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Catenated ring compound serving as protein degradation agent as well as preparation method and application of catenated ring compound

A compound, cycloalkyl technology, applied in the field of compound and its preparation and application as a protein degrading agent, can solve problems such as not necessarily applicable

Active Publication Date: 2021-03-09
SHANGHAI JEMINCARE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This also means that common drug-chemical transformation strategies (such as equivalent replacement of effective fragments, etc.) are not necessarily applicable in the design of such molecules

Method used

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  • Catenated ring compound serving as protein degradation agent as well as preparation method and application of catenated ring compound
  • Catenated ring compound serving as protein degradation agent as well as preparation method and application of catenated ring compound
  • Catenated ring compound serving as protein degradation agent as well as preparation method and application of catenated ring compound

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0149] Reference Example 1: Preparation of Intermediate I-1

[0150]

[0151] [1-(4-Bromophenyl)-cyclopropyl] tert-butyl carbamate (950mg, 3.05mmol), 4-methylthiazole (605mg, 6.1mmol), potassium acetate (600mg, 6.1mmol) and acetic acid Palladium (34mg, 0.153mmol) was mixed in N,N-dimethylacetamide (10mL), heated to 130°C under nitrogen atmosphere, and stirred for 8 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), filtered, the filtrate was diluted with water (60 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain intermediate I-1.

[0152] LC-MS(ESI)[M+H] + 331.3.

reference example 2

[0153] Reference Example 2: Preparation of Intermediate I-2

[0154]

[0155] Intermediate I-1 (370mg, 1.12mmol) was dissolved in hydrogen chloride methanol solution (20mL, 4M), and stirred at room temperature for 4 hours. The reaction solution was concentrated, neutralized by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate I-2. The crude product was directly used in the next reaction without further purification.

[0156] LC-MS(ESI)[M+H] + 231.1.

reference example 3

[0157] Reference Example 3: Preparation of Intermediate I-3

[0158]

[0159] Intermediate I-2 (240mg), Boc-L-hydroxyproline (240mg, 1.04mmol), N,N-diisopropylethylamine (400mg, 3.12mmol) mixed in N,N-dimethylformaldehyde Add O-(7-azabenzotriazol-1-yl)-N,N,N'-tetramethyluronium hexafluorophosphate (600mg, 1.56mmol) to amide (4mL), and stir the reaction at room temperature 16 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain intermediate I-3.

[0160] LC-MS(ESI)[M+H] + 444.3.

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PUM

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Abstract

The invention discloses a catenated ring compound serving as a protein degradation agent as well as a preparation method and application of the catenated ring compound, and particularly discloses a compound shown as a formula (I) and pharmacologically acceptable salt of the compound, and application of the compound serving as an androgen receptor (AR) for degradation.

Description

technical field [0001] The present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and the application of the compound as an androgen receptor (AR) degradation agent. Background technique [0002] Prostate cancer (PCa) is one of the most common cancers, surpassing lung cancer as the most common male cancer in the United States. Prostate cancer has no obvious symptoms in the early stage, so when it is generally discovered, the patient will have symptoms such as frequent urination, dysuria, hematuria, and painful urination, and may spread to other parts. In 2016, the number of new prostate cancer patients in my country was 120,000, and it is estimated that this number will rise to 237,000 by 2030, with a compound annual growth rate of 5% for the number of new patients. It also means that in the next 10 years, the incidence of prostate cancer in my country will enter a peak period and become the number one killer of ma...

Claims

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Application Information

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IPC IPC(8): C07K5/062A61K38/05A61P35/02A61P35/00
CPCC07K5/06034A61P35/02A61P35/00A61K38/00
Inventor 邢唯强吕永聪陆洪福徐强齐保建彭建彪郭海兵
Owner SHANGHAI JEMINCARE PHARMA CO LTD