Dihydroartemisinin and steroid conjugates, and preparation method and application thereof

A technology of dihydroartemisinin and conjugates, which is applied in the direction of steroids, drug combinations, and pharmaceutical formulations, can solve the problems of high price, toxic and side effects, etc., and achieve the effects of reduced dosage, low toxicity, and broad application prospects

Active Publication Date: 2019-11-05
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

Although the emergence and use of immunosuppressants have increased the clinical intervention and treatment ...

Method used

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  • Dihydroartemisinin and steroid conjugates, and preparation method and application thereof
  • Dihydroartemisinin and steroid conjugates, and preparation method and application thereof
  • Dihydroartemisinin and steroid conjugates, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of Compound 1:

[0053]

[0054] At -78°C, boron trifluoride ether (1mL) was slowly added dropwise to the ether solution (50mL) of dihydroartemisinin (569mg, 2.0mmol) and cholic acid (817mg, 2.0mmol), the reaction system naturally rose to Stir overnight after room temperature. After the reaction was monitored by thin-layer silica gel chromatography, the reaction was slowly quenched with saturated aqueous sodium bicarbonate (30 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined and washed with water (50 mL) once, saturated brine ( 50mL) was washed once, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate=1:1) to obtain 726 mg of white solid compound, yield: 53.8%.

[0055] 1 H NMR(400MHz, CDCl 3 ): δ5.47(s,1H), 4.93(d,J=3.3Hz,1H), 4.00(s,1H), 3.88(s,1H), 3.51(t,J=1...

Embodiment 2

[0057] Example 2 Preparation of Compound 2

[0058]

[0059] A white solid was prepared according to the similar method of Example 1. Yield: 54.8%.

[0060] 1 H NMR(400MHz, CDCl 3 ): δ5.47(s,1H), 4.91(d,J=3.4Hz,1H), 4.02(s,1H), 3.67–3.55(m,1H), 2.65–2.56(m,1H), 2.48– 2.25(m,3H),2.07-2.01(m,1H),1.92-1.81(m,5H),1.77-1.70(m,3H),1.68-1.58(m,4H),1.54(m,2H), 1.50–1.34(m,12H),1.27(m,8H),1.18–1.06(m,2H),1.01(d,J=6.2Hz,3H),0.96(d,J=6.3Hz,3H),0.93 -0.85(m,7H),0.71(s,3H).

[0061] 13 C NMR(100MHz, CDCl 3 ): δ179.27(s), 104.03(s), 100.49(s), 88.10(s), 81.30(s), 77.24(s), 73.32(s), 52.62(s), 48.36(s), 47.33 (s), 46.46(s), 44.55(s), 42.00(s), 37.43(s), 36.51(s), 36.06(s), 35.26(s), 35.04(s), 34.66(s), 34.30 (s), 33.79(s), 32.64(s), 31.05-30.54(m), 29.86-29.32(m), 28.98(s), 27.35(d), 26.29(s), 26.06(s), 24.64( d), 23.62(s), 23.34(s), 20.38(s), 17.33(s), 13.20(s), 12.77(s).

Embodiment 3

[0062] Example 3 Preparation of Compound 3

[0063]

[0064] A white solid was prepared according to the similar method of Example 1, and the yield was 54.8%.

[0065] 1 H NMR(400MHz, CDCl 3 ); δ5.46(s,1H), 4.93(d,J=3.1Hz,1H), 3.88(s,1H), 3.48(t,J=10.8Hz,1H), 2.65–2.55(m,1H) , 2.46–2.33(m,2H), 2.27(m,1H), 1.87(m,16H), 1.52–1.13(m,21H), 0.95(m,14H), 0.66(s,3H).

[0066] 13 C NMR(100MHz, CDCl 3 ); δ179.74(s), 104.02(s), 100.40(s), 88.09(s), 81.30(s), 77.49(s), 77.25(s), 68.70(s), 55.79(s), 52.63 (s), 50.53(s), 44.59(s), 42.73(s), 41.33(s), 39.56(s), 39.33(s), 37.47(s), 36.51(s), 35.86(s), 35.30 (d), 34.80(d), 32.88(s), 30.86(d), 29.12(s), 28.18(s), 26.29(s), 24.63(d), 23.70(s), 22.90(s), 20.64 (s), 20.41(s), 18.27(s), 13.20(s), 11.78(s).

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Abstract

The present invention discloses conjugates, having a general formula (I), obtained by condensation of dihydroartemisinin and steroids, or isomers or pharmaceutically acceptable salts or prodrug molecules thereof. The 10-position hydroxyl group of artemisinin and the 3-position hydroxyl group of the steroid compounds are condensed and linked by an ether bond. The invention discloses a preparation method of the compounds, and an application of the compounds in the treatment of autoimmune diseases. The dihydroartemisinin and steroid conjugates of the present invention are novel immunosuppressants, and can be used alone or in combination with other drugs to treat the human autoimmune diseases. The conjugates have the advantages of high curative effect, small toxicity and very broad applicationprospect.

Description

Technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to the preparation method and application of conjugates formed by condensation of dihydroartemisinin 10-position hydroxyl group and various steroid 3-position hydroxyl groups through ether bond and derivatives thereof. Background technique [0002] Artemisinin is a rare sesquiterpene lactone containing peroxide groups isolated and extracted from the traditional Chinese medicine Artemisia annua L.. Artemisinin and its derivatives artemether, artesunate, dihydroartemisinin, etc. are used clinically for the treatment of malaria, and have the characteristics of high efficiency, rapid effect and low toxicity. In addition to their anti-malarial effects, many years of clinical and laboratory studies have found that artemisinin and its derivatives also have excellent immunosuppressive activities. [0003] Immunosuppressants are a class of drugs with immunosuppressive effects. The main...

Claims

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Application Information

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IPC IPC(8): C07J17/00C07J43/00A61K31/58A61P37/00A61P17/06A61P19/02A61P17/00A61P37/08A61P9/10A61P27/02A61P37/06
CPCC07J17/00C07J43/003A61P37/00A61P17/06A61P19/02A61P17/00A61P37/08A61P9/10A61P27/02A61P37/06Y02A50/30
Inventor 沈征武边弘竹
Owner YUN BAI YAO ZHENG WU TECH SHANGHAI CO LTD
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