CN108191750A - Bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5- and preparation method thereof - Google Patents
Bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5- and preparation method thereof Download PDFInfo
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- 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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Abstract
The present invention relates to ten to have antitumor and anti-inflammatory activity 3,5 two aryl methylene N benzenesulfonyls, 4 piperidines ketone compound, belongs to antitumor and anti-inflammatory drug technical field.Preparation method is to carry out Clarkson Schmidt condensation with aromatic aldehyde respectively by 4 piperidone hydrochlorides first to be obtained by the reaction 3; 5 two aryl methylene N H, 4 piperidone hydrochloride intermediates; and then benzene sulfonyl occurs with sulfonylation agent, 3,5 two aryl methylene N benzenesulfonyls, 4 piperidines ketone compound is obtained by the reaction.The compound antitumor and anti-inflammatory activity are good, can avoid the genotoxicity of the antineoplastic used now, to the small toxicity of normal cell, while have anti-inflammatory activity.Preparation method is easy to operate, and reaction condition is mild, and synthetic yield is high, conducive to its being widely popularized in antitumor and anti-inflammatory field.
Description
Technical field
The present invention relates to a series of with antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperazines of 3,5-
Pyridine ketone compound belongs to antitumor and anti-inflammatory drug and preparation method thereof technical field.
Background technology
Curcumin is a kind of yellow phenol sulfonate obtained from zingiberaceous plant (such as turmeric, curcuma zedoary etc.) rhizome, due to it
With anti-inflammatory, antibacterial, antitumor, anti-oxidant, antiprotozoan, antirheumatic, anti-senile dementia, liver protection, cholagogic, analgesic, diuresis, drop blood
The effect of sugar and stomach invigorating is paid much attention to by domestic and international medical field.But since its poorly water-soluble, structural instability, biology can
The shortcomings such as availability is low, seriously affect its clinical practice.Therefore, transformation is optimized to its structure, by two among curcumin
Ketone structure replaces -4- piperidones to replace to obtain novel 3,5-, bis- aryl methylene -4- piperidones with N-, it is expected such compound energy
The shortcomings that enough improving curcumin.
Novel 3,5-, bis- aryl methylene -4- piperidones (3,5-bis (arylmethylene) -4-piperidone, BAP)
Pharmacophore be Isosorbide-5-Nitrae-pentadienone, be the principal binding sites that such compound is combined with tumour cell；When the nitrogen of piperidones
Atom forms an auxiliary anchor position after being substituted；When the aromatic rings quilt of bis- aryl methylene -4- piperidones molecules both sides of 3,5-
After active group substitution, then another auxiliary anchor position can be formed.The coordinative role of three binding sites can effectively improve
The antitumor activity of BAP.Therefore, a large amount of symmetrical BAP derivatives are synthesized and screen activity.More representational is 3,
5- bis- (2- fluorobenzylidenes) -4- piperidones (EF24), can be by activating caspase-3 and enhancing Bax to Bcl-2, Bcl-xL
Etc. inhibiting the proliferation of HCT-116, HT-29, AGS, so as to achieve the effect that inhibit colon cancer and human primary gastrointestinal cancers.(the 2- pyrroles of 3,5- bis-
Pyridine benzylidene base) -4- piperidones (EF31) can inhibit NF- κ B accesses to show antitumor and anti-inflammatory activity.
At present, the structure of modification about 3,5-, bis- aryl methylene -4- piperidones is mainly assisted at two on site.It is existing
Stage research is more deep, obtains preferably a kind of method of modifying of effect.N- alkylation modifications are mainly alkyl, alkenyl, aryl
On nitrogen-atoms Deng introducing piperidones.After transformation, such compound is smaller to the toxicity of normal cell, to the activity of tumour cell
Preferably, preferable selectivity is shown.Such as Hafez under alkaline condition, bis- aryl methylene -4- piperazines of N- ethyls -3,5- have been synthesized
Pyridine ketone derivatives.In addition there are the substituted compounds such as N- isopropyls, N- pi-allyls, N- propargyls, their antitumor activity
Obtain a degree of improvement.
The research that acylation is carried out on the piperidine nitrogen of center is more, different according to the type of acylate group, can be divided into
Aliphatic acylation, aromatic series acylation, phosphorylated and benzene sulfonyl etc..The classical example that aliphatic is acylated is N- (two acyls of butylene
Base) -3,5- bis- (2- chlorobenzenes methylene) -4- piperidones (CLEFMA), which is synthesized by Lagisetty, activity research hair
Existing, which by inducing cell autophagy, can play the effect of potential anti-lung cancer cell Proliferation, it is another studies have found that
CLEFMA can be by the effect of oxidative stress, and selective induction lung carcinoma cell is dead, and nontoxic in vivo and to tumour cell
With selectivity.Lagisetty has synthesized a series of product that EF24 aliphatic are acylated, and summarizing its structure effect by activity research closes
System：1. the unsaturated carboxyl short chain on piperidones nitrogen-atoms can more increase compound activity；2. short fat on piperidones nitrogen-atoms
Matter modification will not have adverse effect on antitumor activity of compound.Dimmock seminars are by acylation reaction in piperidines
A α is introduced on ketone nitrogen-atoms, alpha, beta-unsaturated ketone unit obtains aromatic series acylate, they have significant antitumor, anti-
Malaria and the effect of anti-mycobacteria, Mechanism Study show they by inducing cell apoptosis, autophagy, act on fyn
Kinases and the effect of the mechanisms play of multidrug resistance, and summarize and show that the molecule of 3,5-, bis- aryl methylene -4- derivative of piperidone is close
Degree, molecular topology and geometric index are to determine the main factor of cytotoxicity feature.Phosphorylated is modified to obtain N- phosphoryl -3,
Bis- aryl methylene -4- derivative of piperidone of 5- can be caused by DNA break between activating caspase-3 accesses or causing nucleosome
Successive cell toxicity, and play the role of multi-medicine tolerant reversal.
In comparison, acylated to 3,5-, bis- aryl methylene -4- piperidones progress aliphatic, aromatic series acylation, phosphorylated are ground
Study carefully it is more with product, and to 3,5-, bis- aryl methylene -4- piperidones carry out benzene sulfonyl modification research it is relatively fewer.Contain benzene
The drug of sulfonyl is widely used in clinic always, such as anti-inflammatory agent celecoxib, antimicrobial sulphadiazine, antihypertensive first chlorine
Thiazine, long-acting Rezulin Glimepiride, arthrifuric probenecid, antiarrhymic dofetillide etc..In these drugs, sulphur
The introducing of acyl group can adjust the dissolubility and acid-base property of small molecule, and can improve pharmaceutical activity and bioavilability.If
Benzenesulfonyl is introduced on the nitrogen-atoms of 3,5-, bis- aryl methylene -4- piperidones, it is desired to be able to adjust the dissolubility and acid of molecule
Alkalinity further improves their antitumor activity and anti-inflammatory activity and bioavilability.
In addition, during SARS drug design, fluorine atom and acetylamino rise in terms of drug plays pharmaceutical activity
To important role.Lipophilicity such as (1) fluorine atom can effectively improve the permeability of cell membrane of drug, so as to effectively improve medicine
The bioavilability of object；(2) fluorine atom belongs to strong electronegative group, by enhancing the binding ability between ligand and target into one
Step increases the pharmacological action of drug；(3) C-F keys have stronger stability, increase metabolic stability, so as to extend drug
Internal action time.And the introducing of acetylamino, acid-base property, the bioavilability of drug molecule can be effectively improved, and can
More complicated hydrogen bond action is formed between drug targets, further increases the pharmacological action of drug.(the fragrant methylenes of 3,5- bis-
Base) more representational (2- the fluorobenzylidenes) -4- piperidones of compound 3,5- bis- (EF24) contains in -4- derivative of piperidone
There are two fluorine atoms, and compared with the analog without fluorine atom, antitumor activity significantly improves.If in (the fragrant methylenes of 3,5- bis-
Base) -4- piperidones nitrogen-atoms on introduce 4- fluorophenylsulphonyls or 4- P-acetamido benzene sulfonyl bases, it is desired to be able to adjust molecule
Lipophilicity, acid-base property and bioavilability enhance the binding ability between drug molecule and target, further improve the anti-of them
Tumour and anti-inflammatory activity and bioavilability.
More than reason is based on, we have invented a kind of symmetrical 3,5-, bis- aryl methylene-N- benzenesulfonyl -4- piperidines assimilations
Close object.
Invention content
It is an object of the invention to find antitumor and anti-inflammatory activity good new antitumoral and anti-inflammatory drug, 10 are provided
Bis- aryl methylene-N- benzenesulfonyl -4- derivative of piperidone of symmetrical 3,5-；The preparation side of above-mentioned 10 compounds is provided simultaneously
Method.
The present invention is achieved by the following technical solutions：
With antitumor and anti-inflammatory activity 3,5-, bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds, order respectively
Entitled 3,5- bis- (2- fluorobenzylidenes)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-1), (the 3- nitrobenzene methylenes of 3,5- bis-
Base)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-2), 3,5- bis- (4- cyano benzylidene)-N- (4- fluorophenylsulphonyls) -
4- piperidones (BAP-3), 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-
4), 3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-5), (the 2- fluorine of 3,5- bis-
Benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6), 3,5- bis- (3- nitros benzylidene)-N- (4-
P-acetamido benzene sulfonyl base) -4- piperidones (BAP-7), 3,5- bis- (4- cyano benzylidene)-N- (4- P-acetamido benzene sulfonyls
Base) -4- piperidones (BAP-8), 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4-
Piperidones (BAP-9), 3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones
(BAP-10), it is characterized in that, structural formula is：
The above-mentioned bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5- with antitumor and anti-inflammatory activity
Preparation method, principle are：First, by 4- piperidone hydrochlorides respectively with 2- fluorobenzaldehydes, 3- nitrobenzaldehydes, 4- cyano
Benzaldehyde, 3,4,5-trimethoxybenzaldehyde, 3,5- dimethoxy benzaldehydes carry out Claisen-Schmidt condensation and are obtained by the reaction 3,
Bis- aryl methylene-N-H-4- piperidone hydrochlorides intermediates (BAP-H) of 5-, so with 4- fluorophenylsulfonyl chlorides or 4- acetyl amino phenyls
Sulfonic acid chloride occurs benzene sulfonyl and 3,5-, bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds (BAP) is obtained by the reaction, and closes
It is as follows into route：
Wherein, R1 is 2- fluorine, 3- nitros, 4- cyano, 3,4,5- trimethoxies or 3,5- dimethoxy；R2 is 4- fluorobenzene sulphurs
Acyl group or 4- P-acetamido benzene sulfonyl bases.
Preparation with antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5-
Method is characterized in that it is comprised the following specific steps that：
4- piperidone hydrochlorides and substituted aromatic aldehyde are dissolved according to certain mol proportion in solvent 1, add in catalyst, control
Reaction temperature and reaction time, tlc analysis tracking reaction process, after the reaction was complete, precipitation filters and obtains intermediate B AP-H, so
Afterwards, intermediate and substituted phenylsulfonyl chloride are dissolved in solvent 2, add in phase transfer catalyst and alkali, stirring at normal temperature is overnight, and precipitation is taken out
Filter is washed, and recrystallization or silica gel column chromatography obtain invention product BAP 1-10, and pass through infrared spectrum, nuclear magnetic resonance in solvent 3
The correctness of its structure is verified with elemental analysis.
The substituted aromatic aldehyde refers to 2- fluorobenzaldehydes, 3- nitrobenzaldehydes, 4- cyanobenzaldehydes, 3,4,5- trimethoxy-benzenes
Formaldehyde, 3,5- dimethoxy benzaldehydes；
The certain mol proportion refers to 1:3~3:1；
The catalyst refer to sodium hydroxide, drying hydrogen chloride gas in one kind；
The reaction temperature is 15-50 DEG C, and the reaction time is 6-24 hours；
The solvent 1 refers to one kind in acetic acid, water, methanol, ethyl alcohol, and the solvent 2 is 1,2- dichloroethanes, dichloromethane
One kind in alkane；The solvent 3 refers to one kind in methanol, ethyl alcohol, dichloromethane；
The phase transfer catalyst refers to one kind in tetrabutylammonium bromide, tetrabutylammonium iodide；
The alkali refers to one kind in sodium bicarbonate, sodium carbonate, sodium hydroxide, pyridine；
The silica gel column chromatography refers to 200~300 mesh silica gel of selection, petrol ether/ethyl acetate=10:1~1:1 (volume
Than) be used as and wash
De- agent, carries out column chromatography.
It is provided by the invention that there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidones of 3,5-
Application of the compound in new antitumoral and anti-inflammatory drug is prepared.
It is provided by the invention that there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidones of 3,5-
Compounds process for production thereof is easy to operate, and reaction condition is mild, and synthetic yield is high, conducive to it in the extensive of antitumor and anti-inflammatory field
It promotes.
Description of the drawings
Fig. 1：Compound BAP 1-10 to the IL-6 of LPS induction RAW264.7 cellular inflammations models secretions, TNF-α cell because
The influence that sublist reaches
Specific embodiment
The specific embodiment of the present invention is given below, for the present invention is further described.
Embodiment 1
The synthesis of (2- fluorobenzylidenes)-N- (4- the fluorophenylsulphonyls) -4- piperidones of 3,5- bis- (BAP-1)
The 2- fluorobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in the molten of 15mL first alcohol and waters
In liquid, 20% sodium hydroxide solutions of 2-3mL are added dropwise in room temperature, and 50 DEG C are stirred to react 6 hours, are determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters after completion of the reaction, and gained precipitation rinses to obtain yellow solid, i.e. intermediate with 70% methanol aqueous solution
Then, intermediate B AP-H (1) and 4- fluorophenylsulfonyl chlorides are dissolved in 10mL dichloromethane by BAP-H (1), add in 3-5 drop pyridines,
Stirring at normal temperature is stayed overnight, and reaction end is determined by thin-layered chromatography (TLC).Reaction solution 2mol/L=10:10:1) hydrochloric acid solution
200~300 mesh silica gel column chromatography (eluant, eluents are concentrated under reduced pressure in twice of washing, reaction solution：Petrol ether/ethyl acetate=3:1)
Yellow solid invention product 3,5- bis- (2- fluorobenzylidenes)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-1), yield are
47%.
Mp:169-171℃；IR(cm-1):2938(m),2773(m),1677(s),1620(s),1590(s),1501(m),
1491(s),1452(m),1355(m),1337(m),1254(s),1239(s),1230(s),1216(s),1162(s),1144
(s),1096(s),990(s),840(s),810(m),773(s),729(s),679(m),553(m).1H NMR(400MHz,
CDCl3) δ 7.76 (s, 2H), 7.55 (dd, J=8.5,5.0Hz, 2H), 7.46 (t, J=6.2Hz, 2H), 7.31-7.26 (m,
2H), 7.23-7.16 (m, 4H), 7.11 (t, J=8.4Hz, 2H), 4.59 (s, 4H)13C NMR(100MHz,DMSO)δ
183.51,164.80 (d, J=252.8Hz), 160.26 (d, J=249.6Hz), 133.96 (d, J=3.0Hz), 132.28 (d,
), J=8.7Hz 132.07,131.09,130.30 (d, J=9.8Hz), 129.88 (d, J=4.0Hz), 124.95 (d, J=
3.3Hz), 121.63 (d, J=13.2Hz), 116.66 (d, J=22.9Hz), 116.08 (d, J=21.6Hz),
46.63.Elemental analysis (%) calcd.for C25H18F3NO3S(469.48):C 63.96,H 3.86,N
2.98,S 6.83；Found:C 64.03,H 3.84,N 2.88,S 6.81.
Embodiment 2
The synthesis of 3,5- bis- (3- nitros benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-2)
The 3- nitrobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 15mL methanol
In the solution of water, 20% sodium hydroxide solutions of 2-3mL are added dropwise in room temperature, and 40 DEG C are stirred to react 6 hours, pass through thin-layered chromatography
(TLC) reaction end is determined.Precipitation filters after completion of the reaction, and gained precipitation rinses to obtain yellow solid with 70% methanol aqueous solution,
That is then, intermediate B AP-H (2) and 4- fluorophenylsulfonyl chlorides are dissolved in 10mL dichloromethane by intermediate B AP-H (2), add in 3-
5 drop pyridines, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Reaction solution 2mol/L hydrochloric acid solution water
It washes twice, 200~300 mesh silica gel column chromatography (eluant, eluents are concentrated under reduced pressure in reaction solution：Petrol ether/ethyl acetate=2:1) it obtains yellow
Color solid invention product 3,5- bis- (3- nitros benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-2), yield are
40%.
Mp:206-208℃；IR(cm-1):3101(m),3067(m),1671(s),1606(s),1591(s),1523(m),
1492(s),1347(m),1296(m),1258(m),1237(s),1192(s),1172(s),1155(s),1042(s),1006
(s),998(s),948(s),899(m),826(s),737(s),677(m),547(m).1H NMR(400MHz,DMSO)δ
8.36-8.23 (m, 4H), 7.95 (d, J=7.6Hz, 2H), 7.82 (dd, J=16.1,8.3Hz, 2H), 7.70 (s, 2H), 7.64
(dd, J=8.3,5.1Hz, 2H), 7.47-7.35 (m, 2H), 4.70 (s, 4H)13C NMR(100MHz,DMSO)δ183.85,
164.86 (d, J=252.7Hz), 148.14,136.38,135.43,135.29,133.60 (d, J=2.9Hz), 132.44,
130.53 (d, J=9.5Hz), 130.51,124.84,124.17,116.78 (d, J=22.8Hz), 46.57.Elemental
Analysis (%) calcd.for C25H18FN3O7S(523.49):C 57.36,H 3.47,N 8.03,S 6.13；Found:C
57.30,H 3.44,N 8.18,S 6.15.
Embodiment 3
The synthesis of 3,5- bis- (4- cyano benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-3)
The 4- cyanobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 10mL acetic acid, continuously
Dry hydrogen chloride gas 45min is passed through, 25 DEG C are stirred to react 8 hours, and reaction end is determined by thin-layered chromatography (TLC).
Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, and gained precipitation is with 70%
Methanol aqueous solution rinses to obtain yellow solid, i.e. intermediate B AP-H (3), then, by intermediate B AP-H (3) and 4- fluorophenylsulfonyl chlorides
It is dissolved in 10mL dichloromethane, adds in 3-5 drop pyridines, stirring at normal temperature is overnight, determines reaction eventually by thin-layered chromatography (TLC)
Point.Reaction solution is washed twice with 2mol/L hydrochloric acid solutions, and reaction solution, which is concentrated under reduced pressure, uses (methylene chloride/methanol=1:1) it recrystallizes
Yellow solid invention product 3 is obtained, 5- bis- (4- cyano benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-3) is received
Rate is 49%.
Mp:263-265℃；IR(cm-1):3099(m),3070(m),2226(s),1683(s),1620(s),1587(s),
1502(m),1485(s),1405(m),1353(m),1290(m),1226(s),1191(s),1167(s),1154(s),1086
(s),1016(s),983(s),921(s),838(m),820(s),762(s),678(m),616(m),545(m).1H NMR
(400MHz, DMSO) δ 8.00 (d, J=8.1Hz, 4H ,-C6H4), 7.70 (d, J=8.1Hz, 4H ,-C6H4), 7.70 (d, J=
8.1Hz,4H,-C6H4), 7.60 (s, 2H ,-C=CH), 7.56 (dd, J=8.5,5.2Hz, 2H ,-C6H4), 7.40 (t, J=
8.7Hz,2H,-C6H4),4.69(s,4H,-CH2).13C NMR (100MHz, DMSO) δ 183.93,164.82 (d, J=
252.7Hz), 138.47,135.76,133.89 (d, J=3.0Hz), 132.70,131.62,131.08,130.41 (d, J=
9.7Hz), 118.56,116.76 (d, J=22.8Hz), 111.85,46.54.Elemental analysis (%)
calcd.for C27H18FN3O3S(483.51):C 67.07,H 3.75,N 8.69,S 6.63；Found:C 66.95,H
3.74,N 8.48,S 6.65.
Embodiment 4
The synthesis of 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-4)
The 3,4,5-trimethoxybenzaldehyde of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol is mixed in 10mL second
In acid, dry hydrogen chloride gas 45min is continuously passed through, stirring at normal temperature is reacted 15 hours, is determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, and gained sinks
Form sediment 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid, i.e., in
Then, intermediate B AP-H (4) and 4- fluorophenylsulfonyl chlorides are dissolved in 10mL dichloromethane by mesosome BAP-H (4), add in 3-5 drops
Pyridine, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Reaction solution is washed with 2mol/L hydrochloric acid solutions
Twice, 200~300 mesh silica gel column chromatography (eluant, eluents are concentrated under reduced pressure in reaction solution：Petrol ether/ethyl acetate/methanol=10:10:
1) yellow solid invention product 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones is obtained
(BAP-4), yield 51%.
Mp:194-196℃；IR(cm-1):3014(m),2940(m),2837(s),1668(s),1614(s),1579(s),
1503(m),1448(s),1416(m),1351(m),1316(m),1252(s),1233(s),1166(s),1155(s),1085
(s),1021(s),993(s),931(s),847(m),822(s),764(s),719(m),682(m),635(m),545(m).1H
NMR(400MHz,CDCl3) δ 7.67 (s, 4H), 7.12 (t, J=8.3Hz, 2H), 6.60 (s, 4H), 4.68 (s, 4H), 3.95
(s,6H),3.94(s,12H).13C NMR(100MHz,CDCl3) δ 183.97,164.93 (d, J=256.4Hz), 152.94,
(140.76,139.28,138.54,129.87 d, J=9.4Hz), 128.87 (d, J=78.6Hz), 115.96 (d, J=
22.6Hz), 107.79,107.29,60.61,55.84,46.89.Elemental analysis (%) calcd.For
C31H32FNO9S(613.65):C 60.67,H 5.26,N 2.28,S5.23；Found:C 60.80,H 5.24,N 2.32,S
5.25.
Embodiment 5
The synthesis of (3,5- dimethoxybenzylidens)-N- (4- the fluorophenylsulphonyls) -4- piperidones of 3,5- bis- (BAP-5)
The 3,5- dimethoxy benzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 10mL acetic acid
In, dry hydrogen chloride gas 45min is continuously passed through, stirring at normal temperature is reacted 12 hours, is determined by thin-layered chromatography (TLC) anti-
Answer terminal.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, gained precipitation
With 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate=1:1) yellow solid, i.e. intermediate B AP-H are obtained
(5), then, intermediate B AP-H (5) and 4- fluorophenylsulfonyl chlorides are dissolved in 10mL dichloromethane, add in 3-5 drop pyridines, room temperature
It is stirred overnight, reaction end is determined by thin-layered chromatography (TLC).Reaction solution is washed twice with 2mol/L hydrochloric acid solutions, reaction
200~300 mesh silica gel column chromatography (eluant, eluents are concentrated under reduced pressure in liquid：Petrol ether/ethyl acetate=1:1) yellow solid invention production is obtained
Object 3,5- bis- (3,5- dimethoxybenzyliden)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-5), yield 46%.
Mp:221-223℃；IR(cm-1):3072(m),3008(m),2958(m),2842(m),1684(s),1592(s),
1493(s),1457(s),1428(m),1342(m),1304(m),1223(s),1211(s),1162(s),1150(s),1085
(s),1066(s),1042(s),930(s),909(s),845(m),826(s),762(s),679(m),632(m),541(m)
.1H NMR(400MHz,CDCl3) δ 7.64 (s, 4H), 7.11 (t, J=8.2Hz, 2H), 6.55 (s, 2H), 6.48 (s, 4H),
4.66(s,4H),3.87(s,12H).13C NMR(100MHz,CDCl3) δ 184.14,164.89 (d, J=256.0Hz),
(160.54,138.54,135.51,129.94,129.76 d, J=18.9Hz), 115.90 (d, J=22.6Hz), 107.81,
107.54 (d, J=36.2Hz), 101.25,55.05,46.87.Elemental analysis (%) calcd.For
C29H28FNO7S(553.60):C 62.92,H 5.10,N 2.53,S 5.79；Found:C 61.80,H 5.24,N 2.48,S
5.55.
Embodiment 6
The synthesis of 3,5- bis- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6)
The 2- fluorobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in the molten of 15mL first alcohol and waters
In liquid, 20% sodium hydroxide solutions of 2-3mL are added dropwise in room temperature, and stirring at normal temperature is reacted 7 hours, is determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters after completion of the reaction, and gained precipitation rinses to obtain yellow solid, i.e. intermediate with 70% methanol aqueous solution
Then, intermediate B AP-H (1) and 4- acetamidobenzenesulfonyl chlorides are dissolved in 10mL dichloromethane by BAP-H (1), add in 3-5
Pyridine is dripped, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Gained precipitation is rinsed with dichloromethane
Yellow solid invention product 3,5- bis- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6),
Yield is 49%.
Mp:242-243℃；IR(cm-1):3338(s),3188(m),3082(m),3040(m),1699(s),1673(s),
1618(s),1594(s),1528(s),1484(s),1455(s),1403(s),1351(m),1255(s),1238(m),1217
(s),1156(s),1091(s),1045(s),1032(s),978(m),966(s),839(m),814(s),798(s),735
(m),696(m),642(m),604m),573(m).1H NMR (400MHz, DMSO) δ 10.42 (s, 1H), 7.71 (d, J=
8.6Hz, 2H), 7.59 (s, 3H), 7.45 (dd, J=13.6,5.9Hz, 3H), 7.38 (t, J=8.3Hz, 6H), 4.56 (s,
4H),2.12(s,3H).13C NMR (100MHz, DMSO) δ 183.55,169.21,160.32 (d, J=249.6Hz), 143.81,
132.30,132.23 (d, J=8.8Hz), 131.08,130.66,129.72 (d, J=4.1Hz), 128.50,124.93 (d, J
=3.3Hz), 121.70 (d, J=13.2Hz), 118.43,116.06 (d, J=21.6Hz), 46.65,24.25.Elemental
Analysis (%) calcd.For C27H22F2N2O4S(508.54):C 63.77,H4.36,N 5.51,S 6.31；Found:C
63.71,H 4.36,N 5.42,S 6.32.
Embodiment 7
The synthesis of 3,5- bis- (3- nitros benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-7)
The 3- nitrobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 15mL methanol
In the solution of water, 20% sodium hydroxide solutions of 2-3mL are added dropwise in room temperature, and stirring at normal temperature is reacted 18 hours, passes through thin-layered chromatography
(TLC) reaction end is determined.Precipitation filters after completion of the reaction, and gained precipitation rinses to obtain yellow solid with 70% methanol aqueous solution,
That is then, intermediate B AP-H (2) and 4- acetamidobenzenesulfonyl chlorides are dissolved in 10mL dichloromethane by intermediate B AP-H (2),
3-5 drop pyridines are added in, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Gained precipitation dichloromethane
Rinse to obtain yellow solid invention product 3,5- bis- (3- nitros benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones
(BAP-7), yield 34%.
Mp:246-248℃；IR(cm-1):3339(s),3077(m),1703(s),1674(s),1621(s),1589(s),
1525(s),1433(s),1405(s),1347(m),1308(m),1256(s),1239(m),1191(s),1159(s),1092
(s),1045(s),966(s),891(s),853(m),817(s),800(s),761(m),738(m),698(m),640(m),
604m),552(m).1HNMR (400MHz, DMSO) δ 10.47 (s, 1H), 8.32 (d, J=8.2Hz, 2H), 8.29 (s, 2H),
7.94 (d, J=7.6Hz, 2H), 7.83 (t, J=7.9Hz, 2H), 7.77 (d, J=8.6Hz, 2H), 7.72 (s, 2H), 7.54
(d, J=8.6Hz, 2H), 4.60 (s, 4H), 2.12 (s, 3H)13C NMR(100MHz,DMSO)δ183.89,169.24,
148.09,143.93,136.42,135.47,135.06,132.67,130.51,129.84,128.73,124.73,124.12,
118.66,46.70,24.23.Elemental analysis (%) calcd.For C27H22N4O8S(562.55):C 57.65,
H 3.94,N 9.96,O,22.75,S 5.70；Found:C 57.68,H 3.98,N 9.95,S 5.62.
Embodiment 8
The synthesis of 3,5- bis- (4- cyano benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-8)
The 4- cyanobenzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 10mL acetic acid, continuously
Dry hydrogen chloride gas 45min is passed through, stirring at normal temperature is reacted 15 hours, and reaction end is determined by thin-layered chromatography (TLC).
Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, and gained precipitation is with 70%
Methanol aqueous solution rinses to obtain yellow solid, i.e. intermediate B AP-H (3), then, by intermediate B AP-H (3) and 4- acetyl amino phenyls
Sulfonic acid chloride is dissolved in 10mL dichloromethane, adds in 3-5 drop pyridines, and stirring at normal temperature is overnight, is determined by thin-layered chromatography (TLC) anti-
Answer terminal.Gained precipitation rinses to obtain yellow solid invention product 3,5- bis- (4- cyano benzylidene)-N- (4- second with dichloromethane
Acylamino- benzenesulfonyl) -4- piperidones (BAP-8), yield 43%.
Mp:243-245℃；IR(cm-1):3355(s),3101(m),2903(m),2231(s),1708(s),1674(s),
1603(s),1587(s),1523(s),1502(s),1401(s),1335(m),1308(m),1245(s),1192(s),1156
(s),1087(s),1041(s),959(s),935(s),854(m),823(s),806(s),760(m),734(m),692(m),
655(m),634(m),600(m),559(m).1H NMR (400MHz, DMSO) δ 10.41 (s, 1H), 8.00 (d, J=8.1Hz,
4H), 7.72 (d, J=8.7Hz, 2H), 7.68 (d, J=8.1Hz, 4H), 7.62 (s, 2H), 7.47 (d, J=8.6Hz, 2H),
4.60(s,4H),2.12(s,3H).13C NMR(100MHz,DMSO)δ184.03,169.21,143.78,138.54,135.49,
133.03,132.70,131.03,130.41,128.60,118.69,118.56,111.80,46.55,24.24.Elemental
Analysis (%) calcd.For C29H22N4O4S(522.57):C 66.65,H 4.24,N 10.72,S 6.14；Found:C
66.67,H 4.19,N 10.78,S 6.11.
Embodiment 9
3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-9)
Synthesis
The 3,4,5-trimethoxybenzaldehyde of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol is mixed in 10mL second
In acid, dry hydrogen chloride gas 45min is continuously passed through, stirring at normal temperature is reacted 18 hours, is determined by thin-layered chromatography (TLC)
Reaction end.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, and gained sinks
Form sediment 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid, i.e., in
Then, intermediate B AP-H (4) and 4- acetamidobenzenesulfonyl chlorides are dissolved in 10mL dichloromethane by mesosome BAP-H (4), are added in
3-5 drop pyridines, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Gained precipitation is rinsed with dichloromethane
Obtain yellow solid invention product 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperazines
Pyridine ketone (BAP-9), yield 45%.
Mp:248-250℃；IR(cm-1):3331(s),3106(m),2998(m),2942(m),2837(m),1700(s),
1674(s),1607(s),1579(s),1526(s),1502(s),1450(s),1403(s),1370(m),1334(m),1240
(s),1184(s),1152(s),1090(s),1047(s),999(s),957(s),932(s),838(m),811(s),785
(s),760(m),726(m),670(m),646(m),633(m),613(m),589(m).1H NMR(400MHz,DMSO)δ
10.45(s,1H),7.79(s,1H),7.76(s,1H),7.59(s,4H),6.77(s,4H),4.53(s,4H),3.86(s,
12H),3.75(s,6H),2.11(s,3H).13C NMR(100MHz,CDCl3)δ184.24,168.29,152.89,142.23,
139.11,138.49,131.14,129.36,128.73,128.50,118.64,107.25,60.61,55.82,47.01,
24.30.Elemental analysis (%) calcd.For C33H36N2O10S(652.71):C 60.72,H 5.56,N
4.29,S 4.91；Found:C 60.77,H 5.57,N 4.26,S 4.95.
Embodiment 10
3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-10)
Synthesis
The 3,5- dimethoxy benzaldehydes of the 4- piperidone hydrochlorides of 0.01mol and 0.02mol are mixed in 10mL acetic acid
In, dry hydrogen chloride gas 45min is continuously passed through, stirring at normal temperature is reacted 15 hours, is determined by thin-layered chromatography (TLC) anti-
Answer terminal.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and with sodium hydroxide solution tune pH value to neutrality, gained precipitation
With 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate=1:1) yellow solid, i.e. intermediate B AP-H are obtained
(5), then, intermediate B AP-H (5) and 4- acetamidobenzenesulfonyl chlorides are dissolved in 10mL dichloromethane, add in 3-5 drop pyrroles
Pyridine, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Gained precipitation rinses to obtain yellow with dichloromethane
Solid invention product 3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-
10), yield 46%.
Mp:234-236℃；IR(cm-1):3336(s),3001(m),2940(m),2839(m),1698(s),1671(s),
1586(s),1524(s),1455(s),1425(m),1403(s),1336(m),1312(m),1261(m),1227(s),1201
(s),1155(s),1091(s),1065(s),990(s),974(s),941(s),839(m),813(s),764(m),727(m),
675(m),643(m),609(m),596(m).1H NMR (400MHz, DMSO) δ 10.41 (s, 1H), 7.74 (d, J=8.6Hz),
7.52 (s, 2H), 7.46 (d, J=8.6Hz, 2H), 6.64 (s, 2H), 6.60 (s, 4H), 4.58 (s, 4H), 3.82 (s, 12H),
2.11(s,3H).13C NMR(100MHz,DMSO)δ184.17,169.22,160.57,143.77,137.33,135.88,
131.04,130.32,128.51,118.54,108.09,101.83,55.44,46.81,24.24.Elemental
Analysis (%) calcd.For C31H32N2O8S(592.66):C 62.82,H5.44,N 4.73,S 5.41；Found:C
62.84,H 5.46,N 4.72,S 5.43.
Antitumor activity and normal cell toxicity assessment
The antitumor activity of the bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compound BAP 1-10 of 3,5- of the present invention
And normal cell toxicity assessment.
Antitumor activity and normal cell toxicity assessment use mtt assay (chemical name is [3- (4,5- diformazans in the present invention
Base thiazole -2) -2,5- diphenyltetrazolium bromide bromides]).Use three kinds of liver cancer cell lines (HepG2, QGY-7703, SMMC-7721)
With two kinds of normal liver cell (LO2, HHL-5) expansion experiments, cell from State Administration of Traditional Chinese Medicine of Binzhou Medical College, " imitate by prescription
Should be with clinical evaluation " primary study room.Adriamycin (DOX) is as positive control drug.
The cell in growth period of taking the logarithm is configured to 4 × 104The cell suspension of a/mL is inoculated in 96 well culture plates, per hole
Add 200 μ L, culture adds in the synthesis compound of 20 μ L various concentrations afterwards for 24 hours, after continuing culture for 24 hours, adds in 20 μ L's to every hole
MTT reagents after 37 DEG C are incubated 4 hours, abandon supernatant, 150 μ L DMSO are added per hole, oscillation 10min is fully dissolving crystallized, uses enzyme
Absorbance of the instrument measure at 570nm is marked, calculates IC50.The concentration of BAP 1-10 used is 10 respectively, 8,5,3,2,1,0.5,
0.1st, 0.05,0.01 μ g/mL make positive control with adriamycin (DOX), concentration used is 8 respectively, 6,5,3,1.5,1,0.8,
0.5th, 0.1 μ g/mL, each concentration set 6 multiple holes.
1. compound BAP 1-10 of table are to the half-inhibition concentration IC of tumour cell and normal cell50(μM)
Compound BAP-4, BAP-9 shows remarkable activity to three kinds of tumor cell lines as can be seen from Table 1, especially
It is to QGY-7703, SMMC-7721, IC50Value is below 4 μM.Compound BAP1-10 is to two kinds of normal liver cells simultaneously
IC50Value is all higher than 10 μM, shows relatively low toxicity or even toxicity is less than positive control drug DOX.
Anti-inflammatory activity is evaluated
The anti-inflammatory activity of the bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compound BAP 1-10 of 3,5- of the present invention is commented
Valency.
Anti-inflammatory activity rating induces RAW264.7 cells using external ELISA method detection BAP derivatives to LPS in the present invention
The influence of the IL-6, TNF-α cytokine-expressing of inflammatory model secretion, cell come from State Administration of Traditional Chinese Medicine of Binzhou Medical College
" prescription effect and clinical evaluation " primary study room.PDTC (NF- к B inhibitor) is as positive control drug.It is detected using mtt assay
To the toxic effect of RAW264.7 cells, testing result shows when BAP derivatives concentration≤10 μM BAP derivatives, right
RAW264.7 cytotoxics, anti-inflammatory activity evaluation experimental drug concentration are set as 10 μM.
One bottle of RAW264.7 cells are taken, cell is collected after trypsin digestion, uniform, adjustment cell number is blown and beaten with pipette
To 2 × 105/mL.100 μ L cell suspensions are added in per hole in 96 porocyte culture plates, are placed in CO2Continue to cultivate in incubator
12h.Original fluid is sopped up after taking out culture plate, the BAP derivative serum-free mediums of a concentration of 10 μM of 180 μ L are added in per hole.
20 μ L LPS (whole mass concentration is 1 μ g/mL) are added in after 2h, separately set Normal group and positive control drug group (PDTC：30μM).
After adding in LPS, in vibrating mixing in micropore plate oscillator, it is placed in CO2Continue culture respectively for 24 hours in incubator.It collects in culture
Clear liquid, ELISA method measure TNF-α, the content of IL-6.
Compound BAP1-10 is to IL-6, the TNF-α cell factor table of LPS induction RAW264.7 cellular inflammations model secretions
The influence reached
With LPS stimulations, the TNF-α of induced high levels and IL-6 generate (Fig. 1) in RAW264.7 cells.It can be with from Fig. 1
Find out that, with compound BAP-3, BAP-8 processing group, the level compared to IL-6 in the cell of exclusive use LPS stimulations significantly reduces>
50%, the inhibiting effect of both compounds is even higher than the inhibiting effect of positive drug PDTC.Similary compound BAP-2, BAP-
3rd, BAP-4 processing group significantly reduces, the suppression of these three compounds compared to the level that TNF-α in the cell of LPS stimulations is used alone
It makes of the inhibiting effect for being even higher than positive drug PDTC.Other, compared with the cell of independent LPS stimulations, compound BAP-1,
BAP-5, BAP-6, BAP-7 are significantly reduced the level that IL-6 is generated in RAW264.7 cells, and compound BAP-6, BAP-8 is also shown
Write the level for reducing that TNF-α generates in RAW264.7 cells.
The foregoing is merely the preferred embodiments of the present invention, are not intended to restrict the invention.It is all the present invention basis on
Any change, modification, replacement etc., should be included within the scope of the present invention.
Claims (12)
1. with antitumor and anti-inflammatory activity 3,5-, bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds, name respectively
For 3,5- bis- (2- fluorobenzylidenes)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-1), (the 3- nitrobenzene methylenes of 3,5- bis-
Base)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-2), 3,5- bis- (4- cyano benzylidene)-N- (4- fluorophenylsulphonyls) -
4- piperidones (BAP-3), 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-
4), 3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- fluorophenylsulphonyls) -4- piperidones (BAP-5), (the 2- fluorine of 3,5- bis-
Benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6), 3,5- bis- (3- nitros benzylidene)-N- (4-
P-acetamido benzene sulfonyl base) -4- piperidones (BAP-7), 3,5- bis- (4- cyano benzylidene)-N- (4- P-acetamido benzene sulfonyls
Base) -4- piperidones (BAP-8), 3,5- bis- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4-
Piperidones (BAP-9), 3,5- bis- (3,5- dimethoxybenzylidens)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones
(BAP-10), it is characterized in that, structural formula is：
2. the preparation side with antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5-
Method is characterized in that it includes following synthetic route：
First, it carries out Claisen-Schmidt condensation with aromatic aldehyde respectively by 4- piperidone hydrochlorides and 3,5-, bis- virtue Asias is obtained by the reaction
Methyl-N-H-4- piperidone hydrochlorides intermediate (BAP-H), and then benzene sulfonyl occurs with sulfonylation agent and is obtained by the reaction 3,5-
Two aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds (BAP), synthetic route is as follows：
Wherein, R1 is 2- fluorine, 3- nitros, 4- cyano, 3,4,5- trimethoxies or 3,5- dimethoxy；R2 is 4- fluorophenylsulphonyls
Or 4- P-acetamido benzene sulfonyl bases.
3. the preparation side with antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5-
Method is characterized in that it is comprised the following specific steps that：
4- piperidone hydrochlorides and substituted aromatic aldehyde are dissolved according to certain mol proportion in solvent 1, add in catalyst, control reaction
Temperature and reaction time, tlc analysis tracking reaction process, after the reaction was complete, precipitation filters and obtains intermediate B AP-H, then,
Intermediate and substituted phenylsulfonyl chloride are dissolved in solvent 2, add in phase transfer catalyst and alkali, stirring at normal temperature is overnight, and precipitation filters,
It washes, recrystallization or silica gel column chromatography obtain invention product BAP 1-10 in solvent 3.
4. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The substituted aromatic aldehyde refers to 2- fluorobenzaldehydes, 3- nitrobenzaldehydes, 4- cyanobenzaldehydes, 3,4,5- trimethoxy-benzene first
Aldehyde, 3,5- dimethoxy benzaldehydes.
5. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The certain mol proportion refers to 1:3~3:1.
6. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The catalyst refer to sodium hydroxide, drying hydrogen chloride gas in one kind.
7. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The reaction temperature is 15-50 DEG C, and the reaction time is 6-24 hours.
8. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The solvent 1 refers to one kind in acetic acid, water, methanol, ethyl alcohol, and the solvent 2 is in 1,2- dichloroethanes, dichloromethane
One kind；The solvent 3 refers to one kind in methanol, ethyl alcohol, dichloromethane.
9. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines of 3,5- as claimed in claim 3
The preparation method of ketone compound, it is characterised in that
The phase transfer catalyst refers to one kind in tetrabutylammonium bromide, tetrabutylammonium iodide.
10. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperazines of 3,5- as claimed in claim 3
The preparation method of pyridine ketone compound, it is characterised in that
The alkali refers to one kind in sodium bicarbonate, sodium carbonate, sodium hydroxide, pyridine.
11. there is antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperazines of 3,5- as claimed in claim 3
The preparation method of pyridine ketone compound, it is characterised in that
The silica gel column chromatography refers to 200~300 mesh silica gel of selection, petrol ether/ethyl acetate=10:1~1:1 (volume ratio) is made
For eluant, eluent, column chromatography is carried out.
12. the present invention's has antitumor and anti-inflammatory activity bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5-
Application in new antitumoral and anti-inflammatory drug is prepared.
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|---|---|---|---|---|
| CN108997310A (en) * | 2018-08-06 | 2018-12-14 | 滨州医学院 | Bis- aryl methylene -4- the piperidones of 3,5- and preparation method thereof that asymmetric 3- pyridine replaces |
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| CN109053564A (en) * | 2018-08-06 | 2018-12-21 | 滨州医学院 | The asymmetric piperidines ketone compound and preparation method thereof that N- benzenesulfonyl replaces |
| CN109053565A (en) * | 2018-08-06 | 2018-12-21 | 滨州医学院 | Asymmetric pyridine-piperidines ketone compound and preparation method thereof that N- benzenesulfonyl replaces |
| CN115154447A (en) * | 2022-07-13 | 2022-10-11 | 象山县第一人民医院医疗健康集团 | Application of 2, 6-bis (2- (trifluoromethyl) benzylidene) cyclohexanone in preparation of medicines for treating inflammatory bowel diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108997310A (en) * | 2018-08-06 | 2018-12-14 | 滨州医学院 | Bis- aryl methylene -4- the piperidones of 3,5- and preparation method thereof that asymmetric 3- pyridine replaces |
| CN108997311A (en) * | 2018-08-06 | 2018-12-14 | 滨州医学院 | Bis- aryl methylene -4- the piperidones of 3,5- and preparation method thereof that asymmetric 4- pyridine replaces |
| CN109053564A (en) * | 2018-08-06 | 2018-12-21 | 滨州医学院 | The asymmetric piperidines ketone compound and preparation method thereof that N- benzenesulfonyl replaces |
| CN109053565A (en) * | 2018-08-06 | 2018-12-21 | 滨州医学院 | Asymmetric pyridine-piperidines ketone compound and preparation method thereof that N- benzenesulfonyl replaces |
| CN109053564B (en) * | 2018-08-06 | 2022-05-24 | 滨州医学院 | N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof |
| CN109053565B (en) * | 2018-08-06 | 2022-08-12 | 滨州医学院 | N-benzenesulfonyl substituted asymmetric pyridine-piperidone compounds and preparation method thereof |
| CN108997311B (en) * | 2018-08-06 | 2023-06-23 | 滨州医学院 | Asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof |
| CN108997310B (en) * | 2018-08-06 | 2023-06-27 | 滨州医学院 | Asymmetric 3-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof |
| CN115154447A (en) * | 2022-07-13 | 2022-10-11 | 象山县第一人民医院医疗健康集团 | Application of 2, 6-bis (2- (trifluoromethyl) benzylidene) cyclohexanone in preparation of medicines for treating inflammatory bowel diseases |
| CN115154447B (en) * | 2022-07-13 | 2024-03-12 | 象山县第一人民医院医疗健康集团 | Application of 2, 6-bis (2- (trifluoromethyl) benzylidene) cyclohexanone in preparation of inflammatory bowel disease drugs |
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