Dihydroartemisinin phenyl ether derivatives and their application

A dihydroartemisinin and phenyl technology, applied in the field of medicine, can solve problems such as ineffectiveness, induced drug resistance, and small therapeutic index

Inactive Publication Date: 2017-04-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Once multidrug resistance occurs, even higher doses of drugs may be ineffective, and most cytotoxic antineoplastic drugs have a small therapeutic index, increasing the dose will lead to toxic effects and may further induce drug resistance
Multidrug resistance severely limits the efficiency of chemotherapy in the treatment of various conventional malignancies and is the most prevalent cause of cancer chemotherapy failure

Method used

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  • Dihydroartemisinin phenyl ether derivatives and their application
  • Dihydroartemisinin phenyl ether derivatives and their application
  • Dihydroartemisinin phenyl ether derivatives and their application

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0105] The examples are intended to illustrate, not limit, the scope of the invention. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0106] The nuclear magnetic resonance spectrum of the compound was measured by Bruker ARX-300, and the mass spectrometer was measured by the WaterQuattro micro API triple quadrupole tandem mass spectrometer of Water Company of the United States; after the reaction of the compound containing the dihydroartemisinin mother nucleus, the treatment water was purified water or distilled water, and other Reagents are commercially available products of analytical or chemical purity.

Embodiment 1

[0107] Example 1: Preparation of 10-O-[4-[5-(4-chlorophenyl)-1H-3-pyrazolyl]phenyl]-(10S)-dihydroartemisinin

[0108] Step A: Preparation of 1-(4-hydroxyphenyl)-3-(4-chlorophenyl)-2-propen-1-one

[0109]

[0110] Dissolve 4 g (0.1 mol) of NaOH in 30 ml of anhydrous methanol and stir in an ice bath. Dissolve 1.54g (0.01mol) of p-chlorobenzaldehyde and 1.36g (0.01mol) of p-hydroxyacetophenone in 30mL of anhydrous methanol, and add dropwise to the above solution. After the dropwise addition, the temperature is raised to room temperature, and the reaction is continued for 2 hours. The methanol was distilled off under reduced pressure, and 50 mL of H 2 O, add 5 mol / L hydrochloric acid dropwise, adjust the pH to 8, and filter with suction to obtain a light yellow solid, which is dried under infrared light.

[0111] Step B: Preparation of [1-acetyl-4,5-dihydro-3-(4-hydroxyphenyl)-5-(4-chlorophenyl)]pyrazole

[0112]

[0113] Dissolve 2.58g (0.01mol) of 1-(4-hydroxyphenyl)-3-...

Embodiment 2

[0128] Example 2: Preparation of 10-O-[4-[5-(4-chlorophenyl)-1H-3-pyrazolyl]phenyl]-(10R)-dihydroartemisinin

[0129] According to the preparation method of Example 1, the title compound can be obtained simultaneously.

[0130] LC-MS(m / z):537.2[M+H] + ,559.1[M+Na] +

[0131] 1 H-NMR(DMSO,δ(ppm)):13.28(br,1H,1H-H),7.86(m,2H,Ar-H),7.75(m,2H,Ar-H),7.50(m,2H ,Ar-H),7.19(m,2H,Ar-H),7.14(s,1H,P4-H),5.74(s,1H,H-12),5.30(d,1H,J=9.3Hz, H-10),2.51(m,1H,H-9),2.20(m,1H,H-4),1.35(s,3H,H-14),0.92(m,6H,H-15andH-16) .

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Abstract

The invention relates to the technical field of medicine, and specifically relates to nitrogen-substituted dihydroartemisinin phenyl ether, optical isomers thereof and a preparation method thereof; pharmaceutical compositions with the derivatives as active components; and applications thereof in preparing medicines used for treating and / or preventing various cancers. The compound or pharmaceutically acceptable salts thereof have a structure as the following. The variables are as described in the claims and in the specifications. According to the invention, a pair of epimers with dihydroartemisinin C-10 site of R or S configuration can be prepared at a same time and with an equal amount, and separation can be realized. The prepared compounds have a significant effect in inhibiting cancer cell growth, and a selective killing effect against drug-resistant cells. The compounds have a potential of overcoming multidrug resistance.

Description

[0001] Technical field: [0002] The invention belongs to the technical field of medicine, and specifically relates to a nitrogen-containing substituted dihydroartemisinin phenyl ether, its optical isomer, a preparation method thereof, a pharmaceutical composition with the derivative as an active ingredient, and its preparation for treatment And / or use in medicines for the prevention of various cancers. [0003] Background technique: [0004] Cancer is a serious threat to human health and life. It is estimated that the incidence of cancer worldwide will increase by 50% by 2020, and the number of new cancer patients will reach 15 million each year. Chemotherapy is still one of the effective methods for treating tumors. However, since tumor cells often have primary or acquired drug resistance to chemotherapy drugs, the success rate of chemotherapy is often greatly reduced. Multi-drug resistance (MDR) occurs when tumor cells are not only resistant to a certain chemotherapy drug, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/20A61K31/357A61K31/4155A61K31/4433A61P35/00A61P35/02
CPCC07D493/20
Inventor 赵临襄刘丹钟杭景永奎
Owner SHENYANG PHARMA UNIVERSITY
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