CN106798745A - A kind of medicine for treating tumor disease - Google Patents
A kind of medicine for treating tumor disease Download PDFInfo
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- CN106798745A CN106798745A CN201610541640.2A CN201610541640A CN106798745A CN 106798745 A CN106798745 A CN 106798745A CN 201610541640 A CN201610541640 A CN 201610541640A CN 106798745 A CN106798745 A CN 106798745A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of medicine for treating tumor disease, the medicine contains the acceptable salt of the biology of oxygen azepine trazodone derivative or type I compound with structural formula shown in formula I as active component；Wherein, 1) X is oxygen or sulphur；2) n=0 4；3) m=0 5；R2To be independently selected from：Hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, C1 C4 alkyl, C1 C3 alkoxies, C3 C7 cycloalkyl, halo C1 C6 alkyl, C2 C6 alkenyls, C1 C6 alkyl of hydroxyl substitution etc..Novel compounds with structure shown in formula I of the invention, can effectively suppress the growth of tumour cell, be applied to the treatment and prevention of tumor disease caused by various human body own cells misgrowths.
Description
Technical field
The present invention relates to a kind of heterocyclic compound, more particularly to a kind of oxygen azepine trazodone derivative belongs to biological medicine neck
Domain.
Background technology
Modern society's life rhythm is fast, and people's routine work pressure is big, is chronically at sub-health state.Autoimmunity
Deficiency, causes various exogenous germ invasions and endogenic abnormal growth of cells ratio persistently to increase, and seriously threatens the mankind
Life.The mankind are increasingly turned to organic chemical synthesis for the research of medicine since 20th century, and wherein micromolecular compound is only with its
The features such as stereoeffect, electronics distribution, spatial arrangement of active group of spy, give play to prominent in various disease treatments
The effect for going out.
Oxygen azepine trazodone derivative is to contain oxygen atom, the heterocycle of nitrogen-atoms, and it can be by the lactams in structure and life
In object there is hydrogen bond action in the enzyme related to tumor disease and acceptor 2.On the other hand, the aromatic rings and tumor disease in structure
Related enzyme and acceptor form the effect of aromatic ring stacking.So as to reach the purpose for the treatment of tumor disease.
The content of the invention
Object of the present invention is to provide a kind of oxygen azepine trazodone derivative with structure shown in formula I, while the present invention is also
Method there is provided the compound is prepared.
It is a further object of the present invention to provide a kind of medical compounds or composition for treating tumor disease, the medicine
Compound or composition contain the oxygen azepine trazodone derivative of formula I or the acceptable salt of its biology, used as being active component.
In order to realize foregoing invention purpose, the invention provides following technical scheme：
A kind of medicine for treating tumor disease, the medicine contains the oxygen azepine oxazolone with structural formula shown in formula I and spreads out
The acceptable salt of biology of biological or type I compound is used as active component.
Wherein,
1) X is oxygen or sulphur；
2) n=0-4；
R1It is independently selected from：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, C1-C7 alkyl, C1-C6 alkoxies,
C3-C7 cycloalkyl, C1-C6 alkoxy carbonyls, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl amino-carbonyls, substitution ammonia
Base, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, thiazinyl, pyrroles
Base, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl, furyl, pyranose, it is optionally substituted base
The heterocyclic radical of Y substitutions, is optionally substituted the aryl of base Y substitutions, is optionally substituted heteroaryl of base Y substitutions etc.；
Preferably, described heterocyclic radical is 5-6 former molecular heterocyclic group, has 1-3 hetero atom on heterocyclic radical,
Hetero atom therein is at least one in nitrogen, oxygen, sulphur.It is furthermore preferred that described heterocycle be furans, pyridine, pyrimidine, piperidines,
Thiophene, pyrroles, thiazole, purine, pyrans, oxazoles, imidazoles, pyrazine, quinoline etc..Above-mentioned heterocyclic radical can be by 1-3 low molecule
Alkyl replaces, and described low molecule alkyl is the 1-4 alkyl of carbon atom.
Described aryl is phenyl, naphthyl, tolyl, ethylbenzene, propyl group phenyl, ethenylphenyl, hydroxy phenyl, diformazan
Base phenyl, first ethylphenyl, chlorphenyl, trifluoromethyl, p-aminophenyl, formic acid phenyl etc..
Wherein described substitution base Y be hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, hydroxyl, nitro, aryl,
Amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl etc.；
The substituted-amino include phenyl amino, phenylmethyl amino, substituted-phenyl amino, methylamino, ethylamino,
Propylcarbamic, isopropylamino, cyclopropylamino, Cyclohexylamino, piperidyl amino, methyl piperidine base amino, pyridine radicals ammonia
Base, piperazinyl amino etc.；
The substituted-phenyl amino refers to MethYlphenylamino, ethylphenyl amino, propyl group phenyl amino, 3,5-dimethylphenyl
Amino, methyl (ethyl) phenyl amino, halogen substituted-phenyl amino, nitro-phenylamino, phenylsulfone base phenyl amino, Benzophenone
One in base phenyl amino and benzophenone base amino；
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl
(ethyl) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl.
3) m=0-5；
R2To be independently selected from：Hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, C1-C4 alkyl, C1-C3 alkoxies,
C3-C7 cycloalkyl, halo C1-C6 alkyl, C2-C6 alkenyls, C1-C6 alkyl, two (C1-C6 alkyl) amino-C1- of hydroxyl substitution
C6 alkyl, amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, amino-C1-C6 alkyl ammonia
Base, C1-C6 alkoxy C 1-C6 alkyl aminos, C1-C6 alkoxy carbonyls, C1-C6 alkyl aminos, two (C1-C6 alkoxy -Cs 1-
C6 alkyl) amino, amino carbonyl, C1-C6 alkyl amino-carbonyls, two (C1-C6 alkyl) amino carbonyls, C3-C7 cycloalkyl aminos
Carbonyl, C1-C6 alkoxies, C3-C7 cycloalkyloxies, hydroxyl-C1-C6 alkoxies, halo C1-C6 alkoxies, amino C1-C6 alkane
Base, amino C1-C6 alkoxies, C1-C6 alkyl sulfone, C2-C6 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7 cycloalkyl, halo C3-
C7 cycloalkyl, heterocyclic oxy group, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-C1-C6 alkyl, pyrrolylcarbonyl amido, N-
Methyl piperidine formamido or heterocycle C1-C6 alkyl oxies etc..Arbitrarily substituted base Z is monosubstituted or disubstituted amino.
Heterocycle in described heterocyclic oxy group be furans, pyridine, pyrimidine, piperidines, thiophene, pyrroles, thiazole, purine, pyrans,
Oxazole, imidazoles, pyrazine, quinoline etc..
It can be each independent substitution base that wherein described substitution base Z is, can also be to be interconnected to form when disubstituted
Loop configuration.
When it is each independent substitution base, Z is independently selected from：Hydrogen, halogen, cyano group, nitro, C1-C7 alkyl,
C1-C6 alkoxies, C3-C7 cycloalkyl, C1-C6 alkoxy carbonyls, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl aminos
Carbonyl, arbitrarily arylcarbonyl, substituted base Y arylcarbonyls, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyrrole
Piperidinyl, dihydropyridine base, tetrahydro pyridyl, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl,
Substituted piperazinyl, furyl, pyranose, be optionally substituted base Y substitution heterocyclic radical, be optionally substituted base Y substitution virtue
Base, is optionally substituted heteroaryl of base Y substitutions etc.；
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl
(ethyl) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl
Wherein described substitution base Y be hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, nitro, hydroxyl, aryl,
Amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl etc.；
Wherein described arylcarbonyl includes phenylcarbonyl group, PYRIDYLCARBONYL etc..
Further, preferably described X is oxygen or sulphur.
Further, it is preferred that n=0-3.
Further, it is preferred that R1It is independently selected from：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, C1-C5 alkyl,
C1-C4 alkoxies, C3-C6 cycloalkyl, C1-C4 alkoxy carbonyls, C1-C5 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl aminos
Carbonyl, substituted-amino, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, thiophene
Piperazine base, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl, furyl, pyranose.
Further, it is preferred that m=0-4；
Further, it is preferred that R2It is independently selected from：Hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, C1-C4 alkyl,
C1-C3 alkoxies, C3-C7 cycloalkyl, halo C1-C6 alkyl, C2-C6 alkenyls, C1-C6 alkyl, the two (C1-C6 of hydroxyl substitution
Alkyl) amino-C1-C6 alkyl, amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, ammonia
Base-C1-C6 alkyl aminos, C1-C6 alkoxy C 1-C6 alkyl aminos, C1-C6 alkoxy carbonyls, C1-C6 alkyl aminos, two
(C1-C6 alkoxy -C 1-C6 alkyl) amino, amino carbonyl, C1-C6 alkyl amino-carbonyls, two (C1-C6 alkyl) amino carbonyls,
C3-C7 cycloalkyl amino carbonyls, C1-C6 alkoxies, C3-C7 cycloalkyloxies, hydroxyl-C1-C6 alkoxies, halo C1-C6 alcoxyls
Base, amino C1-C6 alkyl, amino C1-C6 alkoxies, C1-C6 alkyl sulfone, C2-C6 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7
Cycloalkyl, halo C3-C7 cycloalkyl, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-(C1-C6) alkyl, pyrrolylcarbonyl
Amido, N- methyl piperidines formamido or heterocycle C1-C6 alkyl oxies.
The present invention additionally provides a kind of method for preparing above-mentioned type I compound simultaneously.
The method for synthesizing above-mentioned oxygen azepine trazodone derivative, comprises the following steps：
(1) it is with 2- hydroxy acetophenones (or 2- hydroxy acetophenones with substituted radical on phenyl ring) and substituted benzaldehyde
Initiation material, flavanone compound 1 is obtained through mannich condensation reaction；
(2) compound 2 is obtained through ring expansion after；
(3) wherein product 2a (one kind of compound 2, see formulas below) sulfonated, amination obtains compound 2f；
(4) another product 2d and 2h (one kind of compound 2, see formulas below) is the right phenyl ring-NO2Substitution, through reduction
The reduction of Fe powder obtains 3d and/or 3h；
(5) 3d is obtained amide product 4d and/or 4e with aromatic carboxylic acids condensation.
Reaction process is as follows：
Scheme 1.Reagents and conditions:a:PhNH2/I2,CH3OH,45℃,20-30h.b:NaN3,
CH3COOH/H2SO4,0℃-45℃,1-2h.
Scheme 2.Reagents and conditions:c:Fe/HCl, 75%ethyl alcohol.d:
different carboxylic acid treated with thionyl chloride,Dimethyl Formamide
catalyst.e:DIEA(Diisopropylethylamine),CH2Cl2,ice-bath,1-2h.
Scheme3.Reagents and conditions:c1:ClSO3H,ice-bath.d1:ammonium
hydroxide,100℃
The invention provides a kind of novel compounds with structure shown in formula I, can effectively suppress the growth of tumour cell,
It is applied to the treatment and prevention of tumor disease caused by various human body own cells misgrowths.
Application of the above-claimed cpd in preventing and/or treating tumor disease.
Compared with prior art, beneficial effects of the present invention：
1. present invention finds the oxygen azepine trazodone derivative of the novel structure with antitumor activity.
2. for the research and development of anti-cancer agent lay the foundation, for vast tumor patient provides anti-cancer agent.
3. antineoplastic has huge economic benefit.
Brief description of the drawings：
Fig. 1 is flavanones (1a)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 2 is flavanones (1a)13C-NMR (101MHz, DMSO-d6) spectrogram.
Fig. 3 is compound (2a)1H-NMR (400MHz, DMSO-d6) spectrogram.
Fig. 4 is compound (2a)13C-NMR (101MHz, DMSO-d6) spectrogram.
Fig. 5 is compound (3h)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 6 is compound (3h)13C-NMR(101MHz,DMSO-d6) spectrogram.
Fig. 7 is compound (4d)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 8 is compound (4d)13C-NMR(101MHz,DMSO-d6) spectrogram.
Fig. 9 is compound (2f)13C-NMR(101MHz,DMSO-d6) spectrogram.
Specific embodiment
Part technical term is explained as follows in the present invention：
Low alkyl group includes methyl, ethyl, propyl group, isopropyl, cyclopropyl, butyl, isobutyl group, the tert-butyl group, n-pentyl, different
Amyl group, neopentyl, hexyl, heptyl.
Halo includes fluoro, chloro, bromo, iodo.
C1-C5 alkyl includes：Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, n-amyl, iso- penta
Base, neopentyl, sec-amyl, tertiary pentyl etc..C1-C7 alkyl includes：Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, uncle
Butyl, n-amyl, iso- amyl group, neopentyl, sec-amyl, tertiary pentyl, hexyl, heptyl etc..Low-grade alkenyl includes：Vinyl, third
Alkenyl, cyclobutenyl, pentenyl, hexenyl, heptenyl, octenyl etc..
With reference to test example and specific embodiment, the present invention is described in further detail.But this should not be understood
For the scope of above-mentioned theme of the invention is only limitted to following embodiment, all technologies realized based on present invention belong to this
The scope of invention.
The compound of 1 formula of embodiment 1
To 20mL methyl alcohol is added in the dry round-bottomed flasks of 25mL, benzaldehyde (1.0mmol), aniline are sequentially added
(1.5mmol), 2- hydroxy acetophenones (1.2mmol), I2(0.3mmol) is stirred in 45 DEG C, through mannich condensation reaction, thin layer color
Spectrum (TLC) tracking reaction process.After reaction terminates, solvent is removed, add the saturation Na of ice2S2O3Solution 20mL, uses CH2Cl2(3*
20mL) extract.Merge organic phase, washed with saturation NaCl solution, frozen water successively, anhydrous Na2SO4Dry.Concentration organic phase is obtained slightly
Product, cyclohexane-ethyl acetate (V:V=6:1) column chromatography separating purification.Obtain flavanone compound (1a).
The compound of 2 formula of embodiment 2
To addition 4.5mmol flavanones (1a), 6.2mmol NaN in the dry round-bottomed flasks of 25mL3, 3.3mL glacial acetic acids,
It is stirred to dissolve, after ice bath cooling, is slowly added dropwise the dense H of 0.66mL2SO4.In being stirred on ice bath, until bubble is produced and continued
Ice bath completes exothermic reaction.It is transferred to 45-50 DEG C of reaction 45min.Cooling, adds 10%NaHCO3Ice water solution, during tune PH is in
Property.Ethyl acetate extracts (3*20), anhydrous MgSO4Dry, concentration organic phase obtains crude product, cyclohexane-ethyl acetate (V:V=
2:1) column chromatography separating purification.Obtain target compound (2a).
The formula 2f compounds of embodiment 3
Take 2- phenyl -3,4- dihydrobenzos [f] [1,4]-oxygen azatropylidene -5- (2H) -one (2a) 2.5mmol and be placed in 25ml tri-
In mouth bottle, in addition 2ml ClSO on ice bath3H, connects exhaust gas processing device, stirring until bubble-free is produced.Slowly will reaction
During liquid is poured into clean frozen water, it is stirred continuously, has solid to separate out, suction filtration, clear water washing filter cake.Filter cake is placed in reaction bulb, ice
3ml concentrated ammonia liquors are slowly added in bath, 100 DEG C of stirring 20-40min are transferred to, 15ml water is added, continue to stir 5-10min, it is quiet
Put, suction filtration, filtration cakes torrefaction obtains target compound (2f).
Formula 3d, the 3h compound of embodiment 4
PH value is adjusted to the ethanol of 25mL 75%, reduction 8mmol Fe powder, watery hydrochloric acid is added in the dry round-bottomed flasks of 25mL
After 3~4,80 DEG C of stirring 10min, add 2mmol compounds 2d or 2h, 80 DEG C of backflows, thin-layer chromatography (TLC) tracking react into
Journey, after reaction completely, cooling, suction filtration, filtrate uses NaHCO3Solution adjusts pH value 8~9, standing, suction filtration, filtrate ethyl acetate
(3*20mL) is extracted.Merge organic phase, anhydrous MgSO4Dry, concentration organic phase obtains target compound 3d, 3h.
Formula 4d, the 4e compound of embodiment 5
To addition 2mmol carboxylic acids, appropriate SOCl in the dry round-bottomed flasks of 25mL2, catalytic amount DMF
(DimethylFormamide), 80 DEG C of backflows, thin-layer chromatography (TLC) tracking reaction process, after reaction completely, revolving removes many
Remaining SOCl2, molten plus CH2Cl2Dissolving, is slowly added dropwise 3d containing compound, the CH of DIEA to ice bath cooling2Cl2In solution.Thin layer color
Spectrum (TLC) tracking reaction process, after reaction terminates, concentration organic phase obtains crude product, with cyclohexane-ethyl acetate (V:V=2:1)
Column chromatography separating purification.Obtain target compound 4d, 4e.
The Anti-tumor angiogenesis of embodiment 6 benzo [f] [1,4] oxygen azepine trazodone derivative
According to the processing step of embodiment 1-4, multi-stage synthesis obtain in Tables 1 and 2 compound (Coupounds) and by its
Tested for related Anti-tumor angiogenesis.The compound of the above-mentioned synthesis in part is used the measurement of test method of in vitro culture
Its IC for Hep-3B, Hela and MDA-MB-231 tumour cell50Concentration (MIC) is as a result as follows：
Cell growth inhibition assay
Using mtt assay：It is tri- kinds of cells of Hep-3B, Hela, MDA-MB-231 to adjust cell line with complete culture solution respectively
Cell concentration is 2 × 104/ ml, is inoculated in 96 orifice plates, per the μ L of hole 100, overnight incubation, next day respectively with various dose wait sieve
Compound (final concentration is respectively 40,20,10,5,2.5,1.25 μm of ol/L) is selected to process cell, while isometric solvent control
Group, DMSO concentration is 0.1% (0.1% DMSO cell proliferations do not influence).Each sets 5 multiple holes, 37 DEG C, 5%CO2Training
After supporting 48 hours, the μ L of 5mg/ml MTT reagents 20 are added per hole, continue to cultivate 2~4h, abandon supernatant, then add the μ L of DMSO 150,
Vibration mixes 15min, with ELIASA (λ=570nm) mensuration absorbance (A) value (A values are directly proportional to viable count), takes its average
Value.Relative cell proliferation inhibiting rate (%)=(control group A 570- experimental groups A 570)/control group A 570 × 100%, suppresses
Rate is the IC of the 50% compound concentration as compound50Value.Experiment is at least repeated 3 times.Positive control is phonetic using 5-F ureas
Pyridine.
According to the experimental technique of embodiment 1-6, the compound of synthesis, by nuclear magnetic spectrum monitoring analysis verification gained chemical combination
Thing, partial results are as shown in figs 1-9.The compound for obtaining will be synthesized carries out activity of tumor cells suppression experiment, and partial results are shown in
Table 1 is recorded.
The activity characterization result of the partially synthetic compound of table 1
* substituted radical R in the table1、R2Connection position of the numeric representation substituted radical for above recording on mother nucleus structure
Put, specifically the position on corresponding phenyl ring on parent nucleus.
It is good that above-mentioned result of the test shows that there is the compound on tumor cell of the structure shown in formula I of the present invention preparation growth to have
Inhibitory action, can be used for the treatment of various human tumor diseases.
The spectrogram of part of compounds
(1) spectrogram of flavanones midbody compound (1a)
Fig. 1 is flavanones (1a)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 2 is flavanones (1a)13C-NMR (101MHz, DMSO-d6) spectrogram.
(2) spectrogram of compound (2a)
Fig. 3 is (2a)1H-NMR (400MHz, DMSO-d6) spectrogram.
Fig. 4 is compound (2a)13C-NMR (101MHz, DMSO-d6) spectrogram.
(3) spectrogram of compound (3h)
Fig. 5 is compound (3h)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 6 is compound (3h)13C-NMR(101MHz,DMSO-d6) spectrogram.
(4) spectrogram of compound (4d)
Fig. 7 is compound (4d)1H-NMR(400MHz,DMSO-d6) spectrogram.
Fig. 8 is compound (4d)13C-NMR(101MHz,DMSO-d6) spectrogram.
(5) compound (2f) spectrogram
Fig. 9 is compound (2f)13C-NMR(101MHz,DMSO-d6) spectrogram.
The flow of embodiments in accordance with the present invention 1-6 synthesizes following chemical composition：
Table is 2-in-1 into compound situation
| Compound | ||
| 2001 | 2-OH | 3- propyl group epoxides |
| 2002 | 2- cyclohexyl | H |
| 2003 | H | 4- pyrazinyls |
| 2004 | 3-CN | 2- methyl, 3- methoxyl groups |
| 2005 | 3-Br | |
| 2006 | 2- ethylpropylaminos | |
| 2007 | H | 3- (4- methyl isophthalic acids-piperazinyl) |
| 2008 | 2- propyloxycarbonyl groups | H |
| 2009 | 2- piperidyls | |
| 2010 | 1- methyl, 2- ethyls | 3- n-pentyls |
| 2011 | 3- butyl | 2nd, 35 yuan of azacyclo-s of formation, imidazole ring |
| 2012 | H | 4- ethyoxyls |
| 2013 | 2- propylcarbamics | 4- (methyl) ethylamino |
* substituted radical R in the table1、R2The position of the numeric representation substituted radical for above recording.
Claims (10)
1. a kind of medicine for treating tumor disease, the medicine contains the oxygen azepine oxazolone with structural formula shown in formula I and derives
The acceptable salt of biology of thing or type I compound is used as active component；
Wherein,
1) X is oxygen or sulphur；
2) n=0-4；
R1It is independently selected from：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, C1-C7 alkyl, C1-C6 alkoxies, C3-C7 rings
Alkyl, C1-C6 alkoxy carbonyls, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl amino-carbonyls, substituted-amino, oxazole
Base, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, thiazinyl, pyrrole radicals, imidazoles
Base, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl, furyl, pyranose, be optionally substituted base Y1 substitution
Heterocyclic radical, be optionally substituted base Y1 substitution aryl, be optionally substituted base Y1 substitution heteroaryl；
Wherein described substitution base Y1 is hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, hydroxyl, nitro, aryl, ammonia
Base, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl；
The substituted-amino includes phenyl amino, phenylmethyl amino, substituted-phenyl amino, methylamino, ethylamino, propyl group
Amino, isopropylamino, cyclopropylamino, Cyclohexylamino, piperidyl amino, methyl piperidine base amino, pyridinylamino, piperazine
Piperazine base amino；
The substituted-phenyl amino refers to MethYlphenylamino, ethylphenyl amino, propyl group phenyl amino, 3,5-dimethylphenyl ammonia
Base, methyl (ethyl) phenyl amino, halogen substituted-phenyl amino, nitro-phenylamino, phenylsulfone base phenyl amino, Benzophenone base
One in phenyl amino and benzophenone base amino；
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl (second
Base) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl；
3) m=0-5；
R2To be independently selected from：Hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, C1-C4 alkyl, C1-C3 alkoxies, C3-C7
Cycloalkyl, halo C1-C6 alkyl, C2-C6 alkenyls, C1-C6 alkyl, two (C1-C6 alkyl) amino-C1-C6 alkane of hydroxyl substitution
Base, amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, amino-C1-C6 alkyl aminos,
C1-C6 alkoxy C 1-C6 alkyl aminos, C1-C6 alkoxy carbonyls, C1-C6 alkyl aminos, two (C1-C6 alkoxy -C 1-C6 alkane
Base) amino, amino carbonyl, C1-C6 alkyl amino-carbonyls, two (C1-C6 alkyl) amino carbonyls, C3-C7 cycloalkyl amino carbonyls,
C1-C6 alkoxies, C3-C7 cycloalkyloxies, hydroxyl-C1-C6 alkoxies, halo C1-C6 alkoxies, amino C1-C6 alkyl, amino
C1-C6 alkoxies, C1-C6 alkyl sulfone, C2-C6 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkanes
Base, heterocyclic oxy group, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-C1-C6 alkyl, pyrrolylcarbonyl amido, N- methyl piperazines
Pyridine formamido or heterocycle C1-C6 alkyl oxies etc.；Arbitrarily substituted base Z is monosubstituted or disubstituted amino；
Heterocycle in described heterocyclic oxy group is one below：Furans, pyridine, pyrimidine, piperidines, thiophene, pyrroles, thiazole, purine,
Pyrans, oxazoles, imidazoles, pyrazine, quinoline；
It can be each independent substitution base that wherein described substitution base Z is, can also be the ring being interconnected to form when disubstituted
Shape structure；
When it is each independent substitution base, Z is independently selected from：Hydrogen, halogen, cyano group, nitro, C1-C7 alkyl, C1-
C6 alkoxies, C3-C7 cycloalkyl, C1-C6 alkoxy carbonyls, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl amino carbonyls
Base, arbitrarily arylcarbonyl, substituted base Y2 arylcarbonyls, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyridine
Base, dihydropyridine base, tetrahydro pyridyl, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, take
For piperazinyl, furyl, pyranose, be optionally substituted base Y2 substitution heterocyclic radical, be optionally substituted base Y2 substitution virtue
Base, is optionally substituted the heteroaryl of base Y2 substitutions；
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl (second
Base) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl；
Wherein described substitution base Y2 is：Hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, nitro, hydroxyl, aryl, ammonia
Base, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl；
Wherein described arylcarbonyl includes phenylcarbonyl group, PYRIDYLCARBONYL.
2. compound as claimed in claim 1, it is characterised in that in R1, the heterocyclic radical of described substituted base Y1 substitutions is
5-6 former molecular heterocyclic groups, have a 1-3 hetero atom on heterocyclic radical, hetero atom therein be in nitrogen, oxygen, sulphur extremely
Few one kind；Above-mentioned heterocyclic radical can be replaced by 1-3 low molecule alkyl, and described low molecule alkyl is 1-4 carbon atom
Alkyl.
3. compound as claimed in claim 2, it is characterised in that described heterocycle be furans, pyridine, pyrimidine, piperidines, thiophene,
Pyrroles, thiazole, purine, pyrans, oxazoles, imidazoles, pyrazine, quinoline etc..
4. compound as claimed in claim 1, it is characterised in that in R1, the aryl of described substituted base Y1 substitutions is benzene
Base, naphthyl, tolyl, ethylbenzene, propyl group phenyl, ethenylphenyl, hydroxy phenyl, 3,5-dimethylphenyl, first ethylphenyl, chlorobenzene
Base, trifluoromethyl, p-aminophenyl, formic acid phenyl.
5. compound as claimed in claim 1, it is characterised in that n=0-3.
6. compound as claimed in claim 1, it is characterised in that R1It is independently selected from：Hydrogen, halogen, hydroxyl, cyano group, nitre
Base, amino, C1-C5 alkyl, C1-C4 alkoxies, C3-C6 cycloalkyl, C1-C4 alkoxy carbonyls, C1-C5 alkyl-carbonyls, amino
Carbonyl, C1-C6 alkyl amino-carbonyls, substituted-amino, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydro pyrrole
Piperidinyl, tetrahydro pyridyl, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl,
Furyl, pyranose.
7. compound as claimed in claim 1, it is characterised in that m=0-4.
8. compound as claimed in claim 1, it is characterised in that R2It is independently selected from：Hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group,
Nitro, C1-C4 alkyl, C1-C3 alkoxies, C3-C7 cycloalkyl, halo C1-C6 alkyl, C2-C6 alkenyls, the C1- of hydroxyl substitution
C6 alkyl, two (C1-C6 alkyl) amino-C1-C6 alkyl, amino, C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-
C6 alkyl) amino, amino-C1-C6 alkyl aminos, C1-C6 alkoxy C 1-C6 alkyl aminos, C1-C6 alkoxy carbonyls, C1-C6
Alkyl amino, two (C1-C6 alkoxy -C 1-C6 alkyl) amino, amino carbonyl, C1-C6 alkyl amino-carbonyls, two (C1-C6 alkane
Base) amino carbonyl, C3-C7 cycloalkyl amino carbonyls, C1-C6 alkoxies, C3-C7 cycloalkyloxies, hydroxyl-C1-C6 alkoxies, halogen
For C1-C6 alkoxies, amino C1-C6 alkyl, amino C1-C6 alkoxies, C1-C6 alkyl sulfone, C2-C6 alkenyls sulfone, C3-C7 cycloalkanes
Base sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-(C1-C6) alkane
Base, pyrrolylcarbonyl amido, N- methyl piperidines formamido or heterocycle C1-C6 alkyl oxies.
9. a kind of method for preparing above-mentioned type I compound, comprises the following steps：
(1) with the 2- hydroxy acetophenones with substituted radical on 2- hydroxy acetophenones or phenyl ring, and substituted benzaldehyde is starting
Raw material, flavanone compound 1 is obtained through mannich condensation reaction；
(2) compound 2 is obtained through ring expansion after；
(3) wherein product 2a is sulfonated, amination obtains compound 2f；
(4) another product 2d and 2h are the right phenyl ring-NO2Substitution, 3d or 3h is obtained through reducing the reduction of Fe powder；
(5) 3d is obtained amide product 4d and 4e with aromatic carboxylic acids condensation；
Reaction process is as follows：
10. the above-mentioned compound with structure shown in formula I, the application in the medicine for preventing and/or treating tumor disease.
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| CN110615784A (en) * | 2019-10-25 | 2019-12-27 | 南开大学 | Synthesis and application of lactone analogue with flavone skeleton |
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| CN1278797A (en) * | 1997-09-03 | 2001-01-03 | 吉尔福特药品有限公司 | Oxo-substituted compouns, process of making, and compositions and methods for inhibiting parp activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1278797A (en) * | 1997-09-03 | 2001-01-03 | 吉尔福特药品有限公司 | Oxo-substituted compouns, process of making, and compositions and methods for inhibiting parp activity |
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| CN110615784A (en) * | 2019-10-25 | 2019-12-27 | 南开大学 | Synthesis and application of lactone analogue with flavone skeleton |
| CN110615784B (en) * | 2019-10-25 | 2022-10-25 | 南开大学 | Synthesis and application of lactone analogue with flavone skeleton |
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