CN102382111A - Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof - Google Patents
Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof Download PDFInfo
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Abstract
The invention provides a sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, a preparation method for the same and application thereof. The sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative is capable of effectively inhibiting cell proliferation of leukaemia K562, ovarian cancer HO-8910 and liver cancer SMMC-7721. The method includes the steps that firstly, substituted amine (a) and acrylic acid methyl ester are manufactured into N by means of Michael addition reaction, secondly, N-bis (beta-acrylic acid methyl ester) substituted amine (b) further gives Dieckmann condensation under the action of sodium alcoholate and hydrolysis decarboxylation reaction under the action of acid to obtain N-substituted piperidine-4-ketone(d), thirdly, the N-substituted piperidine-4-ketone(d) and aromatic aldehyde are reacted by means of bimolecular dehydration so that N-substituted benzyl-3,5-bis benzylidene-piperidine-4-ketone(e) is obtained, and finally, the N-substituted benzyl-3,5-bis benzylidene-piperidine-4-ketone(e) is further reacted so as to obtain the sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative. The method is simple and high in efficiency, and the derivative prepared by the method can have remarkable inhibitory action on above disease cells.
Description
Technical field
The present invention relates to a kind of verivate that suppresses white blood disease, ovarian cancer and liver cancer, be specifically related to a kind of sulfo-tetrahydropyridine and dihydro-pyrimidin ketone derivatives, with and preparation and use.
Background technology
In all kinds of diseases, cancer is maximum to human life's threat, is the No.1 killer who causes patient death.In all kinds of cancers, white blood disease, ovarian cancer and liver cancer are three very high big common cancers of sickness rate, and therefore, the design research and development can suppress white blood disease, ovarian cancer and hepatoma cell proliferation effectively, make the medicine of its rapid apoptosis very meaningful.
White blood disease is one of disease that mortality ratio is the highest in the world today, and human beings'health has been caused serious prestige evil, and the leukemic sickness rate of China accounts for the 6th in various tumours.Chronic leukemia is onset and development white blood disease relatively slowly clinically, is divided into chronic granulocytic leukemia and chronic lymphocytic leukemia.Chronic granulocytic leukemia; Be called for short slow grain (Chronic Myelognous Leukemia; CML), the cell line k562 in the chronic granulocytic leukemia is 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 ideal efficiently to suppress the medicine of K562 cell proliferation, chronic granulocytic leukemia is difficult to cure.Therefore invent that a kind of to have the active new drug lead compound of efficient inhibition leukemia K 562 cell proliferation be very necessary.
Ovarian cancer is one of women's most common tumor, and according to statistics, the ovarian cancer sickness rate is only second to cervical cancer and carcinoma of uterine body and is listed as and occupies the 3rd.Ovarian cancer has a strong impact on women's physical and mental health even threat to life.The ability that ovarian cancer HO-8910 clone himself is resisted apoptosis is more intense in all cells system of ovarian cancer; Can effectively suppress ovarian cancer HO-8910 cell proliferation be the important symbol that the ovarian cancer result of treatment is weighed in the modern medicine and pharmacology field, and seek out the medicine that can effectively suppress ovarian cancer HO-8910 cell-proliferation activity has become one of focus of studying in medicine initiative and the research and development field for this reason.
Primary hepatocarcinoma is one of modal malignant tumour in the world, though the onset of liver cancer rate in the whole world is ranked the 8th in various tumours, its mortality ratio comes the 4th.China is because HBV hepatitis is numerous with relevant posthepatitic cirrhosis patient, and the sickness rate that causes liver cancer and case fatality rate are apparently higher than world average level, and global liver cancer more than 50% occurs in China.Clone SMMC-7721 in the liver cancer, other SMMC-7721s of ability force rate of its opposing apoptosis are strong, and therefore inventing a kind of new compound with efficient inhibition liver cancer SMMC-7721 cell-proliferation activity is very necessary to curing liver cancer.
But, the compound of several kinds of diseases more than Shang Weiyou can effectively suppress simultaneously.
Summary of the invention
Therefore, the present invention's technical problem that will solve is to provide a kind of compound that can suppress leukemia K 562, ovarian cancer HO-8910 and liver cancer SMMC-7721 cell proliferation simultaneously.
Another technical problem that will solve of the present invention provides the preparation method of this compound.
Technical scheme of the present invention is: sulfo-tetrahydropyridine shown in the formula (I) and dihydro-pyrimidin ketone compound,
Wherein: R
1Be selected from a kind of in methyl, ethyl, methoxyl group, oxyethyl group, fluorine, bromine, the chlorine;
R
2Be 2,3,4 single replacements or dibasic phenyl, said substituting group is a kind of in methyl, ethyl, methoxyl group, oxyethyl group, fluorine, bromine, chlorine, nitro, carboxyl, cyanic acid, the ester group or two kinds.
The preparation method of above-mentioned sulfo-tetrahydropyridine and dihydro-pyrimidin ketone compound, this method may further comprise the steps:
(1) N shown in the formula (b) is processed in the process of replacement amine and methyl acrylate shown in the formula (a) Michael addition reaction, N-two (β-methyl propionate) replaces amine;
(2) with N, N-two (β-methyl propionate) replaces amine (b) hydrolysis decarboxylation under generation Dieckmann condensation under the sodium alkoxide effect and acid effect and obtains N-substituted piperidine-4-ketone (d);
(3) two active methylene radical of N-substituted piperidine-4-ketone (d) and aromatic aldehyde carry out two molecule dehydration reactions and obtain N-substituted benzyl-3, the two benzal base-piperidin-4-one-s (e) of 5-under the effect of alkali;
(4) N-substituted benzyl-3, the two benzal base-piperidin-4-one-s (e) of 5-and thiocarbamide condensation under the sodium hydroxide effect promptly obtain the target compound of general formula for (I).
N shown in the formula (b), N-two (β-methyl propionate) replace the N-substituted piperidine-4-ketone shown in amine and the formula (d) and are all yellow oil.
According to the preparation method of sulfo-tetrahydropyridine according to the invention and dihydro-pyrimidin ketone compound, preferably, the solvent in the said reaction of step (1) is a lower alcohol.The lower alcohol here is meant that carbon atom is 1-4 a alcohol.
Further, this lower alcohol is preferably methyl alcohol.
Preparing method according to sulfo-tetrahydropyridine according to the invention and dihydro-pyrimidin ketone compound is preferably, and the said sodium alkoxide of step (2) is selected from a kind of in sodium methylate or the sodium ethylate.
More preferably be that said sodium alkoxide is a sodium methylate.
Preferably, the said alkali of step (3) is sodium hydroxide or Pottasium Hydroxide.
Further, said alkali is the sodium hydroxide of 8-15% mass concentration.More preferably mass concentration is 10%.
The preparation method of sulfo-tetrahydropyridine and dihydropyrimidinonesand, step is following:
To replace amine and methyl acrylate process Michael addition reaction and process yellow oil N, N-two (β-methyl propionate) replaces amine; Hydrolysis decarboxylation obtains yellow oil N-substituted piperidine-4-ketone under Dieckmann condensation and the acid effect taking place under the sodium alkoxide effect; Products therefrom and two molecule aromatic aldehydes are reacted obtain N-substituted benzyl-3, the two benzal base-piperidin-4-one-s of 5-; Product condensation under the sodium hydroxide effect promptly obtains the new compound that can effectively suppress leukemia K 562, ovarian cancer HO-8910 and liver cancer SMMC-7721 cell proliferation with sulfo-tetrahydropyridine and dihydropyrimidinonesand class formation of general formula for (I).
The reaction formula of above-mentioned preparation process is:
Technical essential of the present invention is:
(1) synthetic N, N-two (β-methyl propionate) replace amine (b) and adopt methyl alcohol as solvent, make to be reflected in the homogeneous system through stirring and carry out, because reflux temperature is lower, can reduce the generation of high temperature secondary reaction, have accelerated reaction process greatly.
(2) synthetic N-replacement-4-piperidone (d) adopts sodium methylate as condensing agent, with 25% (massfraction) hydrochloric acid soln product is extracted, and makes it get into water posthydrolysis decarboxylation and obtains.
(3) synthetic N-replaces-3; The reaction conditions of the two benzal phenylpiperidines of 5--4-ketone (e) is optimized, and selects for use the NaOH solution of 10% massfraction to replace concentrated hydrochloric acid as reaction reagent, has not only reduced cost; Make convenient post-treatment, and played the effect of shortening the reaction times.The employing absolute ethyl alcohol is a solvent, and 0.5h～2h promptly obtains N-replacement-3 under the stirring at normal temperature, the two benzal phenylpiperidines of 5--4-ketone.
(4) condition of synthesising target compound (I) is optimized, and selects for use absolute ethyl alcohol as solvent, and sodium hydroxide is as catalyzer; Utilization microwave-assisted reaction 8-30 minute has not only reduced cost, and has shortened the reaction times greatly; Resultant impurity is few, is convenient to aftertreatment.
The present invention also provides the application of above-claimed cpd in suppressing leukemia K 562, ovarian cancer HO-8910 and liver cancer SMMC-7721 cell-proliferation activity.
The present invention is a raw material to replace amine and methyl acrylate; Through the Michael addition; The Dieckmann condensation; Reaction such as hydrolysis decarboxylation synthetic intermediate N-substituted piperidine-4-ketone reacts N-substituted piperidine-4-ketone and two molecule aromatic aldehydes to such an extent that corresponding N-replaces-3, the two benzal phenylpiperidines of 5--4-ketone compounds again; Then with N-substituted benzyl-3, the two benzal base-piperidin-4-one-s of 5-and thiocarbamide condensation under the sodium hydroxide effect promptly obtain the new compound with tetrahydropyridine and dihydro-pyrimidin thioketones structure of general formula for (I).The preliminary propagation that suppresses leukemia K 562, ovarian cancer HO-8910 and the sick K562 of this compounds dialogue blood of liver cancer SMMC-7721 determination of activity demonstration, ovarian cancer HO-8910 and liver cancer SMMC-7721 clone all has the obvious suppression effect; Ib wherein; Id; Cell proliferation has higher inhibition activity to leukemia K 562 for Ie, Ig.
Advantage of the present invention is:
1, that the propagation of leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell is all had a higher inhibition is active for the target compound of the present invention with sulfo-tetrahydropyridine and dihydropyrimidinonesand class formation.
2, the inventive method utilization microwave-assisted reaction, technology is simple, production is easy.
The present invention is a raw material to replace amine and methyl acrylate, through Michael addition, Dieckmann condensation; Reaction such as hydrolysis decarboxylation synthetic intermediate N-substituted piperidine-4-ketone; N-substituted piperidine-4-ketone and two molecule aromatic aldehydes are reacted again and slough two molecular waters and get corresponding N-and replace-3, the two benzal phenylpiperidines of 5--4-ketone compounds then replace-3 with N-; The two benzal phenylpiperidines of 5--4-ketone compounds and thiocarbamide condensation under the sodium hydroxide effect; The new compound with sulfo-tetrahydropyridine and dihydropyrimidinonesand class formation of general formula for (I) synthesized in the reaction of employing microwave-assisted, design, has tangible novelty and creativeness; The present invention has measured the inhibiting rate of such new compound to the proliferation activity of leukemia K 562, ovarian cancer HO-8910 and liver cancer SMMC-7721 cancerous cell line, and medicine has significant practicality in producing in modern times.
Embodiment
Further set forth technical characterstic of the present invention below in conjunction with specific embodiment.
Can effectively suppress the target compound with sulfo-tetrahydropyridine and dihydropyrimidinonesand class formation of leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell proliferation, general formula is (I):
Wherein: R
1Be alkoxyl groups such as alkyl such as methyl, ethyl, methoxyl group, oxyethyl group, a kind of in fluorine, bromine, the chlorine;
R
2Be 2,3,4 single replacements or dibasic phenyl, substituting group is alkyl such as methyl, ethyl, alkoxyl groups such as methoxyl group, oxyethyl group, a kind of in fluorine, bromine, chlorine, nitro, carboxyl, cyanic acid, the ester group etc.
The instance that can effectively suppress leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell proliferation new compound with tetrahydropyridine and dihydro-pyrimidin thioketones class formation of the present invention's preparation is:
(Ia) 4-phenyl-6-is to luorobenzyl-8-benzal base-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(Ib) 4-to fluorophenyl-6-to luorobenzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(Ic) to methylbenzyl fork base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones to luorobenzyl-8-for 4-p-methylphenyl-6-;
(Id) 4-p-isopropyl phenyl-6-is to methyl-benzyl-8-p-isopropyl benzal base-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(Ie) 4-(3-chloro-phenyl-)-6-is to methyl-benzyl-8-(3-benzyl chloride fork base)-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(If) 4-to fluorine benzyl-6-to methyl-benzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(Ig) 4-to methyl-benzyl-6-to bromobenzyl-8-to methyl benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
(Ih) 4-to luorobenzyl-6-to bromobenzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones;
Embodiment 1 preparation 4-phenyl-6-is to luorobenzyl-8-benzal base-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ia);
Under the room temperature, in the 100mL three-necked bottle, add 0.16mol methyl acrylate and 7mL methyl alcohol, the mixed solution with 0.04mol NSC 158269 and 4mL methyl alcohol under stirring slowly adds in the three-necked bottle, makes temperature of reaction system be no more than 50 ℃.After dropwising, reheat backflow 8h after question response finishes, reclaims methyl alcohol and unreacted methyl acrylate, and underpressure distillation obtains light yellow oily liquid N, two (β-methyl propionate) NSC 158269s (2a) of N-.
In 250mL exsiccant three-necked bottle, add 15mL dry toluene, the backflow of 0.122mol sodium Metal 99.5 stirring heating, add the 0.2mL anhydrous methanol, slowly drip 0.04mol N then, N-two (β-methyl propionate)) NSC 158269 (2a) and 20mL dry toluene mixed solution.After waiting to dropwise, backflow 6h.Reaction finishes postcooling to room temperature, adds 10mL methyl alcohol and removes the intact Na of unreacted, with the hydrochloric acid soln 120mL extraction of mixture with 25% (massfraction), oil bath backflow 6h.Reaction mixture adds concentrated NaOH solution under stirring and is neutralized to alkalescence (about pH=8.5), extracts with ETHYLE ACETATE (30mL * 3).The combined ethyl acetate layer is used anhydrous sodium sulfate drying, and ETHYLE ACETATE is reclaimed in distillation, and the underpressure distillation surplus materials obtains pale yellow oily liquid body N-to luorobenzyl piperidin-4-one-(4a).
In 50mL exsiccant round-bottomed bottle, add 0.005molN-to luorobenzyl piperidin-4-one-(4a) and 0.01mol phenyl aldehyde; Add the 15mL absolute ethyl alcohol, stir adding 1mL 10%NaOH (massfraction), stirring at room 30min; Have yellow solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-luorobenzyl)-3, the two benzal phenylpiperidines of 5--4-ketone (5a).
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-luorobenzyl)-3 again, the thiocarbamide of the two benzal phenylpiperidines of 5--4-ketone and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ia).
Yield：77％；yellow?solid，mp?155-158℃；1H?NMR(400?MHz，DMSO)δ?9.53(s，1H)，9.13(s，1H)，8.65-5.26(m，15H)，4.85(s，1H)，3.64-3.28(m，4H)，3.11(d，J＝16.5Hz，1H)，2.74(d，J＝16.3?Hz，1H)；IR(KBr)：3425，1568，1446，1081，989，857cm-1；Anal.calcd.for?C27H24FN3S?C％?73.44，H％?5.48，F％?4.30，N％?9.52；Found：C％?73.42，H％?5.47，F％?4.32，N％9.53.
Embodiment 2: the preparation 4-to fluorophenyl-6-to luorobenzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ib);
The N-that is obtained by the preparation method of embodiment 1 is to luorobenzyl piperidin-4-one-(4a); Getting N-is blended in the 50mL exsiccant round-bottomed bottle luorobenzyl piperidin-4-one-(4a) 0.005mmol and 0.01mol p-Fluorobenzenecarboxaldehyde; The absolute ethyl alcohol that adds 15mL; Add 1mL 10%NaOH in the stirring, approximately have solid to separate out behind the 40min.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-luorobenzyl)-3, two (the 4-fluorine benzal base) piperidin-4-one-s (5b) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-luorobenzyl)-3 again, the thiocarbamide of two (4-fluorine benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ib).
Yield：82％；yellow?solid，mp?131-133℃；1H?NMR(400MHz，DMSO)δ?9.53(s，1H)，9.14(s，1H)，8.65-5.90(m，13H)，4.88(s，1H)，3.61-3.29(m，4H)，3.08(d，J＝17.0Hz，1H)，2.70(d，J＝16.7Hz，1H)；IR(KBr)：3416，1570，1500，1439，1077，989，879，858cm-1；Anal.calcd.for?C27H22F3N3S?C％67.91，H％4.64，F％11.94，N％8.80；Found：C％67.90，H％4.61，F％，11.92，N％8.82.
Embodiment 3: to methylbenzyl fork base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ic) to luorobenzyl-8-for preparation 4-p-methylphenyl-6-;
The N-that is obtained by the preparation method of embodiment 1 is to luorobenzyl piperidin-4-one-(4a); Getting N-is blended in the 50mL round-bottomed bottle luorobenzyl piperidin-4-one-(4a) 0.005mmol and 0.01mol p-tolyl aldehyde; Add the 15mL absolute ethyl alcohol, stir adding 1mL 10%NaOH (massfraction), stirring at room 30min; Have yellow solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-luorobenzyl)-3, two (the 4-methyl benzal base) piperidin-4-one-s (5c) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-luorobenzyl)-3 again, the thiocarbamide of two (4-methyl benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ic).
Yield：87％；yellow?solid，mp?132-134℃；1H?NMR(400MHz，DMSO)δ9.46(s，1H)，9.08(s，1H)，8.14-6.56(m，13H)，4.78(s，1H)，3.86-3.36(m，4H)，3.06(d，J＝16.6Hz，1H)，2.71(d，J＝16.3Hz，1H)，2.29(d，J＝10.1Hz，6H)；IR(KBr)：3416，1570，1500，1439，1077，989，879，858cm-1；Anal.calcd.for?C29H28FN3S?C％74.17，H％6.01，F％4.05，N％8.95；Found：C％74.14，H％6.00，F％4.07，N％8.97.
Embodiment 4: preparation 4-p-isopropyl phenyl-6-is to methyl-benzyl-8-p-isopropyl benzal base-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Id);
With the preparation method of embodiment 1, change NSC 158269 to methylbenzylamine into, the N-that obtains is to methyl-benzyl piperidin-4-one-(4d).
Getting N-is blended in the 50mL round-bottomed bottle methyl-benzyl piperidin-4-one-(4d) 0.005mmol and 0.01mol cumic aldehyde; Add the 15mL absolute ethyl alcohol; Stir and add 1mL 10%NaOH (massfraction); Stirring at room 30min has yellow solid to separate out, and thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-methyl-benzyl)-3, two (the 4-sec.-propyl benzal base) piperidin-4-one-s (Id) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-methyl-benzyl)-3 again, the thiocarbamide of two (4-sec.-propyl benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Id).
Yield：85％；yellow?solid，mp?179-181℃；1H?NMR(400MHz，DMSO)δ?9.48(s，1H)，9.07(s，1H)，9.06-4.78(m，13H)，4.77(s，1H)，3.59-3.32(m，4H)，3.06(d，J＝16.6Hz，1H)，2.87(tt，J＝13.5，6.8Hz，2H)，2.73(d，J＝16.4Hz，1H)，2.21(s，3H)，1.97(m，12H)；IR(KBr)：3764，3489，2396，2340，1637，1577，1421，1363，1120，1064cm-1；Anal.calcd.for?C34H39N3S?C％78.27，H％7.53，N％8.05，；Found：C％78.25，H％7.52，N％8.06.
Embodiment 5: preparation 4-(3-chloro-phenyl-)-6-is to methyl-benzyl-8-(3-benzyl chloride fork base)-1,2,5, and the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ie);
With the preparation method of embodiment 1, change NSC 158269 to methylbenzylamine into, the N-that obtains is to methyl-benzyl piperidin-4-one-(4d).
Getting N-is blended in the 50mL round-bottomed bottle methyl-benzyl piperidin-4-one-(4d) 0.005mol and 0.01mol3-chlorobenzaldehyde; Add the 15mL absolute ethyl alcohol, stir adding 1mL 10%NaOH (massfraction), stirring at room 30min; Have yellow solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is used ethyl alcohol recrystallization after finishing, and obtains N-(4-methyl-benzyl)-3,5-two (3-benzyl chloride fork base) piperidin-4-one-(5e).
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-methyl-benzyl)-3 again, the thiocarbamide of two (3-benzyl chloride fork base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ie).
Yield：70％；yellow?solid，mp?107-110℃；1H?NMR(400MHz，DMSO)δ9.59(s，1H)，9.20(s，1H)，7.66-6.65(m，13H)，4.92(s，1H)，3.60-3.34(m，4H)，3.12(d，J＝16.7Hz，1H)，2.75(d，J＝16.7?Hz，1H)；IR(KBr)：3422，2342，1560，1608，1451，1078，990，668cm-1；Anal.calcd.for?C28H25Cl2N3S?C％?66.40，H％?4.98，Cl％?14.00，N％?8.30；Found：C％?66.42，H％?4.96，Cl％14.01，N％?8.33.
Embodiment 6: the preparation 4-to fluorine benzyl-6-to methyl-benzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (If);
With the preparation method of embodiment 1, change NSC 158269 to methylbenzylamine into, under identical condition, obtain N-to methyl-benzyl piperidin-4-one-(4d).
In 50mL exsiccant round-bottomed bottle, add 0.005mol N-to methyl-benzyl piperidin-4-one-(4d) and 0.01mol to fluorine formaldehyde; Add the 15mL absolute ethyl alcohol, stir adding 1mL10%NaOH (massfraction), stirring at room 30min; Have yellow solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-methyl-benzyl)-3, two (the 4-fluorine benzal base) piperidin-4-one-s (5f) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-methyl-benzyl)-3 again, the thiocarbamide of two (4-fluorine benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (If).
Yield：78％；yellow?solid，mp?175-177℃；1H?NMR(400?MHz，DMSO)δ?9.52(s，1H)，9.14(s，1H)，7.29-6.93(m，13H)，4.87(s，1H)，3.45-3.34(m，4H)，3.07(d，J＝16.7Hz，1H)，2.70(d，J＝16.5?Hz，1H)，2.21(s，6H)；IR(KBr)：3422，2351，2026，1633，1600，1564，1506，1155，1077cm-1；Anal.calcd.forC28H25F2N3S.C％71.01，H％5.32，F％8.02，N％8.87；Found：C％71.00，H％5.30，F％8.05，N％8.86.
Embodiment 7: the preparation 4-to methyl-benzyl-6-to bromobenzyl-8-to methyl benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ig);
With the preparation method of embodiment 1, change NSC 158269 to bretylium into, under identical condition, obtain N-to bromobenzyl piperidin-4-one-(4g).
In 50mL exsiccant round-bottomed bottle, add 0.005molN-to bromobenzyl piperidin-4-one-(4g) and 0.01mol p-tolyl aldehyde; Add the 15mL absolute ethyl alcohol; Stir and add 1mL 10%NaOH (massfraction); Stirring at room 20min has yellow solid to separate out, and thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-bromobenzyl)-3, two (the 4-methyl benzal base) piperidin-4-one-s (5g) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-bromobenzyl)-3 again, the thiocarbamide of two (4-methyl benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ig).
Yield：79％；yellow?solid，mp?135-137℃；1H?NMR(400?MHz，DMSO)δ?9.46(s，1H)，9.08(s，1H)，7.45-6.89(m，13H)，4.78(s，1H)，3.45-3.05(m，4H)，3.07(d，J＝16.6Hz，1H)，2.70(d，J＝16.4?Hz，1H)，2.29(d，J＝8.9?Hz，6H)；IR(KBr)：3417，1569，1508，1449，1074，1011，869，646cm-1；Anal.calcd.for?C29H28BrN3S?C％?65.65，H％?5.32，Br％?15.06，N％?7.92；Found：C％65.63，H％?5.31，Br％?15.08，N％?7.93.
Embodiment 8: the preparation 4-to luorobenzyl-6-to bromobenzyl-8-to fluorine benzal base-1,2,5, the 6-tetrahydropyridine is [4,3-d]-3 also, 4-dihydro-pyrimidin-2-thioketones (Ih);
With the preparation method of embodiment 1, change NSC 158269 to bretylium into, under identical condition, obtain N-to bromobenzyl piperidin-4-one-(4g).
In 50mL exsiccant round-bottomed bottle, add 0.005mol N-to bromobenzyl piperidin-4-one-(4g) and 0.01mol p-Fluorobenzenecarboxaldehyde; Add the 15mL absolute ethyl alcohol; Stir and add 1mL 10%NaOH (massfraction); Stirring at room 20min has orange solids to separate out, and thin-layer chromatography (TLC) is followed the tracks of reaction process.Question response is washed solid with ethanol after finishing, and with ETHYLE ACETATE and sherwood oil recrystallization, obtains N-(4-bromobenzyl)-3, two (the 4-fluorine benzal base) piperidin-4-one-s (5h) of 5-.
In 100mL exsiccant three-necked bottle, add the 10mL absolute ethyl alcohol; 0.005mol sodium hydroxide at room temperature stir 5min, add 0.001molN-(4-bromobenzyl)-3 again, the thiocarbamide of two (4-fluorine benzal base) piperidin-4-one-s of 5-and 0.002mol; It is 65 ℃ that temperature is set; Adopt microwave-assisted reaction 5-30min, have solid to separate out, thin-layer chromatography (TLC) is followed the tracks of reaction process.After question response finished, vacuum was gone out absolute ethyl alcohol, crosses post with ETHYLE ACETATE and oil, obtains (Ih).
Yield：87％；orange?solid，mp?134-136℃；1H?NMR(400?MHz，DMSO)δ?9.53(s，1H)，9.14(s，1H)，8.45-6.35(m，13H)，4.88(s，1H)，3.46-3.16(m，4H)，3.09(d，J＝16.7Hz，1H)，2.70(d，J＝16.5Hz，1H)；IR(KBr)：3416，1601，1569，1506，1484，1429，1157，1073，841，647cm-1；Anal.calcd.for?C27H22BrF2N3S.C％60.23，H％4.12，Br％14.84，F％7.06，N％7.80；Found：C％60.20，H％4.10，Br％14.86，F％7.08，N％7.81.
Suppress the test of leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 proliferation activity:
1. test medicament and equipment
Experimental drug and reagent: self-control compound (I) is assigned to desired concn (DMSO concentration≤1 ‰) with DMSO, the 4 ℃ of preservations of sterilizing.MTT (tetramethyl-azo azoles is blue) reagent is available from Sigma company.Human leukemia K562 cell is purchased Chinese Academy of Sciences's cell bank in Shanghai.10%SDS reagent (Sino-American Biotechnology product), with RPMI-1640 (the U.S. GiBCo company) nutrient solution that contains 20% calf serum (FBS), other reagent all is commercially available analytical pure.The cultivation of in 37 ℃, the incubator of 5%CO2, saturated humidity, going down to posterity treats to be used for when cell is in logarithmic phase experiment.
Plant and instrument: Bechtop, cleaning＜3.5/L (＞0.5 μ m grit), safe and sound technological ltd; 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 holes are dull and stereotyped, U.S. Costar company; SK2200H type ultrasonic cleaner, Shanghai High Kudos Science Instrument Co., Ltd..
2. TP
Experiment is carried out in 96 orifice plates, and system contains the full nutrient solution of target compound of 1 * 105 cell and different concns.Every hole TV 100 μ L, 8 every group multiple holes are provided with medicine color control wells (not containing cell) and contain the culture hole of cell and medicine; After cultivating 44h respectively, in each hole, add MTT (5mg/mL, 10 μ L); Continue to cultivate 4h; Add 10%SDS 100 μ L termination reactions again, 37 ℃ are spent the night, with the absorbance A value of each hole of enzyme linked immunosorbent detection at 570nm.And according to the computes inhibition rate of tumor growth:
3. result's investigation
Survey the influence of target compound (I) to leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell line proliferation with mtt assay, inhibiting rate is seen table 1.
Table 1 target compound I suppresses the inhibiting rate (%) of leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell-proliferation activity under the concentration of 10ug/ml
Show from the preliminary mensuration that suppresses leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell-proliferation activity of table 1: target compound can effectively suppress leukemia K 562 cell, ovarian cancer HO-8910 cell and liver cancer SMMC-7721 cell proliferation.As shown in table 1, most of target compound propagation to the leukemia K 562 cancer cells when 10 μ g/mL has good inhibitory effect, and wherein Ie reaches 85.2% to the inhibiting rate of leukemia K 562 cancer cell multiplication; Most of target compound propagation to ovarian cancer HO-8910 cancer cells when 10 μ g/mL has certain restraining effect, and wherein Ig reaches 78.2% to the inhibiting rate of ovarian cancer HO-8910 cancer cell multiplication; Most of target compound propagation to liver cancer SMMC-7721 cancer cells when 10 μ g/mL has certain restraining effect.
The embodiment of the invention described above is not limited to the present invention.For a person skilled in the art, the preparation method of product of the present invention can change.All within spirit of the present invention and principle, that is done is equal to replacement, improves etc., all should be included within protection scope of the present invention.
Claims (9)
1. sulfo-tetrahydropyridine shown in the formula (I) and dihydro-pyrimidin ketone compound,
Wherein: R
1Be selected from a kind of in methyl, ethyl, methoxyl group, oxyethyl group, fluorine, bromine, the chlorine;
R
2Be 2,3,4 single replacements or dibasic phenyl, said substituting group is a kind of in methyl, ethyl, methoxyl group, oxyethyl group, fluorine, bromine, chlorine, nitro, carboxyl, cyanic acid, the ester group or two kinds.
2. the preparation method of said sulfo-tetrahydropyridine of claim 1 and dihydro-pyrimidin ketone compound, it is characterized in that: this method may further comprise the steps:
(1) N shown in the formula (b) is processed in the process of replacement amine and methyl acrylate shown in the formula (a) Michael addition reaction, N-two (β-methyl propionate) replaces amine;
(2) with N, N-two (β-methyl propionate) replaces amine (b), and hydrolysis decarboxylation obtains N-substituted piperidine-4-ketone (d) under generation Dieckmann condensation under the sodium alkoxide effect and acid effect;
(3) two active methylene radical of N-substituted piperidine-4-ketone (d) and aromatic aldehyde carry out two molecule dehydration reactions and obtain N-substituted benzyl-3, the two benzal base-piperidin-4-one-s (e) of 5-under the effect of alkali;
(4) N-substituted benzyl-3, the two benzal base-piperidin-4-one-s (e) of 5-and thiocarbamide condensation under the sodium hydroxide effect promptly obtain the target compound of general formula for (I).
3. according to the preparation method of said sulfo-tetrahydropyridine of claim 2 and dihydro-pyrimidin ketone compound, it is characterized in that: the solvent in the said reaction of step (1) is a lower alcohol.
4. according to the preparation method of said sulfo-tetrahydropyridine of claim 3 and dihydro-pyrimidin ketone compound, it is characterized in that: said lower alcohol is a methyl alcohol.
5. according to the preparation method of said sulfo-tetrahydropyridine of claim 2 and dihydro-pyrimidin ketone compound, it is characterized in that: the said sodium alkoxide of step (2) is selected from a kind of in sodium methylate or the sodium ethylate.
6. according to the preparation method of said sulfo-tetrahydropyridine of claim 2 and dihydro-pyrimidin ketone compound, it is characterized in that: the said sodium alkoxide of step (2) is a sodium methylate.
7. according to the preparation method of said sulfo-tetrahydropyridine of claim 2 and dihydro-pyrimidin ketone compound, it is characterized in that: the said alkali of step (3) is sodium hydroxide or Pottasium Hydroxide.
8. according to the preparation method of said sulfo-tetrahydropyridine of claim 7 and dihydro-pyrimidin ketone compound, it is characterized in that: said alkali is the sodium hydroxide of 8-15% mass concentration.
9. the application of the said compound of claim 1 in suppressing leukemia K 562, ovarian cancer HO-8910 and liver cancer SMMC-7721 cell-proliferation activity.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1727343A (en) * | 2005-07-25 | 2006-02-01 | 华中师范大学 | Substitution thieno[3',2':5,6]-pyridino[4,3-d]-pyrimidine-4(3H)-ketone and preparation method |
| CN101686980A (en) * | 2007-04-20 | 2010-03-31 | 先灵公司 | Tetrahydropyrido[4,3-d]pyrimidinone derivatives and methods of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101686980A (en) * | 2007-04-20 | 2010-03-31 | 先灵公司 | Tetrahydropyrido[4,3-d]pyrimidinone derivatives and methods of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| IMRE HUBER ET AL: "Dehydrogenation of 6-Azaquinazoline Derivatives. Formation of Unexpected Quinonediimine Intermediates", 《J.CHEM.SOC.PERKIN TRANS.1》 * |
| 任青云等: "吡啶并嘧啶类化合物的合成研究进展", 《有机化学》 * |
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