Aromatic amine compound and application thereof in preparation of AR and BRD4 dual inhibitors and regulators

A compound and solvate technology, applied in the field of drug synthesis, can solve problems such as adverse reactions and drug resistance of small molecule drugs

Active Publication Date: 2020-10-20
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Traditional small-molecule inhibitors inhibit the function of the target protein by binding to the target protein, but long-term use of small-molecule drugs will inevitably lead to drug resistance, and in order to achieve the desired effect, small-molecule compounds need to be in the cell Maintain a certain concentration, and small molecules with a higher concentration will cause adverse reactions due to off-targets. Therefore, finding small molecule compounds that can overcome these defects is of great significance in the development of new drugs

Method used

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  • Aromatic amine compound and application thereof in preparation of AR and BRD4 dual inhibitors and regulators
  • Aromatic amine compound and application thereof in preparation of AR and BRD4 dual inhibitors and regulators
  • Aromatic amine compound and application thereof in preparation of AR and BRD4 dual inhibitors and regulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1 Synthesis of N-(3-bromo-4-(1H-imidazol-1-yl)phenyl)-5-(3,5-dimethylisoxazol-4-yl)-N-ethyl- 2-Methylaniline (Compound 31)

[0094]

[0095] first step:

[0096] 2-Bromo-1-fluoro-4-iodobenzene (3.0g, 10mmol), imidazole (680mg, 10mmol) and cesium carbonate (4.9g, 15mmol) were sequentially added to 50mL of DMA, heated to 120°C under nitrogen protection After reacting overnight, TLC monitored the completion of the reaction, cooled naturally to room temperature, extracted with 100mL ethyl acetate, washed with saturated brine (3*50mL), dried over anhydrous sodium sulfate, concentrated, separated and purified by chromatographic column (PE / EA=4 / 1 ) to obtain 3.4 g of compound 1-(2-bromo-4-iodobenzene)-1H-imidazole, yield: 95%.

[0097] Step two:

[0098] (1) Synthetic raw material 5-(3,5-dimethylisoxazol-4-yl)-2-methylaniline (ie compound 31-2): (3,5-dimethylisoxazole- 4-yl)boronic acid (16.9g, 120mmol), 5-bromo-2-methylaniline (22.3g, 120mmol) were dissolved in...

Embodiment 2

[0102] Example 2 Synthesis of 5-(3,5-dimethylisoxazole-4-)-N-ethyl-2-methyl-N-(4-(5-methyl-1H-pyrazole-3- ) phenyl) aniline (compound 97)

[0103]

[0104] first step:

[0105] Dissolve 60% sodium hydride (80mg, 2mmol) in 10ml N,N-dimethylformamide, add 3-(4-bromophenyl)-5-methyl-1H-pyrazole (236mg, 1mmol), room temperature Stir for 10 min, add 2-(trimethylsilyl)ethoxymethyl chloride (182 mg, 1.1 mmol), react at room temperature for 3 hours, wash with 10 ml of water, extract with 10 ml of ethyl acetate, concentrate the organic layer under reduced pressure, and perform thin layer chromatography Separation and purification gave 341 mg of compound 3-(4-bromophenyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, yield: 93 %.

[0106] Step two:

[0107] Dissolve 5-(3,5-dimethylisoxazole-4-)-2-methylaniline (202mg, 1mmol) in 5ml 1,4-dioxane, add 3-(4-bromobenzene yl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (341mg, 0.93mmol), add cesium carbonate...

Embodiment 3

[0112] Example 3 Synthesis of 4-(4-((5-(3,5-dimethylisoxazole-4-)-2-methylphenyl)(ethyl)amino)phenyl)thiazol-2-amine (Compound 98)

[0113]

[0114] first step:

[0115] Dissolve 4-(4-bromophenyl)thiazol-2-amine (254mg, 1mmol) in 10ml of dichloromethane, add phthalic anhydride (140mg, 0.96mmol), add triethylamine (202mg, 2mmo) to reflux Stir for 6 hours, wash with 10 ml of 1N hydrochloric acid, extract with 10 ml of ethyl acetate, wash with 10 ml of saturated sodium bicarbonate, and wash with 10 ml of saturated brine. The organic layer was concentrated under reduced pressure, separated and purified by thin layer chromatography to obtain 360 mg of compound 2-(4-(4-bromophenyl)thiazole-2-)isoindoline-1,3-dione, yield: 94% .

[0116] Step two:

[0117] Dissolve 5-(3,5-dimethylisoxazole-4-)-2-methylaniline (202mg, 1mmol) in 5ml 1,4-dioxane, add 2-(4-(4 -Bromophenyl)thiazole-2-)isoindoline-1,3-dione (360mg, 0.94mmol), cesium carbonate (650mg, 2mmol), BINAP (62mg, 0.1mmol), ...

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Abstract

The invention relates to an aromatic amine compound and application thereof in the preparation of AR and BRD4 dual inhibitors and regulators. Specifically, the invention provides a compound shown as aformula I, and the compound has dual inhibition effects on AR and BRD4. The compound not only can inhibit proliferation of prostate cancer cell lines LNCaP / AR with multiple expression of androgen receptor AR, but also shows a good inhibition effect on prostate cancer cell lines VCaP and 22RV1, which are resistant to prostate cancer drugs (enzalutamide) on the market. The compound is used as a compound capable of simultaneously identifying AR and BRD4 double targets; can be used as an AR / BRD4 dual inhibitor, can also be used for preparing protein degradation targeting chimeras (PROTACs) for inducing AR / BRD4 dual-target degradation, and has a good application prospect in preparation of drugs for treating AR and BRD4 related diseases.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to aromatic amine compounds and their use in the preparation of AR and BRD4 dual inhibitors and regulators. Background technique [0002] In the context of a growing and aging global population, the incidence of prostate cancer continues to increase. At present, the main treatment for prostate cancer is androgen deprivation therapy. Androgen receptor (AR) belongs to the nuclear receptor family and is a ligand-dependent transcription factor. Abnormal regulation of AR signaling pathway plays an important role in the occurrence and development of prostate cancer. Studies have shown that castration-resistant prostate cancer (CRPC) still depends on the role of AR. The androgen receptor consists of 918 amino acids and has similar structure and function to other nuclear receptors. It consists of three important domains, namely DNA binding domain (DNA binding domain, DBD), ligand binding doma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12C07D261/08C07D413/04C07D413/12C07D403/12C07D401/14C07D263/32C07D413/14C07D417/12C07D271/06A61P35/00C07B59/00
CPCC07D231/12C07D261/08C07D413/04C07D413/12C07D403/12C07D401/14C07D263/32C07D413/14C07D417/12C07D271/06A61P35/00C07B59/002C07B2200/05A61K31/42A61K31/422A61K31/4245
Inventor 杜武吕海斌秦德锟李海波李宇涂志林陈元伟李兴海
Owner HINOVA PHARM INC
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