CN106187923A - 2 aryl 4 aroyl triazole compounds and application thereof - Google Patents
2 aryl 4 aroyl triazole compounds and application thereof Download PDFInfo
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- CN106187923A CN106187923A CN201610619466.9A CN201610619466A CN106187923A CN 106187923 A CN106187923 A CN 106187923A CN 201610619466 A CN201610619466 A CN 201610619466A CN 106187923 A CN106187923 A CN 106187923A
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- compound
- triazole
- aryl
- benzoyl
- hydrogen
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- -1 aroyl triazole compounds Chemical class 0.000 title claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000002360 preparation method Methods 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 150000004677 hydrates Chemical class 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
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- OJWYYSVOSNWCCE-UHFFFAOYSA-N 2-methoxyethyl hypofluorite Chemical compound COCCOF OJWYYSVOSNWCCE-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 230000009615 deamination Effects 0.000 claims description 2
- 238000006481 deamination reaction Methods 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000007857 hydrazones Chemical class 0.000 claims description 2
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- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 2
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- 235000006408 oxalic acid Nutrition 0.000 claims description 2
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- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 239000007858 starting material Substances 0.000 description 28
- 239000011734 sodium Substances 0.000 description 25
- 206010028980 Neoplasm Diseases 0.000 description 12
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical group C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 6
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- 230000000694 effects Effects 0.000 description 5
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
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- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, relate to a kind of 2 aryl 4 aroyl triazole compounds and application thereof, exactly, relate to this compounds and as tumor cell proliferation inhibitor application in terms of preparing anti-tumor drug.Described compound structure formula is as follows: wherein, and claims and description are shown in the definition of each substituent group.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a 2-aryl-4-aroyl-triazole compound and application thereof, in particular to the compound and application thereof as a tumor cell proliferation inhibitor in preparation of antitumor medicines.
Background
Malignant tumor is a serious disease threatening human health and life, and is the first cause of death in China. The search and discovery of new drugs for the treatment and prevention of tumors is a major issue facing today. Combretastatin A-4(CA-4) is a cis-stilbene natural product separated from willow in south Africa, and the chemical name of the product is (Z) -2-methoxy-5- (3,4, 5-trimethoxystyryl) phenol. CA-4 is a tubulin polymerization inhibitor and shows strong activity of inhibiting tumor cell proliferation, and the prodrug CA-4 sodium phosphate (CA-4P) enters the third clinical research stage in the United states. A great deal of research on designing and synthesizing new anti-tumor active compounds by using CA-4 as a lead compound has been reported, but most CA-4 analogues have the defects of insufficient activity, high toxicity, complex synthesis and the like (see Pettit G.R., et al expert Chemistry, 1989,45, 209; Nam N.H. Current medical Chemistry,2003,10, 1697; Tron G.C., et al journal of medical Chemistry,2006,49(11), 3033-. The 2-aryl-4-aroyl-triazole compound related by the invention has not been reported at present as an antitumor activity research.
Disclosure of Invention
The invention aims to design and synthesize a structural analogue of Combretastatin A-4 with good antitumor activity, namely a 2-aryl-4-aroyl-triazole compound; the prepared compound shows good results in vivo and in vitro anti-tumor activity tests.
The present invention relates to compounds of the general formula M defined below:
wherein, R is hydrogen and amino,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom;
R4is H, C1-C6An alkyl group;
the present invention preferably relates to compounds of the general formula M defined below:
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom;
R4is H, C1-C6An alkyl group;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom.
The present invention preferably relates to compounds of the general formula M defined below:
wherein,
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C3Alkyl radical, C1-C3An alkyloxy group, a halogen atom;
R4is H, C1-C3An alkyl group;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently is hydrogen, C1-C3Alkyl radical, C1-C3An alkyloxy group, a halogen atom.
The invention most preferably relates to compounds of the general formula M defined below:
wherein,
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine;
R4h and methyl;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo.
The compound also comprises pharmaceutically acceptable non-toxic salts and hydrates thereof formed by the compound shown in the structural formula, and the pharmaceutically acceptable non-toxic salts comprise salts formed by the derivative and acid. The acid can be inorganic acid of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or organic acid selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid. The number of crystal water of the hydrate is any real number in 0-16.
Preferred partial compounds of the present invention have the following structure:
compound 1
2-phenyl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 2
2- (2-methylphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 3
2- (4-methylphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 4
2- (4-methoxyphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 5
2- (4-fluorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 6
2- (2-chlorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 7
2- (4-chlorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 8
2- (2-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 9
2- (3-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 10
2- (4-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole
Compound 11
2-phenyl-4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 12
2- (2-methylphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 13
2- (4-methylphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 14
2- (4-methoxyphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 15
2- (4-fluorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 16
2- (2-chlorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 17
2- (4-chlorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 18
2- (2-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 19
2- (3-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 20
2- (4-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole
Compound 21
2-phenyl-4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 22
2- (2-methylphenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 23
2- (4-methylphenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 24
2- (4-methoxyphenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole
Compound 25
2- (4-fluorophenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 26
2- (2-chlorophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole
Compound 27
2- (4-chlorophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole
Compound 28
2- (2-bromophenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 29
2- (3-bromophenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
Compound 30
2- (4-bromophenyl) -4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole
The 2-aryl-4-aroyl-triazole compound can be synthesized according to the following reaction route:
3,4, 5-trimethoxybenzaldehyde is used as a starting material, and the 2-aryl-4-aroyl-triazole compound is prepared by the reactions of condensation, hydrazone formation, condensation cyclization, deamination, oxime formation and the like.
The preparation method of the 2-aryl-4-aroyl-triazole compound provided by the invention is simple and feasible, and the yield is high.
The invention further provides application of the compound in preparing a medicine for treating tumor diseases.
The 2-aryl-4-aroyl-triazole compound has a good effect of treating tumor diseases, and has a good development prospect in preparation of anti-tumor drugs.
Detailed Description
The invention will be understood by the following examples, but the content of the invention is not limited to the examples.
The reagents used in the invention are all commercially available, and the mass spectrum is determined by a Bruker ARX-300 Fourier transform nuclear magnetic resonance spectrometer, and the BrukeeeEqure 2000 and Shimadzu GCMS-QP5050A type mass spectrometer.
Example 1: preparation of 2-O-N-phenyl-2- (3,4, 5-trimethoxyphenyl) cyanoacetylhydrazone
3,4, 5-trimethoxybenzaldehyde (5.34g,23.6mmol), sodium hydride (1.62g,47.2mmol) were dissolved in anhydrous tetrahydrofuran (20mL), anhydrous acetonitrile (1.4mL,23.6mmol) was added dropwise, and the mixture was stirred under reflux for 3 hours; after the reaction is finished, adding water for dilution, evaporating solvent tetrahydrofuran under reduced pressure, adjusting the pH value to be 2 by using dilute hydrochloric acid (1mol/L), precipitating light yellow solid, filtering and drying to obtain the compound 3-oxo-3- (3,4, 5-trimethoxyphenyl) propionitrile, and directly using the compound in the next step without purification. Dissolving the compound 3-oxo-3- (3,4, 5-trimethoxyphenyl) propionitrile (1.5g,6.4mmol) in ethanol (10mL), adding sodium acetate (0.95g,11.6mmol) dissolved in water (10mL), cooling to 0 ℃, dropwise adding aryl diazonium salt (6.4mmol), reacting at 0 ℃ for 0.5 h, and heating to room temperature for 1 h; after the reaction is finished, yellow solid is separated out, filtered and dried to obtain the compound 2-O-N-aryl-2- (3,4, 5-trimethoxyphenyl) cyanoacetylhydrazone, which is directly used in the next step without purification.
Example 2: preparation of 2-phenyl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (compound 1)
Adding 2-oxo-N-phenyl-2- (3,4, 5-trimethoxyphenyl) cyanoacetylhydrazone (339mg, 1.0mmol), hydroxylamine hydrochloride (345mg,5.0mmol) and anhydrous sodium acetate (410mg,5.0mmol) into a microwave reaction tube, adding N, N-dimethylformamide (5mL), and reacting at 160 ℃ for 7 minutes by microwave; after the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice water to precipitate a brown solid. Separating and purifying by column chromatography to obtain compound 1; the yield thereof was found to be 90%.1H NMR(600MHz,CDCl3)8.08(m,2H),7.60(m,3H),7.06(s,2H),3.95(s,3H),3.89(s,6H)ppm；MS(ESI):[M+H]+＝355.1,[M+Na]+＝377.1。
EXAMPLE 3 preparation of 2- (2-methylphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 2)
Compound 2 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 84%.1H NMR(600MHz,CDCl3)7.68(s,2H),7.63(d,J＝7.6Hz,1H),7.36(m,3H),3.94(s,3H),3.92(s,6H),2.48(s,3H)ppm；MS(ESI):[M+H]+＝369.1,[M+Na]+＝391.1。
EXAMPLE 4 preparation of 2- (4-methylphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 3)
Compound 3 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 85%.1H NMR(600MHz,CDCl3)7.58(d,J＝8.5Hz,2H),7.43(s,2H),7.30(d,J＝8.5Hz,2H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝369.1,[M+Na]+＝391.1。
EXAMPLE 5 preparation of 2- (4-methoxyphenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 4)
Compound 4 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 77%.1H NMR(600MHz,CDCl3)7.94(m,2H),7.82(s,2H),6.99(m,2H),3.98(s,6H),3.96(s,3H),3.86(s,3H)ppm；MS(ESI):[M+H]+＝385.1,[M+Na]+＝407.1。
EXAMPLE 6 preparation of 2- (4-fluorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 5)
Compound 5 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 87%.1H NMR(600MHz,CDCl3)7.80(m,2H),7.80(s,2H),7.18(m,2H),3.97(s,6H),3.97(s,3H)ppm；MS(ESI):[M+H]+＝373.1,[M+Na]+＝395.1。
EXAMPLE 7 preparation of 2- (2-chlorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 6)
Compound 6 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 89%.1H NMR(600MHz,CDCl3)8.21(s,1H),7.95(d,J＝8.1Hz,1H),7.82(s,2H),7.48(d,J＝7.9Hz,1H),7.35(t,J＝8.0Hz,1H),3.98(s,6H),3.97(s,3H)ppm；MS(ESI):[M+H]+＝389.1,[M+Na]+＝411.1。
EXAMPLE 8 preparation of 2- (4-chlorophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 7)
Compound 7 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 91%.1H NMR(600MHz,CDCl3)7.90(d,J＝8.6Hz,2H),7.79(s,2H),7.61(d,J＝8.6Hz,2H),3.97(s,9H)ppm；MS(ESI):[M+H]+＝389.1,[M+Na]+＝411.1。
EXAMPLE 9 preparation of 2- (2-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 8)
Compound 8 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 90%.1H NMR(600MHz,CDCl3)8.30(s,1H),8.04(d,J＝8.0Hz,1H),7.69(s,2H),7.53(d,J＝7.5Hz,1H),7.38(t,J＝8.0Hz,1H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝433.0。
EXAMPLE 10 preparation of 2- (3-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 9)
Compound 9 was prepared in the same manner as in example 2, except that the corresponding starting material was used; the yield thereof was found to be 93%.1H NMR(600MHz,CDCl3)7.84(s,2H),7.69(m,1H),7.58(m,1H),7.41(m,2H),3.94(s,9H)ppm；MS(ESI):[M+H]+＝433.0,[M+Na]+＝455.0。
EXAMPLE 11 preparation of 2- (4-bromophenyl) -4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (Compound 10)
Compound 10 was prepared in the same manner as in example 2, except that the corresponding starting materials were used; the yield thereof was found to be 92%.1H NMR(600MHz,CDCl3)7.96(m,2H),7.79(s,2H),7.46(m,2H),3.97(s,9H)ppm；MS(ESI):[M+H]+＝433.0,[M+Na]+＝455.1。
EXAMPLE 12 preparation of 2-phenyl-4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 11)
Adding the compound 1(0.50g,1.14mmol) into an eggplant-shaped bottle, dissolving with a proper amount of tetrahydrofuran, dropwise adding isoamyl nitrite (0.66g,4.56mmol), and carrying out reflux reaction for 1 hour; after the reaction is finished, evaporating tetrahydrofuran under reduced pressure, and separating and purifying by column chromatography to obtain a compound 11; the yield thereof was found to be 82%.1H NMR(600MHz,CDCl3):8.45(s,1H),8.06(m,2H),7.72(s,2H),7.34(m,3H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝340.1,[M+Na]+＝362.1。
EXAMPLE 13 preparation of 2- (2-methylphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 12)
Compound 12 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 92%.1H NMR(600MHz,CDCl3)8.46(s,1H),7.76(s,2H),7.67(d,J＝7.8Hz,1H),7.38(m,3H),3.96(s,3H),3.94(s,6H),2.48(s,3H)ppm；MS(ESI):[M+H]+＝354.1,[M+Na]+＝376.1。
EXAMPLE 14 preparation of 2- (4-methylphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 13)
Compound 13 was prepared in the same manner as in example 12, except that the corresponding starting material was used; the yield thereof was found to be 87%.1H NMR(600MHz,CDCl3)8.44(s,1H),8.06(m,2H),7.74(s,2H),7.58(m,2H),3.99(s,3H),3.97(s,6H)ppm；MS(ESI):[M+H]+＝354.1,[M+Na]+＝376.1。
EXAMPLE 15 preparation of 2- (4-methoxyphenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 14)
Compound 14 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 89%.1H-NMR(600MHz,CDCl3)8.70(d,J＝2.7Hz,1H),8.42(s,1H),8.34(dd,J＝2.7Hz,8.0Hz,1H),7.76(s,2H),7.27(d,J＝8.0Hz,1H),4.06(s,3H),3.98(s,3H),3.97(s,6H)ppm；MS(ESI):[M+H]+＝370.1,[M+Na]+＝392.1。
EXAMPLE 16 preparation of 2- (4-fluorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 15)
Compound 15 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 88%.1H NMR(600MHz,CDCl3)8.41(s,1H),8.04(m,2H),7.72(s,2H),7.67(m,2H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝358.1,[M+Na]+＝380.1。
EXAMPLE 17 preparation of 2- (2-chlorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 16)
Compound 16 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 87%.1H NMR(600MHz,CDCl3)8.42(s,1H),8.35(t,J＝1.9Hz,8.1Hz,1H),8.10(m,1H),7.75(s,2H),7.56(m,1H),7.41(t,J＝1.9Hz,8.1Hz,1H),3.99(s,3H),3.98(s,6H)ppm；MS(ESI):[M+H]+＝374.1。
EXAMPLE 18 preparation of 2- (4-chlorophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 17)
Compound 17 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 91%.1H NMR(600MHz,CDCl3)8.40(s,1H),8.11(m,2H),7.72(s,2H),7.50(m,2H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝374.1,[M+Na]+＝396.1。
EXAMPLE 19 preparation of 2- (2-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 18)
Compound 18 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 92%.1H NMR(600MHz,CDCl3)8.48(s,1H),7.81(d,J＝1.1Hz,1H),7.79(s,2H),7.64(dd,J＝7.7Hz,1.6Hz,1H),7.51(m,1H),7.42(td,J＝7.7Hz,1.6Hz,1H),3.95(s,3H),3.95(s,6H)ppm；MS(ESI):[M+H]+＝418.0,[M+Na]+＝440.1。
EXAMPLE 20 preparation of 2- (3-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 19)
Compound 19 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 88%.1H NMR(600MHz,CDCl3)8.48(s,1H),7.79(s,2H),7.70(dd,J＝7.5Hz,2.0Hz,1H),7.62(dd,J＝7.5Hz,1.6Hz,1H),7.47(m,2H),3.95(s,3H),3.95(s,6H)ppm；MS(ESI):[M+H]+＝418.0,[M+Na]+＝440.0。
EXAMPLE 21 preparation of 2- (4-bromophenyl) -4- (3,4, 5-benzoyl) -1,2, 3-triazole (Compound 20)
Compound 20 was prepared in the same manner as in example 12, except that the corresponding starting materials were used; the yield thereof was found to be 87%.1H NMR(600MHz,CDCl3)8.37(s,1H),8.10(m,2H),7.71(s,2H),7.20(m,2H),3.96(s,3H),3.94(s,6H)ppm；MS(ESI):[M+H]+＝418.0,[M+Na]+＝440.0。
EXAMPLE 22 preparation of 2-phenyl-4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 21)
Dissolving compound 11(0.40g,1.18mmol) in absolute ethanol, adding hydroxylamine hydrochloride (0.81g,11.8mmol) and anhydrous sodium acetate (0.97g,11.8mmol), and refluxing for 2 hours; after the reaction is finished, pouring the reaction liquid into water, extracting with ethyl acetate, washing an organic layer with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, evaporating under reduced pressure to remove a solvent, and separating and purifying by column chromatography to obtain a compound 21(Z: E ═ 3: 1); the yield thereof was found to be 85%. (Z):1H NMR(600MHz,CDCl3):11.72(s,1H),8.46(s,1H),7.92(m,2H),7.51(m,3H),6.84(s,2H),3.81(s,6H),3.73(s,3H)ppm；(E):1HNMR(600MHz,CDCl3):11.08(s,1H),8.38(s,1H),7.85(m,2H),7.03(m,3H),6.72(s,2H),3.78(s,9H)ppm；MS(ESI):[M+H]+＝355.1,[M+Na]+＝377.1。
EXAMPLE 23 preparation of 2- (2-methylphenyl) -4- (3,4, 5-benzoylhydroxyimino) -1,2, 3-triazole (Compound 22)
Compound 22(Z: E ═ 5:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 83%.1H NMR(600MHz,CDCl3)(Z isomer)8.60(s,1H),7.58(m,1H),7.35(m,3H),6.95(s,2H),3.90(s,3H),3.86(s,6H),2.40(s,3H)ppm；(E isomer)8.04(s,1H),7.58(m,1H),7.28(m,3H),6.85(s,2H),3.92(s,3H),3.84(s,6H),2.40(s,3H)ppm；MS(ESI):[M+H]+＝369.2。
EXAMPLE 24 preparation of 2- (4-methylphenyl) -4- (3,4, 5-benzoylhydroxyimino) -1,2, 3-triazole (Compound 23)
Compound 23(Z: E ═ 4:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; yield 84％。1H NMR(600MHz,CDCl3)(Z isomer)11.52(1H,s),8.64(1H,s),7.76(2H,d,J＝8.3Hz),7.36(2H,d,J＝8.3Hz),6.80(2H,s),3.78(6H,s),3.72(3H,s),2.35(3H,s)ppm；(Eisomer)11.02(1H,s),8.30(1H,s),7.74(2H,d,J＝8.5Hz),7.28(2H,d,J＝8.5Hz),6.72(2H,s),3.76(6H,s),3.74(3H,s),2.33(3H,s)ppm；MS(ESI):[M+H]+＝369.1,[M+Na]+＝391.1。
EXAMPLE 25 preparation of 2- (4-methoxyphenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 24)
Compound 24(Z: E) was prepared in the same manner as in example 22, except that the corresponding starting material was used>10: 1); the yield thereof was found to be 83%.1H NMR(600MHz,CDCl3)(Z isomer)9.80(s,1H)；8.57(s,1H)；8.08(d,J＝7.66Hz,2H)；7.46(d,J＝7.66Hz,2H)；6.97(s,2H)；3.93(s,3H)；3.88(s,6H)ppm；MS(ESI):[M+H]+＝385.1,[M+Na]+＝407.1。
EXAMPLE 26 preparation of 2- (4-fluorophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 25)
Compound 25(Z: E ═ 2:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 86%.1H NMR(600MHz,CDCl3)(Z isomer)8.40(s,1H),8.14(m,2H),7.73(s,2H),7.23(m,2H),6.66(s,1H),3.98(s,3H),3.97(s,6H)ppm；(E isomer)8.19(s,1H),8.06(m,2H),7.73(s,2H),7.20(m,2H),6.66(s,2H),3.93(s,3H),3.81(s,6H).ppm；MS(ESI):[M+H]+＝373.1。
EXAMPLE 27 preparation of 2- (2-chlorophenyl) -4- (3,4, 5-benzoylhydroxyimino) -1,2, 3-triazole (Compound 26)
Compound 26(Z: E ═ 8:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 89%.1H NMR(600MHz,DMSO)(Z isomer)8.91(s,1H),8.29(m,2H),7.90(m,2H),6.99(s,2H),3.97(s,3H),3.94(s,6H)；8.93(s,1H),8.41(s,2H),8.18(m,2H),7.14(s,2H),4.06(s,9H)ppm；MS(ESI):[M+H]+＝389.1,[M+Na]+＝411.1。
EXAMPLE 28 preparation of 2- (4-chlorophenyl) -4- (3,4, 5-benzoylhydroxyimino) -1,2, 3-triazole (Compound 27)
Compound 27(Z: E ═ 3:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 86%.1H NMR(600MHz,DMSO)(Z isomer)8.55(s,1H),8.03(d,J＝8.64Hz,2H),7.45(d,J＝8.64Hz,2H),6.94(s,2H),3.91(s,3H),3.86(s,6H)ppm；(Eisomer)8.41(s,1H),8.09(d,J＝8.76Hz,2H),7.72(s,2H),7.51(d,J＝8.76Hz,2H),3.98(s,3H),3.96(s,6H)ppm；MS(ESI):[M+H]+＝389.1,[M+Na]+＝411.1。
EXAMPLE 29 preparation of 2- (2-bromophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 28)
Compound 28(Z: E ═ 3:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 87%.1H NMR(600MHz,CDCl3)(Z isomer)8.65(s,1H),7.73(d,J＝7.5Hz,1H),7.56(d,J＝6.0Hz,1H),7.45(d,J＝7.4Hz,1H),7.36(t,J＝7.2Hz,1H),6.96(s,2H),3.88(s,3H),3.86(s,6H)ppm；(E isomer)8.09(s,1H),7.72(s,1H),7.55(s,1H),7.42(d,J＝7.2Hz,1H),7.32(s,1H),6.87(s,2H),3.90(s,3H),3.85(s,6H)ppm；MS(ESI):[M+H]+＝433.0,[M+Na]+＝455.0。
EXAMPLE 30 preparation of 2- (3-bromophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 29)
Compound 29(Z: E ═ 3:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 86%. (Z):1H-NMR(600MHz,CDCl3):(Z isomer)8.63(s,1H),7.60(dd,J＝1.77Hz,7.57Hz,1H),7.57(dd,J＝1.55Hz,7.90Hz,1H),7.43(dd,J＝1.77Hz,7.90Hz,1H),7.41(dd,J＝1.55Hz,7.57Hz,1H),6.96(s,2H),3.88(s,3H),3.87(s,6H)ppm；(E isomer)8.63(s,1H),7.60(dd,J＝8.64Hz,1H),7.57(dd,J＝8.64Hz,1H),7.43(dd,1H),7.41(dd,1H),6.96(s,2H),3.88(s,3H),3.87(s,6H)ppm；MS(ESI):[M+H]+＝433.0,[M+Na]+＝455.1。
EXAMPLE 31 preparation of 2- (4-bromophenyl) -4- (3,4, 5-benzoyloximino) -1,2, 3-triazole (Compound 30)
Compound 30(Z: E ═ 2:1) was prepared in the same manner as in example 22, except that the corresponding starting material was used; the yield thereof was found to be 89%.1H NMR(600MHz,CDCl3)(Z isomer)12.26(s,1H),8.66(s,1H),8.03(m,2H),7.42(m,2H),6.97(s,2H),3.78(s,6H),3.76(s,3H)ppm；(E isomer)11.83(s,1H),8.27(s,1H),7.95(m,1H),7.47(m,1H),6.86(s,1H),3.73(s,3H),3.72(s,6H)ppm；MS(ESI):[M+H]+＝433.0。
Example 32: in vitro antitumor Activity test of Compounds of the invention
In vitro activity test methods and results are as follows: wherein, the clinical commonly used antitumor drug adriamycin (DOX) is a positive experimental group.
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human gastric cancer cell line (SGC-7901cell line), human lung adenocarcinoma (A549cell line), and human colon cancer cell line (HT-1080cell line)
Acting time: 72 hours
The inhibition rate (30. mu.g/mL) of each compound on the growth of three tumor cells is shown in Table-1.
The inhibition of tumor growth (μ g/mL) by each compound is shown in Table-1:
TABLE-1
Example 33: in vivo anti-tumor Activity testing of Compounds of the invention in animals
A compound 3, a compound 7, a compound 10 and a compound 23 with better in vitro activity are selected to carry out an in vivo anti-tumor activity test of animals, the used model is a mouse S-180 sarcoma model, and a positive control drug is clinical common anti-tumor drug Fluorouracil (Fluorouracil, 5-Fu).
The experimental method comprises selecting 18-22 g female Kunming mouse and well-growing S-180 tumor species of 7-11 days, preparing tumor tissue into cell suspension, and inoculating to the right axillary part of mouse, about 1.0-2.0 × 106Cells/mouse, randomly divided into cages 24 hours after inoculation, and administered by intraperitoneal injection for 7 days continuously. Animals were sacrificed 24 hours after drug withdrawal, the body weight and tumor weight were weighed, the average tumor weight of each group was calculated, and the tumor inhibition rate was determined according to the following formula and subjected to t-test.
The tumor inhibition rate is ═ [ (average tumor weight in placebo-average tumor weight in treated group)/(average tumor weight in placebo) ] × 100%
The results are shown in Table-2:
TABLE-2
Claims (10)
1. 2-aryl-4-aroyl-triazole compounds of general formula M, and salts and hydrates thereof:
wherein, R is hydrogen and amino,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom;
R4is H, C1-C6An alkyl group.
2. The compound according to claim 1, and salts and hydrates thereof, wherein:
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom;
R4is H, C1-C6An alkyl group;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently is hydrogen, C1-C6Alkyl radical, C1-C6An alkyloxy group, a halogen atom.
3. The compound according to claim 1, and salts and hydrates thereof, wherein:
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, C1-C3Alkyl radical, C1-C3An alkyloxy group, a halogen atom;
R4is H, C1-C3An alkyl group;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently is hydrogen, C1-C3Alkyl radical, C1-C3An alkyloxy group, a halogen atom.
4. The compound according to claim 1, and salts and hydrates thereof, wherein:
(1) when R is hydrogen, the compound (A) is,
x is C-N-OR (O, C)4；
R1～R3Each independently is hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine;
R4h and methyl;
(2) when R is an amino group, the amino group,
x is C ═ O;
R1～R3each independently hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo.
5. The compound according to any one of claims 1 to 4, wherein:
the compounds also comprise pharmaceutically acceptable salts formed by the 2-aryl-4-aroyl-triazole compounds and hydrates thereof.
6. The compound according to claim 5, and salts and hydrates thereof, wherein:
the pharmaceutically acceptable salt is formed by the compound and acid, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and apple, and the number of crystal water of the hydrate is any real number in 0-16.
7. A process for producing a 2-aryl-4-aroyl-triazole compound according to claim 1, characterized in that:
3,4, 5-trimethoxybenzaldehyde is used as an initial raw material, and the 2-aryl-4-aroyl-triazole compound is prepared through condensation, hydrazone formation, condensation cyclization, deamination and oxime formation reactions.
8. The method according to claim 7,
(1) preparation of 2-aryl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole compound (I)
Adding 2-oxo-N-aryl-2- (3,4, 5-trimethoxyphenyl) cyanoacetyl hydrazone, hydroxylamine hydrochloride and anhydrous sodium acetate into a microwave reaction tube, adding N, N-dimethylformamide, and carrying out microwave heating reaction; after the reaction is finished, cooling to room temperature, pouring into ice water, separating out brown solid, and separating and purifying by column chromatography to obtain a compound 2-aryl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole;
(2) preparation of 2-aryl-4- (3,4, 5-benzoyl) -1,2, 3-triazole compound (II)
Adding 2-aryl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole into a reaction bottle, dissolving with a proper amount of tetrahydrofuran, dropwise adding isoamyl nitrite, and carrying out reflux reaction; after the reaction is finished, evaporating tetrahydrofuran under reduced pressure, and separating and purifying by column chromatography to obtain a compound 2-aryl-4- (3,4, 5-benzoyl) -1,2, 3-triazole;
(3) preparation of 2-aryl-4- (3,4, 5-benzoyloximino) -1,2, 3-triazole compound (III)
Dissolving a compound 2-aryl-4- (3,4, 5-benzoyl) -1,2, 3-triazole compound in absolute ethyl alcohol, adding hydroxylamine hydrochloride and anhydrous sodium acetate, and performing reflux reaction; after the reaction is finished, cooling to room temperature, pouring the reaction liquid into water, extracting by using an organic solvent, washing and drying an organic layer, evaporating the solvent under reduced pressure, and separating and purifying by column chromatography to obtain the compound 2-aryl-4- (3,4, 5-benzoyl oximido) -1,2, 3-triazole.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and salts and hydrates thereof, and a pharmaceutically acceptable carrier.
10. Use of the 2-aryl-4-aroyl-triazole compounds as claimed in any one of claims 1 to 6, and salts and hydrates thereof, or the composition as claimed in claim 9, in the preparation of an antitumor medicament.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108640922A (en) * | 2018-06-14 | 2018-10-12 | 沈阳药科大学 | Triazole and diazepine -5- ketone compounds |
| CN109020904A (en) * | 2018-06-15 | 2018-12-18 | 沈阳药科大学 | 2- aryl -4- aroyl -5- alicyclic ring amido -2H- triazole compound and application thereof |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102883607A (en) * | 2010-03-01 | 2013-01-16 | Gtx公司 | Compounds for treatment of cancer |
| CN105682661A (en) * | 2013-08-23 | 2016-06-15 | 润新生物公司 | Certain chemical entities, compositions, and methods |
-
2016
- 2016-08-01 CN CN201610619466.9A patent/CN106187923A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102883607A (en) * | 2010-03-01 | 2013-01-16 | Gtx公司 | Compounds for treatment of cancer |
| CN105682661A (en) * | 2013-08-23 | 2016-06-15 | 润新生物公司 | Certain chemical entities, compositions, and methods |
Non-Patent Citations (2)
| Title |
|---|
| SAID AHMED SOLIMAN GHOZLAN ET AL.: "Studies with 2-arylhydrazononitriles: a new convenient synthesis of 2,4-disubstituted- 1,2,3-triazole-5-amines", 《ARKIVOC》 * |
| 尤启冬: "《药物化学》", 31 January 2004 * |
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|---|---|---|---|---|
| CN108640922A (en) * | 2018-06-14 | 2018-10-12 | 沈阳药科大学 | Triazole and diazepine -5- ketone compounds |
| CN109020904A (en) * | 2018-06-15 | 2018-12-18 | 沈阳药科大学 | 2- aryl -4- aroyl -5- alicyclic ring amido -2H- triazole compound and application thereof |
| CN109020904B (en) * | 2018-06-15 | 2021-05-25 | 沈阳药科大学 | 2-aryl-4-aroyl-5-alicyclic amino-2H-triazole compound and application thereof |
| 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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