N-substituted tetrahydropyridine bound indole compound as well as preparation method and application thereof

A technology of tetrahydropyridine-linked indole and compound, which is applied in the field of medicinal chemistry, can solve problems such as chronic myelogenous leukemia that is difficult to cure, and achieve the effects of high-efficiency inhibitory activity, simple process, and easy production

Inactive Publication Date: 2013-06-12
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chronic myelogenous leukemia is difficult to cure because there is no ideal drug that can effectively inhibit the proliferation of K562 cells in the existing technology

Method used

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  • N-substituted tetrahydropyridine bound indole compound as well as preparation method and application thereof
  • N-substituted tetrahydropyridine bound indole compound as well as preparation method and application thereof
  • N-substituted tetrahydropyridine bound indole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 3-[4-(N-(4-fluorobenzyl)-1,2,3,6-tetrahydropyridyl)]indole (Ia)

[0048]At room temperature, add 0.16mol methyl acrylate and 7mL methanol into a 100mL three-necked flask, and slowly add a mixture of 0.04mol p-fluorobenzylamine and 4mL methanol into the three-necked flask while stirring, so that the temperature of the reaction system does not exceed 50°C . After the dropwise addition was completed, it was heated to reflux for 8 hours, the reflux temperature was 63° C., and the reaction progress was tracked by thin layer chromatography (TLC). After the reaction, methanol and unreacted methyl acrylate were recovered and distilled under reduced pressure to obtain light yellow oily liquid N,N-bis(β-methyl propionate)-p-fluorobenzylamine (2a).

[0049] Add 15 mL of anhydrous toluene and 0.122 mol of metallic sodium to a 250 mL dry three-necked flask, stir and heat to reflux. Then add 0.2 mL of anhydrous methanol, and then slowly dropwise add 0.04 mol N, N-bis(β-me...

Embodiment 2

[0052] Example 2 3-[4-(N-(4-methylbenzyl)-1,2,3,6-tetrahydropyridyl)]indole (Ib)

[0053] The same preparation method as in Example 1, but p-fluorobenzylamine was replaced by p-methylbenzylamine, and N-p-methylbenzylpiperidin-4-one (4b) was obtained under the same conditions.

[0054] Add 0.005mol indole, 5ml methanol and 5ml sodium methoxide (30wt% CH 3 OH solution), a mixture of 0.01mol N-p-methylbenzylpiperidin-4-one (4b) and 5ml methanol was added with stirring under ice-water bath conditions. After the dropwise addition, the mixture was stirred at room temperature for 20 min, and then heated to reflux at 63°C for 5h-6h. A yellow solid precipitated out, and the reaction progress was tracked by thin-layer chromatography (TLC). After the reaction, the solid was washed with absolute ethanol and recrystallized with ethyl acetate to obtain 3-[4-(N-(4-methylbenzyl)-1,2,3,6-tetrahydropyridyl) ] Indole (Ib).

[0055] Yield 80%; Light yellow solid; mp 203-205°C; 1 H NMR (400MHz...

Embodiment 3

[0056] Example 3 3-[4-(N-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridyl)]indole (Ic)

[0057] With the preparation method of Example 1, p-fluorobenzylamine was replaced by p-methoxybenzylamine, and N-p-methoxybenzylpiperidin-4-one (4c) was obtained under the same conditions.

[0058] Add 0.005mol indole, 5ml methanol and 5ml sodium methoxide (30wt%) CH 3 OH solution, under the condition of ice-water bath, stir and add the mixed solution of 0.01mol N-p-methoxybenzylpiperidin-4-one (4c) and 5ml methanol. After the dropwise addition, the mixture was stirred at room temperature for 20 min, and then heated to reflux at 63°C for 5h-6h. A yellow solid precipitated out, and the reaction progress was tracked by thin-layer chromatography (TLC). After the reaction, the solid was washed with absolute ethanol and recrystallized with ethyl acetate to obtain 3-[4-(N-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridyl )] indole (Ic).

[0059] Yield 85%; yellow solid; mp 191-193°C; 1 H NMR (400MHz, D...

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Abstract

The invention relates to the field of chemical and medicinal chemistry, and discloses a N-substituted tetrahydropyridine bound indole compound with a structure shown as a formula (I), and the compound can be used for effectively inhibiting cell proliferation of leukemia K562, ovarian cancer HO-8910 and liver cancer SMMC-7721. The preparation method comprises the following steps: preparing N,N-bis(beta-methyl propionate) substituted amine from substituted amine and methyl acrylate by means of a Michael addition reaction; performing Dieckmann condensation in the action of sodium alcoholate, andperforming hydrolysis and decarboxylation in the action of acid to prepare N-substituted piperidine-4-ketone; and performing a condensation reaction to the product and indole or substituted indole. The preparation method has the advantages of simple process and easiness for production; and the compound can be used for preparing medicaments for treating leukemia, ovarian cancer or liver cancer.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and discloses a new compound capable of inhibiting the proliferation of cancer cells; specifically, it is a kind of N-substituted compound that can effectively inhibit the proliferation of leukemia K562 cells, ovarian cancer HO-8910 cells and liver cancer SMMC-7721 cells. Tetrahydropyridine indole compound, its preparation method and its application in the preparation of drugs for inhibiting the above cancer cells. Background technique [0002] Among various diseases, cancer poses the greatest threat to human life and is the number one killer of patients. Among all kinds of cancers, leukemia, ovarian cancer and liver cancer are three common malignant tumors with a high incidence rate. Therefore, it is very useful to design and develop drugs that can effectively inhibit the proliferation of leukemia, ovarian cancer and liver cancer cells and make them rapidly apoptotic. significance. [0003] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D405/14A61K31/4439A61P35/02A61P35/00
Inventor 薛思佳郝志兵孙传文
Owner SHANGHAI NORMAL UNIVERSITY
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