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Water-soluble rubescensin a derivative and preparation method thereof

A technology of oridonin A and its derivatives, which is applied in the field of natural medicine and medicinal chemistry, and can solve the problems of oridonin A, such as difficulty, poor solubility, and limited application

Inactive Publication Date: 2015-02-04
SHENZHEN JYMED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] But Rubescensin A is insoluble in water, soluble in organic solvents such as ether, methanol, ethanol, and its solubility in water is only 0.75mg / ml, and its poor solubility in water greatly limits its clinical application as a drug. application on

Method used

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  • Water-soluble rubescensin a derivative and preparation method thereof
  • Water-soluble rubescensin a derivative and preparation method thereof
  • Water-soluble rubescensin a derivative and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Embodiment 1, the preparation of compound (3)

[0045] When R1 represents CH 2 PO 3 Na 2 , the preparation of oridonin A derivative (3) shown in general formula (1): under nitrogen protection, temperature control 0 ℃, 9mg NaH (0.370mmol) was added to 100mg propylidene-protected oridonin A (0.247mmol) and 5ml THF, stirred for 30min, then added 83mg O-di-tert-butyl chloromethyl phosphate (0.321mmol), after dropping, continued to stir for 1h, returned to room temperature, stirred for 10h, and evaporated to dryness. The residue is put on macroporous adsorption resin column AB-8, washed with water with a pH value of 4, then with water with a pH of 7.0, and finally eluted with ethanol, concentrated to give 105 mg of a white solid, which was dissolved in methanol and The strong acidic cationic resin was stirred for 24 hours, filtered, the filtrate was concentrated, purified by reverse phase, eluted with methanol / water, and neutralized with 1M NaOH to obtain 79 mg of Rubesce...

Embodiment 2

[0047] Embodiment 2, the preparation of compound (4) and its salt

[0048] When R1 stands for CONHCH 2 CH 2 CH 2 N(CH 3 ) 2 or CONHCH 2 CH 2 CH 2 N(CH 3 ) 2 ·HCl or CONHCH 2 CH 2 CH 2 N(CH 3 ) 2 When HOAc, the preparation of oridonin derivative (4) and its salt shown in general formula (1): under the protection of nitrogen, 136 μ l NMM (N-methylmorpholine) was added to 100 mg propylidene protected winter In a mixture of lobecidin (0.247mmol), 78mg N,N-dimethylpropylcarbamoylsuccinimide (0.321mmol) and 10ml acetonitrile, stir for 8h and evaporate to dryness. The residue is put on the macroporous adsorption resin column AB-8, washed with water with a pH value of 4 first, then washed with water with a pH of 7.0, and finally eluted with ethanol, concentrated to give 113 mg of white solid, which was dissolved in methanol and The strongly acidic cationic resin was stirred for 24 hours, filtered, the filtrate was concentrated, purified by reverse phase, and eluted with...

Embodiment 3

[0052] Embodiment 3, the preparation of compound (5) and its salt

[0053] When R1 represents CONHCH (CH 2 )(CH 2 CH 2 ) NCH 3 or CONHCH (CH 2 )(CH 2 CH 2 ) NCH 3 · HCl or CONHCH (CH 2 )(CH 2 CH 2 ) NCH 3 When HOAc, the preparation of oridonine A derivative (5) and its salt shown in general formula (1): under the protection of nitrogen, 136 μ l NMM (N-methylmorpholine) was added to 100 mg propylidene protected winter In a mixture of lobecidin (0.247mmol), 77mg of N-methylpyrrole-3-carbamoylsuccinimide (0.321mmol) and 10ml of acetonitrile, stir for 8h and evaporate to dryness. The residue is put on macroporous adsorption resin column AB-8, washed with water with a pH value of 4, then with water with a pH of 7.0, and finally eluted with ethanol, concentrated to give 109 mg of white solid, which was dissolved in methanol and Strongly acidic cationic resin was stirred for 24 hours, filtered, the filtrate was concentrated, purified by reverse phase, and eluted with meth...

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Abstract

The invention relates to a water-soluble rubescensin a derivative and a preparation method thereof. Specifically, the structure of rubescensin a derivative is modified, and on the basis of reaction of hydroxyl groups in the structure, phosphomonoester, carbamic acid ester or salt and other water soluble groups are introduced, so that water solubility and drug characteristics are significantly improved.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a class of water-soluble oridonin A derivatives and a preparation method thereof. technical background [0002] Oridonin is a natural organic compound of ent-kaurene diterpenoid isolated from Labtea (Labtea) plants of the genus Rabdosia. The main anti-tumor active ingredients in the medicine have the functions of clearing heat and detoxifying, promoting blood circulation and removing blood stasis, antibacterial and anti-inflammatory, and anti-tumor. Studies have found that Rubescensine A has definite anti-tumor activity in vivo and in vitro, and has a broad anti-tumor spectrum. 7402, lung cancer SPCA-1 cells, etc. all have obvious killing effects, and are clinically used to treat primary liver cancer, esophageal cancer, cardia cancer, etc. [0003] But Rubescensin A is insoluble in water, soluble in organic solvents such as ether, methanol, ethanol, and ...

Claims

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Application Information

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IPC IPC(8): C07D493/08A61P35/00
CPCC07D493/08
Inventor 刘自成姚志勇李新宇支钦
Owner SHENZHEN JYMED TECH
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