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Bis-aryl amine compound as well as preparation method and application thereof

A compound and aromatic-based technology, which is applied in the field of bis-arylamine compounds and their preparation, can solve problems such as hindering the use of anti-androgen drugs

Active Publication Date: 2020-11-17
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the target of action has not changed, after a period of treatment, drug resistance caused by amino acid mutations at the hormone-binding pocket (HBP) site greatly hinders the use of this type of anti-androgen drugs

Method used

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  • Bis-aryl amine compound as well as preparation method and application thereof
  • Bis-aryl amine compound as well as preparation method and application thereof
  • Bis-aryl amine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The preparation of embodiment 1 compound 1

[0088] Under anhydrous conditions, 3-(1H-pyrazol-5-yl)aniline (100.0 mg, 0.63 mmol) was dissolved in anhydrous DMF (5.0 mL), and anhydrous K 2 CO 3 (130.2mg, 0.94mmol), under ice-water bath conditions (0°C), add 4-acetylbenzenesulfonyl chloride (164.8mg, 0.75mmol) to the solution, react at 0-4°C for 30min, then turn to room temperature reaction, After 6-8h, TLC showed that 3-(1H-pyrazol-5-yl)aniline disappeared, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with PH test paper, and NaHCO 3 Adjust the pH of the saturated solution between 9-11, wash with water, wash with saturated NaCl solution, anhydrous NaCl 2 SO 4 Drying, concentration, separation and purification by column chromatography (PE / EA=1.5 / 1V / V) gave white floc 1 (112.4 mg, yield: 52.3%).

[0089] Compound 1 was detected by H NMR spectrum ( 1 HNMR) and high resolution mass spectrometry (HRMS) a...

Embodiment 2

[0092] The preparation of embodiment 2 compound 2

[0093] Under anhydrous conditions, 3-(1H-pyrazol-5-yl)aniline (100.0 mg, 0.63 mmol) was dissolved in anhydrous DMF (5.0 mL), and anhydrous K 2 CO 3 (130.2mg, 0.94mmol), under ice-water bath conditions (0°C), 4-fluorobenzenesulfonyl chloride (146.9mg, 0.75mmol) was added to the solution, reacted at 0-4°C for 30min, then turned to room temperature reaction, 6 -8h later, TLC showed that 3-(1H-pyrazol-5-yl)aniline disappeared, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with PH test paper, and NaHCO 3 Adjust the pH of the saturated solution between 9-11, wash with water, wash with saturated NaCl solution, anhydrous NaCl 2 SO 4 Drying, concentration, separation and purification by column chromatography (PE / EA=1.5 / 1V / V) gave white floc 2 (140.3 mg, yield: 70.2%).

[0094] Compound 2 was detected by H NMR spectrum ( 1 HNMR) and high resolution mass spectromet...

Embodiment 3

[0097] The preparation of embodiment 3 compound 3

[0098] Under anhydrous conditions, 3-(1H-pyrazol-5-yl)aniline (100.0 mg, 0.63 mmol) was dissolved in anhydrous DMF (5.0 mL), and anhydrous K 2 CO 3 (130.2mg, 0.94mmol), under ice-water bath conditions (0°C), add 4-chlorobenzenesulfonyl chloride (159.3mg, 0.75mmol) to the solution, react at 0-4°C for 30min, then turn to room temperature reaction, 6 -8h later, TLC showed that 3-(1H-pyrazol-5-yl)aniline disappeared, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with PH test paper, and NaHCO 3 Adjust the pH of the saturated solution between 9-11, wash with water, wash with saturated NaCl solution, anhydrous NaCl 2 SO 4 Drying, concentration, separation and purification by column chromatography (PE / EA=1.5 / 1V / V) gave white floc 3 (118.5 mg, yield: 56.4%).

[0099] Compound 3 was detected by H NMR spectrum ( 1 HNMR) and high resolution mass spectrometry (HRMS) ...

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Abstract

The invention provides a bis-aryl amine compound as well as a preparation method and application thereof. The compound has a structure as shown in a formula 1, wherein the R1 is selected from C1-12 alkyl, C1-6 alkoxy, halogen, C1-3 haloalkyl, CN, NO2, NH2, sulfonyl or aryl, and R2 is selected from C1-4 alkyl, C1-6 alkoxy, halogen, C1-3 haloalkyl, -CN, -NO2, -NH2, sulfonyl or aryl; the R5 is more than one, and R5 and R2 are selected from hydrogen, C1-12 alkyl, C1-6 alkoxy, halogen, C1-3 haloalkyl, -CN, -NO2, -NH2, sulfonyl or aryl; the R3 is selected from substituted or unsubstituted five-membered heterocycles or six-membered heterocycles; wherein the Linker is selected from -SO2NR4-, -CONR4- and -NR4-, and R4 is selected from hydrogen and C1-12 alkyl; the V, W, X, Y and Z are independentlyselected from carbon or nitrogen. The bis-aryl amine compound provided by the invention has the activity of inhibiting an androgen receptor.

Description

technical field [0001] The present invention relates to a compound, in particular to a bisarylamine compound and its preparation method and application. Background technique [0002] Prostate cancer (PCa) is one of the most common male malignant tumors. Its incidence worldwide is second only to lung cancer and ranks second among all male malignant tumors. The mortality rate in developed countries is the total cancer mortality rate. the third place. With changes in lifestyle, environment and other factors, as well as the aggravation of population aging, the incidence of prostate cancer will show a continuous and rapid growth trend in the global region. The pathogenesis and treatment techniques of prostate tumors have also received increasing attention. [0003] Androgen, such as androsterone (Testosterone, T), dihydrotestosterone (Dihydrotestosterone, DHT) and adrenal androsterone, is an important class of steroidal sex hormones in the human body. , AR) combine to promote ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12C07D233/61C07D261/08C07D277/28C07D401/04A61P5/26A61P35/00A61P13/08A61P15/00A61P17/08A61P17/10A61P17/00A61K31/415A61K31/4439A61K31/42A61K31/426
CPCC07D231/12C07D233/61C07D261/08C07D277/28C07D401/04A61P5/26A61P35/00A61P13/08A61P15/00A61P17/08A61P17/10A61P17/00
Inventor 胡来兴刘永华周金明吴萌李鑫
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI