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Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor

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

Active Publication Date: 2015-10-21
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although people have studied a large number of compounds with inhibitory activity on protein kinases, and some protein kinase inhibitors such as crizotinib have been marketed for the treatment of NSCLC, but they will produce drug resistance and have certain defects.

Method used

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  • Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor
  • Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor
  • Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Embodiment 1: Compound (intermediate) shown in preparation formula 2-1

[0108]

[0109] Put the compound shown in formula a (15g, 106.31mmol), potassium carbonate (29.38g, 212.61mmol) in a 500mL round bottom bottle, add 150ml of DMF, add isopropyl mercaptan (compound shown in formula b) under stirring (8.5g, 111.62mmol), the mixture was stirred and heated to 80°C, and reacted for 5 hours. After the reaction was completed, the reaction solvent was evaporated under reduced pressure, and the obtained crude product was washed with water, extracted with ethyl acetate, dried, concentrated, and obtained by column chromatography. The compound shown in c (yield 19.5 g, yield 95%).

[0110] The compound shown in formula c (19.5g, 98.86mmol) and m-chloroperoxybenzoic acid (mCPBA, the compound shown in formula d) (60.2g, 348.84mmol) were placed in a 1000mL round bottom bottle, and 500ml of dichloromethane was added , the mixture was stirred overnight at room temperature, quenc...

Embodiment 2

[0112] Embodiment 2: compound (intermediate) shown in preparation formula 2-2

[0113]

[0114] Compound shown in formula f (14.2g, 0.1mol), potassium carbonate (27.6g, 0.2mol) are placed in 500mL round bottom bottle, add 150 milliliters of DMF, add isopropyl thiol (compound shown in formula b) under stirring ) (8.0g, 0.105mol), the mixture was stirred and heated to 75°C, reacted for 6 hours, after the reaction was completed, the reaction solvent was evaporated under reduced pressure, the obtained crude product was washed with water, extracted with ethyl acetate, dried and concentrated, and obtained by column chromatography Compound represented by formula g (yield: 17.9 g, yield: 92.5%).

[0115] The compound shown in formula g (19.8g, 0.1mol) and m-chloroperoxybenzoic acid (mCPBA, the compound shown in formula d) (60.9g, 0.35mol) were placed in a 1000mL round bottom bottle, and 500ml of dichloromethane was added , the mixture was stirred overnight at room temperature, que...

Embodiment 3

[0117] Embodiment 3: compound (intermediate) shown in preparation formula 2-2

[0118]

[0119] Compound (15.9g, 0.1mmol) shown in formula j, potassium carbonate (27.6g, 0.2mmol) are placed in 500mL round bottom bottle, add 150 milliliters of DMF, add isopropyl mercaptan under stirring (compound shown in formula b ) (8.0g, 0.105mol), the mixture was stirred and heated to 80°C, reacted for 5 hours, after the reaction was completed, the reaction solvent was evaporated under reduced pressure, the obtained crude product was washed with water, extracted with ethyl acetate, dried and concentrated, and obtained by column chromatography Compound represented by formula g (yield: 18.1 g, yield: 93%).

[0120] The compound shown in formula g (19.8g, 0.1mol) and m-chloroperoxybenzoic acid (mCPBA, the compound shown in formula d) (48.7g, 0.28mol) were placed in a 1000mL round bottom bottle, and 500ml of dichloromethane was added , the mixture was stirred overnight at room temperature, ...

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Abstract

The invention provides a pyrimidine derivative used as an ALK inhibitor. The pyrimidine derivative is a compound as shown in a formula I which is described in the specification or a pharmaceutical salt, hydrate, solvate, metabolite or prodrug thereof. R1, R2, R3 and R4 in the formula are as defined in the specification. The compound and a pharmaceutical composition thereof can be used as the ALK inhibitor and for preparation of an antineoplastic therapeutic capable of inhibiting ALK.

Description

technical field [0001] The present invention belongs to the field of medical technology, and relates to a novel compound, a method for preparing the compound, a pharmaceutical composition and a use thereof. Specifically, the present invention relates to novel pyrimidine derivatives as ALK inhibitors, and the preparation of these compounds for the treatment and prevention of cancer use in medicines. Background technique [0002] Non-small-cell lung cancer (NSCLC) is synonymous with "non-small-cell carcinoma". Non-small cell lung cancer, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, has slower growth and division of cancer cells than small cell carcinoma, and relatively late spread and metastasis. Non-small cell lung cancer accounts for about 80-85% of all lung cancers. Statistics show that the current incidence of lung cancer in my country is increasing by 26.9% every year. From 2000 to 2005, the number of lung cancer patients in China is esti...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/12C07D403/12C07D239/48C07D409/12C07D409/14A61K31/506A61K31/5377A61P35/00
CPCC07D239/48C07D401/12C07D401/14C07D403/12C07D409/12C07D409/14A61K31/506A61K31/5377
Inventor 王学海许勇李莉娥盛锡军黄璐张晓林乐洋黄文杰余艳平田华肖强于静杨菁
Owner HUBEI BIO PHARMA IND TECHCAL INST
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