CN108997311B - Asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof - Google Patents
Asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof Download PDFInfo
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Abstract
The invention relates to eleven 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compounds with anti-tumor and anti-inflammatory activities, belonging to the technical field of anti-tumor and anti-inflammatory drugs. Firstly, performing claisen-schmidt condensation reaction on N-methyl-4-piperidone, 4-pyridine formaldehyde and a second aromatic aldehyde to obtain a crude product; then, the asymmetric 3, 5-diarylmethylene-4-piperidone compound (BAP 1-11) substituted by 4-pyridine is obtained through silica gel column chromatography. The compound has good anti-tumor and anti-inflammatory activities, can avoid the genotoxicity of the existing anti-tumor drugs, has small toxicity to normal cells, and has anti-inflammatory activity. The preparation method is simple and convenient to operate, mild in reaction condition and high in synthesis yield, and is favorable for wide popularization in the anti-tumor and anti-inflammatory fields.
Description
Technical Field
The invention relates to a series of 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compounds with anti-tumor and anti-inflammatory activities, belonging to the technical field of anti-tumor and anti-inflammatory drugs and preparation methods thereof.
Background
Curcumin is a yellow phenolic pigment obtained from the rhizome of plants of the family Zingiberaceae (such as turmeric, zedoary, etc.), and has high importance in medical fields at home and abroad because of the effects of anti-inflammatory, antibacterial, anti-tumor, antioxidant, antiprotozoal, antirheumatic, anti-senile dementia, liver protection, cholagogue, analgesic, diuretic, hypoglycemic and stomach invigorating. However, the clinical application of the composition is seriously affected due to the defects of poor water solubility, unstable structure, low bioavailability and the like. Therefore, the structure of the compound is optimized and modified, and the diketone structure in the middle of curcumin is replaced by N-substituted-4-piperidone to obtain novel 3, 5-diarylmethylene-4-piperidone, so that the compound is expected to improve the defects of curcumin.
The pharmacophore of the novel 3, 5-diarylmethylene-4-piperidone (3, 5-bis (arylmethylene) -4-piperidone, BAP) is 1, 4-pentadienone, which is the main binding site for the compound to bind with tumor cells; forming a secondary binding site when the nitrogen atom of piperidone is substituted; when the aromatic rings on both sides of the 3, 5-diarylmethylene-4-piperidone molecule are substituted with a reactive group, another auxiliary binding site is formed. The coordination of the three binding sites can effectively improve the anti-tumor activity of BAP. Thus, a large number of symmetrical BAP derivatives were synthesized and screened for activity. 3,5-bis (2-fluorobenzylidene) -4-piperidone (EF 24) is representative, and can inhibit proliferation of HCT-116, HT-29, AGS by activating caspase-3 and enhancing Bax to Bcl-2, bcl-xL, etc., thereby achieving the effect of inhibiting colon cancer and gastrointestinal cancer. 3,5-bis (2-pyridine benzylidene) -4-piperidone (EF 31) can inhibit NF- κB pathway to exhibit antitumor and anti-inflammatory activity.
At present, structural modification of 3, 5-diarylmethylene-4-piperidone is mainly carried out at two auxiliary sites. Is a modification method with deeper research and better effect at the present stage. N-alkylation modification mainly introduces alkyl, alkenyl, aryl and the like into nitrogen atoms of piperidones. After transformation, the compounds have smaller toxicity to normal cells, better activity to tumor cells and better selectivity. For example, the N-ethyl-3, 5-diarylmethylene-4-piperidone derivative is synthesized by Hafez under alkaline condition. In addition, N-isopropyl, N-allyl, N-propargyl and other substituted compounds are also included, and the antitumor activity of the compounds is improved to a certain extent.
The acylation at the central piperidine nitrogen atom has been widely studied and can be classified into aliphatic acylation, aromatic acylation, phosphorylation, benzenesulfonylation, etc., depending on the type of the acylating group. A classical example of aliphatic acylation is N- (butenedioyl) -3, 5-bis (2-chlorobenzenemethylene) -4-piperidone (CLEFMA), which is synthesized by Lagisetty and has been found to exert a potential anti-lung cancer cell proliferation effect by inducing autophagy, and also has been found to selectively induce lung cancer cell death by oxidative stress, and is non-toxic in vivo and selective for tumor cells. Lagisetty synthesized a series of EF24 aliphatic acylated products, and the structure-activity relationship was summarized through activity studies: (1) the unsaturated carboxyl short chain on the piperidone nitrogen atom can further increase the activity of the compound; (2) short lipid modifications on the piperidone nitrogen atom do not adversely affect the antitumor activity of the compound. Dimmack subject group introduces an alpha, beta-unsaturated ketone unit on piperidone nitrogen atom through acylation reaction to obtain aromatic acylation products, and the aromatic acylation products have remarkable anti-tumor, anti-malaria and anti-mycobacterium effects, and mechanism researches show that the aromatic acylation products play a role in inducing apoptosis, autophagy and acting on fyn kinase and multidrug resistance mechanisms, and summarize that the molecular density, molecular topology and geometric index of the 3, 5-diarylmethylene-4-piperidone derivative are the most important factors for determining cytotoxicity characteristics. The N-phosphoryl-3, 5-diarylmethylene-4-piperidone derivative is obtained by phosphorylating modification, continuous cytotoxicity can be caused by activating a caspase-3 channel or causing DNA breakage among nucleosomes, and the N-phosphoryl-3, 5-diarylmethylene-4-piperidone derivative has the function of reversing multi-drug resistance.
In contrast, there are more studies and products for symmetrical modification of the aromatic rings on both sides of 3, 5-diarylmethylene-4-piperidone, while there are relatively less studies for asymmetrical modification of the aromatic rings on both sides of 3, 5-diarylmethylene-4-piperidone. The electron withdrawing capability and the electron supplying capability of substituents on two side aromatic rings in 3, 5-diarylmethylene-4-piperidone are different, and the polarity, the solubility, the antitumor activity, the bioavailability and the like of molecules can be influenced. Lack of asymmetric substituted derivatives and studies of their activity lack of systemicity in analysis of the structure-activity relationship of 3, 5-diarylmethylene-4-piperidone. Therefore, the invention of the asymmetrically substituted 3, 5-diarylmethylene-4-piperidone derivative has important innovative significance for systematically researching the structure-activity relationship of the 3, 5-diarylmethylene-4-piperidone and developing novel anti-tumor and anti-inflammatory drugs.
In addition, in the process of designing a drug molecule, an electron withdrawing group (halogen, cyano, nitro, trifluoromethyl, etc.), an electron donating group (methoxy, etc.), play an important role in the drug's activity. (1) Increasing these groups, it is expected that the lipophilicity of 3, 5-diarylmethylene-4-piperidone molecules can be improved, and the cell membrane permeability and bioavailability of the drug can be further improved; (2) The addition of these groups is expected to enhance the binding capacity between the 3, 5-diarylmethylene-4-piperidone molecule and the target, thereby increasing the pharmacological effect of the drug; (3) By introducing these groups, it is expected that the stability of the 3, 5-diarylmethylene-4-piperidone compound can be altered, altering the metabolic pathway, and thus modulating the in vivo duration of action of the drug. If one side aromatic ring of 3, 5-diaryl methylene-4-piperidone is changed into 3-pyridine group, the acid-base property, bioavailability and polarity of the medicine molecule can be effectively improved, more complex hydrogen bond action can be formed between the medicine molecule and a medicine target, and the pharmacological action of the medicine is further increased.
For the reasons, one side of the aromatic ring of the 3, 5-diarylmethylene-4-piperidone is modified into a 4-pyridine group, and the other side of the aromatic ring is introduced with an electron withdrawing group such as halogen, cyano, nitro, trifluoromethyl and the like and an electron donating group such as methoxy and the like, so that a series of 4-pyridine substituted asymmetric 3, 5-diarylmethylene-4-piperidone compounds are invented.
Disclosure of Invention
The invention aims to find novel anti-tumor and anti-inflammatory drugs with good anti-tumor and anti-inflammatory activities, and provides 11 asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone derivatives; also provides the preparation method of the 11 compounds.
The invention is realized by the following technical scheme:
4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compounds having antitumor and anti-inflammatory activities, respectively designated 3- (2-methoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-1), 3- (4-methoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-2), 3- (3, 5-dimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-3), 3- (3, 4, 5-trimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-4), 3- (2, 3, 4-trimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-5), 3- (2-fluorobenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-6), 3- (2-fluoro-5-nitrophenylmethylene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-7), 3- (2-bromo-4-fluorobenzylmethylene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-8), 3- (3-nitrophenylmethylene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-9), 3- (4-trifluoromethyl-benzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-10), 3- (4-cyanobenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-11), characterized by the structural formula:
the preparation method of the 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities comprises the following steps: firstly, performing claisen-schmidt condensation reaction on N-methyl-4-piperidone, 4-pyridine formaldehyde and a second aromatic aldehyde to obtain a crude product; then, the asymmetric 3, 5-diarylmethylene-4-piperidone compound (BAP 1-11) substituted by 4-pyridine is obtained through silica gel column chromatography, and the synthetic route is as follows:
wherein R is 1 Is 2-methoxy, 4-methoxy, 3, 5-dimethoxy, 3,4, 5-trimethoxy, 2,3, 4-trimethoxy, 2-fluoro-5-nitro, 2-bromo-4-fluoro, 3-nitro, 4-trifluoromethyl, 4-cyano.
The preparation method of the 4-pyridine substituted asymmetric 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities is characterized by comprising the following specific steps:
dissolving N-methyl-4-piperidone, 4-pyridine formaldehyde and a second aromatic aldehyde in a solvent 1 according to a certain molar ratio, adding a catalyst, controlling the reaction temperature and the reaction time, carrying out thin-layer analysis to track the reaction progress, adding an equal volume of water after the reaction is completed, extracting three times by using the solvent 2, combining the extract, evaporating the solvent under reduced pressure, and carrying out silica gel column chromatography on the residue to obtain the product BAP 1-11. And the correctness of the structure is verified through infrared spectrum, nuclear magnetic resonance and element analysis.
The second aromatic aldehyde refers to one of 2-methoxybenzaldehyde, 4-methoxybenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 2,3, 4-trimethoxybenzaldehyde, 2-fluorobenzaldehyde, 2-fluoro-5-nitrobenzaldehyde, 2-bromo-4-fluorobenzaldehyde, 3-nitrobenzaldehyde, 4-trifluoromethyl benzaldehyde and 4-cyanobenzaldehyde.
The certain molar ratio is 1:1:1.
The catalyst is one of sodium hydroxide and dry hydrogen chloride gas.
The reaction temperature is 15-50 ℃, and the reaction time is 4-24 hours.
The solvent 1 is one of acetic acid and methanol, and the solvent 2 is one of ethyl acetate and dichloromethane.
The silica gel column chromatography is performed by using 200-300 mesh silica gel, petroleum ether/ethyl acetate/methanol=20:20:1-5:5:1 (volume ratio) as an eluent.
The invention provides application of a 4-pyridine substituted asymmetric 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities in preparation of novel anti-tumor and anti-inflammatory drugs.
The 4-pyridine substituted asymmetric 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities is prepared through one-step reaction, is simple and convenient to operate, has mild reaction conditions and high synthesis yield, and is favorable for wide popularization in the anti-tumor and anti-inflammatory fields.
Drawings
Fig. 1: effect of compound BAP1-11 on expression of IL-6, TNF- α cytokines secreted by LPS-induced RAW264.7 cell inflammation model.
Detailed Description
The following description of the invention provides a further illustration of the invention.
Example 1
Synthesis of 3- (2-methoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-1)
In a 25mL round bottom flask, o-methoxybenzaldehyde (0.68 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, 2mL of 10% NaOH solution was added dropwise at normal temperature, and stirred for 12 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (2-methoxybenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-1) as a pale yellow powder in 50% yield.
Mp:116-118℃；IR(cm -1 ):2931(s),2851(m),2780(s),1655(s),1595(s),1487(s),1460(s),1436(m),1414(m),1244(s),1164(s),1111(s),1050(s),1023(s),921(s),811(s),754(s). 1 H NMR(400MHz,CDCl 3 )δ8.67(d,J＝5.5Hz,2H,-C 5 H 4 N),8.10(s,1H,-C＝CH),7.68(s,1H,-C＝CH),7.37(t,J＝7.7Hz,1H,-C 6 H 4 ),7.24(d,J＝5.4Hz,2H,-C 5 H 4 N),7.21(d,J＝7.4Hz,1H,-C 6 H 4 ),6.99(t,J＝7.5Hz,1H,-C 6 H 4 ),6.94(d,J＝8.4Hz,1H,-C 6 H 4 ),3.87(s,3H,-OCH 3 ),3.72(s,2H,-CH 2 ),3.69(s,2H,-CH 2 ),2.43(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.94,158.14,149.61,142.43,136.45,133.05,132.27,131.91,130.47,129.85,123.57,121.01,119.66,110.42,56.52,56.49,55.07,45.25.Elemental analysis(％)calcd.for C 20 H 20 N 2 O 2 (320.38):C,74.98；H,6.29；N,8.74；O,9.99；Found:C,74.93,H,6.89,N,8.96,O,9.92.
Example 2
Synthesis of 3- (4-methoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-2)
In a 25mL round bottom flask, p-methoxybenzaldehyde (0.68 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, 2mL of 10% NaOH solution was added dropwise at normal temperature, and stirred for 15 hours (TLC tracking). The upper layer solution was poured out and the remaining solid was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/methanol=20:20:1) to give 3- (2-methoxybenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-2) as a pale yellow powder in 49% yield.
Mp:119-121℃；IR(cm -1 ):2926(s),2850(m),2786(s),1670(m),1592(s),1575(s),1460(s),1415(m),1314(m),1305(s),1274(s),1256(s),1166(s),1128(s),1061(s),949(s),925(s),811(s),782(s),761(s). 1 H NMR(400MHz,CDCl 3 )δ8.69(d,J＝5.1Hz,2H,-C 5 H 4 N),7.82(s,1H,-C＝CH),7.70(s,1H,-C＝CH),7.41(d,J＝8.5Hz,2H,-C 6 H 4 ),7.32-7.23(m,2H,-C 5 H 4 N),6.98(d,J＝8.5Hz,2H,-C 6 H 4 ),3.88(s,3H,-OCH 3 ),3.82(s,2H,-CH 2 ),3.75(s,2H,-CH 2 ),2.50(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.83,160.20,149.48,142.53,137.14,136.37,132.18,132.01,129.96,127.19,123.62,113.79,56.75,56.09,54.96,45.32.Elemental analysis(％)calcd.for C 20 H 20 N 2 O 2 (320.38):C,74.98；H,6.29；N,8.74；O,9.99；Found:C,74.91,H,6.89,N,8.96,O,9.91.
Example 3
Synthesis of 3- (3, 5-dimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-3)
In a 25mL round bottom flask, 3, 5-dimethoxybenzaldehyde (0.83 g,0.005 mol), 4-pyridylaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at room temperature and stirred for 10 hours (TLC tracking). The upper layer solution was poured out and the remaining solid was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/methanol=5:5:1) to give 3- (3, 5-dimethoxybenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-3) as a pale yellow powder in 47% yield.
Mp:80-82℃；IR(cm -1 ):2939(s),2838(m),2782(s),1661(m),1590(s),1455(s),1425(m),1324(m),1269(s),1204(s),1180(s),1153(s),1060(s),991(s),927(s),837(s),732(s). 1 H NMR(400MHz,CDCl 3 )δ8.69(d,J＝4.5Hz,2H,-C 5 H 4 N),7.76(s,1H,-C＝CH),7.68(s,1H,-C＝CH),7.25(d,J＝5.3Hz,2H,-C 5 H 4 N),6.55(s,2H,-C 6 H 3 ),6.51(s,1H,-C 6 H 3 ),3.84(s,6H,-OCH 3 ),3.78(s,2H,-CH 2 ),3.73(s,2H,-CH 2 ),2.47(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.99,160.30,149.66,142.22,136.85,136.29,136.27,132.64,132.39,123.53,108.03,100.78,56.56,56.33,55.02,45.36.Elemental analysis(％)calcd.for C 21 H 22 N 2 O 3 (350.41):C,71.98；H,6.33；N,7.99；O,13.70；Found:C,72.95,H,6.59,N,8.02,O,13.91.
Example 4
Synthesis of 3- (3, 4, 5-trimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-4)
In a 25mL round bottom flask, 3,4, 5-trimethoxybenzaldehyde (0.98 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL methanol, 2mL10% NaOH solution was added dropwise at room temperature, and stirred for 9 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (3, 4, 5-trimethoxybenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-4) as a pale yellow powder in 43% yield.
Mp:101-103℃；IR(cm -1 )：2935(m),2840(m),2777(m),1672(s),1587(s),1503(s),1455(s),1416(s),1386(s),1328(s),1266(s),1181(s),1004(s),927(m),834(s),778(s),731(m). 1 H NMR(400MHz,CDCl 3 )δ8.67(d,J＝4.5Hz,2H,-C 5 H 4 N),7.76(s,1H,-C＝CH),7.68(s,1H,-C＝CH),7.24(d,J＝5.1Hz,2H,-C 5 H 4 N),6.62(d,J＝12.7Hz,2H,-C 6 H 2 ),3.89(s,9H,-OCH 3 ),3.80(s,2H,-CH 2 ),3.74(s,2H,-CH 2 ),2.47(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.81,152.69,149.67,142.20,137.19,136.18,132.41,131.45,129.99,124.12,123.07,107.51,102.32,60.56,56.57,56.21,55.81,45.31.Elemental analysis(％)calcd.for C 22 H 24 N 2 O 4 (380.44):C,69.46；H,6.36；N,7.36；O,16.82；Found:C,69.52,H,6.40,N,7.29,O,16.91.
Example 5
Synthesis of 3- (2, 3, 4-trimethoxybenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-5)
In a 25mL round bottom flask, 2,3, 4-trimethoxybenzaldehyde (0.98 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL methanol, 2mL10% NaOH solution was added dropwise at room temperature, and stirred for 11 hours (TLC tracking). Three extractions with ethyl acetate, combining the extracts, evaporating the solvent under reduced pressure, and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=5:5:1) to give 3- (2, 3, 4-trimethoxybenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-5) as a pale yellow powder in 44% yield.
Mp:165-167℃；IR(cm -1 )：2962(m),2849(m),2786(m),1670(s),1593(s),1560(s),1494(s),1456(s),1434(s),1386(s),1257(s),1177(s),1093(s),1009(s),973(m),916(m),812(s),733(s). 1 H NMR(400MHz,CDCl 3 )δ8.67(d,J＝5.1Hz,2H,-C 5 H 4 N),8.03(s,1H,-C＝CH),7.68(s,1H,-C＝CH),7.23(d,J＝5.3Hz,2H,-C 5 H 4 N),6.97(d,J＝8.7Hz,1H,-C 6 H 2 ),6.72(d,J＝8.7Hz,1H,-C 6 H 2 ),3.91(s,3H,-OCH 3 ),3.90(d,J＝1.6Hz,6H,-OCH 3 ),3.72(s,2H,-CH 2 ),3.70(s,2H,-CH 2 ),2.44(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.71,154.70,153.38,149.63,142.38,141.95,136.41,132.47,132.14,131.12,124.88,123.54,121.59,106.44,61.28,60.53,56.76,56.39,55.60,45.32.Elemental analysis(％)calcd.for C 22 H 24 N 2 O 4 (380.44):C,69.46；H,6.36；N,7.36；O,16.82；Found:C,69.51,H,6.42,N,7.28,O,16.91.
Example 6
Synthesis of 3- (2-fluorobenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-6)
In a 25mL round bottom flask, 2-fluorobenzaldehyde (1.02 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at normal temperature and stirred for 4 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=20:20:1) to give 3- (2-fluorobenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-6) as a pale yellow powder in 50% yield.
Mp:125-127℃；IR(cm -1 ):3030(m),2852(m),1675(m),1619(s),1591(s),1544(s),1488(s),1468(m),1413(m),1365(s),1275(s),1243(s),1174(s),1052(s),981(s),833(s),811(m),753(m),704(s). 1 H NMR(400MHz,CDCl 3 )δ8.67(d,J＝5.5Hz,2H,-C 5 H 4 N),7.91(s,1H,-C＝CH),7.69(s,1H,-C＝CH),7.38(d,J＝6.5Hz,1H,-C 5 H 4 N),7.31(d,J＝7.3Hz,1H,-C 5 H 4 N),7.28(s,1H,-C 6 H 4 ),7.24(s,1H,-C 6 H 4 ),7.19(d,J＝5.4Hz,1H,-C 6 H 4 ),7.13(d,J＝7.3Hz,1H,-C 6 H 4 ),3.74(s,2H,-CH 2 ),3.66(s,2H,-CH 2 ),2.44(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.57,160.46(d,J＝252.1Hz),149.67,142.16,136.09,133.93,132.79,130.67(d,J＝8.5Hz),130.26(d,J＝2.6Hz),129.44(d,J＝3.8Hz),123.54,122.51(d,J＝13.7Hz),115.54(d,J＝22.0Hz),56.35,56.32,45.24.Elemental analysis(％)calcd.for C 19 H 17 FN 2 O(308.35):C,74.01；H,5.56；F,6.16；N,9.08；O,5.19；Found:C,73.99,H,5.50,F,6.10,N,9.12,O,5.11.
Example 7
Synthesis of 3- (2-fluoro-5-nitrobenzenemethylene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-7)
In a 25mL round bottom flask, 2-fluoro-5-nitrobenzaldehyde (0.84 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at room temperature and stirred for 12 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=20:20:1) to give 3- (2-fluoro-5-nitrobenzenemethylene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-7) as a pale yellow powder in 46% yield.
Mp:168-170℃；IR(cm -1 ):2924(m),2855(m),2771(m),1680(s),1620(s),1595(m),1520(s),1484(m),1465(m),1346(s),1269(s),1176(s),1128(s),1095(s),1056(m),924(s),837(m),769(m),747(s). 1 H NMR(400MHz,CDCl 3 )δ8.71(d,J＝5.2Hz,2H,-C 5 H 4 N),8.36-8.26(m,1H,-C 6 H 3 ),8.23(dd,J＝5.9,2.4Hz,1H,-C 6 H 3 ),7.84(s,1H,-C＝CH),7.72(s,1H,-C＝CH),7.33(t,J＝8.9Hz,1H,-C 6 H 3 ),7.30-7.25(m,2H,-C 5 H 4 N),3.78(s,2H,-CH 2 ),3.70(s,2H,-CH 2 ),2.48(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.08,163.71(d,J＝262.7Hz),149.80,143.61,141.82,136.20,135.58,133.61,126.24(d,J＝3.4Hz),125.92(d,J＝10.4Hz),125.80(d,J＝4.6Hz),123.85(d,J＝16.1Hz),123.54,116.62(d,J＝24.6Hz),56.34,56.02,45.34.Elemental analysis(％)calcd.for C 19 H 16 FN 3 O 3 (353.35):C,64.58；H,4.56；F,5.38；N,11.89；O,13.58；Found:C,63.99,H,4.55,F,5.15,N,12.01,O,13.21.
Example 8
Synthesis of 3- (2-bromo-4-fluorobenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-8)
In a 25mL round bottom flask, 2-bromo-4-fluorobenzaldehyde (1.10 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at room temperature and stirred for 13 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=5:5:1) to give 3- (2-bromo-4-fluorobenzenemethylene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-8) as a pale yellow powder in 48% yield.
Mp:152-154℃；IR(cm -1 ):2923(m),2851(m),2765(m),1732(m),1666(s),1592(s),1481(s),1417(m),1333(m),1279(s),1225(s),1180(s),1137(s),1036(s),986(s),880(s),818(m),723(s). 1 H NMR(400MHz,CDCl 3 )δ8.68(d,J＝5.5Hz,2H,-C 5 H 4 N),7.87(s,1H,-C＝CH),7.70(s,1H,-C＝CH),7.42(dd,J＝8.1,2.2Hz,1H,-C 6 H 3 ),7.24(d,J＝5.6Hz,2H,-C 5 H 4 N),7.20(dd,J＝10.5,4.4Hz,1H,-C 6 H 3 ),7.09(td,J＝8.3,2.2Hz,1H,-C 6 H 3 ),3.72(s,2H,-CH 2 ),3.57(s,2H,-CH 2 ),2.42(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.47,161.91(d,J＝254.2Hz),149.73,142.06,135.85,134.99,133.37,133.16,130.88(d,J＝8.7Hz),125.32(d,J＝9.6Hz),123.55,121.59,120.28(d,J＝24.4Hz),114.10(d,J＝21.4Hz),56.44,55.86,45.28.Elemental analysis(％)calcd.for C 19 H 16 BrFN 2 O(387.25):C,58.93；H,4.16；Br,20.63；F,4.91；N,7.23；O,4.13；Found:C,58.93,H,4.14,Br,20.73,F,4.85,N,7.02,O,4.21.
Example 9
Synthesis of 3- (3-nitrobenzenemethylene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-9)
In a 25mL round bottom flask, 3-nitrobenzaldehyde (0.75 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at room temperature and stirred for 12 hours (TLC tracking). Three extractions with dichloromethane were performed, the extracts were combined, the solvent was evaporated under reduced pressure and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=5:5:1) to give 3- (3-nitrobenzenemethylene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-9) as a pale yellow powder in 55% yield.
Mp:195-197℃；IR(cm -1 ):3088(m),2947(m),2851(m),2774(s),1676(s),1614(s),1590(s),1527(s),1349(s),1268(s),1175(s),1097(s),1057(s),999(s),923(s),816(s),737(s). 1 H NMR(400MHz,CDCl 3 )δ8.72(d,J＝7.6Hz,2H,-C 5 H 4 N),8.27(d,J＝7.6Hz,2H,-C 6 H 4 ),7.84(s,1H,-C＝CH),7.72(s,1H,-C＝CH),7.68(s,1H,-C 6 H 4 ),7.66(t,J＝7.7Hz,1H,-C 6 H 4 ),7.27(m,2H,-C 5 H 4 N),3.80(s,2H,-CH 2 ),3.78(s,2H,-CH 2 ),2.51(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.95,150.16,148.29,142.28,136.48,136.17,136.00,134.96,133.93,133.53,129.71,124.39,123.94,123.64,56.65,56.61,45.83.Elemental analysis(％)calcd.for C 19 H 17 N 3 O 3 (335.36):C,68.05；H,5.11；N,12.53；O,14.31；Found:C,68.01,H,5.14,N,12.53,O,14.21.
Example 10
Synthesis of 3- (4-trifluoromethyl-benzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-10)
In a 25mL round bottom flask, p-trifluoromethylbenzaldehyde (0.87 g,0.005 mol), 4-pyridylaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 5mL of methanol, and 2mL of 10% NaOH solution was added dropwise at room temperature and stirred for 17 hours (TLC tracking). The upper layer solution was poured off and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (4-trifluoromethyl-benzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-10) as a pale yellow powder in 49% yield.
Mp:131-133℃；IR(cm -1 ):952(m),2776(m),1673(s),1614(s),1415(s),1323(s),1275(s),1160(m),1116(s),1066(s),1013(s),926(s),830(s),757(m). 1 H NMR(400MHz,CDCl 3 )δ8.65(d,J＝5.7Hz,2H,-C 5 H 4 N),7.79(s,1H,-C＝CH),7.68(s,1H,-C＝CH),7.66(s,2H,-C 5 H 4 N),7.48(s,1H,-C 6 H 4 ),7.46(s,1H,-C 6 H 4 ),7.24(s,1H,-C 6 H 4 ),7.22(s,1H,-C 6 H 4 ),3.73(s,2H,-CH 2 ),3.72(s,2H,-CH 2 ),2.45(s,3H,-NCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ185.69,150.75,149.62,149.45,142.05,137.95,135.96,134.74,134.05,132.83,129.91,125.07(q,J＝3.8Hz),123.53,56.32,56.24,45.29.Elemental analysis(％)calcd.for C 20 H 17 F 3 N 2 O(358.36):C,67.03；H,4.78；F,15.90；N,7.82；O,4.46；Found:C,67.05,H,4.74,F,15.90,N,7.82,O,4.41.
Example 11
Synthesis of 3- (4-cyanobenzylidene) -5- (4-pyridyl) -N-methyl-4-piperidone (BAP-11)
In a 25mL round bottom flask, p-cyanobenzaldehyde (0.65 g,0.005 mol), 4-pyridinecarboxaldehyde (0.53 g,0.005 mol) and N-methyl-4-piperidone (0.57 g,0.005 mol) were dissolved in 20mL of acetic acid, and dried hydrogen chloride gas was introduced for 30min, followed by stirring for 24 hours (TLC tracking). Three extractions with dichloromethane were performed, the extracts were combined, the solvent was evaporated under reduced pressure and the remaining solid was purified by column chromatography on silica gel (eluent, petroleum ether/ethyl acetate/methanol=20:20:1) to give 3- (4-cyanobenzylidene) -5- (4-pyridinyl) -N-methyl-4-piperidone (BAP-11) as a pale yellow powder in 41% yield.
Mp:89-92℃；IR(cm -1 ):2925(m),2852(m),2778(m),2226(s),1671(s),1599(m),1502(m),1457(s),1413(s),1271(s),1172(s),1092(m),1017(m),916(s),827(s),702(s).Elemental analysis(％)calcd.for C 20 H 17 N 3 O(315.37):C,76.17；H,5.43；N,13.32；O,5.07；Found:C,76.03,H,5.13,N,13.32,O,4.99.
Evaluation of antitumor Activity
The antitumor activity of the 4-pyridine substituted asymmetric 3, 5-diarylmethylene-4-piperidone compound BAP1-11 is evaluated.
In the invention, the evaluation of the antitumor activity adopts an MTT method (chemical name is [3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide ]). The experiments were performed using the human monocytic leukemia cell line THP-1, and the cells were from the national institute of medicine and Chinese medical administration, "prescription Effect and clinical evaluation" major laboratory. Doxorubicin (DOX) was used as a positive control.
Preparing cells in logarithmic growth phase into 4×10 4 Inoculating cell suspension of each/mL into 96-well culture plate, adding 200 μl of each well, culturing for 24 hr, adding 20 μl of synthetic compound with different concentration, culturing for 24 hr, adding 20 μl of MTT reagent, incubating at 37deg.C for 4 hr, discarding supernatant, adding 150 μl of DMSO, shaking for 10min to dissolve crystals, measuring absorbance at 570nm with enzyme-labeled instrument, and calculating IC 50 . BAP1-11 was used at concentrations of 10, 8, 5, 3, 2, 1, 0.5, 0.1, 0.05, 0.01. Mu.g/mL, respectively, and Doxorubicin (DOX) was used as a positive control, at concentrations of 8, 6, 5, 3, 1.5, 1, 0.8, 0.5, 0.1. Mu.g/mL, each with 6 multiplex wells.
TABLE 1 half inhibition concentration IC of Compound BAP1-11 against tumor cells 50 (μM)
From Table 1, it can be seen that compounds BAP-5 and BAP-9 exhibit remarkable activity against HepG2, and IC thereof 50 The values were all below 5. Mu.M. Is very similar to the positive medicine DOX. IC of compound BAP1-11 to two normal liver cells simultaneously 50 Values above 10 μm all show lower toxicity.
Evaluation of anti-inflammatory Activity
Evaluation of anti-inflammatory Activity of 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone Compound BAP1-11 of the present invention.
In the invention, the anti-inflammatory activity evaluation adopts an in-vitro ELISA method to detect the influence of BAP derivatives on the expression of IL-6 and TNF-alpha cytokines secreted by an LPS-induced RAW264.7 cell inflammation model, and the cells come from a key research laboratory of prescription effect and clinical evaluation of the national traditional Chinese medicine administration of the medical college in the coastal state. PDTC (NF-kappa B inhibitor) as a positive control. The MTT method is adopted to detect the toxic effect of BAP derivatives on RAW264.7 cells, and the detection result shows that when the BAP derivatives concentration is less than or equal to 6 mu M, the BAP derivatives are nontoxic on RAW264.7 cells, and the anti-inflammatory activity evaluation experiment drug concentration is set to 6 mu M.
Taking RAW264.7 cells as a bottle, collecting the cells after trypsin digestion, blowing the cells uniformly by a pipette, and adjusting the cell number to 2X 10 5 /mL. 100 μl of cell suspension was added to each well of a 96-well cell culture plate and placed in CO 2 Culturing in an incubator is continued for 12 hours. After the plate was removed, the stock culture was aspirated, and 180. Mu.L of BAP derivative serum-free medium at a concentration of 6. Mu.M was added to each well. After 2h 20. Mu.L LPS (final mass concentration 1. Mu.g/mL) was added, and a normal control group and a positive control group (PDTC: 30. Mu.M) were additionally set. After LPS is added, the mixture is evenly mixed on a microplate oscillator and placed in CO 2 Culturing was continued in the incubator for 24 hours, respectively. Culture supernatants were collected and assayed for TNF- α, IL-6 content by ELISA.
Effect of Compound BAP1-11 on expression of IL-6, TNF-alpha cytokines secreted by LPS-induced RAW264.7 cell inflammation model
Stimulation with LPS induced high levels of TNF- α and IL-6 production in RAW264.7 cells (figure 1). From FIG. 1 it can be seen that the treatment groups with compounds BAP-1, BAP-2, BAP-3, BAP-4, BAP-6, BAP-7, BAP-8, BAP-9 significantly reduced the level of IL-6 by >50% compared to the cells stimulated with LPS alone, the inhibition of these compounds was even higher than that of the positive drug PDTC. Also, the levels of TNF- α in cells stimulated with LPS alone were significantly reduced by >50% in the BAP-1, BAP-2, BAP-7, BAP-8, BAP-9 treated groups, and the inhibition of these compounds was even higher than that of the positive drug PDTC.
The foregoing is only a preferred example of the present invention and is not intended to limit the present invention. Any changes, modifications, substitutions, etc. based on the present invention should be included in the scope of the present invention.
Claims (9)
1. 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compounds with antitumor and anti-inflammatory activities, and have the structural formula:
。
2. a process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity as claimed in claim 1, comprising the steps of:
firstly, performing claisen-Schmidt condensation reaction on N-methyl-4-piperidone and 4-pyridylaldehyde with aromatic aldehyde shown in a reaction formula under the action of a catalyst to obtain a crude product; then, the asymmetric 3, 5-diarylmethylene-4-piperidone compound substituted by 4-pyridine is obtained through silica gel column chromatography:
3. A process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity as claimed in claim 2, comprising the steps of:
dissolving N-methyl-4-piperidone and 4-pyridine formaldehyde and the aromatic aldehyde in a solvent 1, adding a catalyst, controlling the reaction temperature and the reaction time, carrying out thin-layer analysis to track the reaction progress, adding an equal volume of water after the reaction is completed, extracting for three times by using the solvent 2, combining extract liquid, evaporating the solvent under reduced pressure, and carrying out silica gel column chromatography on residues to obtain a product; the solvent 1 refers to one of acetic acid and methanol; the solvent 2 is one of ethyl acetate and dichloromethane.
4. A process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity according to claim 3, wherein the aromatic aldehyde is one of 3, 5-dimethoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 2,3, 4-trimethoxybenzaldehyde, 2-fluoro-5-nitrobenzaldehyde and 2-bromo-4-fluorobenzaldehyde.
5. A process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity as claimed in claim 3, wherein the catalyst is one of sodium hydroxide and dry hydrogen chloride gas.
6. A process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity according to claim 3, wherein the reaction temperature is 15-50 ℃ and the reaction time is 4-24 hours.
7. The method for preparing the 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities according to claim 3, wherein the silica gel column chromatography is performed by using 200-300 mesh silica gel, petroleum ether, ethyl acetate and methanol with a volume ratio of 20:20:1-5:5:1 as eluent.
8. A process for the preparation of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumour and anti-inflammatory activity according to claim 3, wherein the molar ratio of N-methyl-4-piperidone and 4-pyridylaldehyde to araldehyde is 1:1:1.
9. The use of a 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity as described in claim 1 for the preparation of an anti-tumor and anti-inflammatory medicament.
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