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

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

Active Publication Date: 2019-01-18
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 for prolyl hydroxylase and histone deacetylase, preparation method and application thereof
  • Dual inhibitor for prolyl hydroxylase and histone deacetylase, preparation method and application thereof
  • Dual inhibitor for prolyl hydroxylase and histone deacetylase, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Ethyl 4-hydroxy-2-pyrazol-1-ylpyrimidine-5-carboxylate (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 diethyl ethoxymethylidene malonate Ester (1 eq), warmed to reflux and reacted overnight. After the reaction was completed, about half the volume of ethanol was evaporated under reduced pressure, water and ethyl acetate were added for extraction 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, which was 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, ...

Embodiment 2

[0063] Example 2 Ethyl 4-(4-methoxybenzyloxy)-2-pyrazol-1-ylpyrimidine-5-carboxylate (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 the solvent was completely removed under reduced pressure, the residue was slurried with methanol, and the filter cake was washed with the mother liquor. The filter cake was dried to obtain 3 as a white solid powder in a yield ...

Embodiment 3

[0066] Example 3 Ethyl 4-(4-methoxybenzyloxy)-2-pyrazol-1-ylpyrimidine-5-carboxylate (4)

[0067]

[0068]3 and sodium hydroxide (5eq) were dissolved in 10 times the volume of tetrahydrofuran / water mixed solvent (volume ratio 1:1), stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, part of the tetrahydrofuran was evaporated under reduced pressure, and water and ethyl acetate were added for extraction once. 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°C; 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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PUM

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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 dual inhibitor of small molecule prolyl hydroxylase and histone deacetylase, a preparation method of the compound, and the compound is used as prolyl hydroxylase and histone deacetylase Application of dual inhibitors in the preparation of radioprotective drugs. Background technique [0002] The following descriptions of the background related to the present invention are provided to assist an understanding of the present invention and should not be considered as prior art to the present invention. All cited publications are incorporated by reference in their entirety. [0003] Hypoxia-inducible factor (HIF) is a class of nuclear transcription factors induced under hypoxia, which is a heterodimer composed of functional α subunit and structural β subunit. There are three main 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 cellular adaptive hyp...

Claims

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Application Information

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Patent Type & Authority Applications(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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