CN102285993B - Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof - Google Patents
Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN102285993B CN102285993B CN 201110261509 CN201110261509A CN102285993B CN 102285993 B CN102285993 B CN 102285993B CN 201110261509 CN201110261509 CN 201110261509 CN 201110261509 A CN201110261509 A CN 201110261509A CN 102285993 B CN102285993 B CN 102285993B
- Authority
- CN
- China
- Prior art keywords
- tetrahydropyridine
- preparation
- ketone
- benzopyran derivatives
- methyl
- 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.)
- Expired - Fee Related
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a tetrahydropyridine oxapicene derivative and a preparation method thereof. The method comprises the following steps: subjecting substituted amine (a) and methyl acrylate to Michael additive reaction to prepare N,N-bis(beta-methyl propionate) substituted amine (b), subjecting the N,N-bis(beta-methyl propionate) substituted amine (b) to Dieckmann condensation under the action of sodium alkoxide and hydrolysis and decarboxylation under the action of acid to obtain N-substituted piperidine-4-ketone (d), and subjecting two active methylenesand and bimolecular aromatic aldehydes of the N-substituted piperidine-4-ketone (d) to reaction to remove bimolecular water to obtain N-substituted-3,5-2-benzylpiperidine-4-ketone (e); and carrying out reflowing and heating on the N-substituted-3,5-2-benzylpiperidine-4-ketone (e) and malononitrile in normal butanol to obtain a final product shown as a general formula (I). The preparation method is simple in process and convenient for mass production; and the obtained product has a favorable inhibiting effect for the cell proliferation of leukemia K562, oophoroma HO-8910 and liver cancer SMMC-7721.
Description
Technical field
The present invention relates to a kind of pyrido pyran derivate, be specifically related to a class and can effectively suppress tetrahydropyridine benzopyran derivatives of leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and hepatocellular carcinoma cell line SMMC-7721 proliferation and preparation method thereof.
Background technology
Leukemia, ovarian cancer and liver cancer are the three large common cancers that sickness rate is very high, and therefore, the design research and development can suppress leukemia, ovarian cancer and hepatoma cell proliferation effectively, and the medicine of its rapid apoptosis is significant.
Leukemia is a class hemopoietic stem cell clone property disease.Be apt to occur in the teenager, its sickness rate comes first of teenager's tumour, so more obvious and outstanding to the mankind's harm.Chronic leukemia, be onset and development leukemia relatively slowly clinically, is divided into chronic granulocytic leukemia and chronic lymphocytic leukemia.Cell line k562 in chronic granulocytic leukemia, because the resistibility of himself apoptosis is stronger than other clones, therefore, in leukemic therapeutic process, the propagation that suppresses the K562 cell is very important means.Because prior art does not have the medicine of desirable efficient inhibition K562 cell proliferation, chronic granulocytic leukemia is difficult to cure.Therefore it is very necessary inventing a kind of new drug lead compound with efficient inhibition leukemia K 562 cell proliferation activity.
Ovarian cancer is one of modal tumour of women, and the ovarian tumors rate is only second to cervical cancer and carcinoma of uterine body and is listed as and occupies the 3rd.But because ovarian cancer causes the dead, but account for the first place of all kinds of gynecological tumors, women's life is caused to serious threat.Therefore the medicine of the effective treatment of research and development human epithelial ovarian carcinoma cells proliferation has become one of focus of studying in medicine initiative and research and development field.
Liver cancer is the third-largest common cancer that mortality ratio is only second to cancer of the stomach, esophagus cancer.Clone SMMC-7721 in liver cancer, other hepatoma cell line of energy force rate of its opposing apoptosis are strong, and therefore inventing a kind of new drug lead compound with efficient inhibition hepatocellular carcinoma cell line SMMC-7721 proliferation activity is the key point of curing liver cancer.
Summary of the invention
Therefore, the technical problem to be solved in the present invention is to provide a kind of tetrahydropyridine benzopyran derivatives that can simultaneously suppress the propagation of leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells.Preparation method and the application of this derivative are provided simultaneously.
Technical scheme of the present invention is: tetrahydropyridine benzopyran derivatives shown in formula (I):
Wherein, R
1for methyl, methoxyl group, ethyl, oxyethyl group, etc. a kind of in alkyl or-oxyl, fluorine chlorine, bromine;
R
2be 2,3,4 monosubstituted or dibasic phenyl, described substituting group is a kind of in methyl, ethyl, methoxyl group, oxyethyl group, fluorine, bromine, chlorine, nitro, carboxyl, cyano group, ester group.
The present invention also provides the preparation method of above-mentioned tetrahydropyridine benzopyran derivatives, and basic step is as follows:
(1) will replace amine (a) and make N with methyl acrylate process Michael addition reaction, N-two (β-methyl propionate) replaces amine (b);
(2) by step (1) product N, N-two (β-methyl propionate) replaces amine (b), and the Dieckmann condensation occurs under the sodium alkoxide effect, and the lower hydrolysis decarboxylation of acid effect obtains N-substituted piperidine-4-ketone (d);
(3) two active methylene groups of N-substituted piperidine-4-ketone (d) are reacted with two molecule aromatic aldehydes and slough two molecular waters and obtain N-and replace the two benzal phenylpiperidines of-3,5--4-ketone (e);
(4) N-is replaced to the two benzal phenylpiperidines of-3,5--4-ketone (e) and the third dicyan reflux in propyl carbinol and obtain the final product of general formula for (I).
Above-mentioned N, N-two (β-methyl propionate) replaces amine (b) and N-substituted piperidine-4-ketone (d) is all yellow oil.
Preparation method according to tetrahydropyridine benzopyran derivatives of the present invention, be preferably, the alcohol that the solvent in the described reaction of step (1) is C1-C4.
Further, the described solvent of step (1) is more preferably methyl alcohol.
Preferably, the described sodium alkoxide of step (2) is selected from a kind of in sodium methylate or sodium ethylate.In the hydrolysis decarboxylation reaction, can preferably adopt the hydrochloric acid soln hydrolysis decarboxylation of massfraction 25%.
More preferably, the described sodium alkoxide of step (2) is sodium methylate.
Preparation method according to tetrahydropyridine benzopyran derivatives of the present invention, be preferably, and the described alkali of step (3) is sodium hydroxide or potassium hydroxide.It is solvent that step (3) can adopt methyl alcohol or dehydrated alcohol.
Further, described sodium hydroxide mass concentration is 8-15%.More preferably, mass concentration is 10%.
The reaction conditions that preferred NaOH strength of solution can make synthetic N-replace the two benzal phenylpiperidines of-3,5--4-ketone (e) is optimized, and has not only reduced cost, makes convenient post-treatment, and has played the effect of Reaction time shorten.The employing dehydrated alcohol is solvent, 0.5h～2h and get final product under stirring at normal temperature.
Preferably, in step (4), return time is 5h-6h.Adopting propyl carbinol in step (4) is solvent, reflux in propyl carbinol, and temperature of reaction is general 120 ℃.This temperature of reaction is relevant with the boiling point of propyl carbinol, and temperature is slightly unsteady.
The reaction formula of above-mentioned preparation process is:
The present invention also provides the application of above-claimed cpd in the proliferation activity that suppresses leukemia K 562, ovarian cancer HO-8910 and SMMC-7721 liver cancer cells.
Tetrahydropyridine benzopyran derivatives prepared by the present invention, can effectively suppress the propagation of leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells after measured.The IC50 average, lower than the anticarcinogen 5 FU 5 fluorouracil, has potential practicality.
Technical essential of the present invention is:
Synthetic N in preparation method's step of the present invention (1), N-two (β-methyl propionate) replaces amine (b) and adopts methyl alcohol as solvent, by stirring, reaction is carried out in homogeneous system, because reflux temperature is low, reduce the generation of high temperature secondary reaction, greatly accelerated reaction process.
In preparation method's step of the present invention (2), synthetic N-replacements-4-piperidone (d) adopts sodium methylate as condensing agent, and the hydrochloric acid soln that is 25% with massfraction is the extraction of cyclization product, makes it enter hydrolysis decarboxylation after water.
The synthetic N-of preparation method's step of the present invention (3) replaces the two benzal phenylpiperidines of-3,5--4-ketone (e) and makes catalyzer with NaOH solution, and the employing dehydrated alcohol is solvent, and under stirring at normal temperature, 0.5h～2h obtains.
Adopting propyl carbinol in step of the present invention (4) is solvent, and under 120 ℃ of conditions, backflow 5h-6h makes product (I).
The present invention be take and replaced amine and methyl acrylate is raw material, through the Michael addition, the Dieckmann condensation, the reaction such as hydrolysis decarboxylation synthetic intermediate N-substituted piperidine-4-ketone (d), again N-substituted piperidine-4-ketone (d) and two molecule aromatic aldehydes are reacted and slough two molecular waters and obtain corresponding N-and replace-3, the two benzal phenylpiperidines of 5--4-ketone compounds (e), then react with the third dicyan and obtain final product tetrahydropyridine benzopyran derivatives (I).The present invention has measured the inhibition activity of this new drug lead compound to leukemia K 562 cancerous cell line, ovarian cancer MDR-MB-231 clone and SMMC-7721 liver cancer cells system propagation, has significant practicality in modern medicine production.
The invention has the beneficial effects as follows:
1, tetrahydropyridine benzopyran derivatives of the present invention (I) has higher inhibition activity to the propagation of leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells.
2, the inventive method technique is simple, produces easily.
Embodiment
Further set forth technical characterstic of the present invention below in conjunction with specific embodiment.
Tetrahydropyridine benzopyran derivatives (I), can effectively suppress the propagation of leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells, and general formula is:
Wherein: R
1for methyl, methoxyl group, ethyl, oxyethyl group, etc. a kind of in alkyl or-oxyl, fluorine chlorine, bromine;
R
2be 2,3,4 monosubstituted or dibasic phenyl, substituting group is the alkyl such as methyl, ethyl, the alkoxyl groups such as methoxyl group, oxyethyl group, a kind of in fluorine, bromine, chlorine, nitro, carboxyl, cyano group, ester group etc.
Tetrahydropyridine benzopyran derivatives (I) prepared by the embodiment of the present invention, the medical lead compound with efficient inhibition leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and hepatocellular carcinoma cell line SMMC-7721 proliferation is:
(Ia) 6-(4-xylyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Ib) 6-(4-xylyl)-4-(2-chloro-phenyl-)-8-(2-benzyl chloride fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Ic) 6-(4-luorobenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Id) 6-(4-luorobenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Ie) 6-(4-methoxybenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(If) 6-(4-methoxybenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Ig) 6-(4-bromobenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
(Ih) 6-(4-bromobenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans also
Embodiment 1: preparation 6-(4-xylyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ia) also
Under room temperature, add 0.16mol methyl acrylate and 7mL methyl alcohol in the 100mL three-necked bottle, under stirring, by 0.04mol, to the mixed solution of methylbenzylamine (1a) and 4mL methyl alcohol, slowly add in three-necked bottle, temperature rises naturally, the rate of addition of mixed solution is controlled in 4mL/min, makes temperature of reaction system be no more than 50 ℃.After dropwising, under room temperature, stir 20min, reheat backflow 8h, reflux temperature is 63 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, reclaim methyl alcohol and unreacted methyl acrylate, underpressure distillation, obtain light yellow oily liquid N, and N-two (β-methyl propionate) is to xylylamine (2a).
In the three-necked bottle of 250mL drying, add 15mL dry toluene, 0.122mol sodium Metal 99.5 stirring heating to reflux.Add the 0.2mL anhydrous methanol after sodium fusion melts, then slowly drip 0.04mol N, N-two (β-methyl propionate)) to xylylamine (2a) and 20mL dry toluene mixed solution.After dropwising, backflow 6h.In reflux course, the reaction system thickness that becomes gradually, need to strengthen stirring velocity, and the 20mL dry toluene joined in reaction vessel in batches.Reaction is cooled to room temperature after finishing, and adds 10ml methyl alcohol to remove the complete Na of unreacted, the hydrochloric acid soln of 120mL 25% (massfraction) for mixture is extracted to oil bath backflow 6h.Reaction mixture, under stirring, add concentrated NaOH solution to be neutralized to pH=8.5, by ethyl acetate (30mL * 3), extract, the combined ethyl acetate layer, use anhydrous sodium sulfate drying, the Distillation recovery ethyl acetate, the underpressure distillation surplus materials, obtain pale yellow oily liquid body N-to methyl-benzyl piperidin-4-one-(4a).
In the round-bottomed flask of 50ml, add N-to methyl-benzyl piperidin-4-one-(4a) (0.005mol) and p-Fluorobenzenecarboxaldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to methyl-benzyl-3,5-biconjugate fluorine benzal base-4-piperidone (5a).To the 25ml round-bottomed bottle, add N-to methyl-benzyl-bis-benzal bases-4-piperidone (5a) (1mmol), the third dicyan (1.5mmol, 99mg), propyl carbinol (4ml) reflux 5 hours, reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ia).
Yield：82％；white solid，mp 85-87℃；1H NMR (400 MHz，CDCl
3)δ7.122-7.226(m，J，4H)，7.001-7.061(m，8H)，6.870(s，1H)，4.571(s，2H)，3.97(s，1H)，3.46-3.52(m，4H)，2.32(s，3H)，1.58(s，2H)；IR(KBr)：3500，3400，3085，3030，3020，2970，2865，2245，1670，1450，960，985，1050，850，630cm-1；Anal.calcd.for C30H25F2N3O C％74.83，H％5.32，N％8.73；Found：C％74.65，H％5.43，N％8.67。
Embodiment 2: preparation 6-(4-xylyl)-4-(2-chloro-phenyl-)-8-(2-benzyl chloride fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ib) also
With the preparation method of embodiment 1, obtain under the same conditions N-to xylyl piperidin-4-one-(4a).
In the round-bottomed flask of 50ml, add N-to xylyl piperidin-4-one-(4a) (0.005mol) and o-chlorobenzaldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to xylyl-3, the two adjacent benzyl chloride fork base-4-piperidone (5b) of 5-.To the 25ml round-bottomed bottle, add N-to methyl-benzyl-base-4-piperidone (5b) (1mmol) for bis-adjacent benzyl chloride forks, the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ib).
Yield：80％；light yellow solid，mp 96-98℃；1H NMR(400 MHz，CDCl
3)δ7.30-7.45(m，4H)，7.19-7.25(m，2H)，7.13(s，2H)，6.94(s，2H)，4.64(s，2H)3.55-3.59(m，1H)3.18-3.44(m，4H)2.30(s，3H)，1.51(dJ＝1.60HZ，2H)；IR(KBr)：3510，3420，3085，3015，2960，2850，2250，1685，1450，960，990，840，650cm-1；Anal.calcd.ForC30H25Cl2N3O C％ 70.04，H％ 4.90，N％ 8.17；Found：C％69.98，H％4.79，N％8.23。
Embodiment 3: preparation 6-(4-luorobenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ic) also
With the preparation method of embodiment 1, methylbenzylamine being changed into to NSC 158269 (1c), obtain under the same conditions N-to luorobenzyl piperidin-4-one-(4c).
In the round-bottomed flask of 50ml, add N-to luorobenzyl piperidin-4-one-(4c) (0.005mol) and p-Fluorobenzenecarboxaldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to luorobenzyl-3,5-biconjugate fluorine benzal base-4-piperidone (5c).To the 25ml round-bottomed bottle, add N-to luorobenzyl-biconjugate fluorine benzal base-4-piperidone (5c) (1mmol), the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ic).
Yield：85％；white solid，mp 89-91℃；1H NMR (400 MHz，CDCl
3)δ7.30-7.32(d，J＝8.34Hz，2H)，7.14-7.18(m，2H)，7.06-7.10(m，2H)，6.92-6.98(m，6H)，6.85(s，1H)4.57(s，2H)，3.93(s，1H)，3.35-3.43(m，4H)，1.20-1.23(t，J＝7.30Hz2H)；IR(KBr)：3520，3465，3080，3030，3015，2950，2850，2245，1675，1400，1050，950，925，630cm-1；Anal.calcd.for C29H22F3N3OC％71.74，H％4.57，N％8.66；Found：C％71.67，H％4.43，N％8.77。
Embodiment 4: preparation 6-(4-luorobenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Id) also
With the preparation method of embodiment 1, methylbenzylamine being changed into to NSC 158269 (1c), obtain under the same conditions N-to luorobenzyl piperidin-4-one-(4c).
In the round-bottomed flask of 50ml, add N-to luorobenzyl piperidin-4-one-(4c) (0.005mol) and p-tolyl aldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to luorobenzyl-3,5-biconjugate methylbenzyl fork base-4-piperidone (5d).To the 25ml round-bottomed bottle, add N-to luorobenzyl-base-4-piperidone (5d) (1mmol) for biconjugate methylbenzyl fork, the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Id)
Yield：78％；white solid，mp 110-112℃；1H NMR(400 MHz，CDCl3)δ7.29-7.31(m，2H)7.03-7.12(m，8H)，6.93-6.95(m，2H)6.84(s，1H)，4.52(s，2H)，3.87(s，1H)，3.13-3.32(m，4H)，2.34(s，6H)，1.22(d，J＝9.20Hz，2H)；IR(KBr)：3450，3300，3085，3020，2960，2870，2245，1650，1450，1050，970，950，640cm-1；Anal.calcd.for C31H29FN3O C％77.96，H％5.91，N％8.80；Found：C％77.81，H％5.84，N％8.99。
Embodiment 5: preparation 6-(4-methoxybenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ie) also
With the preparation method of embodiment 1, xylylamine being changed into to emilium tosylate (1e), obtain under the same conditions N-to methoxy-benzyl piperidin-4-one-(4e).
In the round-bottomed flask of 50ml, add N-to methoxybenzyl piperidin-4-one-(4e) (0.005mol) and p-Fluorobenzenecarboxaldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to methoxy-benzyl-3,5-biconjugate fluorine benzal base-4-piperidone (5e).To the 25ml round-bottomed bottle, add N-to methoxy-benzyl-biconjugate fluorine benzal base-4-piperidone (5e) (1mmol), the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ie).
Yield：72％；white solid，mp 97-99℃；1H NMR (400 MHz，CDCl
3)δ7.19-7.22(m，2H)7.13-7.16(m，2H)7.01-7.06(m，6H)6.87(s，1H)6.75-6.77(d，J＝8.60Hz，2H)4.58(s，2H)3.97(s，1H)3.79(s，3H)3.40-3.49(m，4H)，1.25-1.28(m，2H)；IR(KBr)：3650，3450，3020，3015，2975，2875，2230，1650，1450，1070，960，920，650cm-1；Anal.calcd.for C30H25F2N3O2C％ 72.42，H％5.06，N％8.45；Found：C％72.24，H％5.14，N％8.40。
Embodiment 6: preparation 6-(4-methoxybenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (If) also
The N-obtained by the preparation method of embodiment 5 is to methoxybenzyl piperidin-4-one-(4e).
In the round-bottomed flask of 50ml, add N-to methoxybenzyl piperidin-4-one-(4e) (0.005mol) and p-tolyl aldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to methoxy-benzyl-3,5-biconjugate methylbenzyl fork base-4-piperidone (5f).To the 25ml round-bottomed bottle, add N-to methoxy-benzyl-base-4-piperidone (5f) (1mmol) for biconjugate methylbenzyl fork, the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (If).
Yield：84％；white solid，mp 83-85℃；1H NMR (400MHz，CDCl
3)δ7.02-7.14(m，10H)，6.88(s，1H)6.74-6.76(d，J＝6.90Hz，2H)4.54(s，2H)3.92(s，1H)，3.78(s，3H)3.37-3.51(m，4H)2.37(s，6H)1.50(d，J＝78.0Hz2H)；IR(KBr)：3600，3450，3080，3045，3020，2975，2865，2245，1670，1420，1050，950，920，640cm-1；Anal.calcd.for C32H31N3O2C％78.50，H％6.38，N％8.58；Found：C％78.23，H％6.21，N％8.49。
Embodiment 7: preparation 6-(4-bromobenzyl)-4-(4-fluorophenyl)-8-(4-fluorine benzal base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ig) also
With the preparation method of embodiment 1, methylbenzylamine being changed into to bretylium (1g), obtain under the same conditions N-to bromobenzyl piperidin-4-one-(4g).
In the round-bottomed flask of 50ml, add N-to bromobenzyl piperidin-4-one-(4g) (0.005mol) and p-Fluorobenzenecarboxaldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to bromo benzyl-3,5-biconjugate fluorine benzal base-4-piperidone (5g).To the 25ml round-bottomed bottle, add N-to the bromo benzyl-biconjugate fluorine benzal base-4-piperidone (5g) (1mmol), the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ig).
Yield：78％；white solid，mp 103-105℃；1H NMR (400 MHz，CDCl
3)δ7.34-7.36(d，J＝8.30Hz，2H)7.18-7.22(m，2H)7.11-7.15(m，2H)6.70-7.06(m，6H)6.88(s，1H)4.61(s，2H)3.96(s，1H)3.39-3.49(m，4H)1.24-1.28(t，J＝7.0Hz，2H)；IR(KBr)：3500，3450，3070，3040，3025，2950，2870，2245，1620，1430，1050，960，920，640cm-1；Anal.calcd.for C29H22BrF2N3O C％63.75，H％4.06，N％7.69；Found：C％63.50，H％4.15，N％7.56。
Embodiment 8: preparation 6-(4-bromobenzyl)-4-(4-tolyl)-8-(4-methylbenzyl fork base)-3-cyano group-2-amino-1,2,5, the 6-tetrahydropyridine is [4,3-b] pyrans (Ih) also
The N-obtained by the preparation method of embodiment 7 is to bromobenzyl piperidin-4-one-(4g).
In the round-bottomed flask of 50ml, add N-to bromobenzyl piperidin-4-one-(4g) (0.005mol) and p-tolyl aldehyde (0.01mol), 15ml dehydrated alcohol and 10% (massfraction) sodium hydroxide 1ml.Stirring at room 0.5-2h, have solid to separate out, suction filtration, then use the absolute ethanol washing product, both obtained N-to bromo benzyl-3,5-biconjugate methylbenzyl fork base-4-piperidone (5h).To the 25ml round-bottomed bottle, add N-to the bromo benzyl-base-4-piperidone (5h) (1mmol) for biconjugate methylbenzyl fork, the third dicyan (1.5mmol, 99mg) propyl carbinol (4ml) reflux is 5 hours, and reflux temperature is 120 ℃, and thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finishes, cooling, there is solid to separate out.Suction filtration, the solid ethyl alcohol recrystallization, both obtained final product (Ih).
Yield：75％；light green solid，mp 92-94℃；1H NMR (400 MHz，CDCl
3)δ7.31-7.32(m，2H)7.06-7.16(m，8H)6.96-6.99(m，2H)6.89(s，1H)4.56(s，2H)3.92(s，1H)3.37-3.51(m，4H)2.37(s，6H)1.27(d，J＝9.50Hz2H)；IR(KBr)：3500，3300，3065，3040，3020，2950，2850，2245，1650，1450，1045，960，920，650cm-1；Anal.calcd.for C31H29BrN3O C％69.15，H％5.24，N％7.80；Found：C％69.35，H％5.32，N％7.66。
Target compound suppresses the active test of rising in value of leukemia K 562, ovarian cancer HO-8910 and SMMC-7721 liver cancer cells:
1, test medicament and equipment:
Experimental drug and reagent: self-control compound (I) is assigned to desired concn (DMSO concentration≤1 ‰) with DMSO, 4 ℃ of preservations of sterilizing.MTT (tetramethyl-azo azoles indigo plant) reagent is purchased from Sigma company.Human leukaemia K562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells all are purchased from Shanghai Chinese Academy of Sciences cell bank.10%SDS reagent (Sino-American Biotechnology product), with RPMI-1640 (the U.S. GiBCo company) nutrient solution containing 20% calf serum (FBS), other reagent is all commercially available analytical pure.The cultivation of being gone down to posterity in 37 ℃, the incubator of 5% CO2, saturated humidity, until cell during in logarithmic phase for experiment.
Plant and instrument: Bechtop, cleaning<3.5/L (>0.5 μ m grit), safe and sound technology company limited; The CO2 cell culture incubator, the Forma Scientific of Thermo company, Inc; Inverted microscope, Japanese Nikon (Nikon) company, model 810818; Enzyme-linked immunosorbent assay instrument, Bio-RAD Model 680; 96 hole flat boards, U.S. Costar company; SK2200H type ultrasonic cleaner, Shanghai High Kudos Science Instrument Co., Ltd..
2, test method:
Experiment is carried out in 96 orifice plates, and system is containing the full nutrient solution of target compound of 1 * 105 cell and different concns.Every hole cumulative volume 100 μ L, every group 8 multiple holes, medicine color control wells (containing cell) is set and containing the culture hole of cell and medicine, after cultivating 44h respectively, add MTT (5mg/mL, 10 μ L) in each hole, continue to cultivate 4h, add 10%SDS 100 μ L termination reactions, 37 ℃ are spent the night, the absorbance A value with each hole of enzyme linked immunosorbent detection at 570nm again.And calculate inhibition rate of tumor growth according to following formula:
3. result investigation
Survey the impact of tetrahydropyridine benzopyran derivatives (I) on leukemia K 562 clone, ovarian cancer MDR-MB-231 clone and SMMC-7721 liver cancer cells system propagation with mtt assay, inhibiting rate is in Table 1.
Table 1: title compound (I) under the concentration of 10ug/ml to leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and the value-added inhibiting rate of SMMC-7721 liver cancer cells (%)
From the preliminary resisting leukemia K 562 of table 1, ovarian cancer MDR-MB-231 and liver cancer SMMC-7721 determination of activity, show: most of title compound has restraining effect preferably to leukemia K 562, ovarian cancer MDR-MB-231 and liver cancer SMMC-7721 cancer cell multiplication.As shown in table 1, some target compound reaches more than 70% the value-added inhibiting rate of leukemia K 562 cancer cells when 10 μ g/mL, Ic has the compound of resisting leukemia K 562 lateral reactivity most in series compound, it reaches 74.0% to the value-added inhibiting rate of leukemia K 562 cancer cells; Ia has the compound of ovarian cancer resistance MDR-MB-231 lateral reactivity most in series compound, it reaches 66% to the value-added inhibiting rate of ovarian cancer MDR-MB-231 cancer cells; Ia has the compound of anti-liver cancer SMMC-7721 lateral reactivity most in series compound, it reaches 75.2% to the value-added inhibiting rate of liver cancer SMMC-7721 cancer cells.Ia and Ie have the compound of anticancer lateral reactivity most in series compound, its increment to leukemia K 562 cell, ovarian cancer MDR-MB-231 cell and SMMC-7721 liver cancer cells has the highest inhibiting rate, is the following PTS lead compound that has DEVELOPMENT PROSPECT most.
The embodiment of the invention described above, be not limited to the present invention.For a person skilled in the art, the preparation method of product of the present invention can change.Within the spirit and principles in the present invention all, that does is equal to replacement, improves etc., within all should being included in protection scope of the present invention.
Claims (10)
1. the benzopyran derivatives of tetrahydropyridine shown in formula I:
Wherein, R
1a kind of in methyl, methoxyl group, fluorine, bromine;
R
2be 4 mono-substituted phenyl, described substituting group is a kind of in methyl, fluorine.
2. the preparation method of the described tetrahydropyridine benzopyran derivatives of claim 1, it is characterized in that: basic step is as follows:
(1) will replace amine (a) and make N with methyl acrylate process Michael addition reaction, N-two (β-methyl propionate) replaces amine (b);
(2) by step (1) product N, N-two (β-methyl propionate) replaces amine (b), and the Dieckmann condensation occurs under the sodium alkoxide effect, and the lower hydrolysis decarboxylation of acid effect obtains N-substituted piperidine-4-ketone (d);
(3) two active methylene groups of N-substituted piperidine-4-ketone (d) are reacted with two molecule aromatic aldehydes and slough two molecular waters and obtain N-and replace the two benzal phenylpiperidines of-3,5--4-ketone (e);
(4) N-is replaced to the two benzal phenylpiperidines of-3,5--4-ketone (e) and the third dicyan reflux in propyl carbinol and obtain the final product of general formula for (I).
3. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 2, is characterized in that: the alcohol that the solvent in step (1) reaction is C1-C4.
4. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 3, it is characterized in that: described solvent is methyl alcohol.
5. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 2 is characterized in that: the described sodium alkoxide of step (2) is selected from a kind of in sodium methylate or sodium ethylate.
6. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 2, it is characterized in that: the described sodium alkoxide of step (2) is sodium methylate.
7. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 2, it is characterized in that: step (3) also adds sodium hydroxide or potassium hydroxide to do alkali.
8. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 7, is characterized in that: the sodium hydroxide that described sodium hydroxide is the 8-15% mass concentration.
9. the preparation method of tetrahydropyridine benzopyran derivatives according to claim 2 is characterized in that: in step (4), return time is 5h-6h.
10. the application of the described compound of claim 1 in the medicine of the proliferation activity for the preparation of suppressing leukemia K 562, ovarian cancer HO-8910 and SMMC-7721 liver cancer cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110261509 CN102285993B (en) | 2011-09-06 | 2011-09-06 | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110261509 CN102285993B (en) | 2011-09-06 | 2011-09-06 | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102285993A CN102285993A (en) | 2011-12-21 |
| CN102285993B true CN102285993B (en) | 2013-12-25 |
Family
ID=45332769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110261509 Expired - Fee Related CN102285993B (en) | 2011-09-06 | 2011-09-06 | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102285993B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898522B (en) * | 2012-10-19 | 2014-12-31 | 上海师范大学 | Tetrahydropyridinopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and preparation method and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011507910A (en) * | 2007-12-21 | 2011-03-10 | ユニバーシティー オブ ロチェスター | Methods for changing the lifetime of eukaryotes |
| CN101973935B (en) * | 2010-08-24 | 2013-04-17 | 上海师范大学 | Preparation method and application of N-substituted-3,5-dibenzal piperidine-4-one |
-
2011
- 2011-09-06 CN CN 201110261509 patent/CN102285993B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102285993A (en) | 2011-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7026196B2 (en) | RET inhibitor | |
| CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
| CN102863376B (en) | N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications | |
| CN111592533B (en) | 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof | |
| CN102276581B (en) | N-substituted tetrahydropyridine bound indole compound as well as preparation method and application thereof | |
| CN116194440A (en) | Quinazolinone HSD17B13 inhibitors and uses thereof | |
| CN104119330B (en) | The synthesis of berberinc derivate and preparing the application in antitumor drug and collaborative Zorubicin antineoplastic pharmaceutical compositions | |
| CN104557863A (en) | Novel nicotinamide ribose phosphate transferase inhibitor as well as synthetic method and application thereof | |
| CN105503730B (en) | Pyrazole derivatives and preparation method and application | |
| Wang et al. | Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo [2, 3-b] pyridin-(3Z)-ylidenemethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamides | |
| CN101973935B (en) | Preparation method and application of N-substituted-3,5-dibenzal piperidine-4-one | |
| CN116323578A (en) | Thiophene HSD17B13 inhibitor and application thereof | |
| TWI597273B (en) | Nitrogen-containing heterocyclic compound | |
| TWI817191B (en) | Novel biaryl derivatives and their use as inhibitors against diacylglycerol acyltransferase 2 | |
| CN105732619B (en) | A kind of synthetic method of 5,6,7,8 tetrahydropyridines simultaneously [2,3 d] pyrimidines | |
| CN105175360B (en) | Ether-type aryl bridged piperazine derivatives and its salt, preparation method and purposes | |
| CN107573327A (en) | Indazolecarboxamides Pyridione derivatives and its production and use | |
| CN102285993B (en) | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof | |
| CN109912571A (en) | Biologically active novel benzoquinoline substituted trinitrogen azole compound and its synthetic method and application | |
| CN107573336B (en) | Benzoheterocycle-formamide-pyridone derivative and preparation method and application thereof | |
| Huang et al. | Design, synthesis and anticancer activity of novel 6-(aminophenyl)-2, 4-bismorpholino-1, 3, 5-triazine derivatives bearing arylmethylene hydrazine moiety | |
| CN102731296B (en) | Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines | |
| CN104016898A (en) | 3,4-disubstituted pyrrole compound as well as preparation method and application thereof | |
| CN102382111B (en) | Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof | |
| CN107531598B (en) | Compositions for treating fibrosis and fibrosis-related disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131225 Termination date: 20160906 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |