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Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof

一种药学、前药的技术，应用在医药领域，能够解决耐药病人疗效差、病人皮疹毒副作用严重等问题

Active Publication Date: 2016-04-27
SHANGHAI HAIYAN PHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the second-generation inhibitors also have strong wild-type EGFR inhibitory activity, and the inhibitory activity to wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation. A small proportion of patients resistant to first-generation EGFR inhibitors respond to these drugs

Method used

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  • Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof
  • Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof
  • Azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0170] Preparation of compound 1-a

[0171]

[0172]

[0173] Step a: In a 4L flask, 25.0g of raw material 1-a-1 (0.19mol) was dissolved in 1L of tetrahydrofuran, stirred at room temperature under nitrogen protection for 20 minutes, and 1M potassium tert-butoxide in tetrahydrofuran (500.0ml, 0.50mol ) was added to the solution and stirred for 1 hour. Then 0.15M chloramine ether solution (2.1L, 0.31mol) was added to the reaction solution within 20 minutes at 10°C, and nitrogen gas was introduced at the same time. After 2 hours, saturated aqueous sodium thiosulfate solution (500ml) was added gradually The reaction solution was added dropwise and stirring was continued for one hour. The organic phase was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure to obtain compound 1-a-2 as an oil. MSm / z(ESI):141.2[M+H] + .

[0174] Step b: Dissolve th...

Embodiment 1

[0196] Example 1: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(7-(1-methyl-1H-pyrazole Preparation of [1,2,4]triazin-2-ylamino)phenyl)acrylamide (J-1) of -4-yl)pyrrolo[1,2-f]

[0197]

[0198]

[0199] Step 1: Compound 1-a (6.0 g, 24.6 mmol), 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (10.2g, 49.0mmol), tetrakistriphenylphosphopalladium (2.84g, 2.46mmol), potassium carbonate (10.2g, 73.8mmol), dioxane 60ml, water 20ml mixture, argon Protected, stirred at 100°C for 4 hours. After the reaction was completed, cool to room temperature, add dichloromethane and water, separate the organic phase, and concentrate under reduced pressure to obtain the crude product, which was purified by Combi-flash column chromatography [PE:EA=100:0~0:100] to obtain compound 1 as a yellow solid -b (5.7g), directly used in the next reaction. Yield: 94.5%; Purity: 98.76% (UV254). MSm / z(ESI):246.0[M+H] + .

[0200] Step 2: Compound 1-b (5.64g, 22.7mmol) w...

Embodiment 2

[0204] Example 2: N-(2-(4-(dimethylamino)piperidin-1-yl)-4-methoxy-5-(7-(1-methyl-1H-pyrazole-4- Preparation of [11,2,4]triazin-2-ylamino)phenyl)acrylamide (J-2) of pyrrolo[1,2-f]

[0205]

[0206] Step: Add compound 1-e (50 mg, 0.098 mmol), compound 3-a (32 mg, 0.1 mmol), tris(dibenzylideneacetone) dipalladium (9 mg, 0.0098 mmol) to 4 ml of dioxane solution, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (9mg, 0.016mmol), cesium carbonate (64mg, 0.196mmol), under argon protection, stirred at 120°C for 10 minutes under microwave. After the reaction was completed, cool to room temperature, filter with diatomaceous earth, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure to obtain a crude product, which was separated and purified by preparative liquid phase to obtain compound J-2 (5.67 mg) as a yellow solid, with a yield of 11.2%; Purity: 100% (UV254). MSm / z(ESI):516.0[M+H] + . 1 HNMR(400MHz,DMSO)δ9.11(s,1H),8.84(s,1H),8.48(s,1H...

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Abstract

The invention relates to azabicyclo derivatives, preparation methods thereof, and pharmaceutical applications thereof. Specifically, the invention discloses compounds represented by a formula (I), or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof. The invention also provides preparation methods of the derivatives, and applications of the derivatives in EGFR inhibitors. The definitions of the groups in the formula are defined in the specifications.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an azabicyclic derivative, a preparation method thereof, an application as an EGFR tyrosine kinase inhibitor, and a pharmaceutical composition and a pharmaceutical composition prepared therefrom. Background technique [0002] Lung cancer is the most common cancer in the world. In China, the incidence of lung cancer ranks first among all cancers, and it is also the cancer with the highest incidence and mortality in China. [0003] Among Chinese lung cancer patients, 30% have EGFR mutations, among which L858R and exon 19 deletion mutations account for more than 90%, and these patients are more sensitive to EGFR inhibitors. The first-generation EGFR inhibitors that are already on the market, such as erlotinib and gefitinib, have good therapeutic effects on such patients, and can shrink the tumors of more than 60% of them, significantly prolonging the progression-free survival of p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/53A61P35/00A61P3/10A61P37/02A61P25/28A61P9/00
CPCA61K31/4985A61K31/4188A61P35/00C07D519/00C07D487/04
Inventor 金云舟卜平何琦兰炯周福生张亮何向宇
Owner SHANGHAI HAIYAN PHARMA TECH
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