CN108191742B - 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof - Google Patents

4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof Download PDF

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CN108191742B
CN108191742B CN201810014190.0A CN201810014190A CN108191742B CN 108191742 B CN108191742 B CN 108191742B CN 201810014190 A CN201810014190 A CN 201810014190A CN 108191742 B CN108191742 B CN 108191742B
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piperidone
acetamidobenzenesulfonyl
diarylmethylene
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侯桂革
王春华
李宁
姚彬荣
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Binzhou Medical College
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Abstract

The invention relates to seven 4-acetamidobenzenesulfonyl 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. The preparation method comprises the steps of firstly carrying out claisen-Schmidt condensation reaction on 4-piperidone hydrochloride and two kinds of aromatic aldehyde respectively, obtaining 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride intermediates (BAP-H) with different substituents through column chromatography, and then carrying out benzenesulfonylation reaction on the intermediates and 4-acetamidobenzenesulfonyl chloride to obtain the 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound (BAP). 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

4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof
Technical Field
The invention relates to a series of 4-acetamidobenzenesulfonyl 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, aliphatic acylation, aromatic acylation, phosphorylation and products are more studied on 3, 5-diarylmethylene-4-piperidone, and benzenesulfonylation modification is relatively less studied on 3, 5-diarylmethylene-4-piperidone. The medicine containing benzenesulfonyl has been widely applied to clinic, such as celecoxib serving as an anti-inflammatory agent, sulfadiazine serving as an antibacterial agent, mechlothiazide serving as an antihypertensive agent, glimepiride serving as a long-acting diabetes agent, probenecid serving as a gout treatment agent, dofetilide serving as an antiarrhythmic agent, and the like. In the medicines, the introduction of sulfonyl can regulate the solubility and acid-base property of small molecules and can improve the activity and bioavailability of the medicines. If benzenesulfonyl groups are introduced on the nitrogen atom of 3, 5-diarylmethylene-4-piperidone, it is desirable to be able to modulate the solubility and acid-base properties of the molecules, further improving their antitumor and anti-inflammatory activity and bioavailability.
Nevertheless, 3,5-bis (arylmethylene) -4-piperidone derivatives have been reported to be symmetrical compounds, and less for unsymmetrical 3,5-bis (arylmethylene) -4-piperidone compounds. In addition, there are few reports of the anti-inflammatory activity of such compounds. The introduction of different substituents, particularly substituents having different electron withdrawing and donating abilities, such as electron withdrawing groups such as fluorine, nitro, cyano, etc., electron withdrawing groups such as methoxy, etc., on both sides of 3, 5-diarylmethylene-4-piperidone may affect the polarity, solubility, antitumor and anti-inflammatory activities, bioavailability, etc., of the molecule, and lack the systemicity in analysis of the structure-activity relationship and antitumor and anti-inflammatory activities of the asymmetric 3, 5-diarylmethylene-4-piperidone substituted with respect to benzenesulfonyl groups.
In addition, acetamido plays an important role in the pharmaceutical activity of the drug in the process of drug molecule design. The introduction of acetamido can effectively improve the acid-base property and bioavailability of drug molecules, and can form more complex hydrogen bond action with drug targets, thereby further increasing the pharmacological action of the drug. If 4-acetamidobenzenesulfonyl is introduced at the nitrogen atom of 3,5-bis (arylmethylene) -4-piperidone, it is desirable to be able to modulate the lipophilicity, acid-base nature and bioavailability of the molecules, enhance the binding capacity between the drug molecules and the target, and further improve their anti-tumor and anti-inflammatory activity and bioavailability.
For the above reasons, we have invented an asymmetric class of 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compounds.
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 7 asymmetric 3, 5-diarylmethylene-4-piperidone derivatives substituted by 4-acetamidobenzenesulfonyl; also provides the preparation method of the 7 compounds.
The invention is realized by the following technical scheme:
4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compounds having antitumor and anti-inflammatory activities, respectively designated 3- (3, 4, 5-trimethoxybenzylidene) -5- (2-fluorobenzenesulfonyl) -5- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-1), 3- (3, 5-dimethoxybenzylidene) -5- (2-fluorobenzenesulfonyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-2), 3- (3-nitrobenzenemethyl) -5- (2-fluorobenzenesulfonyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-3), 3- (4-cyanobenzenemethyl) -5- (2-fluorobenzenesulfonyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-4), 3- (3, 4, 5-trimethoxybenzylidene) -5- (4-cyanobenzenesulfonyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-5-acetamidobenzenesulfonyl), 3- (3, 5-dimethoxy benzylidene) -5- (3, 4, 5-trimethoxy benzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-6), 3- (3-nitrobenzene benzylidene) -5- (3, 4, 5-trimethoxy benzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-7), and is characterized in that the structural formula is as follows:
Figure BDA0001541369800000031
the preparation method of the 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities comprises the following steps: firstly, carrying out claisen-Schmidt condensation reaction on 4-piperidone hydrochloride and two kinds of aromatic aldehyde respectively to obtain 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride intermediates (BAP-H) with different substituents, and then carrying out benzenesulfonylation reaction on the intermediates and 4-acetamidobenzenesulfonyl chloride to obtain a 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound (BAP), wherein the synthetic route is as follows:
Figure BDA0001541369800000041
wherein, when R1 is 2-fluoro, R2 is 3,4, 5-trimethoxy, 3, 5-dimethoxy, 3-nitro, 4-cyano; when R1 is 3,4, 5-trimethoxy, R2 is 4-cyano, 3, 5-dimethoxy or 3-nitro.
The preparation method of the 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities is characterized by comprising the following specific steps:
dissolving 4-piperidone hydrochloride and two kinds of aromatic aldehyde in a molar ratio of 1:1:1 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, precipitating and filtering after the reaction is completed, washing with dilute sodium bicarbonate solution, carrying out silica gel column chromatography on the residue to obtain an intermediate BAP-H, dissolving the intermediate BAP-H and 4-acetamidobenzenesulfonyl chloride in the solvent 2, adding alkali, stirring at normal temperature overnight, precipitating and filtering, washing with water to obtain the product BAP1-7, and verifying the structural correctness of the product by infrared spectrum, nuclear magnetic resonance and elemental analysis.
The two kinds of aromatic aldehyde refer to when one kind is 2-fluorobenzaldehyde and the other kind is 3,4, 5-trimethoxybenzaldehyde, 3, 5-dimethoxy benzaldehyde, 3-nitrobenzaldehyde and 4-cyanobenzaldehyde; when one is 3,4, 5-trimethoxybenzaldehyde, the other is 4-cyanobenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3-nitrobenzaldehyde;
the catalyst is one of sodium hydroxide and dry hydrogen chloride gas;
the reaction temperature is 15-50 ℃, and the reaction time is 6-24 hours;
the solvent 1 is one of acetic acid, water, methanol and ethanol, and the solvent 2 is one of 1, 2-dichloroethane and dichloromethane;
the alkali refers to one of sodium bicarbonate, sodium carbonate, sodium hydroxide and pyridine;
the silica gel column chromatography is performed by selecting 200-300 mesh silica gel, petroleum ether/ethyl acetate=10:1-1:1 (volume ratio) as an eluent.
The invention provides an application of a 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities in preparation of novel anti-tumor and anti-inflammatory drugs.
The preparation method of the 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities is simple and convenient to operate, mild in reaction conditions and high in synthesis yield, and is favorable for wide popularization in the anti-tumor and anti-inflammatory fields.
Drawings
Fig. 1: effect of Compound BAP1-7 on expression of IL-6, TNF-alpha 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- (3, 4, 5-trimethoxybenzylidene) -5- (2-fluorobenzbenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-1)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3,4, 5-trimethoxybenzaldehyde are mixed in 10mL of acetic acid, dry hydrogen chloride gas is continuously introduced for 45min, the mixture is stirred at normal temperature for reaction for 15 hours, and the reaction end point is determined by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, and the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to obtain yellow solid, namely intermediate BAP-H (1), then the intermediate BAP-H (1) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on a 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (3, 4, 5-trimethoxybenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-1) as a yellow solid, the yield was 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). 1 H NMR(400MHz,DMSO)δ10.42(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). 13 C NMR(100MHz,DMSO)δ183.77,169.23,160.32(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 C 28 H 25 F 2 NO 6 S(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.
Example 2
Synthesis of 3- (3, 5-dimethoxybenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-2)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3, 5-dimethoxybenzaldehyde are mixed in 10mL of acetic acid, and dry hydrogen chloride gas is continuously introduced for 45min, and the mixture is stirred at normal temperature for 15 hours to determine the end point of the reaction by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to obtain yellow solid, namely intermediate BAP-H (2), then the intermediate BAP-H (2) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on a 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate=1:1) to give 3- (3, 5-dimethoxybenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-2) as a yellow solid in 30% yield.
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). 1 H NMR(400MHz,DMSO)δ10.39(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). 13 C NMR(100MHz,DMSO)δ183.84,169.24,160.57,160.32(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 C 29 H 27 FN 2 O 6 S(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.
Example 3
Synthesis of 3- (3-nitrobenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-3)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-nitrobenzaldehyde are mixed in a solution of 15mL of methanol and water, 2-3mL of 20% sodium hydroxide solution is added dropwise, and the mixture is stirred at 40℃for reaction for 6 hours, and the reaction end point is determined by Thin Layer Chromatography (TLC). After the reaction, the precipitate was suction-filtered, and the obtained precipitate was subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to obtain a yellow solid, namely intermediate BAP-H (3), then, intermediate BAP-H (3) and 4-acetamidobenzenesulfonyl chloride were dissolved in 10mL of dichloromethane, 3-5 drops of pyridine were added, stirred at room temperature overnight, and the reaction endpoint was determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate=1:1) to give 3- (3-nitrobenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-3) as a yellow solid, the yield was 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). 1 HNMR(400MHz,DMSO)δ10.40(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). 13 C NMR(100MHz,DMSO)δ183.72,169.22,160.34(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 C 27 H 22 FN 3 O 6 S(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.
Example 4
Synthesis of 3- (4-cyanobenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-4)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 4-cyanobenzaldehyde were mixed in 10mL of acetic acid, and the mixture was continuously fed with dry hydrogen chloride gas for 45min and stirred at 25℃for 12 hours to determine the end point of the reaction by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to obtain yellow solid, namely intermediate BAP-H (4), then the intermediate BAP-H (4) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on a 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (4-cyanobenzylidene) -5- (2-fluorobenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-4) as a yellow solid, the yield was 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). 1 H 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). 13 C NMR(100MHz,DMSO)δ183.77,169.21,160.34(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.ForC 28 H 22 FN 3 O 4 S(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.
Example 5
Synthesis of 3- (4-cyanobenzylidene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-5)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 3,4, 5-trimethoxybenzaldehyde and 0.01mol of 4-cyanobenzaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min and stirred at 15℃for 16 hours to determine the end point of the reaction by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, and the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to obtain yellow solid, namely intermediate BAP-H (5), then the intermediate BAP-H (5) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (4-cyanobenzylidene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-5) as a yellow solid, the yield was 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). 1 H NMR(400MHz,DMSO)δ10.41(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). 13 C 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 C 31 H 29 N 3 O 7 S(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.
Example 6
Synthesis of 3- (3, 5-dimethoxybenzylidene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-6)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 3, 5-dimethoxy benzaldehyde and 0.01mol of 3,4, 5-trimethoxy benzaldehyde are mixed in 10mL of acetic acid, dry hydrogen chloride gas is continuously introduced for 45min, stirring is carried out at normal temperature for 8 hours, and the reaction end point is determined by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, and the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to obtain yellow solid, namely intermediate BAP-H (6), then the intermediate BAP-H (6) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on a 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (3, 5-dimethoxybenzylidene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-6) as a yellow solid, the yield was 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). 1 H 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). 13 C 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 C 32 H 34 N 2 O 9 S(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.
Example 7
Synthesis of 3- (3-nitrobenzenemethylene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-7)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 3-nitrobenzaldehyde and 0.01mol of 3,4, 5-trimethoxybenzaldehyde are mixed in 10mL of acetic acid, dry hydrogen chloride gas is continuously introduced for 45min, the mixture is stirred at normal temperature for reaction for 15 hours, and the reaction end point is determined by Thin Layer Chromatography (TLC). After the reaction, the precipitate is filtered by suction, dissolved in water and adjusted to neutral by sodium hydroxide solution, and the obtained precipitate is subjected to 200-300 mesh silica gel column chromatography (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to obtain yellow solid, namely intermediate BAP-H (7), then the intermediate BAP-H (7) and 4-acetamidobenzenesulfonyl chloride are dissolved in 10mL of dichloromethane, 3-5 drops of pyridine are added, stirring is carried out at normal temperature for overnight, and the reaction end point is determined by Thin Layer Chromatography (TLC). The reaction solution was washed twice with 2mol/L hydrochloric acid solution, concentrated under reduced pressure and chromatographed on a 200-300 mesh silica gel column (eluent: petroleum ether/ethyl acetate/methanol=10:10:1) to give 3- (3-nitrobenzylidene) -5- (3, 4, 5-trimethoxybenzylidene) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-7) as a yellow solid, the yield was 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). 1 H 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). 13 C 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.Elementalanalysis(％)calcd.For C 30 H 29 N 3 O 9 S(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.
Evaluation of antitumor Activity and Normal cytotoxicity
The antitumor activity and the normal cytotoxicity of the 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound BAP1-7 are evaluated.
In the invention, the MTT method (chemical name is [3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide ]) is adopted for evaluating the anti-tumor activity and the normal cytotoxicity. Three liver cancer cell lines (HepG 2, QGY-7703, SMMC-7721) and two normal liver cells (LO 2, HIL-5) were used to develop experiments, and the cells were from the national institute of medicine and prescription Effect and clinical evaluation, the "major laboratory of the state medical college. 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 . BAP1-7 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-inhibitory concentration IC of Compound BAP1-7 against tumor cells and Normal cells 50 (μM)
Figure BDA0001541369800000111
From Table 1, it can be seen that the compound BAP-1, BAP-4, BAP-5, BAP-6, BAP-7 show significant activity against all three tumor cell lines, in particular QGY-7703, SMMC-7721, IC thereof 50 The values were all below 5. Mu.M. IC of Compound BAP-5 of seven Compounds for three tumor cell lines 50 The values are all lower than 3 mu M, which is very similar to the positive medicine DOX. IC of compound BAP1-7 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-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone Compound BAP1-7 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 the BAP derivative on RAW264.7 cells, and the detection result shows that when the concentration of the BAP derivative is less than or equal to 10 mu M, the BAP derivative is nontoxic on RAW264.7 cells, and the concentration of the anti-inflammatory activity evaluation experiment drug is set to 10 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 10. 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 BAP1-7 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 group with compounds BAP-2, BAP-4, BAP-5, BAP-6 significantly reduced the IL-6 level by >50% compared to LPS-stimulated cells alone, the inhibition of both compounds being even higher than that of the positive drug PDTC. Also, the levels of TNF- α in the BAP-3 and BAP-5 treated groups were significantly reduced by >50% compared to LPS-stimulated cells alone, and the inhibition of these four compounds was even higher than that of the positive drug PDTC. In addition, the compound BAP-3 also significantly reduced the level of IL-6 production in RAW264.7 cells, and the compounds BAP-4, BAP-6, BAP-7 also significantly reduced the level of TNF- α production in RAW264.7 cells, compared to LPS-stimulated cells alone.
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 (10)

1. 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compounds having antitumor and anti-inflammatory activity are provided, which have the structural formula:
Figure QLYQS_1
。
2. a process for the preparation of a 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity as described in claim 1, comprising the steps of:
firstly, carrying out claisen-Schmidt condensation reaction on 4-piperidone hydrochloride and two aromatic aldehydes shown in a reaction formula under the action of a catalyst to obtain a 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride intermediate BAP-H with different substituents, and then carrying out benzenesulfonylation reaction on the intermediate BAP-H with 4-acetaminophenyl sulfonyl chloride in an alkali solution to obtain a 4-acetaminophenyl sulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound BAP:
Figure QLYQS_2
wherein R is 1 In the case of 2-fluoro, R 2 3,4, 5-trimethoxy, 3, 5-dimethoxy, 3-nitro, 4-cyano; r is R 1 In the case of 3,4, 5-trimethoxy, R 2 Is 4-cyano, 3, 5-dimethoxy, 3-nitro.
3. A process for the preparation of a 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity as described in claim 2, comprising the steps of:
dissolving 4-piperidone hydrochloride and two kinds of aromatic aldehyde in a molar ratio of 1:1:1 in a solvent 1, adding a catalyst, controlling the reaction temperature and the reaction time, tracking the reaction progress by thin-layer analysis, precipitating and filtering after the reaction is completed, washing with dilute sodium bicarbonate solution, performing silica gel column chromatography on the residue to obtain an intermediate BAP-H, dissolving the intermediate BAP-H and 4-acetamidobenzenesulfonyl chloride in the solvent 2, adding alkali, stirring at normal temperature overnight, precipitating and filtering, and washing with water to obtain a product.
4. A process for the preparation of a 4-acetamidobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity according to claim 3, wherein when one of the aromatic aldehydes is 2-fluorobenzaldehyde, the other aromatic aldehyde is 3,4, 5-trimethoxybenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3-nitrobenzaldehyde, 4-cyanobenzaldehyde; when one of the aromatic aldehydes is 3,4, 5-trimethoxybenzaldehyde, the other aromatic aldehyde is 4-cyanobenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3-nitrobenzaldehyde.
5. The method for preparing a 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activities as described in claim 3, wherein said catalyst is one of sodium hydroxide and dry hydrogen chloride gas.
6. The method for preparing a 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity as described in claim 3, wherein the reaction temperature is 15-50 ℃ and the reaction time is 6-24 hours.
7. The method for preparing a 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activity as described in claim 3, wherein the solvent 1 is one of acetic acid, water, methanol and ethanol; the solvent 2 is one of 1, 2-dichloroethane and dichloromethane.
8. The method for preparing a 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound having anti-tumor and anti-inflammatory activities as described in claim 3, wherein the base is one of sodium bicarbonate, sodium carbonate, sodium hydroxide and pyridine.
9. The method for preparing a 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound having antitumor and anti-inflammatory activities as set forth in claim 3, wherein the silica gel column chromatography is performed by selecting 200-300 mesh silica gel, petroleum ether and ethyl acetate in a volume ratio of 10:1-1:1 as eluent.
10. The use of a 4-acetamidobenzenesulfonyl-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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