Tripterine derivative, and preparation method and use thereof

A technology of tripterine and its derivatives, which is applied in the direction of drug combinations, steroids, antineoplastic drugs, etc., can solve the problems of reduced drugability, unstable thioether bonds, weak anticancer activity, etc., and achieves reduced toxicity, Good stability and good anticancer activity

Inactive Publication Date: 2016-10-05
SHANGHAI HUATUO MEDICAL SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent CN102796254A introduces polyethylene glycol to make it into polyethylene glycol ester. Although the water solubility increases, its activity is only 3 to 5% of tripterine; Chinese patent CN101311187A introduces long-chain alkanes to increase its fat solubility. , made long-chain ester at the 29th position, but its anticancer activity is slightly weaker than that of tripteryne (tripteryne cetyl alcohol ester and tripteryne at the same dose, the inhibition rate of U-14 cervical cancer is respectively 63.2% and 55.3%), etc.; Wang Jiaqiang et al. carried out esterification and amidation at the 29th position, and found that its activity was weaker than tripterine (Chinese herbal medicine, 2009 (40) 2: 201-204)
However, there is a thioether bond in tripterine sulfite, the thioether bond is unstable and easily oxidized, and its druggability is reduced

Method used

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  • Tripterine derivative, and preparation method and use thereof
  • Tripterine derivative, and preparation method and use thereof
  • Tripterine derivative, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Example 1 R 1 = R 2 = R 3 When =H, the preparation of compound 1

[0046] The reaction formula is as follows:

[0047]

[0048] Dissolve tripterine (1.0eq) in anhydrous dichloromethane, add indole (2.0eq) and catalyst Sc(OTf) 3 (5mol%), reacted at normal temperature for 24 hours, and TLC detected the reaction. After the reaction, the solvent was spin-dried, and the compound 1 (yield 78%, purity 99.2%) was obtained by column chromatography (petroleum ether / acetone=3 / 1) ): mp114-116°C; [α]20 D-89.78°(MeOH,c=0.2), 1 H-NMR (300MHz, CDCl 3 )δ7.87(s,1H),7.78(d,J=7.2Hz,1H),7.34(d,J=7.5Hz,1H),7.15-7.20(m,2H),6.83(s,1H), 6.32(s,1H),6.23(d,J=6.3Hz,1H),4.94(d,J=5.7Hz,1H),2.41(d,J=15.6Hz,1H),2.03-2.11(m,3H ),1.95(s,3H),1.40-1.68(m,8H),1.38(s,3H),1.31-1.23(m,2H),1.16(s,3H),1.02(s,3H),0.94- 0.89(m,1H),0.75(s,3H).HRMS(ESI-)m / z calcd for C 38 h 46 NO 6 [M+COOH] - 612.3331, found 612.3325.

Embodiment 2

[0049] Example 2 R 1 = R 3 = H, R 2 =-CH 3 , R 2 Preparation of compound 2 when replacing the H on the 7-position of the indole ring

[0050] The reaction formula is as follows:

[0051]

[0052] Except that the indole in Example 1 is replaced by 7-methylindole, all the other reaction conditions are the same as in Example 1 to obtain compound 2 (65% yield, 98.5% purity): mp92-94°C; [α ]20 D-78.39°(MeOH,c=0.2), 1 H-NMR (300MHz, CDCl 3 )7.72(s,1H),6.62(d,J=7.8Hz,1H),6.99-7.10(m,2H),6.84(s,1H),6.33(d,J=1.8Hz,1H),6.21( d,J=6.3Hz,1H),4.93(d,J=6.3Hz,1H),2.46(s,3H),2.39-2.43(dd,J=15.0Hz,0.6Hz,1H),2.03-2.06( m,3H),1.96(s,3H),1.46-1.73(m,9H),1.38(s,3H),1.16(s,3H),1.02(s,3H),1.01(s,3H),0.88 -0.93(m,1H),0.73(s,3H).HRMS(ESI)m / z calcd for C 38 h 47 NO 4 Na[M+Na] + 604.3396, found 604.3397.

Embodiment 3

[0053] Embodiment 3 Parallel reaction

[0054] Referring to the preparation method of compound 1 in Example 1, using the corresponding substituted indole as the reaction substrate, the reaction was carried out to obtain compounds 3-11, the structural formula of which is as follows:

[0055]

[0056] Analysis data of some compounds:

[0057] Compound 4: mp96-98℃; [α]20 D-66.31°(MeOH,c=0.2), 1 H-NMR (300MHz, CDCl 3 )δ7.94(s,1H),7.87(s,1H),7.22(m,3H),6.83(s,1H),6.32(s,1H),6.14(d,J=6.2Hz,1H), 4.86(d,J=5.8Hz,1H),2.41(m,2H),2.15–1.96(m,2H),1.93(s,3H),1.80–1.41(m,8H),1.37(s,3H) ,1.31-1.22(m,2H),1.17(s,3H),1.04(s,3H),1.02(s,3H),0.98–0.87(m,1H),0.73(s,3H).HRMS(ESI )m / z calcd for C 37 h 44 FNO 4 Na[M+Na] + 608.3147, found 608.3141.

[0058] Compound 6: mp90-92℃; [α]20 D-90.36°(MeOH, c=0.2), 1 H-NMR (300MHz, CDCl 3 )δ7.85(s,1H),7.62(dd,J=8.6,5.3Hz,1H),7.06–6.78(m,3H),6.29(d,J=1.1Hz,1H),6.17(d,J =6.3Hz,1H),4.89(d,J=6.1Hz,1H),2.40(d,J=15.1Hz,2H),2.10-2.01(m,3H),1.95(s,3H),1....

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Abstract

The invention discloses a tripterine derivative, and a preparation method and a use thereof. The tripterine derivative has a structure represented by formula I; and in the formula I, R1 is H, an alkyl group, a halogenated alkyl group, an unsaturated alkyl group, a hetero atom-containing alkyl group or an aryl group, R2 is an alkyl group, a halogen, an alkyloxy group or a nitro group, and R3 is H or an alkyl group. In the preparation method of the tripterine derivative, an indolyl group or a substituted indolyl group is introduced to the 6 position of tripterine through a Friedel-Crafts reaction under mild reaction conditions. The tripterine derivative has the characteristics of high anticancer activity, low toxicity, small side effects and stable structure in the treatment of cancers.

Description

technical field [0001] The invention relates to a tripterine derivative, its preparation method and application. Background technique [0002] Cancer is a serious public health problem in the world. According to the statistics released by the International Agency for Research on Cancer in 2008, about 7.6 million people worldwide die of cancer every year. Currently, commonly used clinical tumor treatment methods include surgery, chemotherapy (chemotherapy), radiation therapy (radiotherapy), and biological therapy. [0003] At present, the use of surgery to completely remove the cancer focus is still the first choice for cancer treatment. At present, there are seven main types of tumor treatment drugs: alkylating agents, anti-metabolite drugs, antibiotics, plants, small molecule targeted therapy drugs and others. Among the many anticancer drugs, plant-derived anticancer drugs have always been a major category of leading products in the international anticancer drug market. C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61P35/00
Inventor 唐开勇曾佳烽陈庆花方通潘俊芳
Owner SHANGHAI HUATUO MEDICAL SCI CO LTD
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