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Taxanes dimer, preparation method and preparation thereof

A technology of paclitaxel and dimer, which is applied in the field of biomedicine and can solve the problems of low solubility and the like

Active Publication Date: 2017-01-25
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to solve the problem of low solubility in water of existing paclitaxel pharmaceutical preparations, and provide a paclitaxel dimer, preparation method and preparation thereof

Method used

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  • Taxanes dimer, preparation method and preparation thereof
  • Taxanes dimer, preparation method and preparation thereof
  • Taxanes dimer, preparation method and preparation thereof

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preparation example Construction

[0032] The present invention also provides a preparation method of paclitaxel dimer, the method comprising:

[0033] Step 1: Mixing the paclitaxel solution and linker molecules to obtain a mixed solution;

[0034] Step 2: adding EDC and DMAP to the mixed solution obtained in Step 1 to react to obtain paclitaxel dimers;

[0035] According to the present invention, paclitaxel is first dissolved in an organic solvent to obtain a paclitaxel solution. The organic solvent is not particularly limited as long as it can dissolve paclitaxel, preferably dichloromethane, chloroform, dimethyl sulfoxide or dimethylformamide; the mass concentration of the paclitaxel solution is preferably 10-20mg mL -1 .

[0036] According to the present invention, the above-mentioned paclitaxel solution and linker molecules are mixed and fully dissolved to obtain a mixed solution; the molar ratio of the paclitaxel and linker molecules is preferably 1:(0.55-0.56).

[0037] According to the present inventi...

Embodiment 1

[0052] Example 1: Synthesis of Paclitaxel Dimer Coupled by Suberic Acid

[0053] Weigh paclitaxel (molecular weight is 853.92) (136mg, 0.16mmol) and dissolve in dichloromethane, then add suberic acid (15.5mg, 0.089mmol), EDC (67.1mg, 0.35mmol) and DMAP (2.2mg, 0.018mmol) , After 1 hour, EDC (32.6mg, 0.17mmol) and DMAP (2.2mg, 0.018mmol) were added again, and after reacting at room temperature for 24 hours, filter with an oil phase filter head, then use dichloro and ethyl acetate from 8 :1 to 2:1 slowly increase the polarity to wash the column until the product flows down, and finally spin dry the dichloride and ethyl acetate in the product to obtain a solid powder.

[0054] figure 1 The mass spectrum of paclitaxel dimer prepared for Example 1 of the present invention, figure 1 It shows that the present invention has successfully prepared suberic acid-coupled paclitaxel dimer.

Embodiment 2

[0055] Embodiment 2: Synthesis of paclitaxel dimer containing disulfide bond

[0056] Weigh paclitaxel (molecular weight is 853.92) (204.9mg, 0.24mmol) and dissolve in dichloromethane, then add 3,3'-dihydrooxycholic acid (27.3mg, 0.13mmol), EDC (97.77mg, 0.51mmol) and DMAP (3.05mg, 0.025mmol), after 1 hour, EDC (47.93mg, 0.25mmol) and DMAP (3.05mg, 0.025mmol) were added again, reacted at room temperature for 48 hours, filtered with an oil phase filter, and then washed with two Chlorine and ethyl acetate slowly increase the polarity from 8:1 to 2:1 to wash the column until the product flows down, and finally the organic solvent in the product is spin-dried to obtain a solid powder.

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Abstract

The invention provides a taxanes dimer, a preparation method and a preparation thereof and belongs to the field of biological medicine. The problem of low solubleness of the present taxanes drug in water can be solved. The dimer is composed of taxanes and a joint molecule. The taxanes is taxol or docetaxel and the joint molecule is dicarboxylic acid or dicarboxylic acid containing a disulfide bond. The invention also provides the preparation method for the taxanes dimer. The invention also provides the preparation. The preparation contains an amphiphilic polymer and the taxanes dimer. The taxanes dimer provided by the invention has high solubleness in water or injection; the solution has higher storage stability; the taxanes dimer has hydrolysis reaction under a physiological condition; the taxanes drug is released, so that the curative effect can be achieved.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a paclitaxel dimer, a preparation method and a preparation thereof. Background technique [0002] Paclitaxel is an anti-microtubule agent extracted from the needles and bark of Taxus brevifolia, which has been isolated for the first time since Wani et al. in 1971 and determined by chemical and X-ray crystallography. Since its structure, Phase I clinical studies and Phase II and Phase III clinical trials have shown significant antitumor effects on human cancers. This effect was originally discovered in advanced ovarian and breast tumors, and it has been reported in a large number of literatures to have a significant effect on small cell and non-small cell lung cancer, head and neck cancer, and metastatic melanoma. However, the main difficulty in clinical use is that its chemical structure is high in fat, almost insoluble in water, and its solubility in water is only 0.25 μg ...

Claims

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Application Information

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IPC IPC(8): C07D305/14A61K31/337A61K9/107A61P35/00
CPCA61K9/0019A61K9/1075A61K31/337C07D305/14
Inventor 谢志刚裴晴胡秀丽柳时景遐斌
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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