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Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof

A technology of dihydroindane amide and compound, applied in the field of medicine, can solve problems such as death, adverse reactions of patients, steric hindrance, etc., and achieve the effects of broad anti-cancer spectrum, excellent anti-tumor activity and safety, and wide therapeutic window.

Inactive Publication Date: 2015-02-04
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is because the T315I mutation produces steric hindrance, which prevents the 3-hydroxy-phenylethyl group at the N-9 position of the purine in the inhibitor structure from binding to the hydrophobic pocket of ABL, but the FDA has currently terminated the use of Ponatinib, mainly because Ponatinib produces significant coagulation effects, leading to serious adverse reactions or death of patients

Method used

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  • Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof
  • Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof
  • Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methyl-[N-5-(4-methylpiperazinyl)-tetrahydroindane]benzyl Synthesis of Amide (Compound 1)

[0051]

[0052] 1. Synthesis of 5-fluorenylmethoxycarbonyl amido-indanone

[0053]

[0054] Under the protection of nitrogen, add stirring bar, 5-aminoindanone (14.7 grams, 0.1 moles), 200 milliliters of dichloromethane solution, pyridine (23.7 grams, 0.3 moles) in 500 milliliters of eggplant-shaped bottles, stir while ice-water bath Fluorenemoxycarbonyl chloride (25.8 g, 0.1 mol) was slowly added dropwise in portions. After the dropwise addition, the temperature was raised to room temperature and stirring was continued for 2 hours. The reaction solution was quenched by adding 200 ml of water, the dichloromethane phase was separated and washed with 100 ml of brine, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by column chromatography to obtain 33.8 g of the product with a ...

Embodiment 2

[0077] Example 2 3-(imidazo[1,2-a]pyrimidine-3-ethynyl)-4-methyl-[N-5-(1-imidazolyl)-indane]benzamide (compound 2 )Synthesis

[0078]

[0079] 1. Synthesis of 1-(1-imidazolyl)-5-fluorenylmethoxycarbonamidotetrahydroindene

[0080]

[0081] Add 1-chloro-6-fluorenylmethoxycarbonamidotetrahydroindane (3.11 g, 8 mmol), potassium carbonate (3.31 g, 24 mmol), 40 ml of tetrahydrofuran solvent in a 100 ml eggplant-shaped bottle, N, 10 ml of N-dimethylformamide and N-methylpiperazine (1.00 g, 10 mmol) were stirred at 40° C. for 4 hours to stop the reaction. After the reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate was added to dissolve it. And washed 3 times with 50 ml of saturated saline. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.06 g of the product with a yield of 91%. MS: m / z 422 ([M+H] + ).

[0082]2. Synthesis of 1-(1-imid...

Embodiment 3

[0098] Example 3 3-(imidazo[1,2-a]pyrimidin-3-ethynyl)-4-methyl-[N-5-(4-tert-butoxyyl)-tetrahydroindene]benzamide ( Compound 3) Synthesis

[0099]

[0100] 1. Synthesis of 1-(4-tert-butoxyacyl)-5-fluorenylmethoxycarbonamidotetrahydroindene

[0101]

[0102] Add 1-chloro-6-fluorenylmethoxycarbonamidotetrahydroindane (3.11 g, 8 mmol), potassium carbonate (3.31 g, 24 mmol), 40 ml of tetrahydrofuran solvent in a 100 ml eggplant-shaped bottle, N, 10 ml of N-dimethylformamide and N-methylpiperazine (1.00 g, 10 mmol) were stirred at 40° C. for 4 hours to stop the reaction. After the reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate was added to dissolve it. And washed 3 times with 50 ml of saturated saline. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.62 g of the product with a yield of 84%. MS: m / z 540 ([M+H] + ).

[0103] 2. Syn...

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PUM

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Abstract

The invention relates to substituted-indanyl amide-type compounds as shown in the general formula I, pharmaceutically acceptable salt of the compounds and a preparation method and an application thereof. The invention also provides a pharmaceutical composition of the compounds. Through in vitro and in vivo anti-tumor effect research results and acute toxicity research results, the anti-tumor drug substituted-indanyl amide-type compounds have more excellent antitumor activity and safety, especially resisting imatinib drug-resistant tumors, and can be applied in curing tumors such as leukemia, gastrointestinal stromal tumor, lung cancer, colon cancer, ovarian cancer, kidney cancer and the like. Thus, the compounds have wide therapeutic window and have application value when used as an anti-tumor agent in the field of medicine.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a substituted dihydroindane amide compound which inhibits the growth of tumor cells and exerts an antitumor effect, a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. Background technique [0002] Imatinib competitively inhibits the binding site between adenosine triphosphate (ATP) and thymidine kinase (TK) receptors such as KIT, blocks TK phosphorylation, thereby inhibiting signal transduction, and can inhibit KIT mutations related to kinase activity (causing KIT receptor activation) and wild-type KIT. There are three main targets: Abelson (ABL) protein, KIT protein and platelet-derived growth factor (PDGF) receptor. Imatinib reduces kinase phosphorylation in a GIST-derived cell line (GIST882) through gain-of-function KIT mutations that cause stem cell factor-independent activation, and completely inhibits kinase phosphorylation at a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D495/04A61K31/5025A61K31/4985A61K31/519A61P35/00A61P35/02
CPCC07D487/04C07D495/04
Inventor 陈烨王洋刘晶赵楠宋诗博印丽丽
Owner LIAONING UNIVERSITY
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