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A chiral aminomethyltriazole substituted tricyclic fluoroquinolone carboxylic acid derivative and its preparation method and application

A technology of fluoroquinolone carboxylic acid and aminomethyltriazole, which is applied in the field of innovative drug synthesis to achieve the effect of overcoming drug resistance

Inactive Publication Date: 2017-02-01
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, in order to discover new levofloxacin-like fluoroquinolone compounds, many studies have focused on the changes of the piperazine N-substituent, but there are few changes in the insertion of functional heterocyclic linking chains between the piperazine base and the quinoline ring skeleton.

Method used

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  • A chiral aminomethyltriazole substituted tricyclic fluoroquinolone carboxylic acid derivative and its preparation method and application
  • A chiral aminomethyltriazole substituted tricyclic fluoroquinolone carboxylic acid derivative and its preparation method and application
  • A chiral aminomethyltriazole substituted tricyclic fluoroquinolone carboxylic acid derivative and its preparation method and application

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Experimental program
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Embodiment 1

[0044] S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-7- Oxo-7H-pyridine[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid (I-1), its chemical structure is:

[0045]

[0046] That is, R in formula I is dimethylamino.

[0047] The preparation method of the compound is as follows: using dimethylamine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-1) is obtained, the yield is 66.0%, m.p.223-225°C . 1 H NMR (400MHz, DMSO-d 6 ): δ15.48(brs,1H,COOH),9.26(s,1H,5-H),7.87(s,1H,5″-H),7.72(d,J=13.2Hz,1H,8-H ),5.34(s,2H,NCH 2 ),4.94-4.56(m,3H,OCH 2 CH),2.47(s,6H,NCH 3 ), 1.47 (d, J=4.0Hz, CH 3 ); MS(m / z): Calcd.for C 18 h 18 FN 5 o 4 :387.37[M] + ;Found:388[M+H] + .

Embodiment 2

[0049] S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-diethylaminomethyl-[1,2,3]triazol-1-yl)-7- Oxo-7H-pyridine[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid (I-2), its chemical structure is:

[0050]

[0051] That is, R in formula I is diethylamino.

[0052] The preparation method of the compound is as follows: using diethylamine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-2) is obtained, the yield is 53.0%, m.p.214-216°C . 1 H NMR (400MHz, DMSO-d 6 ):δ15.46(brs,1H,COOH),9.27(s,1H,5-H),7.86(s,1H,5″-H),7.74(d,J=13.2Hz,1H,8-H ),5.31(s,2H,NCH 2 ),4.93-4.52(m,3H,OCH 2 CH),2.45-2.34(m,4H,2×CH 2 ),1.48-1.17(m,6H,2×CH 3 ); MS(m / z): Calcd.for C 20 h 22 FN 5 o 4 :415.43[M] + ;Found:416[M+H] + .

Embodiment 3

[0054] S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-piperidin-1-methyl-[1,2,3]triazol-1-yl)- 7-oxo-7H-pyridine[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid (I-3), its chemical structure is:

[0055]

[0056] That is, R in formula I is piperidin-1-yl.

[0057] The preparation method of the compound is as follows: using piperidine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-3) was obtained with a yield of 57.0%, m.p.224-226°C. 1 H NMR (400MHz, DMSO-d 6 ): δ15.43(brs,1H,COOH),9.25(s,1H,2-H),7.83(s,1H,5″-H),7.73(d,J=13.2Hz,1H,5-H ),5.28(s,2H,NCH 2 ),4.89-4.54(m,3H,OCH 2 CH),3.12-2.30(m,4H,N(CH 2 ) 2 ),1.62-1.15(m,9H,CH 3 and 3 x CH 2 ); MS(m / z): Calcd.for C 21 h 22 FN 5 o 4 :427.44[M] + ;Found:428[M+H] + .

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Abstract

The invention discloses a chiral aminomethyl aminomethyl triazole substituted tricyclic fluoroquinolone carboxylic acid derivative and a preparation method and applications thereof. The chemical structure general formula is shown in the following formula I, in the formula I, R is dimethylamino, lignocaine, piperidyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidyl. By means of the derivative and the preparation method and the applications thereof, function triazole heterocyclic base is added between superior pharmacophore skeleton-chiral tricyclic fluoroquinolone carboxylic acid and effective substituent 7-amino, and accordingly, the new compound anti-drug-resistance activity is improved, and the derivative can be used as a new antibacterial activity substance to develop anti-infection medicine in brand new structure.

Description

technical field [0001] The invention belongs to the field of innovative drug synthesis, and specifically relates to a chiral aminomethyltriazole-substituted tricyclic fluoroquinolone carboxylic acid derivative, and also relates to a chiral aminomethyltriazole-substituted tricyclic fluoroquinolone carboxylic acid derivative The preparation method of the derivative, and its application in anti-infection medicine. Background technique [0002] Fluoroquinolones have attracted much attention as broad-spectrum, high-efficiency, and low-toxic anti-infective drugs widely used in clinical practice. However, due to the increasing severity of bacterial drug resistance, how to overcome bacterial drug resistance has become an urgent social and public health security issue in the field of anti-infective drug therapy. Although there are many options for solving bacterial drug resistance strategies, an effective and economical approach is to optimize the structure based on the structural c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06A61P31/04
CPCC07D498/06
Inventor 倪礼礼张维瑞王蕊闫强吴书敏杨彤胡国强
Owner HENAN UNIVERSITY