PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound

A chemical modifier and stilbene technology, which is applied in the directions of non-active ingredients, such as medical preparations, anti-inflammatory agents, anti-toxic agents, etc., to achieve the effects of simple preparation method, improved and improved drug performance, and increased drug loading capacity.

Inactive Publication Date: 2011-11-23
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this invention, only the acetyl group is used as the connecting arm to prepare PEG or mPEG chemical modifiers, and no other connecting arms, such as succinic anhydride, etc. are involved
In addition, this modifier is only used to modify the compound paclitaxel, and there is no research on whether it can be used to modify other small organic molecules

Method used

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  • PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound
  • PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound
  • PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] This embodiment includes the following steps:

[0041] ①Preparation of PEG2000 carboxylic acid derivatives

[0042] The reaction formula is as follows:

[0043]

[0044] Take 40 g (20 mmol) of dry PEG, dissolve it in 160 mL of chloroform, add 5.0 g (50 mmol) of succinic anhydride, stir well, add 3 mL of pyridine (Py), heat to reflux, react for 36 h, evaporate the solvent, The residue was washed with 80 mL saturated NaHCO 3The solution was dissolved, extracted with ethyl acetate (20 mL×3), cooled the water phase to 0-5 °C, adjusted the pH to 2-3 with 1 mol / L hydrochloric acid, stirred for 20 min, extracted with dichloromethane (25 mL×4), combined The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from anhydrous ether to obtain 37.4 g of PEG2000-succinic acid as a white solid, with a yield of 85.0%;

[0045] ②Synthesis of PEG2000-acyl chloride

[0046] The reaction formula...

Embodiment 2

[0059] This embodiment is carried out according to the following sequence of steps:

[0060] ①The preparation of PEG2000 carboxylic acid derivatives, PEG2000-acyl chlorides, and PEG2000 chemical modifiers connected with citric acid are the same as steps ①~③ in Example 1;

[0061] ②Preparation of PEG2000-succinyl-citric acid-oxidized resveratrol prodrug

[0062] The reaction formula is as follows:

[0063]

[0064] Take 0.5 g (0.20 mmol) of PEG2000 multi-carboxyl chemical modifier linked with citric acid, dissolve it in 5 mL of dichloromethane, add a DMF solution of oxidized resveratrol (0.35 g of oxidized resveratrol dissolved in 6 mL of DMF prepared in ), stirred for 30 min, added EDC.HCl 0.27 g (1.42 mmol), DMAP 1.73 g (1.42 mmol), and reacted at room temperature for 24 h. Acyl-citrate-oxidized resveratrol prodrug 0.30 g, yield 38.0%.

[0065] Since the most commonly used molecular weight of PEG / mPEG as a drug carrier is 2000-75000, this embodiment also replaces the a...

Embodiment 3

[0067] This embodiment is carried out according to the following sequence of steps:

[0068] ①The preparation of PEG2000 carboxylic acid derivatives, the preparation of PEG2000-acyl chloride, the preparation of the chemical modifier of PEG2000 multi-carboxyl group connected with citric acid, the method is the same as the steps ①~③ in Example 1 respectively;

[0069] ② Preparation of PEG2000-succinyl-citric acid-picetanol

[0070] The reaction formula is as follows:

[0071]

[0072] Take 0.5 g (0.20 mmol) of PEG2000 multi-carboxyl chemical modifier linked with citric acid, dissolve it in 5 mL of dichloromethane, add the DMF solution of piceatanol (0.35 g piceatanol dissolved in 6 mL of DMF) obtained), stirred for 30 min, added EDC.HCl 0.27 g (1.42 mmol), DMAP 1.73 g (1.42 mmol), and reacted at room temperature for 24 h. - Citric acid-picetanol prodrug 0.27 g, yield 34.0%.

[0073] Since the most commonly used molecular weight of PEG / mPEG as a drug carrier is 2000-75000, ...

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Abstract

The invention discloses a PEG / mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, a preparation method and application thereof in modification of toluylene compound. In the invention, PEG / mPEG-carboxybutyryl group / acetyl-citric acid is used as a modifier; the modifier is connected with the toluylene compound to prepare toluylene compound prodrug; relatedtoluylene compounds comprise 3,5-dyhydroxy-4-isopropyl toluylene, oxidized resveratrol, pterostilbene, piceatannol and resveratrol; and the prepared prodrug is a branched polyethylene glycol derivative containing multiple carboxyls and can be connected with a plurality of compounds, thereby improving drug loading amount to a large extent. In addition, the prodrug preparation method is simple, thewater solubility and the stability of toluylene compound can be improved, the biological activity of the compound is improved, and the application range of the toluylene compound modified with the modifying agent is wider than that of a pure toluylene compound.

Description

technical field [0001] The invention belongs to the field of compound preparation, and in particular relates to a chemical modifier of PEG / mPEG polycarboxylate connected with citric acid, a preparation method thereof, and the use of modifying stilbene compounds to prepare corresponding prodrugs. Background technique [0002] Stilbene compounds such as 3,5-dihydroxy-4-isopropyl stilbene (drug name: styrene moder), resveratrol, pterostilbene, oxidized resveratrol, piceatanol, etc. Belonging to active polyphenols, they are commonly found in the metabolites of plants or microorganisms. They have anti-inflammatory, anti-oxidation, anti-bacterial, anti-tumor, anti-free radical, anti-platelet aggregation, anti-thrombosis, anti-hyperlipidemia effects, and can be used for The prevention and treatment of fungi, eczema, arteriosclerosis, coronary heart disease, viral hepatitis, AIDS, cancer and other diseases are currently mostly used as health products. Due to the poor water solubil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/48A61P29/00A61P39/06A61P31/00A61P35/00A61P7/02A61P3/06A61P9/10A61P31/12A61P31/18
Inventor 张越黄道伟申丹丹
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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