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Preparation method and application of compound

A technology of a drug and ethoxyphenoxy, applied in the field of medicine, can solve problems such as no reports on synthesis methods and pharmacological effects, no reports on SphK1 inhibitors in literature, etc.

Active Publication Date: 2021-09-14
SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The current published literature only has the physical and chemical properties of the compound, and there are no reports on its synthesis method and pharmacological efficacy, let alone its use as a SphK1 inhibitor

Method used

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  • Preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl ) (methyl) amino) propan-2-ol (SAMS10) synthesis

[0029]

[0030] 2-((2-ethoxyphenoxy)methyl)oxirane (194mg, 1.0mmol) and 1-(3-methoxy-4-(2-(4-methylpiperidine- 1-yl)ethoxy)phenyl)-N-methylmethylamine (354mg, 1.2mmol) was dissolved in isopropanol (15mL), under nitrogen protection, a catalytic amount of pyridine (8.0μL, 0.1mmol) was added , heated to reflux for 6h, TLC detection (developing solvent: dichloromethane-methanol = 10:1) disappearance of raw materials. The reaction solution was diluted with ethyl acetate, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: dichloromethane-methanol=20 :1), a colorless oil (437.9mg, 90%) was obtained. 1 H NMR (CDCl ...

Embodiment 2

[0031] Example 2 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (Methyl)amino)propan-2-ol (abbreviated as SAMS10 in the experiment) for the antagonistic activity of SphK1 and SphK2 kinases

[0032] 1. Experimental instruments and materials

[0033] The multifunctional microplate reader used in the experiment is the SpectraMax M5 multifunctional microplate reader produced by Molecular Devices, USA.

[0034] Table 1 Experimental reagents

[0035]

[0036] 2. Experimental method

[0037] First, 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)( Methyl)amino)propan-2-ol was prepared into 10mM mother solution with DMSO, dissolved by ultrasonic acceleration, and then DMSO and kinase buffer (pH 7.4, 40mM Tris, 10mM MgCl 2 , 0.1g / L BSA, 1mM DTT, 10μM ATP) were serially diluted, and the final concentration of DMSO was less than 1%. The concentration in the initial screening was set to 10 μM, and the IC was determined 5...

Embodiment 3

[0051] Example 3 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (Methyl)amino)propan-2-ol (referred to as SAMS10 in the experiment) to test the growth inhibitory activity of tumor cells

[0052] 1. Experimental instruments and materials

[0053] The multifunctional marker analyzer used in the experiment is Victor 1420 model produced by Perkin Elmer Company of the United States.

[0054] Table 4 Experimental Reagents

[0055]

[0056] Cell lines: human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cell lines, all purchased from the Cell Bank of the Chinese Academy of Sciences, using DMEM containing 15% fetal bovine serum ( High Glucose) medium, placed at 37 ° C, 5% CO 2 Cultured in an incubator.

[0057] 2. Experimental method

[0058] 2.1 MTT experimental principle and preparation method

[0059] MTT is an oxidative yellow dye with a chemical name of 3-(4,5-dimethyl-2-thiazolyl)-2,5...

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Abstract

The invention relates to the technical field of medicines, and relates to a preparation method and new application of a compound. In particular to a preparation method of a compound 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethyoxyl)benzyl)(methyl)amino)propan-2-ol and application of the compound in preparation of drugs for preventing and / or treating diseases related to SphK1 dysfunction. The invention finds that 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethyoxyl)benzyl)(methyl)amino)propan-2-ol has the effect of selectively inhibiting SphK1 for the first time, and can be used for preventing and / or treating diseases related to SphK1 dysfunction.

Description

technical field [0001] The present invention relates to the field of medical technology, and relates to a new application of a compound, in particular to a compound 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4 -Use of methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol in the preparation of drugs for preventing and / or treating diseases related to SphK1 dysfunction. Background technique [0002] Sphingomyelin (sphingomyelin) is an important component of eukaryotic cell membranes, which can be catalyzed and metabolized by a variety of biological enzymes in turn to produce ceramide (Cer), sphingosine (Sphingosine, Sp) and sphingosine-1-phosphate (sphingosine 1-phosphate, S1P). These three metabolites serve as biological effector molecules and have different roles in biology. Cer and Sp, as negative regulators, can mediate cell growth arrest or apoptosis. S1P, which is opposite to their functions, plays a role in promoting cell proliferation and differentiation. On the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22A61K31/44A61P35/00A61P29/00
CPCC07D211/22A61P35/00A61P29/00
Inventor 刘波姚庆强陈海蛟崔学艳智英李莹汪海洋崔正国刘效祥丁天地张飞鹏杨皓然
Owner SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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