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

A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as life-threatening and serious conditions of patients, and achieve the effect of wide therapeutic window, broad anti-cancer spectrum, excellent anti-tumor activity and safety

Active Publication Date: 2011-12-28
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in some patients, the condition is serious and even life-threatening

Method used

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  • Antineoplastic drug tetrahydronaphthalene amide compound and pharmaceutically acceptable salt thereof, preparation method and application thereof
  • Antineoplastic drug tetrahydronaphthalene amide compound and pharmaceutically acceptable salt thereof, preparation method and application thereof
  • Antineoplastic drug tetrahydronaphthalene amide compound and pharmaceutically acceptable salt thereof, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of compound 1 and pharmaceutically acceptable salt thereof

[0053] (one) N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(4-methylpiperazin-1-yl)-5,6,7, The preparation of 8-tetrahydronaphthalene-2-amide (compound 1), the structural formula of compound 1 is as follows:

[0054]

[0055] Step A: Synthesis of 6-Hydroxy-1-tetralone

[0056]

[0057] 6-Methoxyl-1-tetralone (17.6 g, 100 mmol) was reacted in 100 ml of 48% hydrogen bromide solution at 100°C for 24 hours and then cooled to room temperature. Solid precipitated, filtered out the solid and rinsed with 5% aqueous sodium bicarbonate solution, then washed with deionized water until neutral, dried, and the crude product was purified with silica gel column, and eluted with ethyl acetate:n-hexane=1:5 to obtain the product 13.9 grams, yield 86.0%. MS(M+1)=163.14.

[0058] Step B: Synthesis of 5-carbonyl-5,6,7,8-tetrahydronaphthalene-2-trifluoromethanesulfonate

[0059...

Embodiment 2

[0087] Example 2 4-{6-[({4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl]-1,2,3,4 -Preparation of tert-butyl tetrahydronaphthalene-1-yl}piperazine-1-carboxylate

[0088] Its structural formula is as follows:

[0089]

[0090] Step A: Synthesis of 4-[6-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]piperazin-1-yl-carboxylic acid tert-butyl ester

[0091]

[0092] Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate (22.4 g, 100 mmol), potassium carbonate (27.8 g, 200 mmol), piperazine-1-carboxylic acid Tert-butyl ester (20.5 g, 110 mmol) was added to 300 ml of DMF, stirred at 40°C for 5 hours, the insoluble matter was filtered, and the filtrate was added to 800 ml of ethyl acetate, washed with brine (3×800 ml), The organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After silica gel column chromatography, the product was eluted under the condition of ethyl...

Embodiment 3

[0101] Example 3 N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(piperazin-1-yl)-5,6,7,8 -preparation of tetrahydronaphthalene-2-amide

[0102] Its structural formula is as follows:

[0103]

[0104] 4-{6-[({4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl]-1,2,3,4-tetra Hydronaphthalen-1-yl}piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 3 mmol) was dissolved in 10 ml of a mixed solution of trifluoroacetic acid:dichloromethane=1:4. After stirring at room temperature for half an hour, 20 ml of aqueous sodium carbonate solution was added to adjust the pH to weakly alkaline, the organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.48 g of the product, with a yield of 95.1%.

[0105] MS(M+1)=520.22. 1 H-NMR (DMSO- d 6 ppm): δ 10.03 (s, 1H); 9.22 (s, 1H); 8.96(s,1H); 8.64(d, J=4.8 Hz, 1H); 8.52(d, J=5.2 Hz, 1H); 8.36 (d, J=8.0 Hz, 1H); 8.02(...

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Abstract

The invention relates to new antitumor medicament compounds, namely tetralin amide compounds as shown in a general formula I or pharmaceutically acceptable salts thereof used as an antitumor medicament. The invention also provides a preparation method of the compounds and medicament compositions containing the compounds as well as in vitro and in vivo antitumor effect results and acute toxicity researches thereof. The antitumor medicament, namely tetralin amide compounds obtained by the preparation method, has better antitumor activity and safety, and can be applied to treatment of tumors such as leukemia, lung cancer, colon cancer, ovarian cancer, renal cancer and the like, thus the tetralin amide compounds have wide treatment ranges and also have extremely high application value in the medicine field as antitumor agents.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a tetrahydronaphthylamide 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 phosphorylation at a conce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D239/42A61K31/506A61P35/00
CPCC07D239/42A61K31/496A61K31/4406A61K31/506C07D401/04A61P35/00
Inventor 陈烨王洋卢红邓晶晶李文君徐利锋
Owner LIAONING UNIVERSITY
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