CN102093358A - Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament - Google Patents

Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament Download PDF

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CN102093358A
CN102093358A CN 201110040995 CN201110040995A CN102093358A CN 102093358 A CN102093358 A CN 102093358A CN 201110040995 CN201110040995 CN 201110040995 CN 201110040995 A CN201110040995 A CN 201110040995A CN 102093358 A CN102093358 A CN 102093358A
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brominated
dione derivative
indolizinoquinoline
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indolizino
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CN102093358B (en
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安林坤
巫锡伟
吴族平
古练权
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Sun Yat Sen University
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Abstract

The invention discloses a brominated indolizinoquinoline dione derivative and an application of the brominated indolizinoquinoline dione derivative in preparing an antibiotic medicament. An experiment proves that the brominated indolizinoquinoline dione derivative has strong inhibition activity on gram-positive bacteria especially methicillin-resistant staphylococcus aureus, thus the brominated indolizinoquinoline dione derivative can be used for preparing an effective antibiotic medicament. The chemical structure formula of the brominated indolizinoquinoline dione derivative is shown in a formula I, wherein R1 and R2 are defined in the specification.

Description

Bromo indolizino quinolyl dione analog derivative and the application in the preparation antibacterials thereof
Technical field
The present invention relates to a class bromo indolizino quinolyl dione analog derivative and the purposes in the preparation antibacterials thereof.This medicine especially has very strong inhibition activity to methicillin-resistant gold Portugal bacterium to gram-positive microorganism.
Background technology
Along with the universal and application of microbiotic, no matter be that multiple Resistant strain has all appearred in Gram-negative bacteria or gram-positive microorganism in the whole world.Wherein, the resistance problem of gram-positive microorganism is particularly serious.For example, methicillin-resistant gold Portugal bacterium (MRSA), methicillin-resistant staphylococcus epidermidis, penicillin resistant streptococcus pneumoniae and vancomycin-resistant enterococcus etc. cause serious problem clinically.At present,, also lack effective medicine, press for no cross resistance of research and development and more effective, novel antibacterials the microbial infection of these resistances.
In the research in our early stage, indolizino quinolyl dione analog derivative and the application (CN 100441580C) in the preparation antibacterials thereof have been reported.We discover that further its bromo derivative has stronger anti-microbial activity.
Summary of the invention
The purpose of this invention is to provide a class bromo indolizino quinolyl dione analog derivative, and the application of this compounds in the medicine of preparation antibacterials, particularly anti-MRSA.
Bromo indolizino quinolyl dione analog derivative of the present invention is as shown in the formula shown in the I:
Figure 945893DEST_PATH_IMAGE001
R among the formula I 1The group of representative is: C 1-C 3The C that alkyl, fluorine replace 1-C 3The C that alkyl or amido replace 1-C 3Alkyl;
R among the formula I 2The group of representative is :-H or methyl.
Bromo indolizino quinolyl dione analog derivative of the present invention can obtain by chemical synthesis process.Common bromo indolizino quinolyl dione analog derivative of the present invention can prepare by reaction formula II or reaction formula III:
Figure 368784DEST_PATH_IMAGE002
Above-mentioned bromo indolizino quinolyl dione analog derivative can be made medicine with pharmaceutically acceptable auxiliary.This medicine can be made forms such as tablet, pill, capsule, suspension agent, emulsion or injection and use.Its route of administration can be oral, through skin, and vein or intramuscular injection.
Compared with prior art, the present invention has following beneficial effect: show by extracorporeal bacteria inhibitor test, compare with the quinolyl dione derivative of report before us, bromo indolizino quinolyl dione analog derivative of the present invention is to gram-positive microorganism, and particularly MRSA has stronger inhibition activity.
Embodiment:
The present invention will be further described by the following examples.
Embodiment 1: compound 1Synthetic
As reaction formula II, with 6 of 0.10 mol, 7-two chloro-5,8-quinolyl dione and 0.20 mol methyl aceto acetate join in the 300 ml ethanol, under agitation add the 3-bromopyridine of 0.40 mol, back flow reaction 2-15 hour.After the cooling, the concentrating under reduced pressure solvent, resistates obtains target compound through column chromatography for separation 1, its structural formula is as follows with sign:
Figure 437289DEST_PATH_IMAGE004
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.10?(d,? J?=?0.7?Hz,?1H),?9.05?(dd,? J?=?4.6,?1.7?Hz,?1H),?8.57?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.30-8.24?(m,?1H),?7.67?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.56?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.52?(q,? J?=?7.1?Hz,?2H),?1.50?(t,? J?=?7.1?Hz,?3H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.8,?173.3,?162.7,?154.2,?149.2,?138.1,?135.5,?131.9,?131.0,?128.6,?127.8,?127.2,?122.8,?121.6,?113.5,?107.1,?61.4,?14.3.?ESI-MS? m/z:?401.0?(100%),?399.0?(88%)?[M?+?H] +.
Embodiment 2: compound 2Synthetic
As react formula III, and 0.10 mol raw material M is suspended in the 100-200 ml chloroform, stir adding 0.12 mol triethylamine and 0.11 mol thionyl chloride down.This mixed solution reflux 4-8 hour.Stop to reflux, solvent and unnecessary thionyl chloride are removed in decompression.Resistates is dissolved in 100 ml methylene dichloride, and adds 0.11 mol N successively, N-lutidine and 0.11 mol 2,2,2 tfifluoroethyl alcohol.Heat this mixed solution to refluxing 5-10 hour, solvent is removed in decompression, and resistates obtains compound through column chromatography for separation 2, its structural formula is as follows with sign:
Figure 327885DEST_PATH_IMAGE005
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.15?(s,?br,?1H),?9.07?(d,? J?=?3.4?Hz,?1H),?8.60?(d,? J?=?7.0?Hz,?1H),?8.26?(dd,? J?=?9.6,?0.5?Hz,?1H),?7.71?(dd,? J?=?7.8,?4.5?Hz,?1H),?7.64?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.84?(q,? J?=?8.4?Hz,?2H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.5,?173.5,?160.7,?154.4,?149.0,?138.5,?135.7,?132.9,?130.9,?128.6,?128.5,?127.4,?123.4,?121.3,?113.7,?104.1,?60.8?(q,? J?=?36.7?Hz,?1C),?29.7.?ESI-MS?m/z:?453.0?(100%),?455.0?(94%)?[M?+?H] +.
Embodiment 3: compound 3Synthetic
Preparation method A: the preparation method is with embodiment 1, and different is to replace methyl aceto acetate with 0.20 mol methyl acetoacetate, obtains target compound 3
Preparation method B: the preparation method is with embodiment 2, and different is to replace 2,2,2 tfifluoroethyl alcohol with 0.11 mol methyl alcohol, obtains target compound 3, its structural formula is as follows with sign:
Figure 187256DEST_PATH_IMAGE006
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.08?(s,?br,?1H),?9.04?(dd,? J?=?4.6,?1.6?Hz,?1H),?8.55?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.26?(dd,? J?=?9.6,?0.6?Hz,?1H),?7.68?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.55?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.04?(s,?3H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.8,?173.3,?163.1,?154.3,?149.2,?138.2,?135.5,?132.0,?130.9,?128.3,?127.8,?127.2,?122.9,?121.6,?113.6,?106.5,?52.3.?ESI-MS?m/z:?384.9?(100%),?386.9?(96%)?[M?+?H] +.
Embodiment 4: compound 4Synthetic
The preparation method is with embodiment 2, and different is to replace 2,2,2 tfifluoroethyl alcohol with 0.11 mol 2-fluoroethanol, obtains target compound 4, its structural formula is as follows with sign:
Figure 796092DEST_PATH_IMAGE007
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.11?(s,?br,?1H),?9.05?(dd,? J?=?4.6,?1.7?Hz,?1H),?8.57?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.28?(dd,? J?=?9.6,?0.8?Hz,?1H),?7.68?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.58?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.92-4.88?(m,?1H),?4.80-4.77?(m,?1H),?4.75-4.72?(m,?1H),?4.68-4.65?(m,?1H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.7,?173.4,?162.2,?154.3,?149.2,?138.3,?135.6,?132.3,?131.0,?128.4,?128.1,?127.2,?123.1,?121.6,?113.6,?106.0,?81.3?(d,? J?=?169?Hz,?1C),?64.0?(d,? J?=?20?Hz,?1C).?ESI-MS?m/z:?417.0?(100%),?419.0?(96%)?[M?+?H] +.
Embodiment 5: compound 5Synthetic
The preparation method is with embodiment 2, and different is with 0.11 mol N, and N dimethylamine base ethanol replaces 2,2,2 tfifluoroethyl alcohol, obtains target compound 5, its structural formula is as follows with sign:
Figure 782634DEST_PATH_IMAGE008
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.09?(s,?1H),?9.05?(dd,? J?=?4.6,?1.6?Hz,?1H),?8.56?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.36?(d,? J?=?9.6?Hz,?1H),?7.67?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.55?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.56?(t,? J?=?5.8?Hz,?2H),?2.83?(t,? J?=?5.8?Hz,?2H),?2.38?(s,?6H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.8,?173.3,?162.5,?154.3,?149.2,?138.2,?135.5,?131.9,?131.0,?128.3,?127.9,?127.2,?122.8,?121.8,?113.5,?107.0,?62.8,?57.7,?45.7.?ESI-MS?m/z:?442.0?(100%),?444.0?(98%)?[M?+?H] +.
Embodiment 6: compound 6Synthetic
The preparation method is with embodiment 2, and different is to replace 2,2,2 tfifluoroethyl alcohol with 0.11 mol 2-(piperidino) ethanol, obtains target compound 6, its structural formula is as follows with sign:
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.10-10.08?(m,?1H),?9.04?(dd,? J?=?4.6,?1.7?Hz,?1H),?8.57?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.52?(dd,? J?=?9.6,?0.8?Hz,?1H),?7.67?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.54?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.57?(t,? J?=?5.9?Hz,?2H),?2.82?(t,? J?=?5.8?Hz,?2H),?2.54?(s,?br,?4H),?1.68-1.58?(m,?4H),?1.52-1.44?(m,?2H). 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.8,?173.2,?162.2,?154.2,?149.2,?138.2,?135.5,?131.8,?130.9,?128.2,?127.9,?127.2,?122.9,?122.2,?113.5,?107.2,?62.2,?57.1,?54.7,?26.0,?24.2.?ESI-MS?m/z:?482.1?(100%),?484.1?(96%)?[M?+?H] +.
Embodiment 7: compound 7Synthetic
The preparation method is with embodiment 2, and different is to replace 2,2,2 tfifluoroethyl alcohol with 0.11 mol 2-morpholinyl ethanol, obtains target compound 7, its structural formula is as follows with sign:
Figure 823588DEST_PATH_IMAGE010
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.10?(s,?br,?1H),?9.05?(dd,? J?=?4.6,?1.7?Hz,?1H),?8.56?(dd,? J?=?7.9,?1.7?Hz,?1H),?8.43?(dd,? J?=?9.6,?0.7?Hz,?1H),?7.68?(dd,? J?=?7.9,?4.7?Hz,?1H),?7.55?(dd,? J?=?9.6,?1.7?Hz,?1H),?4.58?(t,? J?=?5.8?Hz,?2H),?3.80-3.70?(m,?4H),?2.87?(t,? J?=?5.8?Hz,?2H),?2.67-2.57?(m,?4H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?178.8,?173.3,?162.3,?154.3,?149.2,?138.2,?135.5,?131.9,?130.9,?128.3,?127.9,?127.2,?122.9,?121.9,?113.5,?106.9,?67.0,?61.8,?56.9,?53.7.?ESI-MS?m/z:?486.1?(100%),?484.1?(92%)?[M?+?H] +.
Embodiment 8: compound 8Synthetic
The preparation method is with embodiment 1, and different is to replace the 3-bromopyridine with 0.40 mol 3-chloropyridine, obtains target compound 8
1H?NMR?(400?MHz,?CDCl 3)?δ:?10.01?(s,?br,?1H),?9.05?(d,? J?=?3.6?Hz,?1H),?8.58?(d,? J?=?7.6?Hz,?1H),?8.33?(d,? J?=?9.6?Hz,?1H),?7.68?(dd,? J?=?7.8,?4.6?Hz,?1H),?7.46?(dd,? J?=?9.6,?2.0?Hz,?1H),?4.52?(q,? J?=?7.2?Hz,?2H),?1.51?(t,? J?=?7.2?Hz,?3H).?ESI-MS?m/z:?355.0?(100%),357.0?(34%)?[M?+?H] +.
Embodiment 9: anti-microbial activity is measured
Use the minimal inhibitory concentration (MIC) of agar dilution determination experiment compound, measurement result shows, it is active that experimental compound demonstrates significant inhibition to several gram-positive microorganisms, especially to clinical isolated M RSA(7365) have a good inhibition activity.Compound 1, 2, 3With 4To the inhibition activity of MRSA be positive control medicine vancomycin 32-64 doubly.
The bacteriostatic activity of bromo indolizino quinolyl dione analog derivative
Figure 942909DEST_PATH_IMAGE012
Annotate: the structure of KLT-2 is seen Chinese invention patent CN 100441580C.

Claims (6)

1. suc as formula the bromo indolizino quinolyl dione analog derivative shown in the I:
R among the formula I 1The group of representative is: C 1-C 3The C that alkyl, fluorine replace 1-C 3The C that alkyl or amido replace 1-C 3Alkyl;
R among the formula I 2The group of representative is :-H or methyl.
2. the application of the described bromo indolizino of claim 1 quinolyl dione analog derivative in the preparation antibacterials.
3. according to the described application of claim 2, it is characterized in that described antibacterials are medicines of resisting gram-positive bacteria.
4. according to the described application of claim 2, it is characterized in that described antibacterials are medicines of anti-methicillin-resistant gold Portugal bacterium.
5. one kind is used for the antimicrobial medicine, it is characterized in that this medicine is made up of the described bromo indolizino of claim 1 quinolyl dione analog derivative and pharmaceutically acceptable auxiliary.
6. according to the described medicine of claim 5, it is characterized in that this medicine is tablet, pill, capsule, suspension agent, emulsion or injection.
CN201110040995A 2011-02-21 2011-02-21 Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament Expired - Fee Related CN102093358B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106188054A (en) * 2016-06-30 2016-12-07 中山大学 One class is for preparing compound in antibacterials and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106188054A (en) * 2016-06-30 2016-12-07 中山大学 One class is for preparing compound in antibacterials and application thereof
CN106188054B (en) * 2016-06-30 2018-09-04 中山大学 One kind is used to prepare compound in antibacterials and application thereof

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