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Synthesis of berberine derivatives and their application in the preparation of antineoplastic drugs and synergistic doxorubicin antineoplastic drug compositions

A technology of berberine and its derivatives, applied in the field of medicinal chemistry, can solve the problems of insignificant anti-tumor effect and toxic and side effects of doxorubicin

Inactive Publication Date: 2016-02-03
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This mixed preparation has a certain inhibitory effect on doxorubicin-induced cardiotoxicity, but the antitumor effect of berberine and doxorubicin alone is not obvious
[0006] However, doxorubicin has toxic and side effects on the body, therefore, it is very necessary to improve the anti-tumor effect of berberine alone and synergistically with doxorubicin to achieve the purpose of synergistic effect and attenuation

Method used

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  • Synthesis of berberine derivatives and their application in the preparation of antineoplastic drugs and synergistic doxorubicin antineoplastic drug compositions
  • Synthesis of berberine derivatives and their application in the preparation of antineoplastic drugs and synergistic doxorubicin antineoplastic drug compositions
  • Synthesis of berberine derivatives and their application in the preparation of antineoplastic drugs and synergistic doxorubicin antineoplastic drug compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1, the synthesis of berberine chloride (II)

[0049] Weigh 8g (0.0216mol) of berberine chloride, put it into a 250ml flask, add 120ml of DMF, reflux in an oil bath at 190°C for 25-30min, TLC (dichloromethane:methanol=10:1) detects that the raw material point just disappears and the impurities point The reaction was stopped just before it appeared (product Rf value about 0.4, red). The solvent was evaporated to dryness to obtain 7 g of crude BBR-1 with a yield of 85%, which could be directly used in the next reaction.

Embodiment 29

[0050] Example 29 Synthesis of O-propynylberberine (Compound III)

[0051] Weigh 0.54g (1.67mmol) of berberine chloride (compound II) into a 100ml flask, add 0.24g (2.03mmol) of propargyl bromide, 60ml of acetonitrile, and reflux at 70-80°C for 2.5h. TLC detection (dichloromethane: methanol = 10: 1), the product spot (Rf value is about 0.45, yellow) can be seen, and the product yellow precipitate at the bottom of the flask. Column chromatography (dichloromethane:methanol=25:1) gave 0.35 g of the product with a yield of 65%.

Embodiment 3

[0052] Example 3 Synthesis of compound 1-propyl-4-(9-O-methyleneberberine)-1hydro-1,2,3-triazole (compound 3 in Table 1)

[0053] Add 50mgNaN to a 50ml flask 3 (0.77mmol), 76mg 1-bromo-n-propane (0.6mmol) 10ml DMF was stirred at 70°C for 3h, cooled, 9-O-propynylberberine (II) 160mg (0.4mmol) was added, CuSO 4 .5H 2 O30mg and sodium ascorbate 50mg were respectively prepared into 5ml aqueous solution and added to the reaction system. Continue to react for 3h, TCL detection (dichloromethane:methanol=10:1), the product is yellow (Rf value is about 0.45). 10% ammonia water was added to the reaction solution, extracted three times with 100 ml of dichloromethane, the extract was washed twice with 5 ml of 12% hydrochloric acid, and after concentration, column chromatography was performed (dichloromethane: methanol: triethylamine = 25: 1: trace) , 40 mg of compound 3 were obtained. 1 HNMR (300MHz, DMSO) δ 9.72(s, 1H), 8.95(s, 1H), 8.40(s, 1H), 8.20(dd, J=9.2, 3.8Hz, 1H), 8.00(d, J=...

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Abstract

The invention relates to berberine derivatives as well as a preparation method and an application of the berberine derivatives. The general formula of the berberine derivatives is shown in the specification, where R is alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, a heterocyclic group or a substituted heterocyclic group. The invention also relates to a composition of the berberine derivatives and adriamycin and an application of the compositions in preparation of an anti-tumor drug. The berberine derivatives disclosed by the invention have not only anti-tumor effects alone and in combination with adriamycin and but also have a certain protective effect on myocardial damage, weight loss and intestinal epithelial cells induced by the treatment, thereby being an ideal synergistic combination drug during the treatment of cancer by virtue of adriamycin.

Description

【Technical field】 [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a berberine derivative, a preparation method and application thereof, and a pharmaceutical composition composed of a berberine derivative and adriamycin and use thereof. 【Background technique】 [0002] Malignant tumors, often called cancer, are frequently-occurring and common diseases that seriously threaten human health. At present, the three main methods of treating malignant tumors include chemotherapy (referred to as chemotherapy), surgery and radiation therapy. The application of traditional cytotoxic antitumor drugs or anticancer drugs for chemotherapy still occupies a very important position in the comprehensive treatment of tumors. Some malignant tumors such as choriocarcinoma and malignant lymphoma may be cured by chemotherapy. The emerging targeted therapy in recent years has provided us with new methods and ideas for curing cancer. However, in the face...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03A61K31/704A61K31/4375A61K31/444A61K31/4709A61K31/513A61P35/00
CPCC07D455/03
Inventor 曹永兵孙青金鑫李新民
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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