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Benzofuran-aza-naphthoquinone derivative as well as preparation method, pharmaceutical composition and use thereof

A technology of benzofuran nitrogen and derivatives, which is applied in the field of benzofurazinaphthoquinone derivatives and its preparation, and can solve the problems of cardiotoxicity, cardiotoxicity, toxic side effects, etc.

Inactive Publication Date: 2018-12-21
ASTATECH CHENGDU BIOPHARM CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compound (1) has a strong toxic side effect on the heart
On the basis of the research on mitoxantrone compounds, Yi-Lin Luo reported a new class of benzanthrone compounds (2) Design and synthesis method, compound (2) is confirmed by the anti-tumor cell experiment of the National Cancer Institute of the United States, and it has good anti-cancer effect, but their water solubility is poor, is not convenient for pharmaceutical preparation, and also exists Potential cardiotoxic adverse effects, limiting further clinical application evaluation

Method used

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  • Benzofuran-aza-naphthoquinone derivative as well as preparation method, pharmaceutical composition and use thereof
  • Benzofuran-aza-naphthoquinone derivative as well as preparation method, pharmaceutical composition and use thereof
  • Benzofuran-aza-naphthoquinone derivative as well as preparation method, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 6,8-Dihydroxybenzofuro[3,2-g]quinoline-5,11-dione:

[0055] Under nitrogen protection, sodium methoxide (1.81g, 33.6mmol) was added to 50mL of anhydrous methanol, and 6,7-dichloro-5,8-quinolinedione (3.47g, 15.3mmol) was added in batches at room temperature, Fully stir for 5 minutes after the addition, take another phloroglucinol (2.12g, 16.8mmol) and dissolve it in 25mL of methanol, under ice-cooling, slowly drop into the aforementioned reaction solution, after the dropwise addition is completed, naturally rise to room temperature, stir and react overnight Stop responding. Under cooling in an ice bath, add 3 equivalents of hydrochloric acid solution dropwise to acidify to pH 3-4, collect the precipitated solid, add water / methanol (1:1, v / v) to beat and wash, and filter to obtain a brown-black solid, dissolved in ethyl acetate, Purified by column chromatography (EA / MeOH=20:1) to obtain 1.32 g of the product, yield: 30.7%, and the product has good water solubility.

[...

Embodiment 2

[0058] 8-(2-(Diethylamino)ethoxy)-6-hydroxybenzofuro[3,2-g]quinoline)-5,11-dione:

[0059] Under nitrogen protection, 6,8-dihydroxybenzofuro[3,2-g]quinoline-5,11-dione (42.2mg, 0.15mmol, the preparation method is the same as in Example 1) was dissolved in 5mL of acetonitrile , adding K sequentially at room temperature 2 CO 3 (51.8mg, 0.38mmol), 2-diethylaminochloroethane hydrochloride (28.3mg, 0.17mmol), fully stirred for 5min after addition, heated to 55°C for 8h, stopped the reaction, cooled to room temperature, added acetic acid Ethyl ester extraction, liquid separation, combined organic layer, concentrated, column chromatography (EA / MeOH / NH 3 ·H 2 O 40:1:1) separated and purified to obtain 38.1 mg of the product, yield: 66.7%, and the product had good water solubility.

[0060] ESI-MS:m / z=381.2(M+H) + ; 1 H NMR (400MHz, DMSO-d 6 )δ: 10.12(s, 1H), 8.97(d, J=4.8Hz, 1H), 8.52(d, J=7.6Hz, 1H), 8.10(d, J=8.8Hz, 1H), 7.48(s, 1H), 6.83(s, 1H), 4.70(t, J=4.6Hz, 2H), 3.53(t...

Embodiment 3

[0062] 8-(2-(Dimethylamino)ethoxy)-6-hydroxybenzofuro[3,2-g]quinoline)-5,11-dione:

[0063] Dissolve 6,8-dihydroxybenzofuro[3,2-g]quinoline-5,11-dione (42.2 mg, 0.15 mmol, the preparation method is the same as in Example 1) in 5 mL of acetonitrile, and add K 2 CO 3 (51.8mg, 0.38mmol), 2-chloroethyldimethylamine (17.7mg, 0.16mmol), fully stirred for 5min after addition, heated to 55°C for 8h, stopped the reaction, cooled to room temperature, added ethyl acetate to extract , separation, combined organic layer, concentrated, column chromatography (EA / MeOH / NH 3 ·H 2 O 40:1:1) separated and purified to obtain 27.1 mg of the product, yield: 47.3%, and the product had good water solubility.

[0064] ESI-MS:m / z=353.2(M+H) + ; 1 H NMR (400MHz, DMSO-d 6 )δ: 10.01(s, 1H), 8.92(d, J=4.6Hz, 1H), 8.33(d, J=7.5Hz, 1H), 8.14(d, J=8.7Hz, 1H), 7.51(s, 1H), 6.90(s, 1H), 4.72(t, J=4.7Hz, 2H), 3.61(t, J=7.4Hz, 2H), 2.20(s, 6H).

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Abstract

The invention relates to a benzofuran-aza-naphthoquinone derivative as well as a preparation method, a pharmaceutical composition and uses thereof, and belongs to the field of pharmaceutical chemistry. The benzofuran-aza-naphthoquinone derivative provided by the invention has the structure as shown in general Formula I and utilizes two-step reaction for obtaining the Formula I compound substitutedby mono-hydroxy and three-step reaction for obtaining the Formula I compound substituted by di-hydroxy. The pharmaceutical composition provided by the invention comprises the Formula I compound witheffective amount, at least one of optical isomers, medicinal salts or eutectics as well as at least one of salts acceptable to physiology / pharmacy, carriers acceptable to the physiology / pharmacy and excipients. The benzofuran-aza-naphthoquinone derivative is applicable to various cancer cells, has effect of inhibiting the cancer cells and possesses good application prospects in drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a benzofurazinaphthoquinone derivative, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] In the 1980s, Zheng Jiajun et al first reported the design and synthesis method of the anticancer drug mitoxantrone compound (1) in the document "J Med.Chem, 21:291-4, 1978". It is an anthraquinone antineoplastic drug, which can be embedded in the DNA of cells and inhibit topoisomerase II, thereby inhibiting the reproduction of DNA and achieving the purpose of antitumor. It was approved by the US FDA in 2000 for the treatment of multiple sclerosis. However, compound (1) has a strong toxic side effect on the heart. On the basis of the research on mitoxantrone compounds, Yi-Lin Luo reported a new class of benzanthrone compounds (2) Design and synthesis method, compound (2) is confirmed by the anti-tumor cell experiment ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048A61K31/4355A61K31/4545A61K31/496A61K31/5377A61K31/505A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D491/048
Inventor 董庆郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP