CN106632415A - Copper chloride complex of 1-(2-pyridine)-9-(naphthalene-2-methyl)-beta-carboline and synthesis method and application thereof - Google Patents
Copper chloride complex of 1-(2-pyridine)-9-(naphthalene-2-methyl)-beta-carboline and synthesis method and application thereof Download PDFInfo
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- CN106632415A CN106632415A CN201610852342.5A CN201610852342A CN106632415A CN 106632415 A CN106632415 A CN 106632415A CN 201610852342 A CN201610852342 A CN 201610852342A CN 106632415 A CN106632415 A CN 106632415A
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- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000002798 polar solvent Substances 0.000 claims abstract description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 17
- 239000010949 copper Substances 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 13
- 238000000746 purification Methods 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 230000036961 partial effect Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 5
- AQZMINLSVARCSL-UHFFFAOYSA-N 4-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(C#N)C1=O AQZMINLSVARCSL-UHFFFAOYSA-N 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 5
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 claims description 5
- MSBWDNNCBOLXGS-UHFFFAOYSA-L manganese(2+);diacetate;hydrate Chemical compound O.[Mn+2].CC([O-])=O.CC([O-])=O MSBWDNNCBOLXGS-UHFFFAOYSA-L 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000010668 complexation reaction Methods 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 150000007529 inorganic bases Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000000536 complexating effect Effects 0.000 abstract 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 abstract 1
- 229910052697 platinum Inorganic materials 0.000 abstract 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000005388 borosilicate glass Substances 0.000 description 5
- 239000012531 culture fluid Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011572 manganese Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical class C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 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
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 150000004699 copper complex Chemical class 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229940041022 streptomycins Drugs 0.000 description 2
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DNXUGBMARDFRGG-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1C#N DNXUGBMARDFRGG-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-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
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth 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
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 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
- 244000045947 parasite Species 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- -1 sodium hydrides Chemical class 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
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 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
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a copper chloride complex of 1-(2-pyridine)-9-(naphthalene-2-methyl)-beta-carboline and a synthesis method and application thereof. The structural formula of the complex is a formula (I) as shown in the specification. The synthesis method comprises the following steps: dissolving a compound of formula (II) as shown in the specification, and copper chloride into a polar solvent, and performing a complexing reaction, thereby obtaining the copper chloride complex, wherein the polar solvent is the combination of one or two selected from methanol and ethanol and one or more than two of water, acetone, chloroform, dichloromethane and N,N-dimethyl formamide. The copper chloride complex disclosed by the invention has relatively antitumor activity better than that of ligand and cis-platinum, has relatively good potential medicinal values, and can be used for preparing various antitumor medicines. The formula (I) and the formula (II) are as shown in the specification.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline
Chlorination copper complex and its synthetic method and application.
Background technology
B-carboline is the alkaloid that a class is distributed widely in nature, and they are primarily present in various terrestrial plants and ocean
In biology.Chemically classify in structure, beta-carboline alkaloid belongs to indoles alkaloid, and it is three be made up of trypoline
Member ring systems, its skeleton is a planar molecule, wherein two nitrogen-atoms of 2 and 9 exist with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, is rich pi-electron system, and 2 nitrogen-atoms are sp2Hydridization, is to lack pi-electron system.Two nitrogen-atoms with
The chemical property and biological activity of such compound is closely related.There is such compound extensive biology and pharmacology to live
Property, including：Tranquilizer, anxiety, hypnosis, spasmolytic, antitumor, antiviral, parasite killing and antibacterial activity etc..Therefore β-click
Quinoline alkaloid is increasingly paid attention to by research worker.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active part is studied in recent years with bioinorganic chemistry
Flourish and become hot research field, the first, second and third generation platinum class especially with cisplatin, carboplatin, oxaliplatin etc. as representative
Cancer therapy drug really indicates Metal Drugs research and the arrival using the New Times as the successful Application of front-line chemotherapeutic agents.
But have not yet to see copper chloride (II) coordination compound with 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline as part and its conjunction
Into the relevant report of methods and applications.
The content of the invention
The technical problem to be solved in the present invention be to provide a kind of structure it is novel with 1- (2- pyridines) -9- (naphthalene -2- methyl) -
B-carboline for part copper chloride (II) coordination compound, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
The synthetic method of compound is shown in above-mentioned formula (I)：Take compound and copper chloride as shown in following formula (II)
(CuCl2·2H2O), it is dissolved in polar solvent, carries out complexation reaction, that is, obtains target product；Wherein, described polar solvent is
In methanol and ethanol one or two with water, acetone, chloroform, dichloromethane and the DMF
One or more combination；
Compound shown in the raw material formula (II) being related in above-mentioned synthetic method participates in reacting as part, and its chemical name is
1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline, in this application also referred to as L.The compound shown in formula (II) can be voluntarily
Design synthetic route is prepared, and is preferably prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, through dehydrating condensation compound is obtained
1；Then compound 1 is placed in the second organic solvent, add oxidant cyclization and dehydrogenation obtain compound 2 (1- (2- pyridines)-
B-carboline)；Compound 2 is placed in the aprotic polar solvent of alkaline matter again, adds 2- bromomethyls naphthalene to carry out substitution reaction,
Obtain final product；Wherein：
The first described organic solvent is the one kind or two in toluene, methanol, ethanol, dichloromethane and chloroform
Plant the combination of the above；
The second described organic solvent is the one kind or two in benzene, toluene, xylol, glacial acetic acid and dichloromethane
Plant the combination of the above；
Described oxidant is palladium carbon, manganese acetate hydrate (Mn (Ac)3·nH2O), lead tetraacetate (Pb (Ac)4) or 2,3-
Two chloro- 5,6- dicyan 1,4-benzoquinone (DDQ)；
Described alkaline matter is inorganic base；
Described aprotic polar solvent be the one kind in N,N-dimethylformamide, dimethyl sulfoxide and acetone or
Two or more combinations.
The synthetic route of compound method is as follows shown in above-mentioned preparation formula (II)：
Reagent：(a) first organic solvent；(b) oxidant, the second organic solvent；C () alkaline matter, aprotonic polar is molten
Agent.
The more specifically preparation method of compound shown in above-mentioned formula (II), comprises the following steps：
1. with tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, reaction life is discharged in course of reaction
Into water, question response terminates rear solvent evaporated, obtains compound 1；
2. compound 1 is placed in the second organic solvent, adds oxidant, reacted under heating condition, question response terminates, mistake
Filter, collects filtrate, is evaporated, and obtains compound 2；
3. take alkaline matter to be dissolved in aprotic polar solvent, be subsequently adding compound 2 and 2- bromomethyl naphthalenes are reacted,
Question response terminates, and reactant is put in frozen water, and gained mixture of ice and water is extracted, collection organic faciess, solvent evaporated, i.e.,
Obtain compound (i.e. compound 3) shown in formula (II).
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, the amount of the material of tryptamines and pyridine-2-formaldehyde it
Than being usually 0.8～1.2：1, reaction can be carried out under conditions of being heated or not heated, and water knockout drum can be used in course of reaction
The water that reaction is generated is discharged, whether reaction can adopt completely thin layer chromatography (TLC) tracing detection；Preferably, reaction is adopted
Heating reflux reaction, the time control now reacted is appropriate in 2～6h.In the step, what is obtained is the thick product of compound 1
Thing, in order to reduce subsequent reactions in impurity, improve postorder reaction yield, preferably carry out after purification process to residue obtained
Postorder reaction is carried out again.Specific purification process can be with little polar solvent recrystallization, gained recrystallization product to residue obtained
Thing is used further to postorder reaction.The little polar solvent for recrystallization is same as the prior art, can be specifically petroleum ether and/
Or normal hexane etc..
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, reaction preferably adopt heating reflux reaction, reaction
Whether thin layer chromatography tracing detection can be adopted completely.In the step, what is obtained is the crude product of compound 2, in order to reduce
Impurity in subsequent reactions, improves the yield of postorder reaction, preferably carries out carrying out postorder after purification process again to residue obtained
Reaction.Specific purification process can be to it is residue obtained with methanol, ethanol and dichloromethane one or two with
On combination solvent carry out recrystallization, it is used in upper silica gel column chromatography or by residue obtained upper silica gel column chromatography purification
Eluant be that petroleum ether and dichloromethane press 6：1～1：The mixed solvent of 1 volume ratio composition.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, according to the difference of oxidant, from different
Two organic solvents, it is specific as follows：
(1) when the selection of oxidant is palladium carbon, the second organic solvent is preferably the one kind in benzene, toluene and xylol
Or two or more combinations, when two organic solvents selection for more than above two combination when, the proportioning between them can be with
For any proportioning.Described palladium carbon can be 5%Pd/C or 10%Pd/C, and the addition of the palladium carbon generally presses 10mmol chemical combination
Thing 1 adds 2～4g palladium carbons to calculate.
(2) when the selection of oxidant is manganese acetate hydrate or lead tetraacetate, the second organic solvent is preferably glacial acetic acid；
The addition of the manganese acetate hydrate or lead tetraacetate is usually 2～8 times of the amount of the material of compound 1.When the choosing of oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, preferred reaction uses pH >=7 of alkali liquor regulation system after terminating, then it is extracted
Take, collect organic faciess, the residue obtained by solvent evaporated goes up again silica gel column chromatography purification；Wherein, described alkali liquor can be ammonia,
The aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or potassium carbonate, the concentration of the alkali liquor is preferably 5
～30w/w%；The solvent that system after pH value is adjusted for extraction can be specifically ethyl acetate, dichloromethane, chloroform or ether etc..
(3) when the selection of oxidant 5,6- dicyan 1,4-benzoquinone chloro- for 2,3- bis-, the second organic solvent is preferably benzene, first
One or more combination of benzene and dichloromethane, when the selection of two organic solvents is the combination of more than above two,
Proportioning between them can be any proportioning.The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of the 2,3- bis- is usually compound 1
1～4 times of the amount of material.
Shown in above-mentioned formula (II) the step of compound synthesis method 3. in, the alkaline matter, compound 2 and 2- bromomethyls
The ratio of the amount of the material of naphthalene is usually 1～4：1：1～3, alkaline matter therein can be further sodium hydride, calcium hydride, hydrogen
One or more combination in calcium oxide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, when alkaline matter
When selecting the combination more than for above two, the proportioning between them can be any proportioning.In the step, reaction can be 0
Carry out under the conditions of～80 DEG C, whether reaction can adopt completely thin layer chromatography (TLC) tracing detection；Preferably, reaction is 20
～50 DEG C, the time control now reacted is appropriate in 1～6h.The solvent extracted to mixture of ice and water can be specifically second
The conventional extraction solvent such as acetoacetic ester, dichloromethane, chloroform, petroleum ether or ether.
Involved various solvents are (as the first organic solvent, second have in compound synthesis method shown in above-mentioned formula (II)
Machine solvent and aprotic polar solvent etc.) consumption, so that each step can be dissolved in participate in react raw material be advisable.
What said method was prepared is the crude product of compound shown in formula (II), in order to further improve shown in formula (II)
The purity of compound, is more beneficial for the carrying out of subsequent reactions, preferably above-mentioned gained crude product is carried out being used again after purification process
In the synthetic method of target product of the present invention.Described purification process is same as the prior art, can be specifically by crude product
Upper silica gel column chromatography purification, to obtain pure compounds shown in formula (II)；In upper silica gel column chromatography, eluant used is two
Chloromethanes and methanol press 1000：1～50：The mixed solvent of 1 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, in the composition of polar solvent, methanol or ethanol or
Person is that the ratio shared in polar solvent of combination of methanol and ethanol is preferably 50～98v/v%；When containing in polar solvent
During two or more selection in water, acetone, chloroform, dichloromethane and DMF, do not surpass in their total amount
Under going out 50% precondition, their proportioning can be any proportioning.The consumption of the polar solvent can determine as needed,
Under normal circumstances, the copper chloride of 1mmol and compound shown in 1mmol formulas (II) are dissolved with the polar solvent of 5～80mL.In tool
In the dissolving step of body, typically by additive polarity solvent again after copper chloride and the mixing of compound shown in formula (II)；Also can be by copper chloride
Dissolved with polar solvent respectively with compound shown in formula (II), remix and react together.
In the synthetic method of compound shown in formula (I) of the present invention, the copper chloride and compound shown in formula (II)
The ratio of the amount of material can be 1～6：1.
Compound shown in formula (I) of the present invention specifically in synthesis, can adopt normal pressure solwution method or high pressure solvent heat
Method is synthesized.
When using normal pressure solwution method, its synthetic method includes：Compound shown in formula (II) and copper chloride are taken, polarity is dissolved in
In solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, and isolates
Crystal, obtains final product target product.
In above-mentioned normal pressure solwution method, reaction can be carried out in 20 DEG C to polar solvent of reflow temperature range, preferably be adopted
With back flow reaction, further preferably reaction is carried out in 50 DEG C to polar solvent of reflow temperature range, more preferably 60
React under the conditions of DEG C.Whether reaction can adopt completely thin layer chromatography tracing detection.In this method, product is typically in the form of crystal
It is a large amount of to generate, if the addition of polar solvent is larger in previous step (such as the upper limit of close proportioning) or solvent is to the molten of product
Preferably, then solution may be in clear state to solution property after reacting, this is because the product precipitation for being formed dissolves institute by polar solvent
Cause, now can be by the concentration of gained reactant liquor or vacuum distillation to remove partial solvent, typically concentration removes polar solvent and adds
The 50～90% of amount.Isolated solid can be washed further with ether, acetone, ethanol, methanol or dichloromethane, it
It is dried again afterwards.
When high pressure solvent full-boiled process, its synthetic method includes：Compound shown in formula (II) and copper chloride are taken, polarity is dissolved in molten
In agent, gained mixed liquor is placed in container, and vacuum is evacuated to Jing after liquid nitrogen freezing, and sealing by fusing is then anti-under the conditions of 30～140 DEG C
Should, obtain target product.
In above-mentioned high pressure solvent full-boiled process, described container is usually heavy wall borosilicate glass tube, reacts generally at 30～140 DEG C
Under the conditions of carry out, under this temperature conditions, the time of reaction is preferably controlled in 2～24h, extends to also dependent on practical situation
More than 24h.Further preferably mixed solution is reacted under the conditions of 50～140 DEG C, more preferably mixed solution be 80～
Reacted under the conditions of 100 DEG C.When carrying out under room temperature of the reaction below 80 DEG C or heating condition, when reaction needs longer
Between can just obtain higher yield.
Present invention additionally comprises compound or its pharmaceutically acceptable salt are in antitumor drug is prepared shown in above-mentioned formula (I)
Application.
Present invention additionally comprises prepared as active component with compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I)
Antitumor drug.
Compared with prior art, the invention provides a kind of new with 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline
For copper chloride (II) coordination compound of part, and its synthetic method and application.Applicant is thin to kinds of tumors by investigating it
The inhibitory action of born of the same parents' strain, as a result shows that the coordination compound has stronger anti tumor activity in vitro, and apparently higher than cisplatin, with compared with
Good potential medical value, is expected to be used for the preparation of various antitumor drug.
Description of the drawings
Fig. 1 is the mass spectrum of final product obtained in the embodiment of the present invention 5.
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.
Embodiment 1：Compound shown in formula (II) is the synthesis of 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline (L)
1) 150ml round bottoms are added to burn 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene
Bottle, adds water knockout drum, condensing tube group composition water reflux, is heated to reflux 4 hours, and question response terminates rear solvent evaporated, residue
Compound 1 (2.3g, yield 92%) is recrystallized to give with 100ml normal hexane；
2) 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml xylol are added into 250ml circles
Bottom flask, is heated to backflow, and is terminated to reaction with thin layer chromatography tracing detection, stands sucking filtration and is simultaneously evaporated filtrate, and gained is residual
Silica gel column chromatography purification (V on slagPetroleum ether：VDichloromethane=1:1) compound 2 (2.1g, yield 86%), is obtained；
3) 0.24g (10mmol) sodium hydrides and 15ml DMFs are added to into 50ml round-bottomed flasks, room temperature
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 2- bromomethyl naphthalenes, and uses thin layer chromatography tracing detection
Terminate to reaction, then reactant liquor is put in 500ml frozen water, extracted three times with 100ml ethyl acetate, merge organic faciess, steam
Dry solvent, residue obtained upper silica gel column chromatography purification (VDichloromethane：VMethanol=100:1) compound 3 (2.9g, yield 75%), is obtained.
Products therefrom is characterized：
(1) proton nmr spectra and carbon are composed, and their spectral data is as follows：
1H NMR(500MHz,CDCl3) δ 8.64 (s, 1H), 8.58 (s, 1H), 8.26 (dd, J=7.8,1.0Hz, 1H),
8.16 (s, 1H), 7.72-7.67 (m, 1H), 7.65-7.54 (m, 3H), 7.51 (d, J=8.5Hz, 2H), 7.49-7.45 (m,
1H), 7.42-7.35 (m, 3H), 7.32 (s, 1H), 6.88 (s, 1H), 6.69 (d, J=8.5Hz, 1H), 5.68 (s, 2H).
13C NMR(126MHz,CDCl3)δ156.89,148.28,143.54,142.07,137.26,136.79,
134.66,134.48,133.12,132.62,132.43,129.50,128.27,127.72,127.66,126.22,125.87,
125.54,124.46,123.83,123.45,121.88,121.31,120.71,114.91,110.72,49.10.
(2) high resolution mass spectrum, ESI-MS m/z:386[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline, its chemical structural formula is such as
Shown in following formula (II)s：
Embodiment 2：The synthesis of ligand L
Repeat embodiment 1, except for the difference that：
Step 2) in, with Mn (Ac)3Replace palladium carbon, xylol, control Mn (Ac) are replaced with glacial acetic acid3Addition be
2 times of the amount of the material of compound 1, reaction is carried out under the conditions of 70 DEG C, and TLC tracing detections to reaction terminates, then will with ammonia
The pH of system is adjusted to 7, then is extracted with ethyl acetate three times, merges organic faciess, solvent evaporated, residue obtained upper silicagel column (chromatography
Purification (VPetroleum ether：VDichloromethane=1:1) compound 2, is obtained.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline.
Embodiment 3：The synthesis of ligand L
Repeat embodiment 2, except for the difference that：
Step 2) in, with Pb (Ac)4Replace Mn (Ac)3, control Pb (Ac)4Addition for the material of compound 1 amount 5
Times, reaction is carried out under the conditions of 60 DEG C.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline.
Embodiment 4：The synthesis of ligand L
Repeat embodiment 1, except for the difference that：
Step 2) in, use chloro- 5, the 6- dicyan 1,4-benzoquinone of 2,3- bis- to replace palladium carbon, replace xylol with dichloromethane, 2,
The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of 3- bis- is equal with the amount of the material of compound 1.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline.
Embodiment 5：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol CuCl are directly added into2·2H2O and 0.1mmol parts
L, (volume ratio of methanol and dichloromethane is 3 to add 0.6ml ethanol/methylene mixed solutions:1), in the bar of evacuation
Under part, then opening sealing by fusing fully reacts 20 hours under the conditions of 50 DEG C, obtain green crystal type solid product.
Products therefrom is characterized：
(1) high resolution mass spectrum, ESI-MS m/z:561[Cu(L)(DMSO)Cl]+. (DMSO from mass spectrometric measurement when use
Solvent), as shown in Figure 1.
Therefore can determine that above-mentioned product is the copper (II) with 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline as part
Coordination compound is title complex [Cu (L) Cl2], shown in its structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.2mmol CuCl are directly added into2·2H2O and 0.1mmol parts
L, (volume ratio of ethanol and chloroform is 3 to add 0.6ml ethanol/chloroform mixed solution:1), under conditions of evacuation, will open
Mouth end sealing by fusing, then fully reacts 12 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
Embodiment 7：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.3mmol CuCl are directly added into2·2H2O and 0.1mmol parts
Abbreviation L, adds 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethanol and N, N- dimethyl formyl
The volume ratio of amine is 5：1：1), under conditions of evacuation, by opening sealing by fusing, then fully reaction 4 is little under the conditions of 100 DEG C
When, obtain green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
Embodiment 8：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.4mmol CuCl are directly added into2·2H2O and 0.1mmol parts
L, (volume ratio of ethanol and acetone is 10 to add 0.6ml ethanol/acetone mixed solutions:1), under conditions of evacuation, will
Opening sealing by fusing, then fully reacts 4 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
Embodiment 9：Title complex [Cu (L) Cl2] synthesis
Take 6mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, are added thereto to 80ml ethanol/waters and are mixed
(volume ratio of second alcohol and water is 1 to close solution:1), after stirring and dissolving, 60 DEG C are heated to and are reacted 12 hours, reactant concentrating under reduced pressure
Partial solvent is removed, is stood, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
Embodiment 10：Title complex [Cu (L) Cl2] synthesis
Take 2mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, be added thereto to 50ml methanol/acetones/
(volume ratio of methanol, acetone and water is 30 to water mixed solution：1：10), after stirring and dissolving, be heated to 50 DEG C react 12 hours, instead
Answer thing concentrating under reduced pressure to remove partial solvent, stand, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain
Green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
Embodiment 11：Title complex [Cu (L) Cl2] synthesis
Take 3mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, are added thereto to 30ml methanol/chloroform
(volume ratio of methanol and chloroform is 1 to mixed solution：1), after stirring and dissolving, react 18 hours in 20 DEG C, reactant concentrating under reduced pressure
Partial solvent is removed, is stood, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2]。
In order to absolutely prove purposes of the coordination compound of the present invention in pharmacy, applicant has carried out extracorporeal anti-tumor to it
Activity experiment.
Experimental example 1：Copper chloride (II) coordination compound with 1- (2- pyridines) -9- (naphthalene -2- methyl)-B-carboline as part (is pressed
The methods described of the embodiment of the present invention 5 is obtained) and ligand L (prepared by the methods described of the embodiment of the present invention 1) to various human tumors
Strain carries out vitro inhibition activity experiment.
1st, cell strain and cell culture
This experiment is non-from gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, human bladder cancer cell T-24, people
Small cell lung cancer cell NCI-H460 and human normal cell line HL-7702 totally 5 kinds of cell strains.
All tumor cell lines are cultivated in calf blood containing 10wt%, 100U/mL penicillins, 100U/mL streptomycins
In RPMI-1640 culture fluid, 37 DEG C of 5%CO containing volumetric concentration are put2Cultivate in incubator；Human normal cell line strain is then cultivated and contained
In 10wt% calf blood, 100U/mL penicillins, the DMEM culture fluid of 100U/mL streptomycins.
2nd, the preparation of testing compound
The DMSO liquid storages (concentration is 0.002mol/L) of each testing compound are diluted successively by RMPI1640 culture medium
Into five Concentraton gradient, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.Survey first
Each testing compound of 20 μm of ol/L of examination is considered as primary dcreening operation result for the suppression ratio of tumor cell proliferation；Test respectively again different
Proliferation Ability degree of each testing compound to various tumor cells under gradient concentration, to the Fitting Calculation half-inhibition concentration,
That is IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumor cell of trophophase, Jing after trypsinization, matched somebody with somebody with the culture fluid 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 to cell monolayer bottom hole is paved with, and the medicine 10 of finite concentration gradient is added per hole
μ L, each Concentraton gradient sets 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, observe 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 culture fluid 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 microplate reader wavelength after swinging device mixing, reference wavelength is the optical density value that 450nm determines each hole；
(6) while arranging zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolution of same concentrations are situated between control wells
Matter, culture fluid, MTT, DMSO).
(7) according to the optical density value (OD values) that measures judging living cells quantity, OD values are bigger, and cytoactive is stronger.
Calculate suppression ratio of the compound to growth of tumour cell.For cell of the suppression ratio more than 50% under primary dcreening operation concentration
The suppression ratio data of five Concentraton gradient are further fitted by strain by SPSS softwares, obtain compound to different tumors
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), compound is for the IC of different cell strains50Value is as shown in table 1.
Table 1：IC of the compound of the present invention to 5 kinds of cell strains50Value (μm ol/L)
From the point of view of anti tumor activity in vitro test result, coordination compound of the present invention has stronger anti-tumor activity, its
Activity is substantially better than cisplatin, is expected to develop into antitumor drug.
Claims (10)
1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended：
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and chlorination as shown in following formula (II)
Copper, in being dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent be selected from methanol and
One or two and one or two in water, acetone, chloroform, dichloromethane and the DMF in ethanol
Combination above；
3. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper chloride are taken, is dissolved in
In polar solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, point
Crystal is separated out, target product is obtained final product.
4. synthetic method according to claim 3, it is characterised in that：React the reflux temperature model at 50 DEG C to polar solvent
Carry out in enclosing.
5. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper chloride are taken, is dissolved in
In polar solvent, gained mixed liquor is placed in container, and vacuum, sealing by fusing, then in 30～140 DEG C of conditions are evacuated to Jing after liquid nitrogen freezing
Lower reaction, obtains target product.
6. synthetic method according to claim 5, it is characterised in that：Reaction is carried out under the conditions of 50～140 DEG C.
7. the synthetic method according to any one of claim 2～6, it is characterised in that：Compound shown in the formula (II)
It is prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, through dehydrating condensation compound 1 is obtained；So
Compound 1 is placed in the second organic solvent afterwards, is added oxidant cyclization and dehydrogenation is obtained compound 2；Compound 2 is placed in again
In the aprotic polar solvent of alkaline matter, add 2- bromomethyls naphthalene to carry out substitution reaction, obtain final product；Wherein：
The first described organic solvent be in toluene, methanol, ethanol, dichloromethane and chloroform one or two with
On combination；
The second described organic solvent be in benzene, toluene, xylol, glacial acetic acid and dichloromethane one or two with
On combination；
Described oxidant is the chloro- 5,6- dicyan 1,4-benzoquinone of palladium carbon, manganese acetate hydrate, lead tetraacetate or 2,3- bis-；
Described alkaline matter is inorganic base；
Described aprotic polar solvent is one or two in N,N-dimethylformamide, dimethyl sulfoxide and acetone
Combination above.
8. synthetic method according to claim 7, it is characterised in that：Purification behaviour is carried out to compound shown in gained formula (II)
Make.
9. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antitumor drug is prepared.
10. the antitumor drug for being prepared as active component with compound described in claim 1 or its pharmaceutically acceptable salt.
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