Benzocyclophosphamide phenate derivatives as well as preparation method and application thereof

A technology of benzocyclophosphamide and its derivatives, which is applied in the field of phenolic acid benzocyclophosphamide derivatives and their preparation and application, can solve the problems of bladder toxicity, prolong survival time, inhibit angiogenesis, and achieve excellent results Effect

Inactive Publication Date: 2012-08-15
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But its disadvantage is that it is bladder toxic

Method used

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  • Benzocyclophosphamide phenate derivatives as well as preparation method and application thereof
  • Benzocyclophosphamide phenate derivatives as well as preparation method and application thereof
  • Benzocyclophosphamide phenate derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 7-(3',4'-Dihydroxybenzamido)-2-[bis(2-chloroethyl)amino]-1,3,2-benzoxaphos-2-oxide (1) Preparation of:

[0027] (1) structure see image 3 , under the protection of nitrogen, add 1.54g (0.01mol) 3.4-dihydroxybenzoic acid and 20mL dioxane to the dry reactor, add 2.2mL (0.03mol) of thionyl chloride dropwise, and react at 95-100°C for 3 After 1 hour, add 3.89 g (0.012 mol) of intermediate (II) in 20 mL of dioxane solution, and continue the reaction at 95-100°C for 5-6 hours. The solvent was recovered under reduced pressure, separated and purified by silica gel column chromatography to obtain 7-(3',4'-dihydroxybenzamido)-2-[bis(2-chloroethyl)amino]-1,3,2- Benzoxaphos-2-oxide (1). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.78 (m, 4H, CH 2 ), 3.21 (m, 1H, NH), 3.52-3.92 (m, 6H, CH 2 ), 5.35 (s, 2H, OH), 6.82-7.45 (m, 6H, Ar-H), 9.13 (s, 1H, Ar-NH). Anal Calcd for C 18 h 20 Cl 2 N 3 o 5 P : C, 46.97; H, 4.38; N, 9.13. Found: 46.90; H, 4.37; N, 9.14.

Embodiment 2

[0029] 7-(3',4'-dimethoxybenzamido)-2-[bis(2-chloroethyl)amino]-1,3,2-benzoxaphos-2-oxide ( 2) Preparation:

[0030] (2) structure see Figure 4 , replace 3.4-dihydroxybenzoic acid with 3,4-dimethoxybenzoic acid in Example 1, and others are the same as Example 1 to obtain 7-(3',4'-dimethoxybenzamido) -2-[bis(2-chloroethyl)amino]-1,3,2-benzoxaphos-2-oxide (2). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.80 (m, 4H, CH 2 ), 3.24 (m, 1H, NH), 3.52-3.92 (m, 12H, CH 2 , OCH 3 ), 6.80-7.65 (m, 6H, Ar-H), 9.12 (s, 1H, Ar-NH). Anal Calcd for C 20 h 24 Cl 2 N 3 o 5 P : C, 49.19; H, 4.95; N, 8.61. Found: 49.12; H, 4.95; N, 8.60.

Embodiment 3

[0032] 7-(3',4'-diacetoxybenzamido)-2-[bis(2-chloroethyl)amino]-1,3,2-benzoxaphos-2-oxide ( 3) Preparation:

[0033] (3) structure see Figure 5 , replace 3.4-dihydroxybenzoic acid with 3,4-diacetoxybenzoic acid in Example 1, and the others are the same as Example 1 to obtain 7-(3',4'-diacetoxybenzamido) -2-[bis(2-chloroethyl)amino]-1,3,2-benzoxaphos-2-oxide (3). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.25 (s, 6H, CH 3 ), 2.84(m, 4H, CH 2 ), 3.23 (m, 1H, NH), 3.54-3.91 (m, 6H, CH 2 ), 6.80-7.81 (m, 6H, Ar-H), 9.15 (s, 1H, Ar-NH). Anal Calcd for C 22 h 24 Cl 2 N 3 o 7 P : C, 48.54; H, 4.44; N, 7.72. Found: 48.52; H, 4.44; N, 7.73.

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Abstract

The invention relates to benzocyclophosphamide phenate derivatives or pharmaceutically acceptable salts (I) thereof. The benzocyclophosphamide phenate derivatives or pharmaceutically acceptable salts thereof comprise stereoisomerides or tautomers. In the formula (I), R is 4-hydroxyphenyl, 4-methoxyphenyl, 4-acetoxy-phenyl, 3, 4-dihydroxyphenyl, 3, 4, 5-trihydroxyphenyl, 3, 4-dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, 3, 4-dihydroxy styryl, 3-methoxy-4-hydroxy styryl, 3, 4-dimethoxy styryl, 3, 4-diacetoxy styryl and 3-methoxy-4-acetoxy styryl. The benzocyclophosphamide phenate derivatives disclosed by the invention have significant anti-cancer effect, can effectively prolong the survival time of mice loaded with HL60, have better effects than the cyclophosphamide and have the obvious inhibitory action against the angiogenesis of a chorioallantoic membrane (CAM). Thus, the benzocyclophosphamide phenate derivatives disclosed by the invention can be applied to preparation of anti-tumor medicaments. The invention discloses the preparation method of the benzocyclophosphamide phenate derivatives.

Description

technical field [0001] The invention relates to a phenolic acid benzocyclophosphamide derivative, a preparation method thereof and an application as an anticancer drug. Background technique [0002] Cyclophosphamide is a bifunctional alkylation and cell cycle non-specific drug, which has a broad anti-tumor spectrum and is widely used in clinic. But its disadvantage is bladder toxicity. In order to reduce its toxic and side effects, chemists at home and abroad have modified its structure and synthesized many cyclic or non-cyclic cyclophosphamide analogues, hoping to find a class of compounds with strong effects and low toxicity. It has been reported in the literature that benzocyclophosphamide analogs have certain effects on rat L1210 lymphoid leukemia (Ludeman, Susan M, Zon, Gerald. Journal of Medicinal Chemistry, 1975,18(12):1251), 7-nitrobenzene Cyclophosphamide analogs can improve drug-selective toxicity in gene-activated prodrug therapy (GDEPT) (Zhuorong Li, Jiye Han, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/547A61K31/675A61P35/00
Inventor 史兰香何敬宇刘斯婕张宝华
Owner SHIJIAZHUANG UNIVERSITY
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