CN102093358B - 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 PDFInfo
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- CN102093358B CN102093358B CN201110040995A CN201110040995A CN102093358B CN 102093358 B CN102093358 B CN 102093358B CN 201110040995 A CN201110040995 A CN 201110040995A CN 201110040995 A CN201110040995 A CN 201110040995A CN 102093358 B CN102093358 B CN 102093358B
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- brominated
- dione derivative
- indolizinoquinoline
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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
Technical field
The present invention relates to one type of bromo indolizino quinolyl dione analog derivative and the purposes in the preparation antibacterials thereof.This medicine especially has very strong inhibition active 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 the efficacious therapy 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 one type of 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:
R among the formula I
1The group of representative is: C
1-C
3Alkyl, the substituted C of fluorine
1-C
3The substituted C of alkyl or amido
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 through chemical synthesis process.Common bromo indolizino quinolyl dione analog derivative of the present invention can or react the formula III preparation through reaction formula II:
Above-mentioned bromo indolizino quinolyl dione analog derivative can be processed medicine with pharmaceutically acceptable auxiliary.This medicine can be processed 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 through 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 it is active that particularly MRSA has stronger inhibition.
Embodiment:
Below through embodiment the present invention is further specified.
Embodiment 1: compound
1Synthetic
Like 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 with characterize as follows:
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 with characterize as follows:
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
Preparing 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
Preparing 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 with characterize as follows:
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 with characterize as follows:
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 TMSDMA N dimethylamine base ethanol replaces 2,2,2 tfifluoroethyl alcohol, obtains target compound
5, its structural formula with characterize as follows:
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 with characterize as follows:
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 with characterize as follows:
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; Mensuration result shows; It is active that experimental compound demonstrates significant inhibition to several kinds of gram-positive microorganisms, especially clinical isolated M RSA (7365) had good inhibition activity.Compound
1,
2,
3With
4To the inhibition activity of MRSA be positive control medicine vancomyein 32-64 doubly.
The bacteriostatic activity of bromo indolizino quinolyl dione analog derivative
Annotate: the structure of KLT-2 is seen Chinese invention patent CN 100441580C.
Claims (1)
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
3Alkyl, the substituted C of fluorine
1-C
3The substituted C of alkyl or amido
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 medicine of preparation resisting gram-positive bacteria.
3. the application of the described bromo indolizino of claim 1 quinolyl dione analog derivative in the medicine of the anti-methicillin-resistant gold of preparation Portugal bacterium.
4. 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.
5. according to the described medicine of claim 4, it is characterized in that this medicine is tablet, pill, capsule, suspension agent, emulsion or injection.
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| CN201110040995A CN102093358B (en) | 2011-02-21 | 2011-02-21 | Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083064A (en) * | 1992-04-17 | 1994-03-02 | 史密丝克莱恩比彻姆公司 | Indolizino [1, the 2-b] quinolinones that replaces |
| CN1887884A (en) * | 2006-07-14 | 2007-01-03 | 中山大学 | Quinolyl dione derivative and its application in preparing antibiotic medicine |
| CN101182321A (en) * | 2007-12-11 | 2008-05-21 | 中山大学 | Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof |
-
2011
- 2011-02-21 CN CN201110040995A patent/CN102093358B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083064A (en) * | 1992-04-17 | 1994-03-02 | 史密丝克莱恩比彻姆公司 | Indolizino [1, the 2-b] quinolinones that replaces |
| CN1887884A (en) * | 2006-07-14 | 2007-01-03 | 中山大学 | Quinolyl dione derivative and its application in preparing antibiotic medicine |
| CN101182321A (en) * | 2007-12-11 | 2008-05-21 | 中山大学 | Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 钱立刚，等.喹啉二酮类化合物的合成研究——形成双（二氢喹啉二酮基）甲烷的可能途径.《化学学报》.1985,第43卷463-466. * |
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