CN104725431B - Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof - Google Patents
Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof Download PDFInfo
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- CN104725431B CN104725431B CN201510120661.2A CN201510120661A CN104725431B CN 104725431 B CN104725431 B CN 104725431B CN 201510120661 A CN201510120661 A CN 201510120661A CN 104725431 B CN104725431 B CN 104725431B
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- quinolinone
- polar solvent
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- methyl
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- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 title abstract description 6
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000002798 polar solvent Substances 0.000 claims abstract description 26
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims abstract description 15
- VFEHQRUBPYYOTB-UHFFFAOYSA-N cobalt 1H-quinolin-2-one Chemical compound [Co].C1=CC=C2NC(=O)C=CC2=C1 VFEHQRUBPYYOTB-UHFFFAOYSA-N 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000010668 complexation reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
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- 230000035755 proliferation Effects 0.000 abstract description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 2
- 201000011549 stomach cancer Diseases 0.000 abstract description 2
- 201000007270 liver cancer Diseases 0.000 abstract 2
- 208000014018 liver neoplasm Diseases 0.000 abstract 2
- 206010008342 Cervix carcinoma Diseases 0.000 abstract 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract 1
- 201000010881 cervical cancer Diseases 0.000 abstract 1
- 229940097267 cobaltous chloride Drugs 0.000 abstract 1
- 230000000536 complexating effect Effects 0.000 abstract 1
- 230000005918 in vitro anti-tumor Effects 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 238000005303 weighing Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
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- 239000000047 product Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 9
- 229940126214 compound 3 Drugs 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
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- 239000002253 acid Substances 0.000 description 6
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- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 4
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- -1 Quinoline ketone Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
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- 150000002576 ketones Chemical group 0.000 description 3
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- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
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- 239000005388 borosilicate glass Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000001819 mass spectrum Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- KCOYQXZDFIIGCY-CZIZESTLSA-N (3e)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(N\C(N2)=C/3C(=C4C(F)=CC=CC4=NC\3=O)N)C2=C1 KCOYQXZDFIIGCY-CZIZESTLSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
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- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 244000309466 calf Species 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
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- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
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- 239000006285 cell suspension Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
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- 239000006184 cosolvent Substances 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229950005778 dovitinib Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical class O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229930185107 quinolinone Natural products 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a cobalt (II) complex of quinolinone derivative, and a synthesis method and application thereof. The synthesis method of the quinolinone cobalt complex comprises the following steps: weighing cobaltous chloride and a ligand 3-(1H-benzimidazolyl-2-yl)-6-methyl-2(1H)-quinolinone according to the stoichiometric proportion, dissolving in a polar solvent, and carrying out complexing reaction. The research of the in-vitro antitumor activity indicates that the complex has certain proliferation inhibition activity for human cervical cancer cell Hela229, human stomach cancer cell MGC-803, human liver cancer cell strain Hep G2 and BEL-7404 cell strain, and has the maximum activity for human liver cancer cell strain Hep G2. The quinolinone cobalt complex is disclosed as the following formula (I).
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of cobalt of qualone derivative (II) complex and its synthesis
Method and application.
Background technology
2 (1H)-quinolinone structures are the alkaloids being widely present as quinoline in natural products, contain 2 (1H)-quinoline
The compound of ketone structure has multiple biological activities, and different substitution bases are introduced on its ring or on side chain, can produce and such as resist
The pharmacological activity of the wide spectrum such as tumour, anti-oxidant, anti-inflammatory.It is to work as to seek the low lead compound parent nucleus of good activity, toxicity
A kind of important method of preceding research and development anti-cancer agent, because 2 (1H)-quinolinones are active preferably, structure is easy to modification, toxicity
Low feature, in the design and screening of its antineoplastic that is widely used.Some have the chemical combination of 2 (1H)-quinolinone skeletons
Thing comes into clinic as antineoplastic, for example:Many Weis are that a kind of orally active small molecule is more for Buddhist nun (Dovitinib)
Target spot tyrosine kinase inhibitor, can be done directly on tumour cell and the blood vessel and matrix of nutrition is provided for tumour cell,
By antiproliferative activity and anti-angiogenic existence activity, antitumor action is shown;Tipifarnib (Tipifanib) belongs to farnesyl
Inhibitors, it can prevent the activation of Ras oncogene by suppressing the protein of farnesylation, suppress cell life
It is long, inducing cell apoptosis, and suppress angiogenesis.Such compound has good development prospect.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active part is studied in recent years with bioinorganic chemistry
Flourish and turn into hot research field, the first, second and third generation platinum class especially with cis-platinum, carboplatin, oxaliplatin etc. as representative
Cancer therapy drug really indicates the arrival of Metal Drugs research and application New Times as the successful Application of front-line chemotherapeutic agents.
Have not yet to see cobalt (II) complex with 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone as part and
Its synthesis and the relevant report of application.
The content of the invention
The technical problem to be solved in the present invention is to provide cobalt (II) complex and its conjunction of a kind of new qualone derivative
Into method and application.
Cobalt (II) complex of qualone derivative of the present invention be with the compound of structure shown in lower formula (I) or
Its pharmaceutically acceptable salt:
The synthetic method of compound is shown in above-mentioned formula (I):Stoichiometrically weigh cobalt chloride (i.e. six chloride hydrates
Cobalt) and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, it is dissolved in polar solvent, be coordinated instead
Should, that is, obtain target product.
Part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline involved in synthetic method of the present invention
Quinoline ketone is synthesized using following synthesis thinking:
With para-totuidine as raw material, under conditions of acetic acid or hydrochloric acid are present, add acetic anhydride to be acylated, be acylated
Product (i.e. compound 1);Gained acylate obtains cyclization product (i.e. compound 2) with POCl3 cyclization;Gained cyclization is produced
Thing acid adding is hydrolyzed, and obtains hydrolysate (i.e. compound 3);Gained hydrolysate carries out condensation reaction with o-phenylenediamine, i.e.,
Obtain target product (i.e. compound 4).Specific synthetic route is as follows:
Reagent:(a) acetic anhydride, acetic acid or hydrochloric acid;(b) N,N-dimethylformamide, POCl3;(c) acid;(d) neighbour benzene
Diamines, methyl alcohol and/ethanol.
Above-mentioned part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone more specifically synthetic method, bag
Include following steps:
1. with para-totuidine as raw material, under conditions of acetic acid or hydrochloric acid are present, add acetic anhydride to be reacted, reacted
PH value into rear regulation system is 6~8, reactant suction filtration, and filter cake recrystallization obtains compound 1;
2. gained compound 1 is dissolved in DMF, adds POCl3 to carry out ring closure reaction, gained reaction
Thing is poured into frozen water, suction filtration, obtains compound 2;
3. the gained acid adding of compound 2 is hydrolyzed, and obtains compound 3;
4. gained compound 3 carries out condensation reaction with o-phenylenediamine under conditions of methyl alcohol and/or ethanol are present, and obtains final product mesh
Mark product.
The step of above-mentioned part synthetic method 1. in, the concentration of the acetic acid can be 30~90 (v/v) %, the hydrochloric acid
Concentration can be 15~37w/w%, the consumption of the acetate and hydrochloride typically respectively the amount of para-totuidine material 0.9~
1.2 times, or 1.2 times of amount more than para-totuidine material.The addition of the acetic anhydride is usually para-totuidine material
0.9~1.2 times of amount, or 1.2 times of amount more than para-totuidine material.In the step, due to exothermic heat of reaction, preferably
Reaction is carried out under condition of ice bath.Whether reaction can use thin-layer chromatography (TLC) tracing detection, generally control reaction completely
Time is that 1~4h is appropriate.The pH value that alkali lye regulation system is used after the completion of reaction is 6~8, and described alkali lye can be acetic acid
The aqueous solution of the alkaline matters such as sodium, sodium carbonate, sodium phosphate, sodium acid carbonate or potassium carbonate, the concentration of the alkali lye is preferably 5~
30/w/w%;Preferably it is adjusted using the aqueous solution of sodium acetate.The filter cake of collection is generally using absolute ethyl alcohol and/or anhydrous
Methyl alcohol is recrystallized.
The step of above-mentioned part synthetic method 2. in, the addition of the POCl3 is usually the amount of the material of compound 1
0.9~1.2 times, or 1.2 times of amount more than para-totuidine material.The consumption of the N,N-dimethylformamide can be with
Determine as needed, can specifically be calculated with the amount of 5~11ml by 10mmol compounds 1.Described ring closure reaction generally exists
Carried out under heating condition, preferably carried out under the conditions of 60~90 DEG C, in 60~90 DEG C of conditions more preferably in reflux
Under carry out back flow reaction.Whether reaction can use TLC tracing detections completely, generally control the reaction time relatively to be closed for 8~14h
It is suitable.
The step of above-mentioned part synthetic method 3. in, acid used can be 30~90 (v/v) % ice vinegar when being hydrolyzed
Acid, or 2~6mol/L hydrochloric acid, or 2~6mol/L sulfuric acid;The sour consumption for hydrolyzing is usually every
10mmol compounds 2 are hydrolyzed with 50~80ml acid solutions.The hydrolysis is generally carried out in a heated condition, preferably 60
Carried out under the conditions of~90 DEG C, more preferably flowed back under the conditions of 60~90 DEG C in reflux, in said temperature condition
Lower backflow can obtain settled solution.Hydrolysis whether completely can use TLC tracing detections, generally control the reaction time be 6~
12h is appropriate.After hydrolysis completely, gained reactant cooling has crystal to separate out, and the crystal of precipitation is compound 3.
The step of above-mentioned part synthetic method 4. in, the consumption of the o-phenylenediamine is usually the amount of the material of compound 3
0.9~1.2 times, or 1.2 times of amount more than para-totuidine material.Described methyl alcohol is 70~100v/v% methyl alcohol, institute
The ethanol stated is 70~100v/v% ethanol;The consumption of the methyl alcohol and/or ethanol can determine as needed, specifically can be by
10mmol compounds 3 are calculated with the amount of 50~80ml.Described condensation reaction is generally carried out in a heated condition, is preferably existed
Carried out under the conditions of 60~90 DEG C, back flow reaction is more preferably carried out under the conditions of 60~90 DEG C in reflux.Condensation reaction
Whether TLC tracing detections can be used completely, generally control the reaction time for 6~12h is appropriate.After the completion of reaction, gained
Suction filtration after reactant cooling, collects filter cake and is target product (i.e. part).
The molecular formula of part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone of the present invention is
C17H13N3O, molecular weight is:275.1, structure is as follows:
In the molecule, the nitrogen-atoms on carbonylic oxygen atom and imidazole ring on quinolinone has stronger coordination ability, can
Following coordination mode is formed in complexation reaction:
N, O bidentate chelate mode:With the N of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, O atom with
Metal ions M is coordinated, and forms hexatomic ring chelating body.
Specifically when compound shown in formula (I) described in the invention described above is synthesized, can be carried out using solwution method or solvent-thermal method
Synthesis.
When synthesizing using solwution method, following steps are specifically included:
1) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline are stoichiometrically weighed
Ketone, is dissolved in polar solvent, obtains mixed solution;
2) gained mixed solution is in reaction in 20 DEG C to polar solvent of reflow temperature range;
3) gained reacting liquid filtering, sediment is scrubbed, dry, that is, obtain quinolinone cobalt complex.
The step of above-mentioned solwution method 1) in, when the selection of polar solvent is for methyl alcohol and selected from water, acetone, chloroform and N, N- bis-
During a kind of combination in NMF, preferably methyl alcohol is with the volume ratio of water, acetone, chloroform or DMF
50:1~1:1.When polar solvent selection for methyl alcohol be selected from water, acetone, chloroform and N,N-dimethylformamide in it is any
During two or more combination, the proportioning between them can be any proportioning.The consumption of the polar solvent can be true as needed
It is fixed, it is generally the case that cobalt chloride and 1mmol 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H) of 1mmol-quinolinone is used
The polar solvent of 10~80mL dissolves.In specific dissolving step, can by cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-
Base) -6- methyl -2 (1H)-quinolinone respectively with polar solvent dissolve, remix and react together;Also can be by cobalt chloride and part
Additive polarity solvent again after the mixing of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone.The cobalt chloride and part 3-
The ratio between amount of material of (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone is usually 1:1.
The step of above-mentioned solwution method 2) in, whether reaction can use thin-layer chromatography tracing detection completely.Reaction is preferably used
Back flow reaction, reacts more preferably in 50 DEG C to polar solvent of reflow temperature range.When reaction is molten to polarity at 50 DEG C
Carried out in the reflow temperature range of agent, reaction to taking around 3~18h completely.
The step of above-mentioned solwution method 3) in, it is typically to be washed with ether, acetone or dichloromethane during washing.Dried strip
Part is the vacuum drying or constant pressure and dry under the conditions of 30~50 DEG C.In this method, product typically a large amount of generations in solid form,
If previous step 1) in polar solvent addition larger (such as the upper limit close to proportioning) or solvent to the dissolubility of product compared with
Good, then solution may be in clear state after reacting, because caused by the product precipitation for being formed is by polar solvent dissolving, now
Product can be made main and separated out with powder precipitation or crystal form by the vacuum distillation of gained reaction solution to remove partial solvent, take out
Next step operation is carried out after the solid of precipitation again.Concentration removes partial solvent and typically refers to concentration removing polar solvent addition
50~90%.
When using solvent structure, following steps are specifically included:
A) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline are stoichiometrically weighed
Ketone, is dissolved in polar solvent, obtains mixed solution;
B) gained mixed solution is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, is sealed, then in 50~140 DEG C of bars
Reacted under part, that is, obtain quinolinone cobalt complex.
In the step of above-mentioned solvent-thermal method a), when polar solvent selection for methyl alcohol with selected from water, acetone, chloroform and N, N-
During a kind of combination in dimethylformamide, the preferred volume ratio of methyl alcohol and water, acetone, chloroform or DMF
It is 50:1~1:1.Appointing in the selection of polar solvent is for methyl alcohol and selected from water, acetone, chloroform and N,N-dimethylformamide
During the two or more combinations of meaning, the proportioning between them can be any proportioning.The consumption of the polar solvent can be as needed
It is determined that, it is generally the case that cobalt chloride and 1mmol 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone of 1mmol
Dissolved with the polar solvent of 5~30mL.In specific dissolving step, can by cobalt chloride and part 3- (1H- benzimidazoles-
2- yls) -6- methyl -2 (1H)-quinolinone respectively with polar solvent dissolve, remix and react together;Also by cobalt chloride and can match somebody with somebody
Additive polarity solvent again after the mixing of body 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone.The cobalt chloride and part
The ratio between amount of material of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone is usually 1:1.
In the step of above-mentioned solvent-thermal method b), described container is usually heavy wall borosilicate glass tube, and the time of reaction is usual
Control in 12~72h, also dependent on needing for extend to more than 72h in the reaction time.More preferably mixed solution is at 80~100 DEG C
Under the conditions of reacted, when being carried out under normal temperature of the reaction below 80 DEG C or heating condition, reaction needs the longer time
Yield higher can be obtained.
Antineoplastic is being prepared present invention additionally comprises the compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I)
Application in thing.
The present invention further includes the antineoplastic prepared as active component with the compound shown in above-mentioned formula (I).
Compared with prior art, the invention provides a kind of new quinolinone cobalt complex and its synthetic method and application.
Anti tumor activity in vitro research of the applicant to complex of the present invention shows that it is to human cervical carcinoma cell Hela229, people's stomach
Cancer cell MGC-803, human hepatoma cell strain Hep tetra- kinds of cell lines of G2 and BEL-7404 all show certain Proliferation Ability and live
Property, wherein for human hepatoma cell strain Hep G2 activity highests.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of part used in various embodiments of the present invention;
Fig. 2 is the carbon-13 nmr spectra figure of part used in various embodiments of the present invention;
Fig. 3 is the high resolution mass spectrum spectrogram of part used in various embodiments of the present invention, and its ordinate is relative abundance
Value, abscissa is m/z (molecular weight);
Fig. 4 is the infrared spectrum of final product obtained in the embodiment of the present invention 1;
Fig. 5 is the high resolution mass spectrum figure of final product obtained in the embodiment of the present invention 1, and its ordinate is relative abundance value,
Abscissa is m/z (molecular weight);
Fig. 6 is the x-ray crystal structure figure of final product obtained in the embodiment of the present invention 1.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following examples.
In following embodiment, described part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, under
State the abbreviation that the BMQ occurred in each embodiment is the part) synthesized as follows:
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flasks, is added dropwise over 8ml concentrated hydrochloric acids,
10.2g (0.1mol) acetic anhydride, reacts 4 hours under ice bath, is then with the pH value of the sodium acetate solution regulation system of 20w/w%
7, stand, suction filtration, filter cake absolute ethyl alcohol is recrystallized to give compound 1 (white needle-like crystals, 13.3g, yield 89%).
2) by 3.5ml DMF and 17ml POCl3Mix under ice bath, be stirring evenly and then adding into 2.24g (15mmol) chemical combination
Thing 1, resulting solution is placed in reflux, is heated to 90 DEG C and is flowed back 10 hours, is poured into after cooling in 500ml frozen water, and suction filtration is obtained
To compound 2 (2.7g, yield 87%).
3) 2.05g (10mmol) compound 2 is dissolved in the glacial acetic acid of 80ml 70%, resulting solution is placed in reflux, plus
Hot to 90 DEG C are flowed back 8 hours, and cooling obtains compound 3 (yellow needle-like crystals, 1.70g, yield 91%).
4) 1.87g (10mmol) compound 3 and 1.08g (10mmol) o-phenylenediamine are added in 80ml absolute methanols,
Resulting solution is placed in reflux, is flowed back 8 hours in 90 DEG C, and cooling, suction filtration obtains yellow solid (2.48g, 90%).
Gained yellow solid product is identified:
(1) proton nmr spectra and carbon are composed, and their spectrogram difference is as illustrated in fig. 1 and 2.
1H NMR (500MHz, DMSO-d6) δ 12.65 (s, 1H), 12.40 (s, 1H), 9.00 (d, J=1.7Hz, 1H),
7.74-7.70 (m, 1H), 7.69 (s, 1H), 7.68-7.63 (m, 1H), 7.42 (d, J=8.4Hz, 1H), 7.33 (d, J=
8.4Hz,1H),7.22–7.17(m,2H),2.36(s,3H).13C NMR(126MHz,DMSO-d6)δ160.79,147.96,
142.83,138.90,136.85,134.49,133.15,131.89,128.38,122.41,122.05,119.93,119.19,
118.38,115.29,112.88,20.56.
(2) electrospray ionization mass spectrum, as shown in figure 3, ESI-MS m/z:276.1[M+H]+.
Accordingly, it can be determined that above-mentioned yellow solid product is 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline
Ketone, its chemical structural formula is as follows:
Embodiment 1
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol CoCl are directly added into2·6H2O and 0.1mmol BMQ,
(volume ratio of methyl alcohol and chloroform is 3 to add 0.6ml methyl alcohol/chloroform mixed solution:1).Under conditions of vacuumizing, by opening
End sealing, then fully reacts 72h, you can obtain blue crystalline solids product under the conditions of 80 DEG C.Product is by infrared light
Spectrum (as shown in Figure 4), elementary analysis, electrospray ionization mass spectrum (as shown in Figure 5) carry out structure (such as with reference to the analysis of X-ray single crystal diffraction
Shown in Fig. 6) determine, it is defined as title complex [Co (BMQ) Cl2], shown in its structural formula such as following formula (I).
Embodiment 2
Embodiment 1 is repeated, unlike:
1) polar solvent is changed to methyl alcohol;
2) reaction temperature is changed to 50 DEG C, and the reaction time is changed to 50h.
Products therefrom carries out structure by infrared spectrum, elementary analysis, the analysis of electrospray ionization mass spectrum combination X-ray single crystal diffraction
Determine, be defined as title complex [Co (BMQ) Cl2]。
Embodiment 3
1) 0.1mmol CoCl are weighed respectively2·6H2O and 0.1mmol BMQ, are dissolved in the mixing of 80mL methanol/acetones after mixing
(volume ratio of methyl alcohol and acetone is 1 to solution:1) in, mixed solution is obtained;
2) gained mixed solution is in 100 DEG C of back flow reaction 8h;
3) gained reaction solution is evaporated off partial solvent, stands, and has blue crystalline solid product to separate out, and isolates solid, uses second
Ether is washed, and is dried.
Products therefrom carries out structure by infrared spectrum, elementary analysis, the analysis of electrospray ionization mass spectrum combination X-ray single crystal diffraction
Determine, be defined as title complex [Co (BMQ) Cl2]。
Embodiment 4
Embodiment 3 is repeated, unlike:
1) polar solvent be changed to methanol/water (volume ratio of first alcohol and water be 5:1);
2) reaction temperature is changed to 70 DEG C, and the reaction time is changed to 12h.
In order to absolutely prove purposes of the complex of the present invention in pharmacy, applicant has carried out extracorporeal anti-tumor to it
Activity experiment.
First, quinolinone cobalt complex is to 5 kinds of proliferation inhibition activity experiments of cell line:
1st, cell line and cell culture
This experiment is from gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, BEL-7404, human cervical carcinoma cell
Hela229 and human normal cell line HL-7702 totally 5 kinds of cell lines.
All tumor cell lines are cultivated containing 10wt% small ox bloods, 100U/mL penicillin, 100U/mL streptomysins
In RPMI-1640 nutrient solutions, 37 DEG C of 5%CO containing volumetric concentration are put2Cultivated in incubator;Human normal cell line strain is then cultivated and contained
In the small ox bloods of 10wt%, 100U/mL penicillin, the DMEM nutrient solutions of 100U/mL streptomysins.
2nd, the preparation of testing compound
Quinolinone cobalt complex used is the products therefrom of the embodiment of the present invention 1, purity >=95%, by its DMSO liquid storage
(concentration is 0.001mol/L) is diluted to five concentration gradients successively by RMPI1640 culture mediums, respectively 40,20,10,5,
2.5 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.20 μm of target products of ol/L are tested first to increase for tumour cell
The inhibiting rate grown, is considered as primary dcreening operation result;Test propagation of the target product to various tumour cells under different gradient concentrations respectively again
Inhibition level, to the Fitting Calculation half-inhibition concentration, i.e. IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumour cell in growth period, through Trypsin Induced after, matched somebody with somebody with the nutrient solution containing 10% calf serum
The cell suspension that concentration is 5000/mL is made, is inoculated in 96 well culture plates with the μ L of every hole 190, make cell density to be measured extremely
1000~10000/hole (edge hole is filled with aseptic PBS);
(2) 5%CO2, 37 DEG C are incubated 24h, and bottom hole is paved with to cell monolayer, and the medicine 10 of finite concentration gradient is added per hole
μ L, each concentration gradient sets 4 multiple holes;
(3) 5%CO2, 37 DEG C are incubated 48 hours, are observed under inverted microscope;
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues to cultivate 4h;
(5) terminate culture, carefully suck nutrient solution in hole, add 150 μ L DMSO fully to dissolve first a ceremonial jade-ladle, used in libation precipitation per hole, shake
It is 570nm in ELIASA wavelength after swinging device mixing, reference wavelength is the OD value that 450nm determines each hole;
(6) while setting zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolving of same concentrations are situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) living cells quantity is judged according to the OD value (OD values) for measuring, OD values are bigger, and cytoactive is stronger.
Using formula:
Calculate the inhibiting rate of compound on tumor cell growth.For cell of the inhibiting rate more than 50% under primary dcreening operation concentration
The inhibiting rate data of five concentration gradients are further fitted by strain by SPSS softwares, obtain compound to different tumours
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different lung cancer cell lines50Value is as shown in table 1.
Table 1:
Claims (6)
1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended:
2. the synthetic method of the compound described in claim 1, it is characterised in that:Stoichiometrically weigh cobalt chloride and part
3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, is dissolved in polar solvent, carries out complexation reaction, that is, obtain mesh
Mark product;
Described polar solvent is methyl alcohol, or methyl alcohol with selected from water, acetone, chloroform and DMF
Plant or two or more combinations.
3. synthetic method according to claim 2, it is characterised in that:Comprise the following steps:
1) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone are stoichiometrically weighed, it is molten
In polar solvent, mixed solution is obtained;
2) gained mixed solution is in reaction in 20 DEG C to polar solvent of reflow temperature range;
3) gained reacting liquid filtering, sediment is scrubbed, dry, that is, obtain quinolinone cobalt complex.
4. synthetic method according to claim 2, it is characterised in that:Comprise the following steps:
A) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone are stoichiometrically weighed, it is molten
In polar solvent, mixed solution is obtained;
B) gained mixed solution is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, is sealed, then under the conditions of 50~140 DEG C
Reaction, that is, obtain quinolinone cobalt complex.
5. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antineoplastic is prepared.
6. the antineoplastic for being prepared as active component with compound described in claim 1.
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Granted publication date: 20170517 Termination date: 20200319 |