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Enmein-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and preparation method and application thereof

A technology of santamicin and its derivatives, which is applied in the field of natural medicine and medicinal chemistry, can solve the problems of high toxicity and side effects, unsatisfactory therapeutic effect, lack of specificity of cell action, etc., and achieve the effect of good pharmaceutical activity

Active Publication Date: 2018-07-13
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-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and preparation method and application thereof
  • Enmein-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and preparation method and application thereof
  • Enmein-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023] Take sliverin-type core 2 (55mg, 0.15mmol), dissolve it in dichloromethane (5ml), add chlorambucil (92mg, 0.30mmol), EDCI (89mg, 0.46mmol), 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 20ml 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 6, which was passed through a silica gel column (dichloromethane: Methanol=200:1), separated to obtain a brown oil with a yield of 19%. HR-MS(ESI,M+H)m / z calcd for C 34 h 43 Cl 2 NO 7 :648.2458,found:648.2489. 1 H NMR (CDCl 3 ,400M Hz),δ(ppm):7.04,6.62(each 2H,d,J=8.4Hz,Ar-H),6.20(1H,s,14-CH),5.72(1H,s,6-CH) ,5.55(1H,s,17-CH 2 ),5.33(1H,s,17-CH 2 ), 4.57 (1H, dd, J = 11.5, 5.8Hz, 1-CH), 4.05, 3.93 (each 1H, d, J = 9.4Hz, ...

Embodiment 2

[0025]

[0026] Compound 7 was prepared according to the synthesis method of Example 1. White powder, yield 11%. HR-MS(ESI,M+H)m / z: calcd for C 31 h 37 Cl 2 NO 7 :628.1947,found:628.1968. 1 H NMR (CDCl 3 ,400M Hz), δ(ppm):7.87,6.62(each 2H,d,J A =J B =8.8Hz, Ar-H), 6.24(1H, s, 14-CH), 5.85(1H, s, 6-CH), 5.56(1H, s, 17-CH 2 ),5.36(1H,s,17-CH 2 ),4.57(1H,dd,J=11.5,5.8Hz,1-CH),4.01,4.11(each1H,d,J=9.4Hz,20-CH 2 ),3.64,3.79(each 4H,t,J=7.0Hz,8',9'-CH 2 ,10',11'-CH 2 ), 3.32(1H,d,J=9.4Hz,13-CH),1.05(3H,s,18-CH 3 ),0.98(3H,s,19-CH 3 ). 13 C NMR (CDCl 3 ,100MHz), δ(ppm):198.49,166.56,165.56,150.10,147.94,132.35(×2),120.13,117.64,110.91(×2),101.77,77.22,76.84,76.09,74.61,73.97,630.84 , 53.32, 50.17, 48.53, 41.00, 40.08, 37.10, 32.90, 31.03, 29.64, 23.29, 23.05, 19.79.

Embodiment 3

[0028]

[0029] Compound 8 was prepared according to the synthesis method of Example 1. Yellow oil, yield 25.6%. HR-MS(ESI,M+H)m / z: calcd for C 34 h 41 Cl 2 NO 7 :646.2351,found:646.2333. 1 H NMR (CDCl 3,400M Hz), δ(ppm)8.12(1H,dd,J=7.8,1.0Hz,Ar-H),7.60(1H,d,J=7.8Hz,Ar-H),7.47(1H,m,Ar -H),7.42(1H,d,J=8.2Hz,Ar-H),7.29(1H,m,Ar-H),7.22(1H,m,Ar-H),7.19(1H,m,Ar-H) H),7.16(1H,m,Ar-H),7.07(2H,d,J=8.5Hz,Ar-H),6.64(2H,d,J=8.5Hz,Ar-H),5.99(1H, s,NCH),3.99-4.90(6H,m,-CH 2 ),3.69(4H,m,NCH 2 CH 2 Cl),3.61(4H,m,NCH 2 CH 2 Cl),2.45-3.18(8H,m,-CH 2 ),2.40(3H,s,NCH 3 ),1.74-2.31(8H,m,-CH 2 ); 13 C NMR (CDCl 3 ,100M Hz)δ(ppm)173.62,164.72,151.07,144.25,137.40,132.97,131.05,129.85(×2),129.04,128.67,125.84,124.23,124.19,123.16,122.72,119.71,119.09,113.22,112.53( ×2),109.93,68.00,67.69,67.44,61.52,53.85(×2),40.72,40.53(×2),39.44,36.44,34.15,33.76,30.34,29.12,26.90,20.52.

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Abstract

The invention relates to the technical field of medicines, and relates to enmein-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and a preparation method and application thereof, inparticular to 14-OH spliced nitrogen mustard derivatives of enmein-type ent-kaurane diterpenoid, and a preparation method thereof and application thereof to preparation of anti-tumor medicines. The enmein-type ent-kaurane diterpenoid spliced nitrogen mustard derivatives and pharmaceutically acceptable salts thereof adopt a structural general formula I or II, wherein n is described in claims and adescription.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a 14-OH compound nitrogen mustard derivative of a mesamicin-type diterpene. It specifically relates to the derivatives of these 14-OH mosaic DNA alkylating agent nitrogen mustard compounds in the sliverin-type diterpene, their preparation method 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, induction of apoptosis, anti-mutation and β-receptor blockade, etc. Over the past 30 years, with the in-depth resear...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/10A61K31/37A61P35/00
CPCC07D493/10
Inventor 李达翃华会明李占林高祥吕昊达焦润伟王茗莹
Owner SHENYANG PHARMA UNIVERSITY
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