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Nontoxic methotrexate prodrug and preparation method thereof

A methotrexate and prodrug technology, applied in the field of methotrexate prodrug and its preparation, can solve the problems of limiting clinical application effects, toxic and side effects, etc., and achieve the effect of improving therapeutic effect and reducing toxic and side effects

Inactive Publication Date: 2019-08-23
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The period itself is not selective, so the normal somatic cells in the mitosis process in the body will be inhibited during the administration process, resulting in a series of toxic and side effects, which is also a main reason for limiting its clinical application effect

Method used

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  • Nontoxic methotrexate prodrug and preparation method thereof
  • Nontoxic methotrexate prodrug and preparation method thereof
  • Nontoxic methotrexate prodrug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A preparation method of nontoxic methotrexate prodrug, comprising the steps of:

[0025] 1) Preparation of active small molecules: 4-(hydroxymethyl) phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride were successively dissolved in dichloromethane at a molar ratio of 1:1, fully Stirring reaction to synthesize an active small molecule capable of reversibly binding with methotrexate;

[0026] 2) Preparation of methotrexate prodrug: the active small molecule synthesized in the previous step, methotrexate and triethylamine were dissolved in N,N-dimethylformamide sequentially in a molar ratio of 1:1:1 , fully reacted at 25°C and protected from light to prepare a prodrug of methotrexate.

Embodiment 2

[0028] A preparation method of nontoxic methotrexate prodrug, comprising the steps of:

[0029] 1) Preparation of active small molecules: 4-(hydroxymethyl) phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride were successively dissolved in chloroform at a molar ratio of 1:1.5, fully Stirring reaction to synthesize an active small molecule capable of reversibly binding with methotrexate;

[0030] 2) Preparation of methotrexate prodrug: the active small molecule synthesized in the previous step, methotrexate and triethylamine were dissolved in N,N-dimethylformamide sequentially at a molar ratio of 1:0.8:3 , fully reacted at 20°C and protected from light to prepare the prodrug of methotrexate.

Embodiment 3

[0032] A preparation method of nontoxic methotrexate prodrug, comprising the steps of:

[0033] 1) Preparation of active small molecules: 4-(hydroxymethyl) phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride were sequentially dissolved in N,N-dimethylformamide at a molar ratio of 0.75:1 , fully stirred and reacted at -10°C to synthesize an active small molecule capable of reversibly binding to methotrexate;

[0034] 2) Preparation of methotrexate prodrug: the active small molecule synthesized in the previous step, methotrexate and triethylamine were sequentially dissolved in chloroform at a molar ratio of 0.8:1:2, kept at 25°C and protected from light In the case of sufficient reaction, the methotrexate prodrug is made.

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Abstract

The invention discloses a nontoxic methotrexate prodrug and a preparation method thereof. The preparation method comprises the following two steps: (a) dissolving 4-(hydroxymethyl)phenylboronic acid pinacol ester and p-nitrophenoxybenzoyl chloride serving as raw materials in an organic solvent, performing full stirring and reacting at a temperature of 0 DEG C, and synthesizing an active small molecule that can be in reversible binding to methotrexate; and (b) dissolving the active small molecule synthesized in the previous step, methotrexate and triethylamine into the organic solvent, and performing full reacting in a dark state at a normal temperature so as to obtain the methotrexate prodrug. The methotrexate prodrug prepared by the method disclosed by the invention does not have toxicity, but can be decomposed to produce the methotrexate in the presence of reactive oxygen species (ROS), and achieves effects on lesion sites. The methotrexate prodrug prepared in the invention can be applied to treatment of diseases enriched in ROS in a microenvironment such as tumors and the like, can achieve a therapeutic effect, can also avoid toxic or side effects brought by use of the methotrexate, and has a very ideal disease treatment effect.

Description

technical field [0001] The invention discloses a methotrexate prodrug and a preparation method thereof. The methotrexate prodrug itself is non-toxic, and is decomposed and reduced to methotrexate at the lesion site, thereby exerting its therapeutic effect. Background technique [0002] Methotrexate, as an antifolate drug, has a good therapeutic effect in the treatment of tumors, rheumatoid arthritis and other diseases, and is also one of the current clinical treatment drugs. Its mechanism of action is mainly to inhibit dihydrofolate reductase, thereby inhibiting DNA synthesis, thereby blocking cell mitosis and inhibiting cell proliferation. The period itself is not selective, so the normal somatic cells in the process of mitosis in the body will be inhibited during the administration process, resulting in a series of toxic and side effects, which is also a main reason for limiting its clinical application effect. [0003] Chemical modification of methotrexate, so that the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P19/02A61P35/00
CPCA61P19/02A61P35/00C07F5/025
Inventor 柳森钱程叶玮张超刘静静厉虹
Owner HUAIYIN INSTITUTE OF TECHNOLOGY