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A kind of indole alkaloid compound and its preparation method and application

A compound and alkaloid technology, applied in the field of medicine, can solve problems such as low activity, low specificity, and small number of inhibitors

Active Publication Date: 2021-10-12
GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the research and development of KMT2D inhibitors is currently in the basic research stage, and the number of inhibitors is small, the specificity is not strong, and the activity is not high, which limits its development.

Method used

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  • A kind of indole alkaloid compound and its preparation method and application
  • A kind of indole alkaloid compound and its preparation method and application
  • A kind of indole alkaloid compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: 1-(3-((4-benzylpiperidin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyridine[ Preparation of 3,4-b]indole (compound 1)

[0047] Step 1: Preparation of 3-((4-benzylpiperidin-1-yl)methyl)-4-methoxybenzaldehyde intermediate

[0048]

[0049]Dissolve (0.30g, 1.62mmol) 3-(chloromethyl)-p-anisaldehyde in 5.0ml of acetonitrile, slowly add benzylpiperidine (0.57g, 3.18mmol) in acetonitrile solution, and react at room temperature until the raw material completely disappears Afterwards, distillation under reduced pressure gave a crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether=3:1) to give a colorless oil (0.44g, 83.5%). MS (ESI): 324.1954 [M+H]. 1 H NMR (400MHz, CDCl 3 )δ9.89(s,1H),7.90(s,1H),7.77(d,J=8.5Hz,1H),7.26(t,J=7.4Hz,2H),7.16(dd,J=17.8,7.3 Hz, 3H), 6.95(d, J=8.5Hz, 1H), 3.88(s, 3H), 3.53(s, 2H), 2.89(d, J=11.3Hz, 2H), 2.54(d, J=7.0 Hz, 2H), 1.99(t, J=11.4Hz, 2H), 1.61(d, J=12.8Hz, 2H), 1....

Embodiment 2

[0053] Example 2: 2,3,4,9-tetrahydro-1-(4-methoxy-3-((4-(piperidin-1-yl)piperidin-1-yl)methyl)phenyl )-1H-pyridin[3,4-b]indole (Compound 2)

[0054] Step 1: Preparation of 4-methoxy-3-((4-(piperidin-1-yl)piperidin-1-yl)methyl)benzaldehyde intermediate

[0055]

[0056] Synthesized in a similar manner to 4-methoxy-(3-piperidin-1-yl)methyl)benzaldehyde to obtain a white powder (0.54 g, 65.7%). MS (ESI): 317.2221 [M+H]. 1 H NMR (400MHz, CDCl 3 )δ9.81(s,1H),7.81(s,1H),7.70(d,J=8.4Hz,1H),6.90(d,J=8.5Hz,1H),3.83(s,3H),3.48( s,2H),2.91(d,J=11.3Hz,2H),2.60(s,4H),2.42(t,J=11.6Hz,1H),2.00(t,J=11.6Hz,2H),1.83( d,J=11.7Hz,2H),1.63(dd,J=20.5,8.5Hz,7H),1.41(s,2H). 13 C NMR (101MHz, CDCl 3 )δ190.91, 162.43, 131.21, 131.09, 129.22, 126.71, 110.17, 63.58, 55.60, 54.91, 52.15, 49.57, 26.02, 23.35, 22.74.

[0057] Step 2: 2,3,4,9-Tetrahydro-1-(4-methoxy-3-((4-(piperidin-1-yl)piperidin-1-yl)methyl)phenyl) Preparation of -1H-pyridino[3,4-b]indole (compound 2)

[0058]

[0059] In a ...

Embodiment 3

[0060] Example 3: 2,3,4,9-tetrahydro-1-(4-methoxy-3-((4-morpholine piperidin-1-yl)methyl)phenyl)-1H-pyridine[ Preparation of 3,4-b]indole (compound 3)

[0061] Step 1: Preparation of 4-methoxy-3-(4-morpholinopiperidin-1-yl)methyl)benzaldehyde intermediate

[0062]

[0063] Synthesized in a similar manner to 4-methoxy-(3-piperidin-1-yl)methyl)benzaldehyde to obtain a white powder (0.37 g, 58.7%). MS (ESI): 319.1993 [M+H]. 1 H NMR (400MHz, CDCl 3 )δ9.78(s,1H),7.79(s,1H),7.69(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),3.81(s,3H),3.61( s,4H),3.46(s,2H),3.37(s,2H),3.30(s,2H),2.87(d,J=10.8Hz,2H),2.45(s,4H),2.09(t,J =10.3Hz, 1H), 1.96(t, J=11.6Hz, 2H), 1.72(d, J=11.9Hz, 2H), 1.49(q, J=11.6Hz, 2H).

[0064] Step 2: 2,3,4,9-Tetrahydro-1-(4-methoxy-3-((4-morpholinopiperidin-1-yl)methyl)phenyl)-1H-pyridin[3 , Preparation of 4-b] indole (compound 3)

[0065]

[0066] In a similar manner to Compound 1 in Example 1, a light yellow powder, Compound 3 (0.08 g, 49.6%) was obtained. MS (ESI...

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Abstract

The invention discloses an indole alkaloid compound, a preparation method and application thereof. The structure of the compound is shown in formula (I); wherein, R 1 is hydrogen, halogen, C 1～4 Alkyl, C 1～4 Alkoxy, amine, hydroxyl or C 1～4 Alkylamino; R 2 is hydrogen, halogen, C 1～4 Alkyl, phenyl substituted C 1～4 Alkyl, C 1～4 Alkoxy, amino, hydroxyl, C 1～4 Alkylamino, phenyl, halophenyl, benzyl, halobenzyl, N-piperidinyl, N-morpholinyl, phenylmethylketone or halophenylmethylketone. The compound of the present invention has the characteristics of a new target, basically no toxic and side effects, and has excellent inhibitory effect on histone lysine N-methyltransferase 2D; and animal experiment data show that the compound has a It has a very good inhibitory effect on tumors, thereby inhibiting the growth of tumors, such as human non-small cell lung cancer cells, etc.; but at the same time, it has no effect on normal cells and has high safety.

Description

technical field [0001] The invention relates to the technical field of medicine, and more specifically, relates to an indole alkaloid compound and its preparation method and application. Background technique [0002] Epigenetic mechanisms play an important role in regulating gene expression. As in mammalian genomes, histone modifications have diverse physiological functions. Its free N-terminus can undergo valence modification such as acetylation, methylation, ubiquitination, phosphorylation, ADP ribosylation, etc. It is precisely because these covalent modifications change epigenetic information and regulate gene regulation. Express. Among them, histone lysine N-methyltransferase 2D (KMT2D), known as MLL4, MLL2, and mll4 in humans and mice, respectively, is derived from mammalian histone H3 lysine 4 (H3K4) methyl transfer family of enzymes that are critically linked to early embryonic development and are ubiquitously expressed in adult tissues. The C-terminal SET region...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P35/00A61P35/04
CPCC07D471/04A61P35/00A61P35/04
Inventor 刘中秋廖国超王彩艳廖宗浪喻琦刘丹谢薇卢琳琳吴鹏杨德盈
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE