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Substituted tetrahydronaphthalene amide compound, pharmaceutically acceptable salt thereof, and preparation method and application

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

Active Publication Date: 2014-12-31
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 tetrahydronaphthalene amide compound, pharmaceutically acceptable salt thereof, and preparation method and application
  • Substituted tetrahydronaphthalene amide compound, pharmaceutically acceptable salt thereof, and preparation method and application
  • Substituted tetrahydronaphthalene amide compound, pharmaceutically acceptable salt thereof, and preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methyl-[N-5-(4-methylpiperazinyl)-tetrahydronaphthalene]benzene Synthesis of Amide (Compound 1)

[0072]

[0073] 1. Synthesis of 6-fluorenylmethoxycarbonyl amido-tetralone

[0074]

[0075] Under the protection of nitrogen, add 6-aminotetralone (16.1 grams, 0.1 mole), 200 milliliters of dichloromethane solution, pyridine (23.7 grams, 0.3 moles) in a 500 milliliter eggplant-type bottle, and slowly divide while stirring under the ice-water bath Fluorenemoxycarbonyl chloride (25.8 g, 0.1 mol) was added dropwise. 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 under reduced pressure in vacuo, and separated by silica gel column chromatography to o...

Embodiment 2

[0106] Example 2 3-(imidazo[1,2-b]pyridazin-3-ethynyl)-4-methyl-[N-5-(4-methylpiperazinyl)-chroman]benzamide Synthesis of (Compound 2)

[0107]

[0108] 1. Synthesis of 7-fluorenylmethoxycarbonyl amido-4-chromanone

[0109]

[0110] Under nitrogen protection, add stirring bar, 7-aminochromanone (16.3 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 34.1 g of the product with a yield of 88%....

Embodiment 3

[0133] Example 3 3-([imidazo[1,2-a]pyrimidine-3-ethynyl)-4-methyl-[N-5-(morpholinyl)-tetralin]benzamide (compound 3 )Synthesis

[0134]

[0135] 1. Synthesis of 1-(morpholinyl)-6-fluorenylmethoxycarbonyl amidotetrahydronaphthalene

[0136]

[0137] Add 1-chloro-6-fluorenylmethoxycarbonyl amidotetralin (3.22 grams, 8 mmoles), potassium carbonate (3.31 grams, 24 mmoles), 40 milliliters of tetrahydrofuran solvents in 100 milliliters eggplant type 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 3.27 g of the product, with a yield of 90%. MS:m / z455([M+H] + ).

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Abstract

The invention relates to substituted tetrahydronaphthalene amide compound as shown in a general formula I (in the Specification), pharmaceutically acceptable salt thereof, and a preparation method and application. The substituted tetrahydronaphthalene amide compound can be used as an antitumor drug, the invention also provides a preparation method of compounds similar to the substituted tetrahydronaphthalene amide compound and pharmaceutical compositions containing the compounds, and in vitro and in vivo anti-tumor effect research results and acute toxicity research results. The substituted benzo-cyclic amide compound as the antitumor drug, has better antitumor activity and safety, particularly resists imatinib mesylate resistance tumors, can be applied to curing tumors, such as leukemia, gastrointestinal stromal tumor, lung cancer, colon cancer, ovarian cancer and kidney cancer, is wide in therapeutic window, and as antitumor agent, the compound has high application value in the field of medicine.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a substituted tetrahydronaphthalene amide compound which inhibits the growth of tumor cells and exhibits 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 phosphoryl...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04C07D213/56A61K31/5025A61K31/5377A61K31/437A61K31/496A61K31/4985A61P35/00A61P35/02
CPCC07D213/56C07D471/04C07D487/04
Inventor 陈烨王洋刘晶赵楠宋诗博印丽丽
Owner LIAONING UNIVERSITY
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