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Aromatic amine compounds and their use in the preparation of AR and BRD4 dual inhibitors and regulators

A compound and inhibitor technology, applied in the directions of active ingredients of heterocyclic compounds, introduction of isotopes of heterocyclic compounds, introduction of isotopes into organic compounds, etc., can solve the problems of drug resistance and adverse reactions of small molecule drugs

Active Publication Date: 2021-06-22
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 compounds and their use in the preparation of AR and BRD4 dual inhibitors and regulators
  • Aromatic amine compounds and their use in the preparation of AR and BRD4 dual inhibitors and regulators
  • Aromatic amine compounds and their use in the preparation of AR and BRD4 dual inhibitors and regulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1 Synthesis N- (3-bromo-4- (1H-imidazole-1-yl) phenyl) -5- (3,5-dimethyl oxazole-4-yl) -N-ethyl- 2-metharmiline (Compound 31)

[0094]

[0095] first step:

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

[0097] Step 2:

[0098] (1) Synthesis of raw materials 5- (3,5-dimethyl alioxazole-4-yl) -2-methyl aniline (i.e., compound 31-2): (3,5-dimethyl oxazole) 4-yl) boric acid (16.9 g, 120 mmol), 5-bromo-2-methane (22.3 g, 120 mmol) is dissolved in 240 mL1...

Embodiment 2

[0102] Example 2 Synthesis 5- (3,5-dimethyl oxazole-4 -) - N-ethyl-2-methyl-N- (4- (5-methyl-1H-pyrazole-3- ) Phenyl) aniline (compound 97)

[0103]

[0104] first step:

[0105] 60% sodium hydride (80 mg, 2 mmol) was dissolved in 10 ml N, N-dimethylformamide, and 3- (4-bromo) -5-methyl-1H-pyrazole (236 mg, 1 mmol), room temperature The mixture was stirred for 10 min, 2- (trimethylsilyl) ethoxymethyl chloride (182 mg, 1.1 mmol) was added, and at room temperature for 3 hours, 10 mL washed, 10 ml of ethyl acetate extraction, and the organic layer was concentrated under reduced pressure, thin layer chromatography Purification of 341 mg of Compound 3- (4-bromo) -5-methyl-1 - (2- (trimethylsilicilicidal) ethoxy) methyl) -1H-pyrazole, yield: 93 %.

[0106] Step 2:

[0107] 5- (3,5-dimethyl oxazole-4 -) - 2-methamiline (202 mmol), dissolved in 5 ml 1,4-dioxane, add 3- (4-bromophenyl) Base) -5-methyl-1 - (2- (trimethylsilica) ethoxy) methyl) -1H-pyrazole (341 mg, 0.93 mmol), cesium carb...

Embodiment 3

[0112] Example 3 Synthesis 4- (4 - (5- (3,5-dimethyl otholactazole-4 - 2-methylphenyl) (ethyl) amino) phenyl) thiazole-2-amine (Compound 98)

[0113]

[0114] first step:

[0115] 4- (4-bromo) thiazole-2-amine (254 mg, 1 mmol) was dissolved in 10 ml of dichloromethane, and phthalic anhydride (140 mg, 0.96 mmol) was added, triethylamine (202 mg, 2 mmO) reflux is added. It was stirred for 6 hours, 10 mL 1N hydrochloric acid washed, 10 ml of ethyl acetate extraction, 10 ml of saturated sodium hydrogencarbonate, 10 ml of saturated salt water washed. The organic layer was concentrated under reduced pressure, and the crystal chromatography was separated from 360 mg of Compound 2- (4- (4-bromo-phenyl) thiazole-2-) isoindenam-1,3-diketone, yield: 94% .

[0116] Step 2:

[0117] 5- (3,5-dimethyl oxazole-4 -) - 2-methyl kethane (202 mmol), dissolved in 5 ml 1, 4-dioxane, added 2- (4- (4 - Bromobenzene) thiazole-2-) isoindenam-1,3-dilute (360 mg, 0.94 mmol), cesium carbonate (650 mg, 2 mmo...

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Abstract

The invention relates to an aromatic amine compound and its use in preparing AR and BRD4 dual inhibitors and regulators. Specifically, a compound represented by formula I is provided, which has dual inhibitory effects on AR and BRD4. The compound of the present invention can not only inhibit the proliferation of the prostate cancer cell line LNCaP / AR with overexpression of androgen receptor AR, but also the prostate cancer cell lines VCaP and 22RV1 resistant to the marketed prostate cancer drug (enzalutamide) Good inhibitory effect. The compound of the present invention can be used as a compound capable of simultaneously recognizing dual targets of AR and BRD4, can be used as a dual inhibitor of AR / BRD4, and can also be used to prepare protein degradation targeting chimeras (PROTACs) that induce degradation of AR / BRD4 dual targets , has a good application prospect in the preparation of drugs for treating AR and BRD4-related diseases.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical synthesis, and more particularly to an aromatic amine compound and its use in the preparation of Ar and BRD4 dual inhibitors and regulators. Background technique [0002] In the case where the global population is growing and aging, the incidence of prostate cancer continues to grow, at present, the main treatment for prostate cancer is arogen deprivation treatment. Androgen receptor, AR belongs to a nuclear receptor family, is a class of ligand-dependent transcription factors. The abnormal adjustment of the AR signaling pathway has an important role in the occurrence and development of prostate cancer. Studies have shown that Castration-Resistant Prostate Cancer, CASTRATION-RESITANT Prostate Cancer (CRPC) is still dependent on Ar. Androgen receptors contain 918 amino acids, similar structures and functions with other nuclear receptors, which consists of three important domains, DNA binding domain...

Claims

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Application Information

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Patent Type & Authority Patents(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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