SN38 triglyceride prodrug, lipid preparation as well as preparation method and application of SN38 triglyceride prodrug and lipid preparation

A technology of triglycerides and prodrugs, which is applied in the field of medicine, can solve problems such as side reactions, and achieve the effects of strong repeatability, enhanced stability, and uniform and stable properties

Active Publication Date: 2022-01-28
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for the chemotherapeutic drug SN38, a large amount of systemic exposure can cause serious side effects, so this linkage is not instructive for the design of an oral drug delivery system for SN38

Method used

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  • SN38 triglyceride prodrug, lipid preparation as well as preparation method and application of SN38 triglyceride prodrug and lipid preparation
  • SN38 triglyceride prodrug, lipid preparation as well as preparation method and application of SN38 triglyceride prodrug and lipid preparation
  • SN38 triglyceride prodrug, lipid preparation as well as preparation method and application of SN38 triglyceride prodrug and lipid preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation method of the SN38 class triglyceride prodrug (SN38-SS-OcA) substituted by octanoic acid group comprises the following steps:

[0048] The structure of the prodrug is as follows:

[0049]

[0050] (1) Synthesis of 1,3-diglyceride (1,3-DG): 2.5g (17.34mmol) octanoic acid was dissolved in 50ml dichloromethane, and 5.2g (27.13mmol) EDCI and 1.1g (9mmol) Under the catalysis of DMAP, react with 0.65g (7.22mmol) 1,3-dihydroxyacetone to form an ester, and then react with 0.2g (5.28mmol) sodium borohydride for hydrogenation to obtain 1,3-DG.

[0051] (2) Dissolve 0.7g (2.03mmol) of 4,4'-dithiodibutyric acid in 4ml of acetic anhydride, react at room temperature for 2h, concentrate by rotary evaporation and redissolve in 30ml of anhydrous dichloromethane, And added 0.68g (1.98mmol) 1,3-DG, 22.2mg (0.2mmol) DMAP. Vacuum nitrogen protection at room temperature for 12h. The solvent was removed by rotary evaporation, and the intermediate product was obtained by ...

Embodiment 2

[0057] The preparation method of the SN38-class triglyceride prodrug (SN38-SS-LA) substituted by lauric acid group may further comprise the steps:

[0058] The structure of the prodrug is as follows:

[0059]

[0060] (1) Synthesis of 1,3-diglyceride (1,3-DG): 2.5g (12.48mmol) lauric acid was dissolved in 50ml of dichloromethane, in 3.7g (19.30mmol) EDCI and 0.7g (5.73 Under the catalysis of mmol) DMAP, react with 0.46g (5.11mmol) 1,3-dihydroxyacetone to form an ester, and then react with 0.2g (5.28mmol) sodium borohydride for hydrogenation to obtain 1,3-DG.

[0061] (2) Dissolve 0.7g (2.03mmol) of 4,4'-dithiodibutyric acid in 4ml of acetic anhydride, react at room temperature for 2h, concentrate by rotary evaporation and redissolve in 30ml of anhydrous dichloromethane, And added 0.89g (1.83mmol) 1,3-DG, 28.9mg (0.29mmol) DMAP. Vacuum nitrogen protection at room temperature for 12h. The solvent was removed by rotary evaporation, and the intermediate product was obtained ...

Embodiment 3

[0068] The preparation method of the SN38 class triglyceride prodrug (SN38-SS-PA) substituted by palmitic acid group comprises the following steps:

[0069] The structure of the prodrug is as follows:

[0070]

[0071] (1) Synthesis of 1,3-diglyceride (1,3-DG): 2.5g (9.76mmol) of palmitic acid was dissolved in 50ml of dichloromethane, and 2.4g (12.06mmol) of EDCI and 0.5g (4.10 mmol) DMAP catalyzed with 0.3g (3.33mmol) 1,3-dihydroxyacetone to form an ester reaction, and then hydrogenated with 0.2g (5.28mmol) sodium borohydride to obtain 1,3-DG.

[0072](2) Dissolve 0.7g (2.03mmol) of 4,4'-dithiodibutyric acid in 4ml of acetic anhydride, react at room temperature for 2h, concentrate by rotary evaporation and redissolve in 30ml of anhydrous dichloromethane, And 1.09 g (1.83 mmol) 1,3-DG, 35.6 mg (0.29 mmol) DMAP were added. Vacuum nitrogen protection at room temperature for 12h. The solvent was removed by rotary evaporation, and the intermediate product was obtained by col...

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Abstract

The invention discloses SN38 triglyceride prodrug, a lipid preparation and a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to the SN38 triglyceride prodrugs with different fatty acid chain lengths for lymph-mediated transport and preparation and application thereof. Based on the digestion process of triglyceride in vivo, three fatty acid group substituted triglyceride prodrugs with different chain lengths are designed, so that the stability of SN38 is improved, the oral absorption efficiency of SN38 is improved, and the influence of the chain lengths of first site and third site fatty acid groups on a triglyceride structure on the lymphatic transport efficiency and oral absorption of the prodrugs is investigated. In addition, a reduction-sensitive connecting bond is introduced, so that the anti-tumor drug can be specifically released at a target site while oral absorption of the anti-tumor drug is promoted, the curative effect is improved, and the toxicity is reduced. a: R = (CH2) 6CH3b: R = (CH2) 10CH3c: R = (CH2) 14CH3.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to SN38 triglyceride prodrugs of different fatty acid chain lengths mediated by lymph and their preparation and application. Background technique [0002] Nowadays, the global cancer burden is increasing year by year, and irinotecan (CPT-11) is widely used as a first-line anticancer chemotherapy drug in the clinical treatment of various tumors. Its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN38), is a derivative of camptothecin obtained by improving its chemical structure. It has stronger anticancer effect and anticancer activity, causing more and more lots of scientific attention. The clinical application of irinotecan is intravenous administration, but the commercially available intravenous solution can cause severe diarrhea, and its side effects greatly limit the clinical application. Oral chemotherapy has the advantages of high patient compliance, conveni...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61K47/54A61K9/51A61K9/00A61P35/00
CPCC07D491/22A61K31/4745A61K47/545A61K9/0053A61K9/5123A61P35/00
Inventor 孙进何仲贵王鹤霖田楚彤
Owner SHENYANG PHARMA UNIVERSITY
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