GnRH polypeptide-methotrexate conjugate, and preparation method and application thereof

A technology of methotrexate and conjugates, applied in the field of GnRH polypeptide-methotrexate conjugates, which can solve the problems of normal tissue and organ toxicity and side effects

Active Publication Date: 2015-02-25
上海市生物医药技术研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although methotrexate is a commonly used anti-tumor drug in clinical practice, drug resistance and side effects on normal tissues and organs after long-term use limit the clinical application of methotrexate

Method used

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  • GnRH polypeptide-methotrexate conjugate, and preparation method and application thereof
  • GnRH polypeptide-methotrexate conjugate, and preparation method and application thereof
  • GnRH polypeptide-methotrexate conjugate, and preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0062] The preparation of embodiment 1 methotrexate active ester

[0063] Example 1 Set three groups in parallel (Examples 1.1, 1.2, 1.3), 454 mg (1 mmol) of methotrexate was dissolved in 20 mL of DMSO, and 575.1 mg (3 mmol) of EDC.HCl reagent was added, respectively at 25 ° C, 35 ° C and React at 45°C for two hours, add 345.27mg (3mmol) NHS and 61.22mg (0.5mmol) DMAP after two hours, the whole reaction is carried out under anhydrous, oxygen-free and light-shielding conditions, follow the reaction with thin layer chromatography (TLC) , stop reaction after reacting 24h, suction filtration, remove unreacted solid reagent, then dilute reaction solution with diethyl ether acetone mixed solvent, anhydrous MgSO Dry 24h, suction filtration, rotary evaporation removes solvent, silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) separation and purification to obtain a yellow liquid, weigh the weight of methotrexate active ester, calculate the reaction yield, the r...

Embodiment 2

[0067] The preparation of embodiment 2 methotrexate active esters

[0068] Example 2 Set up three groups in parallel (Example 2.1, 2.2, 2.3), methotrexate 423.66mg (0.93mmol) was dissolved in 20mLDMSO, added the EDC.HCl reagent of 534.8mg (2.79mmol), and the reaction time at room temperature 2 hours respectively, 321.12mg (2.79mmol) NHS and 57.42mg (0.47mmol) DMAP were added after 2 hours, the whole reaction was carried out under anhydrous, anaerobic and light-proof conditions, and the reaction was followed by TLC, followed by Example 2.1, 2.2 and 2.3 The reaction time of the three groups of reactions is set to 4 hours respectively. After 12 hours and 24 hours, the reaction is terminated, the unreacted solid reagent is removed by filtration, and then the reaction solution is diluted with a mixed solvent of ether and acetone, and dried with anhydrous MgSO4 for 24 hours. Suction filtration, rotary evaporation to remove solvent, silica gel column chromatography (V ethyl acetate:V...

Embodiment 3

[0072] The preparation of embodiment 3 methotrexate active esters

[0073] Example 3 Set three groups in parallel (Example 3.1, 3.2, 3.3), methotrexate 448.6mg (0.988mmol) was dissolved in 20mLDMSO (containing 0.2mL of triethylamine), added 465mg (2.96mmol) of EDC. HCl reagent, reaction at room temperature for two hours, add 345.27mg (3mmol) NHS after two hours, the amount of adding DMAP respectively in embodiment 3.1, 3.2 and 3.3 is 61.1mg (0.5mmol), 122.2mg (1.0mmol) and 183.3mg ( 1.5mmol), the whole reaction is carried out under anhydrous, anaerobic and light-shielding conditions, follow the reaction with TLC, terminate the reaction after 24h of reaction, remove unreacted solid reagent by filtration, then dilute the reaction solution with diethyl ether acetone mixed solvent, no Water MgSO Dry 24h, suction filtration, rotary evaporation to remove solvent, silica gel column chromatography (V ethyl acetate:V petroleum ether=1:6) separation and purification, obtain yellow liqui...

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Abstract

The invention discloses a GnRH polypeptide-methotrexate conjugate shown as a formula in the specification, and the GnRH polypeptide-methotrexate conjugate can be prepared from GnRH polypeptide or analogs thereof and methotrexate or derivatives thereof. The invention also provides a preparation method of the GnRH polypeptide-methotrexate conjugate and application of the GnRH polypeptide-methotrexate conjugate to prepare antitumor medicines. The GnRH polypeptide-methotrexate conjugate is simple in preparation technology, high in yield and easy to purify, has good tumor targeting property on the aspect of resisting tumors, and is capable of centralizing a medicine at the tumor position.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a GnRH polypeptide-methotrexate conjugate, its preparation method and application. Background technique [0002] Malignant tumors are a class of diseases that seriously endanger human physical and mental health and affect the social labor force, and have brought heavy economic burdens to many families and society. According to statistics, the incidence of cancer worldwide will increase by 50% in 2020, and the number of new cancer patients worldwide will reach 15 million each year. In the past 20 years, the incidence of cancer in my country has increased by 69%, and the death rate has increased by 29%. There are 2.2 million new cancer cases and 1.6 million cancer deaths every year. One out of every four or five deaths is due to cancer, and cancer has become the main killer threatening human life and health. Prostate cancer is the most common malignant tumor in the male reprodu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/107A61K47/48A61K31/519A61P35/00
Inventor 孙祖越朱圣生
Owner 上海市生物医药技术研究院
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