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4 beta-benseleno-4-desoxy-4-demethylpodophyllotoxin derivant

A nitrobenzyl selenium-based and selenium-based technology, which is applied in the field of compound preparation of anti-tumor drugs, can solve the problems of myelosuppression, high toxicity, and clinical application limitations, and achieve the effect of improving anti-tumor activity and reducing toxicity

Inactive Publication Date: 2004-08-11
陈绍明
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Etoposide (VP-16), a semi-synthetic glycoside derivative of the natural product podophyllotoxin discovered in the 1970s, has become one of the most important anti-tumor drugs currently used clinically, but its toxicity is relatively high, especially bone marrow suppression The clinical application is limited, which has been reported in the article "Research Progress of Podophyllotoxin Antineoplastic Drugs" (from "Chinese Journal of Pharmaceutical Industry", 1997, 28(2): 65-69)

Method used

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  • 4 beta-benseleno-4-desoxy-4-demethylpodophyllotoxin derivant
  • 4 beta-benseleno-4-desoxy-4-demethylpodophyllotoxin derivant
  • 4 beta-benseleno-4-desoxy-4-demethylpodophyllotoxin derivant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Preparation of 4β-benzylselenyl-4-deoxy-4′-desmethylpodophyllotoxin

[0015] Add 4α-podophyllotoxin (II), hydrogen bromide and solvent dichloromethane into the reaction vessel to obtain the product 4β-bromo-4-deoxy-4′-demethylpodophyllotoxin ( III), then benzyl diselenide, sodium borohydride, ethanol and tetrahydrofuran are added, and the compound of the present invention, namely 4β-benzylselenyl-4-deoxy-4′-desmethylpodophyllotoxin (I ) (The substituent R in the formula is benzylselenyl), and its melting point is 129-130°C.

[0016] The relevant detection data of the obtained product of the above structural formula (I) are as follows:

[0017] Mass spectrum (FAB-MS): relative kurtosis (%) m / z

[0018] (1) 100 383

[0019] (2) 6 341

[0020] (3) 25 299

[0021] (4) 6 267

[0022] (5) 31 229

[0023] IR(KBr, cm -1 ): 3440 (OH), 1750 (γ-lactone, C=O), 1610, 1510, 1500 (benzene ring, C=C), 1238, 1190 (C-O-C), 930 ...

Embodiment 2

[0026] Preparation of 4β-p-nitrobenzylselenyl-4-deoxy-4′-desmethylpodophyllotoxin

[0027] Add 4α-podophyllotoxin (II), hydrogen bromide and solvent dichloromethane into the reaction vessel to obtain the product 4β-bromo-4-deoxy-4′-demethylpodophyllotoxin ( III), then add p-nitrobenzyl diselenide, sodium borohydride, ethanol and tetrahydrofuran, and obtain the compound of the present invention, namely 4β-p-nitrobenzylselenyl-4-deoxy-4'-nor Podophyllotoxin (I) (the substituent R in the formula is p-nitrobenzylselenyl), and its melting point is 166-168°C.

[0028] The relevant detection data of the obtained product of the above structural formula (I) are as follows:

[0029] IR(KBr, cm -1 ): 3500 (OH), 1755 (γ-lactone, C=O), 1620, 1510, 1480 (benzene ring, C=C), 1540, 1335 (NO 2 ), 1285, 1150(C-O-C), 935(OCH 2 O).

[0030] 1 H-NMR(CDCL 3 , TMS500Mz)δppm: 7.93(d, 2H, 3″, 5″-H), 7.51(d, 2H, 2″, 6″-H), 6.66(s, 1H, 5-H), 6.57(s, 1H, 4-H), 6.34 (s, 2H, 2', 6'-H), 5.95, 5.91 (brs, J = 1.2...

Embodiment 3

[0032] 4β-p-fluorobenzselenyl-4-deoxy-4′-desmethylpodophyllotoxin

[0033] Add 4α-podophyllotoxin (II), hydrogen bromide and solvent dichloromethane into the reaction vessel to obtain the product 4β-bromo-4-deoxy-4′-demethylpodophyllotoxin ( III), then add p-fluorobenzyl diselenide, sodium borohydride, ethanol and tetrahydrofuran, and obtain the compound of the present invention, namely 4β-p-fluorobenzylselenyl-4-deoxy-4′-demethylated Phlotoxin (I) (the substituent R in the formula is p-fluorobenzylselenyl).

[0034] The relevant detection data of the obtained product of the above structural formula (I) are as follows:

[0035] IR(KBr, cm -1 ): 3500 (OH), 1755 (γ-lactone, C=O), 1620, 1510, 1480 (benzene ring, C=C), 1285, 1150 (C-O-C), 1050 (C-F), 935 (OCH 2 O).

[0036] 1 H-NMR(CDCL 3 , TMS500Mz)δppm: 7.28, 7.06, 7.01, 6.95 (each m, 1H, 2″, 4″, 5″, 6″-H), 6.50(s, 1H, 5-H), 6.39(s, 2H, 2', 6'-H), 6.01, 5.97 (brs, J=1.2, 7.5Hz, 2H, -OCH 2 O-), 5.43 (s, 1H, -OH), 4.47 (d, 1H, 4-H), 4...

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Abstract

The present invention relates to a novel podophyllotoxin derivatives. Its anti-tumor activity is raised and its loxicity is reduced. Said invention also provides its structural formula.

Description

Technical field [0001] The present invention relates to compounds used for preparing anti-tumor drugs. Background technique [0002] Etoposide (VP-16), a semi-synthetic glycoside derivative of the natural product podophyllotoxin discovered in the 1970s, has become one of the most important anti-tumor drugs currently in clinical use, but its toxicity is relatively high, especially for bone marrow suppression The effect has restricted the clinical application, which has been reported in the article "Research Progress of Podophyllotoxin Anti-tumor Drugs" (from "Chinese Journal of Pharmaceutical Industry", 1997, 28(2): 65-69). Summary of the invention [0003] The purpose of the present invention is to provide a new podophyllotoxin derivative with medicinal value, its anti-tumor activity can be maintained or even improved, and the toxicity is significantly lower than that of VP-16. [0004] The compound used in the present invention for preparing antitumor drugs has the chemical nam...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04
Inventor 陈绍明
Owner 陈绍明
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