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Preparation and application of bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative

A technology of dihydroartemisinin and phloroglucinol, which is applied in the field of biomedicine, can solve the problems of high toxicity and narrow therapeutic window, and achieve the effects of low cytotoxicity, simple synthesis and broad application prospects

Active Publication Date: 2022-03-22
YUN BAI YAO ZHENG WU TECH SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the results of pharmacological experiments show that these compounds still show high toxicity, and the therapeutic window is very narrow

Method used

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  • Preparation and application of bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative
  • Preparation and application of bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative
  • Preparation and application of bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The preparation of embodiment 1 compound 14

[0063]

[0064] Under nitrogen protection, dihydroartemisinin (1.30 g, 4.6 mmol) was dissolved in 20 mL of dry dichloromethane, the reaction system was cooled to -30 °C, and DAST (diethylaminosulfur trifluoride, 0.66mL, 4.6mmol), and then continued to stir at -30°C for 1 hour, and monitored the reaction by TLC until the starting material was consumed to obtain intermediate 14-1. Then directly add 1,3,5-trimethoxybenzene (1.55g, 9.2mmol) to the reaction solution and cool down to -78°C, then slowly add BF 3 ·Et 2 O (692 μL, 5.5 mmol), and then the reaction temperature was gradually increased from -78°C to room temperature. TLC monitoring until the end of the reaction, with saturated NaHCO 3 Aqueous solution (20 mL) was used to quench the reaction, the organic phase was separated and the aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate,...

Embodiment 2

[0070] The preparation of embodiment 2 compound 15

[0071]

[0072] Under nitrogen protection, compound 1 (100 mg, 0.15 mmol) was dissolved in 15 mL of acetone, 3-bromopropene (66 μL, 0.75 mmol) and potassium carbonate solid (62 mg, 0.45 mmol) were added, and the reaction system was heated to 70 ° C, refluxed 6 hours. TLC monitors the reaction until the end of the reaction, the reaction solution is diluted with 30 mL of ethyl acetate, then washed twice with saturated brine, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution Agent: petroleum ether / ethyl acetate=5 / 1), 78 mg of white solid product 15 was obtained, and the yield was 74.7%.

[0073] 1 H NMR (400MHz, DMSO-d 6 )δ8.54(d, J=3.4Hz, 2H), 6.02(q, J=10.9Hz, 2H), 5.66(s, 2H), 5.41(dd, J=17.3, 1.8Hz, 1H), 5.26( dd,J=10.7,1.7Hz,1H),5.15(d,J=11.2Hz,1H),5.08(d,J=11.2Hz,1H),4.47(dd,J=12.3,4.6Hz,2H), 2.65-...

Embodiment 3

[0076] The preparation of embodiment 3 compound 16

[0077]

[0078] Compound 2 (190mg, 0.26mmol) was dissolved in a mixed solution of 20mL methanol, 20mL tetrahydrofuran, and 2mL water and cooled to 5°C with an ice-water bath, then LiOH solid (61mg, 2.6mmol) was added and stirred at 5°C for 1 hour . After the reaction was monitored by TLC, 0.05M dilute hydrochloric acid was added dropwise until the pH of the reaction solution was about 5, concentrated under reduced pressure at room temperature to remove most of the solvent, the residue was diluted with 20 mL of water, and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol=15 / 1) to obtain 113 mg of white solid product 16, yield 61.8% .

[0079] 1 H NMR (400MHz, DMSO-d 6 )δ8.54(d, J=2.4Hz, 2H), 5.85(s, 1H), 5.63(d, J=15.9Hz, 2H), 5....

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Abstract

The invention discloses a bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative, the structural formula of the bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative is shown in the specification, and the invention also provides a preparation method of the bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative shown in the general formula (I). The invention also provides an application of the bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative of the general formula (I) in preparation of a medicine for treating autoimmune diseases. The compounds provided by the invention are novel compounds for treating autoimmune diseases, have low cytotoxicity, can significantly inhibit immune cell proliferation, effectively inhibit ear swelling induced by 2, 4-dinitrofluorobenzene and plantar swelling induced by sheep erythrocytes on an ear swelling model and a plantar swelling model of delayed hypersensitivity, and can be used for treating autoimmune diseases. The compound shows a good dose-effect relationship, and has a very wide application prospect as a medicine for treating autoimmune diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a phloroglucinol derivative, in particular to the preparation and application of a bis-(10-deoxydihydroartemisinin)-phloroglucinol derivative. Background technique [0002] Artemisinin is an antimalarial drug extracted and discovered by Chinese scientists from Artemisia annua.L. in the 1970s. It is a class of sesquiterpene lactone compounds with a special peroxide bridge structure. , is also the first internationally recognized natural medicine discovered by China. However, artemisinin is difficult to absorb when taken orally, and its bioavailability is low, so it is difficult to make a suitable dosage form. Scientists have synthesized artemisinin derivatives such as artemether and artesunate with better antimalarial effects by modifying the structure of artemisinin. In addition to good antimalarial activity, a large number of studies in recent years have shown that some artemisinin der...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61P19/02A61P19/08A61P3/10A61P13/12A61P17/06A61P17/00A61P11/02A61P7/06A61P1/00A61P37/06A61K31/357A61K31/405
CPCC07D519/00A61P19/02A61P19/08A61P3/10A61P13/12A61P17/06A61P17/00A61P11/02A61P7/06A61P1/00A61P37/06Y02A50/30
Inventor 沈征武徐威邓斌江亮赵智东杨冲生申阳丽查雨峰张梦麒周铭涛黄加文詹易何志明边泓竹
Owner YUN BAI YAO ZHENG WU TECH SHANGHAI CO LTD
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