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Toll-like receptor stimulant requinimod derivative and preparation and application thereof

A receptor agonist, Requinimod technology, applied in the field of medical materials, can solve the problems of low bioavailability, difficult to achieve ideal efficacy, limited application, etc., achieve huge application potential, and improve adverse pharmacokinetics. Effect

Active Publication Date: 2021-12-21
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the poor water solubility of these agonists leads to low bioavailability, and it is difficult to achieve the desired drug effect with a single administration. The dose limitation and adverse reactions after drug withdrawal hinder repeated systemic administration, which limits its clinical application.

Method used

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  • Toll-like receptor stimulant requinimod derivative and preparation and application thereof
  • Toll-like receptor stimulant requinimod derivative and preparation and application thereof
  • Toll-like receptor stimulant requinimod derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: Preparation of R848-HSEA

[0056]R848-HSEA is prepared by reacting R848 amino group with triphosgene-activated HSEA.

[0057] Preparation of HSEA:

[0058] Weigh 0.065mmol of hydroquinone, 20mmol of triethylamine, and 13mmol of 2-hydroxyethyl disulfide into a reaction vessel, add 200mL of anhydrous THF, and stir in an ice-water bath; extract 100mL of anhydrous THF with a glass needle into In the constant pressure dropping funnel, weigh 13mmol of acryloyl chloride and add it to the constant pressure dropping funnel; in the ice-water bath, slowly add acryloyl chloride dropwise for about 1 hour, and then transfer to room temperature for reaction; react for 24 hours Afterwards, stop the reaction, filter to remove the generated salt, spin the solvent to dryness, add dichloromethane, wash with saturated brine three times, then wash with pure water once, after the organic phase is dried with anhydrous magnesium sulfate, concentrate, and use silica gel column pur...

Embodiment 2

[0062] Embodiment 2: the preparation of R848-HSEMA:

[0063] R848-HSEA is prepared by reacting R848 amino group with triphosgene-activated HSMEA.

[0064] Preparation of HSEMA:

[0065] Weigh 0.065mmol of hydroquinone, 20mmol of triethylamine, and 13mmol of 2-hydroxyethyl disulfide into a reaction vessel, add 200mL of anhydrous THF, and stir in an ice-water bath; extract 100mL of anhydrous THF with a glass needle into In the constant pressure dropping funnel, weigh 13mmol methacryloyl chloride and add it to the constant pressure dropping funnel; in the ice-water bath, slowly add methacryloyl chloride dropwise for about 1 hour, and transfer to room temperature after the dropwise addition reaction; stop the reaction after 24 hours of reaction, filter to remove the generated salt, spin the solvent to dryness, add dichloromethane, wash three times with saturated saline, and then wash once with pure water, dry the organic phase with anhydrous magnesium sulfate, concentrate, and us...

Embodiment 3

[0069] Embodiment 3: Preparation of R848-TEGA

[0070] R848-TEGA is prepared by reacting R848 amino group with triphosgene-activated TEGA.

[0071] Preparation of TEGA:

[0072] Weigh 0.065mmol of hydroquinone, 20mmol of triethylamine, and 13mmol of tetraethylene glycol into a reaction vessel, add 200mL of anhydrous THF, and stir in an ice-water bath; extract 100mL of anhydrous THF with a glass needle at a constant pressure In the dropping funnel, weigh 13mmol of acryloyl chloride and add it to the constant pressure dropping funnel; in the ice-water bath, slowly add acryloyl chloride dropwise for about 1 hour. After the dropwise addition, transfer to room temperature for reaction; stop after 24 hours reaction, filtered to remove the generated salt, the solvent was spin-dried, added dichloromethane, washed three times with saturated brine, and then washed once with pure water, and the organic phase was dried with anhydrous magnesium sulfate, concentrated, and purified using a ...

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Abstract

The invention belongs to the technical field of medicines, and discloses a Toll-like receptor stimulant requinimod derivative and a preparation method and application thereof. The Toll-like receptor stimulant requinimod derivative is one of the following structures. The preparation method comprises the following step: reacting requinimod R848 with an acyl chloride compound, wherein the acyl chloride compound contains acid anhydride, acrylic ester or metacrylic acid ester. The Toll-like receptor agonist requinimod derivative is used for preparing a Toll-like receptor 7 / 8 agonist and an anti-cancer drug, and the requinimod derivative is used for preparing the anti-cancer drug in a bonding manner. The requinimod derivative disclosed by the invention not only keeps the original drug activity, but also the high-activity reactive group of the requinimod derivative is beneficial to bonding of requinimod and is easy to deliver to a tumor site, the poor pharmacokinetics of requinimod is improved, and the bioavailability is improved.

Description

technical field [0001] The invention belongs to the technical field of medical materials, and specifically relates to a class of Toll-like receptor agonist derivatives and their preparation and application. Background technique [0002] Resiquimod (R848), as a small molecule agonist, can effectively activate endosomal toll-like receptors (endosomal toll-like receptors, TLRs) 7 and 8, which are potent activators of innate and adaptive immunity. The activation of TLR7 / 8 receptors has been shown to induce the polarization of macrophages into M1 phenotype macrophages in related studies, and repolarize TAMs from the tumor-promoting M2 phenotype to the anti-tumor growth M1 phenotype, promoting The ability to mount an effective anti-tumor immune response. In fact, some small molecule TLR7 / 8 agonists are undergoing preclinical studies or have been clinically approved (such as imiquimod). However, the poor water solubility of these agonists leads to low bioavailability, and it is d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00
Inventor 杜金志张尧君段奇佳童其松李佳贤王均
Owner SOUTH CHINA UNIV OF TECH
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