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Combretastatin prodrug, pharmaceutical preparation and preparation method

A compretin and drug technology, applied in the field of drug synthesis, can solve problems such as rapid drug release, achieve the effects of prolonging circulation, good clinical application prospect and application value, and improving anti-angiogenesis curative effect

Inactive Publication Date: 2016-12-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In our previous experiments, CA4 was co-assembled with amphiphilic polymers to form nanoparticles, but the results showed that the nanoparticles directly loaded with CA4 had the problem of rapid drug release.

Method used

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  • Combretastatin prodrug, pharmaceutical preparation and preparation method
  • Combretastatin prodrug, pharmaceutical preparation and preparation method
  • Combretastatin prodrug, pharmaceutical preparation and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Butyric acid (51.7 μL, 0.57 mmol), CA4 (compound 1, 180 mg, 0.57 mmol), EDC·HCl (163 mg, 0.855 mmol), DMAP (76.6 mg, 0.627 mmol), DIEA (188.9 μL, 1.14 mmol) were dissolved In 4ml of DCM, stirred overnight at room temperature, added ethyl acetate, respectively with 5% citric acid, saturated NaHCO 3 , saturated brine to wash the organic phase, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure after collecting the filtrate; the solid was separated and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the target The product butyric acid-CA4 conjugate compound 2 (280 mg, yield 93%). Synthetic route such as figure 1 shown.

[0045] The 1H NMR nuclear magnetic data and mass spectral data of product butyric acid-CA are as follows:

[0046] 1 H NMR (400MHz, CDCl 3 ):δ1.00-1.04(t,3H),1.73-1.78(m,2H),2.49-2.53(t,2H),3.71(s,6H),3.80(s,3H),3.83(s,3H ),6.45-6.45(d,2H,J=1.2),6.51(s,2H),...

Embodiment 2

[0049] Heptanoic acid (80.8 μL, 0.57 mmol), CA4 (180 mg, 0.57 mmol), EDC·HCl (163 mg, 0.855 mmol), DMAP (76.6 mg, 0.627 mmol), DIEA (188.9 μL, 1.14 mmol) were dissolved in 4 mL of DCM , stirred overnight at room temperature, added ethyl acetate, and successively washed with 5% citric acid, saturated NaHCO 3 , saturated brine to wash the organic phase, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure after collecting the filtrate; the solid was separated and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the target The product heptanoic acid-CA4 conjugate compound 3 (260 mg, yield 85%). Synthetic route such as figure 2 shown.

[0050] 1 H NMR (400MHz, CDCl 3 ):δ0.88-0.91(t,3H),1.26-1.41(m,6H),1.70-1.74(t,2H),2.51-2.54(t,2H),3.71(s,6H),3.80(s ,3H),3.84(s,3H),6.45-6.45(d,2H,J=1.6),6.51(s,2H),6.83-6.85(d,1H,J=8.4),7.00-7.00(d, 1H, J=1.6), 7.10-7.12(q, 1H).

[0051] HR-ESI Qq-L...

Embodiment 3

[0053] CA4 (CA4 content 0.5mg) and mPEG 5k -PLA 16k (20 times the mass of the drug) was dissolved in 1 mL of acetone, and evenly added dropwise to 10 mL of water. After the dropwise addition, the acetone was removed under reduced pressure to obtain the CA4 nanomedicine (referred to as 1-NP).

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Abstract

The invention discloses a combretastatin prodrug, and discloses a preparation method thereof. The invention also discloses a preparation containing the combretastatin prodrug and a preparation method of the preparation. The combretastatin lipophilic prodrug provided by the invention can hydrolyze rapidly to release active pharmaceutical ingredients and play its efficacy. And the nano-preparation composed of the combretastatin prodrug can slowly release internal drugs, is conducive to prolonging the drug circulation in vivo and improving the drug efficacy, thus having good clinical application prospect and application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a lipophilic prodrug prodrug of an anti-angiogenic drug compretin, a synthesis method, a nano-preparation and a preparation method of the preparation. Background technique [0002] The growth and metastasis of malignant tumors depend on tumor blood vessels. Tumors rely on blood vessels to transport oxygen and nutrients for their rapid cell proliferation and cause tumor cells to metastasize to distant sites. With the in-depth research on the mechanism of tumor angiogenesis, and the good curative effect of drugs targeting tumor blood vessels in clinical treatment of tumors, the concept of inhibiting tumor growth by inhibiting tumor angiogenesis has been confirmed. [0003] Compretastatin A4 (Combretastatin, CA4) is a cis-stilbene natural product isolated from the bark of the African shrub Combretum Caffrum. In the early 1980s, when evaluating the cytotoxicity of a series ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/33C07C67/08C07C67/14A61K31/222A61K47/34A61K9/50A61P35/00
CPCA61K9/5031A61K47/34C07C67/08C07C67/14C07C69/33
Inventor 王杭祥吴佳萍陈建美
Owner ZHEJIANG UNIV
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