CN105017156A - 2-substituted phenyl-4-methyl-5-(3,4,5-trimethoxy benzoyl)-1H-imidazole compound and preparation thereof - Google Patents

2-substituted phenyl-4-methyl-5-(3,4,5-trimethoxy benzoyl)-1H-imidazole compound and preparation thereof Download PDF

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Publication number
CN105017156A
CN105017156A CN201410155351.XA CN201410155351A CN105017156A CN 105017156 A CN105017156 A CN 105017156A CN 201410155351 A CN201410155351 A CN 201410155351A CN 105017156 A CN105017156 A CN 105017156A
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methyl
compound
trimethoxybenzoy
substituting group
group phenyl
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Inventor
张为革
张明亮
吴英良
文志勇
齐欢
左代英
杨欢
韩春明
程增进
徐启乐
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Abstract

The invention belongs to the technical field of medicine and relates to a 2-substituted phenyl-4-methyl-5-(3,4,5-trimethoxy benzoyl)-1H-imidazole compound and its analog and a preparation method and an application thereof, specifically to a compound and its preparation method and an application of the compound used as a tumor cell proliferation inhibitor in the preparation of anti-cancer medicines. The structure of the compound is as shown in M, wherein R1-R4, X and Y are as mentioned in the specification.

Description

2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound and preparation thereof
Technical field
The invention belongs to medical art; relate to a kind of 2-substituting group phenyl-4-methyl-5-(3; 4; 5-trimethoxybenzoy)-1H-glyoxaline compound and its analogue and preparation method thereof and purposes; exactly, relate to this compounds and preparation method thereof and prepare the application in anti-tumor drug as tumor cell proliferation inhibitor.
Background technology
Malignant tumour is the serious disease threatening human health and life, is the first lethal cause of disease in China.Find and find that treatment is the current key subjects faced with the new drug of prophylaxis of tumours.
Combretastatin A-4 (CA-4) is separated the cis-stilbene class natural product obtained from the willow of South Africa, and its chemical name is (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents very strong inhibition tumor cell proliferation activity, and its prodrug CA-4 phosphoric acid salt (CA-4P) enters three phase clinical investigation phase in the U.S..With CA-4 for lead compound designs, synthesizes the existing report in a large number of research of new active compound for anti tumor, but most CA-4 analogue exists or activity is not high enough or toxicity is comparatively large or synthesize the shortcomings such as more complicated.Relevant report see Pettit G.R., et al.Experiential, 1989,45,209; Nam N.H.Current Medicinal Chemistry, 2003,10,1697; Tron G.C., et al.Journal of Medicinal Chemistry, 2006,49 (11), 3033-3044.
2,5-diarylimidazoles has relevant report as antitumor activity.This compounds presents proliferation inhibition activity (see Li W., et al.Journal of Medicinal Chemistry, 2010,53 (20) 7414) to knurl strains such as A375, B16-F1, WM164, LNCaP, PC-3, Du145 and PCC-1.It is significant to note that: the important feature of this compounds is characterized as 4 upper unsubstituteds of imidazole ring.
2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound not yet has relevant report at present as antitumor activity.
Summary of the invention
The object of the invention is to the analog designed, synthesis has the Combretastatin A-4 of good anti-tumor activity, i.e. 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound and its analogue; Good result is manifested in the anti-tumor activity test in vivo and in vitro of prepared compound.
The present invention relates to the compound of the formula M be defined as follows:
Wherein,
(1) X is H, OH, OR 5;
R 5for C 1-C 6alkyl;
Y is C=O, C=N-OH, C=N-OR 6;
R 6for C 1-C 6alkyl;
R 1~ R 4be hydrogen, C independently of one another 1-C 6alkyl, hydroxyl, C 1-C 6alkyl oxy, benzyl oxygen base, C 1-C 6alkylamino, halogen atom, nitro, amino, two C 1-C 6alkylamino, C 1-C 6acyl amino.
(2) compound of the formula M of above-mentioned (1):
Wherein,
R 5for C 1-C 5alkyl; Preferable methyl, ethyl, n-propyl;
(3) compound of the formula M of above-mentioned (1) or (2):
Wherein,
R 6for C 1-C 5alkyl, preferable methyl, ethyl, n-propyl;
(4) compound of the formula M of above-mentioned (1) or (2) or (3):
Wherein:
R 1~ R 4be hydrogen, C independently of one another 1-C 5alkyl, hydroxyl, C 1-C 5alkyl oxy, benzyl oxygen base, C 1-C 5alkylamino, halogen atom, nitro, amino, two C 1-C 5alkylamino, C 1-C 5acyl amino;
(5) compound of the formula M of above-mentioned (1) or (2) or (3) or (4):
Wherein:
R 1~ R 4be hydrogen, C independently of one another 1-C 4alkyl, hydroxyl, C 1-C 4alkyl oxy, benzyl oxygen base, C 1-C 4alkylamino, halogen atom, nitro, amino, two C 1-C 4alkylamino, C 1-C 4acyl amino;
(6) compound of arbitrary formula M in above-mentioned (1)-(5):
Wherein:
X is H, OH, OCH 3;
(7) compound of arbitrary formula M in above-mentioned (1)-(6):
Wherein:
Y is C=O, C=N-OH, C=N-OCH 3;
(8) compound of arbitrary formula M in above-mentioned (1)-(7):
R 1~ R 4be hydrogen, methoxyl group, methyl, chlorine, bromine, hydroxyl, nitro, benzyl oxygen base, amino independently of one another.
Compound of the present invention also comprises the pharmaceutically acceptable non-toxic salt and hydrate thereof that derivative shown in structure above formed, and these pharmaceutically acceptable non-toxic salt comprise the salt that this derivative is formed with acid.Described acid can be the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid or the organic acid being selected from acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.The hydration number of described hydrate is any real number in 0 ~ 16.
The present invention's preferred part of compounds structure is as follows:
Compound 1
2-phenyl-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 2
2-(4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 3
2-(4-aminomethyl phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 4
2-(4-chloro-phenyl-)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 5
2-(3-nitro-4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 6
2-(3-benzyloxy-4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 7
2-phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 8
2-(4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 9
2-(4-aminomethyl phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 10
2-(4-chloro-phenyl-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 11
2-(3-nitro-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 12
2-(3-benzyloxy-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 13
2-(4-bromophenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 14
2-(3-chloro-phenyl-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 15
2-(3,4-Dimethoxyphenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 16
2-(the bromo-4-p-methoxy-phenyl of 3-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 17
2-(3,4-dichlorophenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 18
2-(2,4 dichloro benzene base)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 19
2-(3-hydroxyl-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 20
2-(3-amino-4-methoxyl phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 21
2-phenyl-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 22
2-(4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 23
2-(4-aminomethyl phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 24
2-(4-chloro-phenyl-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 25
2-(3-nitro-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 26
2-(3-benzyloxy-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-miaow
Azoles
Compound 27
2-(4-bromophenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 28
2-(3-chloro-phenyl-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 29
2-(3,4-Dimethoxyphenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 30
2-(the bromo-4-p-methoxy-phenyl of 3-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 31
2-(3,4-dichlorophenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 32
2-(2,4 dichloro benzene base)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 33
2-(3-hydroxyl-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 34
2-(3-amino-4-methoxyl phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles
Compound 35
2-(3,4-Dimethoxyphenyl)-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketoxime-1H-imidazoles
Compound 36
2-(4-methylphenyl)-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketone-O-methyloxime-1H-imidazoles.
2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound of the present invention can obtain according to following reaction scheme synthesis:
The preparation of 1-(3,4,5-trimethoxyphenyl)-2-nitroso-group-1,3-dimethyl diketone (II)
By the 1-(3 of 1 equivalent, 4,5-trimethoxyphenyl)-1,3-dimethyl diketone (preparation method's document: Sonar A.S., et al.J.Chem.Pharm.Res., 2011,3,752) be dissolved in glacial acetic acid, under condition of ice bath, drip the sodium nitrite in aqueous solution of 1-2.5 equivalent, ice bath 10-60 minute, at room temperature reaction 1-12 hour; After completion of the reaction, be poured into water by reaction solution, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain Compound II per through column chromatographic isolation and purification, yield 45% ~ 95%.
The preparation of 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound (III)
The 1-(3,4,5-trimethoxyphenyl)-2-nitroso-group-1,3-dimethyl diketone (II) of 1 equivalent is dissolved in glacial acetic acid, adds the phenyl aldehyde of 1.5-4.5 equivalent, 1.5-4.5 equivalent ammonium acetate successively, 10-100 DEG C of reaction 12-120 hour; Be poured into water by reaction solution, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound III a through column chromatographic isolation and purification, yield 30% ~ 85%;
The compound III a of 1 equivalent is dissolved in anhydrous acetonitrile, adds the trimethylchlorosilane of 2.0-5.0 equivalent and the sodium iodide of 2.0-5.0 equivalent, nitrogen protection, 10-100 DEG C of reaction 2-12 hour; Be poured into water by reaction solution, add 10% aqueous sodium hydroxide solution, be then extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound III b through column chromatographic isolation and purification, yield 50% ~ 90%;
The compound III a of 1 equivalent is dissolved in dry DMF, adds the potash solid of 2.0-5.0 equivalent, under condition of ice bath, drip the halogenated alkyl thing of 2.0-5.0 equivalent, alkyl sulfonic ester or alkyl sulfuric ester, then 10-100 DEG C of reaction 2-12 hour; After completion of the reaction, reaction solution is poured into water, and is extracted with ethyl acetate, and organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound III c through column chromatographic isolation and purification, yield 68% ~ 90%.
The preparation of 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketoxime-1H-glyoxaline compound and analogue (IV) thereof
By the 2-substituting group phenyl-4-methyl-5-(3 of 1 equivalent, 4,5-trimethoxybenzoy)-1H-glyoxaline compound (III) is dissolved in dehydrated alcohol, add hydroxylamine hydrochloride or the O-alkyl hydroxylamine hydrochloride of 2.0-8.0 equivalent, 2.0-8.0 equivalent sodium acetate, 10-100 DEG C of reaction 4-24 hour; React complete, be poured into water, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound IV through column chromatographic isolation and purification, yield 40% ~ 95%.
2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound provided by the present invention and its method for preparing analogue simple possible, yield is better.
2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound and its analogue have the effect for the treatment of tumor disease preferably, can be used for preparing antitumor drug.
Embodiment
To contribute to understanding the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, Bruker ARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by Brukee Esqure2000, Shimadzu GCMS-QP5050A type mass spectrograph.
The preparation of embodiment 1:2-phenyl-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 1)
1-phenyl-2-nitroso-group-1,3-dimethyl diketone (0.500g, 1.789mmol) is dissolved in 20ml glacial acetic acid, add phenyl aldehyde (0.475g successively, 4.473mmol), ammonium acetate (0.365g, 0.473mmol), room temperature reaction 12 hours; After completion of the reaction, reaction solution is poured into water, is extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtain compound 2-phenyl-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles 0.528g through column chromatographic isolation and purification, yield is 80.6%. 1H-NMR(400MHz,CDCl 3)δ2.23(3H,s),3.91(6H,s),3.97(3H,s),7.03(2H,s),7.48(2H,s),8.10(1H,s);8.19(2H,s);MS(ESI):[M+H] +=369.1。
The preparation of embodiment 2:2-(4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 2)
Except using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical, yield is 86.6%. 1H-NMR(400MHz,CDCl 3)δ2.23(3H,s),3.88(3H,s),3.92(6H,s),3.96(3H,s),7.01(2H,s),7.04(1H,d),8.21(2H,d);MS(ESI):[M+H] +=399.1。
The preparation of embodiment 3:2-(4-aminomethyl phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 3)
Except using corresponding raw material, prepare compound 3 with the method that embodiment 1 is identical, yield is 84.2%. 1H-NMR(400MHz,CDCl 3)δ2.24(3H,s),2.42(3H,s),3.92(6H,s),3.96(3H,s),7.02(2H,s),7.32(2H,d),8.08(2H,d),8.10(1H,s);MS(ESI):[M+H] +=383.2。
The preparation of embodiment 4:2-(4-chloro-phenyl-)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 4)
Except using corresponding raw material, prepare compound 4 with the method that embodiment 1 is identical, yield is 84.8%. 1H-NMR(400MHz,CDCl 3)δ2.27(3H,s),3.91(6H,s),3.96(3H,s),7.02(2H,s),7.46(2H,s),8.10(1H,s),8.18(2H,s);MS(ESI):[M+H] +=403.1。
The preparation of embodiment 5:2-(3-nitro-4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 5)
Except using corresponding raw material, prepare compound 5 with the method that embodiment 1 is identical, yield is 89.8%. 1H-NMR(400MHz,CDCl 3)δ2.26(3H,s),3.92(6H,s),3.96(3H,s),4.04(3H,s),7.02(2H,s),7.21(1H,d),8.44(1H,d),8.77(1H,s);MS(ESI):[M+H] +=444.1。
The preparation of embodiment 6:2-(3-benzyloxy-4-p-methoxy-phenyl)-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 6)
Except using corresponding raw material, prepare compound 6 with the method that embodiment 1 is identical, yield is 86.3%. 1H-NMR(400MHz,CDCl 3)2.15(3H,s),3.85(6H,s),3.91(3H,s),3.96(3H,s),5.17(2H,s),6.92(1H,s),7.01(2H,s),7.35(3H,m),7.47(2H,d),7.82(1H,d),8.20(1H,s);MS(ESI):[M+H] +=505.2。
The preparation of embodiment 7:2-phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 7)
By compound 2-phenyl-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.528g, 1.442mmol) be dissolved in anhydrous acetonitrile, add NaI (0.860g, 5.739mmol), trimethylchlorosilane (0.620g, 5.739mmol) successively, nitrogen protection, back flow reaction 4 hours; After completion of the reaction, be poured into water, be extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtain 2-phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazolium compounds 7 through column chromatographic isolation and purification, yield is 90.2%. 1H-NMR(400MHz,CDCl 3)δ2.50(3H,s),3.91(6H,s),3.94(3H,s),7.47(5H,m),7.96(2H,d),10.92(1H,br);MS(ESI):[M+H] +=353.1。
The preparation of embodiment 8:2-(4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 8)
Except using corresponding raw material, prepare compound 8 with the method that embodiment 7 is identical, yield is 87.9%. 1H-NMR(400MHz,CDCl 3)δ2.47(3H,s),3.83(3H,s),3.90(6H,s),3.93(3H,s),6.91(2H,d),7.42(2H,br),7.94(2H,s);MS(ESI):[M+H] +=383.1。
The preparation of embodiment 9:2-(4-aminomethyl phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 9)
Except using corresponding raw material, prepare compound 9 with the method that embodiment 7 is identical, yield is 87.2%. 1H-NMR(400MHz,CDCl 3)δ2.37(3H,s),2.49(3H,s),3.90(6H,s),3.93(3H,s),7.21(2H,d),7.41(2H,br),7.89(2H,d);MS(ESI):[M+H] +=367.1。
The preparation of embodiment 10:2-(4-chloro-phenyl-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 10)
Except using corresponding raw material, prepare compound 10 with the method that embodiment 7 is identical, yield is 87.9%. 1H-NMR(400MHz,CDCl 3)δ2.52(3H,s),3.92(6H,s),3.95(3H,s),7.40(2H,br),7.51(2H,d),7.96(2H,d);MS(ESI):[M+H] +=387.1。
The preparation of embodiment 11:2-(3-nitro-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 11)
Except using corresponding raw material, prepare compound 11 with the method that embodiment 7 is identical, yield is 86.2%. 1H-NMR(400MHz,CDCl 3)δ2.51(3H,s),3.89(6H,s),3.93(3H,s),3.95(3H,s),7.08(1H,d),7.42(2H,s),8.25(1H,dd),8.50(1H,d);MS(ESI):[M+H] +=428.1,[2M+H] +=855.2。
The preparation of embodiment 12:2-(3-benzyloxy-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 12)
Except using corresponding raw material, prepare compound 12 with the method that embodiment 7 is identical, yield is 89.4%. 1H-NMR(400MHz,CDCl 3)δ2.42(3H,s),3.84(6H,s),3.85(3H,s),3.92(3H,s),5.05(2H,s),6.86(1H,d),7.32(7H,m),7.61(1H,dd),7.32(1H,dd);MS(ESI):[M+H] +=489.2。
The preparation of embodiment 13:2-(4-bromophenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 13)
Except using corresponding raw material, prepare compound 13 with the method that embodiment 7 is identical, yield is 89.4%. 1H-NMR(400MHz,CDCl 3)δ2.49(3H,s),3.89(6H,s),3.94(3H,s),7.41(2H,s),7.52(2H,d),7.89(2H,d);MS(ESI):[M+H] +=431.1。
The preparation of embodiment 14:2-(3-chloro-phenyl-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 14)
Except using corresponding raw material, prepare compound 14 with the method that embodiment 7 is identical, yield is 90.2%. 1H-NMR(400MHz,CDCl 3)δ2.51(3H,br),3.89(6H,s),3.93(3H,s),7.37(4H,br),7.84(1H,s),7.97(1H,s);MS(ESI):[M+H] +=387.0。
The preparation of embodiment 15:2-(3,4-Dimethoxyphenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 15)
Except using corresponding raw material, prepare compound 15 with the method that embodiment 7 is identical, yield is 88.9%. 1H-NMR(400MHz,CDCl 3)δ2.46(3H,s),3.84(3H,s),3.88(9H,s),3.91(3H,s),6.84(1H,d),7.41(2H,br),7.58(1H,d),7.65(1H,s);MS(ESI):[M+H] +=413.1。
The preparation of embodiment 16:2-(the bromo-4-p-methoxy-phenyl of 3-)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 16)
Except using corresponding raw material, prepare compound 16 with the method that embodiment 7 is identical, yield is 88.4%. 1H-NMR(400MHz,CDCl 3)δ2.48(3H,s),3.89(9H,s),3.93(3H,s),6.86(1H,d),7.38(2H,s),7.98(1H,dd),8.22(1H,d);MS(ESI):[M+H] +=461.0。
The preparation of embodiment 17:2-(3,4-dichlorophenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 17)
Except using corresponding raw material, prepare compound 17 with the method that embodiment 7 is identical, yield is 88.3%. 1H-NMR(400MHz,CDCl 3)δ2.50(3H,s),3.88(6H,s),3.94(3H,s),7.44(3H,d),7.82(1H,dd),8.08(1H,d);MS(ESI):[M+H] +=421.0。
The preparation of embodiment 18:2-(2,4 dichloro benzene base)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 18)
Except using corresponding raw material, prepare compound 18 with the method that embodiment 7 is identical, yield is 89.1%. 1H-NMR(400MHz,CDCl 3)δ2.59(3H,s),3.91(6H,s),3.94(3H,s),7.34(1H,dd),7.46(1H,d),7.53(2H,br),8.16(1H,d);MS(ESI):[M+H] +=421.0。
The preparation of embodiment 19:2-(3-hydroxyl-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 19)
By 2-(3-benzyloxy-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 1.025mmol) dissolved by 20mL ethyl acetate, by catalytic amount Pd/C (0.010g) catalytic hydrogenation, room temperature reaction 4 hours; After completion of the reaction, be poured into water, be extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtains compound 19 through column chromatographic isolation and purification, and yield is 87.9%. 1H-NMR(400MHz,DMSO)δ2.40(3H,s),3.78(3H,s),3.86(9H,d),7.16(1H,d),7.29(1H,d),7.36(2H,br),7.59(1H,s);MS(ESI):[M+H] +=399.1。
The preparation of embodiment 20:2-(3-amino-4-methoxyl phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 20)
By 2-(3-nitro-4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 1.171mmol) in reaction flask, add ferrous sulfate (3.255g, 11.712mmol), 20mL ammoniacal liquor, back flow reaction 1 hour; After completion of the reaction, be poured into water, be extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtains compound 20 through column chromatographic isolation and purification, and yield is 40.8%. 1H-NMR(400MHz,CDCl 3)δ3.50(3H,s),3.73(3H,s),3.74(3H,s),3.76(6H,s),6.42(2H,s),6.98(1H,d),7.32(1H,dd),7.84(1H,d);MS(ESI):[M+H] +=398.1。
The preparation of embodiment 21:2-phenyl-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (chemical combination 21)
By compound 2-phenyl-1-hydroxy-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.050g, 0.131mmol) be dissolved in dry DMF, add salt of wormwood (0.072g, 0.524mmol), methyl-sulfate (0.066g, 0.524mmol), room temperature reaction 2 hours; After completion of the reaction, reaction solution is poured into water, and is extracted with ethyl acetate, and organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound 21 through column chromatographic isolation and purification, yield 89.7%. 1H-NMR(400MHz,CDCl 3)δ2.23 (3H,s),3.91(6H,s),3.96(3H,s),3.98(3H,s),7.13(2H,s),7.51(3H,m),8.14(2H,d)MS(ESI):[M+H] +=383.1。
The preparation of embodiment 22:2-(4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 22)
Except using corresponding raw material, prepare compound 22 with the method that embodiment 21 is identical, yield is 88.9%. 1H-NMR(400MHz,CDCl 3)δ2.35(3H,s),3.90(3H,s),3.92(6H,s),3.97(3H,s),4.04(3H,s),7.07(2H,d),7.12(2H,s),8.23(2H,s);MS(ESI):[M+H] +=413.1。
The preparation of embodiment 23:2-(4-aminomethyl phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 23)
Except using corresponding raw material, prepare compound 23 with the method that embodiment 21 is identical, yield is 87.8%. 1H-NMR(400MHz,CDCl 3)δ2.23(3H,s),2.44(3H,s),3.91(6H,s),3.96(6H,d),7.13(2H,s),7.32(2H,d),8.04(2H,d)MS(ESI):[M+H] +=397.1。
The preparation of embodiment 24:2-(4-chloro-phenyl-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 24)
Except using corresponding raw material, prepare compound 24 with the method that embodiment 21 is identical, yield is 90.8%. 1H-NMR(400MHz,CDCl 3)2.29(3H,s),3.91(6H,s),3.97(3H,s),4.03(3H,s),7.12(2H,s),7.52(2H,d),8.16(2H,d);MS(ESI):[M+H] +=417.1。
The preparation of embodiment 25:2-(3-nitro-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 25)
Except using corresponding raw material, prepare compound 25 with the method that embodiment 21 is identical, yield is 90.2%. 1H-NMR(400MHz,CDCl 3)2.20(3H,s),3.91(6H,s),3.96(3H,s),4.03(3H,s),4.05(3H,s),7.12(2H,s),7.22(1H,d),8.34(1H,dd),8.65(1H,d);MS(ESI):[M+H] +=458.1。
The preparation of embodiment 26:2-(3-benzyloxy-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 26)
Except using corresponding raw material, prepare compound 26 with the method that embodiment 21 is identical, yield is 92.4%. 1H-NMR(400MHz,CDCl 3)2.18(3H,s),3.77(3H,s),3.90(6H,s),3.95(3H,s),3.97(3H,s),5.25(2H,s),7.01(1H,d),7.10(2H,s),7.31(1H,d),7.38(2H,t),7.48(2H,d),7.73(1H,d),7.76(1H,s);MS(ESI):[M+H] +=519.2。
The preparation of embodiment 27:2-(4-bromophenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 27)
Except using corresponding raw material, prepare compound 27 with the method that embodiment 21 is identical, yield is 90.5%. 1H-NMR(400MHz,CDCl 3)δ2.22(3H,s),3.91(6H,s),3.96(3H,s),4.00(3H,s),7.12(2H,s),7.64(2H,d),8.03(2H,d);MS(ESI):[M+H] +=461.1。
The preparation of embodiment 28:2-(3-chloro-phenyl-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 28)
Except using corresponding raw material, prepare compound 28 with the method that embodiment 21 is identical, yield is 93.5%. 1H-NMR(400MHz,CDCl 3)δ2.21(3H,s),3.91(6H,s),3.95(3H,s),4.00(3H,s),7.12(2H,s),7.44(2H,d),8.03(2H,t),8.15(1H,s);MS(ESI):[M+H] +=417.1。
The preparation of embodiment 29:2-(3,4-Dimethoxyphenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 29)
Except using corresponding raw material, prepare compound 29 with the method that embodiment 21 is identical, yield is 93.8%. 1H-NMR(400MHz,CDCl 3)δ2.18(3H,s),3.88(6H,s),3.92(3H,s),3.94(3H,s),3.96(6H,s),6.96(1H,d),7.09(2H,s),7.67(1H,d),7.74(1H,dd);MS(ESI):[M+H] +=443.1。
The preparation of embodiment 30:2-(the bromo-4-p-methoxy-phenyl of 3-)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 30)
Except using corresponding raw material, prepare compound 30 with the method that embodiment 21 is identical, yield is 95.2%. 1H-NMR(400MHz,CDCl 3)δ2.21(3H,s),3.92(6H,s),3.96(3H,s),3.98(3H,s),3.99(3H,s),7.02(1H,d),7.12(2H,s),8.10(1H,dd),8.36(1H,d);MS(ESI):[M+H] +=491.0。
The preparation of embodiment 31:2-(3,4-dichlorophenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 31)
Except using corresponding raw material, prepare compound 31 with the method that embodiment 21 is identical, yield is 93.7%. 1H-NMR(400MHz,CDCl 3)δ2.20(3H,s),3.89(6H,s),3.95(3H,s),4.01(3H,s),7.10(2H,s),7.57(1H,d),7.99(1H,d),8.25(1H,s);MS(ESI):[M+H] +=451.0。
The preparation of embodiment 32:2-(2,4 dichloro benzene base)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 32)
Except using corresponding raw material, prepare compound 32 with the method that embodiment 21 is identical, yield is 94.3%. 1H-NMR(400MHz,CDCl 3)δ2.29(3H,s),3.81(3H,s),3.92(6H,s),3.96(3H,s),7.14(2H,s),7.40(1H,dd),7.55(1H,d),7.57(1H,d);MS(ESI):[M+H] +=451.0。
The preparation of embodiment 33:2-(3-hydroxyl-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 33)
By 2-(3-benzyloxy-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 0.965mmol), then 20mL ethyl acetate is used to be solvent, add catalytic amount Pd/C (0.010g), room temperature reaction 4 hours; After completion of the reaction, be poured into water, be extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtains compound 32 through column chromatographic isolation and purification, and yield is 96.7%. 1H-NMR(400MHz,CDCl 3)δ2.23(3H,s),3.91(6H,s),3.96(9H,t),6.96(1H,d),7.12(2H,s),7.68(1H,d),7.73(1H,s);MS(ESI):[M+H] +=429.1。
The preparation of embodiment 34:2-(3-amino-4-methoxyl phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (compound 34)
By 2-(3-nitro-4-p-methoxy-phenyl)-1-methoxyl group-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 1.094mmol) in reaction flask, add ferrous sulfate (3.042g, 10.941mmol), 20mL ammoniacal liquor, back flow reaction 1 hour; After completion of the reaction, be poured into water, be extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Evaporated under reduced pressure solvent, obtains compound 34 through column chromatographic isolation and purification, and yield is 37.9%. 1H-NMR(400MHz,CDCl 3)δ2.22(3H,s),3.91(6H,s),3.92(3H,s),3.96(6H,d),6.88(1H,d),7.11(2H,s),7.52(1H,d),7.56(1H,dd);MS(ESI):[M+H] +=428.1。
The preparation of embodiment 35:2-(3,4-Dimethoxyphenyl)-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketoxime-1H-imidazoles (compound 35)
By 2-(3,4-Dimethoxyphenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 1.214mmol) be dissolved in dehydrated alcohol, add oxammonium hydrochloride (0.838g, 12.143mmol), sodium acetate (0.995g, 12.143mmol), back flow reaction 9 hours; React complete, be poured into water, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound 35 through column chromatographic isolation and purification, yield 90.5%. 1H-NMR(400MHz,CDCl 3)δ1.88(3H,s),3.75(6H,s),3.84(3H,s),3.86(6H,d),3.88(3H,s),6.65(2H,s),6.84(1H,d),7.41(1H,d),7.57(1H,s);MS(ESI):[M+H] +=428.1。
The preparation of embodiment 36:2-(4-methylphenyl)-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketone-O-methyloxime-1H-imidazoles (compound 36)
By 2-(4-p-methoxy-phenyl)-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-imidazoles (0.500g, 1.309mmol) be dissolved in dehydrated alcohol, add hydrochloric acid methoxy azanol (1.087g, 13.092mmol), sodium acetate (1.074g, 13.092mmol), back flow reaction 12 hours; React complete, be poured into water, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying; Remove solvent under reduced pressure, obtain compound 36 through column chromatographic isolation and purification, yield 89.6.5%. 1H-NMR(400MHz,CDCl 3)δ1.91(3H,s),1.98(1.7H,s),2.33(3H,s),2.37(1.7H,s),3.75(6H,s),3.80(6H,s),3.83(3.3H,s),3.85(3.1H,s),6.56(2H,d),6.65(1.12H,d),7.14(2H,s),7.22(1.2H,s),7.86(1.3H,d),7.90(2H,d);MS(ESI):[M+H] +=398.1。
Embodiment 59: the anti tumor activity in vitro test of compound of the present invention
External activity testing method and result as follows: wherein, with CA-4 and clinical conventional antitumor drug Zorubicin (Doxorubicin) for positive control experiment group.
Anti-tumor activity body outer screening test-1
Screening method: tetrazolium (MTT) reduction method
Cell strain: human peripheral leukemia T cell Jurkat cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Anti-tumor activity body outer screening test-2
Screening method: tetrazolium (MTT) reduction method
Cell strain: human oral cavity epithelial cancer cells KB cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (MTT) reduction method
Cell strain: human cervical carcinoma cell Hela cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Embodiment 60: anti-tumor activity test in the animal body of compound of the present invention
Select the good compound 8 of external activity and compound 15 to carry out anti-tumor activity test in animal body, model used is mouse S-180 sarcoma model, and positive control medicine is clinical conventional antitumor drug Fluracil (Fluorouracil).
Experimental technique: the S-180 knurl kind selecting 18-22 gram of female KM mouse and well-grown 7-11 days, tumor tissue is made cell suspension, is seeded to right side of mice armpit subcutaneous, about 1.0-2.0 × 106 cell/only, inoculate random point cage after 24 hours, continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, to weigh, knurl weight, calculate each group of average knurl weight, obtain tumor control rate by following formula and carry out t inspection.
Tumor control rate=[(blank group average knurl weight-treatment group average knurl weight)/(the average knurl weight of blank group)] × 100%
Experimental result is in Table-2.
Embodiment 61: in the animal body of compound of the present invention, acute toxicity is tentatively tested
The good compound 8 of anti-tumor activity and compound 15 in animal body is selected to carry out acute toxic test in animal body.
Select each 10 of 18-22 gram of female KM mouse, respectively after intraperitoneal injection compound 8, each 500mg/kg of compound 15, occur that autonomic movement suppresses, writhing, and the suppression to body weight gain, food ration, water uptake, but have no dead mouse.After the drug withdrawal a few days, surviving animals recovers normal.The LD50 value of intraperitoneal administration is greater than 500mg/Kg.
Table-1
Table-2

Claims (10)

1. formula M 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound and and analogue:
Wherein,
X is H, OH, OR 5;
R 5for C 1-C 6alkyl;
Y is C=O, C=N-OH, C=N-OR 6;
R 6for C 1-C 6alkyl;
R 1~ R 4be hydrogen, C independently of one another 1-C 6alkyl, hydroxyl, C 1-C 6alkyl oxy, benzyl oxygen base, C 1-C 6alkylamino, halogen atom, nitro, amino, two C 1-C 6alkylamino, C 1-C 6acyl amino.
2. 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound according to claim 1 and its analogue, is characterized in that:
R 5for C 1-C 5alkyl, preferable methyl, ethyl, n-propyl.
3. 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound according to claim 1 and 2 and its analogue, is characterized in that:
R 6for C 1-C 5alkyl, preferable methyl, ethyl, n-propyl.
4. 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound in claim 1-3 described in any one and its analogue, is characterized in that:
R 1~ R 4be hydrogen, C independently of one another 1-C 5alkyl, hydroxyl, C 1-C 5alkyl oxy, benzyl oxygen base, C 1-C 5alkylamino, halogen atom, nitro, amino, two C 1-C 5alkylamino, C 1-C 5acyl amino, preferred hydrogen, C 1-C 4alkyl, hydroxyl, C 1-C 4alkyl oxy, benzyl oxygen base, C 1-C 4alkylamino, halogen atom, nitro, amino, two C 1-C 4alkylamino, C 1-C 4acyl amino.
5., according to 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of claim 1-4 described in any one and its analogue, it is characterized in that:
X is H, OH, OCH 3.
6., according to 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of claim 1-5 described in any one and its analogue, it is characterized in that:
Y is C=O, C=N-OH, C=N-OCH 3.
7., according to 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of claim 1 ~ 6 described in any one and its analogue, it is characterized in that:
This compounds also comprises 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy) the pharmaceutically acceptable salt that formed of-1H-glyoxaline compound and its analogue and hydrate thereof, the pharmaceutically acceptable non-toxic salt formed is the salt that this derivative is formed with acid; The hydration number of described hydrate is any real number in 0 ~ 16, and described acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.
8. the preparation method of 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound as claimed in claim 1 and its analogue, is characterized in that:
the preparation of 1-(3,4,5-trimethoxyphenyl)-2-nitroso-group-1,3-dimethyl diketone (II):
By the 1-(3,4,5-trimethoxyphenyl)-1 of 1 equivalent, 3-dimethyl diketone is dissolved in glacial acetic acid, under condition of ice bath, drips the sodium nitrite in aqueous solution of 1-2.5 equivalent, ice bath 10-60 minute, at room temperature reaction 1-12 hour, after completion of the reaction, reaction solution is poured into water, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains Compound II per through column chromatographic isolation and purification;
The preparation of 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound (III):
By the 1-(3 of 1 equivalent, 4,5-trimethoxyphenyl)-2-nitroso-group-1,3-dimethyl diketone (II) is dissolved in glacial acetic acid, adds the phenyl aldehyde of 1.5-4.5 equivalent, 1.5-4.5 equivalent ammonium acetate successively, 10-100 DEG C of reaction 12-120 hour, be poured into water by reaction solution, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain compound III a through column chromatographic isolation and purification;
The compound III a of 1 equivalent is dissolved in anhydrous acetonitrile, add the trimethylchlorosilane of 2.0-5.0 equivalent and the sodium iodide of 2.0-5.0 equivalent, nitrogen protection, 10-100 DEG C of reaction 2-12 hour, is poured into water reaction solution, adds 10% aqueous sodium hydroxide solution, then be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains compound III b through column chromatographic isolation and purification;
The compound III a of 1 equivalent is dissolved in dry DMF, add the potash solid of 2.0-5.0 equivalent, under condition of ice bath, drip the halogenated alkyl thing of 2.0-5.0 equivalent, alkyl sulfonic ester or alkyl sulfuric ester, then 10-100 DEG C of reaction 2-12 hour, after completion of the reaction, reaction solution is poured into water, and is extracted with ethyl acetate, and organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain compound III c through column chromatographic isolation and purification;
The preparation of 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxyphenyl)-ketoxime-1H-glyoxaline compound and analogue (IV) thereof:
By the 2-substituting group phenyl-4-methyl-5-(3 of 1 equivalent, 4,5-trimethoxybenzoy)-1H-glyoxaline compound (III) is dissolved in dehydrated alcohol, add hydroxylamine hydrochloride or the O-alkyl hydroxylamine hydrochloride of 2.0-8.0 equivalent, 2.0-8.0 equivalent sodium acetate, 10-100 DEG C of reaction 4-24 hour, react complete, be poured into water, be extracted with ethyl acetate, organic layer washs with saturated nacl aqueous solution and uses anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtains compound IV through column chromatographic isolation and purification;
R 1~ R 4in can by corresponding R containing amino 2-substituting group phenyl-4-methyl-5-(3,4,5-trimethoxybenzoy)-1H-glyoxaline compound 1~ R 4in prepare via reduction reaction containing 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of nitro, reductive agent is ferrous sulfate/ammonia-water systems;
R 1~ R 4in can by corresponding R containing 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of hydroxyl 1~ R 4in prepare through going Benzylation reaction containing 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of benzyloxy, go Benzylation reaction reagent to be hydrogen palladium charcoal reduction reaction.
9. a pharmaceutical composition, comprises 2-substituting group phenyl-4-methyl-5-(3,4,5-the trimethoxybenzoy)-1H-glyoxaline compound of claim 1-7 described in any one and its analogue.
10. the 2-substituting group phenyl-4-methyl-5-(3 in claim 1 ~ 7 described in any one; 4,5-trimethoxybenzoy)-1H-glyoxaline compound and its analogue or composition according to claim 9 preparing the application in antitumor drug.
CN201410155351.XA 2014-04-17 2014-04-17 2-substituted phenyl-4-methyl-5-(3,4,5-trimethoxy benzoyl)-1H-imidazole compound and preparation thereof Pending CN105017156A (en)

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CN113929635A (en) * 2021-11-09 2022-01-14 沈阳药科大学 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Title
MIN XIAO等: ""Discovery of 4-Aryl-2-benzoyl-imidazoles as Tubulin Polymerization Inhibitor with Potent Antiproliferative Properties"", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113929635A (en) * 2021-11-09 2022-01-14 沈阳药科大学 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof
CN113929635B (en) * 2021-11-09 2023-08-22 沈阳药科大学 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof

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Application publication date: 20151104