) was placed in a dry round bottom flask, purged with argon. In an argon atmosphere with stirring 50 ml of dry benzene at room temperature for 30 minutes and then heated under reflux (reflux) at 80°C in accordance with the s 1 hour and then cooled to room temperature to obtain I-9, which without further purification process diethylamine (3.0 ml, 29,0 mmol) and then heated under reflux for 1 hour. After removal of the solvent by evaporation, the mixture separated EtOAc and 50 ml of 10%HCl, then the acid layer is neutralized to pH 7-8, 10%NaHCO3, extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent CH2Cl2-methanol (3:1)and recrystallized from n-hexane-EtOAc to obtain I-9-d as a yellow solid residue (120 mg, 15.1 per cent).

TPL 51,2-51,5°C

Analysis: Calculated for C27H27FN2O: C, 78.23; H, 6.57; N, 6.76.

Found:: C, area of 78.25; H, 6.67; N, 6.74.

6-[(Diethylamino)methyl]-2-(2-forfinal)quinoline-4(1H)-it (I-9-e)

I-9-d (120 mg, 0.3 mmol) was dissolved in glacial acetic acid (5 ml). Add HBr (3 ml) by heating the solution to 60°C., then the mixture is heated to 90°C for 3 hours. After completion of the reaction the mixture is poured into water and extracted with EtOAc. The acid layer is neutralized to pH 7-8 by adding 10%NaHCO3and extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is recrystallized from n-hexane-EtOAc to obtain I-8-d as a gray solid residue (58 mg, 59.6 per cent).

TPL 184,2-184,7°C

Analysis: Calculated for C20 21FN2O: C, 74.05; H, 6.53; N, 8.64.

Found: C, 73.94; H, 6.62; N, 8.67.

Example 10

Ethyl 3-methyl-benzoyl-acetate (I-10-a)

To a vigorously stirred suspension of NaH (564 mg, to 48.5 mmol) and CO(OEt)2(5.73 g of 48.5 mmol) in anhydrous toluene (50 ml) is added dropwise a solution of 3-methylacetophenone (4,33 g, and 32.3 mmol) in toluene at reflux. After the addition the mixture is stirred at reflux for 30 minutes. The mixture is cooled to room temperature and acidified with ice Asón. After adding ice water the mixture is extracted with toluene. The organic layer is dried over MgSO4and evaporated. The remainder chromatographic on silica gel using as eluent CH2Cl2-hexane (3:2) to obtain the I-10-b in the form of a light yellow liquid (3.13 g, 46.9 per cent)

Analysis: Calculated for C12H14O3: C, 69.88; H, 6.84;

Found: C, 69.72; H, 6.95.

6-Methoxy-2-m-trilinolein-4(1H)-it (I-10-b)

A mixture of p-anisidine (2.14 g, of 0.02 mol),I-10-a(of 5.1 g of 0.025 mole) and polyphosphoric acid (PFC) is heated with stirring at 130°C. After the reaction mixture cooled to room temperature and neutralized 4M NaOH. The yellow solid residue is filtered off, washed with water, dried and paracrystalline is up from ethanol to obtain compound I-9-a in the form of a light purple solid residue (2.6 g, 25,8%).

TPL 262,2-264,1°C

1H-NMR (DMSO-d6, 200 MHz): δ 7.70 (1H, d, H-8), 7.55-7.60 (2H, m, H-5, 7), 7.25-7.47 (4H, m, H-2', H-4', H-5', H-6'), 6.33 (1H, s, H-3), 3.80 (3H, s, och3), 2.37 (3H, s, CH3)

MS (m/z) 265 (EI+)

Analysis: Calculated for C17H15NO: C, 76.79; H, 5.70; N, 5.28.

Found: C, 76.81; H, 5.62; N, 5.34.

4-(Benzyloxy)-6-methoxy-2-m-trilinolein (I-10)

I-10-b (795 mg, 3 mmol) dissolved in dry DFA (30 ml) and add portions NaH (360 mg, 15 mmol) under stirring for 30 minutes at room temperature. Add dropwise benzylchloride (750 mg, 6 mmol) and mix at room temperature over night. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent n-hexane-EtOAc (3:1)and recrystallized from n-hexane-CH2Cl2obtaining I-10-c in the form of white crystals (530 mg, 49.7 per cent).

TPL 133,0-134°C

Analysis: Calculated for C24H21NO2: C, 81.10; H, 5.96; N, 3.94.

Found: C, 81.9; H, 5.81; N, 3.97.

N-{[3-(4-(Benzyloxy)-6-methoxyquinoline-2-yl)phenyl]methyl}-N-tiletamine (I-19)

I-10-(530 mg, 2 mmol) andN-bromo-succinimide (NBS, 360 mg, 2 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg, 0.19 mmol) was placed in a dry round bottom flask, purged with argon. In an argon atmosphere p and stirring 50 ml of dry benzene at room temperature for 30 minutes and then heated under reflux (reflux) at 80°C for 1 hour and then cooled to room temperature to obtain I 10-d, which without further purification process diethylamine (3.0 ml, 29,0 mmol) and then heated under reflux for 1 hour. After removal of the solvent by evaporation, the mixture separated EtOAc and 50 ml of 10%HCl, then the acidic layer is neutralized to pH 7-8, 10%NaHCO3, extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is then chromatographic on silica gel, using as eluent CH2Cl2-methanol (3:1)and recrystallized from n-hexane-EtOAc to obtain I-10-e as a yellow solid residue (25 mg, 2.9 per cent).

TPL 89,2-89,5°C

Analysis: Calculated for C28H30N2O2: C, 78.83; H, 7.90; N, 6.57.

Found: C, 78.95; H, 7.14; N, 6.48.

2-{3-[(Diethylamino)methyl]phenyl}-6-methoxyquinoline-4(1H)-it (I-10-f)

I-10-e (42 mg, 0.1 mmol) is dissolved in glacial acetic acid (5 ml). Add HBr (3 ml) by heating the solution to 60°C., then the mixture is heated to 90°C for 3 hours. After completion of the reaction the mixture is poured into water and extracted with EtOAc. The acidic layer is neutralized to pH 7-8 by adding 10%NaHCO3and extracted with EtOAc (100 ml × 5). The organic layer is dried over MgSO4and evaporated. The residue is recrystallized from n-hexane-EtOAc to obtain I-10-f as a gray solid residue (20,8 mg, 61.9 percent).

TPL 152,1-152,7°C

Analysis: Calculated on the I C 21H24N2O2: C.74.97; H, 7.19; N, 8.33.

Found: C, 74.81; H, 7.33; N,8.31.

Anticancer activity

Antitumor activity of compounds I-1 and I-1-b in vivo

(I) the Effect of compounds I-1 and I-1-b xenotransplantation model tumor MCF 7

I-1 Materials and Methods

Female mice GALB/cAnN-Foxn1.E SCID (18-20 g; 6-8 weeks of age) were purchased from a National Animal Centre and held in forced ventilated cage according to the instructions. 2 days before transplantation of tumor mice subcutaneously implanted estradiol (0.7 mg). Cells MCF 7 (2×106) were subcutaneously inoculable in the right flank of the mice. After the emergence of 150 mm3tumor nodule 30 having a tumor mice were randomly divided into five groups for treatment with vehicle (PBS), I-1 or I-1-b. The first group received only the carrier. Group from the second to the fifth received I.P. Pavlova. following treatment three times per week, respectively: I-1 (15 mg/kg)I-1 (30 mg/kg), I-1-b (22,5 mg/kg) and (I-1-b (45 mg/kg). Mice were weighed and measured the tumor size every week using calipers. The tumor size was calculated by the following formula (L+W)/2, where L is length and W is width. On the final day of treatment, the mice were scored; the tumor was excised, weighed and made cuts; tumor sections were placed in the composition for optical coherence tomography (OCT) and frozen at -70°C.

I-2 Results

ISS is adavale action I-1 or I-1-b in vivo. Thirty females SCID mice were individually introduced subcutaneously cells MCF 7. Mice were divided into five groups (six mice in the group) and processed separately by the media, I-1 (15 or 30 mg/kg) and (I-1-b (22.5 or 45 mg/kg). As shown in figure 1, in vivo model of tumor shows a significant reduction in tumor volume in mice treated with 45 mg/kg I-1-b, compared with the control group mice (P<0,001). These results demonstrate that the I-1-b significantly inhibited tumor growth MCF 7 xenotransplantation mouse model.

(II) the Effect of compounds I-1 and I-1-b on intraperitoneal tumor model CT-26

II-1 Material and Methods

30 male Balb/c mice 6 weeks of age were purchased from the National Animal Centre and held in forced ventilated cage according to the instructions. Cells CT-26 (1×106) were injected with in the abdominal cavity at day 0. Carried out a randomized study of antitumor activity (n=10). Seven days after inoculation of tumor mice orally was administered 5 and 10 mg/kg I-1-b (every day for seven days (QD×7). Monitored the survival rate and body weight of animals.

II-2-1 appearance of the mice after treatment

Mice in the control group (filler) showed a pronounced ascites, whereas mice receiving oral I-1-b (5 mg/kg/day, QD×7) and I-1-b (10 mg/kg/day, D×7), showed reduced development of ascites.

II-2-2 the Average lifespan of mice after treatment

As shown in figure 2, all mice in the control group (the introduction of filler) 40 days were dead, while mice receiving compound I-1-b (5 mg/kg/day, QD×7) and compound I-1-b (10 mg/kg/day, QD×7), were all dead, respectively, 45 and 50 day after control of infection. Life expectancy was extended by 140% in the dose (10 mg/kg/day, QD×7) and 120% at a dose (5 mg/kg/day, QD×7). The maximum tolerable dose was not reached.

Study the viability of the cells (MTT method)

Cells were sown in 24-hole microtiter plate (2×104cells/well) overnight, then was treated with dimethylsulfoxide (DMSO) (Control) or various concentrations of the test compounds and incubated for 48 hours. The effect of test compounds on cell growth was investigated using analysis based on the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl, tetrazolium bromide) (MTT method). Briey, each well was added 40 μl of MTT solution (2 mg/ml, Sigma Chemical Co.) to bring the total volume to 500 μl, and incubated 1 hour at 37°C. supernatant was Aspirated and the MTT crystals-formazan formed by metabolically viable cells was dissolved in 200 μl of dimethyl sulfoxide. At the end of the determined coefficient is ogloszenia at 550 nm using an enzyme linked immunosorbent assay (ELISA).

The results:

Cytotoxic activity of compounds I-1-b, I-2-b, I-3-b, I-4-b, I-1-b, I-7-d, I-7-e against cancer cells human breast MCF-7

Cytotoxic effect of compounds I-1-b, I-2-b, I-3-b, I-4-b, I-1-b, I-7-d, I-7-e was evaluated on cancer cells human breast MCF-7. As shown in figure 3, the processing from 0.125 to 10 μm of these compounds caused a dose-dependent decrease in cell viability. These results indicate that compounds I-1-b, I-2-b, I-3-b, I-4-b, I-1-b, I-7-d, I-7-e exhibit significant cytotoxicity against cells µf 7. Therefore, these new derivatives of 2-aryl-quinoline proposed as potential therapeutic agents for the treatment of cancers.

Cytotoxic activity of compound I-7-d

Cytotoxic activity of compound I-7-d was tested in vitro on cells HCT-116, ner G2, NCI-H226, A, A and HL-60. As shown in Table 1, compound I-7-d shows significant inhibitory effect against most of the six cancer cell lines and most active against cells HCT-116 and HL-60. Compound I-7-d is IC500.9 µm against HCT-116 and IC500.5 µm against HL-60 cells. Compound I-7-d is a promising candidate for development as a new anticancer agent.

Table 1
IC50(µm)
STHepG2NCI-H226A549AHL-60
I-7-d0.94.14.98.12.70.5
* Six cancer cell lines were treated with compound I-7-d within 48 hours. After treatment, cells were collected and investigated using the MTT method.
* The value of the IC50mean concentration showing 50%growth - inhibitory effect.
* HCT-116 cell line of colon cancer; ner G2 cancer cell line hepatoma; NCI-H226 cell line large cell lung cancer; A549 cell line of lung cancer; A, cell line kidney cancer; HL-60 cancer cell line leukemia.

Cytotoxic activity of compounds I-8, I-9 and I-10-f

Cytotoxic activity of compounds I-8, I-9 and I-10-f was tested in vitro on ledah HL-60. As shown in Table 2, compound I-8 and I-9-e has a significant inhibitory effect against cancer cell lines HL-60. Compound I-8-e has the IC5015 μm, and compound I-9-e is IC50the 5.8 µm against HL-60 cells. Compound I-9-e is a promising candidate for development as a new anticancer agent.

Table 2
ConnectionIC50(µm)
I-8-C15
I-9-e5.8
I-10-f>50
* Cells HL-60 were treated with compound I-8, I-9 and I-10-f within 48 hours. After treatment, cells were collected and investigated using the MTT method.
* The value of the IC50mean concentration showing 50%growth - inhibitory effect.
* HL-60 cancer cell line leukemia

1. Phosphate derivatives of 2-aryl-4-quinolone of the formula Ia, Ib or Ic:


where R2', R3 ', R4', R5' and R6' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,
where n is an integer 0-4, Y is O or S, X is F, Cl or Br, and R8and R9independently represent (CH2)nCH3where n is an integer 0-4; R2, R3, R4and R5independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,
or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9defined above; and
R1and R1' independently represent H, Li+, Na+, K+N+R8R9R10R11or benzyl, where R10and R11independently represent H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3where n, R8and R9defined as above and m is an integer 0-4.

2. The phosphate derivative according to claim 1, which has the formula Ia.

3. The phosphate derivative according to claim 2, where R2', R3', R4', R5' and R6' all are H; or one of R2', R3', R4', R5' and R6' is F, och3or (CH2)nNR8R9and the others are H, R8and R9independently represent (CH2)nCH3where n is an integer from 0 to 4

4. The phosphate derivative according to claim 2, where R2, R3, R4and R5all represent H; or one of R2, R3, R4and R5represent F, och3, Y(CH2)nCH3or (CH2)nNR8R9and the others are H; or R2and R5are H, and R3and R4together form-O(CH2)nO-, where R8and R9independently represent (CH2)nCH3where n is an integer 0-4.

5. The phosphate derivative according to claim 2, where R1and R1' both represent H or Na+.

6. The phosphate derivative according to claim 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2', R3', R4' and R5' all are H; and R6' is F.

7. The phosphate derivative according to claim 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2', R3', R4' and R6' all are H, and R5' is F.

8. The phosphate derivative according to claim 5, where R4is F, and R2, R3and R5are H; and R2', R3', R4', R5' and R6' all represent N.

9. The phosphate derivative according to claim 5, where R2, R3, R4and R5all are H; and R2', R3', R4', R5' and R6' all before the order N.

10. The phosphate derivative according to claim 5, where R4is the co3and R2, R3and R5are H; and R5' is F, and R2', R3', R4' and R6' represent N.

11. The phosphate derivative according to claim 5, where R2and R5are H, and R3and R4together form-O(CH2)O-; and R2', R3', R4' and R6' all are H, and R5' is och3.

12. The phosphate derivative according to claim 5, where R4is CH2N(C2H5)2and R2, R3and R5are H; and R6' is F, and R2', R3', R4' and R5' represent N.

13. The phosphate derivative according to claim 5, where R4is CH2N(C2H5)2and R2, R3and R5are H; and R2', R3', R4', R5' and R6' all represent N.

14. The phosphate derivative according to claim 5, where R4is the co3and R2, R3and R5are H; and R5' is CH2N(C2H5)2and R2', R3', R4' and R6' represent N.

15. The phosphate derivative according to claim 1, which have the formula Ib.

16. The phosphate derivative according to item 15, where R2, R3, R4and R5all represent H; or one of R2, R3, R4and R5to depict the place F or co 3and the others are H; or R2and R5are H, and R3and R4together form-O(CH2)nO-, where n is an integer from 0 to 4.

17. The phosphate derivative according to item 15, where R2', R3' and R4' all are H; or one of R2', R3' and R4' is F or co3while others represent N.

18. The phosphate derivative according to item 15, where R1and R1' are benzyl.

19. Phosphate derivatives p, where R2', R3', R4', R2and R5all represent H, and R3and R4together form-O(CH2)O-.

20. Pharmaceutical composition for cell lysis, a solid cancer, which comprises as an active ingredient a therapeutically effective amount of a phosphate derivative of 2-aryl-4-quinolone according to any one of claims 1 to 19 or its pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leukemia.

21. The pharmaceutical composition according to claim 20, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, cancer of the kidney, GE is atomos or leukemia.

22. The pharmaceutical composition according to item 21, where the solid cancer is breast cancer in humans or colon cancer.

23. Connection 2-selenophene 4-hinolan the following formula IIb or IIc:

where R2', R3' and R4' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9where n is an integer 0-4, X is F, Cl or Br, and R8and R9independently represent (CH2)nCH3where n is an integer 0-4;
R2, R3, R4and R5independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,
or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9as specified above.

24. Connection item 23, where R2, R3, R4and R5all represent H; or one of R2, R3, R4and R5is F or co3and the others are H; or R2and R5are H, and R3and R4together form-O(CH2)nO-, where n is an integer from 0 to 4.

25. The connection point 24, where R2', R3' and R4' all are H; or one of R2', R3' and R4' is F or co3while others represent N.

26. Connection item 23, having the formula IIb.

27. Soy is inania according p, where R2', R3', R4', R2and R5all represent H, and R3and R4together form-O(CH2)O-.

28. Pharmaceutical composition for cell lysis, a solid cancer, which comprises as an active ingredient a therapeutically effective amount of 2-selenophene 4-quinolone according to any one of p-27 or its pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leukemia.

29. The pharmaceutical composition according p, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, kidney cancer, hepatoma, or leukemia.

30. The compound 2-phenyl 4-hinolan the following formula IIa:

where R2', R3', R4', R5' and R6' independently represent H, Y is(CH2)nCH3X or (CH2)nNR8R9,
where n is an integer 0-4, Y is O or S, X is F, Cl or Br and R8and R9independently represent (CH2)nCH3where n is an integer 0-4;
R2, R3, R4and R5the independent is IMO represent H, Y(CH2)nCH3X or (CH2)nNR8R9,
or R3and R4together form a-Y - (CH2)nY, n, Y, X, R8and R9defined above;
provided that one of R2, R3, R4and R5represents (CH2)qNR8R9or one of R2', R3', R4', R5' and R6' represents (CH2)qNR8R9where q is an integer of 1-4, and R8and R9defined above.

31. Connection item 30, where R4represents (CH2)qNR8R9and R2, R3and R5represent H, where q is an integer of 1-4, and R8and R9independently represent (CH2)nCH3where n is an integer of 1-4.

32. Connection item 30, where R5' represents (CH2)qNR8R9and R2', R3', R4' and R6' represent H, where q is an integer of 1-4, and R8and R9independently represent (CH2)nCH3where n is an integer of 1-4.

33. Connection p, where R4is CH2N(C2H5)2, R6' is F, and R2', R3', R4' and R5' represent N.

34. Connection p, where R4is CH2N(C2H5)2, R2', R3', R4', R5' and R6' all represent N.

35. The compound according to claim 3, where R4is the co3and R2, R3and R5are H; and R5' is CH2N(C2H5)2and R2', R3', R4' and R6' represent N.

36. Pharmaceutical composition for cell lysis, a solid cancer, which comprises as an active ingredient a therapeutically effective amount of 2-phenyl-4-quinolone according to any one of p-35 or its pharmaceutically acceptable salt as an active ingredient, where the solid cancer is breast cancer in humans, colon cancer, lung cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, prostate cancer, carcinoma of the caecum, glioblastoma, bone cancer, epidemology carcinoma of the nasopharynx, hepatoma or leukemia.

37. The pharmaceutical composition according p, where the solid cancer is leukemia.



 

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