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Protein degradation targeting BCR-ABL compound and application thereof to resisting tumors

A technology of compounds and solvates, applied in the field of protein degradation of compounds targeting BCR-ABL fusion proteins, can solve unseen problems such as

Active Publication Date: 2019-09-17
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] So far, there have been no reports of PROTAD compounds that recruit Von Hippel Lindau (VHL) E3 ligase to degrade BCR-ABL protein

Method used

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  • Protein degradation targeting BCR-ABL compound and application thereof to resisting tumors
  • Protein degradation targeting BCR-ABL compound and application thereof to resisting tumors
  • Protein degradation targeting BCR-ABL compound and application thereof to resisting tumors

Examples

Experimental program
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Embodiment

[0162] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. While the disclosure will be described in conjunction with specific embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments.

[0163] The following abbreviations are used throughout the specification and examples:

[0164] Boc tert-butoxycarbonyl

[0165] n-BuOH n-Butanol

[0166] t BuOH tert-butanol

[0167] Con. Concentration

[0168] DCM dichloromethane

[0169] DME ethylene glycol dimethyl ether

[0170] DMF N,N-Dimethylformamide

[0171] DMSO dimethyl sulfoxide

[0172] DIPEA N,N-Diisopropylethylamine

[0173] EDCI carbodiimide

[0174...

preparation example 1

[0207] Intermediate Preparation Example 1: Preparation of Dasatinib Derivatives

[0208]

[0209] plan 1

[0210] N-(2-Chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-yl was prepared according to Scheme 1 Formamide (SIAIS151055):

[0211] N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide (1.0g, 2.54mmol), Add anhydrous piperazine (1.31g, 15.21mmol), N,N-diisopropylethylamine (4.9g, 38.0mmol) and anhydrous n-BuOH (8mL) into a 30mL microwave reaction tube, and stir at room temperature After 10 minutes, argon gas was slowly blown into the microwave tube, and after sealing, the reaction tube was put into a microwave reactor, and the temperature was slowly raised to 120° C., and stirred for 1 h. The reaction solution was lowered to room temperature and left overnight, a large amount of white solids precipitated, suction filtered, the filter cake was washed twice with anhydrous n-butanol, and the ...

preparation example 2

[0212] Intermediate Preparation Example 2: Preparation of Bosutinib Derivatives

[0213]

[0214] Scenario 2

[0215] Preparation of 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(piperazin-1-yl)propoxy)quinone according to Scheme 2 Phenyl-3-carbonitrile (SIAIS151151):

[0216] 7-(3-chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-cyanoquinoline (1.0g, 2.14mmol), anhydrous piperazine (0.93g, 10.7mmol), sodium iodide (0.4g, 2.14mmol) and ethylene glycol dimethyl ether (8mL) were added together in a 30mL microwave reaction tube, stirred at room temperature for 10min, Then argon gas was slowly bubbled into the microwave tube, the reaction tube was placed on the microwave reactor, raised to 95° C. and stirred for 1 h. The reaction solution was lowered to room temperature, the reaction solvent was evaporated under reduced pressure, then 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (4×50 mL), the organic phases...

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Abstract

The invention provides a protein degradation targeting BCR-ABL compound as shown in a formula (I) and an application thereof to resisting tumors. The compound as shown in the formula (I) has the effects of degrading and restraining BCR-ABL targeting protein, and mainly consists of four parts of a first part: BCR-ABL-TKIs which is a compound having BCR-ABL tyrosine kinase restraining activity, a second part: LIN which is a link unit, a third part: ULM which is a VHL or CRBN protease micromolecule ligand having a ubiquitination function, and a fourth part: a group A which is carbonyl and is used for performing covalent bonding on the BCR-ABL-TKIs and the LIN and covalent bonding on the LIN and the ULM. A series of compounds designed and synthesized by the invention have broad pharmacological activity, have the functions of degrading BCR-ABL protein and restraining BCR-ABL activity, and can be used for pertinent tumor treatment. (As shown in the description)

Description

technical field [0001] The present disclosure relates to compounds targeting BCR-ABL fusion protein for protein degradation and their anti-tumor applications. Background technique [0002] T(9;22)(q34;q11) chromosomal translocation, also known as Philadelphia chromosome translocation (Philadelphia translocation) or Philadelphia chromosome (Ph), is characterized by mutual exchange between the long arm of chromosome 9 and the long arm of chromosome 22 Translocation of the Abelson leukemia virus (ABL) 1 gene located on chromosome 9 to the breakpoint cluster region (Bcr) gene on chromosome 22 to form a Bcr-Abl fusion gene[1,2] . This characteristic chromosomal translocation exists in most chronic myeloid leukemia (CML), some acute lymphoblastic leukemia (ALL) and a few acute myeloid leukemia (AML). Under normal conditions, the activity of protein tyrosine kinases is tightly regulated. Compared with normal tyrosine protein kinase, BCR-ABL fusion protein has continuously activa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05C07D417/14C07D401/14A61K31/506A61K31/496A61P35/00A61P35/02
CPCC07K5/06034C07K19/00C07D417/14C07D401/14A61P35/00A61P35/02A61K38/00A61K31/496A61K31/506A61K31/497A61P1/00A61K47/55A61K2300/00A61K45/06
Inventor 杨小宝姜标阴倩倩陈金聚赵全菊任超伟孙仁红孙宁仇星孔莹李岩刘林义
Owner SHANGHAI TECH UNIV
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