Compounds of podophyllotoxins, application and preparation method

A technology of compounds and alcohol esters, applied in the field of new podophyllotoxin compounds, can solve the problems of poor water solubility, strong drug resistance, poor oral effect, etc., to achieve delayed drug resistance, appropriate lipid-water partition coefficient, Good anti-tumor effect

Inactive Publication Date: 2005-01-12
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tests have shown that podophyllotoxin drugs such as VP-16 have an effective effect on many tumor cells such as small cell lung cancer, non-Hodget's disease, acute monocytic leukemia, progressive monocytic leukemia, breast cancer, bladder cancer, and testicular cancer. Good therapeutic effect, but

Method used

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  • Compounds of podophyllotoxins, application and preparation method
  • Compounds of podophyllotoxins, application and preparation method
  • Compounds of podophyllotoxins, application and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 4′-norepipodophyllotoxin of 4β-4-deoxy-nitrogen substituted valine (5-Fu yl)propanol ester

[0023] Take 10mmol ethyl acetoacetate protected amino acid potassium salt and an equivalent amount of N 1 -Bromopropyl 5-Fu was dissolved in dry DMF, and a trace amount of KI was added to react at room temperature for 24 hours. KBr was filtered off, the filtrate was evaporated under reduced pressure to remove DMF, dissolved in 70ml of ethyl acetate, washed with 50ml of 1M sodium bicarbonate and 2×50ml of water, and dried overnight with anhydrous sodium sulfate. Evaporate the solution under reduced pressure, add 20ml of 1M methanol solution of hydrogen chloride and stir at room temperature for 2 hours, evaporate the solvent under reduced pressure, dissolve with 15ml of water, and extract with 2×15ml of ethyl acetate, distill the water layer under reduced pressure to obtain N 1 - The hydrochloride salt of 5-Fuyl-propanol ester. The above hydrochloride was added to 20ml of dichlo...

Embodiment 2

[0029] 4′-norepipodophyllin of 4β-4-deoxy-nitrogen substituted 5-Fu propyl ester of phenylalanine

[0030] The experimental procedure is the same as in Example 1, except that valine is replaced by phenylalanine. The detection data of the product obtained by the reaction are as follows:

[0031] Yield: 33%; m.p.113-115°C; 1 HNMR (CDCl 3 , TMS, 300MHz): 9.34(br, 1H, CONH*CO), 7.32~7.09(m, 5H, Ar-H), 7.03(d, 1H, H-6(5-Fu), J=5.1Hz) , 6.45(s, 1H, H-5), 6.33(s, 1H, H-8), 6.22(s, 2H, H-2', 6'), 5.95(d, 2H, OCH 2 O, J = 1.8Hz), 5.46 (br, 1H, OH), 4.45 (d, 1H, H-1, J = 5.4Hz), 4.26 (d, 2H, H-11, J = 8.7Hz), 4.10 (t, 2H, OCH 2 , J=6.0Hz), 4.02(d, 1H, H-4, J=3.9Hz), 3.74(s, 6H, OCH 3 ), 3.50(t, 2H, CH 2 -5Fu, J=6.6Hz), 3.38(t, CH*CH 2 Ar, J = 6.9Hz) 3.16 (dd, 1H, H-2, J 1 =13.5, 5.4Hz), 3.01 (m, 2H, ArCH 2 -), 2.75(m, 1H, H-3), 1.85(m, 2H, -CH 2 -);IR(KBr)υcm -1 , 3440, 2918, 1772, 1697, 1481, 1230, 1112; HRMS (ESI) C 37 h 36 o 11 N 3 F, theoretical value (M+Na), 740.222...

Embodiment 3

[0034] 4′-norepipodophyllotoxin of 4β-4-deoxy-nitrogen substituted isoleucine 5-Fu propyl ester

[0035] The experimental procedure is the same as in Example 1, except that the valine in Example 1 is replaced with isoleucine. The detection data of the product obtained by the reaction are as follows:

[0036] Yield: 38%; m.p.118-120°C; 1 HNMR (CDCl 3 , TMS, 300MHz): 8.84 (br, 1H, CONH*CO), 7.28 (d, 1H, H-6(5-Fu), J=5.4Hz), 6.65 (s, 1H, H-5), 6.50 (s, 1H, H-8), 6.24 (s, 2H, H-2', 6'), 5.97 (d, 2H, OCH 2 O, J = 5.4Hz), 5.41 (br, 1H, OH), 4.55 (d, 1H, H-1, J = 5.7Hz), 4.33 (s, 1H, OCHa), 4.30 (s, 1H, OCHb) , 4.23(m, 1H, H-4), 3.95(d, 1H, H-11a), 3.82(t, 2H, CH 2 -5Fu, J=6.0Hz), 3.76(s, 6H, OCH 3 ), 3.60(m, 1H, H-11b), 3.47(s, 1H, OH), 3.42(dd, 1H, H-2, J=13.8, 5.4Hz), 3.29(d, 1H, CH*COO, J=5.4Hz), 2.85(m, 1H, H-3), 2.32(m, 1H, CHMe 2 ), 2.08 (m, 2H, -CH 2 -), 1.74(m, 1H, EtCH*Me), 1.41(m, 1H, MeCHa*CHMe), 1.19(m, 1H, MeCHb*CHMe) 0.89(m, 6H, 2CH 3 ); IR(KBr)υcm -1 , 3439...

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Abstract

In this invention, aminoic potassium salt reacts with N1-bromoalkyl 5-Fu, under the protection of N, to produce L-aminoic 5-Fu alcoholate type compound. Said compound is then reacting with 4 beta-Br-4-deoxy-4-demethylepipodophyllum which being produced from podophyllo to obtain 4 beta-4-deoxy-nitrogen substituted aminoic 5 Fu ester-4-demethyl epipodophyllum. This invention compound is used for preparing anti-tumor medicine.

Description

technical field [0001] The present invention relates to a new class of podophyllotoxin compounds, the use of this compound and the synthesis method of this compound. Background technique [0002] Podophyllotoxin and related lignans are a class of natural active substances with significant cytotoxicity. Since King and Shliivan first reported that podophyllotoxin has colchicine-like effects in the 1940s (Stahelin H.F., Eur.J.Cancer, 1970, 6, 303), although it has been used for a period of time because of its toxic side effects Time limits its clinical application. Afterwards, many chemists and pharmacologists modified its structure in order to obtain podophyllotoxin drugs with good antitumor activity and less toxic side effects. In the 1960s and 1970s, Sandoz Company successively discovered that VP-16 (etopside) and VM-26 (teniposide), the β-D-glucose derivatives of 4′-norepipodophyllotoxin, have a strong inhibitory effect on tumor cells. In 1983, VP-16 was officially appro...

Claims

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Application Information

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IPC IPC(8): A61K31/513A61P35/00C07D493/04
Inventor 陈世强田瑄涂永强
Owner LANZHOU UNIVERSITY
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