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Compound with androgen receptor (AR) degradation activity

A compound, halogen technology, applied in the field of medicine, can solve problems such as drug resistance

Active Publication Date: 2020-02-04
SHANGHAI MEIZER PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, about 20% to 40% of prostate cancer patients are congenitally resistant to enzalutamide, and those prostate cancer patients who are initially sensitive to enzalutamide will eventually develop drug resistance after long-term treatment

Method used

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  • Compound with androgen receptor (AR) degradation activity
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  • Compound with androgen receptor (AR) degradation activity

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0264] Compound preparation

[0265] Preparation

[0266] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.

[0267] The preparation method of the compound of formula I of the present invention provided by the present invention is as follows.

[0268] The following reaction schemes illustrate the preparation of compounds of the invention. Unless otherwise indicated, W, Y1, Y2, Y3, X1, X2, X3, R, L, D, n, m in the reaction schemes and subsequent discussions are as defined above; RE 1 、RE 2 、RE 3 、RE 4 When connecting in pairs, one end is (or can b...

Embodiment 1

[0309] The preparation of embodiment 1 compound 5

[0310]

[0311] first step

[0312] Dissolve DL-panthenolactone 1 (7.81g) in anhydrous tetrahydrofuran (200ml), add 60% sodium hydride (3.00g), stir the reaction, and after the gas release is complete, add 4-fluoro-2-(tri Fluoromethyl)benzonitrile (9.46g), react overnight at room temperature. The reaction solution was concentrated, and the residue was purified by a silica gel column to obtain 10.69 g of compound 2 as an off-white solid. Yield: 63%. MS(ESI):300.1[M+H] + .

[0313] second step

[0314] Compound 2 (2.99g) was dissolved in toluene (20ml), at room temperature, 4-(aminomethyl)phenol (1.23g) was added, the reaction solution was heated and reacted for 16 hours, the reaction solution was filtered and concentrated, and the residue was purified by a silica gel column , to obtain 2.74 g of off-white solid. The resulting solid was dissolved in pyridine (10ml), methanesulfonyl chloride (1.26g) was added dropwise ...

Embodiment 2

[0319] The preparation of embodiment 2 compound 11

[0320] first step

[0321] Compound 2 (5.98g) was dissolved in ethanol (60ml), and 2,4-dimethoxybenzylamine (10.00g) was added at room temperature, and the reaction solution was stirred at 60°C overnight. The reaction solution was concentrated by filtration, and the residue was purified by a silica gel column to obtain 6.44 g of off-white solid. The obtained solid was dissolved in pyridine (50ml), and methanesulfonyl chloride (1.89g) was added dropwise in an ice-water bath, and the stirring was continued until the raw material basically disappeared. After washing with brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in anhydrous tetrahydrofuran (50ml), 60% sodium hydride (1.10g) was added in portions, and stirred overnight at room temperature. The reaction solution was quenched with saturated ammonium chloride (50ml), extracted w...

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Abstract

The invention provides a type of compound with androgen receptor (AR) degradation activity, and specifically provides a compound as shown in the following formula I: (please see the specification forthe formula), wherein all groups are as defined in the specification. The compound has the great AR degradation activity, and can be used for preparing drugs for treatment of AR expression-related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a class of novel compounds and their application for degrading androgen receptor (AR). These compounds can degrade AR, and can be used as AR inhibitors or degradation agents for treating diseases such as prostate cancer. Background technique [0002] Prostate cancer has become an important disease that threatens men's health. Prostate cancer is the most common male cancer in North America and Europe, and its mortality rate is second only to lung cancer. In China, the annual incidence of prostate cancer is also increasing at a rate of about 10%. The growth of prostate cancer is almost entirely dependent on the androgen receptor (AR) pathway. As the target of androgen's biological effects, AR has become a research hotspot in the field of biomedicine. [0003] Some men with prostate cancer can be cured with surgery. However, about 30% of prostate cancer patients will relapse due to dista...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D417/14A61K31/454A61K31/427A61P35/00
CPCC07D401/14C07D417/14A61P35/00
Inventor 舒永志王峰林军罗冯军顾磊
Owner SHANGHAI MEIZER PHARM CO LTD
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