CN108640922B - Triazole and diazepine -5- ketone compounds - Google Patents
Triazole and diazepine -5- ketone compounds Download PDFInfo
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- CN108640922B CN108640922B CN201810616402.2A CN201810616402A CN108640922B CN 108640922 B CN108640922 B CN 108640922B CN 201810616402 A CN201810616402 A CN 201810616402A CN 108640922 B CN108640922 B CN 108640922B
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- Prior art keywords
- compound
- triazolo
- diazepin
- dihydro
- acid
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- 150000003852 triazoles Chemical class 0.000 title abstract description 4
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- -1 nitro, amino Chemical group 0.000 claims description 77
- 238000002360 preparation method Methods 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 5
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 4
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- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- HJHHNJAHQGKNIP-UHFFFAOYSA-N triazolo[4,5-e][1,4]diazepine Chemical compound C1=NC=CN=C2N=NN=C21 HJHHNJAHQGKNIP-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of triazole and diazepine -5- ketone compounds 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
Technical Field
The invention belongs to the technical field of medicines, relates to a triazole diazepine-5-ketone compound and application thereof, and particularly relates to application of the compound as a tumor cell proliferation inhibitor in preparation of anti-tumor 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. 4-Substituted method-aryl-thiazole (SMART) is a tubulin polymerization inhibitor obtained by structural optimization using natural product as lead compound, exerts its anticancer activity by acting on colchicine binding site to inhibit tubulin polymerization, can overcome Pgp-mediated multidrug resistance problem, and has lower neurotoxicity compared with vinblastine. The in vivo efficacy of SMART compounds in human melanoma and prostate cancer xenograft models is very strong. The SMART compound has the structural characteristics that: (1) all have a 3,4, 5-trimethoxyphenyl A ring; (2) a Linker formed by a carbonyl and a five-membered heterocyclic ring B; (3) a phenyl group constituting the C ring. Although the activity of SMART compounds is prominent, in vivo studies have shown that the carbonyl group at the Linker site is easily reduced by metabolism to cause a decrease or disappearance of the activity (see, for related reports, Lu Y., et al. journal of Medicinal Chemistry,2009,52, 1701; Chen J., et al. journal of Medicinal Chemistry,2010,53, 7414; XiaoM., et al. journal of Medicinal Chemistry,2013,56, 3318).
The 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compound containing five-membered heterocyclic and seven-membered heterocyclic has a novel structure of a parent nucleus part, and is not reported at present. The compounds are used for antitumor activity research, and are not reported at present.
Disclosure of Invention
The invention aims to design and synthesize a structural analogue of SMART with good anti-tumor activity, namely the SMART analogue with [1,2,3] triazolo [4,5-e ] [1,4] diazepine as an intermediate connecting segment; 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, pharmaceutically acceptable salts, solvates or isomers thereof:
wherein,
R1～R4each independently is hydrogen, C1-C6Alkyloxy, two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogen atom, nitro and amino.
The present invention preferably relates to a compound of formula M, a pharmaceutically acceptable salt, solvate or isomer thereof:
wherein,
R1is hydrogen, R2、R3、R4Are each independently C1-C6Alkyloxy or two or three adjacent substituents being C at the same time1-C6Alkyloxy, or two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogen atom, nitro and amino.
The present invention preferably relates to a compound of formula M, a pharmaceutically acceptable salt, solvate or isomer thereof:
R1is hydrogen, R2、R3、R4Are each independently C1-C3Alkyloxy or two or three adjacent substituents being C at the same time1-C3Alkyloxy, or two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, C1-C4Alkyl radical, C1-C4Alkoxy, halogen atom, nitro and amino.
The present invention most preferably relates to a compound of formula M, a pharmaceutically acceptable salt, solvate or isomer thereof:
R1is hydrogen, R2、R3、R4Each independently is methoxyThe group or two or three adjacent substituents are simultaneously methoxy, or two adjacent substituents are-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, nitro, amino.
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 compound 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-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 2
2-p-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 3
2-o-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 4
2-m-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 5
2- (2, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 6
2- (3, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 7
2- (2, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 8
2- (3, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 9
2- (4-methoxyphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 10
2- (4-fluorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 11
2- (4-chlorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 12
2- (4-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 13
2- (2-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 14
2- (3-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 15
2- (4-Nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 16
2- (4-methoxy-3-nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 17
2- (4-methoxy-3-aminophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 18
2-phenyl-8- (2,3, 4-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 19
2-phenyl-8- (3, 4-dimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 20
2-phenyl-8- (4-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 21
2-phenyl-8- (3-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 22
2-phenyl-8- (3, 4-methylenedioxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
The 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compound can be synthesized according to the following reaction route:
2-aryl-4-aroyl-5-aminotriazole compounds (see D.Feng, et al.RSCAdv.,2017,7, 29103; CN106187923A for related reports) are used as starting materials, and are subjected to chloroacetyl chloride acylation, cyclization and other reactions to prepare the 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compounds. Wherein, the 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compound containing amino in the compound can be prepared by the reduction reaction of a compound containing nitro in the corresponding compound, and the reducing agent is an anhydrous ferric trichloride/hydrazine hydrate/activated carbon system.
The preparation method of the 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compound provided by the invention is simple and feasible, and has high yield.
The invention further provides application of the compound in preparing a medicine for treating tumor diseases.
The 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ketone compound has a good effect of treating tumor diseases, and has a good development prospect in preparing 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-phenyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 1)
Adding 2-phenyl-4- (3,4, 5-benzoyl) -5-amino-1, 2, 3-triazole (354mg,1.0mmol) and anhydrous dichloromethane (30mL) into a 100mL eggplant-shaped bottle, dissolving, and adding N2Protecting, precooling at 0 ℃, dropwise adding chloroacetyl chloride (0.15mL,2.0mmol), and transferring to room temperature after dropwise adding. And (4) continuing the reaction for 24h, after the TLC detection reaction is finished, evaporating the solvent under reduced pressure, washing with ethyl acetate, and performing suction filtration to obtain a compound I. Dissolving a compound 2-chloro-N- (2-phenyl-5- (3,4, 5-trimethoxybenzoyl) -2H-1,2, 3-triazole-4-yl) acetamide (430mg,1.0mmol), urotropine (701mg,5.0mmol) and ammonium acetate (386mg,5.0mmol) in 95% ethanol, carrying out reflux reaction for 5H, carrying out TLC detection reaction, evaporating the solvent under reduced pressure, extracting dichloromethane (20mL) for 3 times, combining organic layers, washing with saturated saline (10mL), drying with anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, recrystallizing with anhydrous ethanol, and carrying out column chromatography separation and purification to obtain a compound 1; the yield thereof was found to be 77%.1H NMR(600MHz,CDCl3)δ9.49(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)δ167.9,162.2,152.9(×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。
EXAMPLE 2 preparation of 2-p-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 2)
Compound 2 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 74%.1H NMR(600MHz,CDCl3)δ9.61(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。
EXAMPLE 3 preparation of 2-o-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 3)
Compound 3 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 76%.1H NMR(600MHz,CDCl3)δ9.74(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。
EXAMPLE 4 preparation of 2-m-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 4)
Compound 4 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 71%.1H NMR(600MHz,CDCl3)δ9.89(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。
EXAMPLE 5 preparation of 2- (2, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 5)
Compound 5 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 73%.1H NMR(600MHz,DMSO)δ11.49(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。
EXAMPLE 6 preparation of 2- (3, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 6)
Compound 6 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 69%.1H NMR(600MHz,CDCl3)δ9.75(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。
EXAMPLE 7 preparation of 2- (2, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 7)
Compound 7 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 78%.1H NMR(600MHz,CDCl3)δ9.39(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。
EXAMPLE 8 preparation of 2- (3, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 8)
Compound 8 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 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。
EXAMPLE 9 preparation of 2- (4-methoxyphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 9)
Compound 9 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 72%.1H NMR(600MHz,CDCl3)δ10.22(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)δ167.8,162.2,159.9,152.9(×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。
EXAMPLE 10 preparation of 2- (4-fluorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 10)
Compound 10 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 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)δ167.8,163.3,161.9(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。
EXAMPLE 11 preparation of 2- (4-chlorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 11)
Compound 11 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 78%.1H NMR(600MHz,CDCl3)δ9.72(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。
EXAMPLE 12 preparation of 2- (4-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 12)
Compound 12 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 75%.1H NMR(600MHz,CDCl3)δ9.45(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。
EXAMPLE 13 preparation of 2- (2-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 13)
Compound 13 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 68%.1H NMR(600MHz,CDCl3)δ9.68(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。
EXAMPLE 14 preparation of 2- (3-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 14)
Compound 14 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 77%.1H NMR(600MHz,DMSO)δ11.5(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。
EXAMPLE 15 preparation of 2- (4-Nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 15)
Compound 15 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 74%.1H NMR(600MHz,CDCl3)δ9.56(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。
EXAMPLE 16 preparation of 2- (4-methoxy-3-nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 16)
Compound 16 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 69%.1H NMR(600MHz,DMSO)δ11.67(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。
EXAMPLE 17 preparation of 2- (4-methoxy-3-aminophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 17)
Adding a compound 16(200mg,0.4mmol) into a 50mL eggplant-shaped bottle, adding 20mg of activated carbon and 20mg of ferric trichloride as catalysts, using absolute ethyl alcohol as a solvent, dropwise adding 0.1mL of 80% hydrazine hydrate under stirring, and carrying out reflux reaction for 3 hours; after TLC detection reaction is finished, filtering to remove activated carbon, evaporating anhydrous ethanol to dryness, adding water, extracting with ethyl acetate, combining organic layers, carrying out reduced pressure distillation to obtain a crude product, and carrying out chromatographic separation to obtain a compound 17; yellow solid, yield: 70 percent.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。
EXAMPLE 18 preparation of 2-phenyl-8- (2,3, 4-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 18)
Compound 18 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 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。
EXAMPLE 19 preparation of 2-phenyl-8- (3, 4-dimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 19)
Compound 19 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 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。
EXAMPLE 20 preparation of 2-phenyl-8- (4-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 20)
Compound 20 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 75%.1H NMR(600MHz,CDCl3)δ11.54(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。
EXAMPLE 21 preparation of 2-phenyl-8- (3-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 21)
Compound 21 was prepared in the same manner as in example 1, except that the corresponding starting material was used; the yield thereof was found to be 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。
EXAMPLE 22 preparation of 2-phenyl-8- (3, 4-methylenedioxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one (Compound 22)
Compound 22 was prepared in the same manner as in example 1, except that the corresponding starting materials were used; the yield thereof was found to be 73%.
1H NMR(600MHz,CDCl3)δ11.56(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。
Example 23: 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-7901 cell line), human lung adenocarcinoma (A549 cell line), and human colon cancer cell line (HT-1080 cell 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 rate of each compound on tumor growth (μ g/mL) is shown in Table-1.
TABLE-1
Example 24: in vivo anti-tumor Activity testing of Compounds of the invention in animals
The compounds 2 and 8 with better in vitro activity are selected to carry out the test of the antitumor activity in animals, the used model is a mouse S-180 sarcoma model, and the positive control drug is clinical common antitumor drug Fluorouracil (5-Fu).
The experimental method comprises the following steps: selecting 18-22 g female Kunming mouse and S-180 tumor with good growth for 7-11 days, making tumor tissue into cell suspension, inoculating to the right axillary part of mouse, and inoculating to the subcutaneous part of the right axillary part of mouse, wherein the cell suspension is 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 experimental results are shown in Table-2
TABLE-2
Claims (12)
1. Triazolodiazepin-5-ones of the general formula M and salts thereof:
R1～R4each independently is hydrogen, C1-C6Alkyloxy, two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently of the otherGround is hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogen atom, nitro and amino.
2. The compound according to claim 1, wherein:
R1is hydrogen, R2、R3、R4Are each independently C1-C6Alkyloxy or two or three adjacent substituents being C at the same time1-C6Alkyloxy, or two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogen atom, nitro and amino.
3. A compound according to claim 1 or 2, and salts thereof, wherein:
R1is hydrogen, R2、R3、R4Are each independently C1-C3Alkyloxy or two or three adjacent substituents being C at the same time1-C3Alkyloxy, or two adjacent substituents being-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, C1-C4Alkyl radical, C1-C4Alkoxy, halogen atom, nitro and amino.
4. A compound according to claim 1 or 2, and salts thereof, wherein:
R1is hydrogen, R2、R3、R4Are respectively and independently methoxy or two or three adjacent substituents are simultaneously methoxy or two adjacent substituents are-OCH2O-thereby forming a five-membered ring;
R5～R8each independently of the others is hydrogen, methyl, methoxy, fluorine, chlorine, bromine,Nitro and amino.
5. A compound according to claim 3, and salts thereof, wherein:
R1is hydrogen, R2、R3、R4Are respectively and independently methoxy or two or three adjacent substituents are simultaneously methoxy or two adjacent substituents are-OCH2O-thereby forming a five-membered ring;
R5～R8each independently is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, nitro, amino.
6. The compound and salts thereof of claims 1,2 or 5, wherein:
the salt is formed by the compound and acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and malic acid.
7. A compound according to claim 3, and salts thereof, wherein:
the salt is formed by the compound and acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and malic acid.
8. The compound and salts thereof according to claim 4, wherein:
the salt is formed by the compound and acid, and the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and malic acid.
9. The following 2, 8-diaryl-2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -ones and salts thereof are selected from:
compound 1
2-phenyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 2
2-p-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 3
2-o-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 4
2-m-tolyl-8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 5
2- (2, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 6
2- (3, 4-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 7
2- (2, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 8
2- (3, 5-dimethylphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 9
2- (4-methoxyphenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 10
2- (4-fluorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 11
2- (4-chlorophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 12
2- (4-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 13
2- (2-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 14
2- (3-bromophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 15
2- (4-Nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 16
2- (4-methoxy-3-nitrophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 17
2- (4-methoxy-3-aminophenyl) -8- (3,4, 5-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 18
2-phenyl-8- (2,3, 4-trimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 19
2-phenyl-8- (3, 4-dimethoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one
Compound 20
2-phenyl-8- (4-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one compound 21
2-phenyl-8- (3-methoxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one compound 22
2-phenyl-8- (3, 4-methylenedioxyphenyl) -2, 6-dihydro- [1,2,3] triazolo [4,5-e ] [1,4] diazepin-5 (4H) -one.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and salts thereof and a pharmaceutically acceptable carrier.
11. Use of a compound or salt thereof according to any one of claims 1 to 9 or a composition according to claim 10 for the preparation of an antitumor agent.
12. The use of claim 11, wherein the tumor is gastric cancer, lung adenocarcinoma or colon cancer.
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