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Artemisinin-base combination compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application

A compound and artemisinin technology, applied in the field of medicine, can solve the problems of significant toxic and side effects, and achieve the effects of good drug resistance, good anti-tumor activity, and low toxic and side effects

Pending Publication Date: 2021-09-28
GUIZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, a number of base-based anti-metabolites have been used in the field of clinical anti-tumor for many years, and their limitations such as significant toxic and side effects and drug resistance need to be improved urgently

Method used

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  • Artemisinin-base combination compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application
  • Artemisinin-base combination compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application
  • Artemisinin-base combination compound or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0066] The main reaction scheme of the preparation method of artemisinin-base complex has:

[0067]

[0068] Het refers to Het as defined above 1 or Het 2 ;

[0069]

[0070] Among them, BF 3 ·Et 2 O is boron trifluoride diethyl ether, TFA is trifluoroacetic acid, Het 1 as defined above;

[0071]

[0072] DIAD is diisopropyl azodicarboxylate, TPP is triphenylphosphine, and X is as defined above.

Embodiment 1

[0073] Example 1: Preparation of 10-O-[2-(9H-9-purinyl)-ethyl]-(10S)-dihydroartemisinin

[0074] Step A: Preparation of 10-O-(2-bromoethyl)-(10S)-dihydroartemisinin

[0075]

[0076] Dissolve 5g (17.6mmol) of dihydroartemisinin (DHA) and 1.25mL (17.6mmol) of 2-bromoethanol in 100mL of refined THF (tetrahydrofuran), and slowly add 3.5mL (0.50g , 3.5mmol) boron trifluoride diethyl ether (BF 3 ·Et 2 O), stirred and reacted for 6 hours. The reaction process was monitored by thin layer chromatography (ethyl acetate:petroleum ether=1:4). After the reaction, add saturated NaHCO 3 solution. The organic layer was collected in layers, the aqueous layer was separated by extraction with ethyl acetate (25 mL×2), and the organic layers were combined. The organic layer was washed with 20 mL of saturated brine solution, and then washed with anhydrous Na 2 SO 4 After drying, the crude product was distilled off under reduced pressure to remove the solvent. The crude product was stat...

Embodiment 2

[0082] Example 2: Preparation of 10-O-[2-(6-amino-9H-9-purinyl)-ethyl]-(10S)-dihydroartemisinin

[0083] According to the preparation method of Example 1, the title compound was prepared by replacing the raw material 9H-purine in Example 1 with adenine;

[0084] LC-MS(m / z):446.2[M+H] +

[0085] 1 H NMR (CDCl 3 ,δ(ppm)):δ8.34(s,1H,Pur-H),7.88(s,1H,Pur-H),6.26(s,2H,-NH 2 ), 5.01 (s, 1H, H-12), 4.77 (d, J=3.5Hz, 1H, H-10), 4.59–4.46 (m, 1H, -OCH 2 C H 2 -),4.41–4.24(m,2H,-OC H 2 C H 2 -),3.76(ddd,J=10.2,6.5,3.6Hz,1H,-OC H 2 CH 2 -),2.63–2.57(m,1H,H-9),2.38–2.30(m,1H,H-4),1.42(s,3H,H-14),0.94(d,J=6.2Hz,3H , H-16), 0.80 (d, J=7.4Hz, 3H, H-15).

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Abstract

The invention discloses an artemisinin-base combination compound or a pharmaceutically acceptable salt thereof. The invention also discloses a medicinal preparation containing the artemisinin-base combination compound or the pharmaceutically acceptable salt thereof, and application of the artemisinin-base combination compound or the pharmaceutically acceptable salt thereof in preparation of medicines for treating and / or preventing primary or multidrug resistant leukemia, breast cancer, prostate cancer, liver cancer and lung cancer. Based on the characteristics of artemisinin and base compounds, a series of artemisinin-base combination compounds are designed and synthesized; according to the compound, the structure of artemisinin is modified and optimized, so that the compound not only has relatively good anti-tumor activity, but also is small in toxic and side effects and good in drug resistance; and the combination compound or the pharmaceutically acceptable salt thereof can be widely used for preparing medicinal preparations and can be applied to treatment and / or prevention of various cancers.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an artemisinin-base complex or a pharmaceutically acceptable salt thereof and a pharmaceutical preparation containing the artemisinin-base complex or a pharmaceutically acceptable salt thereof, and The invention relates to the application of the artemisinin-base complex or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating and / or preventing various cancers. Background technique [0002] In 2020, there will be an estimated 19.3 million new cancer cases and nearly 100 million cancer patient deaths worldwide. The global cancer burden is projected to reach 28.4 million by 2040, a 47% increase from 2020. Malignant tumors are a serious threat to human health, and their mechanism of occurrence is complex, and the acquired drug resistance in their drug treatment significantly reduces the success rate of drug treatment. The multi-target drug strategy ...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D493/20A61P35/00A61P35/02A61K31/52A61K31/513
CPCC07D519/00C07D493/20A61P35/00A61P35/02
Inventor 钟杭李冰清丁洁
Owner GUIZHOU UNIV
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