CN107880036A - A kind of 2 oxo 2 (aryl aniline) ethyls substitution MOXIFLOXACIN series compound with anti-prostate cancer activity - Google Patents
A kind of 2 oxo 2 (aryl aniline) ethyls substitution MOXIFLOXACIN series compound with anti-prostate cancer activity Download PDFInfo
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- CN107880036A CN107880036A CN201710891055.XA CN201710891055A CN107880036A CN 107880036 A CN107880036 A CN 107880036A CN 201710891055 A CN201710891055 A CN 201710891055A CN 107880036 A CN107880036 A CN 107880036A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of 2 oxo 2 (aryl aniline) ethyls with anti-prostate cancer activity to substitute MOXIFLOXACIN series compound, and its structure is formula I, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or halogen or nitro or methyl or methoxy；R3Represent hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitro or methyl or methoxy；R5Represent hydrogen or halogen or nitro or methyl or methoxy.Effective effect is：The compound has higher anti-prostate cancer activity, can make cell membrane shrinkage, enough reduce cancer cell density, slow down growth of cancer cells speed, the research and development to China's anticancer preparation have great importance.
Description
Technical field
The invention belongs to organic chemistry filed, more particularly, to a kind of 2- oxos -2- (virtues with anti-prostate cancer activity
Base aniline) ethyl substitution MOXIFLOXACIN series compound.
Background technology
Cancer is considered as one of most important cause of death in the whole world.Chemotheraping preparation leads in the clinical practice for the treatment of cancer
Often there is serious side effect and lack selectivity.Therefore, new more selectivity and the smaller anticancer of side effect are developed
Preparation is extremely urgent.
Fluoroquinolones synthetic antimicrobial preparation is directed to the DNA gyrases and topoisomerase of bacterium, its have wide spectrum,
Potent active function.Except its antibacterial activity, fluoroquinolone antibiotics also show other bioactivity, such as anti-
Fungi, treating tuberculosis, antitumor, anti-HIV-1 type integrase and HCV-Ab IgG-NS3 unwindase isoreactivities.Moxifloxacin hydrochloride is in recent years
Carry out the more extensive fluoroquinolones preparation of clinical practice, but the antitumor activity of compound has much room for improvement.
The content of the invention
It is an object of the invention to provide a kind of 2- oxos -2- (aryl aniline) ethyl with anti-prostate cancer activity to take
For MOXIFLOXACIN series compound.
The present invention is directed to the problem of being mentioned in background technology, and the technical scheme taken is：There is one kind anti-prostate cancer to live
Property 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound, its structural formula is：
In type I compound, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or halogen or nitro or methyl
Or methoxyl group；R3Represent hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitro or methyl or methoxy
Base；R5Represent hydrogen or halogen or nitro or methyl or methoxy.
Preferably, the preparation method of type I compound is：
Make the compound of formula II with moxifloxacin hydrochloride using triethylamine as acid neutralizing agent, in acetonitrile solvent, reacted in 95-105 DEG C,
Generate type I compound；The rate of charge of the compound of formula II and moxifloxacin hydrochloride is：1-1.3；R in the compound of formula II1、R2、R3、
R4、 R5It is defined as above.
Preferably, the preparation method of the compound of formula II is：
Make the compound of formula III with KI in acetone solvent, in 77-82 DEG C of reaction, the compound of production II；The compound of formula III
Rate of charge with KI is：0.6-0.7；R in the compound of formula III1、R2、R3、R4、R5It is defined as above.
Preferably, the preparation method of the compound of formula III is：
Make the compound of formula IV with chloracetyl chloride using triethylamine as acid neutralizing agent, in dichloromethane solvent, under the conditions of ice-water bath
React the compound of production III；The rate of charge of the compound of formula IV and chloracetyl chloride is 0.8-0.85；R in the compound of formula IV1、R2、
R3、R4、 R5It is defined as above.
Preferably, type I compound can be used for preparing anti-prostate cancer preparation.
Compared with prior art, the advantage of the invention is that：A kind of 2- oxos -2- (aryl aniline) second prepared by the present invention
Base substitution MOXIFLOXACIN series compound has higher anti-prostate cancer activity, can make cell membrane shrinkage, enough reduce cancer cell
Density, slow down growth of cancer cells speed, the research and development to China's anticancer preparation have great importance.
Embodiment
Below by embodiment, the present invention will be further described：
Embodiment 1：
2- oxos -2- anilino-s-ethyl substitution MOXIFLOXACIN, preparation method are：
1) preparation of N- phenyl 2- chloroacetamides：50ml dichloromethane is added into flask, is placed in ice-water bath, is added
0.048mol aniline, 0.06mol chloracetyl chloride being added, then triethylamine is slowly added dropwise, ice-water bath is removed in recession in 10 minutes,
Reaction overnight, after reaction terminates, 50ml dchloromethane is added into flask, adds 50ml hydrochloric acid（0.5mol/L）It is molten
Liquid, extract, collect organic phase, add the washing of 50ml saturated sodium bicarbonate solutions, organic phase, then satisfying with 50ml are collected in extraction
With brine It organic phase, anhydrous sodium sulfate drying, vacuum rotary steam, crude product, crude product re-crystallizing in ethyl acetate, yield are obtained
85%；
2) preparation of N- phenyl 2- iodoacetamides：The acetone that 33.33ml is added into flask is placed in 80 DEG C, condensing reflux, adds
0.0135mol N- phenyl 2- chloroacetamides, 0.0225mol KI is added, judge whether reaction ties by TCL
Beam, after reaction terminates, 50ml water is added, add 100ml ethyl acetate, organic phase is collected in extraction, is eaten with 50ml saturation
Salt water washing organic phase, anhydrous sodium sulfate drying, it is evaporated under reduced pressure, obtains crude product, with re-crystallizing in ethyl acetate, obtain white solid, receives
Rate 90%；
3) preparation of 2- oxos -2- anilino-s-ethyl substitution MOXIFLOXACIN：10ml acetonitriles are added into flask, add 2mmol's
Moxifloxacin hydrochloride, 2mmol N- phenyl 2- iodoacetamides and 4.4mmol triethylamines are added, 100 DEG C of condensing reflux 24h, is subtracted
Pressure rotates to obtain crude product, with recrystallized from acetonitrile, obtains faint yellow solid, yield 90%.
Embodiment 2：
2- oxos -2- anilino-s-ethyl substitution MOXIFLOXACIN, preparation method are：
1) preparation of N- phenyl 2- chloroacetamides：50ml dichloromethane is added into flask, is placed in ice-water bath, is added
0.051mol aniline, 0.06mol chloracetyl chloride being added, then triethylamine is slowly added dropwise, ice-water bath is removed in recession in 10 minutes,
Reaction overnight, after reaction terminates, 50ml dchloromethane is added into flask, adds 50ml hydrochloric acid（0.5mol/L）It is molten
Liquid, extract, collect organic phase, add the washing of 50ml saturated sodium bicarbonate solutions, organic phase, then satisfying with 50ml are collected in extraction
With brine It organic phase, anhydrous sodium sulfate drying, vacuum rotary steam, crude product, crude product re-crystallizing in ethyl acetate, yield are obtained
85%；
2) preparation of N- phenyl 2- iodoacetamides：The acetone that 33.33ml is added into flask is placed in 80 DEG C, condensing reflux, adds
0.01575mol N- phenyl 2- chloroacetamides, 0.0225mol KI is added, judge whether reaction ties by TCL
Beam, after reaction terminates, 50ml water is added, add 100ml ethyl acetate, organic phase is collected in extraction, is eaten with 50ml saturation
Salt water washing organic phase, anhydrous sodium sulfate drying, it is evaporated under reduced pressure, obtains crude product, with re-crystallizing in ethyl acetate, obtain white solid, receives
Rate 90%；
3) preparation of 2- oxos -2- anilino-s-ethyl substitution MOXIFLOXACIN：10ml acetonitriles are added into flask, add 2mmol's
Moxifloxacin hydrochloride, adds 2.6mmol N- phenyl 2- iodoacetamides and 4.4mmol triethylamines, 100 DEG C of condensing reflux 24h,
Vacuum rotary steam obtains crude product, with recrystallized from acetonitrile, obtains faint yellow solid, yield 90%.
Embodiment 3：
2- oxos -2-（2- chloroanilinos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 2- chloroanilines in embodiment 1
Aniline, other conditions are constant, yield 84.2%.
Embodiment 4：
2- oxos -2-（3- chloroanilinos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 3- chloroanilines in embodiment 1
Aniline, other conditions are constant, yield 84.6%.
Embodiment 5：
2- oxos -2-（4- chloroanilinos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 4- chloroanilines in embodiment 1
Aniline, other conditions are constant, yield 85.1%.
Embodiment 6：
2- oxos -2-（2,3,4- trichloro-benzenes amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：With 2,3,4- trichloroanilines
Instead of the aniline in embodiment 1, other conditions are constant, yield 84.4%.
Embodiment 7：
2- oxos -2-（2-aminotoluene base）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 2-aminotoluene
Aniline in example 1, other conditions are constant, yield 85.3%.
Embodiment 8：
2- oxos -2-（3- toluidines）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 3- methylanilines
Aniline in example 1, other conditions are constant, yield 84.4%.
Embodiment 9：
2- oxos -2-（4- toluidines）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 4- methylanilines
Aniline in example 1, other conditions are constant, yield 83.7%.H NMR (400MHz, DMSO) δ 15.26(s, 1H), 9.29
(s, 1H), 8.58(s, 1H), 7.52(d, J=14.2Hz, 1H),7.25(d, J=8.4Hz, 2H), 6.87(d, J=
8.3Hz, 2H), 4.11–3.92(m, 2H), 3.70(dd, J=11.6, 2.7 Hz, 1H), 3.61–3.45(m, 5H),
3.16(dt, J=23.8, 11.8Hz, 3H), 2.88(dd, J=7.4, 4.2Hz, 1H), 2.51–2.35(m, 2H),
2.10(s, 3H), 1.91(d, J=4.7Hz, 1H), 1.75–1.62(m, 2H), 1.57(d, J=10.0Hz, 1H),
1.25–1.10(m, 1H), 1.03–0.94(m, 2H), 0.85–0.70(m, 1H)。
Embodiment 10：
2- oxos -2-（2,3,4- trimethylbenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：With 2,3,4- trimethyls
Aniline replaces the aniline in embodiment 1, and other conditions are constant, yield 84.3%.
Embodiment 11：
2- oxos -2-（2- nitrobenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 2- nitroanilines
Aniline in example 1, other conditions are constant, yield 85.3%.
Embodiment 12：
2- oxos -2-（3- nitrobenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 3- nitroanilines
Aniline in example 1, other conditions are constant, yield 84.3%.
Embodiment 13：
2- oxos -2-（4- nitrobenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replace implementing with 4- nitroanilines
Aniline in example 1, other conditions are constant, yield 83.5%.
Embodiment 14：
2- oxos -2-（2,3,4- trinitrobenzen amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：With 2,3,4- trinitro-s
Aniline replaces the aniline in embodiment 1, and other conditions are constant, yield 83.3%.
Embodiment 15：
2- oxos -2-（2- methoxybenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 2- aminoanisoles
Aniline in embodiment 1, other conditions are constant, yield 85.6%.
Embodiment 16：
2- oxos -2-（3- methoxybenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 3- aminoanisoles
Aniline in embodiment 1, other conditions are constant, yield 84.1%.
Embodiment 17：
2- oxos -2-（4- methoxybenzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 4- aminoanisoles
Aniline in embodiment 1, other conditions are constant, yield 83.4%.
Embodiment 18：
2- oxos -2-（2,3,4- trimethoxy-benzene amidos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：With 2,3,4- front threes
Epoxide aniline replaces the aniline in embodiment 2, and other conditions are constant, yield 85.3%.
Embodiment 19：
2- oxos -2-（4- fluoroanilinos）- ethyl substitutes MOXIFLOXACIN, and preparation method is：Replaced with 4- fluoroanilines in embodiment 1
Aniline, other conditions are constant, yield 85.6%.H NMR (400 MHz, DMSO) δ 15.22(s, 1H), 9.51(s,
1H), 8.60(s, 1H), 7.54(d, J=14.1 Hz, 1H), 7.47–7.40(m, 2H), 6.96(t, J=8.9 Hz,
2H), 4.13–4.00(m, 1H), 3.94(td, J = 9.3, 4.1 Hz, 1H), 3.64(ddd, J=31.5, 15.9,
6.5 Hz, 3H), 3.53(s, 3H), 3.21(dd, J=27.9, 16.2Hz, 3H), 2.87(dd, J=7.4,
4.6Hz, 1H), 2.56–2.38(m, 2H), 1.90(s, 1H), 1.67(d, J=4.7 Hz, 2H), 1.61–1.50
(m, 1H), 1.23–1.09(m, 1H), 1.08–0.94(m, 2H), 0.82(dd, J=11.4, 4.9Hz, 1H)。
Anti tumor activity in vitro, using mtt assay, Prostatic cancer cell lines DU145 (ATCC-HTB-81), embodiment 1-19
The IC of the compound of preparation50(μm ol/L) is as follows：
As seen from table, 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound has excellent anti-prostate
Cancer activity.
Routine operation in the operating procedure of the present invention is well known to those skilled in the art, herein without repeating.
Technical scheme is described in detail embodiment described above, it should be understood that it is described above only
For the specific embodiment of the present invention, it is not intended to limit the invention, all any modifications made in the spirit of the present invention,
Supplement or similar fashion replacement etc., should be included in the scope of the protection.
Claims (8)
1. a kind of 2- oxos -2- (aryl aniline) ethyl substitutes MOXIFLOXACIN series compound, it is characterised in that：The compound
Structural formula be：
In type I compound, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or halogen or nitro or methyl
Or methoxyl group；R3Represent hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitro or methyl or methoxy
Base；R5Represent hydrogen or halogen or nitro or methyl or methoxy.
2. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 1, its
It is characterised by：The preparation method of the compound is：
Make the compound of formula II with moxifloxacin hydrochloride using triethylamine as acid neutralizing agent, in acetonitrile solvent, reacted in 95-105 DEG C,
Generate type I compound；In the compound of formula II, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or halogen or
Nitro or methyl or methoxy；R3Represent hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitro or first
Base or methoxyl group；R5Represent hydrogen or halogen or nitro or methyl or methoxy.
3. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 2, its
It is characterised by：The rate of charge of the compound of formula II and moxifloxacin hydrochloride is：1-1.3.
4. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 2, its
It is characterised by：The preparation method of the compound of formula II is：
Make the compound of formula III with KI in acetone solvent, in 77-82 DEG C of reaction, the compound of production II；The compound of formula III
In, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or halogen or nitro or methyl or methoxy；R3Table
Show hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitro or methyl or methoxy；R5Represent hydrogen or halogen
Element or nitro or methyl or methoxy.
5. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 4, its
It is characterised by：The rate of charge of the compound of formula III and KI is：0.6-0.7.
6. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 4, its
It is characterised by：The preparation method of the compound of formula III is：
Make the compound of formula IV with chloracetyl chloride using triethylamine as acid neutralizing agent, in dichloromethane solvent, under the conditions of ice-water bath
React the compound of production III；In the compound of formula IV, R1Represent hydrogen or halogen or nitro or methyl or methoxy；R2Represent hydrogen or
Halogen or nitro or methyl or methoxy；R3Represent hydrogen or halogen or nitro or methyl or methoxy；R4Represent hydrogen or halogen or nitre
Base or methyl or methoxy；R5Represent hydrogen or halogen or nitro or methyl or methoxy.
7. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 6, its
It is characterised by：The rate of charge of the compound of formula IV and chloracetyl chloride is 0.8-0.85.
8. a kind of 2- oxos -2- (aryl aniline) ethyl substitution MOXIFLOXACIN series compound according to claim 1, its
It is characterised by：The type I compound can be used for preparing anti-prostate cancer preparation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005034856A2 (en) * | 2003-09-05 | 2005-04-21 | The Regents Of The University Of Colorado | Targeted drug-formaldehyde conjugates and methods of making and using the same |
| CN103664940A (en) * | 2014-01-09 | 2014-03-26 | 北京恩成康泰生物科技有限公司 | Preparation method of moxifloxacin impurity |
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2017
- 2017-09-27 CN CN201710891055.XA patent/CN107880036A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005034856A2 (en) * | 2003-09-05 | 2005-04-21 | The Regents Of The University Of Colorado | Targeted drug-formaldehyde conjugates and methods of making and using the same |
| CN103664940A (en) * | 2014-01-09 | 2014-03-26 | 北京恩成康泰生物科技有限公司 | Preparation method of moxifloxacin impurity |
Non-Patent Citations (2)
| Title |
|---|
| AJAY GADGUL ET AL.: "Quinolones Chemistry and its Therapeutic Activities", 《RESEARCH J. PHARM. AND TECH.》 * |
| JYOTI MAREDDY ET AL.: "Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20180406 |