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Preparation method of water-soluble toluylene compound prodrugs

A technology of stilbene and stilbene, which is applied in the field of preparation of compound prodrugs, can solve incomplete problems, achieve a wide range of applications, improve water solubility and stability, and have simple preparation methods

Inactive Publication Date: 2012-01-18
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The applicant's application number is 201010199655.8 Chinese invention patent application, which discloses a "PEG, mPEG chemical modifier and method for preparing resveratrol prodrug", which is based on PEG, mPEG carboxylic acid derivatives and Amino acid links to prepare PEG and mPEG chemical modifiers, and then link with resveratrol to obtain prodrugs. This patent application only studies one of the stilbene compounds, that is, the prodrugs of resveratrol. The modifiers involved There are only 8 kinds of amino acids, and the structure is relatively simple. It does not include all the amino acids necessary for the human body, so it is not comprehensive

Method used

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  • Preparation method of water-soluble toluylene compound prodrugs
  • Preparation method of water-soluble toluylene compound prodrugs
  • Preparation method of water-soluble toluylene compound prodrugs

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Example 1 Preparation method of PEG2000-succinyl-lysine-resveratrol prodrug

[0047] This embodiment includes the following steps:

[0048] ① Preparation of PEG2000 Carboxylic Acid Derivatives

[0049] The reaction formula is as follows:

[0050]

[0051] Take 20 g (10 mmol) of dry PEG, dissolve it in 80 mL of chloroform, add 2.5 g (25 mmol) of succinic anhydride, stir well, add 2 mL of pyridine (Py), heat to reflux, react for 36 h, evaporate the solvent, The residue was washed with 60 mL saturated NaHCO 3 The solution was dissolved, extracted with ethyl acetate (20 mL×3), the aqueous phase was cooled to 0~5 ℃, adjusted to pH 2~3 with 1 mol / L hydrochloric acid, stirred for 20 min, extracted with dichloromethane (20 mL×4), combined The organic phase was neutralized by washing with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from anhydrous ether to obtain 18.04 g of white solid PEG2000-succinic acid,...

Embodiment 2

[0066] Embodiment 2 The preparation method of PEG2000-succinyl-alanine-oxidized resveratrol prodrug

[0067] The specific operation steps are as follows:

[0068] ① The preparation methods of PEG2000 carboxylic acid derivatives and PEG2000 active esters are the same as those in Example 1;

[0069] ② Preparation of alanine-linked PEG2000 chemical modifier

[0070] Reaction equation:

[0071]

[0072] Dissolve 2 g (0.835 mmol) of PEG2000 active ester in 20 mL of DMF, then cool down to 0 to 5 °C, add alanine in NaHCO dropwise 3 solution (0.30 g alanine dissolved in 3 mL 1 mol / L NaHCO 3 solution), reacted at room temperature for 24 h, the reaction was completed, dissolved with 1 mol / L hydrochloric acid, extracted with dichloromethane (10 mL×3), combined the organic layers, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered , concentrated, and recrystallized with anhydrous ether to obtain 1.21 g of PEG2000 chemical modifier with a yiel...

Embodiment 3

[0079] Example 3 Preparation method of PEG6000-succinyl-glycine-pterostilbene prodrug

[0080] ① Preparation of PEG6000 Carboxylic Acid Derivatives

[0081]

[0082] Dissolve 30 g (0.005 mol) of dry PEG6000 in 100 mL of chloroform, add 1.5 g (0.015 mol) of succinic anhydride, stir well, add 2 mL of pyridine (Py), heat to reflux, react for 36 h, evaporate the solvent, The residue was washed with 80 mL saturated NaHCO 3 The solution was dissolved, extracted with ethyl acetate (20 mL×3), the aqueous phase was cooled to 0~5 ℃, adjusted to pH 2~3 with 1 mol / L hydrochloric acid, stirred for 20 min, extracted with dichloromethane (20 mL×4), combined The organic phase was washed with saturated brine until neutral, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized with anhydrous ether to obtain 26.04 g of white solid PEG6000-succinic acid with a yield of 84.0%;

[0083] ② Synthesis of PEG6000 Active Ester

[0084]

[0085] Dissolve 5...

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Abstract

The invention discloses a preparation method of water-soluble toluylene compound prodrugs. PEG (Polyethylene Glycol) or mPEG (monomethoxy-Polyethylene Glycol)-carboxybutyryl or acetyl-amino acid is taken as a modifier for modifying toluylene compounds such as (E)-3,5-dihydroxy-4-isopropyltoluylene, resveratrol oxide, pterostilbene, piceatannol, resveratrol and the like to prepare prodrugs thereof. By adopting the modified prodrugs, the water solubility and stability of these compounds are improved, the bioactivity is increased, the aim of releasing under control is fulfilled, and the application ranges of these compounds in the industries of medicines, foods and the like are further expanded. The method is suitable for preparing prodrugs by modifying toluylene compounds with the PEG (Polyethylene Glycol) or mPEG (monomethoxy-Polyethylene Glycol)-carboxybutyryl or acetyl-amino acid. The prepared prodrugs are further used for preventing and treating diseases such as fungi, eczema, arteriosclerosis, coronary heart disease, virus hepatitis, AIDS, cancers and the like.

Description

technical field [0001] The invention belongs to the field of preparation of a class of compound prodrugs, in particular to a preparation method of water-soluble stilbene compound prodrugs. Background technique [0002] Stilbene compounds such as phenylene modad, resveratrol, pterostilbene, oxidized resveratrol, picatanol, etc., are active non-flavonoid polyphenols, which are widely found in natural foods or plants. Studies have shown that they have anti-inflammatory, anti-oxidant, anti-bacterial, anti-free radical, anti-platelet aggregation, anti-thrombotic, anti-hyperlipidemia effects, and can be used for fungi, eczema, arteriosclerosis, coronary heart disease, viral hepatitis, AIDS, cancer, etc. Disease prevention and treatment. Due to the poor water solubility and stability of the molecules of this type of compound, when it is used as a drug, it will affect the normal performance of its curative effect. In order to change the shortcomings of this type of compound, it is ...

Claims

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Application Information

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IPC IPC(8): C08G65/48A61K47/48A61P31/10A61P17/00A61P9/10A61P31/12A61P31/18A61P35/00A61P29/00A61P39/06A61P3/06A61P7/02
Inventor 张越黄道伟杜红霞赵华耿伟静
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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