CN108191742A - Bis- aryl methylene -4- piperidines ketone compounds of 3,5- of 4- P-acetamido benzene sulfonyls base substitution and preparation method thereof - Google Patents
Bis- aryl methylene -4- piperidines ketone compounds of 3,5- of 4- P-acetamido benzene sulfonyls base substitution and preparation method thereof Download PDFInfo
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Abstract
3,5 two aryl methylene, the 4 piperidines ketone compound that the present invention relates to seven there are antitumor and anti-inflammatory activity 4 P-acetamido benzene sulfonyl bases to replace, belongs to antitumor and anti-inflammatory drug technical field.Preparation method is to carry out Clarkson Schmidt condensation with two kinds of aromatic aldehydes respectively by 4 piperidone hydrochlorides first to react; column chromatography obtains the 3 of different substituents; 5 two aryl methylene N H, 4 piperidone hydrochloride intermediates (BAP H); then; 3,5 two aryl methylene, the 4 piperidines ketone compound (BAP) of 4 P-acetamido benzene sulfonyl bases substitution is obtained by the reaction with 4 acetamidobenzenesulfonyl chlorides generation benzene sulfonyl.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 3,5- bis- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
Aryl methylene -4- piperidines ketone compounds belong 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.
However, it has been reported that 3,5- bis- (aryl methylene) -4- derivative of piperidone be symmetrical compound, it is right
It is reported in asymmetric 3,5- bis- (aryl methylene) -4- piperidines ketone compound less.In addition, the anti-inflammatory activity to such compound
Research report it is also less.If pair introducing different substituent group in 3,5-, bis- aryl methylene -4- piperidones both sides, particularly inhale
The electronic capability substituent group different with electron supplying capacity, such as electron withdrawing group fluorine, nitro, cyano, electron withdrawing group methoxyl group
Deng polarity, dissolubility, antitumor activity and anti-inflammatory activity and bioavilability of molecule etc. may be influenced, and about benzene
The structure-activity relationship of the bis- aryl methylene -4- piperidones of asymmetric 3,5- of sulfonyl substitution and antitumor and anti-inflammatory activity analysis
It is upper to lack systematicness.
In addition, during SARS drug design, acetylamino plays important work in terms of drug plays pharmaceutical activity
With.The introducing of acetylamino can be effectively improved acid-base property, the bioavilability of drug molecule, and can be with drug targets
Between form more complicated hydrogen bond action, further increase the pharmacological action of drug.If in 3,5- bis- (aryl methylene) -4-
4- P-acetamido benzene sulfonyl bases are introduced on the nitrogen-atoms of piperidones, it is desired to be able to adjust lipophilicity, acid-base property and the biology of molecule
Availability enhances the binding ability between drug molecule and target, further improves their antitumor activity and anti-inflammatory activity
And bioavilability.
More than reason is based on, 3,5-, bis- virtues we have invented a kind of asymmetric 4- P-acetamido benzene sulfonyls base substitution are sub-
Methyl -4- piperidines ketone compounds.
Invention content
It is an object of the invention to find antitumor and anti-inflammatory activity good new antitumoral and anti-inflammatory drug, 7 are provided
Bis- aryl methylene -4- the derivative of piperidone of 3,5- of asymmetric 4- P-acetamido benzene sulfonyls base substitution；There is provided above-mentioned 7 simultaneously
The preparation method of compound.
The present invention is achieved by the following technical solutions：
Bis- aryl methylene -4- the piperidones of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
Compound is respectively designated as 3- (3,4,5- trimethoxy benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl amino phenyls
Sulfonyl) -4- piperidones (BAP-1), 3- (3,5- dimethoxybenzylidens) -5- (2- fluorobenzylidenes)-N- (4- acetyl ammonia
Base benzenesulfonyl) -4- piperidones (BAP-2), 3- (3- nitros benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetylaminos
Benzenesulfonyl) -4- piperidones (BAP-3), 3- (4- cyano benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl amino phenyls
Sulfonyl) -4- piperidones (BAP-4), 3- (3,4,5- trimethoxies benzylidene) -5- (4- cyano benzylidene)-N- (4- second
Acylamino- benzenesulfonyl) -4- piperidones (BAP-5), 3- (3,5- dimethoxybenzylidens) -5- (3,4,5- trimethoxy-benzenes
Methylene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6), 3- (3- nitros benzylidene) -5- (3,4,5- tri-
Methoxybenzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-7), it is characterized in that, structural formula
For：
The above-mentioned bis- aryl methylene -4- piperazines of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
The preparation method of pyridine ketone compound, principle are：First, gram Lay is carried out with two kinds of aromatic aldehydes by 4- piperidone hydrochlorides respectively
Bis- aryl methylene-N-H-4- piperidone hydrochloride intermediates (the BAP- of 3,5- of different substituents are obtained by the reaction in gloomy-Schmidt condensation
H), then, the substitution of 4- P-acetamido benzene sulfonyls base is obtained by the reaction in benzene sulfonyl 3,5- occur with 4- acetamidobenzenesulfonyl chlorides
Two aryl methylene -4- piperidines ketone compounds (BAP), synthetic route is as follows：
Wherein, when R1 is 2- fluorine, R2 3,4,5- trimethoxies, 3,5- dimethoxys, 3- nitros, 4- cyano；R1 is 3,
During 4,5- trimethoxy, R2 is 4- cyano, 3,5- dimethoxys, 3- nitros.
Bis- aryl methylene -4- the piperidones of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
The preparation method of compound is characterized in that, it is comprised the following specific steps that：
By 4- piperidone hydrochlorides and two kinds of aromatic aldehydes according to 1:1:1 molar ratio is dissolved in solvent 1, adds in catalyst,
Controlling reaction temperature and reaction time, tlc analysis tracking reaction process, after the reaction was complete, precipitation filters, with dilute sodium bicarbonate
Solution lotion, residue silica gel column chromatography obtain intermediate B AP-H, then, by intermediate B AP-H and 4- P-acetamido benzene sulfonyl
Chlorine is dissolved in solvent 2, adds in alkali, and stirring at normal temperature is overnight, and precipitation filters, and washing obtains invention product BAP 1-7, and pass through infrared
The correctness of its structure is verified in spectrum, nuclear magnetic resonance and elemental analysis.
Described two aromatic aldehydes refer to when one kind is 2- fluorobenzaldehydes, another be 3,4,5-Trimethoxybenzaldehyde,
3,5- dimethoxy benzaldehydes, 3- nitrobenzaldehydes, 4- cyanobenzaldehydes；When one kind is 3,4,5-Trimethoxybenzaldehyde,
Another is 4- cyanobenzaldehydes, 3,5- dimethoxy benzaldehydes, 3- nitrobenzaldehydes；
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 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) as eluant, eluent, carry out column chromatography.
3,5- bis- virtues provided by the invention replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base are sub-
Application of the methyl -4- piperidines ketone compounds in new antitumoral and anti-inflammatory drug is prepared.
3,5- bis- virtues provided by the invention replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base are sub-
Methyl -4- piperidones compounds process for production thereof is easy to operate, and reaction condition is mild, and synthetic yield is high, conducive to it antitumor and
Anti-inflammatory field is widely popularized.
Description of the drawings
Fig. 1：Compound BAP 1-7 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
3- (3,4,5- trimethoxies benzylidene) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4-
The synthesis of piperidones (BAP-1)
By the 3,4,5- trimethoxies of the 2- fluorobenzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol
Benzaldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, and stirring at normal temperature is reacted 15 hours, is led to
It crosses thin-layered chromatography (TLC) and determines reaction end.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and molten with sodium hydroxide
Liquid tune pH value to neutrality, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/methanol=
10:10:1) yellow solid, i.e. intermediate B AP-H (1), then, by intermediate B AP-H (1) and 4- acetamidobenzenesulfonyl chlorides are obtained
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 is concentrated under reduced pressure with (the elution of 200~300 mesh silica gel column chromatographies
Agent：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid invention product 3- (3,4,5- trimethoxy-benzene methylenes are obtained
Base) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-1), yield 32%.
Mp:202-204℃；IR(cm-1):3331(s),3114(m),3072(m),2945(m),2837(m),1702(s),
1668(s),1585(s),1536(s),1502(m),1487(s),1450(s),1435(m),1417(s),1367(m),1334
(m),1261(m),1222(s),1187(s),1149(s),1089(s),1044(s),1010(s),961(s),938(s),829
(m),811(s),760(m),732(m),680(m),658(m),637(m),581(m).1H NMR(400MHz,DMSO)δ
10.42 (s, 1H), 7.76 (d, J=8.6Hz, 2H), 7.63 (s, 1H), 7.58 (s, 2H), 7.52 (d, J=8.6Hz, 2H),
7.47 (d, J=7.5Hz), 7.40 (dd, J=12.5,6.2Hz), 6.78 (s, 2H), 4.60 (s, 2H), 4.48 (s, 2H), 3.86
(s,6H),3.76(s,3H),2.12(s,3H).13C NMR (100MHz, DMSO) δ 183.77,169.23,160.32 (d, J=
249.4Hz), 152.93,143.84,138.94,138.14,132.52,132.11 (d, J=8.8Hz), 131.05,130.00,
(129.64,129.49,129.11 d, J=3.9Hz), 128.64,124.94 (d, J=3.4Hz), 121.74 (d, J=
13.2Hz), 118.57,116.04 (d, J=21.5Hz), 108.08,60.20,56.05,47.06,46.80,
24.24.Elemental analysis (%) calcd.For C28H25F2NO6S(541.56):C 62.10,H 4.65,N
2.59,S 5.92；Found:C 62.11,H 4.63,N 2.57,S 5.91.
Embodiment 2
3- (3,5- dimethoxybenzylidens) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperazines
Pyridine ketone (BAP-2), synthesis
By the 3,5- dimethoxys of the 2- fluorobenzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol
Benzaldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, and stirring at normal temperature is reacted 15 hours, passed through
Thin-layered chromatography (TLC) determines reaction end.Precipitation filters after completion of the reaction, is precipitated and dissolved in water and uses sodium hydroxide solution
Adjusting pH value, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents to neutrality：Petrol ether/ethyl acetate=2:1) it obtains yellow
Then intermediate B AP-H (2) and 4- acetamidobenzenesulfonyl chlorides, are dissolved in 10mL dichloros by color solid, i.e. intermediate B AP-H (2)
In methane, 3-5 drop pyridines are added in, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Reaction solution is used
2mol/L hydrochloric acid solutions are washed twice, and 200~300 mesh silica gel column chromatography (eluant, eluents are concentrated under reduced pressure in reaction solution：Petroleum ether/second
Acetoacetic ester=1:1) yellow solid invention product 3- (3,5- dimethoxybenzylidens) -5- (2- fluorobenzylidenes)-N- (4- are obtained
P-acetamido benzene sulfonyl base) -4- piperidones (BAP-2), yield 30%.
Mp:241-243℃；IR(cm-1):3344(s),2937(m),2839(m),1702(s),1669(s),1590(s),
1523(s),1485(s),1452(s),1421(m),1402(s),1367(m),1342(m),1242(m),1221(s),1206
(s),1154(s),1089(s),1047(s),1008(s),956(s),944(s),839(m),813(s),797(m),754
(m),675(m),641(m),627(m),550(m).1H NMR (400MHz, DMSO) δ 10.39 (s, 1H), 7.70 (d, J=
8.6Hz, 2H), 7.57 (s, 2H), 7.50 (s, 1H), 7.48-7.42 (m, 1H), 7.40 (d, J=8.8Hz, 3H), 7.37 (s,
1H),6.63(s,1H),6.58(s,2H),4.60(s,2H),4.50(s,2H),3.81(s,6H),2.10(s,3H).13C NMR
(100MHz, DMSO) δ 183.84,169.24,160.57,160.32 (d, J=249.4Hz), 143.79,137.75,137.35,
(135.84,132.42,131.04 d, J=4.8Hz), 130.86,130.49,129.37 (d, J=3.8Hz), 128.51,
124.92 (d, J=3.3Hz), 121.72 (d, J=13.2Hz), 118.48,116.04 (d, J=21.5Hz), 108.11,
101.88,55.44,46.81,46.66,24.23.Elemental analysis (%) calcd.For C29H27FN2O6S
(550.60):C 63.26,H 4.94,N 5.09,S 5.82；Found:C 63.21,H 4.93,N 5.07,S5.85.
Embodiment 3
3- (3- nitros benzylidene) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones
(BAP-3) synthesis
By the 3- nitrobenzaldehydes of the 2- fluorobenzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol
It is mixed in the solution of 15mL first alcohol and waters, 2-3mL20% sodium hydroxide solutions is added dropwise, 40 DEG C are stirred to react 6 hours, by thin
Layer chromatography (TLC) determines reaction end.Precipitation filters after completion of the reaction, and gained precipitates 200~300 mesh silica gel column chromatographies
(eluant, eluent：Petrol ether/ethyl acetate=1:1) yellow solid, i.e. intermediate B AP-H (3), then, by intermediate B AP-H are obtained
(3) it is dissolved in 10mL dichloromethane with 4- acetamidobenzenesulfonyl chlorides, adds in 3-5 drop pyridines, stirring at normal temperature is overnight, passes through thin layer
Chromatography (TLC) determines reaction end.Reaction solution is washed twice with 2mol/L hydrochloric acid solutions, and reaction solution is concentrated under reduced pressure with 200~
300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate=1:1) yellow solid invention product 3- (3- nitrobenzene methylenes are obtained
Base) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-3), yield 33%.
Mp:229-231℃；IR(cm-1):3344(s),3191(m),3069(m),1699(s),1670(s),1611(s),
1592(s),1522(s),1483(s),1452(s),1403(m),1344(m),1308(s),1241(m),1203(s),1157
(s),1092(s),1044(s),1004(s),985(s),952(s),842(m),818(s),798(m),782(m),690(m),
639(m),604(m),551(m).1HNMR (400MHz, DMSO) δ 10.40 (s, 1H), 8.31 (d, J=8.0Hz, 1H), 8.26
(s, 1H), 7.92 (d, J=7.5Hz, 1H), 7.81 (t, J=7.8Hz, 1H), 7.72 (d, J=8.6Hz, 2H), 7.67 (s,
1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=8.4Hz, 3H), 7.38 (d, J=7.3Hz, 2H), 4.62 (s, 2H),
4.50(s,2H),2.10(s,3H).13C NMR (100MHz, DMSO) δ 183.72,169.22,160.34 (d, J=249.5Hz),
148.10,143.86,136.44,135.54,135.07,132.69,132.31,132.22 131.08 (d, J=1.4Hz),
(130.49,130.25,129.68 d, J=4.1Hz), 128.62,124.95 (d, J=3.3Hz), 124.65,124.10,
121.64 (d, J=13.1Hz), 118.56,116.07 (d, J=21.5Hz), 46.75,46.60,24.23.Elemental
Analysis (%) calcd.For C27H22FN3O6S(535.54):C 60.55,H 4.14,N7.85,S 5.99；Found:C
60.41,H 4.13,N 7.87,S 5.95.
Embodiment 4
3- (4- cyano benzylidene) -5- (2- fluorobenzylidenes)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones
(BAP-4) synthesis
By the 4- cyano Ji Benjia of the 2- fluorobenzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol
Aldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, 25 DEG C are stirred to react 12 hours, pass through thin layer
Chromatography (TLC) determines 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, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate=1:1) yellow is obtained to consolidate
Then intermediate B AP-H (4) and 4- acetamidobenzenesulfonyl chlorides, are dissolved in 10mL dichloromethane by body, i.e. intermediate B AP-H (4)
In, 3-5 drop pyridines are added in, stirring at normal temperature is overnight, and reaction end is determined by thin-layered chromatography (TLC).Reaction solution 2mol/L
Hydrochloric acid solution is washed twice, and 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- (4- cyano benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl is obtained
Aminobenzenesulfonyl) -4- piperidones (BAP-4), yield 40%.
Mp:223-225℃；IR(cm-1):3334(s),3181(m),3069(m),2228(s),1690(s),1670(s),
1615(s),1584(s),1529(s),1484(s),1451(s),1401(m),1349(m),1315(s),1261(m),1230
(s),1204(s),1183(s),1154(s),1090(s),1043(s),987(s),960(s),835(m),806(s),757
(m),733(m),690(m),647(m),601(m),581(m).1H NMR(400MHz,DMSO)δ10.41(s,1H),8.00
(d, J=8.1Hz, 2H), 7.71 (d, J=8.6Hz, 2H), 7.67 (d, J=8.1Hz, 2H), 7.60 (s, 2H), 7.56 (d, J=
6.5Hz,1H),7.49–7.35(m,5H),4.63(s,2H),4.53(s,2H),2.12(s,3H).13C NMR(100MHz,
DMSO) δ 183.77,169.21,160.34 (d, J=249.6Hz), 143.80,138.59,135.50,133.00,132.69,
(132.29,132.21,131.07 d, J=1.7Hz), 131.01,130.52,129.69 (d, J=4.1Hz), 128.55,
126.12,124.93 (d, J=3.3Hz), 121.64 (d, J=13.1Hz, 118.55,116.06 (d, J=21.5Hz),
111.77,46.65,46.57,24.25.Elemental analysis (%) calcd.ForC28H22FN3O4S(515.56):C
65.23,H 4.30,N 8.15,S 6.22；Found:C 65.29,H 4.23,N 8.18,S 6.27.
Embodiment 5
3- (4- cyano benzylidene) -5- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -
The synthesis of 4- piperidones (BAP-5)
By the 4- piperidone hydrochlorides of 0.01mol and the 3,4,5-trimethoxybenzaldehyde of 0.01mol and the 4- of 0.01mol
Cyanobenzaldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, and 15 DEG C are stirred to react 16 hours,
Reaction end is determined by thin-layered chromatography (TLC).Precipitation filters after completion of the reaction, is precipitated and dissolved in water and uses sodium hydroxide
Solution tune pH value to neutrality, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/methanol=
10:10:1) yellow solid, i.e. intermediate B AP-H (5), then, by intermediate B AP-H (5) and 4- acetamidobenzenesulfonyl chlorides are obtained
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 is concentrated under reduced pressure with (the elution of 200~300 mesh silica gel column chromatographies
Agent：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid invention product 3- (4- cyano benzylidene) -5- (3,4,
5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-5), yield 31%.
Mp:255-257℃；IR(cm-1):3352(s),3196(m),3043(m),2993(m),2823(m),2229(s),
1701(s),1671(s),1602(s),1583(s),1532(s),1504(s),1453(s),1404(m),1375(m),1345
(s),1315(m),1257(m),1206(s),1186(s),1151(s),1053(s),1006(s),972(s),929(s),849
(m),819(s),768(m),757(m),658(m),645(m),635(m),597(m).1H NMR(400MHz,DMSO)δ
10.41 (s, 1H), 7.99 (d, J=8.1Hz, 2H), 7.76 (d, J=8.6Hz, 2H), 7.69 (d, J=8.1Hz, 2H), 7.64
(s, 1H), 7.59 (s, 1H), 7.57 (d, J=8.7Hz, 2H), 6.78 (s, 2H), 4.56 (s, 2H), 4.55 (s, 2H), 3.86
(s,6H),3.76(s,3H),2.12(s,3H).13C NMR(100MHz,DMSO)δ183.99,169.22,152.94,143.84,
139.00,138.67,138.12,134.94,133.22,132.69,130.99,129.88,129.65,129.43,128.70,
118.68,118.59,111.69,108.12,60.21,56.06,46.97,46.77,24.24.Elemental analysis
(%) calcd.For C31H29N3O7S(587.64):C 63.36,H 4.97,N 7.15,S5.46；Found:C 63.33,H
4.95,N 7.12,S 5.47.
Embodiment 6
3- (3,5- dimethoxybenzylidens) -5- (3,4,5- trimethoxies benzylidene)-N- (4- acetyl amino phenyl sulphurs
Acyl group) -4- piperidones (BAP-6) synthesis
By the 3,4 of the 3,5- dimethoxy benzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol,
5- trimethoxybenzaldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, stirring at normal temperature reaction 8
Hour, reaction end is determined by thin-layered chromatography (TLC).Precipitation filters after completion of the reaction, is precipitated and dissolved in water and uses hydrogen
Sodium hydroxide solution tune pH value to neutrality, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/
Methanol=10:10:1) yellow solid, i.e. intermediate B AP-H (6), then, by intermediate B AP-H (6) and 4- acetyl amino phenyls are obtained
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.Reaction solution is washed twice with 2mol/L hydrochloric acid solutions, and reaction solution reduced pressure (is washed with 200~300 mesh silica gel column chromatographies
De- agent：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid invention product 3- (3,5- dimethoxy benzene methylenes are obtained
Base) -5- (3,4,5- trimethoxy benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6), yield is
37%.
Mp:287-289℃；IR(cm-1):3355(s),3093(m),3003(m),2937(m),2842(m),1693(s),
1663(s),1606(s),1593(s),1531(s),1504(s),1466(s),1403(m),1369(m),1341(m),1316
(s),1233(m),1205(s),1187(s),1094(s),1076(s),1019(s),974(s),946(s),850(m),820
(s),728(m),688(m),669(m),641(m),618(m),582(m).1H NMR(400MHz,DMSO)δ10.43(s,
1H), 7.77 (d, J=8.6Hz, 2H), 7.56 (t, J=8.2Hz, 4H), 6.78 (s, 2H), 6.64 (s, 1H), 6.62 (s, 2H),
4.56(s,1H),4.54(s,1H),3.86(s,6H),3.83(s,6H),3.76(s,3H),2.12(s,3H).13C NMR
(100MHz,DMSO)δ184.10,169.23,160.57,152.94,143.84,138.89,137.71,137.11,135.91,
131.11,129.84,129.82,129.52,128.62,118.63,108.07,108.04,101.78,60.20,56.05,
55.42,47.07,46.91,24.23.Elemental analysis (%) calcd.For C32H34N2O9S(622.69):C
61.72,H 5.50,N 4.50,S 5.15；Found:C 61.71,H 5.45,N 4.46,S 5.13.
Embodiment 7
3- (3- nitros benzylidene) -5- (3,4,5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -
The synthesis of 4- piperidones (BAP-7)
By the 3,4,5- front threes of the 3- nitrobenzaldehydes and 0.01mol of the 4- piperidone hydrochlorides of 0.01mol and 0.01mol
Oxygroup benzaldehyde is mixed in 10mL acetic acid, is continuously passed through dry hydrogen chloride gas 45min, and stirring at normal temperature is reacted 15 hours,
Reaction end is determined by thin-layered chromatography (TLC).Precipitation filters after completion of the reaction, is precipitated and dissolved in water and uses sodium hydroxide
Solution tune pH value to neutrality, gained precipitates 200~300 mesh silica gel column chromatography (eluant, eluents：Petrol ether/ethyl acetate/methanol=
10:10:1) yellow solid, i.e. intermediate B AP-H (7), then, by intermediate B AP-H (7) and 4- acetamidobenzenesulfonyl chlorides are obtained
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 is concentrated under reduced pressure with (the elution of 200~300 mesh silica gel column chromatographies
Agent：Petrol ether/ethyl acetate/methanol=10:10:1) yellow solid invention product 3- (3- nitros benzylidene) -5- (3,4,
5- trimethoxies benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-7), yield 36%.
Mp:288-290℃；IR(cm-1):3357(s),3109(m),3069(m),2995(m),2834(m),1700(s),
1668(s),1610(s),1591(s),1523(s),1503(s),1415(s),1401(m),1343(m),1313(s),1258
(m),1207(s),1187(s),1093(s),1055(s),1012(s),973(s),958(s),842(m),821(s),808
(m),770(m),655(m),636(m),622(m),559(m).1H NMR(400MHz,DMSO)δ10.44(s,1H),8.31
(d, J=11.9Hz, 2H), 7.94 (d, J=7.6Hz, 1H), 7.84 (d, J=7.9Hz, 1H), 7.82-7.76 (m, 2H), 7.72
(s,1H),7.62–7.57(m,3H),6.78(s,2H),4.56(s,4H),3.87(s,6H),3.76(s,3H),2.12(s,
3H).13C NMR(100MHz,DMSO)δ183.96,169.24,152.94,148.10,143.92,138.98,138.07,
136.35,135.61,134.50,132.90,130.49,129.70,129.61,129.43,128.74,124.69,124.00,
118.67,108.10,60.21,56.06,46.99,46.88,24.23.Elementalana lysis (%) calcd.For
C30H29N3O9S(607.63):C 59.30,H 4.81,N 6.92,S 5.28；Found:C 60.03,H4.83,N 6.89,S
5.26.
Antitumor activity and normal cell toxicity assessment
Bis- aryl methylene -4- piperidines ketone compound BAP the 1-7 of 3,5- of the 4- P-acetamido benzene sulfonyls base substitution of the present invention
Antitumor activity 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 1-7 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 1-7 of table are to the half-inhibition concentration IC of tumour cell and normal cell50(μM)
Compound BAP-1, BAP-4, BAP-5, BAP-6, BAP-7 is equal to three kinds of tumor cell lines as can be seen from Table 1
Remarkable activity is shown, particularly to QGY-7703, SMMC-7721, IC50Value is below 5 μM.Compound in seven compounds
BAP-5 is to the IC of three kinds of tumor cell lines50Value is below 3 μM, very close with positive drug DOX.Compound BAP1-7 is to two simultaneously
The IC of kind normal liver cell50Value is all higher than 10 μM, shows relatively low toxicity.
Anti-inflammatory activity is evaluated
Bis- aryl methylene -4- piperidines ketone compound BAP the 1-7 of 3,5- of the 4- P-acetamido benzene sulfonyls base substitution of the present invention
Anti-inflammatory activity evaluation.
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 BAP1-7 is to IL-6, the TNF-α cytokine-expressing of LPS induction RAW264.7 cellular inflammations model secretions
Influence
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 with compound BAP-2, BAP-4, BAP-5, BAP-6 processing group, the water of IL-6 in the cell stimulated compared to exclusive use LPS
It is flat to significantly reduce>50%, the inhibiting effect of both compounds is even higher than the inhibiting effect of positive drug PDTC.Similary compound
BAP-3, BAP-5 processing group are significantly reduced compared to the level that TNF-α in the cell of LPS stimulations is used alone>50%, these four
The inhibiting effect of compound is even higher than the inhibiting effect of positive drug PDTC.Other, compared with the cell of independent LPS stimulations, change
It closes object BAP-3 and is significantly reduced the level that IL-6 is generated in RAW264.7 cells, compound BAP-4, BAP-6, BAP-7 are also notable
Reduce the level 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 (10)
1. the bis- aryl methylene -4- piperidines assimilations of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
Object is closed, is respectively designated as 3- (3,4,5- trimethoxy benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl amino phenyl sulphurs
Acyl group) -4- piperidones (BAP-1), 3- (3,5- dimethoxybenzylidens) -5- (2- fluorobenzylidenes)-N- (4- acetylaminos
Benzenesulfonyl) -4- piperidones (BAP-2), 3- (3- nitros benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl amino phenyls
Sulfonyl) -4- piperidones (BAP-3), 3- (4- cyano benzylidene) -5- (2- fluorobenzylidenes)-N- (4- acetyl amino phenyl sulphurs
Acyl group) -4- piperidones (BAP-4), 3- (3,4,5- trimethoxies benzylidene) -5- (4- cyano benzylidene)-N- (4- acetyl
Aminobenzenesulfonyl) -4- piperidones (BAP-5), (3,4,5- trimethoxy-benzenes are sub- by 3- (3,5- dimethoxybenzylidens) -5-
Methyl)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-6), 3- (3- nitros benzylidene) -5- (3,4,5- front threes
Oxygroup benzylidene)-N- (4- P-acetamido benzene sulfonyls base) -4- piperidones (BAP-7), it is characterized in that, structural formula is：
2. the bis- aryl methylene -4- piperidines assimilations of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
The preparation method of object is closed, is characterized in that, it includes following synthetic route：
First, difference is obtained by the reaction with two kinds of aromatic aldehydes progress Claisen-Schmidt condensations respectively by 4- piperidone hydrochlorides to take
3,5-, the bis- aryl methylene-N-H-4- piperidone hydrochlorides intermediates (BAP-H) of Dai Ji, then, with 4- P-acetamido benzene sulfonyls
Bis- aryl methylene -4- piperidines the ketone compounds of 3,5- that the substitution of 4- P-acetamido benzene sulfonyls base is obtained by the reaction in benzene sulfonyl occur for chlorine
(BAP), synthetic route is as follows：
Wherein, when R1 is 2- fluorine, R2 3,4,5- trimethoxies, 3,5- dimethoxys, 3- nitros, 4- cyano；R1 is 3,4,5-
During trimethoxy, R2 is 4- cyano, 3,5- dimethoxys, 3- nitros.
3. the bis- aryl methylene -4- piperidines assimilations of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base
The preparation method of object is closed, is characterized in that, it is comprised the following specific steps that：
By 4- piperidone hydrochlorides and two kinds of aromatic aldehydes according to 1:1:1 molar ratio is dissolved in solvent 1, adds in catalyst, control
Reaction temperature and reaction time, tlc analysis tracking reaction process, after the reaction was complete, precipitation filters, and uses dilute sodium bicarbonate solution
Lotion, residue silica gel column chromatography obtain intermediate B AP-H, then, intermediate B AP-H and 4- acetamidobenzenesulfonyl chloride is molten
In solvent 2, alkali is added in, stirring at normal temperature is overnight, and precipitation filters, and washing obtains invention product BAP 1-7.
4. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, it is characterised in that
Described two aromatic aldehydes refer to that, when one kind is 2- fluorobenzaldehydes, another is 3,4,5-Trimethoxybenzaldehyde, 3,5-
Dimethoxy benzaldehyde, 3- nitrobenzaldehydes, 4- cyanobenzaldehydes；When one kind is 3,4,5-Trimethoxybenzaldehyde, in addition
One kind is 4- cyanobenzaldehydes, 3,5- dimethoxy benzaldehydes, 3- nitrobenzaldehydes.
5. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, it is characterised in that
The catalyst refer to sodium hydroxide, drying hydrogen chloride gas in one kind.
6. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, it is characterised in that
The reaction temperature is 15-50 DEG C, and the reaction time is 6-24 hours.
7. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, 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.
8. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, it is characterised in that
The alkali refers to one kind in sodium bicarbonate, sodium carbonate, sodium hydroxide, pyridine.
9. bis- virtues of 3,5- that there is antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base to replace as claimed in claim 3
The preparation method of methylene -4- piperidines ketone compounds, 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.
10. bis- aryl methylenes of 3,5- replaced with antitumor and anti-inflammatory activity 4- P-acetamido benzene sulfonyls base of the present invention-
Application of the 4- piperidines ketone compounds in new antitumoral and anti-inflammatory drug is prepared.
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