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Prodrugs designed on basis of intestinal MCT1 (monocarboxylate transporter 1) carrier protein and preparation method of prodrugs

A technology of MCT1 and prodrug, applied in the field of medicine, can solve the problems of incomplete release of the parent drug, poor permeability of antitumor drugs, low oral bioavailability, etc., so as to improve oral bioavailability, improve drug efficacy, and increase patients The effect of compliance

Active Publication Date: 2018-10-02
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 on basis of intestinal MCT1 (monocarboxylate transporter 1) carrier protein and preparation method of prodrugs
  • Prodrugs designed on basis of intestinal MCT1 (monocarboxylate transporter 1) carrier protein and preparation method of prodrugs
  • Prodrugs designed on basis of intestinal MCT1 (monocarboxylate transporter 1) carrier protein and preparation method of prodrugs

Examples

Experimental program
Comparison scheme
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 drugs, relates to prodrugs designed on the basis of intestinal MCT1 (monocarboxylate transporter 1) carrier protein and a preparation method of the prodrugs, in particular to a preparation method of short-chain fatty acid analogs with MCT1 as a target. The preparation method comprises structural design and synthesis of the prodrug containing hydroxyl or amino anti-tumor drugs and modified with acetic acid, lactic acid and pyruvic acid analogs. According to a series of the prodrugs, oral bioavailability of the drug can be improved, and the release rate of the prodrugs can be increased. Involved derivatives represented by general formula (I) or (II) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the derivatives have structures as follows in the description, wherein X, Y, n and Drug have definitions given in the description and 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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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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