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Enmein diterpene-melphalan derivative as well as preparation method and application thereof

A technology for prolonging the lifespan and derivatives, which is applied in the field of derivatives modified by -OH, can solve the problems of large toxic and side effects, unsatisfactory treatment effect, lack of specificity of cell action, etc., and achieve the effect of good pharmaceutical activity.

Active Publication Date: 2018-06-01
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is widely used clinically, but its toxic and side effects are relatively large, and it lacks specificity for cell action, and with the occurrence of tumor drug resistance in recent years, the therapeutic effect is not satisfactory. Chemical modification, improving its curative effect has very important value

Method used

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  • Enmein diterpene-melphalan derivative as well as preparation method and application thereof
  • Enmein diterpene-melphalan derivative as well as preparation method and application thereof
  • Enmein diterpene-melphalan derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023] Take samiculin-type intermediate 2 (56mg, 0.16mmol), dissolve it in dichloromethane (5ml), add melphalan methyl butyric acid (154mg, 0.37mmol), EDCI (94mg, 0.50mmol), DMAP (8mg, 0.07mmol), the reaction was stirred at room temperature, the progress of the reaction was monitored by TCL, and the reaction was terminated after 24h. The reaction solution was poured into 10ml of ice-water mixture, extracted with dichloromethane (30ml×3), washed with saturated saline solution, dried over anhydrous sodium sulfate, and recovered dichloromethane to obtain crude product 7, which was passed through a silica gel column (dichloromethane: Methanol=200:1), separated to obtain a brown oil with a yield of 14%. HRMS(ESI,M+H)m / z calcd for C 56 h 70 Cl 4 N 4 o 14 :1163.3643,found:1163.3792. 1 H NMR (CDCl 3 ,400M Hz), δ(ppm):6.98(4H,dd,J=8.7,2.5Hz,Ar-H),6.63(4H,dd,J=8.7,3.3Hz,Ar-H),6.22(1H, s,6-CH),6.15(1H,s,14-CH),6.02(1H,d,J=7.6Hz,NH),5.96(1H,d,J=7.6Hz,NH),5.73(1H,s ,17...

Embodiment 2

[0025]

[0026] Compound 8 was prepared according to the synthesis method of Example 1. Brown oil, yield 35%. HR-MS(ESI,M+H)m / z: calcd for C 38 h 46 Cl 2 N 2 o 10 :783.2640,found:783.2422. 1 H NMR (CDCl 3 ,400M Hz), δ(ppm):6.97,6.63(each 2H,d,J=8.6Hz,Ar-H),6.25(1H,d,J=1.2Hz,14-CH),6.02(1H,d ,J=7.6Hz,6-OH),5.70(1H,s,17-CH 2 ),5.64(1H,s,17-CH 2 ),4.74(1H,dt,J=7.8,5.7Hz,5'-CH),4.58(1H,dd,J=11.5,5.7Hz,1-CH),4.34,4.03(each 1H,d,J= 10.2Hz, 20-CH 2 ),3.73(3H,s,18'-CH 3 ),3.63,3.71(each 4H,t,J=6.2Hz,13',14'-CH 2 ,15',16'-CH 2 ), 3.22(1H,d,J=8.6Hz,13-CH),2.63(2H,m,2'-CH 2 ),2.51(2H,m,3'-CH 2 ),2.38(1H,m,6'-CH 2 ),2.08(1H,m,6'-CH 2 ),1.21(3H,s,18-CH 3 ),1.06(3H,s,19-CH 3 ). 13 C NMR (CDCl 3,100M Hz),δ(ppm):197.17,175.21,172.28,171.98,170.63,166.32,146.93,145.03,130.53(×2),124.84,121.65,112.32(×2),77.24,74.47,73.53,7 59.45, 53.60, 53.42, 52.27, 50.77, 47.43, 45.95, 40.38 (×2), 40.16, 36.62, 36.37, 33.04, 32.25, 30.43, 29.51, 29.44, 23.62, 23.02, 19.17.

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Abstract

The invention relates to the fields of natural drugs and medicinal chemistry, relates to an enmein diterpene-melphalan derivative as well as a preparation method and application thereof and specifically relates to a preparation method of a melphalan derivative with a DNA alkylating agent induced on a 14-OH or 6, 14-OH site in a mother nucleus structure of enmein diterpene and application of the melphalan derivative to an antitumor drug. The structures of enmein diterpene-melphalan derivative and pharmaceutically acceptable salt thereof are shown as the general formula I or the general formulaII, wherein n is described as the claims and the specification.

Description

technical field [0001] The present invention relates to the field of natural medicine and medicinal chemistry, and relates to a class of melphalan derivatives of melphalan-type diterpene and its preparation method and application, specifically to melphalan derivatives modified by 14-OH or 6,14-OH of melamine The derivatives relate to these samiculin derivatives substituted by DNA alkylating agent melphalan derivatives at the 14-OH or 6,14-OH positions, their preparation methods and their application in the preparation of antitumor drugs. Background technique [0002] In 1958, Takshashi et al. obtained enmein from Rabdosia japonica for the first time. In 1966, Natsume et al. determined the three-dimensional structure of enmein by X-ray diffraction. compounds were isolated. Enmein is a natural organic compound of ent-kaurane diterpenoid isolated from the Labiatae genus Rabdosia, which has anti-cell proliferation and inhibits cancer cells. Synthesis of DNA, RNA and protein, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/18C07D493/08A61K31/366A61P35/00A61P35/02
Inventor 李达翃华会明李占林高祥薛晶晶李佳李昊楠
Owner SHENYANG PHARMA UNIVERSITY
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