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Tetrahydroindazole compound as well as preparation method and application thereof

A technology of tetrahydroindazole and hydrazine compounds, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve problems such as life health and mental health threats, achieve low IC50 value, and strongly inhibit tumor cell growth activity , the effect of inhibiting cell proliferation

Active Publication Date: 2022-03-22
SHENZHEN PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, in addition to the number of new cases, the number of cancer deaths in my country also ranks first in the world. Therefore, if no timely treatment and intervention measures are taken for cancer, it will pose a serious threat to human life, health and mental health.

Method used

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  • Tetrahydroindazole compound as well as preparation method and application thereof
  • Tetrahydroindazole compound as well as preparation method and application thereof
  • Tetrahydroindazole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The 4-(4-keto-3,6,6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexylamino)benzamide (compound II) prepared above is used to prepare the compound of the present invention Compound I, the method is as follows:

[0041] Take 4-(4-keto-3,6,6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexylamino)benzamide (2.0g, 4.87mmol, 1eq) dissolved in In 20mL of ethanol, add hydrazine hydrochloride (0.73g, 10.6mmol, 2.2eq) and sodium acetate (0.80g, 9.7mmol, 2eq) and react at 80°C for 10h. After cooling, a solid precipitates out and is suction filtered to obtain a light yellow solid. Recrystallization from ethyl acetate gave 1.86 g of the product, a 90% yield, melting point 283.5-285.0°C. The product is said compound I, and the synthetic reaction formula is as follows:

[0042]

[0043] 1H NMR (500 MHz, DMSO) δ (ppm) 8.37 (d, 1H), 7.84 (s, 1H), 7.70 (d,1H), 7.15 (s, 1H), 6.62-6.72 (m, 2H), 5.96 (s, 2H), 4.59 (s, 1H), 2.74 (s,2H), 2.38 (s, 3H), 2.29 (s, 2H), 2.01 (d, 2H...

Embodiment 2

[0045] The 4-(4-keto-3,6,6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexylamino)benzamide (compound II) prepared above is used to prepare the compound of the present invention Compound I, the method is as follows:

[0046] Take 4-(4-keto-3,6,6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexylamino)benzamide (2.0g, 4.87mmol, 1eq) dissolved in In 20mL of ethanol, add 85% hydrazine hydrate (0.46g, 14.6mmol, 3eq) and sodium acetate (1.19g, 14.6mmol, 3eq) and stir and heat at 80°C for 10h. After cooling, a solid precipitates out, which is filtered by suction to obtain light The yellow solid was recrystallized from ethyl acetate to obtain 1.98 g of the product, the yield was 95.5%, and the melting point was 284.5-286.0°C. The HPLC analysis product was consistent with the product of Example 1, and the product was the compound I.

Embodiment 3

[0048] The growth curve and IC50 value determination of each compound inhibiting tumor cells:

[0049] (1) HepG2, MDA-MB-231, Sw620, A549 and Hct116 were selected as tumor cells to be tested. The culture conditions of HepG2 and MDA-MB-231 cell lines were DMEM medium supplemented with 10% FBS, Sw620 and A549 cell lines The culture condition of the Hct116 cell line was RPMI1640 medium supplemented with 10% FBS, and the culture condition of the Hct116 cell line was McCoy's5A medium supplemented with 10% FBS. All cell lines were stored in 5% CO 2 cultured in a 37°C incubator. Cell viability and growth were assayed in 96-well plates.

[0050] (2) After the cells adhere to the wall, add different concentrations of Compound I, Compound II and GA (Geldanamycin) prepared in Example 1 to each well as the experimental group, and those without adding any drugs as the control Group, cultured for 24h and / or 48h respectively, then added 10μLCCK8 to each well and cultured for 2h, detected ...

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Abstract

The embodiment of the invention discloses a tetrahydroindazole compound, a preparation method thereof and application of the tetrahydroindazole compound in preparation of antitumor drugs. The tetrahydroindazole compound is a compound I with the following chemical structural formula. The compound I is obtained by carrying out mixed reaction on 4-(4-ketone-3, 6, 6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexyl amino) benzamide and a hydrazine compound under an alkaline condition. On the basis of the prior art, a compound I is researched and prepared, and it is proved that compared with 4-(4-keto-3, 6, 6-trimethyl-1-tetrahydroindazole)-2-(4-hydroxycyclohexyl amino) benzamide compounds in the prior art, the compound I has the higher tumor cell growth inhibition activity, has the generally lower IC50 value and has the good application prospect. Especially, apoptosis of colorectal cancer cells can be obviously caused at low concentration, cell proliferation is inhibited by retarding the apoptosis at the G0 / G1 phase, and great significance is achieved for developing novel anti-tumor drugs. (I).

Description

technical field [0001] The technical field of drug synthesis of the present invention particularly relates to a tetrahydroindazole compound and its application as an antitumor drug. Background technique [0002] According to the latest global cancer burden data released by the WHO International Agency for Research on Cancer in 2020, the number of new cancers in my country far exceeds that of other countries in the world, ranking first in the world. Among them, the top ten cancers in the number of new cancer cases include solid tumors such as lung cancer, colorectal cancer, gastric cancer, breast cancer, and liver cancer, accounting for 78% of the number of new cancer cases. In addition, in addition to the number of new cases, the number of cancer deaths in my country also ranks first in the world. Therefore, if no timely treatment and intervention measures are taken for cancer, it will pose a serious threat to human life, health and mental health. [0003] Tetrahydroindazol...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61P35/00
CPCC07D231/56A61P35/00
Inventor 刘凯胜蒋宏香蓝妮周朋君马文辉
Owner SHENZHEN PEOPLES HOSPITAL
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