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A class of tripterine derivatives, its preparation method and use

A technology of tripterine and its derivatives, which is applied in the field of medicines for diseases and the preparation of peroxidase inhibitors, and can solve problems such as weak activity, complex mechanism of action, and unclear targets

Active Publication Date: 2022-02-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism of action of this natural product is complex and the target is not clear. Although heat shock protein 90 has been reported as its target in the literature, its activity is weaker, and the more active target needs to be further elucidated

Method used

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  • A class of tripterine derivatives, its preparation method and use
  • A class of tripterine derivatives, its preparation method and use
  • A class of tripterine derivatives, its preparation method and use

Examples

Experimental program
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preparation example 1

[0054] Preparation Example 1: Preparation of Compound 1-1

[0055]

[0056] Dissolve tripterine (1g, 2.2mmol) in toluene (10ml), add DIPEA (1.16ml, 6.7mmol) and diphenylphosphoryl azide (0.62ml, 2.9mmol) to the solution, and stir at 100°C 3 hours. The reaction solution was diluted with ethyl acetate, extracted with water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (PE:EA=6:1) to obtain 610 mg of a red solid (yield 62 %). 1 H NMR (400MHz, CDCl 3 )δ7.03(d,J=6.0Hz,2H),6.54–6.50(m,1H),6.36(d,J=7.1Hz,1H),2.21(s,3H),2.16–2.05(m,2H ),1.96–1.86(m,3H),1.82–1.64(m,6H),1.60–1.51(m,3H),1.43(s,3H),1.40(s,3H),1.25(s,3H), 1.05(s,3H), 1.03–0.97(m,1H), 0.92(s,3H).

Embodiment 1

[0057] Embodiment 1: the preparation of compound S1

[0058]

[0059] Compound 1-1 (50mg, 0.11mmol) was dissolved in tetrahydrofuran (2ml), and ethyl 1-aminocyclopropanecarboxylate hydrochloride (37mg, 0.22mmol), triethylamine (31μl, 0.22mmol) were added to the solution ), stirred at 50°C for 4 hours, spin-dried the solvent, dissolved it with ethyl acetate, extracted with water, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM:MeOH=30:1 ), to obtain 42 mg of red solid (65% yield). 1 H NMR (400MHz, CDCl 3 )δ7.01(d, J=8.5Hz, 2H), 6.51(s, 1H), 6.35(d, J=6.9Hz, 1H), 4.93(s, 1H), 4.38(s, 1H), 4.07( q,J=7.2Hz,2H),2.89(d,J=14.0Hz,1H),2.20(s,3H),2.11(dd,J=12.8,4.4Hz,1H),2.02–1.60(m,10H ),1.53(m,J=9.1Hz,5H),1.37(s,3H),1.26(s,3H),1.17(t,J=7.1Hz,3H),1.10(s,3H),0.98(m ,2H), 0.75(s,3H). MS(ESI): [M+Na] + m / z 599.4

Embodiment 2

[0060] Embodiment 2: the preparation of compound S2

[0061]

[0062]Compound 1-1 (50mg, 0.11mmol) was dissolved in tetrahydrofuran (2ml), and methyl 1-aminocyclobutanecarboxylate hydrochloride (36mg, 0.22mmol), triethylamine (31μl, 0.22mmol) were added to the solution , stirred at 50°C for 4 hours, spin-dried the solvent, dissolved it with ethyl acetate, extracted with water, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM:MeOH=30:1) , to obtain 45 mg of red solid (yield 71%). 1 H NMR (400MHz, CDCl 3 )δ7.02(d, J=8.6Hz, 2H), 6.49(s, 1H), 6.36(d, J=6.3Hz, 1H), 5.05(s, 1H), 4.35(s, 1H), 3.69( s,3H),2.89(d,J=15.4Hz,1H),2.49(d,J=38.2Hz,2H),2.20(s,3H),1.93(d,J=15.4Hz,7H),1.70( dd,J=12.8,5.9Hz,2H),1.62–1.47(m,6H),1.41(s,3H),1.34(s,3H),1.24(s,3H),1.09(s,3H),0.94 (d, J=12.4Hz, 1H), 0.80(s, 3H). MS(ESI): [M+Na] + m / z 599.4

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Abstract

This application relates to a class of tripteryne derivatives represented by formula I, their preparation method and application. The tripteryne derivatives have significant Prdx1 inhibitory activity, and can be used to prevent or treat the peroxide in vivo Enzyme 1-related diseases, especially for preventing or treating tumor growth and metastasis.

Description

technical field [0001] The present invention relates to a class of tripterine derivatives, its preparation method and its use in the preparation of peroxidase inhibitors and medicines for anti-tumor and other diseases. Background technique: [0002] The peroxidoreductase family (Prdx) is a class of antioxidant enzymes in cells. It has the functions of maintaining the balance of intracellular hydrogen peroxide and removing reactive oxygen species (ROS). It plays an important role in intracellular signal transduction and cell metabolism. Regulation. Peroxidase-1 (Prdx1) is a class of proteases in the Prdx family, composed of homodimers containing conserved cysteine ​​residues at the C-terminus and N-terminus, and its crystal structure is five dimers composed of circular complexes. Prdx1 has a variety of biological functions, including antioxidant function, molecular chaperone function, and regulation of inflammation and tumor cells. Prdx1 is widely distributed in the cytopl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P35/00A61P29/00A61P3/04A61P3/10A61P35/02
CPCC07J63/008A61P35/00A61P29/00A61P3/04A61P3/10A61P35/02A61K31/58A61K31/56C07J63/00
Inventor 张翱罗成丁春勇张豪徐珩李阳蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI