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

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...

Examples

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 ...

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...

Examples

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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