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Novel hydroxyl dihydroartemisinin derivative and application thereof

A technology for dihydroartemisinin and dihydroartemisinin ester, which is applied in the field of chemical medicine, can solve the problems of low bioavailability and poor solubility of artemisinin, and achieves simple preparation method, obvious anti-tumor activity, and obvious immunity. Inhibitory effect

Inactive Publication Date: 2015-11-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dihydroartemisinin is a derivative of artemisinin produced by reduction reaction. Various types of artemisinin derivatives can be prepared from dihydroartemisinin to overcome the disadvantages of poor solubility and low bioavailability of artemisinin.

Method used

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  • Novel hydroxyl dihydroartemisinin derivative and application thereof
  • Novel hydroxyl dihydroartemisinin derivative and application thereof
  • Novel hydroxyl dihydroartemisinin derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of 9α, 12α-di-(cinnamic acid) dihydroartemisinin ester

[0063] Dissolve 150mg (0.5mmol) of 9α-hydroxydihydroartemisinin and 192.6mg (1.3mmol) of cinnamic acid in 10mL of anhydrous dichloromethane. Under nitrogen protection and ice bath conditions, 159mg (1.3mmol) of DMAP and 288mg (1.5mmol) EDCI was added in a three-neck round bottom flask, the temperature was natural, and the reaction was stirred for 12h. After the reaction was detected by TLC, it was spin-dried, dissolved in ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and spin-dried. , the residue was subjected to column chromatography to obtain a white solid. Yield: 32%.

[0064] 1 HNMR (400MHz, Chloroform-d) δ = 7.79 (d, J = 16.0, 1H), 7.71 (d, J = 16.0, 1H), 7.57-7.53 (m, 4H), 7.42-7.38 (m, 6H), 6.49 (d, J=16.0, 1H), 6.44 (d, J=16.0, 1H), 5.94 (d, J=9.8, 1H), 5.60y (s, 1H), 4.64 (td, J=10.9, 4.4 , 1H), 2.69(ddd, J=9.9, ...

Embodiment 2

[0065] Example 2: Preparation of 9α, 12α-di-(p-methylcinnamic acid) dihydroartemisinin ester

[0066] According to the method of Example 1, the title compound was prepared by replacing the raw material cinnamic acid in Example 1 with p-methylcinnamic acid.

[0067] White powder, yield: 54%. 1 HNMR (400MHz, Chloroform-d) δ = 7.79 (d, J = 16.0, 1H), 7.71 (d, J = 16.0, 1H), 7.57-7.53 (m, 4H), 7.42-7.38 (m, 6H), 6.49 (d, J=16.0, 1H), 6.44 (d, J=16.0, 1H), 5.94 (d, J=9.8, 1H), 5.60y (s, 1H), 4.64 (td, J=10.9, 4.4 , 1H), 2.69(ddd, J=9.9, 7.1, 4.7, 1H), 2.49-2.37(m, 1H), 2.20-2.06(m, 2H), 1.93(dt, J=9.1, 4.4, 2H), 1.64-1.54(m, 4H), 1.46(d, J=3.8, 3H), 1.02(d, J=6.2, 3H), 0.91(d, J=7.1, 3H). 13 CNMR(101MHz,Chloroform-d)δ=166.51,165.42,146.25,145.32,134.28,130.53,130.46,128.94,128.23,128.15,117.87,117.46,104.60,91.80,91.22,79.15,75.46,49.08,42.77,41.39, 36.09, 31.71, 27.58, 25.92, 24.58, 15.44, 12.04. HRESIMS (m / z): 611.2615 [M+Na] + (calcdforC 35 h 40 NaO 8 , 611.2615).

Embodiment 3

[0068] Example 3: Preparation of 9α, 12α-di-(p-fluorocinnamic acid) dihydroartemisinin ester

[0069] According to the method of Example 1, the title compound was prepared by replacing the raw material cinnamic acid in Example 1 with p-fluorocinnamic acid.

[0070] White powder, yield 60%. 1 HNMR (400MHz, Chloroform-d) δ = 7.74 (d, J = 16.0, 1H), 7.66 (d, J = 16.0, 1H), 7.59-7.44 (m, 4H), 7.09 (td, J = 8.6, 4.2 , 4H), 6.41(d, J=15.9, 1H), 6.36(d, J=15.9, 1H), 5.93(d, J=9.8, 1H), 5.59(s, 1H), 4.63(td, J= 10.8, 4.4, 1H), 2.77-2.61(m, 1H), 2.50-2.34(m, 1H), 2.19-2.05(m, 2H), 1.98-1.89(m, 2H), 1.71-1.51(m, 4H ), 1.46(s, 3H), 1.01(d, J=6.2, 3H), 0.90(d, J=7.1, 3H). 13 CNMR(101MHz,Chloroform-d)δ=165.37,165.30,162.82,162.77,144.91,144.00,130.53,130.51,130.16,130.08,129.98,117.61,117.19,116.22,116.00,104.61,91.82,91.21,79.12,75.51, 49.06, 42.75, 41.37, 36.08, 31.69, 27.56, 25.90, 24.57, 15.43, 12.03. HRESIMS (m / z): 619.2107 [M+Na] + (calcdforC 33 h 34 f 2 NaO 8 , 619.2114). ...

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Abstract

The invention belongs to the field of chemical medicines and relates to a novel hydroxyl dihydroartemisinin derivative and an application thereof. In particularly, the invention discloses the hydroxyl dihydroartemisinin derivative represented as the formula I and the formula II or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer or a racemate thereof, wherein X and R are defined as the specification. The invention also discloses the application of the compound in drugs of preventing and / or treating cancer and preventing and / or treating autoimmune diseases.

Description

technical field [0001] The invention belongs to the field of chemical medicine. Specifically, it relates to novel hydroxydihydroartemisinin derivatives and applications thereof. Background technique [0002] Artemisinin is a peroxybridge-containing sesquiterpene lactone compound extracted from the traditional Chinese medicine Artemisia annua L. It is a drug for clinical treatment of drug-resistant malaria, and has the characteristics of high efficiency and low toxicity. In addition to antimalarial activity, modern studies have found that it also has antitumor, immunosuppressive, antiviral, antifungal, anti-inflammatory and other activities. Dihydroartemisinin is a derivative of artemisinin produced by reduction reaction. Various types of artemisinin derivatives can be prepared from dihydroartemisinin to overcome the disadvantages of poor solubility and low bioavailability of artemisinin. . Scientists at home and abroad have prepared a large amount of artemisinin C in orde...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/357A61P35/00A61P37/06
CPCC07D493/20
Inventor 刘吉华余伯阳邓婷许藏藏
Owner CHINA PHARM UNIV
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