Novel artemisinin derivatives as well as synthetic method and application thereof

A condensation and halogen technology, applied in the field of new artemisinin derivatives, can solve problems such as poor water solubility and tumor lysis syndrome

Inactive Publication Date: 2019-08-20
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, Venetoclax is poorly water soluble, so that it needs to be administered in large doses in clinical practice. In addition, Venetoclax also has side effects such as tumor lysis syndrome.

Method used

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  • Novel artemisinin derivatives as well as synthetic method and application thereof
  • Novel artemisinin derivatives as well as synthetic method and application thereof
  • Novel artemisinin derivatives as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] The preparation of embodiment 1 compound S1

[0090]

[0091] The synthetic reference method of compound 1-1 (Org. Lett. 2005, 7, 1561-1564.).

[0092] The synthetic reference method of compound 1-2 (J. Med. Chem. 2008, 51, 6902-6915.).

[0093] Synthesis of Compound 1-3:

[0094] Dissolve compound 1-1 in dichloromethane, add (3eq) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [EDCI], (0.3eq) 4-di Methylaminopyridine [DMAP], after stirring at room temperature for half an hour, compound 1-2 (1.2eq) was added, followed by reaction at room temperature for 2-5 hours. After the reaction was complete, the reaction was quenched with water, extracted three times with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was loaded on the column, CH 2 Cl 2 :MeOH=100:1~30:1 to obtain compound 1-3.

[0095] Synthesis of compounds 1-4:

[0096] Compound 1-3 was dissolved in EtOH:H 2...

Embodiment 2

[0101] The preparation of embodiment 2 compound S2

[0102]

[0103] Synthesis of compound 2-1:

[0104] Compound 1-3 was dissolved with glacial acetic acid [HOAc], and activated zinc powder (6eq) was added in batches, and stirred at room temperature for 3 days. After the reaction is complete, use sodium bicarbonate [NaHCO 3 ] solution was adjusted to pH = 7, extracted three times with ethyl acetate [EA], the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was loaded on the column, CH 2 Cl 2 :MeOH=100:1~30:1 to obtain compound 2-1.

[0105] Synthesis of compound 2-2:

[0106] Compound 2-1 was dissolved in EtOH:H 2 To the mixed solvent of O=3:2, (2eq) lithium hydroxide was added, and stirred overnight at room temperature. After the reaction was complete, the reaction solution was spin-dried, dissolved by adding a small amount of water, then adjusted to pH = 6 with 1M aqueous HCl solution, and a white solid w...

Embodiment 3

[0110] The preparation of embodiment 3 compound S3

[0111]

[0112] Synthesis of Compound S3:

[0113] Compound S1 was dissolved in MeCN[acetonitrile]:H 2 In the mixed solvent of O=1:1, add (1.2eq) ferrous sulfate heptahydrate [FeSO 4 .7H 2 O], reacted at 37°C for 1 hour under the protection of nitrogen. After the reaction is complete, wash with water, extract three times with EA, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, mix the sample and put it on the column, CH 2 Cl 2 :MeOH=100:1~40:1 to obtain compound S3.

[0114] 1 H NMR (400MHz, CDCl 3 )δ10.17(s,1H),9.80(s,1H),8.90(d,J=2.3Hz,1H),8.54(t,J=5.5Hz,1H),8.28–8.13(m,2H), 8.00(d, J=9.1Hz, 1H), 7.73(d, J=2.3Hz, 1H), 7.49(t, J=2.8Hz, 1H), 6.92(d, J=9.2Hz, 1H), 6.62– 6.50(m,2H),6.00(d,J=2.3Hz,1H),5.10(s,1H),4.59(q,J=7.2Hz,1H),4.03(dd,J=11.4,3.7Hz,2H ),3.83(d,J=13.5Hz,1H),3.62(s,1H),3.54–3.36(m,5H),3.31–3.03(m,6H),2.57(dd,J=14.9,8.5Hz, 1H), 2.43–2.29(m, 2H), 2.18(s,...

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Abstract

The invention discloses novel artemisinin derivatives as well as a synthetic method and application thereof. The derivatives have a structure represented by a general formula I shown in the description, and each substituent is as defined in the description and claims. The derivatives provided by the invention can be used as an anti-apoptotic protein inhibitor and have better inhibitory effects onBcl-2.

Description

technical field [0001] The invention relates to a class of novel artemisinin derivatives, a synthesis method and use thereof. Background technique [0002] Artemisinin is a kind of sesquiterpene lactone extracted from the Compositae plant Artemisia annua, which contains peroxo bridge group sesquiterpene lactone. Artemisinin and its derivatives such as artemether, artesunate, and dihydroartemisinin have been used clinically for many years as highly effective and low-toxic antimalarial drugs. With the in-depth study on the pharmacology of artemisinin, it is found that it also has various biological activities such as anti-schistosomiasis, anti-fungal, and anti-tumor; among them, the role of artemisinin in anti-tumor has attracted more and more attention. [0003] [0004] In 1991, Chinese scholar Deng Anding reported for the first time that artemisinin had selective killing activity on leukemia P388. Subsequently, scholars at home and abroad also studied the anticancer ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/635A61P35/00A61P35/02A61P37/06A61P29/00A61P19/02A61P1/00A61P3/10A61P1/16A61P5/50A61P5/16
CPCC07D519/00
Inventor 张翱谭文福刘晓华黄文静张宇杨君
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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