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Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof

A prodrug and pharmaceutical technology, applied in the field of medicine, can solve the problems of low oral bioavailability and poor permeability, and achieve the effect of increasing compliance and reducing risks

Active Publication Date: 2016-07-13
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The invention is the first to synthesize a carrier prodrug targeting the intestinal OCTN2 transporter, which provides a solution to the problems of poor permeability and low oral bioavailability of some BCSIII and IV antitumor drugs

Method used

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  • Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof
  • Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof
  • Prodrug based on intestinal OCTN2 carrier protein design and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

example 14

[0039] Preparation of Example 14-Benzyl L-carnitine

[0040] Dissolve 5.3g (32.9mmol) of L-carnitine and 4.50g (26.3mmol) of bromide in 20mL of DMF, heat to reflux at 140°C for 2h, and concentrate under reduced pressure to obtain 5.53g of white solid with a yield of 83.3%. ESI-MS[M+H] + (m / z): 252 (Intermediate 1).

example 2

[0041] Example 22-butyryl-4-benzyl-L-carnitine preparation

[0042] Dissolve 1g (3.9mmol) of the intermediate and 0.48g (4.8mmol) of succinic anhydride in 10mL of DMF, add 2 drops of triethylamine dropwise at 0°C, and vacuum nitrogen protection after dropping, and the reaction is complete after 2 hours. Processing proceeds directly to the next step. ESI-MS[M+H] + (m / z): 352 (Intermediate 2).

example 32

[0043] Preparation of Example 32-hexanoyl-4-benzyl-L-carnitine

[0044] Dissolve 1g (3.9mmol) of the intermediate and 0.59g (4.8mmol) of adipic anhydride in 10mL of DMF, add 2 drops of triethylamine dropwise at 0°C, and vacuum the nitrogen protection after dropping. After 2 hours, the reaction is complete, and no treatment is required for the reaction Proceed directly to the next step. ESI-MS[M+H] + (m / z): 380 (Intermediate 3).

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Abstract

The invention belongs to the technical field of medicine and relates to a preparation method of a carrier prodrug with intestinal novel organic cation transporter 2 (OCTN2) being a target point.The preparation method includes the step of design of a prodrug structure with L / D-carnitine for modifying anti-tumor medicine containing hydroxyl or an amino group through a linker arm.The series of prodrug can improve the oral bioavailability of medicine.The invention relates to an L / D-carnitine derivative shown in the general formula I and the general formula II and pharmaceutically acceptable salt or hydrate or solvate or the pharmaceutically acceptable prodrug.Drug and R have definition given by the specification (please see the formula in specification).

Description

Technical field: [0001] The invention belongs to the technical field of medicine and relates to a class of novel compounds, in particular to a carrier prodrug targeting OCTN2 and its preparation and application. Background technique: [0002] Oral administration is currently the most common route of administration. Oral medication is relatively more convenient, safer and faster, and patients are more likely to adapt to this administration method. However, low oral bioavailability is often an important reason why many drugs cannot be administered orally. Oral absorption of drugs is affected by many factors, such as drug permeability, water solubility, pre-system metabolism and first-pass effect, and efflux of efflux transporters, etc. It is these factors that make BCS III and IV antitumor drugs Oral drug development is facing great challenges. [0003] Carrier prodrug is a prodrug strategy that targets drug transporters in vivo, such as oligopeptide transporter 1 (PEPT1) an...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00C07D487/14A61K31/7068A61K31/407A61K47/48A61P35/00A61K47/54
Inventor 孙进王刚何仲贵王永军孙英华
Owner SHENYANG PHARMA UNIVERSITY
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