CN108912035A - A kind of indole amides class compound having anti-tumor activity - Google Patents
A kind of indole amides class compound having anti-tumor activity Download PDFInfo
- Publication number
- CN108912035A CN108912035A CN201810646267.6A CN201810646267A CN108912035A CN 108912035 A CN108912035 A CN 108912035A CN 201810646267 A CN201810646267 A CN 201810646267A CN 108912035 A CN108912035 A CN 108912035A
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- China
- Prior art keywords
- compound
- reaction
- pharmaceutically acceptable
- cancer
- human
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- -1 indole amides Chemical class 0.000 title claims abstract description 28
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 3
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 10
- 208000019065 cervical carcinoma Diseases 0.000 claims abstract description 9
- 201000007270 liver cancer Diseases 0.000 claims abstract description 9
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 9
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 7
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 7
- 201000005296 lung carcinoma Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
- 208000010749 gastric carcinoma Diseases 0.000 claims abstract description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- BBDPEDLEBUCZDD-UHFFFAOYSA-N [Na].ClC(CCC)O Chemical compound [Na].ClC(CCC)O BBDPEDLEBUCZDD-UHFFFAOYSA-N 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- KDFBGNBTTMPNIG-UHFFFAOYSA-N hydron;2-(1h-indol-3-yl)ethanamine;chloride Chemical compound Cl.C1=CC=C2C(CCN)=CNC2=C1 KDFBGNBTTMPNIG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 201000011510 cancer Diseases 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 150000002475 indoles Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- WHSXTWFYRGOBGO-UHFFFAOYSA-N 3-methylsalicylic acid Chemical compound CC1=CC=CC(C(O)=O)=C1O WHSXTWFYRGOBGO-UHFFFAOYSA-N 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
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- CRDNMYFJWFXOCH-BUHFOSPRSA-N Couroupitine B Natural products N\1C2=CC=CC=C2C(=O)C/1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-BUHFOSPRSA-N 0.000 description 1
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- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
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- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
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- 239000003242 anti bacterial agent Substances 0.000 description 1
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- 230000006907 apoptotic process Effects 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
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- JNLNPCNGMHKCKO-UHFFFAOYSA-N chembl35349 Chemical compound C1=CC=C2C(=O)C(C=3C4=CC=CC=C4NC=3O)=NC2=C1 JNLNPCNGMHKCKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 230000009514 concussion Effects 0.000 description 1
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
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- 210000000981 epithelium Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of indole amides class compounds for having anti-tumor activity, it can be used to treating cancers, in particular for treatment gastric cancer, liver cancer, breast cancer, lung carcinoma cell and cervical carcinoma, especially for inhibiting gastric carcinoma cells MGC-803, human liver cancer cell HepG2, human breast cancer cell line Bcap-37, human lung cancer cell A549 and human cervical carcinoma cell HELA cell strain.Therefore, it is possible to be used as broad-spectrum anti-cancer drug, with good development and application prospects.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a series of indole amides class compounds, preparation method and its
Purposes.
Background technique
Medically, cancer (cancer) refers to the malignant tumour originating from epithelial tissue, is most common in malignant tumour
It is a kind of.Cancer has cell differentiation and proliferative disorder, the growth biological properties such as out of hand, wellability and metastatic, hair
Life is a multiple-factor, the complex process of multi-step, is divided into carcinogenic, rush three cancer, evolution processes, sudden and violent with smoking, infection, occupation
Dew, environmental pollution, unreasonable diet, inherent cause are closely related.The cause of disease of malignant tumour is not fully understood.It is more bright at present
True factor related with cancer can be divided into exogenous and endogenous two major classes.Gastric cancer, liver cancer, breast cancer, lung carcinoma cell and palace
Neck cancer is the higher a few class cancers of China's disease incidence.It is also directed to above-mentioned a few class cancers mostly in current new drug development.
Benzazole compounds are a kind of important heterocyclic compounds, have extensive bioactivity.In brassicaceous vegetable
And indoles secondary metabolite is widely present in a large amount of marine organisms and actinomyces.In recent years, in the work of anticancer aspect
Property causes the common concern of people.Currently, SU11248 (trade name：Sutent), vincaleukoblastinum (VLB, Vinblastine),
Vincristine (VCR, Vincristine), eldisine (VDS, Vindesine), vinorelbine (VBR, Vinorelbine),
The features such as kind containing indole structure has been listed and come into operation indigo red etc. on a small quantity, and toxic side effect is small and selectivity is strong shows especially out
Special-effect (progress of the flat indoles anticancer compound of Liu little Yu, Ou Yanggui, the fining of indoles anticancer compound
Work intermediate, the 5th 1-8 pages of phase of volume 40 in October, 2010).Li Xuelin etc. (CN103214472A) reports a kind of acrylic acid Yin
Diindyl amides compoundThe compound is for lung cancer, breast cancer, osteosarcoma, cervical carcinoma
There is inhibitory activity etc. a variety of cancer cells.Song Jun, wait (《Central China University of Science and Technology's journal (medicine)》, 2004, volume 33, the 6th
Phase, the 720-723 pages) the inducible apoptosis in gastric cancer of indoles U.S. good fortune is reported, but its mechanism is indefinite.
Therefore, the compound that R and D have extensive anticancer activity still has significance.
Summary of the invention
The technical problem to be solved by the present invention is to：A kind of indole amides class compound is provided, can widely be pressed down
Kinds cancer processed.
The first aspect of the invention is to provide a kind of compound of Formula I and its pharmaceutically acceptable salt：
Wherein：R' is selected from Cl or Br；
R is each independently selected from halogen ,-NO2 ,-CN, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 halogenated alkyl；N choosing
From 1,2,3 or 4.
Preferably, R is each independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl；
It is highly preferred that R is each independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, ethyoxyl, trifluoromethyl；
Most preferably, R is each independently selected from methyl, chlorine, bromine.
Preferably, n is selected from 1 or 2；
It is highly preferred that n is 1.
Preferably, the compounds of this invention has the following structure：
Another aspect of the present invention provides a kind of the method for preparing compound of formula I, and synthetic route is as follows：
Wherein, the definition of R', R and n are as described in claim 1；
Specific reaction step is as follows：
Step 1：4- substituted aniline and hydrochloric acid are added in the reaction vessel, sodium nitrite solution is added drop-wise in solution.Instead
Answer 1 hour and filter, filtrate added drop-wise into sodium sulfite solution, 80 DEG C reaction 1-3 hours, then concentrated hydrochloric acid is added dropwise, 95 DEG C of reaction 1-3
Hour is placed on ambient temperature overnight, and 4- substituted phenylhydrazines HCl, solid is precipitated；
Step 2：4- substituted phenylhydrazines hydrochloride, the chloro- 1- hydroxy-butan sodium sulfonate of 4-, second are sequentially added in the reaction vessel
Alcohol, water, then adjust solution PH to 6-7,75 DEG C reaction 5-7 hours；Vacuum distillation removes ethyl alcohol and part water, surplus solution are first used
Methylene chloride washing, then adjusts PH to 8-10, then uses chloroform, is placed in 4 DEG C of refrigerator cool overnights, and 5- substitution tryptamines salt is precipitated
Hydrochlorate solid；
Step 3：Salicyclic acid derivatives, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne are sequentially added in the reaction vessel
Diimmonium salt hydrochlorate, I-hydroxybenzotriazole, acetone, stirring at normal temperature 1-3 hours；It adds 5- obtained by step 2 and replaces tryptamines salt
Hydrochlorate, Anhydrous potassium carbonate, stirring at normal temperature to fully reacting；Column chromatography purifying, obtains compound shown in Formulas I.
Preferably, the molar ratio of the 4- substituted aniline, sodium nitrite and sodium sulfite of step 1 is 1:1-1.5:2-4.5
Preferably 1:1.05:3；
The molar ratio of the chloro- 1- hydroxy-butan sodium sulfonate of the 4- substituted phenylhydrazines hydrochloride and 4- of step 2 is 1:1-1.5, it is excellent
It is selected as 1:1-1.2；
Salicyclic acid derivatives, 1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxyl of step 3
Benzotriazole and 5- replace the molar ratio of tryptamine hydrochloride to be 1:1-2:1-2:0.5-1.5；Preferably 1:1-1.5:1-1.5:
0.8-1.2。
Another aspect of the present invention provides a kind of pharmaceutical composition, it includes Formulas I compound represented or its pharmaceutically may be used
Salt and pharmaceutically acceptable carrier, the excipient of receiving.
Another aspect of the present invention is related to a kind of purposes of compound of formula I in medicine preparation, it is characterised in that the drug
It can be used for cancer；In particular for treatment gastric cancer, liver cancer, breast cancer, lung carcinoma cell and cervical carcinoma；Especially for inhibiting people's stomach
Cancer cell MGC-803, human liver cancer cell HepG2, human breast cancer cell line Bcap-37, human lung cancer cell A549 and human cervical carcinoma cell
HELA cell strain.
Definition：
" alkyl ", which refers to, to be only made of carbon and hydrogen atom, is not contained degree of unsaturation, can is C1-6 alkyl.In some implementations
In scheme, alkyl has 1 to 6 or 1 to 4 carbon atom.Representative straight chain saturated alkyl include but is not limited to-methyl ,-ethyl ,-
N-propyl ,-normal-butyl ,-n-pentyl and-n-hexyl；And be saturated branched alkyl include but is not limited to-isopropyl ,-sec-butyl ,-it is different
Butyl ,-tert-butyl ,-isopentyl, 2- methyl butyl, 3- methyl butyl, 2- Methyl pentyl, 3- methyl amyl, 4- methyl amyl,
2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl-butyl etc..Alkyl is connected by singly-bound
It is connected to parent molecule.Unless in addition statement in the description, otherwise alkyl is optionally by one or more independently including below
Substituent group replaces：Acyl group, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, naphthenic base.In a non-limiting embodiments,
Substituted alkyl can be selected from methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyl, 3- fluoropropyl, hydroxymethyl, 2- hydroxyl second
Base, 3- hydroxypropyl, benzyl and phenethyl.
" alkoxy " refers to that " alkyl " is connected by oxygen atom with parent molecule, determines as described above wherein " alkyl " has
Justice.
" halogenated alkyl " refers to wherein all hydrogen moieties or all by selected from fluoro base, chloro base, bromo base and iodine
The alkyl of the halogen displacement of Dai Ji.In some embodiments, all hydrogen atoms are all respectively replaced by fluoro base.In some implementations
In scheme, all hydrogen atoms are all respectively replaced by chloro base.The example of halogenated alkyl include-CF3 ,-CF2CF3 ,-
CF2CF2CF3 ,-CFCl2 ,-CF2Cl etc..
In certain embodiments, pharmaceutically acceptable form is pharmaceutically acceptable salt, pharmaceutically acceptable
Salt is well known in the art.The example of pharmaceutically acceptable salt is such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, high chlorine
Acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, acetic acid, propionic acid, glycolic, pyruvic acid,
Oxalic acid, lactic acid, trifluoroacetic acid, Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..
" pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " includes any and all solvents, dispersion Jie
Matter, covering, antibacterial agent and antifungal agent, isotonic agent and absorption delaying agent etc..Pharmaceutically acceptable carrier or excipient
The pharmacological activity of disclosed compound is not destroyed, and is nothing when to be enough to deliver the dosage application of the compound of therapeutic dose
Poison.The use of the medium and reagent of pharmaceutically active substance is in the art well known.
Compared with prior art, the beneficial effects of the invention are as follows：
(1) the present invention provides a new class of indole amides class compound with anticancer activity, has widened existing anticancer
The range of compound can be used as lead compound and continue to optimize；
(2) the compounds of this invention indole ring the position 5- introducing-Cl or-Br substituent group so that compound treating cancer
It is applied widely, it can be used for treating kinds cancer.
Specific embodiment
The contents of the present invention are illustrated below by embodiment.In the present invention, following embodiment is in order to more preferable
Ground illustrates the present invention, is not for limiting the scope of the invention.
Embodiment 1
N- (2- (the chloro- 1H- indol-3-yl of 5-) ethyl) -2- hydroxy-3-methyl benzamide (compound R 9)
Step 1：4- chloroaniline (12.75g, 0.1mol) and dilute hydrochloric acid is added in 200ml round-bottomed flask, is contained with 30ml
(7.3g, 0.105mol) sodium nitrite solution is added dropwise in solution.Reaction filters out supernatant liquid in 1 hour or so and is added dropwise to
Containing in (37.8g, 0.3mol) sodium sulfite solution, 80 DEG C are reacted about 2.5 hours, then about 25ml (0.3mol) dense salt are added dropwise 70ml
Acid, 95 DEG C of reactions are placed on ambient temperature overnight for 2 hours or so, 4- chlorophenylhydxazine hydrochloride solid 15.8g are precipitated.Yield：88.3%.
Step 2：Gained (15.8g, about 0.088mol) 4- chlorobenzene in step 1 is sequentially added in 200ml round-bottomed flask
Hydrazine hydrochloride, the chloro- 1- hydroxy-butan sodium sulfonate of (22.2g, 0.106mol) 4-, 45ml ethyl alcohol, 45ml water, then with phosphoric acid hydrogen two
Sodium solution adjusts solution PH to 6-7, and 75 DEG C are condensed back 6 hours or so；Ethyl alcohol and a small amount of water are removed with Rotary Evaporators rotation, is remained
Remaining solution is first washed with methylene chloride, then adjusts PH to 8-10 with sodium carbonate liquor, then with chloroform, it is cold to be placed in 4 DEG C of refrigerators
But overnight, 5- chloramine HCl, solid 12.7g is precipitated.Yield：62.5%.
Step 3：(0.912g, 6mmol) 3- cresotinic acid is sequentially added in 50ml round-bottomed flask, (1.15g,
9mmol) EDCI (1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate), (1.215g, 9mmol) HOBT (1- hydroxyl
Base benzotriazole), 15ml acetone, stirring at normal temperature 2 hours；Add (1.27g, 5.5mmol) 5- chloramine salt obtained by step 2
Hydrochlorate, Anhydrous potassium carbonate, stirring at normal temperature about 24 hours；Column chromatography purifying, eluant, eluent are molten for the mixing of ethyl acetate and petroleum ether
Agent.Obtain 9 (yield of 1.31g compound R：It 75.8%), is brown solid, fusing point is：164-165℃.1H NMR(400MHz,
DMSO) δ 13.30 (s, 1H), 10.94 (s, 1H), 8.99 (t, J=5.6Hz, 1H), 7.67 (dd, J=5.9,2.1Hz, 1H),
7.35 (s, 1H), 7.34 (d, J=3.9Hz, 1H), 7.32-7.30 (m, 1H), 7.28 (d, J=2.3Hz, 1H), 6.96 (td, J
=9.3,2.5Hz, 1H), 6.79 (t, J=7.7Hz, 1H), 3.54 (dd, J=13.3,7.2Hz, 2H), 2.95 (t, J=
7.4Hz,2H),2.16(s,3H)。
Embodiment 2-7
Referring to the method for embodiment 1, following compound is prepared, corresponding data are as follows：
Comparative example 1-4
Referring to the method for embodiment 1, comparative example compound R 30-R33 is prepared, structure is as follows：
R30 is white solid, and fusing point is 147-149 DEG C,1H NMR(400 MHz,DMSO)δ13.30(s,1H),10.94
(s, 1H), 8.99 (t, J=5.6 Hz, 1H), 7.67 (dd, J=5.9,2.1 Hz, 1H), 7.35 (s, 1H), 7.34 (d, J=
3.9 Hz, 1H), 7.32-7.30 (m, 1H), 7.28 (d, J=2.3 Hz, 1H), 6.91 (td, J=9.3,2.5 Hz, 1H),
6.78 (t, J=7.7 Hz, 1H), 3.56 (dd, J=13.3,7.2 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.16 (s,
3H)。
R31 is brown solid, and fusing point is 144-148 DEG C,1H NMR(400 MHz,DMSO)δ12.69(s,1H),10.94
(s, 1H), 8.86 (t, J=5.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.34 (dd, J=5.1,3.6 Hz, 1H),
7.32 (d, J=2.2 Hz, 1H), 7.27 (d, J=2.2 Hz, 1H), 6.91 (td, J=9.2,2.5Hz, 1H), 6.72 (s,
1H), 6.70 (s, 1H), 3.55 (dd, J=13.3,7.2Hz, 2H), 2.94 (t, J=7.4Hz, 2H), 2.27 (s, 3H).
R32 is white solid, and fusing point is 175-180 DEG C,1H NMR(400MHz,DMSO)δ12.93(s,1H),10.94
(s, 1H), 8.97 (t, J=5.5Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.36-7.33 (m, 1H), 7.32-7.30 (m,
1H), 7.27 (d, J=2.2Hz, 1H), 6.99 (dd, J=3.7,2.0Hz, 1H), 6.96 (d, J=2.1Hz, 1H), 6.91 (td,
J=9.2,2.5Hz, 1H), 3.57 (dd, J=13.2,7.2Hz, 2H), 2.94 (t, J=7.3Hz, 2H).
R33 is white solid, and fusing point is 170-172 DEG C,1H NMR(400MHz,DMSO)δ12.61(s,1H),10.95
(s, 1H), 8.99 (t, J=5.4Hz, 1H), 7.93 (d, J=2.6Hz, 1H), 7.43 (dd, J=8.8,2.6Hz, 1H), 7.34
(t, J=4.3Hz, 1H), 7.32 (d, J=3.6Hz, 1H), 7.28 (d, J=2.2Hz, 1H), 6.96-6.92 (m, 1H), 6.90
(dd, J=9.1,2.4Hz, 1H), 3.57 (dd, J=13.2,7.1Hz, 2H), 2.94 (t, J=7.3Hz, 2H).
8 external activity test of embodiment
Cell strain selection MGC-803 (gastric carcinoma cells), HepG2 (human liver cancer cell), MCF-7 (human breast cancer cell),
A549 (human lung carcinoma cell) and HELA (human cervical carcinoma cell).
Culture solution is that DMEM+15%NBS+ is dual anti-
Sample liquid is prepared：After DMSO (Merck) dissolution, concentration is 33333.33 μm of ol/L
1. 96 orifice plates are added in cell suspension by plate in, and every 100 μ l of hole (cell content in every hole is about 8000/hole) is set
It is cultivated for 24 hours in 37 DEG C, 5%CO2 incubator；
2. dosing prepares sample liquid gradient concentration (256,128,64,32,16,8,4,2 μm of ol/L) with culture medium, then discards
Original culture medium on 96 orifice plates, is added the culture medium of drug various concentration, every 100 μ L of hole, and each concentration does 5 secondary orifices.Remaining
Hole is compareed with the culture medium of the DMSO containing 3 ‰, sets 37 DEG C, 5% incubator cultivation 48h；
96 orifice plates are taken out in the test of 3.MTT method, and 10 μ LMTT (3- (4,5- dimethylthiazole -2- are added in every hole under the conditions of being protected from light
Base) -2,5- diphenyltetrazoliumbromide father-in-law's bromide, 5mg/mL) solution, it places into and places 4h in incubator；Culture is discarded after 4 hours
150 μ LDMSO dissolution concussion is added in liquid, every hole, surveys 490nm OD value, calculation of half inhibitory concentration with the full-automatic microplate reader of MK-2
IC50。
Test result is as follows：
It can be seen by upper table, after introducing Cl or Br in the position 5- of indole ring, compound inhibits the range of cancer cell wider,
Specifically, the compound of the present invention is able to suppress gastric cancer, liver cancer, breast cancer, lung carcinoma cell and cervical carcinoma.With comparative example compound
R30-R33 (indole ring 5- are F) is compared, although the position 5- of indole ring is equally halogen, the application compound obviously has
There is the effect for preferably inhibiting cancer, there is unexpected technical effect and significant progress.
Claims (10)
1. a kind of compound of Formula I or its pharmaceutically acceptable salt, have the following structure：
Wherein：R' is selected from Cl or Br；
R is each independently selected from halogen ,-NO2 ,-CN, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 halogenated alkyl；N be selected from 1,
2,3 or 4.
2. compound of formula I as described in claim 1 or its pharmaceutically acceptable salt, R are each independently selected from halogen, C1-
C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl.
3. compound of formula I as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, R be each independently selected from fluorine, chlorine,
Bromine, methyl, ethyl, methoxyl group, ethyoxyl, trifluoromethyl；N is selected from 1 or 2.
4. compound of formula I as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, R be each independently selected from methyl,
Chlorine, bromine；N is 1.
5. compound according to any one of claims 1-4 is selected from following compound：
6. a kind of method for preparing compound of formula I as described in claim 1, reaction route are as follows：
Wherein, the definition of R', R and n are as described in claim 1；
Specific reaction step is as follows：
Step 1：4- substituted aniline and hydrochloric acid are added in the reaction vessel, sodium nitrite solution is added drop-wise in solution.Reaction 1
Hour filter, filtrate added drop-wise into sodium sulfite solution, 80 DEG C reaction 1-3 hours, then concentrated hydrochloric acid is added dropwise, 95 DEG C of reaction 1-3 are small
When be placed on ambient temperature overnight, 4- substituted phenylhydrazines HCl, solid is precipitated；
Step 2：Sequentially add 4- substituted phenylhydrazines hydrochloride in the reaction vessel, the chloro- 1- hydroxy-butan sodium sulfonate of 4-, ethyl alcohol,
Water, then adjust solution PH to 6-7,75 DEG C reaction 5-7 hours；Vacuum distillation removes ethyl alcohol and part water, surplus solution first use two
Chloromethanes washing, then adjusts PH to 8-10, then uses chloroform, is placed in 4 DEG C of refrigerator cool overnights, and 5- substitution tryptamines hydrochloric acid is precipitated
Salt solid；
Step 3：Salicyclic acid derivatives are sequentially added in the reaction vessel, and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne two is sub-
Amine hydrochlorate, I-hydroxybenzotriazole, acetone, stirring at normal temperature 1-3 hours；It adds 5- obtained by step 2 and replaces tryptamines hydrochloric acid
Salt, Anhydrous potassium carbonate, stirring at normal temperature to fully reacting；Column chromatography purifying, obtains compound shown in Formulas I.
7. preparation method as claimed in claim 6, it is characterised in that：
The molar ratio of the 4- substituted aniline of step 1, sodium nitrite and sodium sulfite is 1:1-1.5:2-4.5 preferably 1:
1.05:3；
The molar ratio of the chloro- 1- hydroxy-butan sodium sulfonate of the 4- substituted phenylhydrazines hydrochloride and 4- of step 2 is 1:1-1.5, preferably
1:1-1.2；
Salicyclic acid derivatives, 1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxy benzo of step 3
Triazole and 5- replace the molar ratio of tryptamine hydrochloride to be 1:1-2:1-2:0.5-1.5；Preferably 1:1-1.5:1-1.5:0.8-
1.2。
8. a kind of pharmaceutical composition, it includes compound shown in the Formulas I of any one of claim 1-5 or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable carrier, excipient.
9. compound of any of claims 1-5 or pharmaceutical composition according to any one of claims 8 are in medicine preparation
Purposes, it is characterised in that the drug can be used for treating gastric cancer, liver cancer, breast cancer, lung carcinoma cell and cervical carcinoma.
10. medicinal as claimed in claim 9, which is characterized in that the drug alternative inhibition gastric carcinoma cells MGC-803,
Human liver cancer cell HepG2, human breast cancer cell line Bcap-37, human lung cancer cell A549 and human cervical carcinoma cell HELA.
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| CN108530337A (en) * | 2018-06-25 | 2018-09-14 | 南华大学 | A kind of alternative indole amides class compound for inhibiting stomach cancer cell |
| CN108558732A (en) * | 2018-06-25 | 2018-09-21 | 南华大学 | A kind of indole amides class compound of alternative treatment gastric cancer and cervical carcinoma |
| CN108623511A (en) * | 2018-06-25 | 2018-10-09 | 南华大学 | A kind of indole amides class compound can be used for treating cancer |
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| CN108530337A (en) * | 2018-06-25 | 2018-09-14 | 南华大学 | A kind of alternative indole amides class compound for inhibiting stomach cancer cell |
| CN108558732A (en) * | 2018-06-25 | 2018-09-21 | 南华大学 | A kind of indole amides class compound of alternative treatment gastric cancer and cervical carcinoma |
| CN108623511A (en) * | 2018-06-25 | 2018-10-09 | 南华大学 | A kind of indole amides class compound can be used for treating cancer |
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