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Preparation method of 2-substituted arylethenyl-N-methylated quinoline derivative and application of 2-substituted arylethenyl-N-methylated quinoline derivative in preparation of drug for treating Alzheimer disease

A technology for methylating quinoline and arylvinyl, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problem that the pathogenesis is not fully understood, and achieve the effect of inhibiting Ab aggregation, high medical value, and broad market prospects

Active Publication Date: 2013-10-02
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

So far, its pathogenesis has not been fully understood

Method used

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  • Preparation method of 2-substituted arylethenyl-N-methylated quinoline derivative and application of 2-substituted arylethenyl-N-methylated quinoline derivative in preparation of drug for treating Alzheimer disease
  • Preparation method of 2-substituted arylethenyl-N-methylated quinoline derivative and application of 2-substituted arylethenyl-N-methylated quinoline derivative in preparation of drug for treating Alzheimer disease
  • Preparation method of 2-substituted arylethenyl-N-methylated quinoline derivative and application of 2-substituted arylethenyl-N-methylated quinoline derivative in preparation of drug for treating Alzheimer disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Synthesis of 2-methyl-4-hydroxyquinoline (compound 1)

[0032] Mix 14.5 g (155.3 mmol) aniline with 20.2 g (55.3 mmol) ethyl acetoacetate, add PPA and heat to 90 oC After 2 hours, the reaction was carried out at 130°C for 2 hours. The reaction mixture was then poured into water while hot to hydrolyze the excess PPA. The pH value was adjusted to neutral with hydrochloric acid and a solid was precipitated, which was collected by filtration to obtain a yellow solid. Yield: 77%;

[0033] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 11.58 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 7.61-7.56 (m, 1H), 7.560-7.47 (m, 1H), 7.27-7.23 (m, 1H), 2.33(s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ: 176.67, 149.58, 140.08, 131.35, 124.73, 124.46, 122.61, 117.69, 108.33, 19.40; MS (ESI + APCI) m / z: 160.1 [M+H] +1 .

[0034]

Embodiment 2

[0035] Example 2: Synthesis of 2-methyl-4 chloroquinoline (compound 2)

[0036] Mix 2.5 g (88.9 mmol) 2-methyl-4-hydroxyquinoline and 125 mL phosphorus oxychloride (POCl3) at 120 o C reacted for 2h. Then, the reaction mixture was poured into water to hydrolyze excess POCl3 while still hot, and the pH was adjusted to neutrality with hydrochloric acid to obtain a gray solid, which was collected by filtration.

[0037] 1 H NMR (400 MHz, DMSO-d6) δ: 8.14 (d, 1H, J = 8.0 Hz), 8.02 (d, 1H, J= 8.0 Hz), 7.72-7.68 (m, 1H), 7.56-7.52 (m, 1H), 7.34 (s, 1H), 2.69 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ: 153.53, 143.27, 137.30, 125.10, 123.58, 121.38, 119.41, 118.60, 116.63, 19.78; MS (ESI + APCI) m / z: 179.1 [M+H] +1 .

[0038]

Embodiment 3

[0039] Example 3: Synthesis of 1,2-dimethyl-4-chloro (iodo) quinoline iodide (chloro) compound (compounds 3, 4)

[0040] 28.0 g of intermediate 2-methyl-4-chloroquinoline derivative (compound 2), 50 mL of sulfolane and 11.2 mL of methyl iodide were mixed and sealed in a 250 mL sealed tube, and then placed in 80 o The reaction was carried out in the oil bath of C overnight, and a large amount of purple solid appeared in the reaction solution. Stop the reaction and cool down to remove excess methyl iodide (Note: methyl iodide is highly toxic, be careful not to inhale or touch the skin when removing), then add 250 mL of anhydrous ether was stirred, the sulfolane was removed by suction filtration, and finally washed with anhydrous ethanol to obtain a yellow solid. The yield is 90%;

[0041] 3: 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.67 (d, 1H, J = 8.0 Hz), 8.56 (d, 1H, J = 12.0 Hz ), 8.54 (s, 1H,), 8.33 (t, 1H, J = 8.0 Hz), 8.12 (t, 1H, J = 8.0 Hz), 4.44 (s, 3H), 3.08 (s, ...

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Abstract

The invention relates to the field of medicinal chemistry and pharmacotherapeutics and provides a 2-substituted arylethenyl-N-methylated quinoline derivative, a synthesis method thereof and an application of the 2-substituted arylethenyl-N-methylated quinoline derivative to the preparation of a drug for treating Alzheimer disease. The 2-substituted arylethenyl-N-methylated quinoline derivative has the chemical formula shown in the specification, wherein R1 in the formula is hydrogen, methylpiperazine, piperidine, morpholine, ethoxylpiperazine, dimethylaminoethylpiperazine or dimethylaminopropylpiperazine; R2 is para-substituted chlorine, fluorine, hydroxyl, methoxyl, dimethylamino, diethylin, methylpiperazine and morpholine, or ortho-substituted hydroxyl and methoxyl or meta-substituted methoxyl and nitro; R4 is hydrogen, chlorine, fluorine, hydroxyl, methoxyl, dimethylamino, diethylin, methylpiperazine or morpholine; R2 and R6 are hydrogen, hydroxyl or methoxyl; R3 and R5 are hydrogen, methoxyl or nitro. Experiments prove that the 2-substituted arylethenyl-N-methylated quinoline derivative provided by the invention has anticholinesterase activity, anti-Abeta aggregation and antioxidant activity.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and more specifically, relates to a 2-substituted arylvinyl-N-methylated quinoline derivative and its application in the preparation of multifunctional anti-Alzheimer's disease drugs. Background technique [0002] AD is a neurodegenerative disease that is very common in the elderly and has become the fourth leading cause of death in the elderly after tumors, heart disease, and cerebrovascular diseases. So far, its pathogenesis has not been fully understood. However, after years of research, we know that its production is related to many factors. For these factors, scientific researchers have put forward many hypotheses, including the cholinergic theory, the amyloid cascade hypothesis, and the oxidative stress hypothesis. wait. In response to these hypotheses, scientists have also proposed corresponding solutions. The first is the amyloid cascade hypothesis...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D215/14C07D215/12A61K31/4709A61K31/496A61K31/4545A61K31/5377A61K31/47A61P39/06A61P25/28A61P21/04
Inventor 黄志纾古练权刘真权夏春丽吴家强谭嘉恒欧田苗
Owner SUN YAT SEN UNIV
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