Containing aromatic ring/aromatic heterocycle-triazole-methylene-tcp derivative and its preparation method and application

A technology of aromatic heterocycles and triazoles, which is applied in the field of medicinal chemistry, can solve the problem that LSD1 has no inhibitory effect, and achieve the effects of rich variety, good application prospects, and convenience for mass production and commercial application

Active Publication Date: 2021-06-11
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Our research group filed an application in 2018 (application number 201810077674.X) to disclose a 1,4-disubstituted 1,2,3-triazole ribavirin analog, which links coumarin or quinoline to triazole , but the analog had no inhibitory effect on LSD1 (IC 50 >10000nM), link coumarin or quinoline and other aromatic rings or aromatic heterocycles with 1,2,3-triazole, change the group connected with methylene, and obtain a class of compounds with inhibitory effect on LSD1 , this type of compound has not been reported

Method used

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  • Containing aromatic ring/aromatic heterocycle-triazole-methylene-tcp derivative and its preparation method and application
  • Containing aromatic ring/aromatic heterocycle-triazole-methylene-tcp derivative and its preparation method and application
  • Containing aromatic ring/aromatic heterocycle-triazole-methylene-tcp derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation shown in general formula Ⅰ: wherein R 1 for R 2 is a hydrogen atom, that is, compound 6b(1R,2S)-2-phenyl-N-((1-(7-methoxycoumarin-4-yl)-1H-1,2,3-triazole -4-yl) methyl) cyclopropyl-1-amine, the process is as follows:

[0046] (1) Synthesis of compound 5a (1R, 2S)-2-phenyl-N-propargylcyclopropyl-1-amine): take compound 4a trans-phenylcyclopropylamine free state (2.0g , 15mmol) in a 100mL Shrek bottle, add triethylamine (2.07g, 15mmol), acetonitrile 45mL, propyne bromide (1.17mL, 15mmol), stir at room temperature overnight, concentrate after the reaction is completed, dichloromethane (70mL×3 ), dried over sodium sulfate, and separated by neutral alumina column chromatography to obtain pale yellow liquid 5a (1.54 g, 9 mmol), with a yield of 55%. 1 H NMR (600MHz, Chloroform-d) δ7.25(t, J=7.4Hz, 2H), 7.15(t, J=7.3Hz, 1H), 7.06(d, J=7.7Hz, 2H), 3.49(s , 2H), 2.60(m, 1H), 2.22(s, 1H), 1.97(m, 1H), 1.91(s, 1H), 1.09(m, 1H), 0.98(m, 1H). 13 C NMR (151 MHz, Chl...

Embodiment 2

[0051] Preparation shown in general formula Ⅰ: wherein R 1 for R 2 is a hydrogen atom, that is, compound 6e(1R,2S)-2-phenyl-N-((1-(7-methoxyquinolin-4-yl)-1H-1,2,3-triazole- 4-yl) methyl) cyclopropyl-1-amine, the process is as follows:

[0052] (1) The synthesis process of compound 5a is the same as in Example 1.

[0053] (2) Synthesis of compound 3e (4-azido-7-methoxyquinoline): Take compound 2e (0.97g, 5mmol) in a 50mL round bottom flask, add 15mL of N,N-dimethylformamide, Sodium azide (488 mg, 7.5 mmol) was stirred at room temperature for 8 h. After the reaction was monitored by TLC, it was extracted with ethyl acetate (70 mL×3), dried over sodium sulfate, and concentrated to obtain the crude product 3e.

[0054] (3) Compound 6e(1R, 2S)-2-phenyl-N-((1-(7-methoxyquinolin-4-yl)-1H-1,2,3-triazole-4- Synthesis of base) methyl) cyclopropyl-1-amine: Take compound 5a (171mg, 1mmol) in a 25mL Shrek tube, add 3e (200mg, 1mmol), copper sulfate pentahydrate (12.5mg, 0.05mmol), ...

Embodiment 3

[0056] Preparation shown in general formula Ⅰ: wherein R 1 for R 2 is a fluorine atom, that is, compound 7b(1R,2S)-2-(3,4-difluorophenyl)-N-((1-(7-methoxycoumarin-4-yl)-1H-1 , 2,3-triazol-4-yl) methyl) cyclopropyl-1-amine, the preparation process is as follows:

[0057] (1) Synthesis of compound 5b(1R, 2S)-2-(3,4-difluorophenyl)-N-(propargyl)cyclopropyl-1-amine: take compound 4b( 1R, 2S)-3,4-difluorophenylcyclopropylamine free state (2.5g, 15mmol) in a 100mL Shrek bottle, add potassium carbonate (2.07g, 15mmol), acetonitrile 45mL, propyne bromide (1.17mL, 15mmol ), stirred at room temperature overnight, after the reaction was completed, concentrated, extracted with dichloromethane (70mL × 3), dried over sodium sulfate, and separated by neutral alumina column chromatography to obtain light yellow liquid 5b (1.6g, 7.7mmol), the yield 53%. 1 H NMR (600MHz, Chloroform-d) δ7.02(m, 1H), 6.84(m, 1H), 6.79(m, 1H), 3.49(d, J=2.3Hz, 2H), 2.54(m, 1H) , 2.24(t, J=2.4Hz, 1H), 1.93(m...

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Abstract

The invention discloses aromatic ring / aromatic heterocycle-triazole-methylene-TCP derivatives, which have the structure described in general formula I: have significant biological inhibitory activity on LSD1, can be used to prepare drugs for inhibiting LSD1, and enrich the The types of TCP derivatives have laid the foundation for the development of new LSD1 inhibitors. Especially for the preparation of antitumor drugs, it has a certain degree of antitumor effect on gastric cancer cell lines (MGC‑803, SGC‑7901), breast cancer cell lines (MCF‑7), prostate cancer cell lines (PC‑3) and other tumor cell lines Inhibition of anti-tumor activity, provides a lead compound structure for anti-cancer drugs, and has a good application prospect. The present invention also provides the preparation method of the above-mentioned aromatic ring / aromatic heterocyclic-triazole-methylene-TCP derivative, with (1R, 2S)-phenylcyclopropylamine or (1R, 2S)-3,4 ‑Difluorophenylcyclopropylamine is used as a raw material, which is prepared by alkyne up-cycling and cycloaddition reaction. The preparation method is simple, and it is convenient for batch production and commercial application.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an aromatic ring / aromatic heterocyclic-triazole-methylene-TCP derivative and its preparation method and application. Background technique [0002] With the improvement of living standards, cancer is becoming a serious disease affecting human health, destroying families and placing a heavy burden on society. Due to the characteristics of infinite division and metastasis of cancer cells, cancer has become one of the major diseases affecting human life and health. Therefore, it is urgent and necessary to design and research new anticancer drugs and develop anticancer drugs with good effect and small side effects. In 2004, Dr. Shi Yang's research group discovered histone lysine-specific demethylase (LSD1), which was the earliest discovered histone demethylase. This major discovery confirmed that histone methylation is a reversible reaction. Since then, people began to ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04C07D401/04C07D249/06A61P35/00A61P15/00A61P1/04
CPCA61P1/04A61P15/00A61P35/00C07D249/06C07D401/04C07D405/04
Inventor 黄利华郭佳稳黄明杰符运栋游亚珍
Owner ZHENGZHOU UNIV
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