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Para-nitro aromatic methyl crizotinib hypoxia-activated prodrug for anticancer drugs

A technology of nitroarylmethylcrizotinib and nitrobenzylcrizotinib, applied in the field of p-nitrobenzylcrizotinib, can solve the problem of reduced solubility, poor water solubility, and limited clinical application and other problems, to achieve the effect of high bioavailability, low toxicity and strong tumor selectivity

Active Publication Date: 2014-02-12
济南良福精合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] At the same time, the emergence of drug resistance severely limits its clinical application; in addition, crizotinib solution is unstable at room temperature and has poor water solubility. The solubility of zotinib decreased from more than 10mg / mL to less than 0.1mg / mL

Method used

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  • Para-nitro aromatic methyl crizotinib hypoxia-activated prodrug for anticancer drugs
  • Para-nitro aromatic methyl crizotinib hypoxia-activated prodrug for anticancer drugs
  • Para-nitro aromatic methyl crizotinib hypoxia-activated prodrug for anticancer drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Embodiment 1. p-nitrobenzyl crizotinib and preparation method thereof

[0106] 1) Chemical name of p-nitrobenzyl crizotinib:

[0107] 5-(1-(1-(4-nitrobenzyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro -3-fluorophenyl)ethoxy)pyridin-2-amine.

[0108] The chemical structural formula of p-nitrobenzyl crizotinib:

[0109]

[0110] 2) The preferred preparation method of p-nitrobenzyl crizotinib:

[0111] 3.25 g of p-nitrobenzyl bromide and 4.5 g of crizotinib were dissolved in 67.5 ml of dichloromethane, 2.02 g of triethylamine was added dropwise at 25°C, and stirred at 25°C for 3 hours after the addition was complete.

[0112] 75 ml of water, the organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 ml x 3).

[0113] The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product that was recrystallized with dichloromethane and isopro...

Embodiment 2

[0116] Embodiment 2. Comparison of other preparation methods of p-nitrobenzyl crizotinib:

[0117] 4.73 g of p-nitrobenzyl iodide and 4.5 g of crizotinib were dissolved in 90 ml of tetrahydrofuran, and 3.23 g of diisopropylethylamine was added dropwise at 25°C, and stirred at 25°C for 3 hours after the addition was completed.

[0118] 75 ml of water, the organic phase was separated, and the aqueous layer was extracted with dichloromethane (50 ml x 3).

[0119] The combined organic phases were dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product which was recrystallized with dichloromethane and isopropyl ether, and filtered to obtain 3.16 g of a yellow solid, with a yield of 54%.

Embodiment 3

[0120] Example 3. The application effect of nitrobenzyl crizotinib and the comparison with crizotinib

[0121] 1) Identification of anticancer activity of nitrobenzyl crizotinib and comparative analysis of standard drug crizotinib.

[0122] Subcutaneously inject 5×10 6 Human liver cancer cells MHCC97-H and Hep3B cells in the logarithmic growth phase are on the left flank.

[0123] Among them, MHCC97-H cells highly express c-MET, while Hep3B cells express low c-MET (You H, et al.c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma.Hepatology2011;54:879-9) .

[0124] When the tumor grows to 100mm 3 (day0), the animals were randomly divided into three groups, namely the control group, the crizotinib group and the p-nitrobenzyl crizotinib group, and were given 0.5% hydroxypropyl methylcellulose by intubation Aqueous solution, crizotinib (50 mg / kg) and p-nitrobenzyl crizotinib (50 mg / kg), once daily for 3 weeks.

[0125] Tumor ...

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Abstract

The invention relates to a para-nitro aromatic methyl crizotinib hypoxia-activated prodrug for anticancer drugs, and the chemical name is 5-(1-(1-(4-nitro aromatic methyl) piperidine-4-group)-1H-pyrazol-4-group)-3-((R)-1-(2,6-dichloro-3-fluorophenyl) ethyoxyl) piperidine-2-amine. A para-nitro aromatic methylation modifier is utilized to react with crizotinib for para-nitro aromatic methylation in an alkaline condition so as to prepare the crizotinib hypoxia-activated prodrug, para-nitro aromatic methyl crizotinib. The para-nitro aromatic methyl crizotinib hypoxia-activated prodrug is used as a main effective ingredient for preparing the anticancer drugs, and particularly for preparing the anticancer drugs for curing hepatocellular carcinoma.

Description

Technical field: [0001] The invention relates to a novel antitumor drug p-nitroarylmethyl crizotinib hypoxic activation prodrug (7-ethyl-10-p-nitrobenzyloxy crizotinib, referred to as p-nitrobenzyl gram Rizotinib, HAP-Crizotinib) preparation method, and their therapeutic effects on human cancer, especially liver cancer. [0002] The advantage of p-nitroarylmethyl crizotinib is that it can be specifically activated in the hypoxic microenvironment of tumor tissue and converted into a cytotoxic drug. [0003] Compared with crizotinib, p-nitroarylmethyl crizotinib has higher tumor targeting and lower toxicity. Background technique: [0004] The anti-tumor molecular targeted drug crizotinib, also known as crizotinib, has a chemical name of: [0005] 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidine)-1H-pyrazol-4-yl]- 2-Pyridinamine, the molecular formula is: [0006] [0007] Crizotinib is a multi-kinase inhibitor that can inhibit the activity of anaplastic...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/4545A61P35/00
CPCC07D401/14
Inventor 何银杰李万湖齐放张坤孙学英
Owner 济南良福精合医药科技有限公司
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