CN105601561B - Piperidones Schiff base derivatives of 3,5 2 aryl methylene 4 with antitumor activity and preparation method thereof - Google Patents
Piperidones Schiff base derivatives of 3,5 2 aryl methylene 4 with antitumor activity and preparation method thereof Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/68—One oxygen atom attached in position 4
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Abstract
Being used for antitumor N methyl 3,5 two the present invention relates to five kinds, (3 (2 phenol methylene amino) 4 piperidones compounds and preparation method thereof, belong to antineoplastic and preparation method thereof technical field.Its preparation method is to carry out Clarkson Schmidt condensation by N methylpiperidones and m-nitrobenzaldehyde to react to obtain intermediate, obtained midbody compound is reduced with reducing agent again to obtain reduzate, final product A, B, C, D, E are obtained finally by aldol reaction.3,5 two (3 (the 2 oxybenzene methene amido) benzylidene), 4 derivative of piperidone A~E, can avoid the genotoxicity of antineoplastic used now, antitumor activity is good, and targeting is clear and definite.Preparation method is easy, and reaction condition is gentle, and synthetic yield is high, beneficial to its being widely popularized in antitumor field.
Description
Technical field
Spread out the present invention relates to 5 kinds with antitumor containing the active aryl methylene -4- piperidones schiff bases of phenolic hydroxyl group 3,5- bis-
The preparation method and bioactivity of biology, belong to antineoplastic and preparation method technical field.
Background technology
α, alpha, beta-unsaturated ketone Numerous, is widely used.Because its carbon-carbon double bond and carbonyl are conjugated, therefore have alkene, ketone concurrently
With the property of conjugated diene, there is good reactivity worth, such as carry out Michael addition reactions[1], Diels-Alder is anti-
Should[2]Deng.In addition itself or a kind of important organic synthesis intermediate, are widely used in the fields such as medicine, agricultural chemicals, spices.
Wait people quietly[3]Report the effect of the anti-prodenia litura of chalcone.In addition, α, alpha, beta-unsaturated ketone also show antitumor, anti-
The multiple pharmacological effects such as scorching, anti-malarial effect.
Piperidines, piperidones and its derivative are conventional chemical raw materials or intermediate, because its universal bioactivity
It is widely used in analgesia, anti-inflammatory, antihistamine, anti-arrhythmia cordis, antipsychotic and the synthesis of medicine such as antitumor, it is resulting
Clinical medicine in clinical treatment in occupation of irreplaceable status, therefore, the research for such compound is always to cure
The study hotspot in medicine field.Piperidones and its derivative are extremely important piperidineses, utilize the carbonyl in its structure
And its on ortho position methylene activity, many organic synthesis can be triggered, thus derive many practical medicine, agricultural chemicals,
Chemical intermediate[4]。
Aryl methylene -4- the derivative of piperidone of 3,5- bis- is the medicine that a kind of alpha, beta-unsaturated ketone is combined with beta-amino ketones
Thing.Contain two α in molecule, alpha, beta-unsaturated ketone unit, continuous alkylation twice, this continuousization can be formed to sulfydryl
Learning to combine makes tumor cell ratio normal cell be more vulnerable to injure, therefore has bigger toxicity to tumour cell, and to normal
Cytotoxic or toxicity very little, and after the nitrogen-atoms of piperidones is substituted, then it can be formed and another be combined with tumour cell
Auxiliary anchor position.Research finds, schiff bases in field of medicaments, have antibacterial, sterilization, anti-inflammatory, antituberculosis, leprosy,
Antitumor, antiviral bioactivity.The present invention has synthesized the aryl methylene -4- piperidones Schiff bases derivatives of 3,5- bis-.And
Study its antitumor activity.
The content of the invention
It is contemplated that the new type antineoplastic medicine small to normal cytotoxicity is found, thus, there is provided one kind has anti-
Aryl methylene -4- piperidones the Schiff base derivatives of 3,5- bis- of tumor promotion, it has preferable antitumor activity, and the present invention is together
When provide the preparation method of the derivative.
The present invention is achieved by the following technical solutions：
Aryl methylene -4- piperidones the Schiff base derivatives of 3,5- bis- with antitumor activity, the structure of its target product
Formula is：
It is respectively designated as：
N- methyl -3,5- bis- (3- (2- phenol methylenes amino) 4- piperidones (A),
N- methyl -3,5- bis- (3- (2- hydroxyl-5-fluorines benzylideneamino) 4- piperidones (B),
N- methyl -3,5- bis- (3- (2- hydroxyl -5- bromobenzenes methene amido) 4- piperidones (C),
N- methyl -3,5- bis- (3- (2- hydroxyl -4- methoxybenzylidenes amino) 4- piperidones (D),
(3- (2- hydroxy-3-methoxy -5- bromobenzenes methene amido) the 4- piperidones (E) of N- methyl -3,5- two.
The preparation method of the above-mentioned aryl methylene -4- piperidones Schiff base derivatives of 3,5- bis-, its principle are：Pass through N- first
Methylpiperidone and m-nitrobenzaldehyde carry out Claisen-Schmidt condensation and react to obtain midbody compound, then will obtain
Midbody compound is reduced to obtain reduction amino intermediate with reducing agent to nitro, then by itself and different hydroxy benzaldehydes
Series raw material is reacted, and obtains final product A, B, C, D, E.
The preparation method of the aryl methylene -4- piperidones Schiff base derivatives of 3,5- bis- with antitumor activity, its is special
Part is, comprises the following specific steps that：
By hydroxy benzaldehyde series raw material and N- methyl -3,5- bis- (3- amino benzylidene) -4- piperidones raw materials, in alcohol
Mixed in solution, add catalyst, stirring at normal temperature reaction a period of time, precipitation filters, and obtains invention product 3, bis- fragrant methylenes of 5-
Base -4- piperidones Schiff base derivatives A~E.
And pass through nuclear magnetic resonance, the correctness of infrared spectrum its structure.
In invention product 3, the aryl methylene -4- piperidones Schiff base derivatives A~E of 5- bis- preparation process, hydroxy benzenes
Formaldehyde series raw material refers to Benzaldehyde,2-hydroxy, 2- hydroxyl-5-fluorines benzaldehyde, 2- hydroxyl 5- bromobenzaldehydes, 2- hydroxyl 4- methoxies
Benzaldehyde or 2- hydroxy-3-methoxy -5- bromobenzaldehydes；
In invention product 3, the aryl methylene -4- piperidones Schiff base derivatives A~E of 5- bis- preparation process, alcoholic solution
Alcohol be methanol, ethanol, any one in isopropanol；
In invention product 3, the aryl methylene -4- piperidones Schiff base derivatives A~E of 5- bis- preparation process, addition is urged
Agent is any one in formic acid, acetic acid, and mass concentration is 0.1%~2%；
In invention product 3, the aryl methylene -4- piperidones Schiff base derivatives A~E of 5- bis- preparation process, to ensure
N- methyl -3,5- bis- (3- amino benzylidene) -4- piperidines reactive ketones are complete, hydroxy benzaldehyde series raw material and N- in the present invention
The mol ratio of methyl -3,5- two (3- amino benzylidene) -4- piperidones raw materials is more than 2:1；
In invention product 3, the aryl methylene -4- piperidones Schiff base derivatives A~E of 5- bis- preparation process, at one section
Between refer to 2~18 hours.
3,5- bis- (3- (2- oxybenzenes methene amido) benzylidene) -4- piperidones that the present invention has antitumor activity spreads out
Biological A~E, the genotoxicity of antineoplastic used now can be avoided, antitumor activity is good, and targeting is clear and definite.Preparation method
Simplicity, reaction condition is gentle, and synthetic yield is high, beneficial to its being widely popularized in antitumor field.
Embodiment
Embodiment of the invention given below, for the present invention is further described.
Embodiment 1
The synthesis of N- methyl -3,5- two (3- amino benzylidene) -4- piperidones
The m-nitrobenzaldehyde of 0.01mol N- methyl -4- piperidones and 0.022mol is mixed in 20mL first alcohol and waters
Solution in, at room temperature add the sodium hydroxide solutions of 20mL 20%, stirring at normal temperature reaction 12h, pass through thin-layered chromatography (TLC)
Tlc analysis determines reaction end.Precipitation filter intermediate is buff powder.By intermediate and 0.065mol stannous chlorides
6~8h of stirring reaction in 25mL concentrated hydrochloric acids is added to, is analyzed by thin-layered chromatography (TLC) and determines reaction end, precipitation filters,
10% sodium carbonate liquor lotion, 15mL ethanol/waters (volume ratio 1:1) yellow powder, i.e. N- methyl -3,5- bis- are recrystallized to give
(3- amino benzylidene) -4- piperidones.
Embodiment 2
(3- (2- phenol methylenes amino) the 4- piperidones (A) of N- methyl -3,5- two
By (3- amino the benzylidene) -4- piperidones of 0.001molN- methyl -3,5- two and 0.0025mol2- hydroxy benzenes first
Aldehyde is miscible in 30mL ethanol, 3 drop formic acid is added dropwise at room temperature, stirring at normal temperature reacts more than 9h, true by thin-layered chromatography (TLC)
Determine reaction end.Filtering after completion of the reaction, gained precipitation is washed with ethanol, and yellow powder is recrystallized to give with 30mL ethanol/waters,
That is N- methyl -3,5- bis- (3- (2- hydroxy-benzylidenes amino) 4- piperidones (A) derivative 0.2978g, yield 52%.
IR(cm-1):1675(w),1615(m),1563(m),1278(m),1182(w),1152(w),1102(w),1058
(w),974(w),922(w),881(w),800(s),743(m),691(m),539(w),424(w).1H NMR(400MHz,
CDCl3,25℃,TMS,ppm):δ12.95(s,2H),8.50-8.35(m,2H),7.74-7.58(m,2H),7.40-7.00(m,
12H),6.95-6.70(m,4H),3.70-3.50(m,4H),2.40-2.20(m,3H).13C NMR(125MHz,CDCl3):δ
186.62,163.47,161.08,148.94,136.49,135.80,133.73,133.48,132.46,129.63,128.58,
122.99,121.58,119.22,119.05,117.29,56.98,45.89.Elemental analysis (%)
caled.For C34H29N3O3:C 77.40,H5.54,N 7.96.Found:C 77.38,H 5.57,N 7.98.
Embodiment 3
(3- (2- hydroxyl-5-fluorines benzylideneamino) the 4- piperidones (B) of N- methyl -3,5- two
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.0022mol 2- hydroxyls -
5- fluorobenzaldehydes are miscible in 20mL methanol, and 2 drop formic acid are added dropwise at room temperature, stirring at normal temperature reaction 3h, pass through thin-layered chromatography
(TLC) reaction end is determined.Filtering after completion of the reaction, gained precipitation is washed with methanol, obtains yellow powder, i.e. N- methyl -3,
5- bis- (3- (2- hydroxyl-5-fluorines benzylideneamino) 4- piperidones (B) derivative 0.366g, yield 65%.
IR(cm-1):2937(br),1672(w),1617(m),1568(s),1488(m),1354(w),1327(w),1277
(s),1244(m),1213(m),1182(s),1141(s),1102(w),1056(m),1033(w),1006(w),908(w),
867(w),822(s),797(s),784(s),687(m),672(w),606(w),576(w),539(m),518(w),509(m)
.1H NMR(400MHz,CDCl3,25℃,TMS,ppm):δ12.79(s,2H),8.60(s,2H),7.98(s,2H),7.53(t,J
=8HZ 2H), 7.33 (d, J=8HZ 4H), 7.27 (s, 2H), 7.15 (d, J=8HZ 4H), 7.02 (q, J=4HZ 2H),
4.02 (s, 4H), 2.59 (s, 3H) .Elemental analysis (%) caled.For C34H27F2N3O3:C 72.46,H
4.83,N 7.46.Found:C 72.48,H 4.80,N 7.44.
Embodiment 4
(3- (2- hydroxyl -5- bromobenzenes methene amido) the 4- piperidones (C) of N- methyl -3,5- two
By (3- amino the benzylidene) -4- piperidones of 0.001molN- methyl -3,5- two and 0.0022mol 2- hydroxyls 5-
Bromobenzaldehyde is miscible in 20mL isopropanols, at room temperature 2 drop formic acid, stirring at normal temperature reaction 3h, by thin-layered chromatography (TLC) really
Determine reaction end.Filter after completion of the reaction, gained precipitation is washed with isopropanol, obtains orange-yellow powder, i.e. N- methyl -3,5- bis-
(3- (2- hydroxyl -5- bromobenzenes methene amido) 4- piperidones (C) derivative 0.44g, yield 64%.
IR(cm-1):1672(w),1614(s),1593(w),1561(s),1476(m),1352(m),1277(s),1225
(m),1182(s),1103(m),1107(m),936(w),907(m),810(s),794(s),713(w),683(s),628(m),
604(w),538(m),519(w).1H NMR(400MHz,CDCl3,25℃,TMS,ppm):δ13.02(s,2H),8.59(s,
2H), 8.04 (s, 2H), 7.59-7.46 (m, 6H), 7.32 (t, J=4Hz 4H), 7.27 (s, 2H), 6.97 (d, J=8Hz
2H), 4.13 (s, 4H), 2.62 (s, 3H) .Elemental analysis (%) caled.For C34H27Br2N3O3:C 59.58,
H 3.97,N 6.13.Found:C 59.55,H 4.01,N 6.13.
Embodiment 5
(the synthesis of 3- (2- hydroxyl -4- methoxybenzylidenes amino) 4- piperidones (D) of N- methyl -3,5- two
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.003mol 2- hydroxyls 4-
Methoxybenzaldehyde is miscible in 35mL ethanol, and 6 drop formic acid are added dropwise at room temperature, stirring at normal temperature reaction more than 8h, pass through thin layer color
Spectrometry (TLC) determines reaction end.Filter after completion of the reaction, gained precipitation is washed with isopropanol, is recrystallized with 20mL ethanol/waters
Obtain yellow powder, i.e. (3- (2- hydroxyl -4- methoxybenzylidenes amino) 4- piperidones (D) derivative of N- methyl -3,5- bis-
0.32g, yield 54%.
IR(cm-1):1672(w),1614(s),1590(m),1563(s),1512(w),1399(w),1434(w),1287
(m),1210(s),1181(m),1163(s),1135(m),1115(m),1055(w),1031(w),966(w),915(w),834
(m),791(m),686(m),647(w),536(m).1H NMR(400MHz,CDCl3):δ13.57(s,2H),8.56(s,2H),
7.89 (s, 2H), 7.50 (t, J=8Hz 2H), 7.36-7.20 (m, 8H), 6.54 (d, J=4Hz 4H), 3.87 (s, 10H),
2.18 (s, 3H) .Elemental analysis (%) caled.For C36H33N3O5:C 73.58,H 5.66,N
7.15.Found:C 73.61,H5.65,N 7.18.
Embodiment 6
(the synthesis of 3- (2- hydroxy-3-methoxy -5- bromobenzenes methene amido) 4- piperidones (E) of N- methyl -3,5- two
By (3- amino the benzylidene) -4- piperidones of 0.001mol N- methyl -3,5- two and 0.003mol 2- hydroxyls -3-
Methoxyl group -5- bromobenzaldehydes are miscible in the solution of 30mL second alcohol and waters, and 5 drop formic acid, stirring at normal temperature reaction 5bh are added dropwise at room temperature
More than, reaction end is determined by thin-layered chromatography (TLC).Filter after completion of the reaction, gained precipitation is washed with ethanol, obtains Huang
Color powder, i.e. N- methyl -3,5- bis- (3- (2- hydroxy-3-methoxy -5- bromobenzenes methene amido) 4- piperidones (E) derivative
0.45g, yield 60%.
IR(cm-1):1672(w),1614(m),1590(w),1567(m),1469(s),1394(w),1330(w),1276
(w),1253(s),1182(s),1104(w),973(m),908(w),865(m),832(m),791(w),751(w),684(m),
570(m),551(w),533(m),504(w).1H NMR(400MHz,CDCl3):δ13.60(s,2H),8.58(s,2H),7.87
(s, 2H), 7.51 (t, J=8Hz 2H), 7.37-7.27 (m, 6H), 7.19 (s, 2H), 7.09 (s, 2H), 3.95 (s, 6H),
3.86 (s, 4H), 2.51 (s, 3H) .Elemental analysis (%) caled.For C36H31Br2N3O5:C 58.00,H
4.19,N 5.64.Found:C 57.97,H 4.21,N 5.65.
Antitumor activity evaluation
The antitumor activity evaluation of the aryl methylene -4- piperidones Schiff base derivatives of 3,5- bis- of the present invention.
Antitumor activity evaluation uses mtt assay in the present invention.
5 kinds of cell lines are used in the present invention altogether, are Human normal hepatocyte cell line LO2, Human cervical cancer cell lines respectively
Hela, human hepatoma cell line HepG2, human leukemia cell line K562 and people's monokaryon myeloid leukemia cell line THP-1, one
Four tumor cell lines of normal cell system, all from China Concord Medical Science University.The RPMI- of 10% hyclone of cell
1640 culture medium 37 DEG C, 5%CO2, saturated humidity incubator in cultivate.
The cell in growth period of taking the logarithm is configured to 4 × 104/mL cell suspension, is inoculated in 96 well culture plates, per hole
Add 200 μ L, culture adds the synthesis compound of 20 μ L various concentrations after 24 hours, after continuing culture 24 hours, added to every hole
20 μ L MTT reagents, after 37 DEG C are incubated 4 hours, supernatant is abandoned, add 150 μ L DMSO, vibration 10min fully to dissolve knot per hole
Crystalline substance, the absorbance at 570nm is determined with ELIASA, calculates IC50.The concentration of compound used therefor is 10 μ g/mL, 6 μ g/ respectively
ML, 5 μ g/mL, 3 μ g/mL, 2 μ g/mL, 1.5 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.1 μ g/mL, the positive is done with adriamycin (DOX)
Control, concentration used is 8 μ g/mL, 6 μ g/mL, 5 μ g/mL, 3 μ g/mL, 1.5 μ g/mL, 1 μ g/mL, 0.8 μ g/mL, 0.5 respectively
μ g/mL, 0.1 μ g/mL, each concentration set 6 multiple holes.
The half-inhibition concentration IC50 (μM) of 5 kinds of compounds, it is as shown in the table.
The half-inhibition concentration (μM) of 15 kinds of compounds of table
5 kinds of compounds are less than 5 μM to the IC50 values equal 90% of 4 tumor cell lines as can be seen from the table, to normal thin
The toxicity of born of the same parents is small compared with tumour cell, particularly compound A to THP-1, B to HePG2, D to THP-1, E to THP-1.5 kinds of medicines
10 μM are all higher than to the toxicity of LO2 cells.Illustrate that this 5 kinds of compounds have preferable activity to tumor cell line used, and
To the toxicity very little of normal cell.
Bibliography:
[1] Ou Yangyan, in Haifeng county, Dong Dewen, the mikey of thiol equivalents and alpha, beta-unsaturated ketone under condition of no solvent is waited
That addition reaction [J] Northeast China Normal University journal:Natural science edition, 2006,38 (1):67-71.
[2] cycloaddition reaction of Pei Wen, Zheng Minghua, Xu Mingzhe benzenesulfonyls alpha, beta-unsaturated ketone and cyclopentadiene activity
Research [J] Yanbian Universitys journal:Natural science edition, 1997 (3):37-40.
[3] insecticidal activity [J] the tropical crops of Zhang Jing, Hu Linfeng, Feng Gang .3 kinds Chalcone Compounds to prodenia litura
Journal, 2010 (10):1821-1824.
[4]Comins D L,Brooks C A,Ingalls C L.Reduction of N-Acyl-2,3-dihydro-
4-pyridones to N-Acyl-4-piperidones Using Zinc/Acetic Acid.[J].Cheminform,
2001,32(29):56-56.
Claims (8)
1. aryl methylene -4- piperidones the Schiff base derivatives of 3,5- bis- with antitumor activity, its structural formula are：
It is respectively designated as：
N- methyl -3,5- two（3-（2- phenol methylene amino）4- piperidones A,
N- methyl -3,5- two（3-（2- hydroxyl-5-fluorine benzylideneaminos）4- piperidones B,
N- methyl -3,5- two（3-（2- hydroxyl -5- bromobenzene methene amidos）4- piperidones C,
N- methyl -3,5- two（3-（2- hydroxyl -4- methoxybenzylidene amino）4- piperidones D,
N- methyl -3,5- two（3-（2- hydroxy-3-methoxy -5- bromobenzene methene amidos）4- piperidones E.
2. the system of the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- with antitumor activity described in claim 1
Preparation Method, it is characterised in that comprise the following steps that：
By hydroxy benzaldehyde series raw material withN- methyl -3,5- two（3- amino benzylidenes）- 4- piperidones raw materials, it is water-soluble in alcohol
Being mixed in liquid, add catalyst, stirring at normal temperature reaction a period of time, precipitation filters, and obtains invention product 3, the aryl methylenes of 5- bis--
4- piperidones Schiff base derivatives A ~ E；And pass through nuclear magnetic resonance, the correctness of infrared spectrum its structure.
3. there is the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- of antitumor activity as claimed in claim 2
Preparation method, be characterised by
Hydroxy benzaldehyde series raw material refers to Benzaldehyde,2-hydroxy, 2- hydroxyl-5-fluorines benzaldehyde, 2- hydroxyl 5- bromobenzaldehydes, 2-
Hydroxyl 4-methoxybenzaldehyde or 2- hydroxy-3-methoxy -5- bromobenzaldehydes.
4. there is the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- of antitumor activity as claimed in claim 2
Preparation method, be characterised by
The alcohol of alcohol solution is any one in methanol, ethanol, isopropanol.
5. there is the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- of antitumor activity as claimed in claim 2
Preparation method, be characterised by
Addition catalyst is any one in formic acid, acetic acid, and mass concentration is 0.1% ~ 2%.
6. there is the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- of antitumor activity as claimed in claim 2
Preparation method, be characterised by
Hydroxy benzaldehyde series raw material withN- methyl -3,5- two（3- amino benzylidenes）The mol ratio of -4- piperidones raw materials is big
In 2:1.
7. there is the aryl methylene -4- piperidones Schiff base derivatives A ~ E of 3,5- bis- of antitumor activity as claimed in claim 2
Preparation method, be characterised by
A period of time refers to 2~18 hours.
8. aryl methylene -4- piperidones Schiff base derivatives of 3,5- bis- with antitumor activity described in claim 1 with
In preparing the application in antineoplastic.
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