CN109053564B - N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof - Google Patents

N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof Download PDF

Info

Publication number
CN109053564B
CN109053564B CN201810882254.9A CN201810882254A CN109053564B CN 109053564 B CN109053564 B CN 109053564B CN 201810882254 A CN201810882254 A CN 201810882254A CN 109053564 B CN109053564 B CN 109053564B
Authority
CN
China
Prior art keywords
substituted
piperidone
diarylmethylene
reaction
bap
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201810882254.9A
Other languages
Chinese (zh)
Other versions
CN109053564A (en
Inventor
侯桂革
王春华
姚彬荣
辛文妤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Binzhou Medical College
Original Assignee
Binzhou Medical College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Binzhou Medical College filed Critical Binzhou Medical College
Priority to CN201810882254.9A priority Critical patent/CN109053564B/en
Publication of CN109053564A publication Critical patent/CN109053564A/en
Application granted granted Critical
Publication of CN109053564B publication Critical patent/CN109053564B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to nine N-substituted benzenesulfonyl 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, respectively carrying out claisen-Schmidt condensation reaction on 4-piperidone hydrochloride, 2-fluorobenzaldehyde and 3-pyridinecarboxaldehyde, carrying out column chromatography to obtain an intermediate 3-pyridine substituted 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride (BAP-H), and then carrying out benzenesulfonyl reaction on the intermediate and R1 substituted benzenesulfonyl chloride to obtain an asymmetric N-substituted benzenesulfonyl-3, 5-diarylmethylene-4-piperidone compound (BAP 1-9). 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 simultaneously has anti-inflammatory activity. The preparation method has simple and convenient operation, mild reaction conditions and high synthesis yield, and is beneficial to the wide popularization of the compound in the fields of anti-tumor and anti-inflammatory.

Description

N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof
Technical Field
The invention relates to a series of asymmetric N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compounds with antitumor and anti-inflammatory activities, belonging to the technical field of antitumor and anti-inflammatory drugs and preparation methods thereof.
Background
Curcumin is a yellow phenolic pigment obtained from rhizomes of plants of Zingiberaceae (such as Curcuma longa, Curcuma zedoaria, etc.), and has highly important effects in resisting inflammation, bacteria, tumors, oxidation, protozoa, rheumatism, senile dementia, protecting liver, promoting bile flow, relieving pain, promoting urination, reducing blood sugar and invigorating stomach. But the clinical application of the medicine is seriously influenced due to the defects of poor water solubility, unstable structure, low bioavailability and the like. Therefore, the structure of the curcumin is optimized and modified, the diketone structure in the middle of the curcumin is replaced by N-substituted-4-piperidone to obtain novel 3, 5-diarylmethylene-4-piperidone, and the compound is expected to improve the defects of the curcumin.
The pharmacophore of the novel 3, 5-diarylidene-4-piperidone (BAP) is 1, 4-pentadienone, which is the main binding site for the compound to combine with tumor cells; when the nitrogen atom of piperidone is substituted, an auxiliary binding site is formed; when the aromatic rings on both sides of the 3, 5-diarylmethylene-4-piperidone molecule are substituted by active groups, another auxiliary binding site is formed. The coordination of the three binding sites can effectively improve the antitumor activity of BAP. Thus, a large number of symmetric BAP derivatives were synthesized and screened for activity. The typical example is 3,5-bis (2-fluorobenzylidene) -4-piperidone (EF24), which can inhibit the proliferation of HCT-116, HT-29 and AGS by activating caspase-3 and enhancing Bax to Bcl-2, Bcl-xL and the like, thereby achieving the effect of inhibiting colon cancer and gastrointestinal cancer. 3,5-bis (2-pyridylphenylmethylene) -4-piperidone (EF31) can inhibit NF-kB pathway and show antitumor and anti-inflammatory activities.
At present, the structural modification of 3, 5-diarylmethylene-4-piperidone is mainly carried out on two auxiliary sites. The method is a modification method which is researched more deeply at the present stage and has better effect. The N-alkylation modification is mainly to introduce an alkyl group, an alkenyl group, an aryl group, etc. to the nitrogen atom of piperidone. After modification, the compound has low toxicity to normal cells, good activity to tumor cells and good selectivity. For example, under the alkaline condition, Hafez synthesizes N-ethyl-3, 5-diarylmethylene-4-piperidone derivatives. In addition, N-isopropyl, N-allyl, N-propargyl and other substituted compounds have improved antitumor activity to a certain extent.
Acylation at the central piperidine nitrogen atom has been studied more often, and depending on the kind of the acylated group, it can be classified into aliphatic acylation, aromatic acylation, phosphorylation, benzenesulfonylation, and the like. The classical example of aliphatic acylation is N- (butenedioyl) -3, 5-bis (2-chlorobenzylidene) -4-piperidone (CLEFMA), which is synthesized by Lagisetty, and the activity research shows that the compound can exert potential anti-lung cancer cell proliferation effect by inducing cell autophagy, and the research also shows that CLEFMA can selectively induce lung cancer cell death by the action of oxidative stress, and is nontoxic in vivo and selective for tumor cells. Lagisetty synthesized a series of EF24 aliphatic acylation products, and summarized the structure-activity relationship through activity studies: unsaturated carboxyl short chains on the piperidone nitrogen atoms can increase the activity of the compound; ② the short lipid modification on the piperidone nitrogen atom will not have adverse effect on the antitumor activity of the compound. The Dimmock subject group introduces an alpha, beta-unsaturated ketone unit on a piperidone nitrogen atom through acylation reaction to obtain aromatic acylation products, the aromatic acylation products have remarkable anti-tumor, anti-malaria and anti-mycobacteria effects, mechanism researches show that the aromatic acylation products play a role through mechanisms of inducing apoptosis, autophagy, acting on fyn kinase and multidrug resistance, and the molecular density, the molecular topology and the geometric index of the 3, 5-diarylmethylene-4-piperidone derivatives are summarized as the most main factors for determining the cytotoxicity characteristics. The N-phosphoryl-3, 5-diarylmethylene-4-piperidone derivative is obtained by phosphorylation modification, can cause continuous cytotoxicity by activating a caspase-3 passage or causing DNA breakage between nucleosomes, and has the effect of reversing multidrug resistance.
In contrast, more studies on aliphatic acylation, aromatic acylation and phosphorylation of 3, 5-diarylmethylene-4-piperidone and more studies on benzenesulfonyl modification of 3, 5-diarylmethylene-4-piperidone were conducted. The medicine containing benzenesulfonyl has been widely used in clinic, such as anti-inflammatory drug celecoxib, antibacterial drug sulfadiazine, antihypertensive drug methyclothiazide, long-acting diabetes drug glimepiride, analgesic drug probenecid, antiarrhythmic drug dofilide and the like. In the medicines, the introduction of sulfonyl can adjust the solubility and the pH value of small molecules and improve the activity and the bioavailability of the medicines. If the benzenesulfonyl group is introduced into the nitrogen atom of 3, 5-diarylmethylene-4-piperidone, it is expected to regulate the solubility and acid-base property of the molecules and further improve the antitumor activity and anti-inflammatory activity and bioavailability thereof.
Nevertheless, the 3,5-bis (arylmethylene) -4-piperidone derivatives have been reported as symmetrical compounds, and less have been reported for asymmetrical 3,5-bis (arylmethylene) -4-piperidone compounds. In addition, there are few reports on the anti-inflammatory activity of this class of compounds. If different substituents, especially substituents with different electron withdrawing ability and electron donating ability, such as electron withdrawing group fluorine, nitro group, cyano group, etc., and electron withdrawing group methoxy group, etc., are introduced on both sides of 3, 5-diarylmethylene-4-piperidone, the polarity, solubility, antitumor activity and anti-inflammatory activity of the molecule, bioavailability, etc., may be affected, and the structure-activity relationship and the analysis of antitumor and anti-inflammatory activity of asymmetric 3, 5-diarylmethylene-4-piperidone with respect to benzenesulfonyl group substitution are lack of systematicness.
In addition, in the process of designing drug molecules, the acetamido group plays an important role in the drug's activity. The introduction of the acetamido can effectively improve the pH value and bioavailability of the drug molecules, and can form more complex hydrogen bond action with the drug target, thereby further increasing the pharmacological action of the drug. If the R1 substituted benzenesulfonyl group is introduced into the nitrogen atom of 3,5-bis (arylmethylene) -4-piperidone, the lipophilicity, the acid-base property and the bioavailability of the molecule can be adjusted, the binding capacity between a drug molecule and a target can be enhanced, and the antitumor activity and the anti-inflammatory activity and the bioavailability of the drug molecule can be further improved.
Based on the reasons, the invention provides asymmetric N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compounds.
Disclosure of Invention
The invention aims to search a novel anti-tumor and anti-inflammatory medicament with good anti-tumor and anti-inflammatory activity, and provides 9 asymmetric N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone derivatives; also provides a preparation method of the 9 compounds.
The invention is realized by the following technical scheme:
n-substituted benzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidones having antitumor and antiinflammatory activities were named 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N-benzenesulfonyl-4-piperidone (BAP-1), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-methylbenzenesulfonyl) -4-piperidone (BAP-2), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-nitrobenzenesulfonyl) -4-piperidone (BAP-3), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N-, (BAP-3) 4-trifluoromethylbenzenesulfonyl) -4-piperidone (BAP-4), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-fluorobenzenesulfonyl) -4-piperidone (BAP-5), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-chlorobenzenesulfonyl) -4-piperidone (BAP-6), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-bromobenzenesulfonyl) -4-piperidone (BAP-7), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-cyanobenzenesulfonyl) -4- Piperidone (BAP-8), 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-9) with the structural formula:
Figure GDA0003561981790000031
the preparation method of the N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound with the antitumor and anti-inflammatory activities comprises the following steps: firstly, performing claisen-Schmidt condensation reaction on 4-piperidone hydrochloride, 2-fluorobenzaldehyde and 3-pyridinecarboxaldehyde to obtain an intermediate 3-pyridine substituted 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride (BAP-H), and then performing benzenesulfonylation reaction on the intermediate and R1 substituted benzenesulfonyl chloride to obtain an asymmetric N-substituted benzenesulfonyl-3, 5-diarylmethylene-4-piperidone compound (BAP 1-9), wherein the synthetic route is as follows:
Figure GDA0003561981790000041
wherein R is14-hydrogen, 4-methyl, 4-nitro, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-acetamido.
The preparation method of asymmetric N-substituted benzenesulfonyl-3, 5-diarylmethylene-4-piperidone compound with antitumor activity comprises the following specific steps:
dissolving equimolar amounts of 4-piperidone hydrochloride, 2-fluorobenzaldehyde and 3-pyridinecarboxaldehyde in acetic acid, continuously introducing dry hydrogen chloride gas for 45min, stirring at normal temperature for reaction for 15H, determining a reaction end point by thin-layer chromatography (TLC), after the reaction is completed, adding water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, carrying out precipitation suction filtration, carrying out column chromatography on obtained solid silica gel to obtain an intermediate BAP-H, then respectively dissolving the intermediate and R1 substituted benzenesulfonyl chloride in a solvent, adding a catalyst, stirring at normal temperature overnight, carrying out precipitation suction filtration, and washing with water to obtain the product BAP 1-9.
The catalyst is one of pyridine and potassium carbonate.
The solvent is one of 1, 2-dichloroethane and dichloromethane.
The silica gel column chromatography refers to column chromatography by using 200-300-mesh silica gel and petroleum ether/ethyl acetate/methanol (volume ratio) of 5:5:1 as an eluent.
The N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound with anti-tumor and anti-inflammatory activities is applied to the preparation of novel anti-tumor and anti-inflammatory medicines.
The preparation method of the asymmetric N-substituted benzenesulfonyl-3, 5-diarylmethylene-4-piperidone compound with antitumor activity, provided by the invention, is simple and convenient to operate, mild in reaction conditions and high in synthesis yield, and is beneficial to wide popularization in the antitumor field.
Drawings
FIG. 1: influence of the compound BAP1-9 on the expression of IL-6 and TNF-alpha cytokines secreted by an LPS-induced RAW264.7 cell inflammation model.
Detailed Description
The following description of the present invention is provided to further illustrate the present invention.
Example 1: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N-benzenesulfonyl-4-piperidone (BAP-1)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and benzenesulfonyl chloride in 10mL dichloromethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed, concentrated and recrystallized to obtain a yellow solid product, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N-benzenesulfonyl-4-piperidone (BAP-1), with the yield of 60%.
Mp:158-160℃；IR(cm-1):3020(m),2325(m),2097(s),1679(s),1622(m),1552(m),1479(s),1445(s),1349(s),1232(m),1211(m),1163(s),1090(s),1052(s),984(m),942(s),850(m),796(s),732(m),627(s),544(s).1H NMR(400MHz,DMSO)δ8.90(s,1H),8.81(d,J＝4.7Hz,1H),8.28(d,J＝7.9Hz,1H),7.88(dd,J＝7.4,5.5Hz,1H),7.72-7.69(m,1H),7.60(s,1H),7.57(s,2H),7.53(s,1H),7.50(t,J＝6.0Hz,3H),7.40(dd,J＝15.2,8.0Hz,3H),4.73(s,2H),4.58(s,2H).13C NMR(100MHz,DMSO)δ183.46,160.29(d,J＝249.7Hz),145.39,144.20,143.35,137.45,134.20,133.73,132.40(d,J＝8.7Hz),132.19,131.92,131.75,131.15,130.04(d,J＝4.0Hz),129.50,127.23,126.30,124.97(d,J＝3.4Hz),121.53(d,J＝13.2Hz),116.09(d,J＝21.5Hz),46.53,46.48.Elemental analysis(％)calcd.For C24H19FN2O3S(434.48):C 66.34,H 4.41,F 4.37,N 6.45,O 11.05,S 7.38；Found:C 66.11,H 4.31,F 4.35,N 6.25,O 11.08,S 7.35.
Example 2: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-methylbenzenesulfonyl) -4-piperidone (BAP-2)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography (eluent: petroleum ether/ethyl acetate/methanol: 5:1) on the obtained precipitate to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-methylbenzenesulfonyl chloride in 10mL of dichloromethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-methylbenzenesulfonyl) -4-piperidone (BAP-2), is obtained by recrystallization, and the yield is 57%.
Mp:241-243℃；IR(cm-1):3029(s),2469(m),2094(m),1682(s),1620(s),1597(s),1574(m),1491(s),1446(s),1342(m),1307(s),1227(s),1214(m),1162(s),1090(m),1055(m),986(m),963(s),866(s),835(s),810(s),757(s),734(s),705(s),666(s),618(m),597(s),547(m).1H NMR(400MHz,DMSO)δ8.95(s,1H),8.85(d,J＝5.0Hz,1H),8.36(d,J＝7.7Hz,1H),7.99-7.90(m,1H),7.63(s,1H),7.57(d,J＝10.9Hz,2H),7.47(t,J＝7.5Hz,1H),7.39(dd,J＝15.3,6.8Hz,4H),7.34(t,J＝7.2Hz,2H),4.69(s,2H),4.53(s,2H),2.50(s,3H).13C NMR(100MHz,DMSO)δ183.62,162.01-161.07,159.05,146.43,145.28,144.17,142.25,134.43,133.96,132.43-132.38,132.31,132.12,131.82,131.11,129.91,127.31,125.87,124.98,121.58(d,J＝13.2Hz),116.08(d,J＝21.5Hz),46.52,46.48-46.42,21.10.Elemental analysis(％)calcd.For C25H21FN2O3S(448.51):C 66.95,H 4.72,F 4.24,N 6.25,O 10.70,S 7.15；Found:C 66.96,H 4.70,F 4.23,N 6.28,O 10.72,S 7.18.
Example 3: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-nitrobenzenesulfonyl) -4-piperidone (BAP-3)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-nitrobenzenesulfonyl chloride in 10mL of dichloromethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-nitrobenzenesulfonyl) -4-piperidone (BAP-3), is obtained by recrystallization, and the yield is 43 percent.
Mp:204-206℃；IR(cm-1):3092(s),1685(s),1628(s),1601(s),1524(m),1485(s),1455(s),1354(m),1307(s),1240(s),1173(m),1097(m),1045(m),1033(s),992(m),962(s),867(s),853(s),833(s),759(s),739(s),679(s),633(s),598(m),549(m).1H NMR(400MHz,DMSO)δ8.74(s,1H),8.66(d,J＝4.3Hz,1H),8.35(s,1H),8.32(s,1H),7.95(dd,J＝15.5,8.5Hz,2H),7.79(d,J＝8.7Hz,2H),7.57(t,J＝6.1Hz,3H),7.48(t,J＝7.4Hz,1H),7.38(d,J＝7.3Hz,2H),4.76(s,2H),4.60(d,J＝6.1Hz,2H).13C NMR(100MHz,DMSO)δ183.56,160.31(d,J＝249.6Hz),154.52-153.96,150.10,143.10,133.54,132.56,132.46,131.82,131.61,131.18,130.25,128.96,126.93,126.02,125.01,124.74,123.39,121.40(d,J＝13.2Hz),116.13(d,J＝21.6Hz),46.60,46.54-46.46.Elemental analysis(％)calcd.For C24H18FN3O5S(479.48):C 60.12,H 3.78,F 3.96,N 8.76,O 16.68,S 6.69；Found:C 60.10,H 3.88,F 3.90,N 8.73,O 16.58,S 6.67.
Example 4: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-trifluoromethylbenzenesulfonyl) -4-piperidone (BAP-4)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-trifluoromethylbenzenesulfonyl chloride in 10mL of dichloromethane, adding 1g of potassium carbonate, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-trifluoromethylbenzenesulfonyl) -4-piperidone (BAP-4), is obtained by recrystallization, and the yield is 51 percent.
Mp:182-184℃；IR(cm-1):2916(s),2585(m),1683(s),1628(s),1593(s),1485(m),1449(s),1413(s),1310(m),1236(s),1216(s),1192(m),1069(m),1022(m),978(s),930(m),824(s),768(s),736(s),628(s),599(s),550(m).1H NMR(400MHz,DMSO)δ9.01(s,1H),8.88(d,J＝5.0Hz,1H),8.43(d,J＝7.9Hz,1H),7.98(dd,J＝7.6,5.7Hz,1H),7.93(d,J＝8.1Hz,2H),7.79(d,J＝8.1Hz,2H),7.67(s,1H),7.59(dd,J＝13.6,6.6Hz,2H),7.49(t,J＝7.4Hz,1H),7.44-7.36(m,2H),4.81(s,2H),4.61(s,2H).13C NMR(100MHz,DMSO)δ183.53,161.55,159.07,146.08,144.82,142.78,141.45,133.73,133.14(d,J＝32.4Hz),132.47(d,J＝8.9Hz),132.30,131.89,131.70,131.14,130.06(d,J＝4.1Hz),128.30,126.71(d,J＝3.7Hz),126.05,124.98(d,J＝3.4Hz),121.43(d,J＝13.2Hz),116.11(d,J＝21.6Hz),46.68,46.37.Elemental analysis(％)calcd.For C25H18F4N2O3S(502.48):C 59.76,H 3.61,F 15.12,N 5.58,O 9.55,S 6.38；Found:C 59.66,H 3.62,F 15.11,N 5.55,O 9.45,S 6.35.
Example 5: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-fluorobenzenesulfonyl) -4-piperidone (BAP-5)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-fluorobenzenesulfonyl chloride in 10mL dichloromethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). Washing the reaction solution twice with 2mol/L hydrochloric acid solution, decompressing and concentrating the reaction solution, recrystallizing to obtain a yellow solid product, namely 3- (2-fluorobenzylidene)
-5- (3-pyridinyl) -N- (4-fluorobenzenesulfonyl) -4-piperidone (BAP-5) in 41% yield.
Mp:185-187℃；IR(cm-1):3036(s),1676(m),1620(s),1587(s),1484(s),1451(m),1414(s),1350(s),1289(m),1210(s),1162(s),1086(m),1031(m),982(m),955(s),847(m),828(s),797(s),759(s),728(s),706(s),690(m),619(s),548(m).1H NMR(400MHz,DMSO)δ8.74(s,1H),8.67(d,J＝4.2Hz,1H),7.95(d,J＝7.7Hz,1H),7.64-7.54(m,6H),7.48(t,J＝7.4Hz,1H),7.39(t,J＝6.1Hz,4H),4.73(s,2H),4.58(s,2H).13C NMR(100MHz,DMSO)δ183.59,164.81(d,J＝252.7Hz),160.27(d,J＝249.6Hz),151.17,150.23,137.34,134.42,133.92(d,J＝3.0Hz),132.27(d,J＝8.6Hz),132.06,132.02,131.10(d,J＝1.8Hz),130.37(d,J＝9.8Hz),129.94,129.72(d,J＝4.0Hz),124.95(d,J＝3.4Hz),123.91,121.60(d,J＝13.2Hz),116.70(d,J＝22.9Hz),116.08(d,J＝21.6Hz),46.71,46.49.Elemental analysis(％)calcd.For C24H18F2N2O3S(452.47):C 63.71,H 4.01,F 8.40,N 6.19,O 10.61,S 7.09；Found:C 63.70,H 4.03,F 8.42,N 6.20,O 10.60,S 7.04.
Example 6: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-chlorobenzenesulfonyl) -4-piperidone (BAP-6)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-chlorobenzenesulfonyl chloride in 10mL of 1, 2-dichloroethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-chlorobenzenesulfonyl) -4-piperidone (BAP-6), is obtained by recrystallization, and the yield is 57%.
Mp:160-162℃；IR(cm-1):3089(s),2567(m),1682(s),1612(s),1598(s),1479(m),1447(s),1352(s),1276(m),1237(s),1213(s),1160(m),1089(m),1029(m),984(s),953(m),830(s),820(s),755(s),705(s),684(s),647(m),543(s),514(m).1H NMR(400MHz,DMSO)δ8.94(s,1H),8.83(d,J＝4.9Hz,1H),8.34(d,J＝8.0Hz,1H),7.97-7.85(m,1H),7.63(d,J＝8.6Hz,2H),7.60(s,2H),7.53(d,J＝8.5Hz,2H),7.47(t,J＝7.4Hz,1H),7.43-7.36(m,3H),4.75(s,2H),4.58(s,2H).13C NMR(100MHz,DMSO)δ183.54,160.28(d,J＝249.7Hz),146.43(d,J＝113.1Hz),141.81,138.69,136.31,133.51,132.58,132.43(d,J＝8.7Hz),131.68(d,J＝26.0Hz),131.10,130.11,129.62,129.15,127.77,127.48,125.68,125.01,121.45(d,J＝13.2Hz),116.09(d,J＝21.5Hz),46.59,46.46.Elemental analysis(％)calcd.For C24H18ClFN2O3S(468.93):C 61.47,H 3.87,Cl 7.56,F 4.05,N 5.97,O 10.24,S 6.84；Found:C 61.40,H 3.88,Cl 7.54,F 4.03,N 5.97,O 10.24,S 6.82.
Example 7: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-bromobenzenesulfonyl) -4-piperidone (BAP-7)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-bromobenzenesulfonyl chloride in 10mL of dichloromethane, adding 2 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-bromobenzenesulfonyl) -4-piperidone (BAP-7), is obtained by recrystallization, and the yield is 46%.
Mp:200-202℃；IR(cm-1):3088(s),2099(m),1677(s),1617(s),1573(s),1485(m),1349(s),1211(s),1162(m),1088(s),1068(s),983(m),968(m),827(m),801(s),743(m),682(s),627(s),588(s),530(s).1H NMR(400MHz,DMSO)δ8.92(s,1H),8.81(d,J＝4.7Hz,1H),8.30(d,J＝7.9Hz,1H),7.88(dd,J＝7.4,5.6Hz,1H),7.76(d,J＝8.4Hz,2H),7.65(s,1H),7.59(s,2H),7.47(t,J＝8.3Hz,3H),7.42-7.37(m,2H),4.74(s,2H),4.57(s,2H).13C NMR(100MHz,DMSO)δ183.55,160.30(d,J＝249.6Hz),146.55,145.33,142.32,135.19(d,J＝302.5Hz),132.58,132.39,131.83,131.75,131.12,130.67,130.07,129.24,127.78,127.74,125.88,124.98,121.48(d,J＝13.1Hz),116.10(d,J＝21.5Hz),46.62,46.47.Elemental analysis(％)calcd.For C24H18BrFN2O3S(513.38):C 56.15,H 3.53,Br 15.56,F 3.70,N 5.46,O 9.35,S 6.25；Found:C 56.15,H 3.53,Br 15.53,F 3.72,N 5.46,O 9.45,S 6.25.
Example 8: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-cyanobenzenesulfonyl) -4-piperidone (BAP-8)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-cyanobenzene sulfonyl chloride in 10mL1, 2-dichloroethane, adding 1g of potassium carbonate, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-cyanobenzene sulfonyl) -4-piperidone (BAP-8) is obtained by recrystallization, and the yield is 45 percent.
Mp:208-210℃；IR(cm-1):3093(m),2233(s),1683(s),1619(s),1485(m),1453(s),1356(s),1236(m),1183(s),1164(s),1117(m),1031(m),987(m),957(s),838(m),760(s),732(s),660(s),620(s),560(m),540(m).1H NMR(400MHz,DMSO)δ8.99(s,1H),8.86(d,J＝4.9Hz,1H),8.39(d,J＝7.8Hz,1H),8.04(d,J＝8.2Hz,2H),7.94(dd,J＝7.5,5.6Hz,1H),7.72(d,J＝8.3Hz,2H),7.64(s,1H),7.61-7.55(m,2H),7.51(t,J＝7.5Hz,1H),7.42(d,J＝10.9Hz,1H),7.38(d,J＝7.5Hz,1H),4.82(s,2H),4.63(s,2H).13C NMR(100MHz,DMSO)δ183.55,161.51,159.03,145.86(d,J＝122.0Hz),142.39,141.73,133.62,133.47,132.60,132.55-132.39,131.72,131.66,131.20,130.14,128.02,125.90,125.03,121.43(d,J＝13.1Hz),117.57,116.12(d,J＝21.5Hz),115.92,46.61,46.49.Elemental analysis(％)calcd.For C25H18FN3O3S(459.49):C 65.35,H 3.95,F 4.13,N 9.14,O 10.45,S 6.98；Found:C 65.35,H 3.96,F 4.13,N 9.15,O 10.45,S 6.99.
Example 9: synthesis of 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-9)
0.01mol of 4-piperidone hydrochloride, 0.01mol of 2-fluorobenzaldehyde and 0.01mol of 3-pyridineformaldehyde were mixed in 10mL of acetic acid, and dried hydrogen chloride gas was continuously introduced for 45min, and the reaction was stirred at normal temperature for 15 hours, and the end point of the reaction was determined by Thin Layer Chromatography (TLC). And after the reaction is finished, performing suction filtration on the precipitate, dissolving the precipitate in water, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, performing silica gel column chromatography on the obtained precipitate by using 200-300 meshes (eluent: petroleum ether/ethyl acetate/methanol is 5:5:1) to obtain a yellow solid, namely an intermediate BAP-H, dissolving the intermediate BAP-H and 4-acetamidobenzenesulfonyl chloride in 10mL dichloromethane, adding 3-5 drops of pyridine, stirring at normal temperature overnight, and determining the reaction end point by using Thin Layer Chromatography (TLC). The reaction solution is washed twice by 2mol/L hydrochloric acid solution, the reaction solution is decompressed and concentrated, and the yellow solid product of the invention, namely 3- (2-fluorobenzylidene) -5- (3-pyridyl) -N- (4-acetamidobenzenesulfonyl) -4-piperidone (BAP-9), is obtained by recrystallization, and the yield is 50%.
Mp:146-148℃；IR(cm-1):3173(m),3046(s),1688(s),1616(s),1586(m),1537(s),1481(s),1448(m),1401(s),1333(s),1316(m),1232(m),1213(m),1181(s),1149(m),1091(s),1028(s),990(s),949(s),835(m),793(m),748(m),730(s),649(s),604(s),552(s),540(m).1H NMR(400MHz,DMSO)δ10.38(s,1H),8.72(s,1H),8.67(d,J＝4.1Hz,1H),7.72(d,J＝8.6Hz,2H),7.62-7.55(m,4H),7.51-7.31(m,6H),4.65(s,2H),4.53(s,2H),2.12(s,3H).13C NMR(100MHz,DMSO)δ183.67,169.20,160.33(d,J＝249.5Hz),151.17,150.18,143.79,137.26,134.14,132.33,132.21(d,J＝8.6Hz),131.08,130.58,129.99,129.54(d,J＝4.1Hz),128.54,124.93(d,J＝3.4Hz),123.90,121.69(d,J＝13.2Hz),118.54,116.06(d,J＝21.5Hz),48.62,46.67,46.57,24.25.Elemental analysis(％)calcd.For C26H22FN3O4S(491.53):C 63.53,H 4.51,F 3.87,N 8.55,O 13.02,S 6.52；Found:C 63.53,H 4.50,F 3.87,N 8.56,O 13.02,S 6.52.
Evaluation of antitumor Activity and Normal cytotoxicity
The anti-tumor activity and normal cytotoxicity evaluation of the N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound BAP1-9 are realized.
The antitumor activity and normal cytotoxicity evaluation of the invention adopts an MTT method (chemical name is [3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide ]). Experiments were conducted using three hepatoma cell lines (HepG2, QGY-7703, SMMC-7721) and two normal hepatocytes (LO2, HHL-5) from the national institute of medicine and drug administration, the Binzhou institute of medicine "prescription Effect and clinical evaluation". Doxorubicin (DOX) was used as a positive control.
Taking cells in logarithmic growth phase to prepare 4 × 104Inoculating each/mL cell suspension into a 96-well culture plate, adding 200 mu L of each well, adding 20 mu L of synthetic compounds with different concentrations after culturing for 24h, adding 20 mu L of MTT reagent into each well after continuously culturing for 24h, incubating for 4 hours at 37 ℃, removing supernatant, adding 150 mu L of DMSO into each well, oscillating for 10min to fully dissolve crystals, measuring absorbance at 570nm by using a microplate reader, and calculating IC50. BAP1-9 was used at concentrations of 10, 8, 5, 3, 2, 1, 0.5, 0.1, 0.05, 0.01. mu.g/mL, Doxorubicin (DOX) was used as a positive control, 8, 6, 5, 3, 1.5, 1, 0.8, 0.5, 0.1. mu.g/mL, and 6 duplicate wells were used for each concentration.
TABLE 1 combination ofHalf inhibitory concentration IC of BAP1-9 on tumor cells50(μM)
Figure GDA0003561981790000111
As can be seen from Table 1, the compound BAP-4 showed significant activity on three tumor cell lines, the IC of which50The values are all lower than 10 mu M and are very similar to the positive drug DOX. IC of Simultaneous Compound BAP1-9 on two Normal hepatocytes50The values are all greater than 10. mu.M, showing lower toxicity.
Evaluation of anti-inflammatory Activity
Evaluation of anti-inflammatory Activity of N-substituted benzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone Compound BAP1-9 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 cells come from a key research laboratory of 'prescription effect and clinical evaluation' of the national traditional Chinese medicine administration of Binzhou medical college. PDTC (NF-. kappa.B inhibitor) was used 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 the BAP derivative has no toxicity on RAW264.7 cells when the concentration of the BAP derivative is less than or equal to 6 mu M, and the concentration of the anti-inflammatory activity evaluation experiment drug is set to 6 mu M.
Taking a bottle of RAW264.7 cells, collecting the cells after trypsinization, evenly blowing and beating the cells by a pipette, and adjusting the number of the cells to 2 multiplied by 105and/mL. Add 100. mu.L of cell suspension to each well of 96-well cell culture plate and place in CO2The incubator continues to culture for 12 h. After removing the plate, the original culture medium was aspirated, and 180. mu.L of BAP derivative serum-free culture medium was added to each well at a concentration of 6. mu.M. After 2h, 20. mu.L LPS (final concentration of 1. mu.g/mL) was added, and a normal control group and a positive control group (PDTC: 30. mu.M) were added. Adding LPS, mixing with the mixture in a microplate oscillator, and placing in CO2The cultivation in the incubator was continued for 24 hours, respectively. Collecting culture supernatant, and determining the contents of TNF-alpha and IL-6 by ELISA method.
Influence of compound BAP1-9 on expression of IL-6 and TNF-alpha cytokines secreted by LPS-induced RAW264.7 cell inflammation model
Stimulation with LPS induced high levels of TNF-. alpha.and IL-6 production in RAW264.7 cells (FIG. 1). From figure 1 it can be seen that the level of IL-6 in the cells stimulated with LPS alone was significantly reduced by > 50% in the group treated with compound BAP-4, which was even more inhibitory than the positive drug PDTC. The compound BAP-4 also significantly reduced the level of TNF- α production in RAW264.7 cells.
The above description is only a preferred example of the present invention and is not intended to limit the present invention. Any changes, modifications, substitutions and the like on the basis of the present invention should be included in the scope of the present invention.

Claims (6)

  1. An N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound characterized by the structural formula:
    Figure 347204DEST_PATH_IMAGE001
    。
  2. 2. a process for producing an N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound as described in claim 1, which comprises the steps of:
    firstly, performing claisen-Schmitt condensation reaction on 4-piperidone hydrochloride, 2-fluorobenzaldehyde and 3-pyridinecarboxaldehyde to obtain an intermediate 3-pyridine substituted 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride; then with R1The substituted benzene sulfonyl chloride is subjected to benzene sulfonylation reaction to obtain an N-substituted benzene sulfonyl-3, 5-diarylmethylene-4-piperidone compound; the synthetic route is as follows:
    Figure 194943DEST_PATH_IMAGE002
    wherein R is1Is 4-hydrogen, 4-methyl, 4-nitro, 4-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-cyano or 4-acetylamino.
  3. 3. The process for producing an N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound as described in claim 2, comprising the steps of:
    dissolving equimolar amounts of 4-piperidone hydrochloride, 2-fluorobenzaldehyde and 3-pyridineformaldehyde in acetic acid, continuously introducing dry hydrogen chloride gas for 45min, stirring at normal temperature for reaction for 15 hours, determining a reaction end point by using a thin-layer chromatography, after the reaction is completed, adding water, adjusting a pH value to be neutral by using a saturated sodium bicarbonate solution, precipitating and filtering, and performing column chromatography on the obtained solid silica gel to obtain an intermediate 3-pyridine-substituted 3, 5-diarylmethylene-N-H-4-piperidone hydrochloride; then, the intermediate is reacted with R1Dissolving substituted benzene sulfonyl chloride in a solvent, adding a catalyst, stirring at normal temperature overnight, precipitating, filtering, and washing to obtain a product; the catalyst is one of pyridine or potassium carbonate.
  4. 4. The method of claim 3, wherein the solvent is one of 1, 2-dichloroethane and dichloromethane.
  5. 5. The method for preparing an N-substituted benzenesulfonyl-substituted 3, 5-diarylmethylidene-4-piperidone compound as claimed in claim 3, wherein the silica gel column chromatography is performed by using 200-300 mesh silica gel and petroleum ether, ethyl acetate and methanol at a volume ratio of 5:5:1 as an eluent.
  6. 6. The use of the N-substituted benzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidinone compound of claim 1 for the preparation of anti-hepatoma and anti-inflammatory drugs.
CN201810882254.9A 2018-08-06 2018-08-06 N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof Active CN109053564B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810882254.9A CN109053564B (en) 2018-08-06 2018-08-06 N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810882254.9A CN109053564B (en) 2018-08-06 2018-08-06 N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof

Publications (2)

Publication Number Publication Date
CN109053564A CN109053564A (en) 2018-12-21
CN109053564B true CN109053564B (en) 2022-05-24

Family

ID=64831717

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810882254.9A Active CN109053564B (en) 2018-08-06 2018-08-06 N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof

Country Status (1)

Country Link
CN (1) CN109053564B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108191750A (en) * 2018-01-08 2018-06-22 滨州医学院 Bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5- and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108191750A (en) * 2018-01-08 2018-06-22 滨州医学院 Bis- aryl methylene-N- benzenesulfonyl -4- piperidines ketone compounds of 3,5- and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Design, Synthesis and Bioevaluation of Novel N-Substituted-3,5-Bis(Arylidene)-4-piperidone Derivatives as Cytotoxic and Antitumor Agents with Fluorescent Properties;Jufeng Sun， et al;《Chem Biol Drug Des》;20141231;第83卷;第392-400页 *
硝基与杂环取代的 N-甲基-4-哌啶酮化合物的合成及活性研究;杨威等;《化学试剂》;20170831;第39卷(第8期);第816～818;883页 *

Also Published As

Publication number Publication date
CN109053564A (en) 2018-12-21

Similar Documents

Publication Publication Date Title
CN108191750B (en) 3, 5-diarylmethylene-N-benzenesulfonyl-4-piperidone compound and preparation method thereof
Vicini et al. Synthesis and antiproliferative activity of benzo [d] isothiazole hydrazones
Xie et al. Design and synthesis of novel 5, 6-disubstituted pyridine-2, 3-dione-3-thiosemicarbazone derivatives as potential anticancer agents
El‐Adl et al. 5‐(4‐Methoxybenzylidene) thiazolidine‐2, 4‐dione‐derived VEGFR‐2 inhibitors: design, synthesis, molecular docking, and anticancer evaluations
Sun et al. Discovery of novel NF-кB inhibitor based on scaffold hopping: 1, 4, 5, 6, 7, 8-hexahydropyrido [4, 3-d] pyrimidine
CN106366151B (en) Oleanolic acid -3- ketone derivatives with antitumor action and its preparation method and application
CN108191742B (en) 4-acetamidobenzenesulfonyl-substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof
CN108191751B (en) 4-fluorobenzenesulfonyl substituted 3, 5-diarylmethylene-4-piperidone compound and preparation method thereof
CN109053564B (en) N-benzenesulfonyl substituted asymmetric piperidone compounds and preparation method thereof
CN111704603B (en) Anti-tumor compound and application thereof
CN109053565B (en) N-benzenesulfonyl substituted asymmetric pyridine-piperidone compounds and preparation method thereof
CN108276424B (en) Plectranthin type kaurane diterpene assembled nitrogen mustard derivative and preparation method and application thereof
CN104586842B (en) Anti-cancer activity indole derivative, synthesis method and uses thereof
CN106543194A (en) Narciclasine derivative and its preparation and the application in antineoplastic is prepared
CN108299455A (en) Podophyllotoxin-derivatives of indirubin, its preparation method and its medical usage
CN106966986A (en) N benzyls heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof
EP2070908A1 (en) Compound having benzamide skeleton and cyclooxygenase (cox-1)-selective inhibitory activity
CN108997311B (en) Asymmetric 4-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof
CN104262327B (en) A kind of nitrogen heteroaromatic rings alkylamino dihydroketoacridine-4-amides and preparation method thereof and application
CN108997310B (en) Asymmetric 3-pyridine substituted 3, 5-diarylmethylene-4-piperidone and preparation method thereof
Reddy et al. Design, synthesis and docking studies of new indazole derivatives as potent cytotoxic and antibacterial agents
CN114031523A (en) Synthesis method and application of histone deacetylase and microtubule dual-target inhibitor
CN109608513B (en) 18 β -glycyrrhetinic acid carbamate derivative and preparation method and application thereof
CN114436975B (en) 2-trifluoromethyl-4-aminoquinazoline compound and application thereof
CN106946974B (en) Ursolic amide derivative containing pyrazole heterocycle and synthesis and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant