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Combination of deoxypodophyllin and 5-fluorouracil and its preparation and use

A kind of technology of deoxypodophyllin and fluorouracil, which is applied in the field of compound preparation, the combination of deoxypodophyllin and 5-fluorouracil

Inactive Publication Date: 2011-11-30
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen that the overall performance of podophyllotoxin compounds has good biological activity, but different compounds may have different mechanisms of action, so the discovery of new podophyllotoxin compounds with high efficiency and low toxicity is still an effective way to discover anti-tumor drugs

Method used

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  • Combination of deoxypodophyllin and 5-fluorouracil and its preparation and use
  • Combination of deoxypodophyllin and 5-fluorouracil and its preparation and use
  • Combination of deoxypodophyllin and 5-fluorouracil and its preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of N-5-fluorouracil acetic acid 4′-nor-4-deoxypodophyllotoxin ester

[0024] Take 77 mg (0.2 mmol) of the compound of formula III and dissolve it in 10 ml of dry dichloromethane, add N-5-fluorouracil acetic acid (40 mg, 0.22 mmol) and a catalytic amount of N, N-dimethylaminopyridine at room temperature under nitrogen protection, Stirring was continued until the reaction was completed. The white solid compound was separated by direct column chromatography. The detection data of the product obtained by the reaction are as follows:

[0025] Yield: 62%; m.p.: 180-182°C; (c 0.3, CHCl 3 ); IR (cm -1 ) 3194, 3072, 3004, 2943, 2915, 2844, 1773, 1706, 1670, 1601, 1505, 1483, 1463, 1420, 1378, 1337, 1227, 1159, 1130, 1093, 1037, 996; 1 HNMR (400MHz, CDCl 3 )δ9.40(br, 1H, NH), 7.31(d, J=5.6Hz, 1H), 6.67(s, 1H), 6.51(s, 1H), 6.39(s, 2H), 5.95(d, J =7.6Hz, 2H), 4.77(s, 2H), 4.63(d, J=4.4Hz, 1H), 4.46(t, J=8.8Hz, 1H), 3.92(t, J=8.8Hz, 1H), 3.70(s, 6H, 2OMe), 3.07...

Embodiment 2

[0028] Preparation of N-5-fluorouracil acetyl-L-alanine 4′-nor-4-deoxypodophyllotoxin ester

[0029] The experimental procedure is the same as in Example 1, except that N-5-fluorouracil acetyl-alanine is used instead of N-5-fluorouracil acetic acid. The detection data of the product obtained by the reaction are as follows:

[0030] Yield: 70%; m.p.: 168-170°C; (c 0.3, CHCl 3 ); IR (cm -1 )3518, 3316, 3206, 3071, 2920, 2846, 1768, 1696, 1670, 1601, 1505, 1483, 1462, 1422, 1379, 1338, 1227, 1130, 1037, 996; 1 HNMR (400MHz, CDCl 3 )δ9.71 (brs, 1H, NH), 7.36-7.33 (m, 1H, NH), 7.17 (d, J=7.2Hz, 1H), 6.66 (s, 1H), 6.49 (s, 1H), 6.37 (s, 2H), 5.93(d, J=7.6Hz, 2H), 4.88-4.83(m, 1H), 4.60(d, J=4.0Hz, 1H), 4.45(t, J=6.4Hz, 1H) , 4.36-4.33(m, 2H), 3.90(t, J=8.8Hz, 1H), 3.66(s, 6H, 2OMe), 3.06(dd, J=12.0, 4.0Hz, 1H), 2.80-2.72(m , 3H), 1.55(d, J=7.2Hz, 3H); 13 C NMR (100MHz, CDCl 3 ( d, J=33Hz, 1C), 128.4, 127.2, 110.3, 108.5, 107.8, 101.2, 72.1, 56.2 (2OMe), 49.9, 48.4, 47.2, ...

Embodiment 3

[0033] Preparation of N-5-fluorouracil acetyl-L-valine 4-deoxy-4′-norpodophyllotoxin ester

[0034] The experimental procedure is the same as in Example 1, except that N-5-fluorouracil acetyl-valine is used instead of N-5-fluorouracil acetic acid. The detection data of the product obtained by the reaction are as follows:

[0035] Yield: 65%; m.p.: 183-185°C; (c 0.3, CHCl 3 ); IR (cm -1 )3316, 3204, 3070, 3002, 2966, 2938, 2844, 1765, 1703, 1601, 1505, 1483, 1465, 1422, 1378, 1338, 1227, 11154, 1131, 1038, 996; 1 H NMR (400MHz, CDCl 3 )δ7.35(d, J=5.6Hz, 1H), 7.05(br, 1H), 6.67(s, 1H), 6.50(s, 1H), 6.37(s, 2H), 5.94(d, J=3.2 Hz, 2H), 4.88-4.84(m, 1H), 4.61(d, J=3.2Hz, 1H), 4.46(t, J=6.8Hz, 1H), 4.36(q, J=3.6Hz, 2H), 3.90(t, J=8.8Hz, 1H), 3.66(s, 6H, 2OMe), 3.07(dd, J=13.2, 4.4Hz, 1H), 2.80-2.67(m, 3H), 2.46-2.35(m, 1H), 1.01(d, J=6.8Hz, 6H); 13 C NMR (100MHz, CDCl 3 )δ175.0, 174.9, 169.4, 166.2, 157.2 (d, J=27Hz, 1C), 151.1, 151.0, 149.9, 147.1, 146.7, 140.3 (d, J=236H...

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Abstract

The invention discloses deoxypodophyllo and 5-fluorouracil spliced compounds, and a preparation method and application of the compounds. The structure of the deoxypodophyllo and 5-fluorouracil spliced compounds is shown as a formula I or II. The preparation method for the spliced compounds comprises the following steps of: mixing 4'-demethyl-4-deoxypodophyllo and 5-FUalkyl acyl-N-substituted amino acid or 5-FU substituted fatty acid, and reacting in the presence of a condensing agent of dicyclohexylcarbodiimide (DCC) and a catalyst of N,N-dimethyl-aminopyridine to obtain the target compounds shown as the formula. The deoxypodophyllo and 5-fluorouracil spliced compounds can be applied to preparing medicines for treating tumors.

Description

technical field [0001] The invention relates to an organic compound used for preparing medicine, a preparation method and application of the compound. Specifically, the present invention is a combination of deoxypodophyllin and 5-fluorouracil, as well as the preparation method and application of this compound. Background technique [0002] Podophyllotoxin (PT) and related lignans are a class of natural active substances with significant cytotoxicity. Its biological activities are mainly anti-tumor, anti-virus, etc., but due to its high toxicity, its direct use as a drug is limited. For this reason, a large number of structural modifications have been carried out on podophyllotoxin, and many active compounds have been obtained, among which Etoposide (VP-16) and Teniposide (VM-26) developed in the mid-1970s and Etopophos released in the mid-1990s (Prodrugs of VP-16) are used as clinical first-line anti-tumor drugs, and are widely used in small cell lung cancer, non-Hodget's ...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07K5/078C07K1/10A61P35/00A61P35/02
Inventor 陈世武向蓉惠玲
Owner LANZHOU UNIVERSITY
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