CN107311937A - The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity - Google Patents
The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity Download PDFInfo
- Publication number
- CN107311937A CN107311937A CN201710650028.3A CN201710650028A CN107311937A CN 107311937 A CN107311937 A CN 107311937A CN 201710650028 A CN201710650028 A CN 201710650028A CN 107311937 A CN107311937 A CN 107311937A
- Authority
- CN
- China
- Prior art keywords
- licochalcone
- compound
- reaction
- synthetic method
- guanidine
- 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
Links
- 0 CCc(cc1CC(CC(C(*)=CC=C(C=C)O)=N2)NC2=N)c(C)cc1OC Chemical compound CCc(cc1CC(CC(C(*)=CC=C(C=C)O)=N2)NC2=N)c(C)cc1OC 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the licochalcone A dihydro amino-metadiazine compound and its synthetic method that a class has antitumor activity.Such compound is obtained using licochalcone A, guanidine compound as raw material in ethanol 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
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to a class has the licochalcone A dihydro amino of antitumor activity
Pyrimidines 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 dihydro Aminopyrimidines that a class has antitumor activity
Compound 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 substituent is：Halogen, C1-C4 alkoxy, cyano group, trifluoromethyl, phenoxy group.
The synthetic method of compound shown in general structure (I), using licochalcone A, guanidine compound as raw material, to have
Machine alkali is synthesized as catalyst under conditions of ethanol is as reaction dissolvent；
Specifically include following steps,
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A and guanidine compound, add organic solvent
It is well mixed, organic alkali catalyst is added, 60 DEG C~85 DEG C, back flow reaction 3~8 hours are heated to；
(2) after the solidliquid mixture of step (1) reaction system is concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain mesh
Mark product.
Licochalcone A described in step (1)：The molar ratio range of guanidine compound is 1:1~1:1.3；It is organic molten
Agent is ethanol；Reaction temperature is 70 DEG C~80 DEG C；Organic alkali catalyst is 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 dihydro amino-metadiazine compound of one class tool antitumor activity, is specifically included
Following steps：
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A, guanidine compound, plus ethanol mixing is
Even, wherein solvent volume is less than the 2/3 of reactor volume, adds organic alkali catalyst triethylamine, is placed on magnetic stirring apparatus and stirs
Mix, be heated to 60 DEG C~85 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) by the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, 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
4- (6- (4- hydroxy phenyls) -2- imino group -3- methyl -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -2- (2- first
Base butyl- 3- alkene -2- bases) phenol (1) preparation.
Licochalcone A 200mg and 1- methylguanidine 46.16mg is added into reactor, plus 50mL ethanol is solvent, plus 0.5mL
Triethylamine is placed on magnetic stirring apparatus and stirred, be heated to 75 DEG C, back flow reaction 3 hours as catalyst.Used in course of reaction
Thin-layer chromatography is followed the trail of, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, removes condensing unit.Will
The mixture of above-mentioned reaction system is after being concentrated under reduced pressure, filtering, column chromatography for separation purification, is dried to obtain target product
127.87mg, yield is 54.98%.
Brown solid powder.1H NMR(400MHz,DMSO-d6,300K)：d 9.40(1H,s),7.88(2H,d),6.98
(2H,d),6.92(1H,s),6.83(2H,d),6.37(1H,s),6.25(1H,m),6.10(2H,d),5.32(2H,s),
5.00-4.98(2H,m),4.2(1H,m),3.76(3H,s),2.30(3H,s),1.89-1.62(2H,m),1.70(6H,s)；13CNMR(75MHz,DMSO-d6)δ(ppm):164.3,161.2,154.9,149.0,141.8,133.4,129.7,128.9,
128.0,125.2,121.4,117.0,115.8,111.0,103.9,66.1,56.4,40.8,39.5,28.4,20.7；MS
(ESI)for(M+H)+:470.2.
Embodiment 2
4- (3- benzyls -6- (4- hydroxy phenyls) -2- imino group -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -2- (2- first
Base butyl- 3- alkene -2- bases) phenol (2) preparation.
Licochalcone A 200mg and 1- benzyl guanidine 104.63mg is added into reactor, plus 50mL ethanol makees solvent, plus
0.5mL triethylamines are placed on magnetic stirring apparatus and stirred, be heated to 75 DEG C, back flow reaction 6 hours as catalyst.Course of reaction
Middle use thin-layer chromatography is followed the trail of, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, removes condensation dress
Put.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target product
164.53mg, yield is 59.28%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.72(2H,s),9.40(1H,s),7.80(2H,d),
7.39-7.30(6H,m),6.85(2H,d),6.44(1H,s),6.30(1H,m),5.00-4.98(2H,m),4.66(2H,s),
4.0(1H,m),3.78(3H,s),2.80-2.55(2H,m),1.43(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):
164.3,161.2,156.3,155.4,153.4,153.2,147.8,136.9,133.6,129.0,128.8,127.6,
127.2,125.8,116.4,110.1,101.8,56.6,54.9,47.5,41.9,40.5,28.3；MS(ESI)for(M+H)+:
470.2.
Embodiment 3
4- (6- (4- hydroxy phenyls) -2- imino group -3- phenyl -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -2- (2- first
Base butyl- 3- alkene -2- bases) phenol (3) preparation.
Licochalcone A 200mg and 1- guanidines 93.85mg is added into reactor, plus 50mL ethanol is solvent, plus 0.5mL
Triethylamine is placed on magnetic stirring apparatus and stirred, be heated to 75 DEG C, back flow reaction 5 hours as catalyst.Used in course of reaction
Thin-layer chromatography is followed the trail of, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, removes condensing unit.Will
The mixture of above-mentioned reaction system is after being concentrated under reduced pressure, filtering, column chromatography for separation purification, is dried to obtain target product
136.54mg, yield is 50.71%.
Yellow-brown solid powder.1H NMR(400MHz,DMSO-d6)：9.73(2H,s),9.35(1H,s),7.80(2H,
d),7.31(1H,s),7.15(2H,t),6.85(2H,d),6.77(2H,m),6.60(1H,t),6.47(1H,s),6.30(1H,
t),5.00-4.98(2H,m),4.0(1H,m),3.78(3H,s),2.77-2.55(2H,m),1.48(6H,s)；13C NMR
(100MHz,DMSO-d6)δ(ppm):164.9,161.2,155.3,154.2,147.8,144.4,133.2,129.2,125.7,
121.5,120.4,120.3,116.5,116.7,110.1,101.8,65.7,56.6,40.4,39.5,28.3；MS(ESI)for
(M+Na)+:478.2.
Embodiment 4
4- (3- (2- fluorophenyls) -6- (4- hydroxy phenyls) -2- imino group -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -
The preparation of 2- (2- methyl butyl- 3- alkene -2- bases) phenol (4).
Licochalcone A 200mg and 1- (2- fluorophenyls) guanidine 117.68mg is added into reactor, plus 50mL ethanol makees solvent,
Plus 0.5mL triethylamines are as catalyst, it is placed on magnetic stirring apparatus and stirs, be heated to 75 DEG C, back flow reaction 6 hours.Reacted
Followed the trail of in journey using thin-layer chromatography, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, remove condensation
Device.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target product
131.69mg, yield is 47.05%.
Brown solid powder.1H NMR(400MHz,DMSO-d6)：9.72(2H,s),9.40(1H,s),7.79(2H,d),
7.27(1H,s),7.00(2H,t),6.89(2H,d),6.60(2H,d),6.48(1H,s),6.30(1H,m),5.00-4.98
(2H,m),4.0(1H,m),3.78(3H,s),2.75-2.37(2H,m),1.44(6H,s)；13C NMR(100MHz,DMSO-d6)
δ(ppm):164.9,161.3,154.9,147.9,133.6,130.3,129.0,128.6,125.0,121.0,116.8,
116.2,115.5,110.1,101.8,65.6,56.6,40.9,40.8,28.3；MS(ESI)for(M+Na)+:496.2.
Embodiment 5
4- (3- (3- bromophenyls) -6- (4- hydroxy phenyls) -2- imino group -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -
The preparation of 2- (2- methyl butyl- 3- alkene -2- bases) phenol (5).
Licochalcone A 200mg and 1- (3- bromophenyls) guanidine 164.47mg is added into reactor, plus 50mL ethanol makees solvent,
Plus 0.5mL triethylamines are as catalyst, it is placed on magnetic stirring apparatus and stirs, be heated to 75 DEG C, back flow reaction 8 hours.Reacted
Followed the trail of in journey using thin-layer chromatography, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, remove condensation
Device.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target product
137.33mg, yield is 43.48%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.72(2H,s),9.33(1H,s),7.80(2H,d),
7.41(1H,s),7.05(2H,m),6.85(2H,d),6.79(2H,d),6.41(1H,s),6.30(1H,m),5.00-4.98
(2H,t),4.0(1H,m),3.78(3H,s),2.76-2.50(2H,m),1.44(6H,s)；13C NMR(100MHz,DMSO-d6)
δ(ppm):165.1,161.3,154.9,147.6,146.4,133.5,130.6,129.0,128.5,125.3,123.6,
121.0,120.5,118.6,116.2,116.0,112.7,110.1,101.8,65.5,56.6,40.7,40.8,28.2；MS
(ESI)for(M+H)+:536.1.
Embodiment 6
4- (3- (3- chlorphenyls) -6- (4- hydroxy phenyls) -2- imino group -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -
The preparation of 2- (2- methyl butyl- 3- alkene -2- bases) phenol (6).
Licochalcone A 200mg and 1- (3- chlorphenyls) guanidine 110.32mg is added into reactor, plus 50mL ethanol makees solvent,
Plus 0.5mL triethylamines are as catalyst, it is placed on magnetic stirring apparatus and stirs, be heated to 70 DEG C, back flow reaction 6 hours.Reacted
Followed the trail of in journey using thin-layer chromatography, the carry out degree of monitoring reaction in time, after stopping heating after raw material reaction completely, remove condensation
Device.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target product
138.93mg, yield is 47.97%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.72(2H,s),9.33(1H,s),7.80(2H,d),
7.35(1H,s),7.17(1H,t),6.98-6.50(5H,m),6.47(1H,s),6.30(1H,m),5.00-4.98(2H,m),
4.0(1H,m),3.80(3H,s),2.80-2.57(2H,m),1.44(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):
164.9,161.2,155.0,154.3,147.8,146.3,135.0,133.8,130.4,129.0,127.9,125.7,
121.5,120.7,117.0,116.1,110.1,101.8,65.7,56.6,40.7,40.2,28.3；MS(ESI)for(M+H
)+:490.2.
Embodiment 7
4- (6- (4- hydroxy phenyls) -2- imino groups -3- (3- methoxyphenyls) -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxies
The preparation of base -2- (2- methyl butyl- 3- alkene -2- bases) phenol (7).
Licochalcone A 200mg and 1- (3- aminomethyl phenyls) guanidine 126.92mg is added into reactor, plus 50mL ethanol does molten
Agent, plus 0.5mL triethylamines are as catalyst, are placed on magnetic stirring apparatus and stir, are heated to 80 DEG C, back flow reaction 6 hours.Reaction
During followed the trail of using thin-layer chromatography, in time monitoring reaction carry out degree, after raw material reaction completely after stop heating, remove cold
Solidifying device.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target production
Thing 139.42mg, yield is 48.58%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.72(2H,s),9.33(1H,s),7.80(2H,d,J
=7.52Hz), 7.31 (1H, s), 7.12 (1H, t), 6.86 (2H, d, J=7.52Hz), 6.46 (1H, s), 6.42-6.36 (3H,
m),6.30(1H,m),5.00-4.98(2H,m),4.02(1H,t),3.75(6H,s),2.75-2.55(2H,m),1.44(6H,
s).13C NMR(100MHz,DMSO-d6)δ(ppm):165.1,161.0,160.5,155.0,154.3,147.8,145.0,
133.5,129.7,128.4,125.5,124.1,121.7,117.8,116.5,110.9,108.2,101.8,65.6,55.9,
40.9,40.3,28.3.MS(ESI)for(M+H)+:486.2.
Embodiment 8
4- (6- (4- hydroxy phenyls) -2- imino groups -3- (3- Phenoxyphenyls) -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxies
The preparation of base -2- (2- methyl butyl- 3- alkene -2- bases) phenol (8).
Licochalcone A 200mg and 1- (3- Phenoxyphenyls) guanidine 174.61mg is added into reactor, plus 50mL ethanol is done
Solvent, plus 0.5mL triethylamines are as catalyst, are placed on magnetic stirring apparatus and stir, are heated to 75 DEG C, back flow reaction 6 hours.Instead
Followed the trail of during answering using thin-layer chromatography, the carry out degree of monitoring reaction in time, stop heating after raw material reaction is complete, remove
Condensing unit.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target
Product 139.44mg, yield is 43.08%.
Red solid powder.1H NMR(400MHz,DMSO-d6):9.72(2H,s),9.33(1H,s),7.79(2H,d,J
=7.52Hz), 7.44 (2H, t), 7.19 (1H, s), 7.18-7.15 (4H, m), 6.85 (2H, d, J=7.52Hz), 6.46 (1H,
s),6.40(1H,m),6.30(2H,m),6.19(1H,m),5.00-4.98(2H,m),4.03(1H,t),3.78(3H,s),
2.70-2.56(2H,m),1.44(6H,s).13C NMR(100MHz,DMSO-d6)δ(ppm):164.2,160.3,157.8,
157.3,154.9,147.8,133.0,129.1,128.4,125.2,121.7,118.2,116.0,112.5,111.1,
107.3,103.5,100.2,65.7,56.6,41.6,40.5,28.3.MS(ESI)for(M+H)+:548.3.
Embodiment 9
4- (6- (4- hydroxy phenyls) -2- imino groups -3- (4- methoxyphenyls) -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxies
The preparation of base -2- (2- methyl butyl- 3- alkene -2- bases) phenol (9).
Licochalcone A 200mg and 1- (4- aminomethyl phenyls) guanidine 126.92mg is added into reactor, plus 50mL ethanol does molten
Agent, plus 0.5mL triethylamines are as catalyst, are placed on magnetic stirring apparatus and stir, are heated to 60 DEG C, back flow reaction 6 hours.Reaction
During followed the trail of using thin-layer chromatography, in time monitoring reaction carry out degree, after raw material reaction completely after stop heating, remove cold
Solidifying device.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain target production
Thing 132.43mg, yield is 46.15%.
Brown ceramic powder.1H NMR(400MHz,DMSO-d6):9.73 (2H, s), 9.35 (1H, s), 7.79 (2H, d, J=
7.52Hz), 7.31 (1H, s), 6.95 (2H, d), 6.80 (4H, d, J=7.52Hz), 6.46 (1H, s), 6.30 (1H, m),
5.00-4.96(2H,m),4.03(1H,t),3.80(3H,s),3.75(3H,s),2.70-2.57(2H,m),1.44(6H,s)
.13C NMR(100MHz,DMSO-d6)δ(ppm):164.3,161.3,155.0,154.2,151.4,147.8,136.3,
129.0,128.5,125.0,121.3,116.0,115.6,114.3,110.6,101.8,65.7,56.6,55.4,40.7,
40.3,28.2.MS(ESI)for(M+H)+:486.2.
Embodiment 10
4- (6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -2- imido
(the 2H)-yl of base -5,6- dihydropyridines 1) benzonitrile (10) preparation.
Licochalcone A 200mg and 1- (4- cyano-phenyls) guanidine 123.07mg 1.3mmol, plus 50mL are added into reactor
Ethanol does solvent, plus 0.5mL triethylamines as catalyst, is placed on magnetic stirring apparatus and stirs, is heated to 75 DEG C, back flow reaction 6
Hour.Followed the trail of in course of reaction using thin-layer chromatography, the carry out degree of reaction is monitored in time, stop adding after raw material reaction is complete
Heat, removes condensing unit.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification, dry
To target product 140.42mg, yield is 49.44%.
Class yellow solid powder.1H NMR(400MHz,DMSO-d6):9.71(2H,s),9.32(1H,s),7.80(2H,d,
), J=7.52Hz 7.45 (2H, d, J=7.43Hz), 7.31 (1H, s), 6.88-6.81 (4H, m, J=7.52Hz), 6.46 (1H,
s),6.30(1H,m),5.0-4.98(2H,m),4.04(1H,t),3.78(3H,s),2.75-2.58(2H,m),1.48(6H,
s).13C NMR(100MHz,DMSO-d6)δ(ppm):164.4,161.3,155.0,154.4,147.8,133.1,129.2,
128.5,125.5,121.2,118.0,116.5,114.0,110.8,101.8,100.6,65.7,56.6,40.7,40.2,
28.3.MS(ESI)for(M+H)+:481.2.
Embodiment 11
4- (3- (4- fluorophenyls) -6- (4- hydroxy phenyls) -2- imino group -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxyl groups -
The preparation of 2- (2- methyl butyl- 3- alkene -2- bases) phenol (11).
Licochalcone A 200mg (1mmol) and 1- (4- fluorophenyls) guanidine 117.68mg (1.3mmol) is added into reactor, plus
50mL ethanol does solvent, plus 0.5mL triethylamines as catalyst, is placed on magnetic stirring apparatus and stirs, and is heated to 85 DEG C, backflow is anti-
Answer 6 hours.Followed the trail of in course of reaction using thin-layer chromatography, the carry out degree of monitoring reaction in time is stopped after after raw material reaction completely
Only heat, remove condensing unit.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, column chromatography for separation purification is done
Dry to obtain target product 142.63mg, yield is 50.96%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.73(2H,s),9.36(1H,s),7.77(2H,d,J
=7.52Hz), 7.31 (1H, s), 7.04 (2H, t), 6.85 (2H, d, J=7.52Hz), 6.60 (2H, m), 6.44 (1H, s),
6.30(1H,m),5.00-4.98(2H,m),4.0(1H,t),3.77(3H,s),2.80-2.50(2H,m),1.44(6H,s).13C
NMR(100MHz,DMSO-d6)δ(ppm):165.2,161.3,155.3,154.2,147.7,140.5,133.5,129.5,
128.0,125.7,121.8,116.5,115.1,110.1,101.8,65.5,56.6,40.7,40.2,28.3.MS(ESI)for
(M+H)+:474.2.
Embodiment 12
4- (6- (4- hydroxy phenyls) -2- imino groups -3- (4- Phenoxyphenyls) -2,3,4,5- tetrahydropyrimidine -4- bases) -5- methoxies
The preparation of base -2- (2- methyl butyl- 3- alkene -2- bases) phenol (12).
Licochalcone A 200mg (1mmol) and 1- (4- Phenoxyphenyls) guanidine 174.61mg is added into reactor
(1.3mmol), plus 50mL ethanol do solvent, plus 0.5mL triethylamines as catalyst, are placed on magnetic stirring apparatus and stir, heating
To 75 DEG C, back flow reaction 6 hours.Followed the trail of in course of reaction using thin-layer chromatography, the carry out degree of monitoring reaction in time treats raw material
Stop heating after reaction completely, remove condensing unit.By the mixture of above-mentioned reaction system after being concentrated under reduced pressure, filtering, post layer
Separating-purifying is analysed, target product 167.35mg is dried to obtain, yield is 51.70%.
Brown solid powder.1H NMR(400MHz,DMSO-d6):9.74(2H,s),9.35(1H,s),7.81(2H,d,J
=7.52Hz), 7.43 (2H, t), 7.20 (1H, s), 7.17 (1H, m), 7.08-6.85 (8H, m), 6.46 (1H, s), 6.30
(1H,m),5.01-4.97(2H,m),4.04(1H,t),3.79(3H,s),2.72-2.59(2H,m),1.43(6H,s).13C
NMR(100MHz,DMSO-d6)δ(ppm):165.1,161.0,157.2,154.9,147.8,142.3,137.6,133.0,
129.0,128.3,125.5,121.9,118.4,116.9,116.0,113.4,110.8,101.8,65.7,56.6,40.7,
40.0,28.3.MS(ESI)for(M+H)+:548.3.
Embodiment 13
The antitumor activity test of the compounds of this invention
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 liver cancer cell (HepG2), human lung carcinoma cell (A-549), gastric carcinoma cells (SGC-7901).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。
The antineoplastic cytarabine (Ara-C) of listing 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, with 2 × 104/ mL density is inoculated in 96 well culture plates
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 that the licochalcone A dihydro amino prepared in corresponding embodiment is phonetic
Pyridine analog 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)
Compound 5 and compound 2 show good antitumor activity, chemical combination in the 3 kinds of cell lines tested
Thing 1 and 11 takes second place, and good antitumor activity is also shown in different cell lines.Above test result indicates that, this hair
Bright compound has the work of good antitumor activity, particularly part licochalcone A dihydro aminopyrimidine analog derivative
Property specific cells strain in antitumor activity be better than or be equal to cytarabine, the research available for antineoplastic.
Claims (7)
1. general structure（Ⅰ）Shown compound：
Wherein：R is C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl
Base, nitro, described substituent are 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 original by licochalcone A, guanidine compound
Material, using organic base as catalyst, is synthesized under conditions of ethanol is 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 and guanidine compound, add solvent second
Alcohol is well mixed, and is added organic alkali catalyst triethylamine, is heated to 60 DEG C ~ 85 DEG C, back flow reaction 3 ~ 8 hours；
（2）By step（1）After the solidliquid mixture of reaction system is concentrated under reduced pressure, filtering, column chromatography for separation purification is dried to obtain mesh
Mark product.
4. synthetic method according to claim 3, it is characterised in that：Step（1）Described in licochalcone A：Guanidine
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 70 DEG C ~
80℃。
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 liver cancer, lung cancer, stomach cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016112660317 | 2016-12-31 | ||
| CN201611266031.7A CN106674129A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107311937A true CN107311937A (en) | 2017-11-03 |
Family
ID=58850132
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611266031.7A Withdrawn CN106674129A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound |
| CN201710650028.3A Pending CN107311937A (en) | 2016-12-31 | 2017-08-02 | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611266031.7A Withdrawn CN106674129A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN106674129A (en) |
Families Citing this family (4)
| 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 |
| 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 |
| 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 |
Citations (1)
| 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 |
-
2016
- 2016-12-31 CN CN201611266031.7A patent/CN106674129A/en not_active Withdrawn
-
2017
- 2017-08-02 CN CN201710650028.3A patent/CN107311937A/en active Pending
Patent Citations (1)
| 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)
| 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 |
|---|---|
| CN106674129A (en) | 2017-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101580477B (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
| CN104292170B (en) | There is quinazoline-Arylurea derivatives and the application thereof of antitumor action | |
| CN101628912B (en) | Anti-tumor compound containing triazole heterocyclic structure and application thereof | |
| CN107311937A (en) | The licochalcone A dihydro amino-metadiazine compound 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 | |
| CN107235917A (en) | The licochalcone A Dihydropyrimidines 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 | |
| CN107540658A (en) | A kind of lappaconitine azepine cinnamic acid heterozygote and its synthetic method for having antitumor activity | |
| CN107382864A (en) | A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN108997341B (en) | Amide-troger's base derivative and its synthesis method and use | |
| CN104230915B (en) | Phenylpiperazine derivatives containing thiazolidinedione and preparation method thereof and purposes | |
| CN106966986B (en) | N- benzyl heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof | |
| CN107200731B (en) | Thiazole ring-containing pyridone derivative and preparation method and application thereof | |
| CN108864089A (en) | A kind of new indole and pyridone drug molecule and its preparation method and application | |
| CN108033913A (en) | A kind of pyrazoline quinoline derivant and its preparation method and application | |
| CN105237512B (en) | The 6 substitution formic acid of 1 ((base of 1 substituted-phenyl, 1,2,3 triazole 4) methyl) 4 carbonyl quinoline 3 or pharmaceutical salts, preparation and application | |
| CN108864110B (en) | Naphthoquinone pyran derivative and synthesis method and application thereof | |
| 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 | |
| CN111875588A (en) | Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof | |
| CN104230786B (en) | Indole-structure-containing compound with anti-tumor activity and synthesis method thereof | |
| CN104193749A (en) | Double-spiro compound containing isatin mother nucleus with antineoplastic activity and synthesis method thereof | |
| CN104402886A (en) | 7-aza isatin nuclear parent-containing dispirocyclic compound with antitumor activity and synthetic method thereof | |
| CN107445903A (en) | A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method | |
| CN107235915A (en) | A kind of licochalcone A with antitumor activity and buformin 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: 20171103 |
|
| WD01 | Invention patent application deemed withdrawn after publication |