CN109053725A - A kind of 2- (tetrahydroquinoline -6- base)-tetrahydro -1,8- naphthyridine type compound and the preparation method and application thereof - Google Patents
A kind of 2- (tetrahydroquinoline -6- base)-tetrahydro -1,8- naphthyridine type compound and the preparation method and application thereof Download PDFInfo
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- CN109053725A CN109053725A CN201810973000.8A CN201810973000A CN109053725A CN 109053725 A CN109053725 A CN 109053725A CN 201810973000 A CN201810973000 A CN 201810973000A CN 109053725 A CN109053725 A CN 109053725A
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- Prior art keywords
- tetrahydro
- tetrahydroquinoline
- acid
- base
- preparation
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- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003863 metallic catalyst Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- -1 hydrogen quinolines Chemical class 0.000 claims description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000011097 chromatography purification Methods 0.000 claims description 3
- 229940011182 cobalt acetate Drugs 0.000 claims description 3
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 3
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229940071125 manganese acetate Drugs 0.000 claims description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 claims 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 6
- 150000005054 naphthyridines Chemical class 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 229910001873 dinitrogen Inorganic materials 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000000132 electrospray ionisation Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JZICUKPOZUKZLL-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1 JZICUKPOZUKZLL-UHFFFAOYSA-N 0.000 description 3
- MLFRLYOJELUIOR-UHFFFAOYSA-N 3-methyl-2-phenyl-1,8-naphthyridine Chemical class CC1=CC2=CC=CN=C2N=C1C1=CC=CC=C1 MLFRLYOJELUIOR-UHFFFAOYSA-N 0.000 description 3
- YIIPMCFBCZKCFB-UHFFFAOYSA-N 8-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1CCNC2=C1C=CC=C2C YIIPMCFBCZKCFB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- ZCZVGQCBSJLDDS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine Chemical class C1=CC=C2CCCNC2=N1 ZCZVGQCBSJLDDS-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- 150000005058 1,8-naphthyridines Chemical class 0.000 description 1
- DAKOVVGRYRXCEP-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine Chemical class N1CCCC2=CC(=CC=C12)C1NC2=NC=CC=C2CC1 DAKOVVGRYRXCEP-UHFFFAOYSA-N 0.000 description 1
- FBRBUGVSEJYVDD-UHFFFAOYSA-N 2-(4-bromophenyl)-1,8-naphthyridine Chemical class C1=CC(Br)=CC=C1C1=CC=C(C=CC=N2)C2=N1 FBRBUGVSEJYVDD-UHFFFAOYSA-N 0.000 description 1
- STCTVADMIRRKNK-UHFFFAOYSA-N 2-(4-chlorophenyl)-1,8-naphthyridine Chemical class C1=CC(Cl)=CC=C1C1=CC=C(C=CC=N2)C2=N1 STCTVADMIRRKNK-UHFFFAOYSA-N 0.000 description 1
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- OBHWOLDGXCOBAK-UHFFFAOYSA-N [F].CS(O)(=O)=O Chemical compound [F].CS(O)(=O)=O OBHWOLDGXCOBAK-UHFFFAOYSA-N 0.000 description 1
- UMRSVAKGZBVPKD-UHFFFAOYSA-N acetic acid;copper Chemical compound [Cu].CC(O)=O UMRSVAKGZBVPKD-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000013096 assay test Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of 2- (tetrahydroquinoline -6- base)-tetrahydro -1,8- naphthyridine type compounds and the preparation method and application thereof, and the general molecular formula of the compound is shown in formula I:Wherein, R in the Formulas I1For phenyl, nitrobenzene or halogenophenyl；R2For hydrogen or methyl；R3For hydrogen or methyl；R4For hydrogen or methyl.The preparation method comprises the following steps: S1, in the reaction vessel, Tetrahydroquinolinesas and 1 is added, after 8 naphthyridine type compounds, 1~5% metallic catalyst of Tetrahydroquinolinesas quality is added, acid and solvent are added, is stirred to react at 80 DEG C~160 DEG C 5~24 hours；S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude by column chromatography purifies to obtain.
Description
Technical field
The present invention relates to medication chemistry synthesis technical fields, and in particular to a kind of 2- (tetrahydroquinoline -6- base)-tetrahydro -1,
8- naphthyridine type compound and the preparation method and application thereof.
Background technique
In recent years, heterocyclic compound, especially nitrogenous heterocyclic compound play heavy to closing in modern medicines research
The effect wanted, the construction method for developing efficient nitrogen-containing heterocycle compound have also attracted more and more concerns.Naphthyridines azacyclo-
Compound is a kind of particularly important heterocyclic system, is common in pharmaceutical intermediate and a variety of natural products, is had potential raw
Object activity.Wherein, Tetrahydronaphthyridderivates are also a kind of important heterocyclic system, in organic intermediate, medicine, pesticide, material science etc.
Field all has wide practical use.In addition, tetrahydro chinolines organic compound is a kind of relatively conventional nitrogen heterocyclic,
Its unique molecular structure is largely present in nature, its various derivatives all have biology and pharmacological activity mostly.From
Most of biologically active natural products all contains one or more azepine ring skeleton in right boundary.By single heterocyclic compound
When object combines to form new double heterocycles or more heterocycle structures, often retain original bioactivity, and can generate imaginary
Less than new features.Therefore, promote the coupling between nitrogen heterocyclic, form functional more superior dinitrogen heterocyclic compound
It is the hot spot of current research.
With the development of organic chemistry and material, medical cross discipline development, scientists are from nitrogen-containing heterocycle compound
In have found a large amount of new drugs and novel functional material, the dinitrogen jeterocyclic chemistry that two heterocycles are combined in different ways
Close object plays highly important role in terms of biological medicine and functional material.Tetrahydroquinoline and naphthyridines structure are azepine cyclisation
The basic framework of object is closed, all contains these structures in the molecular structure of many natural products, and some compounds can be shown
Good bioactivity.Carbon-carbon bond coupling is always the hot and difficult issue of organic field research between two nitrogen heterocyclics,
The more complicated dinitrogen heterocyclic skeleton molecule of structure will could synthesize greatly by being permitted multistep reaction, and not only operating procedure is extremely numerous
It is trivial, and atom and step economy are low, therefore, in the synthesis of complicated dinitrogen heterocycle, reduction synthetic route is to improve complicated nitrogen
A kind of effective means of heterocyclic compound ultimate yield.However, for the synthesis side of tetrahydroquinoline and naphthyridines building dinitrogen heterocycle
Method does not have document to be reported so far using no metal catalytic, this is based on, if a kind of non-metal catalyst can be moused out
Synthetic method participate in, green, efficient, easy to operate, will carry out between tetrahydroquinoline and Tetrahydronaphthyridderivates structural unit
Efficient combination, building is a series of will to be of great significance containing the active dinitrogen heterocyclic skeleton molecule of potential drug.
Summary of the invention
The technical problems to be solved by the present invention are: providing a kind of couple of inhibited 2- of tumour (1,2,3,4- tetra-
Hydrogen quinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type compound and the preparation method and application thereof.
In order to solve the above-mentioned technical problem, a kind of the technical solution adopted by the present invention are as follows: 2- (1,2,3,4- tetrahydroquinoline-
6- yl) -1,2,3,4- tetrahydro -1,8- naphthyridine type compounds, the general molecular formula of the compound is as shown in following formula I:
Wherein, R in the Formulas I1For phenyl, nitrobenzene or halogenophenyl；R2For hydrogen or methyl；R3For hydrogen or methyl；R4For
Hydrogen or methyl.
The invention also includes above-mentioned 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type chemical combination
The preparation method of object, comprising the following steps:
Tetrahydroquinolinesas and 2- phenyl -3- methyl-1,8 naphthyridine type compounds are added in S1, in the reaction vessel
Afterwards, 1~5% metallic catalyst (Catalyst, Cat.) of Tetrahydroquinolinesas quality is added, adds sour and molten
Agent is stirred to react 5~24 hours at 80 DEG C~160 DEG C, wherein the Tetrahydroquinolinesas and 1,8 naphthyridine type chemical combination
The molar ratio of object is 1~2: 1, and the quality of the acid is the 10~100% of Tetrahydroquinolinesas quality, wherein described four
Hydrogen quinolines are preferably 2- methyl-tetrahydro quinoline or 8- methyl-tetrahydro quinoline, and described 1,8 naphthyridine type compounds are preferred
2- phenyl -3- methyl-1 after being replaced for phenyl by halogen or nitro, 8 naphthyridine type compounds；
S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, crude product warp
Column Chromatographic purification obtains 2- tetrahydric quinoline group-Tetrahydronaphthyridderivates class compound.
Further, the room temperature is 20~30 DEG C.
Further, in the step S1, the metallic catalyst is copper acetate, copper trifluoromethanesulfcomposite, copper sulphate, chlorination
The mixing of one or more of copper, stannous chloride, iron chloride, cobalt acetate, cobalt chloride, manganese acetate.
As can be seen from the above description, the beneficial effects of the present invention are: it can be realized effectively using cheap metallic catalyst
Catalysis, greatly reduce production cost.
Further, solvent described in the step S1 is ethyl alcohol, tert-pentyl alcohol, isopropanol, Isosorbide-5-Nitrae-dioxane, N, N- diformazan
The mixing of one or more of base formamide, dimethyl sulfoxide, toluene, paraxylene and water；The addition of the solvent
Amount and the molal volume ratio of Tetrahydroquinolinesas are preferably Tetrahydroquinolinesas: solvent=0.5mmol:1~3ml.
Further, acid described in the step S1 is formic acid, acetic acid, methanesulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, hydrochloric acid, three
The mixing of one or more of fluorine methanesulfonic acid, trifluoroacetic acid；The acid is excellent with the molar ratio of Tetrahydroquinolinesas
It is selected as Tetrahydroquinolinesas: acid=0.5mmol:0.05mmol.
Further, reaction vessel described in the step S1 is preferably schlenk pipe (Schlenk pipe), and reaction process is excellent
Choosing carries out under a nitrogen atmosphere.
Further, the eluent that uses of the operation of column Chromatographic purification described in the step S2 is for volume ratio
(0.5~50): (0~20): 1 petroleum ether: methylene chloride: the mixed solution of ethyl acetate.
Wherein, part reaction equation involved in above-mentioned preparation method is as follows:
Wherein, the R1For phenyl, nitrobenzene, halogenic substituent benzene；R2For hydrogen or methyl；R3For hydrogen or methyl；R4For
Hydrogen or methyl.
The invention also includes above-mentioned 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type chemical combination
Object is preparing anti-tumor agent comprising salmosin or is preventing and treating the application in tumour medicine.
Further, the application is the reagent or medicine in anti-human cancer K562, HL-60, HeLa and/or BGC-823 cell
In object.
The beneficial effects of the present invention are: the present invention provides a kind of 2- (1,2,3,4- tetrahydros with anti-tumor activity
Quinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type compounds and the preparation method and application thereof, it efficiently solves with anti-
The preparation problem of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine compounds of tumor promotion.It is logical
Crossing preparation method of the invention can be efficiently synthesized 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridines
Class dinitrogen heterocyclic compound has many advantages, such as that simple synthesis step, safe operation, advantages of nontoxic raw materials and raw material are cheap and easy to get, this hair
Bright preparation process is selectively good and Atom economy is high, and obtained dinitrogen heterocycle product structure novel can further develop its life
Object activity；Novel 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type compound pair of the invention
Experimenter's cancer K562, HL-60, HeLa, BGC-823 cell has good inhibiting effect, and therefore, such compound is both as anti-
Tumor reagent is in anti tumor activity in vitro screening, it can also be used in the drug of anti-curing oncoma.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of product 3a made from the embodiment of the present invention 1；
Fig. 2 is the carbon spectrogram of product 3a made from the embodiment of the present invention 1；
Fig. 3 is the hydrogen spectrogram of product 3b made from the embodiment of the present invention 2；
Fig. 4 is the carbon spectrogram of product 3b made from the embodiment of the present invention 2；
Fig. 5 is the hydrogen spectrogram of product 3c made from the embodiment of the present invention 3；
Fig. 6 is the carbon spectrogram of product 3c made from the embodiment of the present invention 3；
Fig. 7 is the hydrogen spectrogram of product 3d made from the embodiment of the present invention 4；
Fig. 8 is the carbon spectrogram of product 3d made from the embodiment of the present invention 4；
Fig. 9 is the hydrogen spectrogram of product 3e made from the embodiment of the present invention 5；
Figure 10 is the carbon spectrogram of product 3e made from the embodiment of the present invention 5.
Specific embodiment
To explain the technical content, the achieved purpose and the effect of the present invention in detail, below in conjunction with embodiment and cooperate attached
Figure is explained.
The embodiment of the present invention 1 is a kind of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3 with anti-tumor activity,
The preparation method of 4- tetrahydro -1,8- naphthyridines, comprising the following steps: in the reactor, 1.0 mMs of tetrahydroquinolines and 0.5 is added
MM 2- phenyl -3- methyl-1,8- naphthyridines are added 1% copper trifluoromethanesulfcomposite (Catalyst, Cat.), add 50%
Trifluoromethanesulfonic acid, 1.5ml toluene is stirred to react 5 hours at 80 DEG C, is cooled to room temperature after reaction, dilute reaction solution,
Filtering, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude by column chromatography purifies to obtain 3a, which is in yellow oil
Shape.
Hydrogen spectrogram and carbon the spectrogram difference of products therefrom 3a is as depicted in figs. 1 and 2, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3):
δ 7.49 (d, J=7.5Hz, 2H), 7.40 (t, J=7.5Hz, 2H), 7.32 (t, J=7.2Hz, 1H), 7.12 (s,
1H), 6.95 (d, J=7.7Hz, 2H), 6.43 (d, J=7.8Hz, 1H), 4.98 (s, 1H), 4.44 (dd, J=9.1,2.8Hz,
1H),3.33-3.23(m,2H),2.89-2.80(m,1H),2.76-2.66(m,3H),2.18(s,3H),2.11-2.05(m,
1H),1.96-1.86(m,3H)；
13C NMR(101MHz,CDCl3):
δ154.28,144.15,141.15,139.07,132.32,128.95,128.02,127.43,127.35,
124.77,121.45,118.86,114.72,114.18,55.79,42.02,30.92,27.04,25.53,22.20,18.77；
Products therefrom 3a is measured into its infrared suction by infrared spectrometer (infrared spectrometer, IR (KBr))
Spectral results discovery is received, the compound is in 2928,1588,1452,1308,1131,819,750,699cm-1There is characteristic absorption at place
Peak shows the present invention program and the product with target group has been made.
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, C24H26N3[M+H]+: theoretical value
(Calculated value, Calcd.): 356.2121；Actually measured value (found): 356.2125.
The embodiment of the present invention 2 is a kind of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- with anti-tumor activity
The preparation method of tetrahydro -1,8- naphthyridine type compound, comprising the following steps: in the reactor, 0.8 mM of 2- methyl four is added
The iron chloride of 2- methyl tetrahydroquinoline quality 5% is added in hydrogen quinoline and 0.5 mM of 2- phenyl -3- methyl-1,8- naphthyridines, then
60% methanesulfonic acid is added, 1.0ml toluene is stirred to react 12 hours at 160 DEG C, is cooled to room temperature after reaction, dilutes
Reaction solution, filtering, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude by column chromatography purifies to obtain product 3b, described
Product 3b is in yellow oily.
Hydrogen spectrogram and carbon the spectrogram difference of products therefrom 3b is as shown in Figure 3 and Figure 4, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ 7.87 (d, J=4.8Hz, 1H), 7.18 (d, J=7.1Hz, 1H), 6.95 (d, J
=9.8Hz, 2H), 6.54-6.47 (m, 1H), 6.44 (d, J=7.9Hz, 1H), 5.04 (s, 1H), 4.43 (dd, J=9.0,
2.8Hz,1H),3.55-3.28(m,1H),2.88-2.77(m,2H),2.72-2.64(m,2H),2.11-2.02(m,1H),
1.97-1.82 (m, 2H), 1.65-1.53 (m, 1H), 1.21 (d, J=6.2Hz, 3H)；
13C NMR(101MHz,CDCl3)δ156.41,145.85,144.28,136.02,132.11,127.20,
124.78,121.15,115.94,113.99,112.70,55.72,47.21,30.54,30.10,26.63,25.84,22.59；
IR (KBr) the result shows that, product 3b 2936,2845,1860,1819,1489,1352,1330,1292,1194,
1170、771、739cm-1There is characteristic absorption peak, which has target group.
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, C18H22N3[M+H]+Theoretical value
(Calcd.):280.1808；Actually measured value (found): 280.1804.
The embodiment of the present invention 3 is a kind of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3 with anti-tumor activity,
The preparation method of 4- tetrahydro -1,8- naphthyridine type compound, comprising the following steps: in the reactor, 0.75 mM of 2- first is added
Base tetrahydroquinoline and 0.5 mM of 2- (3- nitrobenzophenone) -1,8- naphthyridines, the cobalt acetate that 2- methyl tetrahydroquinoline 2% is added are urged
Agent, adds 10% p-methyl benzenesulfonic acid, and 1.2ml toluene is stirred to react 15 hours at 130 DEG C, cools down after reaction
To room temperature, dilute reaction solution, filtering, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude by column chromatography purifies to obtain
Product 3c, the product 3c are in yellow oily.
Hydrogen spectrogram and carbon the spectrogram difference of products therefrom 3c is as shown in Figure 5 and Figure 6, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ 8.80 (s, 1H), 8.27 (d, J=7.8Hz, 1H), 8.16 (d, J=8.1Hz,
1H), 7.56 (d, J=7.9Hz, 1H), 7.30 (d, J=7.4Hz, 1H), 7.03 (d, J=7.4Hz, 1H), 6.96 (d, J=
12.5Hz, 2H), 6.45 (d, J=8.0Hz, 1H), 5.19 (s, 1H), 4.47 (d, J=7.5Hz, 1H), 3.72 (s, 1H),
3.44-3.37 (m, 1H), 2.89-2.70 (m, 4H), 2.11 (dd, J=12.9,3.9Hz, 1H), 2.00-1.91 (m, 2H),
1.64-1.53 (m, 1H), 1.21 (d, J=6.2Hz, 3H)；
13C NMR(101MHz,CDCl3)δ156.39,151.04,148.69,144.37,141.66,136.77,
132.30,131.79,129.29,127.22,124.82,122.68,121.47,121.19,116.17,114.00,109.58,
55.80,47.23,30.42,30.12,26.66,25.70,22.59；
IR (KBr) the result shows that, product 3c 3415,1638,1618,1527,1442,1348,1121,870,792,
734cm-1There is characteristic absorption peak, which has target group.
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, Calcd.for C24H25N4O2[M+
H]+:401.1972；found:401.1975.
The embodiment of the present invention 4 is a kind of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3 with anti-tumor activity,
The preparation method of 4- tetrahydro -1,8- naphthyridine type compound, comprising the following steps: in the reactor, 0.8 mM of 8- methyl is added
The acetic acid copper catalyst of 8- methyl tetrahydroquinoline 3% is added in tetrahydroquinoline and 0.4 mM of 2- (4- chlorphenyl) -1,8- naphthyridines,
50% trifluoroacetic acid is added, 1.2ml tert-pentyl alcohol is stirred to react 10 hours at 100 DEG C, is cooled to room after reaction
Temperature, dilute reaction solution, filtering, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude by column chromatography purifies to obtain product
3d, the product 3d are in brown solid, and fusing point is 140-141 DEG C.
Hydrogen spectrogram and carbon the spectrogram difference of products therefrom 3d is as shown in Figure 7 and Figure 8, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ 7.86 (d, J=8.5Hz, 2H), 7.36 (d, J=8.5Hz, 2H), 7.25 (t, J
=3.7Hz, 1H), 6.93 (d, J=7.5Hz, 1H), 6.88 (d, J=10.2Hz, 2H), 5.15 (s, 1H), 4.44 (dd, J=
9.1,3.1Hz,1H),3.40-3.30(m,2H),2.87-2.71(m,4H),2.12-2.07(m,1H),2.07(s,3H),
1.96-1.88(m,3H)；
13C NMR(101MHz,CDCl3)δ156.18,152.54,142.20,138.28,136.76,134.12,
131.35,128.61,127.87,125.96,125.34,121.33,120.91,115.09,109.37,55.89,42.36,
30.75,27.36,25.81,22.14,17.22；
IR (KBr) the result shows that, product 3d 2928,2857,1665,1627,1594,1462,1304,1088,806,
752cm-1There is characteristic absorption peak, which has target group.
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, Calcd.for C24H25ClN3[M+
H]+:390.1731；found:390.1735.
The embodiment of the present invention 5 is a kind of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3 with anti-tumor activity,
The preparation method of 4- tetrahydro -1,8- naphthyridine type compound, comprising the following steps: in the reactor, 0.4 mM of 8- methyl is added
Tetrahydroquinoline and 0.4 mM of 2- (4- bromophenyl) -1,8- naphthyridines, the copper chloride that 8- methyl tetrahydroquinoline quality 3% is added are urged
Agent, adds 80% p-methyl benzenesulfonic acid, 1.2ml paraxylene, is stirred to react 10 hours at 150 DEG C, after reaction
It is cooled to room temperature, dilute reaction solution, filters, vacuum rotary steam, which removes solvent, can be obtained crude product, crude by column chromatography purification
3e is obtained, the product 3e is in yellow solid, and fusing point is 173-174 DEG C.
Hydrogen spectrogram and carbon the spectrogram difference of products therefrom 3e is as shown in Figure 9 and Figure 10, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3) δ 7.84 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.32-7.27
(m, 1H), 6.97 (d, J=7.5Hz, 1H), 6.92 (d, J=10.3Hz, 2H), 5.18 (s, 1H), 4.48 (dd, J=9.2,
3.0Hz,1H),3.46-3.36(m,2H),2.90-2.75(m,4H),2.18-2.11(m,1H),2.11(s,3H),1.99-
1.88(m,3H)；
13C NMR(101MHz,CDCl3)δ156.21,142.20,136.76,131.56,131.34,128.19,
125.96,125.34,122.42,121.33,120.90,115.17,109.34,55.89,42.36,30.75,27.37,
25.83,22.14,17.22；
IR (KBr) the result shows that, product 3e is in 2928,1633,1591,1501,1462,1321,807cm-1There is feature
Absorption peak, the product have target group.
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, Calcd.for C24H25BrN3[M+
H]+:434.1226；found:434.1224.
By noval chemical compound 3a-3e obtained by above-described embodiment 1-5, anti-tumor activity test is carried out: by each compound
It is configured to 100 μ gmL respectively-1Methanol solution, positive control drug 5 FU 5 fluorouracil (5-fluorouracil, 5-FU) and more
Alkene taxol (docetaxol) is made into 100 μ gmL respectively-1Dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) it is molten
Liquid, respectively using methanol and DMSO solvent as blank control, using tetramethyl azo azoles salt (methyl thiazolyl
Tetrazolium method, MTT) method tests each compound to the inhibiting effect of K562, HL-60, HeLa, BGC-823 cell,
Concrete operations are as follows:
1, the preparation of cell culture fluid: one bag of RPMI-1640 culture medium powder (net content 10.4g) is taken to pour into clean
In beaker, dissolved with the ultra-clean water of 900mL, and 100mgmL is added-1Streptomysin 1mL, penicillin 0.5mL and NaHCO3
2g.After magnetic agitation is uniform, removed with autoclaved Cai Shi (Zeiss) filter through 0.22 μm of membrane filtration in super-clean bench
Bacterium, filtrate are directly stored in (450mL/ bottles) in the vial after moist heat sterilization.Culture medium is before use, take the blood of freezing
Clearly, after 56 DEG C of inactivation 30min, addition has prepared in RPMI-1640 culture solution and (50mL serum has been added in 450mL culture medium), gently
After jog is even, covers, sealed with masking foil, saved in 4 DEG C of refrigerators.
MTT solution is prepared: the MTT powder of 50mg is dissolved in the PBS solution of 10mL, with 0.22 μm of membrane filtration, in 4
It is saved in DEG C refrigerator.
2, anti-tumor activity test: take respectively growth logarithmic phase K562, HL-60, HeLa, BGC-823 cell, in 4 DEG C,
It is centrifuged 3min on 3000rpm centrifuge, sucks supernatant, fresh RPMI-1640 culture medium is added and is diluted to 1 × 105A/milli
The cell suspension risen.Every 200 μ L of hole is inoculated in 96 orifice plates, in 37 DEG C, 5%CO2Cell incubator in cultivate 1h after, every hole
Respectively plus 2 μ L of sample solution, each sample set 3 parallel holes, separately set the blank control in two groups of each three holes, with the same terms after sample-adding
Culture is for 24 hours.After for 24 hours, cell is observed under an optical microscope whether there is or not metamorphosis, preliminary judgement sample has missing cytotoxic activity,
It takes pictures when necessary.5mgmL is added in every hole-1Each 20 μ L of MTT solution, continue in incubator to cultivate 4h.Take out 96 orifice plates
It is centrifuged (4 DEG C, 2000rpm, 20min) and removes supernatant, every hole adds 150 μ L DMSO, and sufficiently oscillation keeps violet precipitate complete
Dissolution.Its optical density OD value is measured under 570nm in microplate reader, every group of sample is averaged and by inhibiting rate
(inhibition rate, IR) %=(ODBlank-ODSample)/ODBlank× 100% formula calculates.
It is miscellaneous that mtt assay tests five kinds of 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type dinitrogens
Cyclics are as shown in table 1 to the proliferation activity suppression result of four kinds of tumour cells:
Result of the table 1MTT method test class compound to the proliferation activity inhibiting effect of four kinds of tumour cells
The compound made from the present invention program it can be seen from upper table 1 is equal to K562, HL-60, HeLa, BGC-823 cell
With certain inhibiting effect.
In conclusion a kind of 2- (tetrahydroquinoline -6- base)-tetrahydro -1,8- naphthyridine type compound provided by the invention and its
Preparation method and application, such compound on tumor is inhibited, and the preparation method of the present invention program is environmentally protective and passes through
It helps profitable, there is good production application prospect.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalents made by bright specification and accompanying drawing content are applied directly or indirectly in relevant technical field, similarly include
In scope of patent protection of the invention.
Claims (10)
1. a kind of -1,2,3,4- tetrahydro -1,8- naphthyridine type compounds of 2- (1,2,3,4- tetrahydroquinoline -6- base), it is characterised in that:
The general molecular formula of the compound is as shown in following formula I:
Wherein, R in the Formulas I1For phenyl, nitrobenzene or halogenophenyl；R2For hydrogen or methyl；R3For hydrogen or methyl；R4For hydrogen or
Methyl.
2. a kind of preparation method of -1,2,3,4- tetrahydro -1,8- naphthyridine type compounds of 2- (1,2,3,4- tetrahydroquinoline -6- base),
It is characterized by comprising following steps:
S1, in the reaction vessel, is added Tetrahydroquinolinesas and 1, and after 8- naphthyridine type compound, tetrahydro chinolines are added
1~5% metallic catalyst for closing amount of substance adds acid and solvent, is stirred to react at 80 DEG C~160 DEG C 5~24 hours,
Wherein, the Tetrahydroquinolinesas and 1, the molar ratio of 8- naphthyridine type compound are 1~2: 1, and the quality of the acid is four
The 10~100% of hydrogen quinolines quality；
S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude product is through column layer
Analysis purification obtains the 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type compound.
3. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close the preparation method of object, it is characterised in that: in the step S1, the metallic catalyst is copper acetate, copper trifluoromethanesulfcomposite, sulphur
The mixing of one or more of sour copper, copper chloride, stannous chloride, iron chloride, cobalt acetate, cobalt chloride, manganese acetate.
4. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close the preparation method of object, it is characterised in that: solvent described in the step S1 is ethyl alcohol, tert-pentyl alcohol, isopropanol, Isosorbide-5-Nitrae-dioxy six
The mixing of one or more of ring, N,N-dimethylformamide, dimethyl sulfoxide, toluene, paraxylene and water.
5. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close the preparation method of object, it is characterised in that: the molal volume ratio of the additional amount of the solvent and Tetrahydroquinolinesas is four
Hydrogen quinoline: solvent=0.5mmol:1~3ml.
6. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close object preparation method, it is characterised in that: acid described in the step S1 be formic acid, acetic acid, methanesulfonic acid, benzoic acid, to toluene sulphur
The mixing of one or more of acid, hydrochloric acid, trifluoromethanesulfonic acid, trifluoroacetic acid.
7. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close the preparation method of object, it is characterised in that: the molar ratio of the acid and Tetrahydroquinolinesas is Tetrahydroquinolinesas:
Acid=0.5mmol:0.05mmol.
8. 2- (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type according to claim 2
Close the preparation method of object, it is characterised in that: column Chromatographic purification described in the step S2 operates the eluent used and is for volume ratio
(0.5~50): (0~20): 1 petroleum ether: methylene chloride: the mixed solution of ethyl acetate.
9. a kind of 2- as described in claim 1 (1,2,3,4- tetrahydroquinoline -6- base) -1,2,3,4- tetrahydro -1,8- naphthyridine type
Compound is preparing anti-tumor agent comprising salmosin or is preventing and treating the application in tumour medicine.
10. application as claimed in claim 9, it is characterised in that: the application be anti-human cancer K562, HL-60, HeLa and/
Or in the reagent or drug of BGC-823 cell.
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| CN110117282A (en) * | 2019-05-13 | 2019-08-13 | 五邑大学 | A kind of zinc ion fluorescent compound and the preparation method and application thereof |
| CN110872291A (en) * | 2019-11-26 | 2020-03-10 | 五邑大学 | Tetrahydropyridopyrimidine compound and preparation method and application thereof |
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| CN110117282A (en) * | 2019-05-13 | 2019-08-13 | 五邑大学 | A kind of zinc ion fluorescent compound and the preparation method and application thereof |
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| CN110872291A (en) * | 2019-11-26 | 2020-03-10 | 五邑大学 | Tetrahydropyridopyrimidine compound and preparation method and application thereof |
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