Synthesis method of novel estrogen receptor targeting inhibitor and application of novel estrogen receptor targeting inhibitor in breast cancer treatment

A technology of estrogen receptor and synthesis method, which is applied in the synthesis method of new estrogen receptor targeting inhibitor and its application in the treatment of breast cancer, which can solve the problem of low bioavailability and limited clinical application of lonidamine and other issues to achieve good catalytic effect, cost reduction, and high recycling rate

Inactive Publication Date: 2021-11-23
杨锦飞
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, the low bioavailability of

Method used

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  • Synthesis method of novel estrogen receptor targeting inhibitor and application of novel estrogen receptor targeting inhibitor in breast cancer treatment
  • Synthesis method of novel estrogen receptor targeting inhibitor and application of novel estrogen receptor targeting inhibitor in breast cancer treatment
  • Synthesis method of novel estrogen receptor targeting inhibitor and application of novel estrogen receptor targeting inhibitor in breast cancer treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Synthesis of 1-(2-chloro-4-fluorobenzyl)-1H-indazole-3-carboxylic acid 4a:

[0264]

[0265] Add 0.20mmol of compound 1a, 0.22mmol of 2a and 0.9mmol of potassium carbonate to the reaction flask in sequence, then add 2mL of acetone, and stir the reaction under reflux at 70°C for 12 hours. After the reaction is completed, add water to quench the reaction, and add 5mL of acetic acid Diluted with ethyl ester, washed with 5 mL of saturated brine, dried the organic phase with anhydrous magnesium sulfate, spin-dried and recrystallized with dichloromethane / n-hexane system to obtain intermediate 3a. Subsequently, the intermediate 3a obtained by recrystallization, 0.40 mmol sodium hydroxide and 2 mL of methanol / water (1:1) mixed solvent were added to the reaction flask, and the reaction was refluxed and stirred at 60 ° C for 24 hours. After the reaction was completed, water was added to quench The reaction was quenched, diluted with 5 mL of ethyl acetate, washed with 5 mL of s...

Embodiment 2

[0268] Synthesis of 1-(2,4-difluorobenzyl)-1H-indazole-3-carboxylic acid 4b:

[0269]

[0270] Add 0.20mmol of compound 1a, 0.22mmol of 2b and 0.9mmol of potassium carbonate into the reaction flask in sequence, then add 2mL of acetone, and stir the reaction under reflux at 70°C for 12 hours. After the reaction is completed, add water to quench the reaction, add 5mL of Diluted with ethyl acetate, washed with 5 mL of saturated brine, dried the organic phase with anhydrous magnesium sulfate, spin-dried and recrystallized with dichloromethane / n-hexane system to obtain intermediate 3b. Subsequently, the intermediate 3b obtained by recrystallization, 0.40 mmol potassium hydroxide and 2 mL methanol / water (1:1) mixed solvent were added to the reaction flask, and the reaction was refluxed and stirred at 60 ° C for 24 hours. After the reaction was completed, water was added to quench The reaction was quenched, diluted with 5 mL of ethyl acetate, washed with 5 mL of saturated brine, d...

Embodiment 3

[0273] Synthesis of 1-(2,6-dichlorobenzyl)-1H-indazole-3-carboxylic acid 4c:

[0274]

[0275] Add 0.20mmol of compound 1a, 0.22mmol of 2c and 0.9mmol of sodium carbonate to the reaction flask in sequence, then add 2mL of acetone, and stir the reaction under reflux at 70°C for 12 hours. After the reaction is over, add water to quench the reaction, add 5mL of Diluted with ethyl acetate, washed with 5 mL of saturated brine, dried the organic phase with anhydrous magnesium sulfate, spin-dried and recrystallized with dichloromethane / n-hexane system to obtain intermediate 3c. Subsequently, the intermediate 3c obtained by recrystallization, 0.40 mmol sodium hydroxide and 2 mL of ethanol / water (1:1) mixed solvent were added to the reaction flask, and the reaction was refluxed and stirred at 60 ° C for 24 hours. After the reaction was completed, water was added to quench The reaction was quenched, diluted with 5 mL of ethyl acetate, washed with 5 mL of saturated brine, dried with a...

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Abstract

The invention provides a synthesis method of a novel estrogen receptor targeting inhibitor and application of the novel estrogen receptor targeting inhibitor in breast cancer treatment, and belongs to the technical field of pharmaceutical chemical application. According to the technical scheme, a series of estrogen receptor targeting inhibitors containing indazole and indole skeletons are synthesized, the inhibitory activity of the inhibitors on breast cancer cells is tested respectively, and a series of compounds with higher cancer cell inhibitory activity than lonidamine are found; wherein the compounds (21) and (23) show the best breast cancer cell inhibition activity, and the IC50 values of the compounds (21) and (23) are 45 mu M and 53 mu M respectively. The synthesis method and applicationhave the beneficial effects that a series of bilonidamine small molecule compounds with higher breast cancer cell inhibitory activity are provided, the compounds (21) and (23) show the strongest biological activity, and molecular docking experimental results prove that the compounds (21) and (23) play a role in inhibiting breast cancer cells through a targeted estrogen receptor.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical and chemical applications, in particular to a method for synthesizing a novel estrogen receptor targeting inhibitor and its application in the treatment of breast cancer. Background technique [0002] Breast cancer is the most common malignant tumor in women worldwide, and it is also the main cause of cancer-related death in women. According to the latest survey data from the International Agency for Research on Cancer (IARC), the incidence of breast cancer in women's cancers in the world is 24.2%, ranking first among women's cancers. , 52.9% occurred in developing countries. In China, more than 300,000 women are diagnosed with breast cancer every year, and the trend is increasing year by year. In the eastern coastal areas and economically developed large cities, the incidence of breast cancer has increased significantly. Therefore, breast cancer has become the first killer that seriously...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D209/42A61P35/00
CPCC07D231/56C07D209/42A61P35/00
Inventor 杨锦飞姚伟伟
Owner 杨锦飞
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