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Prodrugs designed based on intestinal mct1 carrier protein and preparation method thereof

A prodrug and intestinal absorption technology, applied in the field of medicine, can solve the problems of low oral bioavailability, incomplete release of parent drug, poor permeability of anti-tumor drugs, etc., to improve oral bioavailability and increase patient compliance , improve the efficacy of the drug

Active Publication Date: 2022-02-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention provides a solution for solving the problems of poor permeability, incomplete release of parent drug and low oral bioavailability of some BCS III antitumor drugs

Method used

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  • Prodrugs designed based on intestinal mct1 carrier protein and preparation method thereof
  • Prodrugs designed based on intestinal mct1 carrier protein and preparation method thereof
  • Prodrugs designed based on intestinal mct1 carrier protein and preparation method thereof

Examples

Experimental program
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Effect test

example 1

[0055] Example 1 gemcitabine-succinate monoester prodrug preparation (prodrug 1)

[0056] Dissolve 0.35g (3mmol) of succinic acid in 15ml of anhydrous dioxane, add 0.25g (2.5mmol) of triethylamine, dropwise add 0.28g (2.4mmol) of thionyl chloride, and vacuum the nitrogen after dropping Protected, refluxed at 110°C for 4h, concentrated the reaction solution under reduced pressure to obtain a light yellow oil, which was redissolved in 10ml DMF. 0.78 g (3.2 mmol) of gemcitabine was added, and 0.19 g (1.5 mmol) of triethylamine was added dropwise at room temperature. After the dropping was completed, the mixture was vacuumed under nitrogen protection and reacted overnight, and the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure to obtain a reddish-brown oil. Column chromatography gave a white solid with a yield of 75%. MS(ESI): m / z=364[M+H + ]. The purity determined by HPLC was 97.5%. 1 H NMR (400MHz,D 2 O) δ7.73(d, J=...

example 4

[0061] Example 4 gemcitabine-suberate monoester prodrug preparation (prodrug 4)

[0062] Dissolve 0.61g (3mmol) of sebacic acid in 15ml of anhydrous dioxane, add 0.25g (2.5mmol) of triethylamine, then add 0.28g (2.4mmol) of thionyl chloride dropwise, and vacuum nitrogen after dropping Protected, refluxed at 110°C for 4h, concentrated the reaction solution under reduced pressure to obtain a light yellow oil, which was redissolved in 10ml DMF. 0.78 g (3.2 mmol) of gemcitabine was added, and 0.19 g (1.5 mmol) of triethylamine was added dropwise at room temperature. After the dropping was completed, the mixture was vacuumed under nitrogen protection and reacted overnight, and the reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure to obtain a reddish-brown oil. Column chromatography gave a white solid with a yield of 53%. MS(ESI): m / z=448[M+H + ]. The purity determined by HPLC was 97.6%. 1H NMR (400MHz, DMSO) δ11.81(s, 1H), ...

example 5

[0063] Example 5 gemcitabine-succinate prodrug preparation (prodrug 5)

[0064] Dissolve 0.35g (3mmol) of succinic acid in 15ml of anhydrous dioxane, add 0.25g (2.5mmol) of triethylamine, dropwise add 0.28g (2.4mmol) of thionyl chloride, and vacuum the nitrogen after dropping Protected, refluxed at 110°C for 4h, concentrated the reaction solution under reduced pressure to obtain a light yellow oil, which was redissolved in 10ml DMF. 0.39 g (1.6 mmol) of gemcitabine was added, and 0.09 g (0.9 mmol) of triethylamine was added dropwise at room temperature. After the dropping, vacuum was applied under nitrogen protection, and the reaction was carried out overnight, and the reaction was monitored by TLC to complete. The reaction solution was concentrated under reduced pressure to obtain a reddish-brown oil. Column chromatography gave a white solid with a yield of 55%. MS(ESI): m / z=464[M+H + ]. The purity determined by HPLC was 98.3%. 1 H NMR (400MHz, MeOD) δ8.01(s, 1H), 7.55(d...

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Abstract

The invention belongs to the technical field of medicine, and relates to a prodrug designed based on intestinal MCT1 carrier protein and a preparation method thereof, in particular to a short-chain fatty acid targeting intestinal monocarboxylic acid transporter 1 (Mono-carboxylate transporter 1, MCT1) The preparation method of analogues includes designing and synthesizing the prodrug structure of acetic acid, lactic acid and pyruvate analogues containing hydroxyl or amino antineoplastic drugs. The series of prodrugs provided by the invention can increase or improve the oral bioavailability of drugs and adjust the release speed of the prodrugs. The involved derivatives represented by the general formula (I) or (II), and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the following structures, wherein X, Y, n, and Drug have the following descriptions and Definitions given in the claims.

Description

Technical field: [0001] The invention belongs to the technical field of medicine and relates to a prodrug designed based on intestinal MCT1 carrier protein, in particular to a carrier prodrug targeting MCT1 and its preparation and application. Background technique: [0002] Intravenous chemotherapy is one of the main means of cancer treatment, but it has caused problems such as infection, blood clots and tissue necrosis. In contrast, oral chemotherapy is safe and convenient, and can adapt to pharmacokinetic characteristics to enhance curative effect and improve the quality of life of patients. For example, the oral chemotherapy drug capecitabine (J.Gastrointest.Oncol .,2017,8(6):945-952) and topotecan (OncoTargets Ther.,2017,8(14):23851-23861). However, low oral bioavailability and large individual differences often restrict the development of most oral anticancer drugs. The oral bioavailability of drugs is affected by many factors, such as membrane permeability, water sol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/00C07H19/073A61K31/7068A61K47/54A61P35/00
CPCA61K47/542A61P35/00C07H1/00C07H19/073
Inventor 孙进何仲贵王刚
Owner SHENYANG PHARMA UNIVERSITY
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