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4-Substituted anilino epipodophyllotoxin derivatives and their uses

An epipodophyllotoxin and anilino-based technology, which is applied in the field of 4-substituted anilino epipodophyllotoxin derivatives and applications, and can solve problems such as poor water solubility, bone marrow suppression, and easy drug resistance

Inactive Publication Date: 2012-02-01
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although the above two compounds have been used clinically for many years, there are still problems such as poor water solubility, bone marrow suppression, and easy drug resistance, which limit their application.

Method used

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  • 4-Substituted anilino epipodophyllotoxin derivatives and their uses
  • 4-Substituted anilino epipodophyllotoxin derivatives and their uses
  • 4-Substituted anilino epipodophyllotoxin derivatives and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Embodiment 1 The synthetic general formula of the present invention is:

[0014]

Embodiment 2

[0015] Example 2: Preparation of compound 4'-O-desmethyl-4-deoxy-[4-(4"-p-methoxybenzamido)anilino]epipodophyllotoxin (GL1)

[0016] first step: (Refer to literature method: Francesco Troisi et al. Tetrahedron Letters 2007, 48, 7986-7989)

[0017] 5.05g di-tert-butyl dicarbonate (Boc 2 (2, 23mmol) was dissolved in dioxane, under ice-bath conditions, was added dropwise in the dioxane solution of 5g p-phenylenediamine (compound 1, 46.3mmol), stirred overnight at room temperature after the dropwise addition, Then the reaction solution was concentrated under reduced pressure, and the remaining residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether=7 / 3) to obtain compound II, yield: 92.7%; yellow solid, melting point: 108.9 -113.7°C.

[0018] Step two:

[0019] Under nitrogen protection, 5g etoposide (compound III, 8.5mmol) and 5.11g sodium iodide (34mmol) were dissolved in 50mL anhydrous acetonitrile; another dry 4.3mL trimethylchlorosilane ...

Embodiment 3

[0026] Example 3: Preparation of compound 4'-O-desmethyl-4-deoxy-[4-(4"-p-fluorobenzamido)anilino]epipodophyllotoxin (GL2)

[0027] The operating process is as in Example 1, except that p-fluorobenzoic acid is used instead of p-methoxybenzoic acid. A yellow solid was obtained, yield: 57%, melting point: 157.2-158.9°C, 1 HNMR (500MHz, CDCl 3)δ7.86 (m, 2H, 2"', 6"'-H), 7.66 (s, 1H, -CONH-), 7.44 (d, J=8.5Hz, 2H, 3", 5"-H) , 7.14(t, J=8.5Hz, 3"', 5"'-H), 6.76(s, 1H, 5-H), 6.55(d, J=9.0Hz, 2H, 2", 6"-H ), 6.52 (s, 1H, 8-H), 6.34 (s, 2H, 2', 6'-H), 5.95 and 5.97 (AB q, J=1.0Hz, 2H, -OCH 2 O-), 4.66(m, 1H, 4-H), 4.59(d, J=5.5Hz, 1H, 1-H), 4.36(t, J=8.0Hz, 1H, 11-H), 3.98(t , J=8.0Hz, 1H, 11-H), 3.85 (br, 1H, -CONH), 3.79 (s, 6H, 3', 5'-OCH 3 ), 3.13(dd, J=5.0Hz, 14.0Hz, 1H, 2-H), 3.00(m, 1H, 3-H).

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Abstract

The present invention provides a class of 4-substituted anilino epipodophyllotoxin derivatives, which refers to 4'-O-demethyl-4-deoxy-4-substituted anilino epipodophyllotoxin derivatives, which utilize existing drugs Etoposide was used as a lead compound to synthesize a series of compounds with anti-tumor activity through structural modification. Preliminary in vitro screening and in vivo anti-tumor experiments showed that these compounds had good anti-tumor activity, and compound GL3 was effective in improving tumor inhibition. While acting, its toxicity is also significantly reduced, and an antitumor drug with high antitumor activity, low toxicity, and effective for multidrug-resistant tumors can be prepared; the general structural formula of the present invention: .

Description

technical field [0001] The invention belongs to the preparation and use of compounds, and mainly relates to the preparation of 4'-O-desmethyl-4-deoxy-4-substituted anilino epipodophyllotoxin derivatives and their application in the preparation of antitumor drugs. Background technique [0002] Etoposide and teniposide are currently clinically used antineoplastic drugs, both of which are semi-synthetic derivatives of 4'-O-desmethyl epipodophyllotoxin. 4'-O-desmethyl epipodophyllotoxin derivatives can destroy the structure and function of DNA by inhibiting the activity of DNA topoisomerase II, thereby exerting an anti-tumor effect. [0003] Although the above two compounds have been used clinically for many years, they still have problems such as poor water solubility, bone marrow suppression, and easy drug resistance, which limit their application. Therefore, in order to overcome the above shortcomings and find more efficient and low-toxic podophyllotoxin compounds, researche...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/365A61P35/00
Inventor 胡永洲汪丽杨波何俏军
Owner ZHEJIANG UNIV
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