CN108640922A - Triazole and diazepine -5- ketone compounds - Google Patents

Triazole and diazepine -5- ketone compounds Download PDF

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CN108640922A
CN108640922A CN201810616402.2A CN201810616402A CN108640922A CN 108640922 A CN108640922 A CN 108640922A CN 201810616402 A CN201810616402 A CN 201810616402A CN 108640922 A CN108640922 A CN 108640922A
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compound
dihydros
trimethoxyphenyls
triazol
diaza
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CN108640922B (en
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张为革
冯东杰
吴英良
王灏
包凯
关奇
左代英
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Shenyang Pharmaceutical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to pharmaceutical technology field, it is related to a kind of triazole and 5 ketone compounds of diazepine and application thereof, exactly, is related to application of such compound as tumor cell proliferation inhibitor in terms of preparing anti-tumor drug.The structural formula of the compound, pharmaceutically acceptable salt, solvate or isomers is as follows：R1~R8Definition as described in claims and specification.

Description

Triazole and diazepine -5- ketone compounds
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of triazole and diazepine -5- ketone compounds and application thereof, Exactly, it is related to application of such compound as tumor cell proliferation inhibitor in terms of preparing anti-tumor drug.
Background technology
Malignant tumour is to threaten the serious disease of human health and life, is the first lethal cause of disease in China.It finds and sends out Now treatment and the new drug of pre- preventing tumor are the key subjects currently faced.4-Substituted methoxybenzoyl-aryl- Thiazole (SMART) is that tubulin polymerization obtained from carrying out structure optimization as lead compound using natural products inhibits Agent inhibits tubulin polymerization to play its active anticancer by acting on colchicin binding site, and it can overcome Pgp to mediate Multidrug resistance sex chromosome mosaicism, compared with vincaleukoblastinum have lower neurotoxicity.SMART class compounds are in human melanoma and forefront In vivo efficacy in gland cancer heteroplastic transplantation model is very strong.The design feature of SMART class compounds is：(1) all there are one 3,4, 5- trimethoxyphenyl A rings；The Linker that (2) carbonyls and a five-ring heterocycles B ring are constituted；The C that (3) phenyl are constituted Ring.Although the activity of SMART class compounds is prominent, In vivo study, which shows that the carbonyl at the positions Linker is easy to be metabolized reduction, leads Activation decline or disappear (relevant report referring to：Lu Y.,et al.Journal of Medicinal Chemistry, 2009,52,1701；Chen J.J.,et al.Journal of Medicinal Chemistry,2010,53,7414；Xiao M.,et al.Journal of Medicinal Chemistry,2013,56,3318)。
2,8- diaryl -2,6- dihydros-[1,2,3] triazole of the present invention containing five-ring heterocycles and seven membered heterocyclic And [4,5-e] [Isosorbide-5-Nitrae] diazepine -5 (4H) -one class compound nucleus part structure novel, it is not yet reported.Such is changed Object is closed as antitumor activity, is also had not been reported at present.
Invention content
It is an object of the invention to design, synthesize the analogue of the SMART with good antitumor activity, i.e., [1, 2,3] triazole simultaneously [4,5-e] [1,4] diazepine be intermediate junction fragment SMART analogs；Prepared compound exists Show good result in the antitumor activity test of inside and outside.
The present invention relates to the compound for defining formula M, pharmaceutically acceptable salt, solvate or isomers：
Wherein,
R1~R4It is each independently hydrogen, C1-C6Alkyl oxy, adjacent two substituent groups are-OCH2O- is to constitute five Membered ring；
R5~R8It is each independently hydrogen, C1-C6Alkyl, C1-C6Alkyl oxy, halogen atom, nitro, amino.
Present invention is preferably related to the compound for defining formula M, pharmaceutically acceptable salt, solvate or isomers：
Wherein,
R1For hydrogen, R2、R3、R4It is separately C1-C6Alkyl oxy or two or three adjacent substituent groups are simultaneously C1-C6Alkyl oxy or adjacent two substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, C1-C6Alkyl, C1-C6Alkyl oxy, halogen atom, nitro, amino.
Present invention is preferably related to the compound for defining formula M, pharmaceutically acceptable salt, solvate or isomers：
R1For hydrogen, R2、R3、R4It is separately C1-C3Alkyl oxy or two or three adjacent substituent groups are simultaneously C1-C3Alkyl oxy or adjacent two substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, C1-C4Alkyl, C1-C4Alkyl oxy, halogen atom, nitro, amino.
The present invention is most preferably related to defining the compound of formula M, pharmaceutically acceptable salt, solvate or isomery Body：
R1For hydrogen, R2、R3、R4Be separately methoxyl group or two or three adjacent substituent groups be simultaneously methoxyl group, Or two adjacent substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, nitro, amino.
The compound of the present invention further include compound shown in structure above be formed by it is pharmaceutically acceptable nontoxic Salt and its hydrate, these pharmaceutically acceptable nontoxic salts include that the compound is formed by salt with acid.The acid can be with For hydrochloric acid, sulfuric acid, hydrobromic acid, the inorganic acid of phosphoric acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid Organic acid.The hydration number of the hydrate is the arbitrary real number in 0~16.
Currently preferred part of compounds structure is as follows：
Compound 1
2- phenyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine Miscellaneous -5 (4H) -one
Compound 2
2- p-methylphenyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] Diaza -5 (4H) -one
Compound 3
2- o-tolyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] Diaza -5 (4H) -one
Compound 4
Tolyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] between 2- Diaza -5 (4H) -one
Compound 5
2- (2,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one
Compound 6
2- (3,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one
Compound 7
2- (2,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one
Compound 8
2- (3,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one
Compound 9
2- (4- methoxyphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 10
2- (4- fluorophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 11
2- (4- chlorphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 12
2- (4- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 13
2- (2- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 14
2- (3- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 15
2- (4- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 16
2- (4- methoxyl group -3- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 17
2- (4- methoxyl group -3- aminophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 18
2- phenyl -8- (2,3,4- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine Miscellaneous -5 (4H) -one
Compound 19
2- phenyl -8- (3,4- Dimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza - 5 (4H) -one
Compound 20
2- phenyl -8- (4- methoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 21
2- phenyl -8- (3- methoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 22
2- phenyl -8- (3,4- methylenedioxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine Miscellaneous -5 (4H) -one
2,8- diaryl -2,6- dihydros-[1,2,3] triazole simultaneously [4,5-e] [1,4] diazepine -5 of the present invention (4H) -one class compound can synthesize to obtain according to following reaction route：
With 2- aryl -4- aroyl -5- amino triazole compound, (relevant report is referring to D.Feng, et al.RSC Adv.,2017,7,29103；CN106187923A it is) starting material, through the reactions such as chloracetyl chloride acylation and cyclisation, is made 2,8- Diaryl -2,6- dihydros-[1,2,3] triazole simultaneously [4,5-e] [1,4] diazepine -5 (4H) -one class compound.Wherein, change Close simultaneously [4,5-e] [1,4] diazepine -5 of 2,8- diaryl -2,6- dihydros-[1,2,3] triazole containing amino in object (4H) -one class compound can be prepared by the compound containing nitro in corresponding compound through reduction reaction, and reducing agent is anhydrous Ferric trichloride/hydrazine hydrate/activated carbon system.
2,8- diaryl -2,6- dihydros provided by the present invention-[1,2,3] triazole simultaneously [4,5-e] [1,4] diaza Tall and erect -5 (4H) -one class compounds process for production thereof simple possibles, yield are higher.
Invention further provides application of the above compound in the drug for preparing treatment tumor disease.
2,8- diaryl -2,6- dihydros-[1,2,3] triazole simultaneously [4,5-e] [1,4] diazepine -5 (4H) -one class Closing object has the function of preferably treating tumor disease, has preferable development prospect in the preparation of antitumor drugs.
Specific implementation mode
It will be helpful to understand the present invention by following examples, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, nuclear magnetic resoance spectrum AVANCE-400, Bruker ARX-300 Fourier transforms Nuclear magnetic resonance chemical analyser measures, and mass spectrum is measured by BrukeeEsqure 2000, Shimadzu GCMS-QP5050A type mass spectrographs.
Embodiment 1：2- phenyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] preparation (compound 1) of diaza -5 (4H) -one
2- phenyl -4- (3,4,5- benzoyls) -5- amino -1,2,3- triazoles are added in the eggplant-shape bottle of 100mL (354mg, 1.0mmol), anhydrous methylene chloride (30mL) dissolving, N2It protects, is pre-chilled at 0 DEG C, chloracetyl chloride is added dropwise dropwise (0.15mL, 2.0mmol) is transferred to room temperature after being added dropwise.The reaction was continued for 24 hours, and TLC is detected after completion of the reaction, and decompression boils off Solvent, ethyl acetate are washed, and are filtered, are obtained compound I.By the chloro- N- of compound 2- (2- phenyl -5- (3,4,5- trimethoxy-benzene first Acyl group) -2H-1,2,3- triazole-4-yls) acetamide (430mg, 1.0mmol), methenamine (701mg, 5.0mmol), ammonium acetate (386mg, 5.0mmol) is dissolved in 95% ethyl alcohol, and after completion of the reaction, decompression boils off solvent, dichloro for back flow reaction 5h, TLC detection Methane (20mL) extracts 3 times, merges organic layer, and saturated salt solution (10mL) is washed, anhydrous magnesium sulfate drying, evaporated under reduced pressure solvent, Absolute ethyl alcohol recrystallizes, and can be obtained compound 1 through column chromatographic isolation and purification；Yield 77%.1H NMR(600MHz,CDCl3)δ 9.49 (s, 1H), 8.10 (d, J=8.5Hz, 2H), 7.52 (dd, J=7.4Hz, J=8.5Hz, 2H), 7.43 (t, J=7.4Hz, 1H),7.32(s,2H),4.59(s,2H),3.93(s,3H),3.90(s,6H)ppm；13C NMR(100MHz,CDCl3)δ 167.9,162.2,152.9(×2),147.2,140.8,139.1,134.5,131.6,129.6(×2),128.8,118.9 (×2),106.7(×2),61.0,57.4,56.2(×2)ppm。
Embodiment 2:2- p-methylphenyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one preparation (compound 2)
Other than using corresponding raw material, with 1 identical method prepare compound 2 of embodiment；Yield 74%.1H NMR (600MHz,CDCl3) δ 9.61 (s, 1H), 7.96 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.30 (s, 2H), 4.59(s,2H),3.92(s,3H),3.89(s,6H),2.42(s,3H)ppm；13C NMR(100MHz,CDCl3)δ168.0, 162.2,152.9(×2),147.1,140.8,139.0,137.0,134.3,131.7,130.1(×2),118.8(×2), 106.7(×2),61.0,57.5,56.2(×2),21.1ppm。
Embodiment 3:2- o-tolyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- E] [1,4] diaza -5 (4H) -one preparation (compound 3)
Other than using corresponding raw material, with 1 identical method prepare compound 3 of embodiment；Yield 76%.1H NMR (600MHz,CDCl3) δ 9.74 (s, 1H), 7.63 (m, 0.5H), 7.55 (d, J=7.7Hz, 1H), 7.43 (m, 0.5H), 7.30 (m,1H),7.26(m,1H),7.18(s,2H),4.51(s,2H),3.82(s,3H),3.79(s,6H),2.39(s,3H)ppm；13C NMR(100MHz,CDCl3)δ167.8,162.5,153.0(×2),146.8,141.0,138.7,134.3,132.3, 132.0,129.6,126.9(×2),125.0,106.8(×2),60.9,57.2,56.2(×2),19.4ppm。
Embodiment 4:Tolyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5- between 2- E] [1,4] diaza -5 (4H) -one preparation (compound 4)
Other than using corresponding raw material, with 1 identical method prepare compound 4 of embodiment；Yield 71%.1H NMR (600MHz,CDCl3) δ 9.89 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.40 (dd, J=8.0Hz, J= 7.3Hz, 1H), 7.32 (s, 2H), 7.23 (d, J=7.3Hz, 1H), 4.55 (s, 2H), 3.93 (s, 3H), 3.89 (s, 6H), 2.39(s,3H)ppm；13C NMR(100MHz,CDCl3)δ168.0,162.3,152.9(×2),147.2,140.9,139.9, 139.1,134.4,131.5,129.6,129.4,119.5,116.1,106.7(×2),61.0,57.4,56.2(×2), 21.5ppm。
Embodiment 5:2- (2,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] three The preparation (compound 5) of azoles simultaneously [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 5 of embodiment；Yield 73%.1H NMR (600MHz, DMSO) δ 11.49 (s, 1H), 7.53 (s, 1H), 7.43 (d, J=7.8Hz, 2H), 7.18 (d, J=7.8Hz, 2H), 6.81(s,2H),5.92(s,2H),3.79(s,6H),3.74(s,3H),2.24(s,3H),2.20(s,3H)ppm。
Embodiment 6:2- (3,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] three The preparation (compound 6) of azoles simultaneously [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 6 of embodiment；Yield 69%.1H NMR (600MHz,CDCl3) δ 9.75 (s, 1H), 7.50 (d, J=7.9Hz, 1H), 7.26 (s, 2H), 7.16 (s, 1H), 7.12 (d, J =7.9Hz, 1H), 4.58 (s, 2H), 3.90 (s, 3H), 3.87 (s, 6H), 2.43 (s, 3H), 2.39 (s, 3H) ppm；13C NMR (100MHz,CDCl3)δ167.9,162.3,152.9(×2),147.1,140.8,138.2,137.7,137.1,134.1, 131.7,130.6,120.0,116.3,106.7(×2),61.0,57.4,56.2(×2),20.0,19.5ppm。
Embodiment 7:2- (2,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] three The preparation (compound 7) of azoles simultaneously [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 7 of embodiment；Yield 78%.1H NMR (600MHz,CDCl3) δ 9.39 (s, 1H), 7.46 (s, 1H), 7.27 (s, 2H), 7.24 (d, J=7.7Hz, 1H), 7.19 (d, J =7.7Hz, 1H), 4.59 (s, 2H), 3.90 (s, 3H), 3.88 (s, 6H), 2.44 (s, 3H), 2.38 (s, 3H) ppm；13C NMR (100MHz,CDCl3)δ168.0,162.4,153.0(×2),146.7,140.8,138.5,136.9,134.3,132.0, 131.8,130.4,129.0,125.5,106.6(×2),60.9,57.5,56.2(×2),20.8,18.9ppm。
Embodiment 8:2- (3,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] three The preparation (compound 8) of azoles simultaneously [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 8 of embodiment；Yield 79%.1H NMR (600MHz,CDCl3)δ9.17(s,1H),7.71(s,2H),7.31(s,2H),7.06(s,1H),4.59(s,2H),3.93(s, 3H),3.90(s,6H),2.40(s,6H)ppm；13C NMR(100MHz,CDCl3)δ167.8,162.2,153.0(×2), 147.0,140.8,139.6,139.0(×2),134.3,131.7,130.5,116.7(×2),106.7(×2),61.0, 57.5,56.2(×2),21.4(×2)ppm。
Embodiment 9:2- (4- methoxyphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazole And the preparation (compound 9) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 9 of embodiment；Yield 72%.1H NMR (600MHz,CDCl3) δ 10.22 (s, 1H), 7.97 (d, J=9.2Hz, 2H), 7.30 (s, 2H), 7.00 (d, J=9.2Hz, 2H),4.51(s,2H),3.91(s,3H),3.88(s,6H),3.86(s,3H)ppm；13C NMR(100MHz,CDCl3)δ 167.8,162.2,159.9,152.9(×2),147.0,140.7,134.1,132.7,131.8,120.4(×2),114.6 (×2),106.7(×2),60.9,57.5,56.2(×2),55.6ppm。
Embodiment 10:2- (4- fluorophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 10) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 10 of embodiment；Yield 70%.1H NMR (600MHz,CDCl3)δ9.22(s,1H),8.08(m,2H),7.28(s,2H),7.22(m,2H),4.59(s,2H),3.93(s, 3H),3.89(s,6H)ppm；13C NMR(100MHz,CDCl3) δ 167.8,163.3,161.9 (d, J=234.2Hz), 153.0 (× 2), 147.2,140.9,135.4 (d, J=11.4Hz, 1H), 134.6,131.6,120.8 (d, J=34.5Hz, × 2), 116.6 (d, J=92.6Hz, × 2), 106.7 (× 2), 61.0,57.4,56.3 (× 2) ppm.
Embodiment 11:2- (4- chlorphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 11) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 11 of embodiment；Yield 78%.1H NMR (600MHz,CDCl3) δ 9.72 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.27 (s, 1H), 4.59(s,1H),3.92(s,3H),3.89(s,6H)ppm；13C NMR(100MHz,CDCl3)δ168.1,162.1,153.0(× 2),147.4,141.0,137.6,134.8 134.6,131.5,129.8(×2),120.1(×2),106.7(×2),61.0, 57.4,56.3(×2)ppm。
Embodiment 12:2- (4- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 12) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 12 of embodiment；Yield 75%.1H NMR (600MHz,CDCl3) δ 9.45 (s, 1H), 7.98 (d, J=8.5Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 7.27 (s, 2H), 4.58(s,2H),3.92(s,3H),3.89(s,6H)ppm；13C NMR(100MHz,CDCl3)δ168.0,162.1,153.0(× 2),147.4,140.9,138.1,134.8,132.8(×2),131.5,122.5,120.3(×2),106.7(×2),61.0, 57.4,56.2(×2)ppm。
Embodiment 13:2- (2- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 13) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 13 of embodiment；Yield 68%.1H NMR (600MHz,CDCl3) δ 9.68 (s, 1H), 7.69 (d, J=7.9Hz, 1H), 7.52 (d, J=7.0Hz, 1H), 7.42 (t, J= 7.4Hz, J=7.0Hz, 1H), 7.34 (t, J=7.9Hz, J=7.4Hz, 1H), 7.20 (s, 2H), 4.53 (s, 2H), 3.84 (s, 9H)ppm；13C NMR(100MHz,CDCl3)δ167.9,162.3,153.0(×2),147.1,141.0,139.0,134.8, 134.1,131.7,128.4(×2),128.2,119.1,106.8(×2),60.9,57.3,56.3(×2)ppm。
Embodiment 14:2- (3- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 14) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 14 of embodiment；Yield 77%.1H NMR (600MHz, DMSO) δ 11.5 (s, 1H), 8.23 (s, 1H), 8.04 (d, J=7.6Hz, 1H), 7.58 (d, J=6.9Hz, 1H), 7.45 (t, J=7.6Hz, 1H), 7.28 (s, 2H), 4.50 (s, 2H), 3.91 (s, 6H), 3.86 (s, 3H) ppm；13C NMR (100MHz,DMSO)δ166.4,160.8,152.1(×2),147.9,139.8,139.4,134.3,131.0,130.7, 130.6,122.2,121.1,116.8,105.9(×2),60.0,57.4,55.5(×2)ppm。
Embodiment 15:2- (4- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol The preparation (compound 15) of [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 15 of embodiment；Yield 74%.1H NMR (600MHz,CDCl3) δ 9.56 (s, 1H), 8.41 (d, J=9.0Hz, 2H), 8.28 (d, J=9.0Hz, 2H), 7.25 (s, 2H), 4.63(s,2H),3.93(s,3H),3.89(s,6H)ppm；13C NMR(100MHz,CDCl3)δ168.0,161.8,153.1(× 2),148.0,147.2,143.0,141.2,136.1,131.3,125.5(×2),119.3(×2),106.7(×2),61.0, 57.4,56.3(×2)ppm。
Embodiment 16:2- (4- methoxyl group -3- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1, 2,3] preparation (compound 16) of triazol [4,5-e] [1,4] diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 16 of embodiment；Yield 69%.1H NMR (600MHz, DMSO) δ 11.67 (s, 1H), 8.46 (d, J=2.5Hz, 1H), 8.27 (dd, J1=2.5Hz, J2=9.2Hz, 1H), 7.60 (d, J=9.2Hz, 1H), 7.32 (s, 2H), 4.46 (s, 2H), 4.02 (s, 3H), 3.82 (s, 6H), 3.75 (s, 3H) ppm。
Embodiment 17:2- (4- methoxyl group -3- aminophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1, 2,3] preparation (compound 17) of triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 16 (200mg, 0.4mmol) is added in 50mL eggplant-shape bottles, activated carbon 20mg and ferric trichloride is added 20mg makees catalyst, and solvent is made with absolute ethyl alcohol, stirs 80% hydrazine hydrate 0.1mL of lower dropwise addition, back flow reaction 3 hours；TLC is detected After completion of the reaction, deactivation charcoal is filtered out, absolute ethyl alcohol is evaporated, adds water, ethyl acetate extraction to merge organic layer, decompression is steamed Crude product is evaporated to obtain, chromatographic isolation obtains compound 17；Yellow solid, yield：70%.1H NMR(600MHz,DMSO)δ11.52(s, 1H), 7.36 (d, J=2.6Hz, 1H), 7.28 (s, 2H), 7.18 (dd, J1=2.6Hz, J2=8.8Hz, 1H), 6.95 (d, J= 8.8Hz,1H),5.27(s,2H),4.43(s,2H),3.83(s,3H),3.82(s,6H),3.75(s,3H)ppm。
Embodiment 18:2- phenyl -8- (2,3,4- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] preparation (compound 18) of diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 18 of embodiment；Yield 75%.1H NMR (600MHz,CDCl3)δ11.61(s,1H),7.95(dd,J1=1.1Hz, J2=8.8Hz, 2H), 7.57 (m, 2H), 7.44 (m, 1H), 7.19 (d, J=8.7Hz, 1H), 6.90 (d, J=8.7Hz, 1H), 4.43 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.48(s,3H)ppm；13C NMR(100MHz,CDCl3)δ167.2,162.1,155.9,152.3,147.4,141.7,139.1, 137.1,130.4(×2),128.9,125.6,125.4,118.9(×2),107.9,61.1,60.7,58.5,56.4pm。
Embodiment 19:2- phenyl -8- (3,4- Dimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] preparation (compound 19) of diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 19 of embodiment；Yield 77%.1H NMR (600MHz,CDCl3)δ11.55(s,1H),8.03(dd,J1=1.1Hz, J2=8.8Hz, 2H), 7.61 (m, 2H), 7.58 (d, J =2.0Hz, 1H), 7.56 (dd, J1=2.0Hz, J2=8.4Hz, 1H), 7.49 (m, 1H), 7.05 (d, J=8.4Hz, 1H), 4.43(s,2H),3.83(s,3H),3.79(s,3H)ppm；13C NMR(100MHz,CDCl3)δ167.7,161.2,151.8, 148.9,148.5,139.3,135.2,130.4(×2),129.3,129.0,123.4,119.2(×2),111.7,111.3, 58.2,56.0,55.9pm。
Embodiment 20:2- phenyl -8- (4- methoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two The preparation (compound 20) of azepine -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 20 of embodiment；Yield 75%.1H NMR (600MHz,CDCl3) δ 11.54 (s, 1H), 8.02 (d, J=7.8Hz, 2H), 7.92 (d, J=8.9Hz, 2H), 7.63 (dd, J1 =7.6Hz, J2=8.3Hz, 2H), 7.50 (dd, J1=7.3Hz, J2=7.6Hz, 1H), 7.04 (d, J=8.9Hz, 2H), 4.43 (s,2H),3.83(s,3H)pm；13C NMR(100MHz,CDCl3)δ167.7,162.0,161.3,148.5,139.3,135.2, 131.1(×2),130.4(×2),129.4,129.1,119.2(×2),114.1(×2),58.2,55.8pm。
Embodiment 21:2- phenyl -8- (3- methoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two The preparation (compound 21) of azepine -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 21 of embodiment；Yield 70%.1H NMR (600MHz,CDCl3)δ11.63(s,1H),8.01(dd,J1=1.0Hz, J2=8.7Hz, 2H), 7.61 (t, J=8.2Hz, 2H),7.50(m,3H),7.40(dd,J1=7.8Hz, J2=8.0Hz, 1H), 7.12 (dd, J1=2.5Hz, J2=8.2Hz, 1H),4.48(s,2H),3.80(s,3H)ppm；13C NMR(100MHz,CDCl3)δ167.4,161.9,159.6,148.6, 139.3,138.2,135.0,130.4(×2),129.8,129.1,122.1,119.2(×2),117.4,114.2,58.5, 55.7pm。
Embodiment 22:2- phenyl -8- (3,4- methylenedioxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] preparation (compound 22) of diaza -5 (4H) -one
Other than using corresponding raw material, with 1 identical method prepare compound 22 of embodiment；Yield 73%.
1H NMR(600MHz,CDCl3) δ 11.56 (s, 1H), 7.99 (d, J=7.7Hz, 2H), 7.62 (dd, J1= 7.7Hz,J2=8.2Hz, 2H), 7.52 (dd, J1=1.6Hz, J2=8.0Hz, 1H), 7.49 (t, J=8.0Hz, 1H), 7.46 (d, J=1.6Hz, 1H), 6.99 (d, J=8.2Hz, 1H), 6.13 (s, 2H), 4.41 (s, 2H) ppm；13C NMR(100MHz, CDCl3)δ167.6,161.2,150.2,148.5,147.9,139.3,135.1,131.1,130.4(×2),129.1, 124.9,119.2(×2),108.9,108.4,102.1,58.2pm。
Embodiment 23：The anti tumor activity in vitro of the compound of the present invention is tested
External activity test method and result are as follows：Wherein, clinically used antitumor drug adriamycin (DOX) is the positive Experimental group.
Screening technique：Tetrazolium (micoculturetetrozolium, MTT) reduction method
Cell strain：Human stomach cancer cell line (SGC-7901 cell line), human lung adenocarcinoma (A549 cell line), people's knot Colon-cancer cell strain (HT-1080 cell line)
Action time：72 hours
The inhibiting rate (30 μ g/mL) of three kinds of growth of tumour cell of each compound pair is shown in Table -1.
The inhibiting rate (μ g/mL) of each compound on tumor growth is shown in Table -1.
Table -1
Embodiment 24：Antitumor activity is tested in the animal body of the compound of the present invention
The preferable compound 2 of selection external activity, compound 8 have carried out antitumor activity in animal body and have tested, mould used Type is mouse S-180 sarcoma models, and positive control medicine is clinically used antitumor drug fluorouracil (Fluorouracil,5-Fu)。
Experimental method：18-22 grams of female KM mouse and well-grown 7-11 days S-180 tumor kinds are selected, by tumor group Cell suspension is woven into, it is subcutaneous to be seeded to right side of mice armpit, about 1.0-2.0 × 106Cell/only, it is random after being inoculated with 24 hours Divide cage, continuous 7 days of intraperitoneal injection.It puts to death animal within 24 hours after drug withdrawal, weighs, knurl weight, calculate each group average knurl weight, press Following formula finds out tumor control rate and carries out t inspections.
Tumor control rate=[(blank control group average knurl weight-treatment group's average knurl weight)/(blank control group is averaged tumor Weight)] × 100%
Experimental result is shown in Table -2
Table -2

Claims (10)

1. the triazole of formula M and diazepine -5- ketone compounds and its salt, solvate or hydrate：
R1~R4It is each independently hydrogen, C1-C6Alkyl oxy, adjacent two substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, C1-C6Alkyl, C1-C6Alkyl oxy, halogen atom, nitro, amino.
2. compound as described in claim 1 and its salt, solvate or hydrate, it is characterised in that：
R1For hydrogen, R2、R3、R4It is separately C1-C6Alkyl oxy or two or three adjacent substituent groups are C simultaneously1-C6 Alkyl oxy or adjacent two substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, C1-C6Alkyl, C1-C6Alkyl oxy, halogen atom, nitro, amino.
3. compound as claimed in claim 1 or 2 and its salt, solvate or hydrate, it is characterised in that：
R1For hydrogen, R2、R3、R4It is separately C1-C3Alkyl oxy or two or three adjacent substituent groups are C simultaneously1-C3 Alkyl oxy or adjacent two substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, C1-C4Alkyl, C1-C4Alkyl oxy, halogen atom, nitro, amino.
4. compound and its salt, solvate or hydrate as described in claim 1-3 any one, it is characterised in that：
R1For hydrogen, R2、R3、R4It is separately methoxyl group or two or three adjacent substituent groups while is methoxyl group or phase Two adjacent substituent groups are-OCH2O- is to constitute five-membered ring；
R5~R8It is each independently hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, nitro, amino.
5. the compound and its salt, solvate as described in Claims 1 to 4 any one or hydrate, it is characterised in that：
The salt is that the compound and acid are formed by salt, the acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, Citric acid, oxalic acid, tartaric acid, benzoic acid, apple, the hydration number of the hydrate are the arbitrary real number in 0~16.
6. following 2,8- diaryl -2,6- dihydros-[1,2,3] triazole simultaneously [4,5-e] [1,4] diazepine -5 (4H) -one Class compound and its salt, solvate or hydrate, are selected from：
Compound 1
2- phenyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 2
2- p-methylphenyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine Miscellaneous -5 (4H) -one
Compound 3
2- o-tolyls -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine Miscellaneous -5 (4H) -one
Compound 4
Tolyl -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] phenodiazine between 2- Miscellaneous -5 (4H) -one
Compound 5
2- (2,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 6
2- (3,4- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 7
2- (2,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 8
2- (3,5- 3,5-dimethylphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 9
2- (4- methoxyphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1, 4] diaza -5 (4H) -one
Compound 10
2- (4- fluorophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two Azepine -5 (4H) -one
Compound 11
2- (4- chlorphenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two Azepine -5 (4H) -one
Compound 12
2- (4- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two Azepine -5 (4H) -one
Compound 13
2- (2- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two Azepine -5 (4H) -one
Compound 14
2- (3- bromophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazols [4,5-e] [1,4] two Azepine -5 (4H) -one
Compound 15
2- (4- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] Diaza -5 (4H) -one
Compound 16
2- (4- methoxyl group -3- nitrobenzophenones) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4, 5-e] [1,4] diaza -5 (4H) -one
Compound 17
2- (4- methoxyl group -3- aminophenyls) -8- (3,4,5- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4, 5-e] [1,4] diaza -5 (4H) -one
Compound 18
2- phenyl -8- (2,3,4- trimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 19
2- phenyl -8- (3,4- Dimethoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one
Compound 20
2- phenyl -8- (4- methoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one Compound 21
2- phenyl -8- (3- methoxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one Compound 22
2- phenyl -8- (3,4- methylenedioxyphenyls) -2,6- dihydros-[1,2,3] triazol [4,5-e] [1,4] diaza -5 (4H) -one.
7. a kind of 2,6- dihydros-[1,2,3] triazole as described in claim 1 simultaneously [4,5-e] [1,4] diazepine -5 The preparation method of (4H) -one class compound, it is characterised in that：
It is anti-through chloracetyl chloride acylation and cyclisation using 2- aryl -4- aroyl -5- amino triazole compounds as starting material It answers, 2,8- diaryl -2,6- dihydro-[1,2,3] triazole simultaneously [4,5-e] [Isosorbide-5-Nitrae] diazepine -5 (4H) -one class chemical combination is made Object.
8. a kind of pharmaceutical composition, including the compound and its salt, solvate described in claim 1~6 any one or water Close object and pharmaceutically acceptable carrier.
9. 2,6- dihydros-[1,2,3] triazole described in any one of claim 1~6 simultaneously [4,5-e] [1,4] diaza Tall and erect -5 (4H) -one class compounds and its salt, solvate or hydrate or composition according to any one of claims 8 prepare it is antitumor Application in drug.
10. application as claimed in claim 9, which is characterized in that the tumour is gastric cancer, adenocarcinoma of lung or colon cancer.
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