CN102863376B - N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications - Google Patents
N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications Download PDFInfo
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- -1 benzal Chemical class 0.000 title claims abstract description 44
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical class COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 28
- 208000032839 leukemia Diseases 0.000 claims abstract description 28
- 201000007270 liver cancer Diseases 0.000 claims abstract description 23
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 22
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 22
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 21
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 21
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 21
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 19
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000035755 proliferation Effects 0.000 claims abstract description 13
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 150000003935 benzaldehydes Chemical class 0.000 claims abstract description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006228 Dieckmann condensation reaction Methods 0.000 claims abstract description 3
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 16
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 10
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- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
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- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000000250 methylamino group Chemical class [H]N(*)C([H])([H])[H] 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 20
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 abstract description 6
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- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 abstract 1
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- 238000003756 stirring Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
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- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 2
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 description 2
- WBIZZNFQJPOKDK-UHFFFAOYSA-N 4-hydroxy-2-methoxybenzaldehyde Chemical compound COC1=CC(O)=CC=C1C=O WBIZZNFQJPOKDK-UHFFFAOYSA-N 0.000 description 2
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- NOYASZMZIBFFNZ-UHFFFAOYSA-N (2-bromophenyl)methanamine Chemical compound NCC1=CC=CC=C1Br NOYASZMZIBFFNZ-UHFFFAOYSA-N 0.000 description 1
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- CYJWXRGJMXJKTO-UHFFFAOYSA-N 1,1,2,3-tetramethyltetrazol-1-ium Chemical compound CN1N([N+](C=N1)(C)C)C CYJWXRGJMXJKTO-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- SQMIXHCJWRQFCT-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperidin-4-one Chemical compound C1=CC(F)=CC=C1CN1CCC(=O)CC1 SQMIXHCJWRQFCT-UHFFFAOYSA-N 0.000 description 1
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 description 1
- ZDVRPKUWYQVVDX-UHFFFAOYSA-N 2-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC=C1C=O ZDVRPKUWYQVVDX-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
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- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 1
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- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to organic synthesis and field of medicaments, disclose the preparation method of N-substituent methyl-3,5-two replacement benzal base-4-piperidone and efficiently suppress the biological activity of the cell line proliferations such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer.By all kinds of substituted methylamine and methyl acrylate, successively through Michael addition, Dieckmann condensation, acidolysis decarboxylation obtains N-substituent methyl-4-piperidone, the target compound N-substituent methyl-3,5-pairs that the latter and substituted benzaldehyde obtain through aldol reaction replaces benzal base-4-piperidone.Target compound optionally can efficiently suppress the cell line proliferations such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, and its activity suppressing above-mentioned cancerous cell line to be bred is all apparently higher than the chemotherapeutics 5-fluor-uracil of routine.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone which can be used as a lead compound of medicines for treating leukemia, ovarian cancer, breast cancer, liver cancer and esophageal cancer.
Background
Cancer is one of the diseases with the highest mortality in the world at present, and according to epidemiological statistics released in China, the incidence rates of leukemia and primary liver cancer in various regions of China respectively account for the sixth and 8 th tumors. Leukemia is a hematopoietic cell malignant disease, which is better to be developed in adolescents, the incidence rate of the leukemia is the first of tumors of the adolescents, at least 400 ten thousand leukemia patients are at present, and about 4 ten thousand leukemia patients are newly added every year.
Primary liver cancer is one of the most common malignant tumors in the world, and more than 50% of liver cancer occurs in China globally. Although the incidence of liver cancer is ranked 8 th among various tumors worldwide, the mortality rate is ranked 4 th.
Ovarian cancer and breast cancer are the most common tumor diseases of women, and seriously affect the physical and mental health of the women and even endanger life. According to data statistics, the incidence rate of ovarian cancer and breast cancer is second to that of cervical cancer and uterine corpus cancer.
At present, the various cancers are still treated by adopting a chemotherapy method, and the chemotherapy can only kill a large number of cancer cells with high proliferation to relieve the patients for a short time, but cannot radically cure the cancers. Because most of the chemotherapy drugs used at present lack specificity, the toxic and side effects are great. More tricky, most cancer cells in relapsed patients often develop resistance to existing chemotherapeutic drugs.
The common defects of the chemotherapy drugs commonly used in clinic at present are that the selectivity is not strong, the drugs have almost the same killing effect on normal cells and tumor cells, and also have strong killing effect on bone marrow, digestive tract cells and germ cells, so the toxicity is large.
Disclosure of Invention
The invention aims to provide a series of N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidones, and the series of compounds can be used as lead compounds of medicaments for treating leukemia, ovarian cancer, breast cancer, liver cancer and esophagus cancer.
The second purpose of the invention is to provide a preparation method of N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone.
The third purpose of the invention is to use N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone for preparing
The N-substitution can be used for treating leukemia, ovarian cancer, breast cancer, hepatocarcinoma, esophageal cancer, etc
The methyl-3, 5-disubstituted benzylidene-4-piperidone compound has the biological activity of efficiently inhibiting the proliferation of a plurality of cancer cell lines such as leukemia, ovarian cancer, breast cancer, liver cancer, esophagus cancer and the like, and the IC50 value is obviously lower than that of 5-fluorouracil (5 Fu) which is a conventional chemotherapeutic medicament.
The purpose of the invention is realized by the following technical scheme:
the invention provides an anticancer drug with high-efficiency activity of killing various cancer cells such as leukemia, ovarian cancer, breast cancer, liver cancer, esophageal cancer and the like, wherein the structural formula of a lead compound N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone of the anticancer drug is shown as a formula (I):
R1is substituted phenyl, five-membered heterocyclic substituent or six-membered heterocyclic substituent; the substituted phenyl is one of 4-tolyl, 2-tolyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-bromophenyl, 2-bromophenyl, 3-bromophenyl, 2-fluorophenyl and 3-fluorophenyl, the five-membered heterocyclic substituent is one of 2-tetrahydrofuryl, 2-furyl, 2-thienyl and 5-chloro-2-thiazolyl, and the six-membered heterocyclic ring is one of 3-pyridyl and 6-chloro-3-pyridyl;
R2is one of substituents such as 4-cyano, 2-cyano, 3, 4-dichloro, 2, 4-dichloro, 3-nitro, 2-nitro, 3-chloro, 2-bromo, 3-bromo, 4-bromo, 2-fluoro, 3-fluoro, 4-fluoro, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, 4-hydroxy-3-methoxy and the like.
The present invention provides a process for the preparation of a compound of formula (I) comprising the steps of:
(1) carrying out Michael addition reaction on substituted methylamine with a structure shown in a formula (a) and methyl acrylate to prepare N, N-bis (beta-methyl propionate) substituted methylamine shown in a formula (II); the molar ratio of the substituted methylamine to the methyl acrylate with the structure of the formula (II) is 1: 2-1: 4, taking alcohols as a solvent, preferably methanol or ethanol, and carrying out reflux reaction for 6-10 hours; specifically, dripping alcohol solution containing substituted methylamine into alcohol solution containing methyl acrylate under ice bath condition, and controlling the temperature not to exceed 50 ℃; stirring for 20-60 min after the dropwise adding is finished, and performing reflux reaction for 6-10 hours;
(2) carrying out Dieckmann condensation on the product obtained in the step (1) under the action of sodium alkoxide, extracting by acid hydrolysis, carrying out water phase reflux reaction for 6-10 hours, adjusting the pH to be = 8-9, and decarboxylating to obtain N-substituted methyl-4-piperidone shown in the formula (III);
R1-CH2NH2R1CHN(CH2CH2COOCH3)2
（a）（II）
(3) performing aldol condensation and dehydration on the product N-substituted methyl-4-piperidone obtained in the step (2) and substituted benzaldehyde with a structure shown in a formula (IV),
obtaining N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone with a general formula (I); the mol ratio of the N-substituted methyl-4-piperidone to the substituted benzaldehyde is 1: 2;
R1is substituted phenyl, five-membered heterocyclic substituent or six-membered heterocyclic substituent;
R2is 4-cyano, 2-cyano, 3, 4-dichloro, 2, 4-dichloro, 3-nitro, 2-nitro, 3-chloro, 2-bromo, 3-bromo, 4-bromo, 2-fluoro, 3-fluoro, 4-fluoro, 2-trifluoromethyl, 4-dimethylamino, N-trifluoromethyl, N,2-dimethylamino group, or 4-hydroxy-3-methoxyl group.
The reaction formula of the preparation process is as follows:
the compound N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone can be applied to preparing medicines for treating leukemia, ovarian cancer, breast cancer, liver cancer, esophageal cancer and other cancers.
The lead compound N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone of the anticancer drug provided by the invention has bioactivity of efficiently inhibiting the proliferation of various cancer cell lines, and specifically comprises the following cancer cell lines: 2 leukemia cell lines such as leukemia K562 and Jarket cell line, ovarian cancer HO-8910 cell line, breast cancer MCF-7 cell line, liver cancer SMMC-7721 cell line and esophageal cancer ECA-109 cell line. The compound can be applied to the preparation of drugs for inhibiting the proliferation of cancer cell lines such as leukemia cell lines, ovarian cancer cell lines, breast cancer cell lines, liver cancer cell lines, esophagus cancer cell lines and the like.
The anticancer medicine lead compound N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone has obviously higher activity of inhibiting the proliferation of 2 leukemia cell lines such as leukemia K562, ovary HO-8910 cell line, breast cancer MCF-7 cell line, liver cancer SMMC-7721 cell line and esophagus cancer ECA-109 cell line than that of the conventional anticancer chemotherapeutic medicine 5-fluorouracil (IC)50The values are all obviously lower than 5-fluorouracil), and the medicine is possible to become a novel anti-leukemia medicine with special effect and small toxic and side effect, and has potential practicability.
Detailed Description
The examples of the lead compound of the N-substituted methyl-3, 5-dibenzylidene piperidine-4-ketone anticancer drug with anticancer activity prepared by the invention are as follows:
(Ia) N- (4-methoxybenzyl) -3, 5-bis (4-cyanobenzylidene) -4-piperidone;
(Ib) N- (4-methoxybenzyl) -3, 5-bis (3, 4-dichlorobenzylidene) -4-piperidone;
(Ic) N- (4-methoxybenzyl) -3, 5-bis (2, 4-dichlorobenzylidene) -4-piperidone;
(Id) N- (2-fluorobenzyl) -3, 5-bis (3-nitrobenzylidene) -4-piperidone;
(Ie) N- (2-fluorobenzyl) -3, 5-bis (2-trifluoromethylbenzylidene) -4-piperidone;
(If) N- (2-fluorobenzyl) -3, 5-bis (4-trifluoromethylbenzylidene) -4-piperidone;
(Ig) N- (2-bromobenzyl) -3, 5-bis (3-chlorobenzylidene) -4-piperidone;
(Ih) N- (2-bromobenzyl) -3, 5-bis (4-dimethylaminobenzylidene) -4-piperidone;
(Ii) N- (2-bromobenzyl) -3, 5-bis (4-hydroxy-2-methoxybenzylidene) -4-piperidone;
(Ij) N- (4-fluorobenzyl) -3, 5-bis (2, 4-dichlorobenzylidene) -4-piperidone.
Example 1N- (4-methoxybenzyl) -3, 5-bis (4-cyanobenzylidene) -4-piperidone (Ia)
In an ice-water bath at 0 ℃, 0.4mol of methyl acrylate and 7mL of methanol are added to a 100mL three-necked flask, and after stirring for 30min, a mixed solution of 4-methoxybenzylamine and 10mL of methanol is slowly added dropwise thereto at a rate controlled so that the temperature of the system does not exceed 50 ℃ (the rate of addition is about 1 drop/sec). After the addition was complete, the mixture was stirred at room temperature for 30min, the temperature was further raised to 65 ℃, refluxed and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After about 8 hours of reaction, the reaction was stopped, methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure,
intermediate (2a) was obtained as a pale yellow oily liquid.
At room temperature, 15mL of anhydrous toluene and 0.1mol of metallic sodium (cut into blocks) were put into a 250mL dry three-necked flask, and the mixture was stirred and heated under reflux for about 40min until the sodium blocks appeared to be bead-like, and a mixture of 0.1mol of intermediate (2a) and 20mL of anhydrous toluene was slowly added dropwise, and 3 drops of anhydrous methanol were added dropwise with a dropper immediately before the reaction to promote the reaction. During the dropping process, the reaction system gradually becomes light yellow viscous, the stirring speed needs to be increased, after the dropping is finished, 40mL of anhydrous toluene is added into the reaction container in batches if needed, the temperature of the system is controlled at 110 ℃, and the reflux is carried out for 6 hours.
After completion of the reflux, the reaction mixture was cooled to room temperature, 1mL of anhydrous methanol was added thereto and stirred for 1 hour to remove unreacted sodium metal, and then the mixture was extracted with 40mL × 3 by a 25% hydrochloric acid solution by mass fraction, an extract (aqueous phase) was collected, the extract was refluxed for 8 hours in an oil bath, after completion of the reaction, the reaction system was cooled to room temperature, and then the pH of the reaction system was adjusted to alkaline (pH =8.5 or so) with NaOH solution under stirring, and extracted with 40mL × 3 of ethyl acetate. The ethyl acetate layers were combined, dried over 10g of anhydrous sodium sulfate, and distilled under reduced pressure to recover ethyl acetate, and the substrate was distilled to give a pale yellow oily liquid, N-4-methoxybenzyl-4-piperidone (3 a).
A50 mL round-bottom flask was charged with intermediate (3a) (0.005 mol), 4-cyanobenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol, and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ia).
Yield 76.3%, yellowsoli, mp139-141 ℃, 1HNMR (400MHz, CDCl)3);1HNMR(400MHz,CDCl3)3.67(s,2H),3.64(s,3H),3.82(s,4H),7.04(d,J=8.7Hz,2H),7.14(d,J=8.7Hz,2H),7.23(d,J=8.0Hz,4H),7.37(d,J=8.0Hz,4H),7.75(s,2H)IR(KBr):3138,2814,1672,1594,1525,1342,1261,1109,1005,854cm-1;Anal.calcd.forC29H23N3O2.C%78.18,H%5.20,N%9.43;Found:C%78.16,H%5.19,N%9.45
Example 2N- (4-methoxybenzyl) -3, 5-bis (3, 4-dichlorobenzylidene) -4-piperidone (Ib)
(2 b) and (3b) were prepared in the same manner as in (2a) and (3 a).
A50 mL round-bottom flask was charged with the intermediates N-4-methoxybenzyl-4-piperidone (3b) (0.005 mol) and 3, 4-dichlorobenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ib).
The yield is 80.2 percent, yellowsolid, mp131-133 ℃;1HNMR(400MHz,CDCl3)3.65(s,2H),3.71(s,3H),3.85(s,4H),7.02(d,J=8.7Hz,2H),7.13(d,J=8.7Hz,2H),7.24(d,J=8.0Hz,4H),7.36(d,J=8.0Hz,2H),7.71(s,2H);IR(KBr):2805,2745,1667,1615,1575,1480,1260,1185,1085,821cm-1;Anal.calcd.forC27H21Cl4NO2C%60.81,H%3.97,N%2.63;Found:C%60.72H%3.95,N%2.68
example 3N- (4-methoxybenzyl) -3, 5-bis (2, 4-dichlorobenzylidene) -4-piperidone (Ic)
(2 c) and (3c) were prepared in the same manner as in (2a) and (3 a).
A50 mL round-bottom flask was charged with the intermediates N-4-methoxybenzyl-4-piperidone (3c) (0.005 mol) and 3, 4-dichlorobenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ic).
The yield is 73.7 percent, yellowsoli, mp183-185 ℃;1HNMR(400MHz,CDCl3)3.62(s,2H),3.75(s,3H),3.82(s,4H),7.03(d,J=8.7Hz,2H),7.12(d,J=8.7Hz,2H),7.22(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,4H),7.73(s,2H);;IR(KBr):2805,2743,1664,1603,1574,1487,1262,1185,1094,821cm-1;Anal.calcd.forC27H21Cl4NO2C%60.81,H%3.97,N%2.63;Found:C%60.72H%3.95,N%2.68
example 4N- (2-Fluorobenzyl) -3, 5-bis (3-nitrobenzylidene) -4-piperidone (Id)
In an ice-water bath at 0 ℃, 0.4mol of methyl acrylate and 7mL of methanol are added into a 100mL three-necked flask, and after stirring for 30min, a mixed solution of 2-fluorobenzylamine and 10mL of methanol is slowly added dropwise thereto at a rate such that the temperature of the system does not exceed 50 ℃ (about 1 drop/sec). After the addition was complete, the mixture was stirred at room temperature for 30min, the temperature was further raised to 65 ℃, refluxed and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After about 8 hours of the reaction, the reaction was stopped, and methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure to obtain intermediate (2d) as a pale yellow oily liquid.
At room temperature, 15mL of anhydrous toluene and 0.1mol of metallic sodium (cut into blocks) were put into a 250mL dry three-necked flask, and stirred and heated under reflux for about 40min until the sodium blocks appeared to be bead-like, and a mixture of 0.1mol of intermediate (2d) and 20mL of anhydrous toluene was slowly added dropwise, and 3 drops of anhydrous methanol were added dropwise with a dropper immediately before the start of the reaction to promote the reaction. During the dropping process, the reaction system gradually becomes light yellow viscous, the stirring speed needs to be increased, after the dropping is finished, 40mL of anhydrous toluene is added into the reaction container in batches if needed, the temperature of the system is controlled at 110 ℃, and the reflux is carried out for 6 hours.
After completion of the reflux, the reaction mixture was cooled to room temperature, 1mL of anhydrous methanol was added thereto and stirred for 1 hour to remove unreacted sodium metal, and then the mixture was extracted with 40mL × 3 by a 25% hydrochloric acid solution by mass fraction, an extract (aqueous phase) was collected, the extract was refluxed for 8 hours in an oil bath, after completion of the reaction, the reaction system was cooled to room temperature, and then the pH of the reaction system was adjusted to alkaline (pH =8.5 or so) with NaOH solution under stirring, and extracted with 40mL × 3 of ethyl acetate. The ethyl acetate layers were combined, dried over 10g of anhydrous sodium sulfate, and distilled under reduced pressure to recover ethyl acetate, the substrate was distilled to give a pale yellow oily liquid, N-2-fluorobenzyl-4-piperidone (3 d).
A50 mL round-bottom flask was charged with intermediate (3d) (0.005 mol), 3-nitrobenzaldehyde (0.01 mmol), 15mL anhydrous ethanol, and 1mL 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Id).
The yield is 75.2 percent, yellowsolid, mp129-131 ℃;1HNMR(400MHz,CDCl3)3.65(s,2H),3.85(s,4H),7.05(d,J=7.8Hz,2H),7.14(d,J=7.9Hz,2H),7.55(d,J=8.6Hz,4H),7.87(s,2H),8.18(d,J=8.6Hz,4H);IR(KBr):2824,1603,1487,1456,1264,11802,1096,1004,819cm-1;Anal.calcd.forC26H20FN3O5C%65.96,H%4.26,N%8.88;Found:C%65.82H%4.17,N%8.78.
example 5N- (2-Fluorobenzyl) -3, 5-bis (2-trifluoromethylbenzylidene) -4-piperidone (Ie)
(2 e) and (3e) were prepared in the same manner as in (2d) and (3 d).
A50 mL round-bottom flask was charged with the intermediates N-2-fluorobenzyl-4-piperidone (3e) (0.005 mol) and 2-trifluoromethylbenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ie).
The yield is 87.7 percent, yellowsoli, mp121-123 ℃;1HNMR(400MHz,CDCl3)3.63(s,2H),3.87(s,4H),7.05(d,J=7.8Hz,2H),7.16(d,J=7.9Hz,2H),7.55(d,J=8.6Hz,4H),7.92(s,2H),8.24(d,J=8.6Hz,4H);IR(KBr):3127,2983,1679,1615,1506,1267,1224,1193,996,763cm-1;Anal.calcd.forC28H20F7NOC%64.74,H%3.88,N%2.70;Found:C%64.72H%3.97,N%2.78.
example 6N- (2-Fluorobenzyl) -3, 5-bis (4-trifluoromethylbenzylidene) -4-piperidone (If)
(2 f) and (3f) were prepared in the same manner as in (2d) and (3 d).
A50 mL round-bottom flask was charged with the intermediates N-2-fluorobenzyl-4-piperidone (3f) (0.005 mol) and 4-trifluoromethylbenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (If).
The yield is 76.6 percent, yellowsoli, mp143-145 ℃;1HNMR(400MHz,CDCl3)3.67(s,2H),3.84(s,4H),7.05(d,J=7.8Hz,2H),7.21(d,J=7.9Hz,2H),7.51(d,J=8.6Hz,4H),7.94(s,2H),8.21(d,J=8.6Hz,4H);IR(KBr):3124,2996,1665,1615,1504,1267,1221,1193,997,763cm-1;Anal.calcd.forC28H20F7NOC%64.74,H%3.88,N%2.70;Found:C%64.72H%3.97,N%2.78.
example 7N- (2-bromobenzyl) -3, 5-bis (3-chlorobenzylidene) -4-piperidone (Ig)
In an ice-water bath at 0 ℃, 0.4mol of methyl acrylate and 7mL of methanol are added into a 100mL three-necked bottle, and after stirring for 30min, a mixed solution of 2-bromobenzylamine and 10mL of methanol is slowly added dropwise thereto at a rate such that the temperature of the system does not exceed 50 ℃ (about 1 drop/sec). After the addition was complete, the mixture was stirred at room temperature for 30min, the temperature was further raised to 65 ℃, refluxed and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After about 8 hours of the reaction, the reaction was stopped, and methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure to obtain a pale yellow oily liquid intermediate (2 g).
At room temperature, 15mL of anhydrous toluene and 0.1mol of metallic sodium (cut into blocks) were put into a 250mL dry three-necked flask, and the mixture was stirred and heated under reflux for about 40min until the sodium blocks appeared to be beads, and a mixture of 0.1mol of intermediate (2g) and 20mL of anhydrous toluene was slowly added dropwise, and 3 drops of anhydrous methanol were added dropwise with a dropper immediately before the start of the reaction to promote the reaction. During the dropping process, the reaction system gradually becomes light yellow viscous, the stirring speed needs to be increased, after the dropping is finished, 40mL of anhydrous toluene is added into the reaction container in batches if needed, the temperature of the system is controlled at 110 ℃, and the reflux is carried out for 6 hours.
After completion of the reflux, the reaction mixture was cooled to room temperature, 1mL of anhydrous methanol was added thereto and stirred for 1 hour to remove unreacted sodium metal, and then the mixture was extracted with 40mL × 3 by a 25% hydrochloric acid solution by mass fraction, an extract (aqueous phase) was collected, the extract was refluxed for 8 hours in an oil bath, after completion of the reaction, the reaction system was cooled to room temperature, and then the pH of the reaction system was adjusted to alkaline (pH =8.5 or so) with NaOH solution under stirring, and extracted with 40mL × 3 of ethyl acetate. The ethyl acetate layers were combined, dried over 10g of anhydrous sodium sulfate, and distilled under reduced pressure to recover ethyl acetate, the substrate was distilled to give N-2-bromobenzyl-4-piperidone (3g) as a pale yellow oily liquid.
A50 mL round-bottom flask was charged with intermediate (3g) (0.005 mol), 3-chlorobenzaldehyde (0.01 mmol), 15mL anhydrous ethanol, and 1mL 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ig).
The yield is 85.1 percent, yellowsoli, mp172-175 ℃;1HNMR(400MHz,CDCl3)3.66(s,2H),3.78(s,4H),7.14(d,J=8.4Hz,2H),7.23-7.24(m,2H),7.26-7.37(m,8H),7.73(s,2H);;IR(KBr):2825,1606,1486,1455,1263,1181,1096,1001,817cm-1;Anal.calcd.forC26H20BrCl2NOC%60.84,H%3.93,N%2.73;Found:C%60.78H%3.97,N%2.78.
example 8N- (2-bromobenzyl) -3, 5-bis (4-dimethylaminobenzylidene) -4-piperidone (Ih)
(2 h) and (3h) were prepared in the same manner as in (2g) and (3 g).
A50 mL round-bottom flask was charged with the intermediates N/-2-bromobenzyl-4-piperidone (3h) (0.005 mol) and 4-dimethylaminobenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ih).
The yield is 67.4 percent, yellowsoli, mp109-111 ℃;1HNMR(400MHz,CDCl3)2.85（s，12H），3.63(s,2H),3.78(s,4H),7.14(d,J=8.4Hz,2H),7.22-7.24(m,2H),7.25-7.37(m,8H),7.75(s,2H);;IR(KBr):2821,1604,1489,1455,1265,1254,1181,1093,1002,817cm-1;Anal.calcd.forC30H32BrN3OC%67.92,H%6.08,N%7.92;Found:C%67.82H%5.97,N%7.78.
example 9N- (2-bromobenzyl) -3, 5-bis (4-hydroxy-2-methoxybenzylidene) -4-piperidone (Ii)
(2 i) and (3i) were prepared in the same manner as in (2g) and (3 g).
A50 mL round-bottom flask was charged with the intermediates N-2-bromobenzyl-4-piperidone (3i) (0.005 mol) and 4-hydroxy-2-methoxybenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol, and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, and washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ii).
The yield is 66.3 percent, yellowsoli, mp167-169 ℃;1HNMR(400MHz,CDCl3)3.62(s,2H),3.83(s,4H),3.92(s,6H),5.03(s，2H),7.05(d,J=7.8Hz,2H),7.14(d,J=7.9Hz,2H),7.26(d,J=8.3Hz,2H),7.44(d,J=8.4Hz,4H),7.81(s,2H);;IR(KBr):3125,2995,1668,1615,1507,1269,1223,1195,997,764cm-1;Anal.calcd.forC28H26BrNO5C%62.69,H%4.89,N%2.61;Found:C%62.72H%4.97,N%2.68.
example 10N- (4-Fluorobenzyl) -3, 5-bis (2, 4-dichlorobenzylidene) -4-piperidone (Ii)
In an ice-water bath at 0 ℃, 0.4mol of methyl acrylate and 7mL of methanol are added into a 100mL three-necked flask, and after stirring for 30min, a mixed solution of 4-fluorobenzylamine and 10mL of methanol is slowly added dropwise thereto at a rate such that the temperature of the system does not exceed 50 ℃ (about 1 drop/sec). After the addition was complete, the mixture was stirred at room temperature for 30min, the temperature was further raised to 65 ℃, refluxed and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After about 8 hours of the reaction, the reaction was stopped, and methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure to obtain a pale yellow oily liquid intermediate (2 j).
At room temperature, 15mL of anhydrous toluene and 0.1mol of metallic sodium (cut into blocks) were added to a 250mL dry three-necked flask, and the mixture was stirred and heated under reflux for about 40min until the sodium blocks appeared to be bead-like, and a mixture of 0.1mol of intermediate (2j) and 20mL of anhydrous toluene was slowly added dropwise, and 3 drops of anhydrous methanol were added dropwise with a dropper immediately before the reaction to promote the reaction. During the dropping process, the reaction system gradually becomes light yellow viscous, the stirring speed needs to be increased, after the dropping is finished, 40mL of anhydrous toluene is added into the reaction container in batches if needed, the temperature of the system is controlled at 110 ℃, and the reflux is carried out for 6 hours.
After completion of the reflux, the reaction mixture was cooled to room temperature, 1mL of anhydrous methanol was added thereto and stirred for 1 hour to remove unreacted sodium metal, and then the mixture was extracted with 40mL × 3 by a 25% hydrochloric acid solution by mass fraction, an extract (aqueous phase) was collected, the extract was refluxed for 8 hours in an oil bath, after completion of the reaction, the reaction system was cooled to room temperature, and then the pH of the reaction system was adjusted to alkaline (pH =8.5 or so) with NaOH solution under stirring, and extracted with 40mL × 3 of ethyl acetate. The ethyl acetate layers were combined, dried over 10g of anhydrous sodium sulfate, and distilled under reduced pressure to recover ethyl acetate, the substrate was distilled to give a pale yellow oily liquid, N-4-fluorobenzyl-4-piperidone (3 j).
A50 mL round-bottom flask was charged with intermediate (3j) (0.005 mol), 2, 4-dichlorobenzaldehyde (0.01 mmol), 15mL of anhydrous ethanol, and 1mL of 10% (mass fraction) sodium hydroxide. Stirring for 1h at room temperature (15-25 ℃), separating out solids, performing suction filtration, washing the product with absolute ethyl alcohol, or recrystallizing with ethyl acetate and petroleum ether to obtain the target compound (Ij).
The yield is 74.7 percent, yellowsoli, mp119-121 ℃;1HNMR(400MHz,CDCl3)3.63(s,2H),3.79(s,4H),7.13(d,J=8.4Hz,2H),7.21-7.24(m,2H),7.26-7.37(m,6H),7.76(s,2H);IR(KBr):2827,1603,1487,1455,1265,1263,1182,1094,1002,815cm-1;Anal.calcd.forC26H18Cl4FNOC%59.91,H%3.48,N%2.69;Found:C%60.12H%3.57,N%2.78.
EXAMPLE 11 Compound (I) inhibits the proliferation of leukemia, ovarian, breast, liver and esophageal cancer cell lines IC50The test of (1).
1. Test agent and apparatus
Experimental drugs and reagents: self-made compound (I) is dissolved by DMSO, distilled water is added to the mixture to be prepared to the required concentration (the concentration of the DMSO is less than or equal to 1 per mill), and the mixture is sterilized and stored at 4 ℃. MTT (Tetramethyltetrazolium blue) reagent was purchased from Sigma. Human leukemia cell lines K562, Jarket, ovarian cancer HO-8910, breast cancer MCF-7, liver cancer SMMC-7721, and esophageal cancer ECA-109 were purchased from Shanghai national academy of sciences cell banks. 10% SDS reagent (Sino-American Biotechnology product) was prepared by using RPMI-1640 (GiBCo, USA) containing 20% bovine serum (FBS), and other reagents were commercially available as analytical materials. At 37 deg.C, 5% CO2And subculturing in an incubator with saturated humidity, and performing experiments when the cells are in a logarithmic growth phase.
The instrument equipment comprises: clean bench and clean<3.5 grains/L of (>0.5 μm dust particles), available from clean and clean facilities, ltd, offshore; CO 22Cell culture incubator, Thermo corporation forma scientific, Inc; inverted microscope, OLYMPUS, japan, model number CKX 41; enzyme linked immunosorbent assay device, Bio-RADPode 680; 96-well plates, Costar, usa; model SK2200H ultrasonic cleaner, shanghai kodao ultrasonic instruments ltd.
2. Test method
The experiment was performed in 96-well plates, the cells were collected in log phase, the cell suspension concentration was adjusted and divided into 96-well plates, 1X 104And (2) setting drug color control wells (without cells) and culture wells containing cells and drugs with different concentrations in 8 multiple wells per group, respectively culturing for 44 hours, adding MTT (5mg/mL,10 muL) into each well, continuously culturing for 4 hours, adding 10% SDS100 muL to terminate the reaction, standing overnight at 37 ℃, detecting the absorbance OD value of each well at 570nm by enzyme-linked immunosorbent assay, and calculating the survival rate according to the following formula: survival (%) = OD administration/OD control × 100%; and calculating 50% Inhibitory Concentration (IC) by LOGIT method based on survival rate at each concentration50)。
3. Results survey
Determination of IC of N-substituted-3, 5-bis-benzylidene piperidine-4-one (I) for inhibiting proliferation of 2 cancer cell lines such as leukemia K562 and the like, ovarian cancer, breast cancer, liver cancer and esophagus cancer cell line by MTT method50Value, IC50The values are shown in Table 1.
TABLE 1 IC inhibition of proliferation of 2 leukemia, ovarian, breast, liver and esophageal cancer cell lines by compounds Ia-Ij50Value of
4. And (4) conclusion: table 1 shows the IC of the compounds Ia to Ij for inhibiting the proliferation of 2 human cancer cell lines of leukemia, ovarian cancer, breast cancer, liver cancer and esophagus at the in vitro cell level50. As can be seen from the data in Table 1, the compounds Ia to Ij inhibit the 2 leukemia, ovarian cancer, breast cancer,IC for liver cancer and esophagus cancer cell line proliferation50The values are all obviously lower than that of the conventional chemotherapeutic drug 5-fluorouracil (5 Fu).
Claims (7)
- An N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone having a structure represented by the formula (I):in the formula: r1Is 4-methoxyphenyl, R2Is 4-cyano, 3, 4-dichloro or 2, 4-dichloro; or,R1is 2-fluorophenyl, R2Is 3-nitro, 2-trifluoromethyl or 4-trifluoroA methyl group; or,R1is 2-bromophenyl, R2Is 3-chloro, 4-dimethylamino; or,R1is 4-fluorophenyl, R2Is 2, 4-dichloro.
- 2. The process for preparing N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidones as claimed in claim 1 comprising the steps of:(1) carrying out Michael addition reaction on substituted methylamine with a structure shown in a formula (a) and methyl acrylate to prepare N, N-bis (beta-methyl propionate) substituted methylamine shown in a formula (II);(2) carrying out Dieckmann condensation on the product N, N-bis (beta-methyl propionate) substituted methylamine obtained in the step (1) under the action of sodium alkoxide, and carrying out acid hydrolysis decarboxylation to obtain N-substituted methyl-4-piperidone shown in a formula (III);(3) performing aldol condensation and dehydration on the product N-substituted methyl-4-piperidone obtained in the step (2) and substituted benzaldehyde with a structure shown in a formula (IV),obtaining N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone with a general formula (I);wherein R is1And R2Is as defined in claim 1.
- 3. The process for preparing N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidones as claimed in claim 2 wherein in step (1) the molar ratio of substituted methylamine to methyl acrylate of formula (II) is 1: 2-1: and 4, carrying out reflux reaction for 6-10 hours by using methanol or ethanol as a solvent.
- 4. The process for producing N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidone as claimed in claim 2, wherein in the step (3), the molar ratio of N-substituted methyl-4-piperidone to substituted benzaldehyde is 1: 2.
- 5. use of the N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidinones of claim 1 for the manufacture of a medicament for the treatment of leukemia, ovarian, breast, liver and esophageal cancer.
- 6. The use of N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidones as defined in claim 1 for the preparation of a medicament for inhibiting the proliferation of leukemia cell lines, ovarian cancer cell lines, breast cancer cell lines, liver cancer cell lines and esophageal cancer cell lines.
- 7. The use of N-substituted methyl-3, 5-disubstituted benzylidene-4-piperidinones according to claim 1 for the preparation of a medicament for inhibiting the proliferation of leukemia K562 cell line, leukemia Jarket cell line, ovarian cancer HO-8910 cell line, breast cancer MCF-7 cell line, liver cancer SMMC-7721 cell line and esophageal cancer ECA-109 cell line.
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| CN104262240B (en) * | 2014-07-31 | 2016-04-20 | 滨州医学院 | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof |
| CN104592098B (en) * | 2015-01-31 | 2017-08-25 | 滨州医学院 | For antineoplastic piperidones of 3,5 2 aryl methylene of N methyl 4 and its quaternary ammonium salt derivative |
| CN105037252B (en) * | 2015-05-21 | 2018-05-04 | 温州医科大学 | N- substitutions -3,5- two (2- (trifluoromethyl) benzal) piperidin-4-one-derivative and preparation method and application |
| US9655913B2 (en) * | 2015-06-23 | 2017-05-23 | Hong Kong Baptist University | Anti-esophageal cancer compound and method of use thereof |
| CN105503709B (en) * | 2015-12-10 | 2019-06-14 | 中国广州分析测试中心 | Bis- (aryl methylene) -1- substitution -4- piperidones series compounds of 3,5- and its in the application for preparing anti esophageal cancer drug |
| US9486444B1 (en) | 2016-03-21 | 2016-11-08 | King Saud University | Anti-cancer compound |
| CN108976122B (en) * | 2018-09-13 | 2021-01-12 | 南通纺织丝绸产业技术研究院 | Method for producing 1, 3-dicarbonyl compounds based on metal hydride/palladium compound systems |
| CN109053446B (en) * | 2018-09-13 | 2021-01-01 | 苏州大学张家港工业技术研究院 | Application of metal hydride/palladium compound system in preparation of 1, 3-dicarbonyl compound by series reaction of electron-deficient alkene compound |
| WO2020056564A1 (en) | 2018-09-17 | 2020-03-26 | 南通纺织丝绸产业技术研究院 | Method for preparing 1,3-dicarbonyl compound based on metal hydride/palladium compound system |
| CN114276330B (en) * | 2021-11-04 | 2023-04-18 | 华中师范大学 | Piperidone compound and preparation method and application thereof |
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| N-取代-3，5-双苄叉基-哌啶-4-酮的合成及其抗癌活性的测定;单振国 等;《应用化学》;20120229;第29卷(第2期);144-148 * |
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