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4'-demethylpodoph-yllotoxin derivative, its production and use

A technology for removing epipodophyllin and derivatives, which is applied in the field of synthesis of organic compounds, and can solve the problems of changing respiratory function, non-significant difference, damage, etc.

Inactive Publication Date: 2007-11-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since Topo II is a cell cycle-dependent enzyme and a good substrate for P170 glycoprotein, tumor cells are more likely to develop drug resistance to Topo II than Topo I; in addition, cancer cells are transformed from normal cells, The difference between the two types of cells is not significant. While killing cancer cells, etoposide has a damaging effect on normal cells in the body, especially bone marrow and intestinal mucosa cells that divide rapidly, resulting in myelosuppression, neutrophil Toxic and side effects such as reduction, nausea, hyaline membrane disease and changes in normal respiratory function, thereby inhibiting the dosage of the drug and hindering the efficacy of the drug

Method used

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  • 4'-demethylpodoph-yllotoxin derivative, its production and use
  • 4'-demethylpodoph-yllotoxin derivative, its production and use
  • 4'-demethylpodoph-yllotoxin derivative, its production and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1: Preparation of 4β-[N-(4H-1,2,4-triazol-4 base)]amino-4-deoxy-4'-norepipodophyllotoxin (compound IIIa)

[0017] Dissolve 88 mg (0.15 mmol) of etoposide and 90 mg (0.6 mmol) of sodium iodide in 1.5 mL of anhydrous acetonitrile, and stir at room temperature; in addition, dissolve 76 μL of dry trimethylchlorosilane in 1.5 mL of anhydrous acetonitrile, and This solution was slowly added dropwise to the reaction solution, stirred at room temperature for 1 hour to obtain the intermediate 4β-iodo-4-deoxy-4'-norepipodophyllotoxin (compound II), and 90 mg of anhydrous barium carbonate was added to the reaction solution (0.45mmol), stirred for 10 minutes, added a few drops of anhydrous triethylamine until the reaction solution was alkaline, added 3-amino-4H-1,2,4-triazole (0.18mmol), stirred at room temperature for 8-10 hours , suction filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and pu...

Embodiment 2

[0019] Example 2: Preparation of 4β-[N-(6-aminopyridin-2 bases)]amino-4-deoxy-4'-norepipodophyllotoxin (compound IIIb)

[0020] The operation process is the same as in Example 1, except that 2,6-diaminopyridine is used instead of 3-amino-4H-1,2,4-triazole. 62 mg of yellow solid IIIb was obtained, yield: 84%. Melting point: 131-135°C.

[0021] 1 H NMR (400MHz, DMSO) δ8.27(brs, 1H, 4'-OH), 7.05(t, J=8.0Hz, 1H, pyridine-H), 6.83(s, 1H, H-5), 6.52( s, 1H, H-8), 6.45(d, J=8Hz, 1H, 4-NH), 6.26(s, 2H, H-2', H-6'), 5.97(d, J=11.6Hz, 2H, OCH 2 O), 5.69 (dd, J=17.6, 8.0Hz, 2H, pyridine-H), 5.45 (brs, 2H, NH 2 ), 5.37(m, 1H, H-4), 4.50(d, J=5.2Hz, 1H, H-1), 4.34(t, J=7.8Hz, 1H, H-11a), 3.74(m, 1H , H-11b), 3.64(s, 6H, 3', 5'-OCH 3 ), 3.26(dd, J=14.4, 5.2Hz, 1H, H-2), 2.91(m, 1H, H-3).

Embodiment 3

[0022] Example 3: Preparation of 4β-[N-(2-chloropyridin-3-yl)]amino-4-deoxy-4'-norepipodophyllotoxin (compound IIIc)

[0023] The operation process is the same as in Example 1, except that 3-amino-4H-1,2,4-triazole is replaced with 2-chloro-3-aminopyridine. 61 mg of yellow solid IIIc was obtained, yield: 80%. Melting point: 129-134°C.

[0024] 1H NMR (400MHz, DMSO) δ7.84 (brs, 1H, 4'-OH), 7.27 (s, 1H, pyridine-H), 7.17 (m, 1H, pyridine-H), 6.84 (m, 1H, pyridine -H), 6.74(s, 1H, H-5), 6.59(s, 1H, H-8), 6.34(s, 2H, H-2', H-6'), 5.99(m, 2H, OCH 2 O), 4.69(m, 2H, H-4, 4-NH), 4.57(m, 1H, H-1), 4.36(t, J=8.0Hz, 1H, H-11a), 3.87(m, 1H , H-11b), 3.80 (s, 6H, 3', 5'-OCH 3 ), 3.15(dd, J=14.4, 5.2Hz, 1H, H-2), 3.07(m, 1H, H-3).

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Abstract

A 4'-demethylepipodophyllotoxin derivative IIIa-n is prepared by taking etoposide as raw material, reacting with sodium iodide to generate 4-bit iodine substitute and obtain intermediate II, agitating while adding into barium carbonate, regulating reactive system pH 7-8, adding into amino-compound, and reacting to room temperature for 8-10 hrs to obtain final product. It's simple and efficient, it can avoid 4-bit surface isomerization and 4-bit demethylation, it has strong inhibiting function of multiple tumor cell strain and non-toxic.

Description

technical field [0001] The invention belongs to a synthesis method of organic compounds, and relates to a 4'-norepipodophyllotoxin derivative and a preparation method, mainly involving 4β-substituted amino-4-deoxy-4'-norepipodophyllotoxin derivatives and The preparation method, and the application in the preparation of antitumor drugs. Background technique [0002] Etoposide is a semi-synthetic derivative of the natural product podophyllotoxin. As a kind of glycoside compound with high anti-tumor activity, it is widely used in the clinical treatment of testicular cancer, lymphoma, leukemia, non-small cell lung cancer, acute myeloid leukemia and other cancers. treat. [0003] Etoposide acts as a Topo II inhibitor to exert antitumor effects. Since Topo II is a cell cycle-dependent enzyme and a good substrate for P170 glycoprotein, tumor cells are more likely to develop drug resistance to Topo II than Topo I; in addition, cancer cells are transformed from normal cells, The d...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D519/00A61K31/4196A61K31/443A61K31/53A61K31/404A61K31/437A61K31/52A61K31/357A61K31/4025A61K31/4525A61P35/00
Inventor 胡永洲杜文婷何俏军杨波杨晓春
Owner ZHEJIANG UNIV
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