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Deoxy-podophyllotoxin type compound and preparation and application thereof

A technology for methyl deoxypodophylloyloxyformyl and compounds, which is applied in the field of deoxypodophyllotoxin compounds, can solve the problems that water solubility has not been fundamentally improved and the stability of compounds is not high, and achieves mild conditions, simple methods, and raw materials. Inexpensive and easy to get effects

Inactive Publication Date: 2011-05-25
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The structural transformation of deoxypodophyllum is generally through the demethylation reaction at the 4′ position, and then forms ester compounds. On the one hand, some compounds show better biological activity, but these compounds are not stable and their water solubility has not been obtained. fundamental improvement

Method used

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  • Deoxy-podophyllotoxin type compound and preparation and application thereof
  • Deoxy-podophyllotoxin type compound and preparation and application thereof
  • Deoxy-podophyllotoxin type compound and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 4′-Desmethyl deoxypodophyllo (VIII)

[0034] Get 8.0g of 10% Pd / C and 200mL of acetic acid into the autoclave, under H 2 Stir under atmosphere until no more H 2 Until it is absorbed, take 12.0g (19.3mmol) 4′-norepipodophyllophyllum (VI) and add it, and the mixture is kept at 85°C under 2atm H 2 The reaction was stirred under atmosphere for 5 hours, cooled naturally, the catalyst was filtered off, and concentrated to obtain a crude product. The crude product was further recrystallized from methanol to obtain 5.8 g of white solid. Yield 78%, m.p.: 244-245°C, (c 0.5CHCl 3 ). 1 H NMR (400MHz, CDCl 3 )δ6.66(s, 1H), 6.52(s, 1H), 6.35(s, 2H), 5.94(d, J=9.2Hz, 2H), 5.41(s, 1H), 4.60(s, 1H), 4.45-4.42 (m, 1H), 3.93-3.90 (m, 1H), 3.78 (s, 6H), 3.08-3.05 (m, 1H), 2.77-2.72 (m, 3H).

[0035] In the tumor cell proliferation inhibition experiment described later, the sample number of this embodiment is VII.

Embodiment 2

[0037] 4′-Desmethyl deoxypodophylloyloxyformyl p-nitrophenyl ester (IX)

[0038] Dissolve p-nitrophenyl chloroformyl ester (1.3g, 6.35mmol) in 10ml of dry dichloromethane, and add 0.6ml of dry pyridine. Under the protection of nitrogen, 5 ml of dichloromethane solution dissolved with deoxypodophyllophyllum (7.2 g, 1.87 mmol) was added. The mixture was reacted at room temperature for 1 h. After the reaction, 10 ml of water was added to the above reaction solution, and extracted three times with dichloromethane. The organic layers were combined, washed with water and saturated brine successively, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 8.9 g of compound IV by column chromatography, yield: 92%. 1 H NMR (400MHz, CDCl 3 )δ8.30(d, J=8.8Hz, 2H, p-Ph), 7.50(d, J=9.2Hz, 2H, p-Ph), 6.68(s, 1H, H-5), 6.52(s, 1H, H-8), 6.43(s, 1H, H-2', 6'), 5.96(s, 2H, OCH 2 O), 4.66(d, J=4.2Hz, 1H, 1-H), 4.49-4.45(m, 1H, H-11a), 3.96-3.9...

Embodiment 3

[0040] 4′-Desmethyl-deoxypodophyllooxyformyl 4-N-4-methylphenylpiperazine amide

[0041] 110 mg (0.2 mmol) of compound IX was dissolved in 5 ml of dry dichloromethane, and N-methylpiperazine (22 mg, 0.22 mmol) and triethylamine (25 mg, 0.22 mmol) were added sequentially at room temperature under nitrogen protection. Stirring was continued until the reaction was completed, and a white solid compound Ia was obtained by direct column chromatography. The product detection data are as follows:

[0042] Yield: 72%; m.p.: 232-234°C; (c 0.3, CHCl 3 ); IR (cm -1 )3397, 2923, 1771, 1722, 1599, 1483, 1458, 1421, 1228, 1038, 999; 1 H NMR (400MHz, CDCl 3 )δ7.26(s, 1H), 6.66(s, 1H), 6.52(s, 1H), 6.37(s, 2H), 5.94(d, J=6.8Hz, 2H), 4.71(brs, 1H), 4.63(t, J=6.4Hz, 1H), 4.47-4.42(m, 1H), 3.93-3.88(m, 1H), 3.71(brs, 8H), 3.57(br, 2H), 3.08-3.04(m, 1H), 2.80-273(m, 3H), 2.44(t, J=4.4Hz, 4H), 2.33(s, 3H); 13 C NMR (100MHz, CDCl 3 )δ174.8, 153.3, 151.8(2C), 147.0, 146.7, 138.4, 138.7, 130...

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Abstract

The invention discloses a deoxy-podophyllotoxin type compound, and a preparation method and a use of the compound. The structural formula of the compound is as shown in formula I, and a substituting group NR1R2 in the formula I is a piperazine type compound as shown in formula II, or the NR1R2 is an amino acid amide type compound as shown in formula III. The compound of the invention can be applied in the preparation of anti-tumor medicaments. The formula I, the formula II and the formula III are as follows.

Description

technical field [0001] The invention relates to a deoxypodophyllotoxin compound, a preparation method and application of the compound. Background technique [0002] Podophyllotoxin and related lignans are a class of natural active substances with significant cytotoxicity. Etoposide (VP-16) and Teniposide (VM-26) developed in the mid-1970s and Etopophos (prodrug of VP-16) launched in the mid-1990s are anti-tumor drugs developed based on the research on the parent of podophyllotoxin . In terms of mechanism of action, drugs such as VP-16 can inhibit small cell lung cancer, non-Hodge's disease, acute mononuclear leukemia, myeloid mononuclear cell by inhibiting topoisomerase-II (TOP-II). Treatment of various tumors such as leukemia, breast cancer, bladder cancer, and testicular cancer (Liu Changjun et al., Research and Development of Natural Products. 1997, 9, 81-89). In recent years, another group of podophyllotoxin drug candidates are undergoing clinical trials, such as NK-6...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/496A61P35/00A61P35/02
Inventor 陈世武惠玲金岩
Owner LANZHOU UNIVERSITY
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