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Pyrimidine-quinolone hybrids, and preparation method and application thereof

A technology of quinolones and hybrids, which is applied in the field of pyrimidine-quinolones hybrids and their preparation, can solve the problems of drug toxicity and side effects limiting clinical application, and achieve good broad-spectrum anti-tumor activity, novel structure, and good antibacterial activity Effect

Active Publication Date: 2018-09-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, although dozens of drugs have been approved by the FDA for the clinical treatment of malignant tumors, most drugs have serious side effects that severely limit their clinical application.

Method used

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  • Pyrimidine-quinolone hybrids, and preparation method and application thereof
  • Pyrimidine-quinolone hybrids, and preparation method and application thereof
  • Pyrimidine-quinolone hybrids, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of intermediate 1

[0045]

[0046]Dissolve 2,4-difluorobenzoyl chloride (18.1mmol), ethyl 3-(N,N-dimethylamino)acrylate (18.1mmol), and triethylamine (27.1mmol) in 30mL of toluene, and stir at 90°C for 4h , concentration, and column chromatography to obtain intermediate 1. Yield 65%, 1 H NMR (400MHz, CDCl 3 )δ0.95-0.99(t, J=7.2Hz, 3H), 2.89(s, 3H), 3.31(s, 3H), 3.98-4.03(q, J=7.2Hz, 2H), 6.74-6.80(m ,1H), 6.89-6.93(m,1H), 7.62-7.68(m,1H), 7.79(s,1H).

Embodiment 2

[0047] Embodiment 2: the synthesis of intermediate 4

[0048]

[0049] Intermediate 1 (3mmol) and various substituted amines (3.6mmol) were stirred in THF (5mL) at 50°C for 3h and concentrated to obtain Intermediate 2, which was directly used in the next reaction without separation and purification.

[0050] Intermediate 2 (1.5mmol), K 2 CO 3 (2.3mmol) was added to DMF (10mL), stirred overnight at 60-90°C, cooled, poured into ice water, filtered, washed with water to obtain intermediate 3, which was directly used in the next reaction without separation and purification.

[0051] Dissolve intermediate 3 (1 mmol) in THF (3 mL), add 10% NaOH aqueous solution (3 mL), stir at 50 °C for 0.5-5 h, cool, concentrate, adjust pH to 2 with 5% hydrochloric acid, filter, wash with water, Intermediate 4 was obtained by drying.

[0052] 4a(R 1 =t-Butyl): yield 70%; 1 H NMR (400MHz, DMSO-d 6 )δ14.81(s,1H),9.13(s,1H),8.66(dd,J=9.0,6.8Hz,1H),7.74(dd,J=11.8,2.2Hz,1H),7.32(td,J =7.3,2.2H...

Embodiment 3

[0056] Embodiment 3: the synthesis of intermediate 6

[0057]

[0058] Intermediate 4 (1.0 mmol) was dissolved in DMSO (2 mL), 2,4-dimethoxybenzylamine (3.0 mmol) was added, N 2 React at 85°C for 6 h under protection, pour into ice water after cooling, and adjust the pH to about 5 with 6N HCl, filter, wash with ethanol, and dry to obtain intermediate 5, which is directly used in the next step without further purification.

[0059] Intermediate 5 (5.0 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (15.0 mmol) was added, and stirred at room temperature for 5 h. After the reaction was completed, poured into ice water (250 mL) and stirred vigorously for 20 min, and filtered. After the filter cake was dried, it was poured into dichloromethane (500 mL) and sonicated for 10 min, and the insoluble matter was removed by filtration, and the dichloromethane was removed from the filtrate under reduced pressure to obtain intermediate 6.

[0060] Intermediate 6 (1...

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Abstract

The invention specifically relates to pyrimidine-quinolone hybrids, and a preparation method and application thereof, belonging to the technical field of medicines. The pyrimidine-quinolone hybrids are prepared through hybridization of two structures, i.e., pyrimidine compounds and quinolone compounds. The invention also provides medicinal salts, hydrates and solvates of the hybrids, polycrystalsor eutectics of the hybrids, and precursors and derivatives with same biological functions as the hybrids. The invention also provides a preparation method for the hybrids. Pharmacological experimentresults show that the hybrids have substantial antineoplastic activity and antibacterial activity and can be used for preparing related drugs used for treating cancer and resisting bacteria.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a pyrimidine-quinolone hybrid compound and a preparation method and application thereof. Background technique [0002] At present, malignant tumor is one of the major fatal diseases that seriously threaten human life and health. So far, although dozens of drugs have been approved by the FDA for the clinical treatment of malignant tumors, most of them have serious side effects that severely limit their clinical application. Therefore, it is imminent to use new methods of drug design to develop new anti-tumor drugs with high efficiency and low toxicity. [0003] In addition, with the widespread use of antibacterial drugs, bacterial resistance is also increasing. Methicillin-resistant Staphylococcus aureus (MRSA) is a common and highly virulent bacterium in clinical practice. Since its discovery, the infection has spread almost all over the world, and it has become on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/506A61P35/00A61P31/04
CPCA61P31/04A61P35/00C07D401/12
Inventor 何秋琴范仁华宋润喆
Owner FUDAN UNIV
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