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Aminoquinoline compounds, and preparation method and application thereof

An aminoquinoline and compound technology, applied in the field of medicine, can solve the problems of hepatotoxicity, azole drug resistance, clinical application limitation and the like, and achieve the effect of good antifungal activity

Active Publication Date: 2018-12-18
CHENGDU MILITARY GENERAL HOSPITAL OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the inhibitors of CYP51 used in the clinical treatment of deep fungal infections only have one structural type of azoles, but azoles have two major problems of drug resistance and hepatotoxicity, which greatly restrict their clinical application

Method used

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  • Aminoquinoline compounds, and preparation method and application thereof
  • Aminoquinoline compounds, and preparation method and application thereof
  • Aminoquinoline compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1. Preparation of compound A1

[0034] Weigh 3-aminoquinoline (144mg, 1mmol), add 15ml of acetonitrile to dissolve, add N,N-diisopropylethylamine DIPEA (157mg, 1.2mmol) and valeryl chloride (145mg, 1.2mmol) successively, mix well Stir overnight at room temperature.

[0035] After the reaction was completed, the solvent acetonitrile was removed under reduced pressure, an appropriate amount of water (10ml) was added, and the aqueous layer (20ml*3) was extracted with ethyl acetate, and the ethyl acetate layer was washed twice with saline; Ether: ethyl acetate = 1:1 mixed solvent was used as the eluent for column chromatography to obtain 116 mg of the product.

[0036] The hydrogen spectrum of A1 is as follows:

[0037] 1 H NMR (400MHz, CDCl 3 )δ8.83(s,1H),8.77(d,J=2.4Hz,1H),8.02(t,J=12.7Hz,1H),7.92-7.76(m,2H),7.63(t,J=7.6 Hz,1H),7.54(t,J=7.5Hz,1H),2.43(dt,J=30.5,7.5Hz,2H),1.86–1.66(m,2H),1.57-1.34(m,2H),1.01 -0.89(m,3H).

Embodiment 2

[0038] Embodiment 2. Preparation of compound A2

[0039] Weigh 3-aminoquinoline (144mg, 1mmol), add 15ml of acetonitrile to dissolve, add N,N-diisopropylethylamine DIPEA (144mg, 1.1mmol) and hexanoyl chloride (148mg, 1.1mmol) successively, mix well Stir overnight at room temperature.

[0040] After the reaction was completed, the solvent acetonitrile was removed under reduced pressure, an appropriate amount of water (10ml) was added, and the aqueous layer (20ml*3) was extracted with ethyl acetate, and the ethyl acetate layer was washed twice with saline; Ether: ethyl acetate = 1:1 mixed solvent was used as the eluent for column chromatography to obtain 124 mg of the product.

[0041] The hydrogen spectrum of A2 is as follows:

[0042] 1 H NMR (400MHz, CDCl 3 )δ8.79(t, J=9.6Hz, 2H), 8.02(d, J=7.6Hz, 2H), 7.78(d, J=8.2Hz, 1H), 7.57(dt, J=38.4, 7.5Hz, 1H), 2.96(s, 1H), 2.89(s, 1H), 2.52-2.08(m, 2H), 1.78(dd, J=14.1, 7.2Hz, 2H), 1.33(dd, J=23.0, 20.1Hz ,4H),0.90(t,J=6.0Hz,3H...

Embodiment 3

[0043] Embodiment 3. Preparation of compound A3

[0044] Weigh 3-aminoquinoline (144mg, 1mmol), add 15ml of acetonitrile to dissolve, add N,N-diisopropylethylamine DIPEA (144mg, 1.1mmol) and heptanoyl chloride (178mg, 1.2mmol) successively, mix well Stir overnight at room temperature.

[0045] After the reaction was completed, the solvent acetonitrile was removed under reduced pressure, an appropriate amount of water (10ml) was added, and the aqueous layer (20ml*3) was extracted with ethyl acetate, and the ethyl acetate layer was washed twice with saline; Ether: ethyl acetate = 1:1 mixed solvent was used as the eluent for column chromatography to obtain 130 mg of the product.

[0046] The hydrogen spectrum of A3 is as follows:

[0047] 1 H NMR (400MHz, CDCl 3)δ8.91-8.60 (m, 3H), 7.99 (d, J = 8.4Hz, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.59 (dd, J = 8.2, 7.1Hz, 1H), 7.49(t, J=7.5Hz, 1H), 2.39(dt, J=24.0, 7.5Hz, 2H), 1.79-1.54(m, 2H), 1.44-1.08(m, 6H), 0.94-0.68(m, 3H).

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Abstract

The invention relates to the technical field of medicines and especially relates to aminoquinoline compounds, and a preparation method and an antifungal application thereof. The aminoquinoline compounds generally have great antifungal activity and have the potential of development into non-azole antifungal medicines.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of aminoquinoline compounds, a preparation method thereof and an antifungal application thereof. Background technique [0002] The long-term clinical use of broad-spectrum antibiotics, the widespread development of catheter intubation and endoscopic techniques, immunosuppressants and tumor radiotherapy and chemotherapy have caused the destruction of the symbiotic relationship of normal human flora, and the morbidity and mortality of fungal infections, especially deep fungi, are high. The current clinical treatment drugs can not meet the treatment needs, and it is a very urgent problem to find high-efficiency, broad-spectrum and safe antifungal drugs. [0003] Currently, the most clinically studied and most widely used antifungal drugs are lanosterol 14α demethylase (CYP51) inhibitors. Lanosterol 14α demethylase (CYP51), a member of cytochrome P450 superfamily proteins, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/38A61P31/10
CPCA61P31/10C07D215/38
Inventor 吴娟唐辉郑伟车晓颖周小明
Owner CHENGDU MILITARY GENERAL HOSPITAL OF PLA
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