CN104725431A - 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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- CN104725431A CN104725431A CN201510120661.2A CN201510120661A CN104725431A CN 104725431 A CN104725431 A CN 104725431A CN 201510120661 A CN201510120661 A CN 201510120661A CN 104725431 A CN104725431 A CN 104725431A
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- Prior art keywords
- quinolinone
- polar solvent
- methyl
- benzimidazolyl
- compound
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- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 title abstract description 7
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 239000002798 polar solvent Substances 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 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 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 17
- 238000010189 synthetic method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims description 7
- 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
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 4
- 206010017758 gastric cancer Diseases 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract 2
- 208000014018 liver neoplasm Diseases 0.000 abstract 2
- 206010008342 Cervix carcinoma Diseases 0.000 abstract 1
- 208000005718 Stomach Neoplasms 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
- 201000011549 stomach cancer Diseases 0.000 abstract 1
- 238000005303 weighing Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 229940126214 compound 3 Drugs 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 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 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-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
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000005388 borosilicate glass Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 208000010749 gastric carcinoma Diseases 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 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
- 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
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 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
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 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
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229950005778 dovitinib Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 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
- 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
- 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
- 229960001756 oxaliplatin Drugs 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 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
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000003756 stirring Methods 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
- 238000001291 vacuum drying Methods 0.000 description 1
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 medical art, be specifically related to a kind of cobalt (II) title complex of qualone derivative and synthetic method thereof and application.
Background technology
2 (1H)-quinolinone structures are and the quinoline equally extensive alkaloid existed in natural product, compound containing 2 (1H)-quinolinone structures has multiple biological activity, on its ring or on side chain, introduce different substituting groups, the pharmacologically active of the wide spectrums such as such as antitumor, anti-oxidant, anti-inflammatory can be produced.Seek good activity, a kind of important method that lead compound parent nucleus that toxicity is low is current research and development anti-cancer agent, due to 2 (1H)-quinolinones have active better, structure is easy to features such as modifying, toxicity is low, in the design of its antitumor drug that is widely used and screening.Some compounds with 2 (1H)-quinolinone skeletons have entered clinical as antitumor drug, such as: many Weis are a kind of orally active small molecules multiple receptor tyrosine kinases inhibitors for Buddhist nun (Dovitinib), tumour cell can be directly acted on and provide blood vessel and the matrix of nutrition for tumour cell, by antiproliferative activity and anti-angiogenic existence activity, show antitumor action; Tipifarnib (Tipifanib) belongs to farnesyl transferase inhibitor, and it, by suppressing the protein of farnesylation, can prevent the activation of Ras oncogene, cell growth inhibiting, cell death inducing, and inhibiting angiogenesis.This compounds has good development prospect.
On the other hand, Pharmaceutical Inorganic Chemistry research based on medical active part is becoming hot research field along with the flourish of bio-inorganic chemistry in recent years, especially using be representative first, second and third platinum-containing anticancer drug such as cis-platinum, carboplatin, oxaliplatin as the successful Application of front-line chemotherapeutic agents, really indicate the arrival of Metal Drugs research and apply New Times in generation.Having not yet to see with 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone is cobalt (II) title complex of part and the relevant report of synthesis and application thereof.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of cobalt (II) title complex of new qualone derivative and synthetic method thereof and application.
Cobalt (II) title complex of qualone derivative of the present invention is for having compound or its pharmacy acceptable salt of structure shown in following formula (I):
Shown in above-mentioned formula (I), the synthetic method of compound is: stoichiometrically take cobalt chloride (i.e. cobalt chloride hexahydrate) and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, carry out coordination reaction, namely obtain target product.
Part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone involved in synthetic method of the present invention adopts following synthesis thinking to synthesize:
Take para-totuidine as raw material, under acetic acid or hydrochloric acid existent condition, add diacetyl oxide and carry out acidylate, obtain acylate (i.e. compound 1); Gained acylate closes ring with phosphorus oxychloride, obtains closing ring product (i.e. compound 2); Gained closes ring product acid adding and is hydrolyzed, and obtains hydrolysate (i.e. compound 3); Gained hydrolysate and O-Phenylene Diamine carry out condensation reaction, obtain target product (i.e. compound 4).Concrete synthetic route is as follows:
Reagent: (a) diacetyl oxide, acetic acid or hydrochloric acid; (b) DMF, phosphorus oxychloride; (c) acid; (d) O-Phenylene Diamine, methyl alcohol and/ethanol.
Above-mentioned part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone more specifically synthetic method, comprises the following steps:
1. be raw material with para-totuidine, under acetic acid or hydrochloric acid existent condition, add diacetyl oxide and react, the pH value of having reacted rear regulation system is 6 ~ 8, reactant suction filtration, and filter cake recrystallization, obtains compound 1;
2. gained compound 1 is dissolved in DMF, and add phosphorus oxychloride and carry out ring closure reaction, gained reactant is poured in frozen water, suction filtration, obtains compound 2;
3. gained compound 2 acid adding is hydrolyzed, and obtains compound 3;
4. gained compound 3 and O-Phenylene Diamine carry out condensation reaction under methyl alcohol and/or ethanol existent condition, obtain target product.
The step of above-mentioned part synthetic method 1. in, the concentration of described acetic acid can be 30 ~ 90 (v/v) %, the concentration of described hydrochloric acid can be 15 ~ 37w/w%, the consumption of described acetate and hydrochloride is respectively 0.9 ~ 1.2 times of para-totuidine amount of substance usually, or is greater than 1.2 times of para-totuidine amount of substance.The add-on of described diacetyl oxide is generally 0.9 ~ 1.2 times of para-totuidine amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.In this step, due to exothermic heat of reaction, preferred reaction is carried out under condition of ice bath.Whether reaction can adopt thin-layer chromatography (TLC) tracing detection completely, and usually controlling the reaction times is that 1 ~ 4h is more suitable.The pH value of having reacted rear employing alkali lye regulation system is 6 ~ 8, and described alkali lye can be the aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or salt of wormwood, and the concentration of described alkali lye is preferably 5 ~ 30/w/w%; The aqueous solution of sodium acetate is preferably adopted to regulate.The filter cake collected adopts dehydrated alcohol and/or anhydrous methanol to carry out recrystallization usually.
The step of above-mentioned part synthetic method 2. in, the add-on of described phosphorus oxychloride is generally 0.9 ~ 1.2 times of compound 1 amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.The consumption of described DMF can be determined as required, specifically can calculate by the amount of 10mmol compound 1 with 5 ~ 11ml.Described ring closure reaction carries out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and under 60 ~ 90 DEG C of conditions, carries out back flow reaction in reflux.Whether reaction can adopt TLC tracing detection completely, and usually controlling the reaction times is that 8 ~ 14h is more suitable.
The step of above-mentioned part synthetic method 3. in, acid used when being hydrolyzed can be 30 ~ 90 (v/v) % Glacial acetic acid, or the hydrochloric acid of 2 ~ 6mol/L, or the sulfuric acid of 2 ~ 6mol/L; The consumption of the described acid for being hydrolyzed is generally every 10mmol compound 2 50 ~ 80ml acid solution and is hydrolyzed.Described hydrolysis is carried out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and refluxes under 60 ~ 90 DEG C of conditions in reflux, and under said temperature condition, backflow can obtain settled solution.Whether hydrolysis can adopt TLC tracing detection completely, and usually controlling the reaction times is that 6 ~ 12h is more suitable.After hydrolysis completely, gained reactant cools, and have crystal to separate out, the crystal of precipitation is compound 3.
The step of above-mentioned part synthetic method 4. in, the consumption of described O-Phenylene Diamine is generally 0.9 ~ 1.2 times of compound 3 amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.Described methyl alcohol is 70 ~ 100v/v% methyl alcohol, and described ethanol is 70 ~ 100v/v% ethanol; The consumption of described methyl alcohol and/or ethanol can be determined as required, specifically can calculate by the amount of 10mmol compound 3 with 50 ~ 80ml.Described condensation reaction is carried out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and under 60 ~ 90 DEG C of conditions, carries out back flow reaction in reflux.Whether condensation reaction can adopt TLC tracing detection completely, and usually controlling the reaction times is that 6 ~ 12h is more suitable.After having reacted, suction filtration after the cooling of gained reactant, collects filter cake and is target product (i.e. part).
The molecular formula of part 3-of the present invention (1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone is C
17h
13n
3o, molecular weight is: 275.1, and structure is as follows:
In this molecule, the carbonylic oxygen atom on quinolinone and the nitrogen-atoms on imidazole ring have stronger coordination ability, can form following coordination mode in coordination reaction:
N, O bidentate chelating mode: with the N of 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, O atom and metal ions M coordination, form six-ring chelating body.
Specifically when the shown compound of formula (I) described in synthesis the invention described above, solution method or solvent-thermal method can be adopted to synthesize.
When adopting solution method synthesis, specifically comprise the following steps:
1) stoichiometrically take cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, obtain mixing solutions;
2) gained mixing solutions reacts to the reflow temperature range of polar solvent in 20 DEG C;
3) gained reacting liquid filtering, throw out, through washing, drying, namely obtains quinolinone cobalt complex.
The step 1 of above-mentioned solution method) in, being chosen as methyl alcohol and being selected from water, acetone, chloroform and N when polar solvent, during a kind of combination in dinethylformamide, the volume ratio of particular methanol and water, acetone, chloroform or DMF is 50:1 ~ 1:1.When polar solvent be chosen as methyl alcohol with the two or more arbitrarily combination be selected from water, acetone, chloroform and DMF time, the proportioning between them can be any proportioning.The consumption of described polar solvent can be determined as required, and under normal circumstances, the cobalt chloride of 1mmol and 1mmol 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone polar solvent of 10 ~ 80mL dissolve.In concrete dissolving step, cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone can be dissolved with polar solvent respectively, remix reacts together; Also can by additive polarity solvent again after cobalt chloride and the mixing of part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone.The ratio of the amount of substance of described cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone is generally 1:1.
The step 2 of above-mentioned solution method) in, whether reaction can adopt thin-layer chromatography tracing detection completely.Reaction preferably adopts back flow reaction, is more preferably and reacts to the reflow temperature range of polar solvent at 50 DEG C.When reaction carries out in 50 DEG C to the reflow temperature range of polar solvent, reaction is to completely approximately needing 3 ~ 18h.
The step 3 of above-mentioned solution method) in, normally wash with ether, acetone or methylene dichloride during washing.Drying conditions is vacuum-drying under 30 ~ 50 DEG C of conditions or constant pressure and dry.In present method, product generally generates in solid form in a large number, if previous step 1) add-on of Semi-polarity solvent comparatively large (upper limit as close to proportioning) or the solvability of solvent to product better, then after reaction, solution may be clear state, this is because caused by the product precipitation formed dissolved by polar solvent, now can by the underpressure distillation of gained reaction solution with remove portion solvent, product is mainly separated out with powder precipitation or crystalline form, after taking out the solid of separating out, carries out next step operation again.Concentrated remove portion solvent typically refers to 50 ~ 90% of concentrated removing polar solvent add-on.
When adopting solvent structure, specifically comprise the following steps:
A) stoichiometrically take cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, obtain mixing solutions;
B) gained mixing solutions is placed in container, after liquid nitrogen freezing, be evacuated to vacuum, sealing by fusing, then reacts under 50 ~ 140 DEG C of conditions, namely obtains quinolinone cobalt complex.
The step of above-mentioned solvent-thermal method a) in, being chosen as methyl alcohol and being selected from water, acetone, chloroform and N when polar solvent, during a kind of combination in dinethylformamide, the volume ratio of particular methanol and water, acetone, chloroform or DMF is 50:1 ~ 1:1.When polar solvent be chosen as methyl alcohol with the two or more arbitrarily combination be selected from water, acetone, chloroform and DMF time, the proportioning between them can be any proportioning.The consumption of described polar solvent can be determined as required, and under normal circumstances, the cobalt chloride of 1mmol and 1mmol 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone polar solvent of 5 ~ 30mL dissolve.In concrete dissolving step, cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone can be dissolved with polar solvent respectively, remix reacts together; Also can by additive polarity solvent again after cobalt chloride and the mixing of part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone.The ratio of the amount of substance of described cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone is generally 1:1.
The step b of above-mentioned solvent-thermal method) in, described container is generally heavy wall borosilicate glass tube, and the time of reaction controls usually at 12 ~ 72h, also as required the reaction times can be extended to more than 72h.More preferably mixing solutions reacts under 80 ~ 100 DEG C of conditions, and when carrying out under the normal temperature reacted below 80 DEG C or heating condition, the time that reaction needed is longer just can obtain higher productive rate.
The present invention also comprises described compound or its pharmacy acceptable salt shown in above-mentioned formula (I) and is preparing the application in antitumor drug.
It is the antitumor drug of active fraction preparation that the present invention comprises with described compound above-mentioned formula (I) Suo Shi further.
Compared with prior art, the invention provides a kind of new quinolinone cobalt complex and synthetic method thereof and application.The anti tumor activity in vitro research of applicant to title complex of the present invention shows, it all shows certain proliferation inhibition activity to human cervical carcinoma cell Hela229, gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2 and BEL-7404 tetra-kinds of cell strains, wherein the highest for human hepatoma cell strain Hep G2 activity.
Accompanying drawing explanation
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 zou is relative abundance value, and X-coordinate is m/z (molecular weight);
Fig. 4 is the infrared spectrum of the final product that the embodiment of the present invention 1 obtains;
Fig. 5 is the high resolution mass spectrum figure of the final product that the embodiment of the present invention 1 obtains, and its ordinate zou is relative abundance value, and X-coordinate is m/z (molecular weight);
Fig. 6 is the x-ray crystal structure figure of the final product that the embodiment of the present invention 1 obtains.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
In following embodiment, described part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, the BMQ occurred in following each embodiment is the abbreviation of this part) synthesize all as follows:
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flask, dropwise add 8ml concentrated hydrochloric acid, 10.2g (0.1mol) diacetyl oxide, react 4 hours under ice bath, then be 7 by the pH value of the sodium acetate solution regulation system of 20w/w%, leave standstill, suction filtration, filter cake dehydrated alcohol recrystallization obtains compound 1 (white needle-like crystals, 13.3g, productive rate 89%).
2) by 3.5ml DMF and 17ml POCl
3mix under ice bath, add 2.24g (15mmol) compound 1 after stirring, gained solution is placed in reflux, be heated to 90 DEG C of backflows 10 hours, pour in 500ml frozen water after cooling, suction filtration obtains compound 2 (2.7g, productive rate 87%).
3) 2.05g (10mmol) compound 2 is dissolved in 80ml 70% Glacial acetic acid, gained solution is placed in reflux, and be heated to 90 DEG C of backflows 8 hours, cooling obtains compound 3 (yellow needle-like crystals, 1.70g, productive rate 91%).
4) join in 80ml anhydrous methanol by 1.87g (10mmol) compound 3 and 1.08g (10mmol) O-Phenylene Diamine, gained solution was placed in reflux, in 90 DEG C of backflows 8 hours, cooling, suction filtration, obtains yellow solid (2.48g, 90%).
Gained yellow solid product is identified:
(1) proton nmr spectra and carbon spectrum, their spectrogram respectively as illustrated in fig. 1 and 2.
1H NMR(500MHz,DMSO-d6)δ12.65(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]
+.
Therefore, can determine that above-mentioned yellow solid product is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, its chemical structural formula is as follows:
Embodiment 1
In the heavy wall borosilicate glass tube of at one end opening, directly add 0.1mmol CoCl
26H
2o and 0.1mmol BMQ, then add 0.6ml methyl alcohol/chloroform mixing solutions (volume ratio of methyl alcohol and chloroform is 3:1).Under the condition vacuumized, by opening end sealing by fusing, then under 80 DEG C of conditions, fully react 72h, blue crystalline solids product can be obtained.Product carries out structure (as shown in Figure 6) in conjunction with the analysis of X-ray single crystal diffraction measure through infrared spectra (as shown in Figure 4), ultimate analysis, electrospray ionization mass spectrum (as shown in Figure 5), is defined as title complex [Co (BMQ) Cl
2], its structural formula is as shown in the formula shown in (I).
Embodiment 2
Repeat embodiment 1, unlike:
1) polar solvent changes methyl alcohol into;
2) temperature of reaction changes 50 DEG C into, and the reaction times changes 50h into.
Products therefrom carries out structure determination through infrared spectra, ultimate analysis, electrospray ionization mass spectrum in conjunction with the analysis of X-ray single crystal diffraction, is defined as title complex [Co (BMQ) Cl
2].
Embodiment 3
1) 0.1mmol CoCl is taken respectively
26H
2o and 0.1mmol BMQ, is dissolved in after mixing in 80mL methanol/acetone mixing solutions (volume ratio of methyl alcohol and acetone is 1:1), obtains mixing solutions;
2) gained mixing solutions is in 100 DEG C of back flow reaction 8h;
3) gained reaction solution steams except partial solvent, leaves standstill, has blue crystalline solid product to separate out, isolate solid, with washed with diethylether, dry.
Products therefrom carries out structure determination through infrared spectra, ultimate analysis, electrospray ionization mass spectrum in conjunction with the analysis of X-ray single crystal diffraction, is defined as title complex [Co (BMQ) Cl
2].
Embodiment 4
Repeat embodiment 3, unlike:
1) polar solvent changes methanol/water (volume ratio of first alcohol and water is 5:1) into;
2) temperature of reaction changes 70 DEG C into, and the reaction times changes 12h into.
In order to absolutely prove the purposes of title complex of the present invention in pharmacy, applicant has carried out anti tumor activity in vitro experiment to it.
One, quinolinone cobalt complex is tested the proliferation inhibition activity of 5 kinds of cell strains:
1, cell strain and cell cultures
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 strains are selected in this experiment.
All tumor cell lines are all cultivated in the RPMI-1640 nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, put 37 DEG C containing volumetric concentration 5%CO
2cultivate in incubator; Human normal cell line strain is then cultivated in the DMEM nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate.
2, the preparation of testing compound
Quinolinone cobalt complex used is the embodiment of the present invention 1 products therefrom, purity >=95%, its DMSO liquid storage (concentration is 0.001mol/L) is diluted to five concentration gradients successively by RMPI1640 substratum, be respectively 40,20,10,5,2.5 μm of ol/L, wherein solubility promoter DMSO final concentration≤1%.First test the target product of 20 μm of ol/L for the inhibiting rate of tumor cell proliferation, be considered as primary dcreening operation result; Under testing different gradient concentration more respectively, target product is to the Proliferation Ability degree of various tumour cell, in order to the Fitting Calculation half-inhibition concentration, i.e. IC
50value.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of taking the logarithm vegetative period, after tryptic digestion, the cell suspension that concentration is 5000/mL is mixed with the nutrient solution containing 10% calf serum, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to 1000 ~ 10000 to be measured/hole (the aseptic PBS of marginal pore fills);
(2) 5%CO
2, hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, every hole adds the medicine 10 μ L of finite concentration gradient, and each concentration gradient establishes 4 multiple holes;
(3) 5%CO
2, hatch 48 hours for 37 DEG C, observe under inverted microscope;
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in hole, every hole adds 150 μ L DMSO and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, and after vibrator mixing, be 570nm at microplate reader wavelength, reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO) is set simultaneously, control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO).
(7) according to the optical density value (OD value) recorded, judge viable cell quantity, OD value is larger, and cytoactive is stronger.
Utilize formula:
Computerized compound is to the inhibiting rate of growth of tumour cell.For the cell strain of inhibiting rate more than 50% under primary dcreening operation concentration, carry out matching further by the inhibiting rate data of SPSS software to five concentration gradients, obtain the half-inhibition concentration (IC of compound to different tumor line
50value, unit μm ol/L), compound is for the IC of different lung cancer cell line
50be worth as shown in table 1.
Table 1:
Claims (7)
1. compound shown in following formula (I) or its pharmacy acceptable salt:
2. the synthetic method of compound according to claim 1, it is characterized in that: stoichiometrically take cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, carry out coordination reaction, namely obtain target product.
3. synthetic method according to claim 2, is characterized in that: comprise the following steps:
1) stoichiometrically take cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, obtain mixing solutions;
2) gained mixing solutions reacts to the reflow temperature range of polar solvent in 20 DEG C;
3) gained reacting liquid filtering, throw out, through washing, drying, namely obtains quinolinone cobalt complex.
4. synthetic method according to claim 2, is characterized in that: comprise the following steps:
A) stoichiometrically take cobalt chloride and part 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, be dissolved in polar solvent, obtain mixing solutions;
B) gained mixing solutions is placed in container, after liquid nitrogen freezing, be evacuated to vacuum, sealing by fusing, then reacts under 50 ~ 140 DEG C of conditions, namely obtains quinolinone cobalt complex.
5. the synthetic method according to any one of claim 2 ~ 4, is characterized in that: described polar solvent is methyl alcohol, or methyl alcohol and one or more the combination that is selected from water, acetone, chloroform and DMF.
6. compound described in claim 1 or its pharmacy acceptable salt are preparing the application in antitumor drug.
7. with the antitumor drug that compound described in claim 1 is active fraction preparation.
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| CN109020997A (en) * | 2018-07-05 | 2018-12-18 | 桂林医学院 | 3- benzimidazole -6,7- piperonyl cyclonene -2 (1H)-quinolinone-Zn complex and its preparation method and application |
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| CN109020997A (en) * | 2018-07-05 | 2018-12-18 | 桂林医学院 | 3- benzimidazole -6,7- piperonyl cyclonene -2 (1H)-quinolinone-Zn complex and its preparation method and application |
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