Quinoline derivative, preparation method and application thereof

A quinoline and compound technology, applied in the field of medicine, can solve the problems of increasing the hidden danger of drug use, reducing the effective blood drug concentration, increasing the adverse drug reaction and the like

Inactive Publication Date: 2016-11-30
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such as the interaction between rifampicin (RIF) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), which reduces the effective blood concentration of the latter; 3) antiviral and anti-tuberculosis treatment Both require long-term medication and combined treatment, which increases the adverse reactions of drugs, and the overlapping toxic and side effects increase the potential safety hazards of medication

Method used

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  • Quinoline derivative, preparation method and application thereof
  • Quinoline derivative, preparation method and application thereof
  • Quinoline derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0318] Preparation of 3-(4-N,N-dimethylaminomethyl)phenyl-2-(1-naphthylmethoxy)-6-bromoquinoline (1)

[0319]

[0320] (1-1) Preparation of intermediate 3-iodo-6-bromoquinoline

[0321]

[0322]Dissolve 6-bromoquinoline (5.00g, 24.03mmol) in 40mL of acetic acid, add N-iodosuccinimide (5.95g, 26.44mmol) in batches, stir and react at 80°C for 20 hours, add 150mL of water , extracted three times with dichloromethane, combined the organic phases, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and column chromatography (petroleum ether / ethyl acetate 4:1) gave 3.80 g of yellow solid, yield: 47.37%. 1 H NMR (300MHz, CDCl 3 )δ9.03(d, J=2.1Hz, 1H), 8.45(d, J=1.5Hz, 1H), 7.93(d, J=9.0Hz, 1H), 7.87(d, J=2.1Hz, 1H) ,7.79(dd,J=9.0,2.1Hz,1H).m / z[M+H] + : 333.8715.

[0323] (1-2) Preparation of intermediate N-oxo-6-bromo-3-iodoquinoline

[0324]

[0325] Dissolve 6-bromo-3-iodoquinoline (3.40g, 10.21mmol) in 40mL of chloroform, add 3-chloroperoxy...

Embodiment 2

[0336] Preparation of 3-((4-N-methylpiperazine)phenyl)-2-(1-naphthylmethoxy)-6-bromoquinoline (2)

[0337]

[0338] Dissolve 2-(1-naphthylmethoxy)-6-bromo-3-iodoquinoline (100mg, 0.21mmol) in 3mL of toluene, add Pd(PPh 3 ) 4 (13mg, 0.01mmol), 1mL aqueous solution of sodium carbonate (43mg, 0.41mmol), 4-(N-methylpiperazine) phenylboronic acid (55mg, 0.25mmol), stirred at 80°C for 10 hours, added 5mL of water, Chloromethane was extracted three times, and the combined organic phases were subjected to column chromatography (dichloromethane / methanol 20:1) to obtain 89 mg of a yellow solid with a yield of 78.90%. m.p.:134-135℃.1H NMR (400MHz, Acetone-d 6 )δ8.26(d, J=8.5Hz, 1H), 8.14(s, 1H), 8.10(d, J=2.2Hz, 1H), 7.96(d, J=7.6Hz, 1H), 7.91(d, J=8.3Hz, 1H), 7.84(d, J=8.9Hz, 1H), 7.80–7.74(m, 2H), 7.63–7.59(m, 1H), 7.59–7.53(m, 3H), 7.49(dd ,J=8.2,7.1Hz,1H),6.96–6.87(m,2H),6.09(s,2H),3.24–3.15(m,4H),2.50–2.41(m,4H),2.24(s,3H ).m / z[M+H] + :538.1482.

Embodiment 3

[0340] Preparation of 3-(4-(morpholine-1-methyl)phenyl)-2-(1-naphthylmethoxy)-6-bromoquinoline (3)

[0341]

[0342] Dissolve 2-(1-naphthylmethoxy)-6-bromo-3-iodoquinoline (150mg, 0.31mmol) in 3mL of toluene, add Pd(PPh 3 ) 4 (18mg, 0.02mmol), 2mL aqueous solution of sodium carbonate (97mg, 0.92mmol), 4-(4-morpholine-1-methyl) phenylboronic acid (81mg, 0.26mmol), stirred at 80°C for 10 hours, added water 5 mL was extracted three times with dichloromethane, the organic phases were combined, and column chromatography (dichloromethane / methanol 15:1) gave 122 mg of a yellow solid with a yield of 76.15%. 1 H NMR (600MHz, Acetone-d 6 )δ8.22(d, J=8.4Hz, 1H), 8.17(s, 1H), 8.09(d, J=2.3Hz, 1H), 7.94(dd, J=8.3, 0.9Hz, 1H), 7.88( d,J=8.3Hz,1H),7.85(d,J=8.9Hz,1H),7.78(dd,J=8.8,2.3Hz,1H),7.71(d,J=6.5Hz,1H),7.61– 7.56(m,3H),7.56–7.52(m,1H),7.45(dd,J=8.2,7.0Hz,1H),7.30(d,J=8.3Hz,2H),6.06(s,2H),3.59 (t,J=4.6Hz,4H),3.45(s,2H),2.36(br.s,4H).m / z[M+H] + :539.1293.

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Abstract

The invention discloses a new quinoline derivative shown as the structural general formula (I) in the specification, a preparation method thereof, pharmaceutical compositions containing the same, and application thereof as an antituberculosis drug. The invention also relates to physiologically acceptable inorganic acid or organic acid composed salts, N-oxide. The compounds have excellent antituberculosis activity, and can be used as drugs for treatment of tuberculosis including multidrug resistant tuberculosis. (formula (I)).

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a new class of quinoline derivatives, a preparation method thereof, a pharmaceutical composition containing them, and their use as anti-tuberculosis drugs. Background technique [0002] Tuberculosis is a chronic infectious disease that poses a serious threat to human health and life. It can invade many organs, and pulmonary tuberculosis is most common in the lungs. In the past 30 years, tuberculosis has been well controlled in industrialized countries, but currently tuberculosis is still the second most infectious disease after AIDS. In the past 10 years, due to the prevalence of multidrug-resistant tuberculosis strains and AIDS-associated tuberculosis infection, the anti-tuberculosis research has attracted human attention again. In 2012, there were 8.6 million new tuberculosis cases worldwide, of which 13% were HIV-positive, about 450,000 of the new cases were multidrug-resistan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/227C07D401/10C07D401/04C07D401/12C07D215/36C07D215/38C07D413/10A61K31/47A61K31/5377A61K31/496A61K31/4709A61P31/04A61P31/06
CPCC07D215/227C07D215/36C07D215/38C07D401/04C07D401/10C07D401/12C07D413/10
Inventor 何春娴崔华清尹大力
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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