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Preparation of HIF-2alpha small-molecule inhibitor and application thereof
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A small molecule inhibitor, HIF-2 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: 2021-06-18
中国医科大学
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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 kidneycancer 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
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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, then the reaction solution was extracted with ethyl acetate, several layers were washed with water, dried over anhydrousmagnesiumsulfate, filtered, and concentrated to dryness to obtain the product (intermediate a) without further purification. in the next step.
[0101] Step 2. Sodiumborohydride (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% glacia...
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 medicines, and relates to an HIF-2 alpha small-molecule inhibitor as well as a preparation method and an application thereof. The HIF-2alpha small-molecule inhibitor is a compound as shown in a structural general formula I and a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. According to the invention, molecular simulationdrugdesign software MOE is used for screening and molecular docking of pharmacophores, according to a final docking dominant structure and an isosteric principle, a series of compounds are designed and synthesized, and an in-vitro anti-tumor activity screening test shows that the compounds have anti-tumor activity. The HIF-2 alpha small-molecule inhibitor provided by the invention has a relatively good application prospect in the aspect of preventing or treating cancers, particularly 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. ...
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