CN106214677B - A kind of single carbonyl curcumin class compound application in preparation of anti-tumor drugs replaced containing allyl - Google Patents

A kind of single carbonyl curcumin class compound application in preparation of anti-tumor drugs replaced containing allyl Download PDF

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CN106214677B
CN106214677B CN201610573488.6A CN201610573488A CN106214677B CN 106214677 B CN106214677 B CN 106214677B CN 201610573488 A CN201610573488 A CN 201610573488A CN 106214677 B CN106214677 B CN 106214677B
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allyl
bis
class compound
compound
cyclopropyl
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CN106214677A (en
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王怡
刘志国
朱和平
邹鹏
邱晨宇
张文欣
蔡跃飘
梁广
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Wenzhou Medical University
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Abstract

The invention discloses a kind of single carbonyl curcumin class compound application in preparation of anti-tumor drugs replaced containing allyl, single carbonyl curcumin class compound is structure such as formula (I) compound represented or its pharmaceutical salts;In formula (I), A C, S, O or-NR1, wherein R1Independently selected from H, C1~C5One or more of alkyl, benzene sulfuryl, benzyl;N is 0 or 1;R is independently selected from one or more H, hydroxyl, allyl, C1~C4Alkoxy, pyrrolidinyl, morpholinyl or N methyl piperazine base.Test result shows that this kind of single carbonyl curcumin class compound has preferable stability and anti-tumor activity, can be used as a kind of potential anti-tumor drug.

Description

It is a kind of containing allyl replace single carbonyl curcumin class compound preparing antineoplastic Application in object
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of single carbonyl curcumin class antineoplastic replaced containing allyl Object and its prepare anti-tumor drug and therapeutic agent with tumor-related illness in application.
Background technique
Cancer is to seriously threaten the major disease of human life and health.2013, it was reported that there are about 7,900,000 people are dead in the whole world In cancer, wherein lung cancer death about 1,300,000, mortality of gastric carcinoma about 80.3 ten thousand, colorectal cancer death about 63.9 ten thousand, PLC mortality about 61 Ten thousand, breast cancer deaths about 51.9 ten thousand.Therefore, the problem of new anti-tumor drug is always scientific worker's concern is found.
Curcumin is the main active that Turmeric plays pharmacological action, in India, Brazil, Philippine, Japan, Korea Spro There is the edible and medicinal record of more than one thousand years on the ground such as state.In recent years, pharmaceutical chemistry and pharmaceutical research discovery curcumin have anti- The multiple pharmacological effects such as tumour, anti-angiogenesis, anti-mutation, antibacterial, antiviral, anti-oxidant and neuroprotection, antitumor Aspect includes the advantages that wide Antitumor test, multiple target point, reverse multiple drug resistance of tumor, causes the extensive concern of people.Curcumin I phase clinical trial is come into the U.S..Exactly because more bioactivity and low molecular weight, it is nontoxic the features such as, turmeric Element was once considered as one of ideal chemotherapeutic agent.However, further investigation revealed that the activity of curcumin in vivo is inclined It is low, body absorption is few, tachytrophism and bioavilability are low, significantly limit its application.But, it is contemplated that it is exact Bioactivity, relatively simple molecular structure, curcumin still be can yet be regarded as a kind of outstanding structural modification and screening anti-tumor medicine Lead compound.
Currently, the curcumin analogue for the purpose of retaining its drug safety, increase anti-tumor activity and water solubility is set Meter, synthesis, assessment and screening study have attracted many medicament research and development mechanisms and pharmaceutical companies.It is looked by a large amount of document and patent It reads, it has been found that although the active group for generally believing in curcumin structure at present is its phenolic hydroxyl group and beta-diketon group, Curcumin analogue without containing the two active groups studies aspect, it has been found that stronger activity is sometimes also shown, this Query is proposed for the essential groups that beta-diketon group is curcumin.Moreover, because the presence of beta-diketon structure, turmeric The stability of element is weaker, only just has preferable stability in pH < 6.5.
Summary of the invention
The present invention provides a kind of single carbonyl curcumin class compounds replaced containing allyl in the preparation of antitumor drugs Application, such single carbonyl curcumin class compound avoids beta-diketon structure bring unstability, while with higher Anti-tumor activity.
A kind of single carbonyl curcumin class compound application in preparation of anti-tumor drugs replaced containing allyl, it is described Single carbonyl curcumin class compound is structure such as formula (I) compound represented or its pharmaceutical salts;
In formula (I), A CH2, S or-NR1, wherein R1Independently selected from H, C1~C5One of alkyl, benzene sulfuryl, benzyl Or it is a variety of;
N is 0 or 1;
R is independently selected from one or more H, hydroxyl, allyl, C1~C4Alkoxy, pyrrolidinyl, morpholinyl or N- Methyl piperazine base.
In formula (I), the C1~C5Alkyl includes C1~C5Alkyl group and C1~C5Naphthenic base, such as: methyl, ethyl, N-propyl, isopropyl or cyclopropyl.
In formula (I), when n is 0, intermediate ring is five-membered ring, such as A is CH at this time2When, intermediate ring is cyclopentanone base;Work as n When being 1, intermediate ring is hexatomic ring.
In formula (I), the number for the substituent group that R is indicated can be multiple, the different location of difference substituted benzene ring, such as simultaneously Contain an allyl at 3, and contains a hydroxyl at 2.
Preferably, single carbonyl curcumin class compound be one of following compound or pharmaceutically acceptable salt thereof or It is several:
Bis- (3- allyl -4- phenol methylene) piperidin-4-ones (L1) of (3E, 5E) -3,5-;
Bis- (3- allyl -4- the phenol methylene) -1- methyl piperidine -4- ketone (L2) of (3E, 5E) -3,5;
Bis- (3- allyl -4- the phenol methylene) -1- ethyl piperidine -4- ketone (L3) of (3E, 5E) -3,5;
Bis- (3- allyl -4- the phenol methylene) -1- propylpiperdine -4- ketone (L4) of (3E, 5E) -3,5;
Bis- (3- allyl -4- the phenol methylene) -1- isopropyl piperidin-4-ones (L5) of (3E, 5E) -3,5;
Bis- (3- allyl -4- the phenol methylene) -1- cyclopropyl piperidine -4- ketone (L6) of (3E, 5E) -3,5;
Bis- (3- allyl -4- phenol methylene) -1- (benzenesulfonyl) piperidin-4-ones (L7) of (3E, 5E) -3,5;
Bis- (3- allyl -4- the phenol methylene) -1- benzyl piepridine -4- ketone (L8) of (3E, 5E) -3,5;
Bis- (3- allyl -4- phenol methylene) cyclopentanone (L9) of (2E, 5E) -2,5;
Bis- (3- allyl -4- phenol methylene) cyclohexanone (L10) of (2E, 6E) -2,6;
Bis- (3- allyl -4- hydroxyl benzyloxy) dihydro -2H- thiapyran -4 (3H) -one (L11) of (3Z, 5Z) -3,5-;
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,5- trimethoxy-benzene methylene Base) piperidin-4-one (L12);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (3,4- dimethoxybenzyliden) Piperidin-4-one (L13);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,6- trimethoxy-benzene methylene Base) piperidin-4-one (L14);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4- dimethoxybenzyliden) Piperidin-4-one (L15);
(3E, 5E) -3- (3- allyl l-4- phenol methylene) -5- (4- (tert-butoxy) benzylidene) -1- cyclopropyl Phenylpiperidines -4- ketone (L16);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (4- methylpiperazine-1-yl) benzene Methylene) piperidin-4-one (L17);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- morpholine benzylidene) piperidines - 4- ketone (L18);
(3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (pyrrolidin-1-yl) benzene methylene Base) piperidin-4-one (L19).
Wherein, bis- (3- allyl -4- phenol methylene) piperidin-4-ones (3E, 5E) -3,5-Bis of (3E, 5E) -3,5- The structural formula of (3-allyl-4-hydroxybenzylidene) piperidin-4-one is as follows, is denoted as L1:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- methyl piperidine -4- ketone (3E, 5E) -3, The structural formula of 5-Bis (3-allyl-4-hydroxybenzylidene) -1-methylpiperidin-4-one is as follows, It is denoted as L2:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- ethyl piperidine -4- ketone (3E, 5E) -3, The structural formula of 5-Bis (3-allyl-4-hydroxybenzylidene) -1-ethylpiperidin-4-one is as follows, note For L3:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- propylpiperdine -4- ketone (3E, 5E) -3, The structural formula of 5-Bis (3-allyl-4-hydroxybenzylidene) -1-propylpiperidin-4-one is as follows, It is denoted as L4:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- isopropyl piperidin-4-ones (3E, 5E) - The structural formula of 3,5-Bis (3-allyl-4-hydroxybenzylidene) -1-isopropylpiperidin-4-one is as follows It is shown, it is denoted as L5:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- cyclopropyl piperidine -4- ketone (3E, 5E) - The structural formula of 3,5-Bis (3-allyl-4-hydroxybenzylidene) -1-cyclopropylpiperidin-4-one is such as Shown in lower, it is denoted as L6:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- (benzenesulfonyl) piperidin-4-ones (3E, E) -3,5-Bis (3-allyl-4-hydroxybenzylidene) -1- (phenylsulfonyl) piperidin-4-one Structural formula is as follows, is denoted as L7:
Wherein, (3E, 5E) -3,5 bis- (3- allyl -4- phenol methylene) -1- benzyl piepridine -4- ketone (3E, 5E) -3, The structural formula of 5-Bis (3-allyl-4-hydroxybenzylidene) -1-benzylpiperidin-4-one is as follows, It is denoted as L8:
Wherein, (2E, 5E) -2,5 bis- (3- allyl -4- phenol methylene) cyclopentanone (2E, 5E) -2,5-Bis (3- Allyl-4-hydroxybenzylidene) structural formula of cyclopentanone is as follows, is denoted as L9:
Wherein, (2E, 6E) -2,6 bis- (3- allyl -4- phenol methylene) cyclohexanone (2E, 6E) -2,6-Bis (3- Allyl-4-hydroxybenzylidene) structural formula of cyclohexanone is as follows, is denoted as L10:
Wherein, bis- (3- allyl -4- hydroxyl benzyloxy) dihydro -2H- thiapyran -4 (3H) -one of (3Z, 5Z) -3,5- (3Z, 5Z) the structure of -3,5-Bis (3-allyl-4-hydroxybenzylidene) dihydro-2H-thiopyran-4 (3H)-one Formula is as follows, is denoted as L11:
Wherein, (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,5- trimethoxy-benzenes Methylene) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- (2, 4,5-trimethoxybenz ylidene) piperidin-4-one structural formula it is as follows, be denoted as L12:
Wherein, (3,4- dimethoxy benzenes are sub- by (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- Methyl) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- (3,4- Dimethoxybenzyli dene) piperidin-4-one structural formula it is as follows, be denoted as L13:
Wherein, (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,6- trimethoxy-benzenes Methylene) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- (2, 4,6-trimethoxybenz ylidene) piperidin-4-one structural formula it is as follows, be denoted as L14:
Wherein, (2,4- dimethoxy benzenes are sub- by (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- Methyl) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- (2,4- Dimethoxybenzyli dene) piperidin-4-one structural formula it is as follows, be denoted as L15:
Wherein, (3E, 5E) -3- (3- allyl l-4- phenol methylene) -5- (4- (tert-butoxy) benzylidene) -1- Cyclopropyl piperidine -4- ketone (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -5- (4- (tert-butoxy) Benzylidene) structural formula of -1-cyclo propylpiperidin-4-one is as follows, is denoted as L16:
Wherein, (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (4- methyl piperazine -1- Base) benzylidene) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl- The structural formula of 5- (4- (4-methylpiperazin-1-yl) benzylidene) piperidin-4-one is as follows, is denoted as L17:
Wherein, (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- morpholine benzylidene) Piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- (4- Morpholinobenzyli dene) piperidin-4-one structural formula it is as follows, be denoted as L18:
Wherein, (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (pyrrolidin-1-yl) Benzylidene) piperidin-4-one (3E, 5E) -3- (3-Allyl-4-hydroxybenzylidene) -1-cyclopropyl-5- The structural formula of (4- (pyrrolidin-1-yl) be nzylidene) piperidin-4-one is as follows, is denoted as L19:
Preferably, the anti-tumor drug is for treating tumour or disease relevant to tumour.This 19 kinds of compounds Antitumor test is wider, and the example of treatable cancer includes but are not limited to, cutaneum carcinoma, lung cancer, carcinoma of testis, lymph cancer, Leukaemia, cancer of the esophagus, gastric cancer, colon cancer, breast cancer, carcinoma of endometrium, oophoroma, central nervous system cancer, liver cancer and forefront Gland cancer.
Preferably, the anti-tumor drug includes the active constituent and pharmaceutic adjuvant of therapeutically effective amount, wherein activity Ingredient is single carbonyl curcumin class compound.
The pharmaceutic adjuvant refers to the pharmaceutical carrier of pharmaceutical field routine, such as: diluent, excipient such as water etc., filling Agent such as starch, sucrose etc.;Adhesive such as cellulose derivative, alginates, gelatin and polyvinylpyrrolidone;Wetting agent is for example sweet Oil;Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate;Sorbefacient such as quaternary ammonium compound;Surfactant such as hexadecanol; Absorption carrier such as kaolin and soap clay;Lubricant such as talcum powder, calcium stearate/magnesium, polyethylene glycol etc..In addition it can in group It closes in object and other adjuvants such as flavouring agent, sweetener etc. is added.
Preferably, the active constituent of the anti-tumor drug is by single carbonyl curcumin class compound and other Anti-tumor drug composition, other described anti-tumor drugs include various biological alkylating agents, antimetabolite, antitumor antibiotics And molecular targeted agents etc..
The various dosage forms of anti-tumor drug of the present invention can be prepared according to the conventional production process of pharmaceutical field.Such as make to live Property ingredient is mixed with one or more carriers, is then made into required dosage form.The dosage form of the drug includes injection Agent, tablet, capsule, aerosol, suppository, film, pill, ointment, controlled release or sustained release agent or nanometer formulation.The present invention can In the form of compositions by oral, the mode of nasal inhalation, rectum or parenteral administration is applied to the trouble for needing this treatment Person.When for taking orally, it can be made into conventional solid pharmaceutical preparation such as tablet, pulvis, granula, capsule etc., liquid preparation is made such as Water or oil-suspending agent or other liquid preparations such as syrup, elixir etc.;When for parenteral administration, the molten of injection can be made into Liquid, water or oleaginous suspension etc..
Compared with the existing technology, the beneficial effects of the present invention are embodied in: single carbonyl curcumin class compound has Better stability, while there is preferable antitumor activity energy, can be used for preparing treatment tumour and with tumor-related illness Drug.
Detailed description of the invention
Fig. 1 is the Detection of Stability figure of representative compound L9, L10, L11 of the present invention and curcumin (Curcumin).
Fig. 2 (A) show 19 compounds (L1-L19) of the invention to the Survival curves figure of human bile duct cancer RBE cell; It (B) is reactive compound L6, L9, L11 of the present invention to the IC of human bile duct cancer RBE cell50Value;It (C) is reactive compound of the present invention IC of the L11 to human bile duct cancer RBE cell, HUCCA cell and QBC-939 cell50Value;It (D) is L11 pairs of reactive compound of the present invention The IC of people's normal hepatocytes HL-7702 cell people's intrahepatic biliary epithelium HIBEC cell50Value.
Fig. 3 (A) and (B) are respectively the compounds of this invention L11 induction human bile duct cancer RBE cell, HUCCA cell and QBC- 939 cell G2/M Cycle Arrest figures;(C) the compounds of this invention L11 is detected to human bile duct cancer for Western Blotting method RBE cell, HUCCA cell p53 albumen related to the period of QBC-939 cell and Cdc2 protein expression situation.
Fig. 4 (A) and (B) are that the compounds of this invention L11 induces human bile duct cancer RBE cell, HUCCA cell and QBC-939 thin Born of the same parents' apoptosis detection figure;(C) for Western Blotting method detect the compounds of this invention L11 to human bile duct cancer RBE cell, HUCCA cell BAX albumen related to the apoptosis of QBC-939 cell, Bcl-2 albumen and cle-PARP protein expression situation.
Specific embodiment
Below in conjunction with specific embodiment detailed description of the present invention content.It should be noted that being retouched in following embodiments The combination of the technical characteristic or technical characteristic stated is not construed as isolated, they can be combined with each other to reaching Superior technique effect.
Embodiment 1
The structure of 1~L19 of compound L is as shown in table 1.
Table 1
The method for preparing the above-mentioned single carbonyl curcumin analog replaced containing allyl, includes the following steps:
Compound (L1-L11) in type I synthesis step (step a- step c):
Step a: synthesis 4- (allyloxy) benzaldehyde (2): by allyl bromide, bromoallylene (14.0ml, 163.7mmol) and anhydrous carbon Sour potassium (5.6g, 40.9mmol) is added in acetone (40ml) solution of 4- hydroxy benzaldehyde (1) (10.0g, 81.9mmol), instead Liquid is answered to be stirred at reflux at 65 DEG C overnight.Vacuum distillation removes solvent acetone after reaction.Residue is dissolved in ethyl acetate Three times, organic layer is dry with anhydrous magnesium sulfate for extraction in (30mL) and distilled water (30mL), and ethyl acetate is removed in vacuum distillation.It is residual Object is stayed to obtain intermediate benzaldehyde 2 (9.96g, yield 75%, colourless liquid) with silica gel column chromatography method.
Step b synthesis 3- allyl -4- hydroxy benzaldehyde (3): take 4- (allyloxy) benzaldehyde (2) (2.3g, It 18.5mmol) is added in reaction flask, later in N2N, N- diethylaniline (8.0ml) are added dropwise under protection.Reaction flask is set 5 hours are stirred at reflux under the conditions of 200 DEG C of sand-baths.After reaction, reaction flask is cooled to room temperature, and utilizes silica gel column chromatography The intermediate 3- allyl -4- hydroxy benzaldehyde (3) (996mg, yield 33.2%, brown liquid) after resetting can be directly obtained.
The general step of step c synthesis final product L1-L11: 3- allyl -4- hydroxy benzaldehyde (3) (1.0mmol) is molten For solution in glacial acetic acid (10ml) solution, piperidones or substituted piperidine ketone (0.5mmol) are also dissolved in glacial acetic acid (4.0ml) solution In.Two kinds of reactants use HCl gas to be saturated respectively.Then under stirring conditions, by the piperidones or substitution piperazine after saturation Pyridine ketone solution is added dropwise in the reaction flask containing intermediate 3.Reaction is placed in 48 hours of room temperature reaction after adding.Reaction knot The pH value of Shu Houyong saturated sodium bicarbonate condition solution is 7.0.Later three times with ethyl acetate (3 × 20ml) extraction.Acetic acid second Ester layer is dried, filtered with anhydrous magnesium sulfate, and vacuum distillation removes ethyl acetate.The purifying of residue silica gel column chromatography method can obtain To the final product L1-L11 (gross production rate 20-30%) in type I.
Compound (L12-L19) in Type II synthesis (step d- step f):
Step d synthesizes the benzaldehyde (5) of OH protection: by 3- allyl -4- hydroxy benzaldehyde (3) (1.0g, 6.17mmol) It is dissolved in anhydrous methylene chloride (10mL), 3,4- dihydro -2H- pyrans (2.59g, 30.83mmol) is added portionwise later, then It is added catalyst PPTS (200mg, 0.617mmol).Reaction mixture is stirred at reflux overnight at 40 DEG C.It after reaction will be anti- Liquid distilled water (40mL) and methylene chloride (3 × 50mL) is answered to extract.Obtained dichloromethane layer is dry with anhydrous magnesium sulfate, mistake Filter, purifies to obtain intermediate benzaldehyde 5 (1.29g, yield 85%, yellow liquid) using silica gel column chromatography method after concentration.
Step e synthesizes alpha, beta-unsaturated ketone (6): the benzaldehyde intermediate 5 (500mg, 2.03mmol) after hydroxyl is protected is molten 1- cyclopropyl piperidine -4- ketone (310.83mg, 2.33mmol) and pyrrolidines is added in anhydrous methylene chloride (15ml) in solution (433.13mg,6.09mmol).Reaction flask is stirred at reflux 4 hours under the conditions of being placed in 40 DEG C.Vacuum distillation removes solvent dichloro Methane is directly purified to obtain α, alpha, beta-unsaturated ketone intermediate 6 (5.26g, yield 40%, brown liquid) with silica gel column chromatography.
The universal method of step f synthesis L12-L19: it is added among alpha, beta-unsaturated ketone in dehydrated alcohol (10ml) solution Body 6 (0.544mmol) and different substituted benzaldehydes (0.544mmol), reaction is placed in stirs under room temperature, adds dropwise later Enter 20% (w/v) NaOH aqueous solution (0.8ml), reaction mixture be stirred overnight under room temperature.After reaction with saturation Sodium bicarbonate solution (10mL) and ethyl acetate (3 × 20mL) extraction.Combined organic layer is with saturated sodium chloride solution (40mL) It washes 3 times, anhydrous magnesium sulfate dry filter, vacuum distillation removes ethyl acetate.Residue is then dissolved in dehydrated alcohol (5mL) In, 1M HCl (1ml) is added dropwise.Reaction flask is placed in 5 hours of stirring under room temperature.Saturated ammonium chloride is used after reaction Solution (5mL) and ethyl acetate solution (3 × 10mL) extraction.Combined organic layer is washed 3 times with saturated sodium chloride solution (20mL), Anhydrous magnesium sulfate dry filter, vacuum distillation remove ethyl acetate.Residue can purify to obtain class using silica gel column chromatography method Compound L 12-L19 (gross production rate 20%-40%) in type II.
The following are the nuclear magnetic resoance spectrum diagram datas of obtained 1~L19 of compound L:
Compound (L1): bis- (3- allyl -4- phenol methylene) piperidin-4-ones of (3E, 5E) -3,5-:
Yellow power.Yield:25%.m.p:196.2-198.3 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 9.96 (2H, s, Ar-OH), 7.46 (2H, s, H- β, H- β '), 7.19 (2H, d, J=8.4Hz, H-6, H-6'), 7.18 (2H, s, H-2, H-2'), 6.88 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH2 CH=CH2), 5.07-5.02(4H,m,A,B-ArCH2CH=CH2 ),3.94(4H,s,piperidone-CH2 -N-CH2 ),3.31(4H,s,A, B-ArCH2 CH=CH2).13C NMR(150MHz,DMSO-d6)δ(ppm):186.8,156.2×2,136.7×2,134.1×2, 132.7×2,132.6×2,130.3×2,126.4×2,126.0×2,115.6×2,115.2×2,47.5×2,33.5× 2.ESI-MS,m/z:385.9[M-H]-.
Compound (L2): bis- (3- allyl -4- the phenol methylene) -1- methyl piperidine -4- ketone of (3E, 5E) -3,5:
Yellow power.Yield:30%.m.p:185.9-187.6 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.00 (2H, s, Ar-OH), 7.48 (2H, s, H- β, H- β '), 7.20 (2H, d, J=8.4Hz, H-6, H-6'), 7.19 (2H, s, H-2, H-2'), 6.89 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH 2CH=CH2), 5.07-5.02(4H,m,A,B-ArCH2CH=CH2 ),3.66(4H,s,piperidone-CH2 -N-CH2 ),3.31(4H,s,A, B-ArCH2 CH=CH2),2.38(3H,s,N-CH3).13C NMR(150MHz,DMSO-d6)δ(ppm):185.8,156.4×2, 136.7×2,134.7×2,132.8×2,130.6×2,130.1×2,126.5×2,125.8×2,115.6×2,115.2 ×2,56.6×2,45.4,33.5×2.ESI-MS,m/z:400.0[M-H]-.
Compound (L3): bis- (3- allyl -4- the phenol methylene) -1- ethyl piperidine -4- ketone of (3E, 5E) -3,5:
Yellow power.Yield:30%.m.p:181.3-183.2 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.00 (2H, s, Ar-OH), 7.49 (2H, s, H- β, H- β '), 7.22 (2H, d, J=8.4Hz, H-6, H-6'), 7.20 (2H, s, H-2, H-2'), 6.90 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH2 CH=CH2), 5.08-5.03(4H,m,A,B-ArCH2CH=CH2 ),3.71(4H,s,piperidone-CH2 -N-CH2 ), 3.31 (4H, d, J= 6.6Hz,A,B-ArCH2 CH=CH2), 2.56 (2H, q, J=7.2Hz, N-CH2 CH3), 0.98 (3H, t, J=7.2Hz, N- CH2 CH3 ).13C NMR(150MHz,DMSO-d6)δ(ppm):186.2,156.4×2,136.7×2,134.8×2,132.7× 2,130.7×2,130.2×2,126.5×2,125.8×2,115.6×2,115.3×2,53.9×2,50.6,33.4×2, 12.1.ESI-MS,m/z:414.1[M-H]-.
Compound (L4): bis- (3- allyl -4- the phenol methylene) -1- propylpiperdine -4- ketone of (3E, 5E) -3,5:
Yellow power.Yield:30%.m.p:172.9-175.2 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.01 (2H, s, Ar-OH), 7.49 (2H, s, H- β, H- β '), 7.21 (2H, d, J=8.4Hz, H-6, H-6'), 7.20 (2H, s, H-2, H-2'), 6.89 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH2 CH=CH2), 5.07-5.02(4H,m,A,B-ArCH2CH=CH2 ),3.71(4H,s,piperidone-CH2 -N-CH2 ), 3.31 (4H, d, J= 6.6Hz,A,B-ArCH2 CH=CH2), 2.46 (2H, t, J=7.2Hz, N-CH2 CH2CH3),1.43-1.37(2H,m,N- CH2 CH2 CH3), 0.80 (3H, t, J=7.2Hz, N-CH2CH2 CH3 ).13C NMR(150MHz,DMSO-d6)δ(ppm):186.2, 156.4×2,136.7×2,134.8×2,132.7×2,130.8×2,130.2×2,126.5×2,125.8×2,115.6 ×2,115.3×2,58.6,54.3×2,33.4×2,19.7,11.6.ESI-MS,m/z:428.3[M-H]-.
Compound (L5): bis- (3- allyl -4- the phenol methylene) -1- isopropyl piperidin-4-ones of (3E, 5E) -3,5:
Yellow power.Yield:30%.m.p:205.3-207.2 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 9.99 (2H, s, Ar-OH), 7.46 (2H, s, H- β, H- β '), 7.22 (2H, d, J=8.4Hz, H-6, H-6'), 7.20 (2H, s, H-2, H-2'), 6.90 (2H, d, J=7.8Hz, H-5, H-5'), 6.01-5.95 (2H, m, A, B-ArCH2 CH=CH2), 5.09-5.04(4H,m,A,B-ArCH2CH=CH2 ),3.75(4H,s,piperidone-CH2 -N-CH2 ),3.31(4H,s,A, B-ArCH2 CH=CH2),2.91-2.87(1H,m,N-CH(CH3)2), 1.01 (6H, d, J=6.6Hz, N-CH(CH3)2 ).13C NMR(150MHz,DMSO-d6)δ(ppm):186.6,156.2×2,136.7×2,134.2×2,132.5×2,131.4×2, 130.2×2,126.4×2,125.9×2,115.7×2,115.3×2,53.1,50.1×2,33.3×2,18.0× 2.ESI-MS,m/z:428.1[M-H]-.
Compound (L6): bis- (3- allyl -4- the phenol methylene) -1- cyclopropyl piperidine -4- ketone of (3E, 5E) -3,5:
Yellow power.Yield:40%.m.p:82.5-85.1 DEG C1H NMR(600MHz,DMSO-d6)δ(ppm): 10.01 (2H, s, Ar-OH), 7.49 (2H, s, H- β, H- β '), 7.22 (2H, d, J=7.8Hz, H-6, H-6'), 7.21 (2H, s, H-2, H-2'), 6.91 (2H, d, J=8.4Hz, H-5, H-5'), 6.01-5.94 (2H, m, A, B-ArCH2 CH=CH2),5.08- 5.03(4H,m,A,B-ArCH2CH=CH2 ),3.89(4H,s,piperidone-CH2 -N-CH2 ),3.31(4H,s,A,B- ArCH2 CH=CH2),1.98-1.95(1H,m,-N-CH-(CH2)2),0.46-0.43(2H,m,-N-CH-(CH2 )2),0.26- 0.25(2H,m,-N-CH-(CH2 )2).13C NMR(150MHz,DMSO-d6)δ(ppm):186.1,156.4×2,136.7×2, 134.9×2,132.8×2,130.7×2,130.0×2,126.5×2,125.8×2,115.6×2,115.3×2,54.5 ×2,37.5,33.4×2,6.3×2.ESI-MS,m/z:426.1[M-H]-.
Compound (L7): bis- (3- allyl -4- phenol methylene) -1- (benzenesulfonyl) piperidines -4- of (3E, 5E) -3,5 Ketone:
Yellow power.Yield:35%.m.p:84.7-87.0 DEG C1H NMR(600MHz,DMSO-d6)δ(ppm): 10.17(2H,s,Ar-OH),7.74-7.71(1H,m,-N-SO2-Ar-H-4),7.59-7.57(4H,m,N-SO4-Ar-H-2,3, 5,6),7.47(2H,s,H-β,H-β'),7.21(2H,dd,J1=8.4Hz, J2=1.8Hz, H-6, H-6'), 7.14 (2H, s, H- 2, H-2'), 6.95 (2H, d, J=7.8Hz, H-5, H-5'), 6.04-5.97 (2H, m, A, B-ArCH2 CH=CH2),5.13- 5.07(4H,m,A,B-ArCH2CH=CH2 ),4.49(4H,s,piperidone-CH2 -N-CH2 ), 3.35 (4H, d, J= 6.6Hz,A,B-ArCH2 CH=CH2).13C NMR(150MHz,DMSO-d6)δ(ppm):183.7,156.9×2,137.2×2, 136.8,136.6×2,133.5,132.5×2,130.6×2,129.4×2,127.5×2,127.2×2,126.7×2, 125.2×2,115.8×2,115.5×2,46.9×2,33.4×2.ESI-MS,m/z:526.3[M-H]-.
Compound (L8): bis- (3- allyl -4- the phenol methylene) -1- benzyl piepridine -4- ketone of (3E, 5E) -3,5:
Yellow power.Yield:35%.m.p:135.9-137.8 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm):10.16(2H,s,Ar-OH),7.74-7.71(1H,m,N-CH2-Benzene-4),7.60-7.59(4H,m,N-CH2- Benzene-2,3,5,6),7.47(2H,s,H-β,H-β'),7.21(2H,dd,J1=8.4Hz, J2=1.8Hz, H-6, H-6'), 7.14 (2H, s, H-2, H-2'), 6.95 (2H, d, J=8.4Hz, H-5, H-5'), 6.05-5.98 (2H, m, A, B-ArCH2 CH= CH2),5.13-5.08(4H,m,A,B-ArCH2CH=CH2 ),4.49(4H,s,piperidone-CH2 -N-CH2 ),3.35(4H, D, J=6.6Hz, A, B-ArCH2 CH=CH2),3.35(2H,s,N-CH2 -Benzene).13C NMR(150MHz,DMSO-d6)δ (ppm):186.1,156.4×2,136.6×2,134.9×2,132.4×2,130.6×2,130.4×2,129.0×2, 128.2,128.1×2,127.1,126.5×2,125.7×2,115.7×2,115.2×2,61.2,54.2×2,33.4× 2.ESI-MS,m/z:476.0[M-H]-.
Compound (L9): bis- (3- allyl -4- phenol methylene) cyclopentanone of (2E, 5E) -2,5:
Yellow power.Yield:60%.m.p:119.5-122.3 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.04 (2H, s, Ar-OH), 7.39 (2H, d, J=8.4Hz, H-6, H-6 '), 7.39 (2H, s, H- β, H- β '), 7.30 (2H, s, H-2, H-2 '), 6.91 (2H, d, J=7.8Hz, H-5, H-5 '), 6.02-5.95 (2H, m, A, B-ArCH2 CH=CH2), 5.08-5.03(4H,m,A,B-ArCH2CH=CH2 ),3.32(4H,s,A,B-ArCH2 CH=CH2),3.00(4H,s, cyclopentanone-CH2 -CH2 ).13C NMR(150MHz,DMSO-d6)δ(ppm):194.7,156.7×2,136.6×2, 134.4×2,132.6×2,132.4×2,130.5×2,126.7×2,126.7×2,115.6×2,115.4×2,33.6 ×2,25.9×2.ESI-MS,m/z:371.0[M-H]-.calcd for C25H24O3:372.17
Compound (L10): bis- (3- allyl -4- phenol methylene) cyclohexanone of (2E, 6E) -2,6:
Yellow power.Yield:45%.m.p:140.3-142.1 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 9.91 (2H, s, Ar-OH), 7.51 (2H, s, H- β, H- β '), 7.27 (2H, d, J=8.4Hz, H-6, H-6'), 7.25 (2H, s, H-2, H-2'), 6.87 (2H, d, J=8.4Hz, H-5, H-5'), 6.00-5.93 (2H, m, A, B-ArCH2 CH=CH2), 5.07-5.01(4H,m,A,B-ArCH2CH=CH2 ), 3.31 (4H, d, J=6.6Hz, A, B-ArCH2 CH=CH2),2.84(4H, T, J=4.8Hz, cyclohexanone-CH2 -CH2-CH2 ),1.71-1.69(2H,m,cyclohexanone-CH2-CH2 - CH2).13C NMR(150MHz,CD3OD)δ(ppm):192.3,157.5×2,138.7×2,138.0×2,134.7×2, 134.0×2,131.5×2,128.6×2,128.1×2,115.9×2,115.7×2,35.0×2,29.5×2, 24.2.ESI-MS,m/z:385.3[M-H]-.calcd for C26H26O3:386.18
Compound (L11): bis- (3- allyl -4- hydroxyl benzyloxy) dihydro -2H- thiapyrans -4 of (3Z, 5Z) -3,5- (3H) -one:
Yellow power.Yield:40%.m.p:152.4-154.1 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 9.96 (2H, s, Ar-OH), 7.50 (2H, s, H- β, H- β '), 7.25 (2H, d, J=8.4Hz, H-6, H-6'), 7.23 (2H, s, H-2, H-2'), 6.88 (2H, d, J=7.8Hz, H-5, H-5'), 6.00-5.94 (2H, m, A, B-ArCH2 CH=CH2), 5.07-5.01(4H,m,A,B-ArCH2CH=CH2 ),3.94(4H,s,CH2 -S-CH2 ), 3.31 (4H, d, J=6.6Hz, A, B- ArCH2 CH=CH2).13C NMR(150MHz,DMSO-d6)δ(ppm):187.5,156.3×2,136.7×2,135.6×2, 132.5×2,131.2×2,130.1×2,126.5×2,125.6×2,115.6×2,115.2×2,33.5×2,29.4× 2.ESI-MS,m/z:402.9[M-H]-.calcd for C25H24O3S:404.14
Compound (L12): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,5- tri- Methoxybenzylidene) piperidin-4-one:
Yellow power.Yield:25%.m.p:138.2-140.5 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.05 (1H, s, Ar-OH), 7.79 (1H, s, H- β '), 7.50 (1H, s, H- β), 7.22 (1H, d, J=8.4Hz, H- 6), 7.22 (1H, s, H-2), 6.91 (1H, d, J=8.4Hz, H-5), 6.85 (1H, s, H-6'), 6.76 (1H, s, H-3'), 6.01-5.94(1H,m,A-ArCH2 CH=CH2),5.08-5.03(2H,m,A-ArCH2CH=CH2 ),3.86(6H,s,4',5'- OCH3 ),3.85(3H,s,2'-OCH3 ),3.74(4H,s,piperidone-CH2 -N-CH2 ),3.31(2H,s,A-ArCH2 CH= CH2),1.98-1.93(1H,m,-N-CH-Cyclopropyl),0.43-0.42(2H,m,N-CH2 -CH2-Cyclopropyl), 0.25-0.24(2H,m,N-CH2-CH2 -Cyclopropyl).13C NMR(150MHz,DMSO-d6)δ(ppm):186.1, 153.7,151.4,142.1,137.4,136.7,135.3,133.0,131.3,130.7,130.1,130.0,126.6, 125.9,115.7,115.3,114.5,114.3,97.7,56.5,56.2,56.0×3,37.4,33.5,6.3×2.ESI-MS, m/z:462.3[M+H]+.calcd for C28H31NO5:461.21
Compound (L13): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (3,4- diformazan Oxygroup benzylidene) piperidin-4-one:
Yellow power.Yield:28%.m.p:143.8-145.9 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 7.54 (1H, s, H- β '), 7.50 (1H, s, H- β), 7.17 (1H, d, J=8.4Hz, H-6), 7.17 (1H, s, H-2), 7.09 (1H, s, H-2'), 7.07 (1H, d, J=8.4Hz, H-6'), 7.04 (1H, d, J=8.4Hz, H-5), 6.80 (1H, d, J =8.4Hz, H-5'), 6.03-5.96 (1H, m, A-ArCH2 CH=CH2),5.08-5.02(2H,m,A-ArCH2CH=CH2 ), 3.92(2H,s,piperidone-CH2 -N-CH2),3.90(2H,s,piperidone-CH2-N-CH2 ),3.81(3H,s,3'- OCH3 ),3.80(3H,s,4'-OCH3 ), 3.30 (2H, d, J=6.0Hz, A-ArCH2 CH=CH2),1.99-1.96(1H,m,-N-CH-Cyclopropyl),0.46-0.45(2H,m,N-CH2 -CH2-Cyclopropyl),0.26(2H,s,N-CH2-CH2 - Cyclopropyl).13C NMR(150MHz,DMSO-d6)δ(ppm):185.7,149.6,148.5×2,137.2×2, 136.1,134.0,133.0,132.2,130.6,127.7,127.1,123.3,116.1,115.2,114.3,111.7×2, 55.5×2,54.8,54.4,37.5,33.7,6.3×2.ESI-MS,m/z:431.9[M+H]+.calcd for C27H29NO4: 431.21
Compound (L14): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4,6- tri- Methoxybenzylidene) piperidin-4-one:
Yellow power.Yield:25%.m.p:195.3-198.2 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.02 (1H, s, Ar-OH), 7.50 (1H, s, H- β '), 7.44 (1H, s, H- β), 7.23 (1H, d, J=8.4Hz, H- 6), 7.22 (1H, s, H-2), 6.91 (1H, d, J=8.4Hz, H-5), 6.29 (2H, s, H-5', H-3'), 6.01-5.95 (1H, m,A-ArCH2 CH=CH2),5.08-5.04(2H,m,A-ArCH2CH=CH2 ),3.86(3H,s,4'-OCH3 ),3.83(4H,s, piperidone-CH2 -N-CH2 ),3.79(6H,s,2',6'-OCH3 ),3.38(2H,s,A-ArCH2 CH=CH2),1.86-1.83 (1H,m,-N-CH-Cyclopropyl),0.39-0.38(2H,m,N-CH2 -CH2-Cyclopropyl),0.19-0.18(2H,m, N-CH2-CH2 -Cyclopropyl).13C NMR(150MHz,DMSO-d6)δ(ppm):185.5,162.0,158.7×3,137.3 ×2,136.5×2,133.9,133.0,130.7,127.2×2,115.2,115.2,105.0,90.7×2,55.6×2, 55.5,55.3,54.9,37.5,33.8,6.2×2.ESI-MS,m/z:462.0[M+H]+.calcd for C28H31NO5: 461.21
Compound (L15): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (2,4- diformazan Oxygroup benzylidene) piperidin-4-one:
Yellow power.Yield:25%.m.p:182.6-184.5 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.02 (1H, s, Ar-OH), 7.79 (1H, s, H- β '), 7.49 (1H, s, H- β), 7.24 (1H, d, J=6.0Hz, H- 6'), 7.22 (1H, d, J=7.8Hz, H-6), 7.22 (1H, s, H-2), 6.69 (1H, s, H-3'), 6.91 (1H, d, J= 7.8Hz, H-5), 6.64 (1H, d, J=6.0Hz, H-5'), 6.01-5.95 (1H, m, A-ArCH2 CH=CH2),5.08-5.03 (2H,m,A-ArCH2CH=CH2 ),3.89(2H,s,A-ArCH2 CH=CH2),3.85(4H,s,piperidone-CH2 -N-CH2 ),3.82(6H,s,2',4'-OCH3 ),1.97-1.93(1H,m,-N-CH-Cyclopropyl),0.45-0.42(2H,m,N-CH2 -CH2-Cyclopropyl),0.26-0.23(2H,m,N-CH2-CH2 -Cyclopropyl).13C NMR(150MHz,DMSO- d6)δ(ppm):186.0,159.6,156.4,136.7,135.2,131.3,131.1×2,130.7,130.1,129.8, 129.6,126.5,125.8,115.6,115.3,105.2×2,98.4,55.4×2,54.8,54.5,37.5,33.4,6.3× 2.ESI-MS,m/z:431.9[M+H]+.calcd for C27H29NO4:431.21
Compound (L16): (4- (tert-butoxy) benzene is sub- by (3E, 5E) -3- (3- allyl l-4- phenol methylene) -5- Methyl) -1- cyclopropyl piperidine -4- ketone:
Yellow power.Yield:25%.m.p:163.2-165.1 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.04 (1H, s, Ar-OH), 7.53 (1H, s, H- β '), 7.50 (1H, s, H- β), 7.43 (2H, d, J=8.4Hz, H- 6', H-2'), 7.23 (1H, s, J=8.4Hz, H-6), 7.22 (1H, s, H-2), 7.08 (1H, d, J=8.4Hz, H-5), 6.92 (2H, d, J=7.8Hz, H-5', H-3'), 6.01-5.95 (1H, m, A-ArCH2 CH=CH2),5.08-5.03(2H,m,A- ArCH2CH=CH2 ),3.93(2H,s,piperidone-CH2 -N-CH2),3.91(2H,s,piperidone-CH2-N-CH2 ), 3.46-3.42(2H,m,A-ArCH2 CH=CH2),1.99-1.98(1H,m,-N-CH-Cyclopropyl),1.36(9H,s,-OC (CH3)3),0.46-0.45(2H,m,N-CH2 -CH2-Cyclopropyl),0.27(2H,m,N-CH2-CH2 -Cyclopropyl) .13C-NMR(150MHz,DMSO-d6)δ(ppm):186.2,156.5,156.3,136.6×2,135.2,133.9,132.9, 132.4,131.7×2,130.6,130.1,129.1,126.6,122.8×2,115.6,115.3,78.7,56.0,54.6, 37.5,33.4,28.5×3,6.4×2.ESI-MS,m/z:444.5[M+H]+.calcd for C29H33NO3:443.51
Compound (L17): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (4- methyl Piperazine -1- base) benzylidene) piperidin-4-one:
Yellow power.Yield:20%.m.p:210.3-213.1 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 7.47 (2H, s, H- β ', H- β), 7.34 (2H, d, J=9.0Hz, H-6', H-2'), 7.15 (2H, s, H-6, H-2), 7.00 (2H, d, J=9.0Hz, H-5', H-3'), 6.77 (1H, d, J=7.2Hz, H-5), 6.02-5.96 (1H, m, A- ArCH2 CH=CH2),5.08-5.01(2H,m,A-ArCH2CH=CH2 ),3.89(2H,s,piperidone-CH2 -N-CH2), 3.88(2H,s,piperidone-CH2-N-CH2 ), 3.29 (2H, d, J=6.6Hz, A-ArCH2 CH=CH2),3.26(4H,t,J =4.8Hz ,-N- (CH2 CH2)2-N-CH3), 2.43 (4H, t, J=4.8Hz ,-N- (CH2 CH2 )2-N-CH3),2.21(3H,s,-N-CH3 ),1.99-1.96(1H,m,-N-CH-(CH2)2),0.45-0.44(2H,m,-N-CH-(CH2 )2),0.27-0.25(2H,m,- N-CH-(CH2 )2).13C NMR(150MHz,DMSO-d6)δ(ppm):185.5,151.0,137.3×2,135.7,134.2, 132.9,132.0×4,130.6,130.5,127.2,124.6,116.2,115.2,114.3×2,54.8,54.7,54.3× 2,46.8×2,45.7,37.6,33.8,6.3×2.ESI-MS,m/z:470.4[M+H]+.
Compound (L18): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- morpholine benzene Methylene) piperidin-4-one:
Yellow power.Yield:28%.m.p:196.5-198.7 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 10.00 (1H, s, Ar-OH), 7.51 (1H, s, H- β '), 7.48 (1H, s, H- β), 7.39 (2H, d, J=9.0Hz, H- 6', H-2'), 7.22 (1H, d, J=7.8Hz, H-6), 7.19 (1H, s, H-2), 7.03 (2H, d, J=9.0Hz, H-5', H- 3'), 6.91 (1H, d, J=7.8Hz, H-5), 6.01-5.95 (1H, m, A-ArCH2 CH=CH2),5.08-5.03(2H,m,A- ArCH2CH=CH2 ),3.92(2H,s,piperidone-CH2 -N-CH2),3.89(2H,s,piperidone-CH2-N-CH2 ), 3.74 (4H, t, J=4.8Hz ,-N- (CH2 CH2 )2- O), 3.27 (2H, d, J=6.6Hz, A-ArCH2 CH=CH2),3.24(4H, T, J=4.8Hz ,-N- (CH2 CH2)2-O),2.00-1.96(1H,m,-N-CH-(CH2)2),0.47-0.46(2H,m,-N-CH- (CH2 )2),0.27-0.26(2H,m,-N-CH-(CH2 )2).13C NMR(150MHz,DMSO-d6)δ(ppm):185.9,156.4, 151.2,136.7,134.8,134.7,132.8,132.1×2,130.8,130.4,130.0,126.5,125.8,124.9, 115.6,115.3,114.1×2,65.9×2,54.7,54.5,47.1×2,37.6,33.4,6.4×2.ESI-MS,m/z: 457.3[M+H]+.
Compound (L19): (3E, 5E) -3- (3- allyl -4- phenol methylene) -1- cyclopropyl -5- (4- (pyrroles Alkane -1- base) benzylidene) piperidin-4-one:
Yellow power.Yield:25%.m.p:186.8-188.5 DEG C1H NMR(600MHz,DMSO-d6)δ (ppm): 7.50 (1H, s, H- β '), 7.46 (1H, s, H- β), 7.34 (2H, d, J=9.0Hz, H-6', H-2'), 7.17 (1H, d, J=5.4Hz, H-6), 7.17 (1H, s, H-2), 6.85 (1H, d, J=8.4Hz, H-5), 6.62 (2H, d, J=8.4Hz, H-5', H-3'),6.02-5.95(1H,m,A-ArCH2 CH=CH2),5.08-5.04(2H,m,A-ArCH2CH=CH2 ),3.90(2H,s, piperidone-CH2 -N-CH2),3.87(2H,s,piperidone-CH2-N-CH2 ), 3.30 (2H, d, J=6.6Hz, A- ArCH2 CH=CH2),3.30(4H,s,-N-(CH2 -CH2)2),1.99-1.95(5H,m,-N-CH-(CH2)2,-N-(CH2-CH2 )2),0.47-0.45(2H,m,-N-CH-(CH2 )2),0.27-0.25(2H,m,-N-CH-(CH2 )2).13C NMR(150MHz, DMSO-d6)δ(ppm):185.5,148.0,137.0×2,135.5,134.7,132.7×2,132.5,130.5,130.1, 130.0,128.5,126.7,121.7,115.4×2,111.7×2,54.9,54.7,47.1×2,37.7,33.6,24.9× 2,6.3×2.ESI-MS,m/z:441.4[M+H]+.
The stability test of 2 compound L 9 of embodiment, L10, L11 and curcumin
Stability test condition: under the conditions of 25 DEG C, each compound is dissolved separately in the phosphate buffer of PH=7.4 In, form the solution of 20uMol/mL.With the OD value of microplate reader measurement 250-600 nanometers, time point is set as 0-25 minutes, It is primary every acquisition in 5 minutes, degradation curve is eventually formed, the stability of compound is assessed, obtained the result is shown in Figure 1.
The anti tumor activity in vitro of 3 compound L 1-L19 of embodiment detects
Cell line and reagent: Human normal hepatocyte, including HL-7702, HIBEC and NRK-602E cell are purchased from American Type Culture Collection,Manassas,VA,USA.Fetal calf serum is purchased from HyClone, Logan, UT, USA, and Heat inactivation 30 minutes at 65 DEG C.Lipopolysaccharides (LPS) and reagent are purchased from Sigma-Aldrich, St Louis, MO, USA.Primary antibody, packet Anti-Bcl-2, anti-Bax, anti-Cdc2 are included, anti-Cyclin B1, anti-GAPDH and secondary antibody are purchased from Santa Cruz Biotechnology,Santa Cruz,CA,USA。
Cell culture and administration: containing 5%CO237 DEG C of environment under, cell culture in contain 10% fetal calf serum RPMI In 1640 culture mediums.Compound is dissolved in DMSO, is configured to the stock solution of 50 μ g/ml and is stored in -20 DEG C of refrigerators.Dosage Control is in 0,5,7.5,10 μM of 4 concentration.Each working solution concentration makes DMSO concentration with basal medium and is less than 0.1% whole solution.The cell group of compound is not added as negative control group, gives the group of 20 μM of curcumins as positive Control group.
The anti-human cholangiocarcinoma cell proliferation assay of 4 compound of embodiment
Cell culture is in 96 orifice plates (5000 cells/wells) of 1640 culture medium of RPMI comprising 10%FBS, thin Intracellular growth gives the compound of various concentration after 24 hours.Fresh MTT (5mg/ml) solution that PBS is prepared is added to each hole It is interior.First a ceremonial jade-ladle, used in libation crystal is formed in living cells, and after the DMSO solution dissolution of 150 μ L, the absorbance of compound uses enzyme at 490nm Mark instrument measurement.The IC of compound50Value can be calculated with 5.0 software of Graphpad Prism.It is examined using different compounds It surveys, shown in obtained result such as Fig. 2 (A), Fig. 2 (B), Fig. 2 (C) and Fig. 2 (D).
5 cell cycle determination of embodiment
Cell cycle status and core DNA content are determined using propidium iodide (PI) dyeing and flow cytometry.People's bile duct Cancerous cell line includes that QBC-939, RBE and HUCCA cell with two milliliters of culture mediums are laid on six orifice plates (3 × 105Cells/well) in. After incubated overnight, the cells in compound L 11 (5,7.5,10 μM) and (20 μM) of curcumin processing serum free mediums are used respectively, Effect 24 hours.Cell is collected later and 70% ice ethyl alcohol is added.After PBS cleaning, cell is dyed at 4 DEG C with PI.Cell Cell-Quest software (Becton-Dickinson, USA) can be passed through in the percentage in different G1, S and G2/M periods The FACSort flow-cytometer of offer is measured.
6 flow cytometry of embodiment (Annexin V-FITC dyeing) measures human bile duct carcinoma apoptosis rate
Measurement apoptosis situation is dyed using Annexin V-FITC/PI.Human bile duct carcinoma system, including QBC-939, RBE, HUCCA is laid in 60-mm plate, is hatched 24 hours, compound L 11 (5,7.5,10 μM) and curcumin (20 μM) are handled respectively later 24 hours.After administration, cell is collected, is cleaned twice with ice-cold PBS.FITC conjugated Annexin V and iodate third Pyridine (PI) double dyes after acting on 30 points in combination buffer, utilize FACSCalibur flow cytometer (BDBiosciences, CA) measures Apoptosis situation.It is detected using different compounds, obtained result such as Fig. 3 (A), Fig. 3 (B), Fig. 4 (A) and Fig. 4 (B) are shown.
7 Western blotting of embodiment (Western Blotting) measurement
After processing, cell is collected, with protein lysis buffer lytic cell, 12000rpm revolving speed is centrifuged at 4 DEG C later 10 minutes removing impurity.Bradford protein assay kit (Bio-Rad, Hercules, CA) method measures all samples The protein concentration of product.After sample sample-loading buffer is added, protein sample is transferred to poly vinylidene difluoride after electrophoresis Transfer membrane.After 2 hours, trace is terminated with 5% skim milk of TBST Fresh at room temperature, later in 4 DEG C in TBST With the primary antibody incubated overnight of specificity.Next it is cleaned 3 times with TBST, the secondary antibody hatching 1 combined with horseradish peroxidase is small When, band-like object is immunoreacted by ECL kit (Bio-Rad, Hercules, CA) visualization.It is immunoreacted the density of band-like object It is analyzed and is obtained with Image J computer software (National Institute of Health, MD).Using difference Compound detected, shown in obtained result such as Fig. 3 (C) and Fig. 4 (C).
Statistical analysis
All experiments are independent in triplicate, as a result presented with mean+/-standard error (SD).The statistics of experimental result Meaning is learned to be evaluated with Student's T-test.Think statistically significant in P < 0.05.
Although having been presented for some embodiments of the present invention herein, it will be appreciated by those of skill in the art that Without departing from the spirit of the invention, the embodiments herein can be changed.Above-described embodiment is only exemplary, no It should be using the embodiments herein as the restriction of interest field of the present invention.

Claims (3)

1. a kind of single carbonyl curcumin class compound application in preparation of anti-tumor drugs replaced containing allyl, feature exist In single carbonyl curcumin class compound is one of following compound or pharmaceutically acceptable salt thereof or several:
Bis- (3- allyl -4- phenol methylene) cyclopentanone (L9) of (2E, 5E) -2,5;
Bis- (3- allyl -4- phenol methylene) cyclohexanone (L10) of (2E, 6E) -2,6;
Bis- (3- allyl -4- hydroxyl benzyloxy) dihydro -2H- thiapyran -4 (3H) -one (L11) of (3Z, 5Z) -3,5-;
The anti-tumor drug is for treating human bile duct cancer.
2. the single carbonyl curcumin class compound according to claim 1 replaced containing allyl is in the preparation of antitumor drugs Application, which is characterized in that the anti-tumor drug includes the active constituent and pharmaceutic adjuvant of therapeutically effective amount, wherein living Property ingredient be single carbonyl curcumin class compound.
3. the single carbonyl curcumin class compound according to claim 1 replaced containing allyl is in the preparation of antitumor drugs Application, which is characterized in that the active constituent of the anti-tumor drug is by single carbonyl curcumin class compound and its He forms anti-tumor drug.
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