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Quinoline compound as well as preparation method, pharmaceutical composition and application thereof

A compound and pharmaceutical technology, applied in the field of medicinal chemistry, which can solve problems such as irreversible damage to the nervous system

Active Publication Date: 2020-10-16
瀚海新拓(杭州)生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the results of toxicology tests show that taking hydroxychloroquine for a long time can cause retinopathy and irreversible damage to the nervous system

Method used

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  • Quinoline compound as well as preparation method, pharmaceutical composition and application thereof
  • Quinoline compound as well as preparation method, pharmaceutical composition and application thereof
  • Quinoline compound as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0279] Embodiment 1: the synthesis of compound S1

[0280] (R)-2-((4-((7-chloroquinolin-4-yl)amino)pentyl)(ethyl)amino)ethyl dimethyl phosphate

[0281]

[0282]Add DCM (10mL) to compound 2 (500mg, 1.49mmol), cool to 0°C, add compound 1 (215mg, 1.49mmol) to the above suspension, then add triethylamine (0.25mL, 1.64mmol) . The temperature of the reaction solution was raised to room temperature, and the reaction was stirred for 3h. The solvent was distilled off under reduced pressure, and purified by column chromatography to obtain compound S1 (370 mg, 56%). 1 H NMR (500MHz, Chloroform-d) δ8.48(d, J=5.7Hz, 1H), 7.87(d, J=2.3Hz, 1H), 7.79(d, J=8.4Hz, 1H), 7.26(dd ,J=8.4,2.2Hz,1H),7.05(d,J=5.7Hz,1H),4.51(d,J=9.3Hz,1H),4.10(ddt,J=11.2,8.6,6.5Hz,1H) ,4.00(ddt,J=11.2,8.6,6.5Hz,1H),3.85–3.76(m,1H),3.73(d,J=11.0Hz,6H),2.90(dt,J=12.9,6.4Hz,1H ),2.73(dt,J=12.9,6.5Hz,1H),2.67–2.58(m,1H),2.61–2.51(m,2H),2.52–2.43(m,1H),1.67–1.54(m,1H ),1.57–1.51(m,1H),1.51(ddt,J=6.2,2.7,1.5Hz,1H),...

Embodiment 2

[0284] Embodiment 2: the synthesis of compound S2

[0285] (R)-2-((4-((7-chloroquinolin-4-yl)amino)pentyl)(ethyl)amino)ethyl diethyl phosphate

[0286]

[0287] 1 H NMR (300MHz, DMSO-d 6 )δ8.48(d, J=5.7Hz, 1H), 7.87(d, J=2.3Hz, 1H), 7.79(d, J=8.4Hz, 1H), 7.27(dd, J=8.4, 2.2Hz, 1H), 7.04(d, J=5.5Hz, 1H), 4.51(d, J=9.3Hz, 1H), 4.22–3.94(m, 6H), 3.62–3.51(m, 1H), 3.01(dt,J =12.7,6.4Hz,1H),2.77–2.45(m,5H),1.67–1.56(m,1H),1.57–1.46(m,2H),1.50–1.40(m,1H),1.37–1.30(m ,6H),1.14(d,J=6.2Hz,3H),1.06(t,J=7.2Hz,3H). 13 C NMR (125MHz, DMSO-d 6 )δ145.91,145.70,143.75,131.71,127.08,125.07,123.75,123.18,99.76,64.87,64.83,64.27,64.22,54.30,53.95,53.90,48.27,47.57,31.56,24.31,20.39,16.10,16.06,12.06.

Embodiment 3

[0288] Embodiment 3: the synthesis of compound S3

[0289] (R)-2-((4-((7-chloroquinolin-4-yl)amino)pentyl)(ethyl)amino)ethylbis(2,2,2-trichloroethyl)phosphate

[0290]

[0291] 1 H NMR (300MHz, DMSO-d 6 )δ8.45(d, J=5.7Hz, 1H), 7.87(d, J=2.1Hz, 1H), 7.79(d, J=8.4Hz, 1H), 7.27(dd, J=8.4, 2.2Hz, 1H), 7.00(d, J=5.5Hz, 1H), 5.03(dd, J=9.3, 8.4Hz, 2H), 4.80(dd, J=9.3, 8.5Hz, 2H), 4.45(d, J=9.3 Hz, 1H), 4.09(ddt, J=11.2, 8.6, 6.5Hz, 1H), 3.99(ddt, J=11.0, 8.4, 6.4Hz, 1H), 3.62–3.50(m, 1H), 3.02(dt, J=12.9,6.5Hz,1H),2.71(dq,J=12.1,7.2Hz,1H),2.60–2.40(m,4H),1.69–1.57(m,1H),1.58–1.39(m,3H) ,1.13(d,J=6.2Hz,3H),1.05(t,J=7.2Hz,3H). 13 C NMR (125MHz, DMSO-d 6 )δ146.03,145.94,143.98,131.37,127.13,124.66,123.65,123.18,99.76,95.77,95.72,70.77,70.72,70.68,64.93,64.88,54.34,53.96,53.91,48.27,47.57,31.55,24.32,20.35,12.03 .

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Abstract

The invention discloses a compound shown as a general formula I, pharmaceutically acceptable salt or metabolite of the compound, and a preparation method, a pharmaceutical composition and applicationof the compound. The compound shown in the general formula I, the pharmaceutically acceptable salt thereof or the metabolite thereof has a good treatment effect on virus infection, has small toxic andside effects, and can be used for preventing or treating virus infection.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a quinoline compound, its preparation method, pharmaceutical composition and application. Background technique [0002] Hydroxychloroquine is an antimalarial drug that has attracted much attention in the past 50 years. The sulfate form of hydroxychloroquine, namely hydroxychloroquine sulfate, is currently one of the most commonly used drugs for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism research experiments, it has been shown that hydroxychloroquine has anti-inflammatory and immunomodulatory activities, which can reduce the production of inflammatory factors. For example, in vitro experiments have shown that hydroxychloroquine can inhibit the production of interleukin 1 (IL-1), interleukin 6 (IL-2), tumor necrosis factor (TNF) and interferon gamma (IFN gamma) in monocytes. In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/60A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61K31/675
CPCC07F9/60A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22Y02A50/30
Inventor 张霁蒋晟
Owner 瀚海新拓(杭州)生物医药有限公司