Fluoroquinolone amino derivatives and application thereof

An alkyl and hydroxyl technology, which is applied in the field of fluoroquinolone amino derivatives, can solve the problems of increased difficulty in dose control, poor patient compliance, and increased risk of drug compatibility, so as to reduce the types of drugs and reduce the dosage of drugs , the effect of shortening the treatment cycle

Active Publication Date: 2018-04-06
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the different compositions and targets, multi-targets can be divided into "multi-drug and multi-target" drugs (drug combination), "multi-drug single-target" drugs (multi-component drugs), "single-drug multi-target" drugs "Three types of drugs, the first two types of drug administration involve two or more drugs, due to the complexity of drug interactions, these two drug administration methods may have increased difficulty in dose control and increased risk of drug compatibility. Therefore, the design of single-drug multi-target compounds has gradually become a hot spot in the design of new drugs

Method used

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  • Fluoroquinolone amino derivatives and application thereof
  • Fluoroquinolone amino derivatives and application thereof
  • Fluoroquinolone amino derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1-24

[0079] Add 1mmol Floxacin and 2mL DCM to a 100mL round bottom flask, cool in an ice bath, stir magnetically, add 3mmolNaHCO 3 After 20min, 2.5mmol chloroacyl chloride (Cl-(CH 2 ) n COCl, n = 1, 2, 3) in DCM (2mL) solution (the drop rate is about 1d / 2s), the reaction continued in an ice bath (at 2-CC, moved to -5°C) after dropping, and TLC tracked and monitored to The reaction is over. Stirring was stopped and H was added 2 O 15mL and DCM 20mL, under stirring, use 1N HCl solution to adjust pH=3-4, if there is solid, then stand still, filter with suction, wash the filter cake 3 times with DCM, and keep the filter cake for further purification; the filtrate is transferred to a separatory funnel, Liquid separation, the aqueous phase was extracted with DCM (15mL×1), the organic phases were combined, washed with saturated NaCl solution (15mL×1), the organic phase was collected, anhydrous NaCl 2 SO 4 dry. The crude product was spin-dried by a rotary evaporator, and the pure pro...

Embodiment 1-35

[0085] In the 100mL round bottom flask, add 1mmol of the intermediate of formula X, 5mL of toluene, 2mmol of Et 3 N, stir for 20-30min, add 2mmol isonicotinic acid (INA) or pyrazinecarboxylic acid (POA), after 10min, move to 110℃~120℃ oil bath for reflux reaction, monitor by TLC until the reaction is complete. Spin the reaction solution to dryness with a rotary evaporator, add 30mL DCM and stir to dissolve, filter with suction, wash the filter cake 3 times with DCM, wash the filtrate with 10% citric acid solution (15mL×1), collect the organic phase, anhydrous Na 2 SO 4 dry. The crude product was spin-dried by a rotary evaporator, the pure product was obtained by column chromatography, and the target product was obtained by vacuum drying.

[0086] Table 2 target compound formula XI synthetic result

[0087]

[0088]

[0089]

[0090] Table 3 target compound formula XI synthetic result

[0091]

[0092]

[0093]

[0094] Synthesis of formula XII series com...

Embodiment 36-41

[0097] Add 2mmol isoniazid, 4mmol NaHCO 3 and 5mL DCM, stirred at -5°C for 20min, then added dropwise 3mmol of chloroacetyl chloride solution (dropping speed is about 1d / 2s) with a constant pressure dropping funnel, and continued to react at -5°C, followed by TLC monitoring until the end of the reaction . While stirring, add DCM-CH 3 OH solution (V DCM :V CH3OH =2:1) ​​until the solids in the reaction flask no longer decrease, let stand, filter with suction, and use DCM-CH for the filter cake 3 OH solution was washed 3 times, and the filtrate was washed with anhydrous Na 2 SO 4 Dry and spin dry with a rotary evaporator to obtain a crude product, then add 5 mL of DCM and stir for 20 min, filter with suction, wash the filter cake with DCM 3 times, and dry in vacuo to obtain an intermediate for future use.

[0098] Add 1mmol of Floxacin and 4mmol of Et in a 100mL round bottom flask 3 N and 2mL DMF, after stirring for 20min, add the above-mentioned intermediate, and after 1...

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to fluoroquinolone derivatives and an application thereof. The compounds shown in a formula (I) are obtained by structural modification of fluoroquinolone medicines. The compounds provided by the invention can not only treat the infection caused by mycobacterium tuberculosis and common bacteria, but also can has activity inhibition effects on bacterial persister, citrus pathogenic bacteria, nicotinamide N-methyltransferase (NNMT) and interleukin IL-17 PPI; and the compounds have a simple and easy preparation process and mild conditions, a plurality of the compounds with enhanced antibacterial activity, improved water solubility and reduced toxic and side effects are obtained, and the compounds are expectedto reduce the dosage, shorten the treatment cycle and improve patient compliance, thereby providing novel molecular types and research ideas for medicines of tuberculosis and other diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a fluoroquinolone amino derivative and its application. Background technique [0002] Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mycoabcterium tuberculosis, MTB). In addition to mainly causing tuberculosis, MTB can also affect all other organs of the human body. It is one of the major diseases that seriously endanger human health, and it is also a long-term global public health and social problem of common concern. During the administration of anti-tuberculosis drugs, drug-resistant tuberculosis (DR-TB), especially multi-drug-resistant tuberculosis (DR-TB), is emerging and increasing, and curbing drug-resistant tuberculosis has become a very urgent research topic. [0003] The results and experience of global tuberculosis treatment show that no matter how strong the bactericidal activity of a single anti-tuberculosis dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D471/04C07D401/04C07D215/56A61K31/496A61K31/4709A61K31/497A61P31/04A61P29/00A61P35/00A61P19/02A61P11/00A61P1/00A61P27/02A61P17/06A61P9/10A61P1/16A61P13/12A61P37/02A61P31/06A01N43/42A01N43/90A01N43/60A01P3/00
CPCC07D401/04C07D401/14A61P35/00A61P29/00A61P31/04A61P31/10A61P1/00A61P19/02A61P11/06A61P11/00A61P9/10A61P19/08A61P1/16A61P13/12A61P19/04A61P37/02Y02A50/30
Inventor 杨大成冯计周范莉黄敏谢建平刘洁胡军华陈菲菲牟希徐兴然郭思瑶付彬龙艳玲杨真王帆张书虹
Owner SOUTHWEST UNIVERSITY
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