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Carbostyril pyrimidine compounds and preparation method and application thereof

A quinolone pyrimidine and quinolone technology, applied in the field of quinolone pyrimidine compounds and their preparation, can solve the problems of limited clinical treatment effect, weak drug resistance, concern about drug resistance, etc. The effect of preparing raw materials is simple

Active Publication Date: 2019-06-28
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical efficacy is limited due to widespread clinical use of quinolones and growing concerns about drug resistance due to weaker resistance to certain Gram-positive bacteria

Method used

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  • Carbostyril pyrimidine compounds and preparation method and application thereof
  • Carbostyril pyrimidine compounds and preparation method and application thereof
  • Carbostyril pyrimidine compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1, the preparation of compound I-1

[0031]

[0032] Add 2-chloropyrimidine (0.150g, 1.310mmol), norfloxacin (0.427g, 1.310mmol) and potassium carbonate (0.354g, 1.572mmol) into a 50mL round bottom flask, then add 10mL of acetonitrile, at 80°C Stir at reflux for 24 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with an eluent (methanol / dichloromethane, 1 / 10, V / V) to obtain 0.289 g of compound I -1, as a yellow solid. Yield: 72.8%; 1 H NMR(600MHz,DMSO)δ15.35(s,1H,COOH),8.97(s,1H,quinolone-2-H),8.42(d,J=4.7Hz,2H,pyrimidine-4,6-2H) , 7.95 (d, J=13.1Hz, 1H, quinolone-5-H), 7.24 (d, J=7.0Hz, 1H, quinolone-8-H), 6.69 (t, J=4.7Hz, 1H, pyrimidine- 5-H), 4.60 (dd, J=13.9, 6.8Hz, 2H, CH 2 CH 3 ),3.98–3.95(m,4H,piperazine-2,2-N-(CH 2 ) 2 ), 3.41(d, J=4.3Hz, 4H, piperazine-3,3-N-(CH 2 ) 2 ), 1.43(t, J=7.1Hz, 3H, CH 2 CH 3 )ppm.

Embodiment 2

[0033] Embodiment 2, the preparation of compound 1-2

[0034]

[0035] Add 2-chloro-5-methylpyrimidine (0.150g, 1.167mmol), norfloxacin (0.373g, 1.167mmol) and potassium carbonate (0.193g, 1.400mmol) to a 50mL round bottom flask, and then add 10mL Acetonitrile was stirred under reflux at 80°C for 24 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with an eluent (methanol / dichloromethane, 1 / 10, V / V) to obtain 0.311 g of compound I -2, as a yellow solid. Yield: 75.7%; 1 HNMR(600MHz,DMSO)δ15.35(s,1H,COOH),8.96(s,1H,quinolone-2-H),8.28(s,2H,pyrimidine-4,6-2H),7.96(d,J =13.2Hz, 1H, quinolone-5-H), 7.24 (d, J = 7.2Hz, 1H, quinolone-8-H), 4.60 (dd, J = 14.1, 7.1Hz, 2H, CH 2 CH 3 ),3.94–3.88(m,4H,piperazine-2,2-N-(CH 2 ) 2 ),3.41–3.38(m,4H,piperazine-3,3-N-(CH 2 ) 2 ),2.11(s,3H,CH 3), 1.42(t, J=7.1Hz, 3H, CH 2 CH 3 )ppm.

Embodiment 3

[0036] Embodiment 3, the preparation of compound 1-3

[0037]

[0038] Add 2-chloro-5-ethylpyrimidine (0.150g, 1.052mmol), norfloxacin (0.336g, 1.052mmol) and potassium carbonate (0.174g, 1.262mmol) to a 50mL round bottom flask, and then add 10mL Acetonitrile was stirred under reflux at 80°C for 24 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with an eluent (methanol / dichloromethane, 1 / 10, V / V) to obtain 0.298 g of compound I -3, as a yellow solid. Yield: 70.1%; 1 HNMR(600MHz,DMSO)δ15.34(s,1H,COOH),8.96(s,1H,quinolone-2-H),8.31(s,2H,pyrimidine-4,6-2H),7.96(d,J =13.2Hz, 1H, quinolone-5-H), 7.24 (d, J = 7.2Hz, 1H, quinolone-8-H), 4.60 (q, J = 7.1Hz, 2H, quinolone-CH 2 CH 3 ),3.94–3.91(m,4H,piperazine-2,2-N-(CH 2 ) 2 ),3.41–3.38(m,4H,piperazine-3,3-N-(CH 2 ) 2 ), 2.46 (s, 2H, pyrimidine-CH 2 CH 3 ), 1.42(t, J=7.1Hz, 3H, quinolone-CH 2 CH 3 )...

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Abstract

The invention relates to carbostyril pyrimidine compounds and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. The carbostyril pyrimidine compounds are shown in general formulas I-IV, the compounds have the certain inhibitory activity for one or more of Gram positive bacteria, Gram negative bacteria and fungi, can be used for preparing anti-bacterial and / or anti-fungi drugs, and therefore have opportunity to provide safer and more efficient diversified candidate drugs for clinical anti-microbial treatment, and the clinical treatment problems of drug resistance on the rise, stubborn invasive organisms and emerging harmful microorganisms are solved. Preparation raw materials are simple, cheap and easy to obtain, the synthesis path is short, and the compounds have the important significance in application of infection resistance.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to quinolone pyrimidine compounds and their preparation methods and applications. Background technique [0002] Biological infection has posed a serious threat to human health, especially for patients with low immunity. The demand for novel antimicrobial agents has increased year by year due to the increase in the resistance to traditional antimicrobial agents and the increasing mortality due to microbial infections, which limits the therapeutic efficacy of many drugs. In recent years, only seven new chemical entities have received Food and Drug Administration approval as systemic antimicrobials, and only two of these, linezolid and daptomycin, are therapeutics via novel modes of action that were previously unrelated. Many new antibiotics entering the market are active against resistant clinical strains due to increased potency of the drug or reduced suscepti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14A61P31/04A61P31/10A61K31/506
CPCY02A50/30
Inventor 周成合李迪陈金平巴绨倪·纳塞亚安萨里·穆罕默德·福阿德
Owner SOUTHWEST UNIV
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