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Dual inhibitor of prolyl hydroxylase and histone deacetylase, preparation method and application thereof

A reaction and compound technology, applied in the application field of preparing radiation protection drugs, can solve the problem of lack of similar compounds

Active Publication Date: 2020-04-24
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention aims at the defects of the prior art, and provides a preparation method and application of a new dual inhibitor compound of prolyl hydroxylase and histone deacetylase, so as to solve the lack of a similar compound in the prior art technical problems;
[0008] Another technical problem to be solved by the present invention is that the existing compounds cannot be selected to novelly stabilize HIF-2α protein;

Method used

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  • Dual inhibitor of prolyl hydroxylase and histone deacetylase, preparation method and application thereof
  • Dual inhibitor of prolyl hydroxylase and histone deacetylase, preparation method and application thereof
  • Dual inhibitor of prolyl hydroxylase and histone deacetylase, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 4-Hydroxy-2-pyrazol-1-ylpyrimidine-5-carboxylic acid ethyl ester (2)

[0061]

[0062] Add pyrazole-1-carboxamide hydrochloride (1eq) and N,N-diisopropylethylamine (2.2eq) to 5 times the volume of ethanol, stir at room temperature for 20min, add ethoxymethylenemalonate diethyl Ester (1eq), warmed to reflux and reacted overnight. After the reaction was complete, about half of the volume of ethanol was evaporated under reduced pressure, water and ethyl acetate were added to extract twice, the organic layer was washed once with water, and the aqueous layers were combined. The pH of the aqueous layer was adjusted to 3-4, and a large amount of white insoluble matter was precipitated, filtered and dried to obtain a white powder of 2 with a yield of about 90.25%. m.p.162.8-163.8℃; ESI-MS(m / z):235.0822[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 )δ13.28(s,1H),8.63–8.56(m,2H),7.96(dd,J=1.6,0.7Hz,1H),6.67(dd,J=2.8,1.6Hz,1H),4.26(q ,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H)

Embodiment 2

[0063] Example 2 4-(4-methoxybenzyloxy)-2-pyrazol-1-ylpyrimidine-5-carboxylic acid ethyl ester (3)

[0064]

[0065] Add 2 and anhydrous potassium carbonate (1.4eq) to 5 times the volume of N,N-dimethylformamide, stir at room temperature for 30min, add a catalytic amount of potassium iodide (0.1eq), and then p-methoxychloride Benzyl chloride was dissolved in 5 times the volume of N,N-dimethylformamide, added dropwise to the system, heated to 80°C, and reacted overnight. TLC monitoring, after the reaction is complete, add 10 times the volume of water to the system, then extract twice with ethyl acetate, combine the organic layers, and then use saturated NaHCO 3 The solution was washed twice, and the organic layer was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was pulped with methanol, and the filter cake was washed with the mother liquor. The white solid powder of 3 was obtained after the filter cake was dried, and t...

Embodiment 3

[0066] Example 3 4-(4-methoxybenzyloxy)-2-pyrazol-1-ylpyrimidine-5-carboxylic acid ethyl ester (4)

[0067]

[0068]3 and sodium hydroxide (5eq) were dissolved in 10 volumes of tetrahydrofuran / water mixed solvent (volume ratio 1:1), stirred at room temperature, and the reaction was monitored by TLC. After the reaction was complete, part of the tetrahydrofuran was distilled off under reduced pressure, extracted once by adding water and ethyl acetate, and the pH of the aqueous layer was adjusted to 3-4 to precipitate a white solid, which was filtered and dried to obtain a white powder of 4 with a yield of about 87.97%. m.p.126.3-126.5℃; ESI-MS(m / z):327.3[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 )δ13.17(s,1H),8.95(s,1H),8.74(d,J=2.7Hz,1H),7.93(d,J=1.4Hz,1H),7.50(d,J=8.6Hz, 2H), 6.93(d, J=8.6Hz, 2H), 6.64(dd, J=2.8, 1.6Hz, 1H), 5.57(s, 2H), 3.75(s, 3H).

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Abstract

The invention discloses a new dual inhibitor for prolyl hydroxylase and histone deacetylase shown as formula I, a preparation method and an application thereof. The new dual inhibitor is capable of selectively promoting the level of hypoxia-inducible factor -2alpha(HIF-2alpha) by simultaneously inhibiting activities of prolyl hydroxylase (PHD) and histone deacetylase (HDAC) and is expected to become a new radiation protection drug.

Description

technical field [0001] The present invention relates to a novel small-molecule prolyl hydroxylase and histone deacetylase dual inhibitor, a method for preparing the compound, and the compound as a prolyl hydroxylase and histone deacetylase inhibitor Application of dual inhibitors in the preparation of radioprotective medicines. Background technique [0002] The following background introduction related to the present invention is used to help the understanding of the present invention, but should not be considered as the prior art of the present invention. All cited publications are incorporated by reference in full. [0003] Hypoxia-inducible factor (HIF) is a kind of nuclear transcription factor induced by hypoxia, which is a heterodimer composed of functional α subunit and structural β subunit. There are three subtypes of HIF, namely HIF-1, HIF-2 and HIF-3, among which HIF-1 and HIF-2 are mainly involved in the regulation of cell adaptation to hypoxia. Molecular biolog...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D401/14A61K31/506A61P39/00
CPCA61P39/00C07D401/14C07D403/04
Inventor 李祎亮魏会强高骏毕常芬宁洪鑫于江勾文峰段玉清
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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