Artesunate derivatives, preparation methods and applications thereof

A technology of artesunate and reaction, applied in the directions of drug combination, skin diseases, bone diseases, etc., can solve the problems such as inability to fundamentally control the occurrence and development of diseases, incapable of long-term continuous application, large toxic and side effects, etc. Down-regulation of cellular immune response, simple and easy preparation method, and little effect of environmental pollution

Active Publication Date: 2018-05-08
KPC PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The first three are immunosuppressants that have been used clinically. Although the curative effects of these drugs have been proven, they can only improve symptoms, and cannot effectively control the occurrence and development of the disease fundamentally. They also have large toxic and side effects and cannot be used continuously for a long time
Antibody immunosuppressants can specifically act on lymphocytes, but at the same time they are expensive and cause serious adverse reactions, which need further improvement

Method used

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  • Artesunate derivatives, preparation methods and applications thereof
  • Artesunate derivatives, preparation methods and applications thereof
  • Artesunate derivatives, preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] Weigh 100g of artesunate (ART) into a 2L round bottom flask, add 47.9g of N-hydroxysuccinimide (NHS) and 80g of EDC hydrochloride (EDC.HCl), add 1200ml of acetonitrile, control Warm at 30°C and react overnight with stirring. Spin-dry acetonitrile under reduced pressure, add 1000ml ethyl acetate (EA) to dissolve, wash with 500ml water three times each time, wash once with 500ml saturated sodium chloride, and dry the organic phase with anhydrous sodium sulfate for 1h.

[0039] Filter through a Buchner funnel, evaporate EA under reduced pressure to about 250ml, heat the solution to reflux, slowly add 140ml of petroleum ether until the precipitate just precipitates, and put it in the refrigerator (4°C) overnight to precipitate crystals.

[0040] Filter with a G3 funnel, wash the solid twice with 150 ml of anhydrous diethyl ether, and pump dry to obtain 113 g of solid artesunate succinimide ester (ART-NHS) crude product, which is directly used for the next reacti...

Embodiment 2

[0042]

[0043] Put 14.5g of LYS-OH in a 2L round bottom flask, add 1000ml of methanol (MeOH), stir for 1h, add 100g of ART-NHS crude product prepared in Example 1, add N, N diisopropylethylamine (DIEA) 17.3 ml, control the internal temperature to 35°C, and react for 8 hours under stirring.

[0044] Spin-dry methanol under reduced pressure, add 100ml of 1N HCL, 300ml of water, 1000ml of EA for extraction, wash the organic phase with 500ml of 13% sodium chloride solution, wash with 500ml of saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate for 1h, filter, reduce Press dry. After passing through a 200-300 mesh silica gel column, EA was eluted to obtain 40 g of sample ART2-Lys-OH, with a yield of 45% and a purity of 98.5% (HPLC).

Embodiment 3

[0045]Embodiment 3 The compound of the present invention inhibits delayed hypersensitivity in mice

[0046] In the present invention, the effect of the compound ART2-Lys-OH prepared in Example 1 on the biological function of the ear and spleen of the delayed-type hypersensitivity mouse is discussed, and the immune regulation mechanism of compound I is explored, using the typical cellular immune response-delayed-type hypersensitivity The response (delayed-type hypersensitivity, DTH) was used as an index, and the immunomodulatory function of compound Ⅰ was explored by in vivo administration. DTH mice were established by referring to the literature (Hirasaki Y, Iwamura C, Yamashita M, et al. Repressor of GATA Negatively regulates murine contact hypersensitivity through the inhibition of type-2 allergic responses. Clin Immunol. 2011; 139(3): 267-276.) Model: 1 day before the experiment, the abdomen of the mice was shaved about 3 cm. On the first day (Day 0) and the first day, 40 ...

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Abstract

The invention provides a compound shown as formula (I) and a preparation method and application thereof. The compound provided herein is an artesunate derivative; through the comparison of influence on DTH (delayed type hypersensitivity) mouse ear swelling degree and spleen index to that of a matrix control group, the compound shown as the formula (I) and transdermally delivered can significantly inhibit DTH mouse ear swelling and reduce spleen index, the differences are of great significance, and it is indicated that the compound shown as the formula (I) under experimental conditions shows certain immunosuppression effect, is effective for down-regulating body cellular immune response and is more effective than artesunate.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to an artesunate derivative, its preparation method and its application. Background technique [0002] Immunosuppressant is a class of drugs with immunosuppressive effect, the main function is to suppress the abnormal immune response of the body, it is used in autoimmune diseases and allergic reactions and after organ transplantation (such as heart, liver, kidney, lung and bone marrow transplantation, etc.) Treatment of rejection. Autoimmune diseases are the corresponding clinical symptoms caused by the excessive or prolonged autoimmune response that destroys its normal tissue structure; allergic reaction is a physiological function produced by the continuous stimulation of the body antigen or the re-stimulation of the same antigen. Disorder and tissue damage are the main manifestations of pathological immune response; after clinical organ transplantation, the immune system ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/20A61P37/06A61P29/00A61P19/02A61P17/06
CPCC07D493/20
Inventor 宋立明黄照昌曾涛刘一丹李鹏辉
Owner KPC PHARM INC
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