Prodrug of oridonin with polyethylene glycol serving as vector and preparation method thereof

A technology of oridonin A and polyethylene glycol is applied in the field of natural medicine and polymer materials to achieve the effects of improving solubility, improving performance and improving performance

Active Publication Date: 2013-01-02
山东希力药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are relatively few domestic studies on PEG-modified small molecule technology. In the absence of relevant reports in the prior art, a drug with good efficacy, good biocompatibility, high bioavailability, and long acting time in vivo has been developed. The PEGylated Rubescensin A prodrug and its preparation method, which are suitable for large-scale industrial production, are difficult points, which require creative work, a large number of tests and condition screening

Method used

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  • Prodrug of oridonin with polyethylene glycol serving as vector and preparation method thereof
  • Prodrug of oridonin with polyethylene glycol serving as vector and preparation method thereof
  • Prodrug of oridonin with polyethylene glycol serving as vector and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Synthesis of carboxylated oridonin

[0033] Disperse and dissolve 0.6552g oridonin and 0.9006g succinic anhydride in 12mL dichloromethane. Add 3mL anhydrous pyridine to the system. The reaction temperature is 35℃. The reaction is magnetically stirred for 24 hours. The reaction solvent is concentrated and evaporated to dryness. Afterwards, the residue containing the reaction product was purified by a silica gel column (mobile phase: anhydrous ether: acetone: glacial acetic acid = 4.5:1:0.01, volume ratio; stationary phase: 200-300 mesh silica gel), and the solvent was evaporated after purification , The product is dried under vacuum to obtain a colorless oily succinic oridonin.

[0034] (2) Synthesis of oridonin prodrug modified by methoxy polyethylene glycol amine (40K)

[0035] Weigh out 0.1044g succinic oridonin, 0.0203g HOBT and 0.0309g DCC, disperse and dissolve them in 12mL dichloromethane, stir and react for 2h under an ice bath at 0~5℃, remove the ice bath and add ...

Embodiment 2

[0037] (1) Synthesis of carboxylated oridonin: the same as in Example 1.

[0038] (2) Synthesis of oridonin prodrug modified by methoxy polyethylene glycol amine (20K)

[0039] Weigh 0.1040g of succinic oridonin, 0.0207g HOBT and 0.0308g DCC, disperse and dissolve in 12mL dichloromethane, stir at 0~5℃ in an ice bath for 2h, remove the ice bath and add to the system 1.5g monomethoxypolyethylene glycol amine (20K), naturally warm to room temperature, continue the reaction for 48h, then concentrate and evaporate the solvent, the obtained solid is dispersed and stirred with isopropanol for 6h, so that unreacted small molecules are dissolved in In isopropanol, the small molecule impurities in the product are washed away. The isopropanol is washed three times, the supernatant is discarded by centrifugation, and the precipitate is vacuum dried to obtain a white solid product, which is methoxy polyethylene glycol amine (20K ) The infrared spectrum of the modified oridonin prodrug is as i...

Embodiment 3

[0044] (1) Synthesis of carboxylated oridonin: the same as in Example 1.

[0045] (2) Synthesis of oridonin prodrug modified by methoxy polyethylene glycol amine (10K)

[0046] Weigh 0.1392g of succinic oridonin, 0.0405g HOBT and 0.0619g DCC, disperse and dissolve in 15mL dichloromethane, stir and react for 2h in an ice bath at 0~5℃, remove the ice bath and add to the system 1.5g of methoxy polyethylene glycol amine (10K), naturally warm to room temperature, continue the reaction for 48h, then concentrate and evaporate the solvent, the obtained solid is dispersed and stirred with isopropanol for 6h, so that the unreacted small molecules are dissolved in the isopropyl alcohol In order to wash away the small molecule impurities in the product in propanol, wash three times with isopropanol, centrifuge to discard the supernatant, and vacuum dry the precipitate to obtain a white solid product, which is methoxy polyethylene glycol amine (10K) A modified oridonin prodrug.

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Abstract

The invention discloses a prodrug of oridonin with polyethylene glycol serving as a vector. The prodrug has the structural formula shown in the specification, wherein n is an integer from 110 to 910. The preparation method comprises the following steps: (1) preparing carboxylation oridonin: performing reaction to oridonin and succinic anhydride, thus obtaining carboxylation oridonin; and (2) synthesizing prodrug of oridonin modified via methoxypolyethylene glycol amine: reacting the mono-methoxypolyethylene glycol amine with carboxylation oridonin, thus obtaining the prodrug of oridonin which is in form of white solid. According to the prodrug of oridonin with polyethylene glycol serving as the vector disclosed by the invention, the succinic acid serves as a joint arm for combining the oridonin with the hydrophilic polyethylene glycol derivative, so that the dissolubility of the oridonin is improved, the performance of the medicine is enhanced and improved, and the stability of the oridonin is improved; and the prodrug can be decomposed and fallen at a proper environment, so as to release the oridonin, so that the acting time in the organism can be increased, and the purpose of long circulation can be achieved.

Description

Technical field [0001] The invention relates to a prodrug of oridonin with polyethylene glycol as a carrier and a preparation method thereof, belonging to the field of natural medicine and polymer materials. Background technique [0002] Oridonin A (Oridonin, ORI) is a diterpenoid compound extracted from Rubescens vulgaris. It accounts for more than 90% of the active ingredients of Rubescens vulgaris. It is the main anti-tumor active ingredient. , Colon cancer, cervical cancer, lung cancer, nasopharyngeal cancer, stomach cancer, etc. have certain curative effects. In addition, studies have found that Rubescensine A can selectively act on the M 2b acute myeloid leukemia cell line Kasumi-1 with t(8;21) chromosome translocation, and Rubescensine A is tested in mice It also showed anti-leukemia effect. In short, Rubescensine A, as an anti-tumor drug with good activity but low toxicity, has attracted the attention of domestic and foreign scholars in the past 20 years. [0003] Althou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/352A61P35/00
Inventor 赵忠熙沈婧祎张典瑞杨新美贾乐姣郑丹丹刘光璞
Owner 山东希力药业有限公司
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