S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application

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

Inactive Publication Date: 2012-07-25
陈烨 +1
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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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  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application
  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application
  • S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1: (S)-N-{4-methyl-3-[(4-pyridin-3 base)pyrimidine-2-amino]phenyl}-5-(4-methylpiperazin-1-yl )-5,6,7,8-tetrahydronaphthalene-2-amide preparation

[0091]

[0092] Step A: Synthesis of (S)-methyl 5-hydroxy-5,6,7,8-tetralin-2-carboxylate

[0093]

[0094] Add 1 ml of 1.0 M (R)-2-methyl-CBS-oxazoborane (1 mmol) toluene solution, 10 ml of borane-N, N-diethylaniline complex ( 10.5 mmol) toluene solution, the mixed solution was heated to 30°C, and at this moment, 30 ml of toluene-diluted 5-carbonyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (2.04 g, 10 mmol), the dropwise addition was completed within half an hour, and after continuing to stir for 2 hours at 30°C, it was cooled to room temperature, 5 milliliters of methanol solution was added to the reaction solution, and after stirring for 10 minutes, 15 milliliters of 1N hydrochloric acid aqueous solution was slowly added, and the mixture was Stir for 20 minutes, then extract with 100 ml of...

Embodiment 2

[0105] Example 2: (R)-N-{4-methyl-3-[(4-pyridin-3 base)pyrimidine-2-amino]phenyl}-5-(4-methylpiperazin-1-yl )-5,6,7,8-tetrahydronaphthalene-2-amide preparation

[0106]

[0107] Step A: Synthesis of (R)-methyl 5-hydroxy-5,6,7,8-tetralin-2-carboxylate

[0108]

[0109] Dissolve 5 carbonyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate methyl ester (3.06 g, 15 mmol) in 20 ml of tetrahydrofuran solution, add active Molecular sieve 5 g, N 2 Slowly add 1.5ml of 1.0M (S)-2-methyl-CBS-oxazoborolane (1.5mmol) toluene solution dropwise at -20°C under protection, and then add borane dimethyl sulfide complex (1.14 g, 15 mmol) in 5 ml of dry tetrahydrofuran solution, after 20 minutes of dropwise addition, stirred at -15 to 20°C for 1 hour, carefully quenched the solution with 20 ml of methanol solution, raised to room temperature and continued to stir for 12 After 1 hour, 1.92 g of the product was obtained by column chromatography under reduced price vacuum drying, and the yield wa...

Embodiment 3

[0120] Example 3 (S)-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidine-2-amino]phenyl}-5-(3-methylimidazolidin-1-yl) -Synthesis of 5,6,7,8-tetrahydronaphthalene-2-amide

[0121]

[0122] Step A: Synthesis of 1-methylimidazolidine

[0123]

[0124] N-methylethylenediamine (1 g, 13.5 mmol) was added to formaldehyde (0.4 g, 13.5 mmol), potassium carbonate (6.4 g, 47.2 mmol), magnesium sulfate (5.6 g, 47.2 mmol) in 25 mL of chloroform suspension, stirred at room temperature for 18 hours, filtered, the filtrate was concentrated under reduced pressure, purified by neutral alumina column chromatography under the condition of dichloromethane:methanol=9:1 to obtain 0.81 g of product 1-methylimidazolidine, Yield 70%, MS(M+1)=87.11.

[0125] Step B: Synthesis of (S)-methyl 5-(3-methylimidazolidin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0126]

[0127] Dissolve (S)-methyl 5-chloro-5,6,7,8-tetralin-2-carboxylate (2.41 g, 10 mmol) in 20 ml of DMF solvent, add potassium carbo...

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Abstract

The invention relates to a novel compound R1 represented by general formula I. The compound R1 is an S-type or R-type tetrahydro-naphthalene amides compound, or a pharmaceutically acceptable salt or pro-drug of the compound, and is used as an antitumor drug. The invention also provides a preparation method of the compound, and a pharmaceutical composition containing the compound, and an antitumor research in vitro. The antitumor drug R1 obtained by the invention is the S-type or R-type tetrahydronaphthalene amides compound, is better in antitumor activity and safety and can be applied to treating tumors such as leukemia, lung cancer, liver cancer, colon cancer and ovarian cancer, so that the therapeutic window is wide, and the compound as an antitumor agent in the medicine field is very valuable.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts or prodrugs thereof which inhibit tumor cell growth and exert antitumor effects, as well as their preparation method and application. 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 ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D239/42A61K31/506A61P35/00A61P35/02
Inventor 陈烨王洋林小琳
Owner 陈烨
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