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Low-toxicity 1,8-naphthalene dimethimide derivative as well as preparation method and application thereof

A synthesis method and reaction technology, applied in the field of medicine, can solve the problems of retention, adverse reactions, toxic and side effects, etc., and achieve the effects of small toxic and side effects, significant inhibitory activity, and significant biological activity

Inactive Publication Date: 2018-05-15
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Existing studies have shown that the study of naphfemate on breast cancer has entered phase II clinical trials, but as a chemotherapy drug, it has certain adverse reactions to human bone marrow; it is easily acetylated by N-acetyltransferase II (NAT2) in vivo. N-acetylaminonaphtamide is produced by chemical synthesis, and the metabolism of the acetylated product in the body due to individual differences will produce uncertain toxic and side effects, making it currently in phase III clinical research

Method used

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  • Low-toxicity 1,8-naphthalene dimethimide derivative as well as preparation method and application thereof
  • Low-toxicity 1,8-naphthalene dimethimide derivative as well as preparation method and application thereof
  • Low-toxicity 1,8-naphthalene dimethimide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Get 1mmol of naphthalene, add it to 4mL of acetonitrile and stir to dissolve, dissolve 1.5mmol of 3-fluorobenzoyl chloride in 2mL of acetonitrile, put it in a constant pressure dropping funnel, and use nitrogen to protect the reaction system, and pour into the nadafetil-acetonitrile solution Slowly add 3-fluorobenzoyl chloride-acetonitrile solution dropwise, react for 2.5h after the dropwise addition is completed, remove the solvent after the reaction, and purify using silica gel column chromatography (dichloromethane:methanol=20:1, v / v) , to obtain a pale yellow solid (about 90% yield).

[0032] The obtained light yellow solid is identified:

[0033] (1) Proton nuclear magnetic resonance spectrum and carbon spectrum, their spectrogram data are as follows:

[0034] 1 H NMR (500MHz, DMSO-d6) δ11.05(s, 1H), 9.00(d, J=1.9Hz, 1H), 8.93(d, J=2.0Hz, 1H), 8.42(dd, J=12.0, 7.7Hz, 2H), 8.02–7.91(m, 2H), 7.85(t, J=7.7Hz, 1H), 7.65(dd, J=13.9, 7.9Hz, 1H), 7.51(td, J=8.5, 2.1 H...

Embodiment 2

[0040] Repeat Example 1, the difference is:

[0041] The reaction time was changed to 1 h, and the rest of the reaction conditions remained unchanged (the yield was about 73%).

[0042] The product obtained in this example was analyzed by proton nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and it was determined to be the target product.

Embodiment 3

[0044] Repeat Example 1, the difference is:

[0045] The reaction time was changed to 3 h, and the rest of the reaction conditions remained unchanged (the yield was about 88%).

[0046] The product obtained in this example was analyzed by proton nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and it was determined to be the target product.

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Abstract

The invention discloses a low-toxicity 1,8-naphthalene dimethimide derivative as well as a preparation method and application thereof. The preparation method of the 1,8-naphthalene dimethimide derivative mainly comprises the following steps: dissolving amonafide and 3-fluorobenzoyl chloride into an organic solvent, performing reaction, and removing the solvent after reaction to obtain a target crude product. The experiment of the applicant indicates that the derivative has remarkable bioactivity, particularly has remarkable inhibition activity on a non-small cell lung cancer cell strain HCC-827 and other tumor cell strains, has smaller toxic and side effects on human normal cells, and is expected to be developed into a targeted therapy medicine. The structure of the 1,8-naphthalene dimethimide derivative is as shown in the formula (I): (the formula is as shown in the description).

Description

technical field [0001] The invention relates to a 1,8-naphthalimide derivative with low toxicity and its preparation method and application, belonging to the technical field of medicine. Background technique [0002] Naphthalimide derivatives have a unique planar rigid structure, which enables them to have a strong ability to embed DNA. More and more studies have shown that naphthalimide and its derivatives have good anti-tumor activity. It has a high affinity for DNA molecules, can bind to DNA through intercalation, and exhibits a micromolar level of IC in the experiment of inhibiting tumor cell growth in vitro 50 , but they are also more toxic to normal cells. [0003] At present, naphthalimide derivatives that have entered clinical research include mitonafide, amonafide, elinafide and bisnafide. Wherein the structure of nafate is as shown in the following formula (II): [0004] [0005] Existing studies have shown that the study of naphfemate on breast cancer has en...

Claims

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Application Information

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IPC IPC(8): C07D221/14A61K31/473A61P35/00
CPCC07D221/14
Inventor 张国海石镇豪李亮萍彭艳曾淑兰
Owner GUANGXI NORMAL UNIV
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