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ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof

An inhibitor and solvate technology, applied in the field of ALK protein degrader and its anti-tumor application, can solve the problems of ALK protein drug resistance and inability to clear ALK protein, etc.

Active Publication Date: 2019-06-21
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because traditional ALK-TKIs can only inhibit the activity of ALK protein, but cannot clear ALK protein, the secondary mutation of ALK protein after treatment leads to the occurrence of drug resistance.

Method used

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  • ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof
  • ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof
  • ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0277] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. The present invention 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 invention. While the invention will be described in conjunction with specific embodiments, it will be understood that they are not intended to limit the invention to those embodiments.

[0278] The following abbreviations are used throughout the specification and examples:

[0279] Boc tert-butoxycarbonyl

[0280] Con. Concentration

[0281] DCM dichloromethane

[0282] DMF N,N-Dimethylformamide

[0283] DMSO dimethyl sulfoxide

[0284] DIPEA N,N-Diisopropylethylamine

[0285] EDCI carbodiimide

[0286] ESI electrospray ionization

[0287] equiv equivalent

[0288] EtOH ethanol

[0289] HOAT 1-Hydroxy-7-azobenzot...

preparation Embodiment 1

[0357] Intermediate Preparation Example 1: Preparation of Brigatinib Derivative A (SIAIS1197135)

[0358] Brigatinib derivative A (SIAIS1197135) was prepared according to Scheme 1.

[0359] Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS1197111):

[0360] Under open conditions, 5-fluoro-2-nitroanisole (7g, 40.9mmol) was dissolved in 60mL of DMF solution, followed by adding K 2 CO 3 (8.4g, 60.8mmol), N-tert-butoxycarbonylpiperazine (9.1g, 48.9mmol), stirred overnight at room temperature. After the reaction was completed, quenched with water, extracted with ethyl acetate, washed the organic phase with water, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, beating with a mixed solvent of petroleum ether:ethyl acetate=5:1, and filtered through a sand core 11.1 g of yellow target solid SIAIS1197111 was obtained with a yield of 80%. 1 H NMR (500MHz, DMSO) δ7.89(d, J=9.3Hz, 1H), 6.57(d, J=9.5 Hz, 1H), 6.52(s, 1H),...

preparation Embodiment 2

[0366] Intermediate Preparation Example 2: Preparation of Brigatinib Derivative B

[0367] Using a method similar to that of the brigatinib derivative A in Example 1 of intermediate preparation, the brigatinib derivative B was prepared according to Scheme 1, and the intermediate synthesis data and structural characterization data are as follows:

[0368]

[0369] tert-Butyl(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate (SIAIS151054).(Yellow solid, 1.81g, 88%) 1 H NMR (500MHz, CDCl 3 )δ7.99(t, J=8.9Hz, 1H), 6.41(dd, J=9.4, 2.5Hz, 1H), 6.30(d, J=2.5Hz, 1H), 4.49(s, 1H), 3.94( s,3H),3.86–3.82(m,2H),3.71(s,1H),3.09–3.00(m,2H),2.11–2.03(m,2H),1.89–1.75(m,2H),1.45( s,9H).

[0370]

[0371] tert-Butyl(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)carbamate (SIAIS151062).(gray purple solid, 411.6mg, 90%) 1 H NMR (500MHz, DMSO) δ6.82(d, J=7.6Hz, 1H), 6.50(d, J=8.5Hz, 1H), 6.48(d, J=2.5Hz, 1H), 6.28(dd, J =8.4,2.4Hz,1H),4.20(s,2H),3.73(s,3H),3.33–3.26(m,3H),2.56–2.50(m,2H),...

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Abstract

The invention discloses a compound in a formula (I) and an anti-tumor application thereof. The compound in the formula (I) has degradation and inhabitation functions on ALK target protein and mainly comprises four parts, the first part ALK-TKIs is a compound with ALK tyrosine kinase inhabitation activity; the second part LIN is different linkers; the third part ULM (ubiquitin ligase binding moiety) of VHL, CRBN or other protease micromolecular ligand with a ubiquitination function; the fourth part group A is carboxyl or deficiency and covalently binds ALK-TKIs with LIN and covalently binds LINwith ULM. A series of designed and synthesized compounds have wide pharmacological activity, have functions of degrading ALK protein and inhibiting ALK activity and can be applied to related tumor therapy.

Description

technical field [0001] The present invention relates to the compound of formula (I) for preventing or treating cancer and its anti-tumor application, especially the anti-tumor application to related proteins such as ALK, ROS1, EGFR and FLT3. [0002] Background technique [0003] Lung cancer is the leading cause of cancer death worldwide. In my country, the incidence of lung cancer has exceeded the incidence of various malignant tumors, and nearly 800,000 people die of lung cancer every year. The current five-year survival rate of lung cancer is very low, only 17%, and this survival rate has not changed much since the 1970s. This is largely due to the fact that conventional treatment measures cannot effectively control lung cancer. Conventional radiotherapy and chemotherapy not only kill cancer cells, but also kill normal cells in patients, reduce immunity, and cause damage to patients' normal physiological functions. In recent years, the precision medicine program has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07D401/14C07D417/14C07D405/14C07D487/04A61K31/675A61K31/506A61K31/519A61K31/501A61K31/496A61K31/53A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/14C07D405/14C07D417/14C07D487/04C07F9/6561A61K47/55A61K31/506A61K31/4025A61K31/496A61K31/519A61K31/501A61K31/53A61K31/675C07D417/12C07F9/6558A61K31/4439A61K31/454A61K31/662A61K45/06
Inventor 杨小宝姜标宋肖玲林海帆孙宁陈金聚仇星任超伟孔莹
Owner SHANGHAI TECH UNIV
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