CN107235917A - The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity - Google Patents

The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity Download PDF

Info

Publication number
CN107235917A
CN107235917A CN201710650037.2A CN201710650037A CN107235917A CN 107235917 A CN107235917 A CN 107235917A CN 201710650037 A CN201710650037 A CN 201710650037A CN 107235917 A CN107235917 A CN 107235917A
Authority
CN
China
Prior art keywords
licochalcone
synthetic method
reaction
compound
dmso
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.)
Pending
Application number
CN201710650037.2A
Other languages
Chinese (zh)
Inventor
梁承远
田丹妮
贾敏
贾敏一
鞠伟会
裴少萌
田蕾
丁顺军
刘柯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shaanxi University of Science and Technology
Original Assignee
Shaanxi University of Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shaanxi University of Science and Technology filed Critical Shaanxi University of Science and Technology
Publication of CN107235917A publication Critical patent/CN107235917A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Abstract

The invention discloses the licochalcone A Dihydropyrimidines and its synthetic method that a class has antitumor activity.Such compound is obtained using licochalcone A, carbamide compounds as raw material in toluene as reaction synthesis under solvent.This method processing safety is high, and reaction condition is gentle, it is adaptable to industrialized production.Show that the type compound has preferable antitumor activity through preliminary biological activity test, the research available for antitumor lead compound.

Description

The licochalcone A Dihydropyrimidines of one class tool antitumor activity and its conjunction Into method
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to a class has the licochalcone A dihydro of antitumor activity phonetic Pyridine class compound and its synthetic method.
Background technology：
Tumour has seriously threatened the health of the mankind, finds the small antineoplastic of effective and safe, toxic side effect and is always The target that tumour medicine R＆D worker seek assiduously.With pharmaceutical chemical development, using pyrimidine ring as the chemical combination of structure parent nucleus Effect of the thing in oncotherapy causes extensive concern.
Licochalcone A is considered as the species specificity composition of swollen fruit Radix, and its structure is as follows.
In recent years, research finds that licochalcone A has anti-inflammatory, antibacterial, anti-oxidant, antitumor, lipid-loweringing, spasmolysis and antimalarial The multiple biological activities such as anti parasitic, have very big Development volue in field of medicaments.But licochalcone A is that flatness is strong Molecule, poorly water-soluble, so, strengthen the water solubility of licochalcone A by reasonable, safe structural modification, exploitation is natural More bioactivity of product licochalcone A turn into urgent problem to be solved.
The content of the invention：
It is an object of the present invention to provide the licochalcone A Dihydropyrimidines that a class has antitumor activity And its synthetic method.
The implementation process of the present invention is as follows：
Compound shown in general structure (I),
Wherein：R be C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, Nitro；
Described being substituted by is monosubstituted or polysubstituted, and substituent is：Halogen, C1-C4 alkoxy, cyano group, trifluoromethyl, benzene oxygen Base.
The synthetic method of compound shown in general structure (I), using licochalcone A, carbamide compounds as raw material, to have Machine alkali is catalyst, is synthesized under conditions of toluene is as reaction dissolvent：
Specifically, comprise the following steps,
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A, carbamide compounds, add organic solvent It is well mixed, add organic alkali catalyst, 80 DEG C~120 DEG C back flow reactions 3~8 hours；
(2) after the solidliquid mixture of step (1) reaction system is concentrated under reduced pressure, column chromatography for separation purification is dried to obtain target production Thing.
The mol ratio of licochalcone A and thiourea described in step (1) is preferably 1:1~1:1.3, it is organic Solvent is toluene or DMF, and reaction temperature is preferably 105 DEG C~115 DEG C, and organic base is preferably triethylamine.
Pyrimidine ring is the core texture unit in many native compounds and synthetic drug, is used as one in heterocyclic compound Individual important branch, pyrimidines because its have efficiently, low toxicity, and its ring substituents can with multi-faceted conversion It is used widely in drug field.Pyrimidine ring is introduced into the chemical constitution of licochalcone A, being expected to enhancing, it is biological living Property, selectivity is improved, with important theory value and actual application value.
The advantage of the invention is that：Raw material environmental protection, production cost is low, and processing safety is high, and reaction condition is gentle, can be achieved Reaction raw materials make full use of, it is adaptable to industrialized production, the problem of solving prior art low yield, while pyrimidine ring is drawn Enter into the chemical constitution of licochalcone A, have to the bioactivity for probing into such compound with summary structure-activity relationship important Theory value and application value.
Embodiment
With reference to specific embodiment, the present invention is further elaborated.These embodiments are only in order at the mesh of explanation , and do not limit the scope of the invention and essence.
The synthetic method of the licochalcone A Dihydropyrimidines of one class tool antitumor activity comprises the following steps：
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A, carbamide compounds, add toluene or DMF Well mixed, wherein solvent volume is less than the 2/3 of reactor volume, adds organic alkali catalyst triethylamine, is placed in magnetic agitation Stirred on device, be heated to 80 DEG C~120 DEG C, back flow reaction 3~8 hours；
(2) followed the trail of in course of reaction using thin-layer chromatography, the carry out degree of monitoring reaction in time stops after after raw material reaction completely Heating, removes condensing unit；
(3) after the solidliquid mixture of step (2) reaction system is concentrated under reduced pressure, column chromatography for separation purification is dried to obtain target production Thing.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
Embodiment 1
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- methyl -5,6- The preparation of dihydro-pyrimidin -2 (1H) -one (1).
200mg licochalcone As and 56.92mg 1- MUs are added in the reactor, plus 50ml toluene and 5mLDMF react Solvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 3 hours.Thin layer color Following response is composed, after reaction terminates, is concentrated under reduced pressure, column chromatography is de- dry to obtain brown ceramic powder 113.41mg, total recovery 48.65%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：8.04(2H,d),7.03(1H,s),6.83 (2H,d),6.48(1H,s),6.31(1H,m),5.31(2H,s),5.06-4.95(2H,m),5.03(1H,t),3.81(3H, s),3.51(3H,s),1.97-1.61(2H,m),1.56(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):165.3, 161.3,156.6,155.4,154.2,147.7,133.4,129.2,125.7,116.2,110.6,101.5,56.6,53.2, 40.6,39.2,35.6,28.3；MS(ESI)for(M+H)+:395.2.
Embodiment 2
1- benzyls -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -5,6- The preparation of dihydro-pyrimidin -2 (1H) -one (2).
200mg licochalcone As and 115.39mg 1- benzylureas are added in the reactor, plus 50ml toluene and 5mLDMF make anti- Solvent is answered, 0.5mL triethylamines are added as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 5 hours.Thin layer Chromatogram following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 121.79mg, total recovery 43.79%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.89(2H,d),7.25-7.20(5H, m),6.98(1H,s),6.90(2H,d),6.47(1H,s),6.31(1H,m),5.41(2H,s),5.03-4.97(2H,m), 4.94(1H,s),4.26(2H,s),3.87(3H,s),1.87-1.62(2H,m),1.53(6H,s)；13C NMR(100MHz, DMSO-d6)δ(ppm):165.6,161.8,156.5,155.3,154.0,147.4,136.6,133.5,129.2,128.6, 127.6,125.4,116.2,110.6,101.8,56.6,51.5,50.4,41.2,39.5,28.3；MS(ESI)for(M+H)+: 471.2.
Embodiment 3
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- phenyl -5,6- The preparation of dihydro-pyrimidin -2 (1H) -one (3).
200mg licochalcone As and 104.61mg 1- phenylureas are added in the reactor, plus 50ml toluene and 5mL DMF make anti- Solvent is answered, 0.5mL triethylamines are added as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer Chromatogram following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 130.64mg, total recovery 48.42%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.94-7.85(4H,m),7.43(3H, t),6.93(1H,t),6.85(2H,d),6.47(1H,s),6.33(1H,m),5.37(2H,s),5.03-4.98(2H,m), 4.94(1H,s),3.87(3H,s),1.95-1.63(2H,m),1.59(6H,s)；13C NMR(100MHz,DMSO-d6)δ (ppm):165.6,161.3,154.9,147.3,139.5,133.2,129.0,128.1,127.5,125.8,121.6, 116.0,110.1,102.8,61.3,56.6,40.4,39.8,28.3；MS(ESI)for(M+H)+:457.2.
Embodiment 4
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (adjacent toluene Base) -5,6- dihydro-pyrimidins -2 (1H) -one (4) preparation.
Add 200mg licochalcone As and 115.39mg 1- (o-tolyl) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 8 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 136.41mg, always Yield 49.05%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.89(2H,d),7.86(2H,t),7.25 (1H,t),7.08(1H,t),6.95(1H,s),6.90(2H,d),6.47(1H,s),6.32(1H,m),5.39(2H,s), 5.03-4.98(2H,m),4.94(1H,s),3.82(3H,s),2.17(3H,s),1.96-1.68(2H,m),1.50(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):164.7,161.3,155.4,154.8,147.7,136.6,134.3,133.5, 130.7,129.2,125.5,121.6,118.4,116.3,110.9,101.8,61.9,56.4,40.1,28.6,17.5；MS (ESI)for(M+H)+:471.2.
Embodiment 5
1- (2- fluorophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (5) preparation.
Add 200mg licochalcone As and 118.43mg 1- (2- fluorophenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 120 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 140.11mg, always Yield 49.96%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.25(5H,m),7.01(1H,t),6.98 (2H,d),6.87(2H,d),6.41(1H,s),5.35(2H,s),5.00-4.98(2H,d),4.9(1H,t),3.83(3H,s), 1.91-1.66(2H,m),1.69(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):165.2,162.8,160.8, 154.9,153.7,148.8,133.2,129.1,128.0,125.2,125.2,123.6,121.6,115.9,110.3, 101.8,61.7,56.4,40.8,39.4,28.4；MS(ESI)for(M+H)+:475.2.
Embodiment 6
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (2- methoxyl groups Phenyl) -5,6- dihydro-pyrimidins -2 (1H) -one (6) preparation.
Add 200mg licochalcone As and 127.68mg 1- (2- methoxyphenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 105 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder (141.72mg), Total recovery 49.28%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.84(2H,d),7.61(1H,d),7.11 (2H,d),6.97(1H,t),6.86(1H,s),6.81(2H,d),6.46(1H,s),6.32(1H,m),5.40(2H,s), 5.00-4.97(2H,m),4.92(1H,t),3.84(6H,s),1.97-1.68(2H,m),1.58(6H,s)；13C NMR (100MHz,DMSO-d6)δ(ppm):164.7,161.3,160.6,154.9,153.4,147.8,133.2,129.5,128.2, 126.0,125.2,121.4,118.3 116.4,112.8,110.3,103.8,61.6,55.9,40.4,39.8,28.3；MS (ESI)for(M+H)+:487.2.
Embodiment 7
1- (2- bromophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (7) preparation.
Add 200mg licochalcone As and 165.23mg 1- (2- bromophenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 115 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 142.35mg, always Yield 44.98%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.86(2H,d),7.81(1H,d),7.65 (1H,d),7.36(1H,t),7.11(1H,t),6.85(1H,s),6.78(2H,d),6.44(1H,s),6.30(1H,m),5.35 (2H,s),5.04-4.98(2H,m),4.93(1H,m),3.89(3H,s),1.91-1.66(2H,m),1.57(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):164.6,161.5,154.9,153.7,148.8,140.9,133.2,131.8, 129.5,128.3,125.2,122.6,121.6,116.0,110.9,103.8,60.6,56.5,40.9,39.9,28.2；MS (ESI)for(M+H)+:535.1.
Embodiment 8
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (toluene Base) -5,6- dihydro-pyrimidins -2 (1H) -one (8) preparation.
Add 200mg licochalcone As and 115.39mg 1- (tolyl) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 147.88mg, always Yield 53.17%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.86(2H,d),7.76(1H,s),7.64 (1H,d),7.31(1H,t),6.97(2H,m),6.84(2H,d),6.47(1H,s),6.32(1H,m),5.36(2H,s), 5.08-4.98(2H,m),4.93(1H,t),3.82(3H,s),2.34(3H,s),1.96-1.62(2H,m),1.57(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):165.1,161.1,154.9,153.7,147.8,138.9,133.2,129.1, 128.3,125.4,124.6,121.6,121.3,116.3,110.6,103.8,61.6,56.6,40.2,28.6,21.3；MS (ESI)for(M+H)+:471.2.
Embodiment 9
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -1- (3- hydroxy phenyls) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (9) preparation.
Add 200mg licochalcone As and 116.90mg 1- (3- hydroxy phenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 80 DEG C, magnetic agitation back flow reaction 6 Hour.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 147.31mg, always Yield 52.75%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.87(2H,d),7.35(2H,m),7.27 (1H,t),6.96(1H,s),6.82(2H,d),6.71(1H,d),6.45(1H,s),6.32(1H,m),5.37(3H,s), 5.04-4.98(2H,m),4.92(1H,t),3.85(3H,s),1.98(1H,m),1.57(6H,s),1.68(1H,m)；13C NMR (100MHz,DMSO-d6)δ(ppm):165.1,161.4,158.7,154.9,153.7,147.8,141.6,133.2,130.3, 129.1,128.3,125.2,121.6,120.3,116.3,114.6,110.9,106.3,101.8,61.5,56.6,40.2, 28.2；MS(ESI)for(M+H)+:473.2.
Embodiment 10
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (3- (trifluoros Methyl) phenyl) -5,6- dihydro-pyrimidins -2 (1H) -one 10) and preparation.
200mg licochalcone As and 156.85mg 1- (3- (trifluoromethyl) phenyl) urea, plus 50ml first are added in the reactor Benzene and 5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 100 DEG C, and magnetic agitation is returned Stream reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 131.67mg, total recovery 42.47%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：8.34(1H,s),7.87(3H,d),7.38 (2H,d),6.94(1H,s),6.83(2H,d),6.46(1H,s),6.32(1H,m),5.40(2H,s),5.05-4.95(2H, m),4.94(1H,t),3.85(3H,s),1.95-1.63(2H,m),1.54(6H,s)；13C NMR(100MHz,DMSO-d6)δ (ppm):165.1,161.4,154.9,153.7,147.8,139.4,133.2,130.9,129.1,128.3,125.2, 124.1,121.6,120.7,116.3,114.6,110.9,102.8,61.3,56.6,39.9,28.2；MS(ESI)for(M+H )+:525.2.
Embodiment 11
1- (4- fluorophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (11) preparation.
Add 200mg licochalcone As and 118.43mg 1- (4- fluorophenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 129.11mg, always Yield 46.04%.
Brown crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.88(2H,d),7.74(2H,d),7.22 (2H,t),6.95(1H,s),6.86(2H,d),6.46(1H,s),6.32(1H,m),5.37(2H,s),5.02-4.98(2H, m),4.92(1H,t),3.85(3H,s),1.93(1H,m),1.57(6H,s),1.68(1H,m)；13C NMR(100MHz,DMSO- d6)δ(ppm):165.1,162.5,161.6,154.9,153.7,148.8,134.7,133.2,129.4,125.2,123.2, 121.6,115.9,110.7,103.8,61.4,56.4,40.2,28.2；MS(ESI)for(M+H)+:475.2.
Embodiment 12
1- (4- chlorphenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (12) preparation.
Add 200mg licochalcone As and 131.07mg 1- (4- chlorphenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 140.22mg, always Yield 48.32%.
Brown crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.83(2H,d),7.82(2H,d),7.47 (2H,d),6.85(2H,d),6.41(1H,s),6.30(1H,m),5.34(3H,s),5.02-4.98(2H,m),4.92(1H, t),3.81(3H,s),1.95(1H,m),1.73(6H,s),1.57(1H,m)；13C NMR(100MHz,DMSO-d6)δ(ppm): 164.2,161.3,154.9,153.7,147.8,134.2,133.2,128.9,125.4,121.6,116.0,110.8, 103.8,61.3,56.1,40.2,28.0；MS(ESI)for(M+H)+:491.2.
Embodiment 13
1- (4- aminophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes Base) -5,6- dihydro-pyrimidins -2 (1H) -one (13) preparation.
Add 200mg licochalcone As and 116.15mg 1- (4- aminophenyls) urea in the reactor, plus 50ml toluene and 5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 139.67mg, always Yield 50.12%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.85(2H,d),7.05(2H,d),6.95 (1H,s),6.85(2H,d),6.61(2H,d),6.41(1H,s),6.30(1H,m),6.27(2H,s),5.35(2H,s), 5.00-4.98(2H,m),4.9(1H,t),3.83(3H,s),1.94(1H,m),1.63(6H,s),1.69(1H,m)；13C NMR (100MHz,DMSO-d6)δ(ppm):164.2,161.3,154.9,153.7,149.0,144.2,133.4,132.2,129.0, 127.7,125.4,121.8,116.4,110.9,104.0,61.3,56.6,40.2,28.3；MS(ESI)for(M+H)+: 472.2.
Embodiment 14
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (4- methoxyl groups Phenyl) -5,6- dihydro-pyrimidins -2 (1H) -one (14) preparation.
Add 200mg licochalcone As and 127.68mg 1- (4- methoxyphenyls) urea in the reactor, plus 50ml toluene and 5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 100 DEG C, and magnetic agitation backflow is anti- Answer 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 136.83mg, Total recovery 47.58%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.96(1H,d),7.82(2H,d),6.92 (3H,m),6.86(2H,d),6.46(1H,s),6.31(1H,t),5.38(2H,s),5.03-4.98(2H,m),4.92(1H, t),3.85(3H,s),1.93(1H,m),1.63(6H,s),1.59(1H,m)；13C NMR(100MHz,DMSO-d6)δppm): 164.2,161.3,159.0,154.9,153.8,148.9,133.2,131.6,129.2,128.5,125.4,122.8, 121.9,116.2,114.7,111.0,103.9,61.3,55.9,40.2,28.3；MS(ESI)for(M+H)+:487.2.
Embodiment 15
1- (2,4- 3,5-dimethylphenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxyls Base phenyl) -5,6- dihydro-pyrimidins -2 (1H) -one (15) preparation.
200mg licochalcone As and 126.16mg 1- (2,4- 3,5-dimethylphenyl) urea, plus 50ml toluene are added in the reactor Make reaction dissolvent with 5mLDMF, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, and magnetic agitation backflow is anti- Answer 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder (142.12mg), total recovery 49.62%.
Yellow crystalline powder solid.1H NMR(400MHz,DMSO-d6)：7.89(2H,d),7.61(2H,d),7.08 (1H,s),7.01(1H,d),6.82(2H,d),6.46(1H,s),6.30(1H,m),5.35(2H,s),5.03-4.98(2H, m),4.9(1H,t),3.83(3H,s),2.34(3H,s),2.29(3H,s),1.91(1H,m),1.69(6H,s),1.66(1H, m)；13C NMR(100MHz,DMSO-d6)δ(ppm):164.2,161.0,154.9,153.5,148.9,143.6,134.2, 133.2,131.3,129.3,128.3,126.4,125.1,121.7,116.1,111.0,104.0,61.6,55.9,40.2, 28.3,21.9,17.3；MS(ESI)for(M+H)+:485.2.
The antitumor activity test of the compounds of this invention of embodiment 16
Compound to the present invention has carried out Cytostatic to tumor cell experiment, and test method is using conventional mtt assay.
Cell line is selected：Human prostata cancer (PC-3), human gastric adenocarcinoma (SGC-7901), human lung carcinoma cell (A-549).Culture Liquid is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After being dissolved with DMSO (Merck), add 100 μm of ol/L solution that PBS (-) is made into or Uniform suspension, then with DMSO PBS (-) dilution, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ mol/L。
Antineoplastic 5 FU 5 fluorouracil (5-FU) is made into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation NBCS and penicillin, strepto- In the 1640 culture medium of plain (each 1,000,000 U/L), 37 DEG C, 5%CO are placed in2, cultivate in the CO2gas incubator of saturated humidity. Cell attachment grows, and passes on 1 time within every 2~3 days, pours out nutrient solution during passage first, PBS is washed 2 times, after pancreatin digestion, adds new Fresh nutrient solution piping and druming is uniform, and adjustment cell to debita spissitudo is moved into new blake bottle, and addition nutrient solution is to appropriate.Take the logarithm Growth period cell is used to test.
Mtt assay detects cytoactive and IC50Measure：
Experimental principle：The MTT of yellow can be reduced into water insoluble bluish violet Chan Wu formazans by dehydrogenase in living cells mitochondria (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell does not have this work( Energy.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the absorbance value determined with ELIASA Cell survival rate can be reflected.
Experimental method：Take the logarithm growth period cell, digestion, count, 96 well culture plates are inoculated in 3 × 105/mL density In, per the μ l of hole 100.Culture 24 hours after, by testing compound with 0.1,1,10,20,40,60,80,100 μm of ol/L concentration at Manage cell.The each concentration of experimental group sets 5 multiple holes, is compared with the nutrient solution containing 0.4%DMSO.After medicine is acted on 48 hours, Supernatant is removed, 100 μ l MTT (2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazoliums hydrobromate) are added per hole (1mg/mL), continues to cultivate 4 hours, abandons supernatant, and 100 μ l DMSO are added per hole, and vibration is mixed, surveyed with ELIASA at 570nm Absorbance is determined, using IC50Software for calculation obtains half-inhibition concentration (IC50)。
Result of the test refers to table 1, wherein, sample refers to the licochalcone A dihydropyridine prepared in corresponding embodiment Derivative, sample number into spectrum correspondence prepares the specific numbering of compound resulting in embodiment.
Half-inhibition concentration IC of the compound of table 1 to different tumour cells50(unit：μmol/L)
The result of table 1 shows, compound 1-15 shows different degrees of antitumor in the 3 kinds of cell lines tested The activity of activity, wherein compound 11,12 and 5 preferably, stronger inhibition is presented to cell, is swollen in specific cells strain moderate resistance Tumor activity is better than or is equal to 5 FU 5 fluorouracil, has obvious selectivity to different tumor cell lines.To sum up, radix glycyrrhizae of the invention Chalcone A dihydro-pyrimidin analog derivative can further carry out preclinical study as antitumor drug candidate, can also be as anti- Tumour lead compound is further studied.

Claims (7)

1. general structure（Ⅰ）Shown compound：
Wherein：R be C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, Nitro；Described substituent is：Halogen, C1-C4 alkoxy, cyano group, trifluoromethyl, phenoxy group.
2. general structure（I）The synthetic method of shown compound, it is characterised in that：It is by licochalcone A, carbamide compounds
Raw material, using organic base as catalyst, is synthesized under conditions of toluene or DMF are as reaction dissolvent；
。
3. the synthetic method according to claim 2, it is characterised in that comprise the following steps,
（1）It is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A, carbamide compounds, add organic solvent Toluene or DMF are well mixed, add organic alkali catalyst triethylamine, 80 DEG C ~ 120 DEG C back flow reactions 3 ~ 8 hours；
（2）By step（1）After the solidliquid mixture of reaction system is concentrated under reduced pressure, column chromatography for separation purification is dried to obtain target production
Thing.
4. synthetic method according to claim 3, it is characterised in that：Step（1）Described in licochalcone A：Ureas
The molar ratio range of compound is 1:1 ~1:1.3.
5. the synthetic method according to claim 3, it is characterised in that：Step（1）Described in reaction temperature for 105 ~ 115℃。
6. application of the compound described in claim 1 in treatment antineoplastic is prepared.
7. applied according to claim 6, it is characterised in that the tumour is prostate cancer, sdenocarcinoma of stomach, lung cancer.
CN201710650037.2A 2016-12-31 2017-08-02 The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity Pending CN107235917A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611265734.8A CN106632074A (en) 2016-12-31 2016-12-31 Licochalcone A dihydropyrimidine compound with antitumor activity and synthesizing method thereof
CN2016112657348 2016-12-31

Publications (1)

Publication Number Publication Date
CN107235917A true CN107235917A (en) 2017-10-10

Family

ID=58837966

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201611265734.8A Withdrawn CN106632074A (en) 2016-12-31 2016-12-31 Licochalcone A dihydropyrimidine compound with antitumor activity and synthesizing method thereof
CN201710650037.2A Pending CN107235917A (en) 2016-12-31 2017-08-02 The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201611265734.8A Withdrawn CN106632074A (en) 2016-12-31 2016-12-31 Licochalcone A dihydropyrimidine compound with antitumor activity and synthesizing method thereof

Country Status (1)

Country Link
CN (2) CN106632074A (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107311953A (en) * 2016-12-31 2017-11-03 陕西科技大学 A kind of dihydro-isoxazole licochalcone A and its synthetic method for having antitumor activity
CN107445903A (en) * 2017-02-24 2017-12-08 陕西科技大学 A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method
CN107235915A (en) * 2017-02-24 2017-10-10 陕西科技大学 A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method
CN107311936A (en) * 2017-02-24 2017-11-03 陕西科技大学 A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104961735A (en) * 2015-07-20 2015-10-07 武汉理工大学 Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104961735A (en) * 2015-07-20 2015-10-07 武汉理工大学 Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
杜立林: "含氮查尔酮衍生物CDK1抑制剂的设计、合成及构效关系研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 *

Also Published As

Publication number Publication date
CN106632074A (en) 2017-05-10

Similar Documents

Publication Publication Date Title
CN107235917A (en) The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity
CN107235916A (en) A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity
CN101580477A (en) Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments
CN107382864A (en) A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity
CN107311937A (en) The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity
CN107235902A (en) The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity
CN106632379A (en) Bergenin azacinnamate compound with anti-tumor activity and synthetic method thereof
CN106432259A (en) Bergenin derivative and synthetic method and application thereof
CN107573318A (en) A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity
CN107200731B (en) Thiazole ring-containing pyridone derivative and preparation method and application thereof
CN105693738A (en) 3'-phenyl spirono[indoline-3, 2'-pyrrolidine]-2-ketone derivative and preparation method and application thereof
CN108033913A (en) A kind of pyrazoline quinoline derivant and its preparation method and application
CN106632315A (en) Dissymmetrical disubstituted isatin Schiff base type compound with antitumor activity and compounding method thereof
CN106565657A (en) Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof
CN104402886B (en) 7-aza isatin nuclear parent-containing dispirocyclic compound with antitumor activity and synthetic method thereof
CN104193749B (en) Double-spiro compound containing isatin mother nucleus with antineoplastic activity and synthesis method thereof
CN103214422A (en) Preparation methods and anti-cancer effect of novel substituted amido imidazolone derivatives
CN107253949A (en) One class thia Rutaecarpine compound and its application in antineoplastic
CN104230915B (en) Phenylpiperazine derivatives containing thiazolidinedione and preparation method thereof and purposes
CN104230786B (en) Indole-structure-containing compound with anti-tumor activity and synthesis method thereof
CN102971301B (en) Antitubercular agents
CN104829534A (en) Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs
CN107445903A (en) A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method
CN103435574B (en) Mercapto benzothiazole substituent acenaphtho-heterocycle compound and application thereof
CN107311936A (en) A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20171010

WD01 Invention patent application deemed withdrawn after publication