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Preparation and application of a class of hif-2α small molecule inhibitors

A dosage form, 3-a technology, applied in the field of medicine to achieve the effects of reduced toxicity, broad anti-cancer spectrum, and good inhibitory effect

Active Publication Date: 2022-07-08
中国医科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that the effective rate of treating human glioma with TMZ is about 45%.
At present, there is no HIF-2α inhibitor on the market, only the small molecule P2977, which can target and inhibit pVHL-deficient kidney cancer cells, is currently in phase II clinical trials, and there is no HIF-2α that can be used for other tumors such as glioma. 2α inhibitor reports

Method used

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  • Preparation and application of a class of hif-2α small molecule inhibitors
  • Preparation and application of a class of hif-2α small molecule inhibitors
  • Preparation and application of a class of hif-2α small molecule inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1 1-([1,2,4]Triazolo[4,3-a]pyrazin-8-yl)-N-benzyl-N-(furan-2-ylmethyl)methanamine ( Preparation of A1).

[0100] Step 1. Dissolve 3-bromo-2-chloropyrimidine (10g, 0.052mol) in toluene (200ml), cool down to -65°C, add DMF (dimethylformamide) (6.2ml, 0.08mol) dropwise , After dropping, n-butyllithium (1.57M solution in n-hexane; 51 mL, 0.08 mol) was added dropwise. After stirring for 20 minutes, the reaction was terminated with 1N hydrochloric acid, and then the reaction solution was extracted with ethyl acetate. Several layers were washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to obtain the product (intermediate a) without further purification. in the next step.

[0101] Step 2. Sodium borohydride (2 g, 0.052 mol) was slowly added in batches to the solution of intermediate a dissolved in ethanol (30 mL) at room temperature, and stirred for 30 minutes after the addition. After quenching the reaction with 36% gl...

Embodiment 2

[0107] Example 2 1-([1,2,4]Triazolo[4,3-a]pyrazin-8-yl)-N-(4-fluorobenzyl)-N-(furan-2-ylmethane yl) methylamine (A2).

[0108] The preparation method is the same as that of Example 1, ESI-MS m / z: 337.36; 1 H-NMR (400MHz, DMSO-d 6 )δ9.13(s,1H),8.36(d,J=2.7Hz,1H),7.68(d,J=2.7Hz,1H),7.44(dd,J=0.32Hz,2H),7.36(d, J=4.3Hz, 1H), 7.07(t, 2H), 6.52(d, J=0.88Hz, 1H), 6.30(t, J=0.88Hz, J=4.3Hz, 1H), 3.99(s, 2H) , 3.82(s, 2H), 3.54(s, 2H).

Embodiment 3

[0109] Example 3 1-([1,2,4]Triazolo[4,3-a]pyrazin-8-yl)-N-(3-bromophenyl)-N-(furan-2-ylmethane yl) methylamine (A3).

[0110] The preparation method is the same as that of Example 1, ESI-MS m / z: 398.26.

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Abstract

The invention belongs to the technical field of medicine, and relates to a class of HIF-2α small molecule inhibitors and a preparation method and application thereof. The HIF-2α small molecule inhibitor is the compound shown in the general structural formula I and its stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, and the present invention utilizes molecular simulation drug design The software MOE was used to screen the pharmacophore and molecular docking. According to the dominant structure of the final docking and the isosteric principle, a series of compounds were designed and synthesized. The in vitro anti-tumor activity screening test showed that these compounds have anti-tumor activity. The HIF-2α small molecule inhibitor provided by the present invention has a good application prospect in preventing or treating cancer, especially glioma.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a class of HIF-2α small molecule inhibitors and a preparation method and application thereof. Background technique [0002] Cancer is a malignant tumor, generally normal cells in the body have abnormal cell differentiation and proliferation due to external stimuli, grow out of control, and have invasive and metastatic properties. Glioma is the abbreviation of glioma (Gliomas), also known as gliocytoma, which is the most common primary central nervous system tumor in the brain. half. Temozolomide (TMZ) is an oral alkylating agent that can cross the blood-brain barrier and reach the lesions directly. It is one of the first-line chemotherapy drugs for the clinical treatment of glioma. However, studies have shown that the effective rate of treating human gliomas with TMZ is about 45%. Among them, the resistance of gliomas to TMZ is the main reason for the failure of chemotherapy. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61K31/4985A61K31/506
CPCC07D487/04A61P35/00
Inventor 颜媛媛朴浩哲祝妍
Owner 中国医科大学