4-hydroxy-2-quinolone-nitrogen-(4-quinazolinone)-3-formamide derivatives

A technology of quinazolinone and formamide, applied in the field of antibacterial drugs

Active Publication Date: 2019-07-23
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Up to now, the compounds involved in this patent have not been reported at home and abroad to inhibit the growth...

Method used

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  • 4-hydroxy-2-quinolone-nitrogen-(4-quinazolinone)-3-formamide derivatives

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Experimental program
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Effect test

Embodiment 1

[0074] Embodiment 1: Preparation and detection of compound XWJ-10

[0075]

[0076] Add 1.64mL (12mmol) of triethylamine to the DMF solution of 2.11g (10mmol) of methyl 2-amino-3,4-dimethoxybenzoate, add hexanoyl chloride (12mmol) dropwise at 0°C, and drop to room temperature The reaction was stirred and reacted for 3 hours. After the reaction was monitored by TLC, the reaction solution was poured into ice water, and a solid was precipitated, which was filtered by suction and dried. The obtained solid was dissolved in absolute ethanol, and 3 mL of 80% hydrazine hydrate (36 mmol) was added, and the reflux reaction was carried out for 8 After cooling for a few hours, the solid was precipitated, filtered with suction, and dried to obtain 1.82 g of the intermediate 3-amino-6,7-dimethoxy-2-pentyl-4-quinazolinone (yield: 62.5%).

[0077] 12.8mL (73.6mmol) of diisopropylethylamine was added to the DMF solution of 10g (61.3mmol) isatoic anhydride, and 9.6g (73.6mmol) ethyl iodide w...

Embodiment 2

[0082] Embodiment 2: Preparation and detection of compound XWJ-1

[0083] Using 2-amino-5-chlorobenzoic acid methyl ester and hexanoyl chloride as starting materials, the synthesis method is the same as that of the intermediate 3-amino-6,7-dimethoxy-2-pentyl-4-quinazolinone , to obtain the intermediate 3-amino-6-chloro-2-pentyl-4-quinazolinone (yield: 72.9%).

[0084] Using 3-amino-6-chloro-2-pentyl-4-quinazolone and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid as starting materials, the synthesis method is the same as the final product XWJ-10 The preparation of 1-ethyl-4-hydroxyl-2-quinolone-nitrogen-(6-chloro-2-pentyl-4-quinazolinone-3-yl)-3-formamide (XWJ-1) .

[0085]

[0086] White solid, yield 19.1%. 1 H NMR (500MHz, DMSO-d 6 )δ8.06(s,1H),8.19(d,J=8.0Hz,1H),7.81(d,J=8.6Hz,1H),7.67(d,J=8.6Hz,1H),7.64(t, J=7.8Hz, 1H), 7.53(d, J=7.9Hz, 1H), 7.24(t, J=7.5Hz, 1H), 4.23(q, J=7.3Hz, 2H), 2.95(t, J= 7.8Hz, 2H), 1.79(p, J=6.9Hz, 2H), 1.41-1.36(m, 4H), 1.19(t, J=7.1Hz,...

Embodiment 3

[0087] Embodiment 3: Preparation and detection of compound XWJ-2

[0088] Using methyl 2-amino-5-bromobenzoate and hexanoyl chloride as starting materials, the synthesis method is the same as that of the intermediate 3-amino-6,7-dimethoxy-2-pentyl-4-quinazolinone , to obtain the intermediate 3-amino-6-bromo-2-pentyl-4-quinazolinone (yield: 63.2%).

[0089] Using 3-amino-6-bromo-2-pentyl-4-quinazolone and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid as starting materials, the synthesis method is the same as the final product XWJ-10 The preparation of 1-ethyl-4-hydroxyl-2-quinolone-nitrogen-(6-bromo-2-pentyl-4-quinazolinone-3-yl)-3-formamide (XWJ-2) .

[0090]

[0091] Brown solid, yield 24.1%. 1 H NMR (500MHz, DMSO-d 6 )δ8.30(d, J=2.5Hz, 1H), 8.18(d, J=8.0Hz, 1H), 7.93(dd, J=8.6, 2.4Hz, 1H), 7.64(t, J=7.8Hz, 1H), 7.54(d, J=7.9Hz, 1H), 7.52(d, J=8.7Hz, 1H), 7.54(d, J=7.9Hz, 1H), 7.24(t, J=7.5Hz, 1H) ,4.23(q,J=7.3Hz,2H),2.98-2.91(m,2H),1.79(p,J=7.4Hz,2H),1.43-1.35(m,4...

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Abstract

The invention belongs to the technical field of antibacterial drugs and relates to 4-hydroxy-2-quinolone-nitrogen-(4-quinazolinone)-3-formamide derivatives as well as a preparation method and an application thereof as an antibacterial drug. The compounds are shown in a formula (I), wherein R1 is selected from hydrogen, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy and halogen; R2 is selected from hydrogen, nitryl, C1-C8 alkyl, C1-C8 alkoxy and halogen; R3 is selected from C1-C8 alkyl and aryl methyl; R4 is selected from C1-C8 alkyl. The 4-hydroxy-2-quinolone-nitrogen-(4-quinazolinone)-3-formamidederivatives are first discovered antibacterial compounds of novel structures, the compounds have higher inhibition functions on gram-positive bacteria including staphylococcus aureus, staphylococcusepidermidis, enterococcus and the like, particularly, drug-resistant gram-positive bacteria (MRSA (methicillin-resistant staphylococcus aureus), MRSE (methicillin-resistant staphylococcus epidermidis)and VRE (vancomycin-resistant enterococci)) and can be used for following further modification and development.

Description

technical field [0001] The invention belongs to the technical field of antibacterial drugs, and specifically relates to 4-hydroxy-2-quinolone-nitrogen-(4-quinazolinone)-3-carboxamide derivatives, a preparation method and an application as antibacterial drugs. Background technique [0002] Bacterial infection is an infection caused by pathogenic bacteria or conditional pathogenic bacteria invading the body to grow and reproduce, producing toxins and other metabolites. Bacterial infection is one of the main factors that endanger human health, and the emergence of bacterial drug resistance in recent years has made the challenge of global public health more severe. Among resistant Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant surface Staphylococcus (MRSE), and vancomycin-resistant enterococci (VRE) were the most common. The discovery of antibacterial drugs with new structures or new mechanisms of action has important clinical ...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/517A61P31/04
CPCC07D401/12A61P31/04
Inventor 吴松夏杰薛文杰冯波
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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