CN102850337A - Multi-azole linked spirorenone compound and preparation method and application thereof - Google Patents
Multi-azole linked spirorenone compound and preparation method and application thereof Download PDFInfo
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- CN102850337A CN102850337A CN2011101807917A CN201110180791A CN102850337A CN 102850337 A CN102850337 A CN 102850337A CN 2011101807917 A CN2011101807917 A CN 2011101807917A CN 201110180791 A CN201110180791 A CN 201110180791A CN 102850337 A CN102850337 A CN 102850337A
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- Prior art keywords
- phenyl
- triazole
- reaction
- amino
- preparation
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- -1 spirorenone compound Chemical class 0.000 title claims description 61
- 229950004131 spirorenone Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 22
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 11
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical class COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- JSIAIROWMJGMQZ-UHFFFAOYSA-N 2h-triazol-4-amine Chemical group NC1=CNN=N1 JSIAIROWMJGMQZ-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- VWSJWBOJVICIGJ-UHFFFAOYSA-N 2,2,2-trifluoro-1-(2-iodophenyl)ethanone Chemical compound FC(F)(F)C(=O)C1=CC=CC=C1I VWSJWBOJVICIGJ-UHFFFAOYSA-N 0.000 claims description 2
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- 229910010082 LiAlH Inorganic materials 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims 2
- 239000007800 oxidant agent Substances 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- SNIVHZRVLQLTLY-UHFFFAOYSA-N (2-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1I SNIVHZRVLQLTLY-UHFFFAOYSA-N 0.000 claims 1
- IHBVNSPHKMCPST-UHFFFAOYSA-N 3-bromopropanoyl chloride Chemical compound ClC(=O)CCBr IHBVNSPHKMCPST-UHFFFAOYSA-N 0.000 claims 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims 1
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical class COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 claims 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 150000002429 hydrazines Chemical class 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims 1
- 229940031826 phenolate Drugs 0.000 claims 1
- LHDMBYWDIBGTAR-UHFFFAOYSA-N phenyl hypoiodite Chemical compound IOC1=CC=CC=C1 LHDMBYWDIBGTAR-UHFFFAOYSA-N 0.000 claims 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 239000004215 Carbon black (E152) Chemical group 0.000 abstract 1
- 229930195733 hydrocarbon Chemical group 0.000 abstract 1
- 150000002430 hydrocarbons Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical group 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 150000001408 amides Chemical class 0.000 description 38
- 238000000746 purification Methods 0.000 description 38
- 238000000926 separation method Methods 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 38
- 229910002027 silica gel Inorganic materials 0.000 description 38
- 238000003756 stirring Methods 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 20
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 18
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 10
- 229960003280 cupric chloride Drugs 0.000 description 10
- 238000003810 ethyl acetate extraction Methods 0.000 description 10
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000010025 steaming Methods 0.000 description 8
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 201000008275 breast carcinoma Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 4
- 229940067157 phenylhydrazine Drugs 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- 150000003852 triazoles Chemical group 0.000 description 4
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- 230000015572 biosynthetic process Effects 0.000 description 3
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- 230000031700 light absorption Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 2
- HEFDFMDWXOYXSZ-UHFFFAOYSA-N 3-ethyl-1-phenyl-2H-triazol-4-amine Chemical compound CCN1C(=CN(N1)C2=CC=CC=C2)N HEFDFMDWXOYXSZ-UHFFFAOYSA-N 0.000 description 2
- WPABWPFYHBRUSZ-UHFFFAOYSA-N 3-ethyl-4-phenyl-2H-triazol-1-amine Chemical compound CCN1C(=CN(N1)N)C2=CC=CC=C2 WPABWPFYHBRUSZ-UHFFFAOYSA-N 0.000 description 2
- KNHQIDVZZFTVNH-UHFFFAOYSA-N 3-methyl-1-phenyl-2H-triazol-4-amine Chemical compound CN1C(=CN(N1)C2=CC=CC=C2)N KNHQIDVZZFTVNH-UHFFFAOYSA-N 0.000 description 2
- HNZQFKCCAMKTQT-UHFFFAOYSA-N 3-methyl-4-phenyl-2H-triazol-1-amine Chemical compound CN1C(=CN(N1)N)C2=CC=CC=C2 HNZQFKCCAMKTQT-UHFFFAOYSA-N 0.000 description 2
- ISFJVACNYFGLBS-UHFFFAOYSA-N 5-(4-nitrophenyl)-2-phenyl-1,2,4-triazol-3-amine Chemical compound C1=CC=C(C=C1)N2C(=NC(=N2)C3=CC=C(C=C3)[N+](=O)[O-])N ISFJVACNYFGLBS-UHFFFAOYSA-N 0.000 description 2
- 0 CCC(C(C)(C(*)=C(*C)C1=O)C(I)=C1N)*(CC)=C Chemical compound CCC(C(C)(C(*)=C(*C)C1=O)C(I)=C1N)*(CC)=C 0.000 description 2
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 1
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- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
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- 238000002835 absorbance Methods 0.000 description 1
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- 230000036592 analgesia Effects 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
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- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FBSMERQALIEGJT-UHFFFAOYSA-N chlorpromazine hydrochloride Chemical compound [H+].[Cl-].C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 FBSMERQALIEGJT-UHFFFAOYSA-N 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
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- 150000002463 imidates Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
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- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Plural Heterocyclic Compounds (AREA)
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Abstract
多氮唑联螺烯酮类化合物及其制备方法和用途。多氮唑联螺烯酮类化合物的结构如式(I)所示，式中各取代基R可以同时或分别为氢、烃基、烃氧基、卤元素等，Y为-O-、-S-、-NH-，n＝1或2。实验显示，该多氮唑联螺烯酮类化合物具有显著的抗肿瘤活性，具有作为抗肿瘤药物的应用价值。 Polyazole bispirenone compound and its preparation method and application. The structure of the polyazazole bispirinone compound is shown in formula (I), in which each substituent R can be hydrogen, hydrocarbon group, hydrocarbon oxygen group, halogen element, etc. at the same time or respectively, and Y is -O-, -S -, -NH-, n=1 or 2. Experiments show that the polyazazole bispirinone compound has significant antitumor activity and has application value as an antitumor drug.
Description
Technical field
The application relates to a kind of many nitrogen azoles connection helicene ketones derivant and preparation method thereof and as the application of antitumor drug.
Background technology
Antitumor drug is one of Field of Drug Discovery ten large medicines of greatest concern at present.Especially how the research of antitumor drug obtain the research based on the drug-fast new type antineoplastic medicine of not tool of different structure activity relationships, different action target spots, is significant.
Research finds, many nitrogen azole compounds is often to have a multiple bioactive structural unit, at the aspect such as medicine, agricultural chemicals even often become crucial active structure unit in its molecule, and particularly 1,2, the 4-triazole class compounds is again a wherein important class formation.Such as in the structure of the medicines such as some antibacteriums, antimycotic, antiviral, tuberculosis, anticancer, antidepressant, anticonvulsion, anti-inflammatory, analgesia, 1,2,4-triazole has quite widely biological activity.Many 1,2, the 4-triazole derivative in the medicines structures such as antitumour drug vorozole (Vorozole), letrozole (Letrozole), arna department azoles (Anastrozole), all has 1,2,4-triazole structure unit as clinical medicine.
Existing 3-phenylquinazoline ketone, benzoxazole [2.3-b] quinazolinone, benzimidazole thiophanate nitrogen azoles [2.3-b] quinazolinone, benzo [b] naphtho-[2.3-d] furans-6 of studies show that, 11-diketone, 5H-benzo [b] naphtho-[2.3-d] pyrroles-6, the screening of the compound external activities such as 11-diketone shows to have good anti-tumor activity.And the common feature of these compounds is all to comprise quinonoid structure unit, nitrogen-atoms and tricyclic structure.
Summary of the invention
For above-mentioned situation, the present invention at first provides a kind of new many nitrogen azoles connection helicene ketone heterogeneous ring compound, and its preparation method further is provided, and this compound is in the application of anti-tumor aspect.
Many nitrogen azoles connection helicene ketone compounds of the present invention, structure is suc as formula shown in (I):
R in the formula (I)
1, R
2, R
3And R
4Can be H at the same time or separately, C
1-3-alkyl, C
1-3--oxyl or halogen element; R
5, R
6Can be H at the same time or separately, C
1-3-alkyl, halogen element, phenyl or by methyl, methoxyl group, Cl, Br, amino, nitro is with 2-, 3-, the single of 4-position replaces, or such as 2-, the 4-position, 2-, the 5-position, 3-, the 5-position, 2-, dibasic phenyl of the non-ortho position forms such as 6-position, naphthyl or by methyl, methoxyl group, halogen element, amino, the α of nitro-, β-list replaces or dibasic naphthyl, thiophene 2-base, quinoline 6-base, or by methyl, methoxyl group, halogen element, amino, nitro is with 3-, 4-, the mono-substituted thiophene 2-base in 5-position, or by methyl, methoxyl group, halogen element, amino, nitro is with 2-, 3-, 4-, 5-, 7-, 8-is mono-substituted quinoline 6-base; R
7Can be H or C
1-3-alkyl, and because the triazole ring at its place can have different isomeric forms because of two key transpositions, so R
6And R
7In each isomer of triazole ring, be not simultaneous; Y can for-O-,-S-,-NH-; N=1 or 2.
In above-mentioned formula (I) compound structure, said halogen element in each substituting group, all with the most frequently used and stable high Cl or Br as preferred.
In addition, in above-mentioned formula (I) compound structure, R
5, R
6Be preferably and be at the same time or separately H, C
1-3-alkyl, Cl, Br, phenyl, thiophene 2-base or quinoline 6-base.
The basic preparation method of many nitrogen of above-mentioned formula (I) azoles connection helicene ketone compounds can be undertaken by following mode.R in the reaction formula
1, R
2, R
3, R
4, R
5, R
6, R
7, Y and n be identical with each corresponding substituting group in above-mentioned formula (I) compound:
1 ': 5-amino-triazole ring derivative raw material (II) and halogen acyl halide are reacted in the organic basic environment, obtain corresponding intermediate (III);
2 ': with the intermediate (III) in upper step and the reaction of formula (V) compound, obtain corresponding intermediate (IV), wherein, the YA in formula (V) compound is-ONa ,-SNa or-NH
2
3 ': intermediate (IV) after cyclization under oxygenant and the catalyzer, is obtained corresponding target product (I).Said oxygenant comprises iodobenzene acetic ester, trifluoroacetyl iodobenzene, iodosobenzene, lead tetra-acetate or Manganse Dioxide; Said catalyzer comprises at least a in cupric chloride, cuprous iodide, cupric bromide, trifluoromethayl sulfonic acid copper or the acetic acid rhodium.Reaction medium can select to comprise chloroform, DMF (DMF), tetrahydrofuran (THF) (THF), 1, at least a in the multi-solvents such as 2-ethylene dichloride, toluene, acetone or methylene dichloride.Experiment shows that this step reaction can be carried out and be finished smoothly under-15 ℃～100 ℃ wide temperature condition.Such as needs, after this step, reaction was finished, can also further reaction soln be carried out separation and purification with common methods such as polymeric amide or silica gel, can obtain formula (I) the structure product of purifying.
The reaction that above-mentioned the 1st ' step prepares corresponding intermediate (III) by 5-amino-triazole ring derivative raw material (II) and halogen acyl halide, generally comprising methylene dichloride, chloroform, 1, all allow in the mediums such as 2-ethylene dichloride, tetracol phenixin, DMF (DMF) or toluene.Said organic basic environment, can select normally used such as quadrol, N, formed alkaline condition under at least a existence in N-dimethyl-ethylenediamine, 1.8-diazabicylo [5.4.0] 11 rare-7 (DBU), NaH, potassium tert.-butoxide or the triethylamine.Said halogen acyl halide can be selected any as in chloroacetyl chloride, bromoacetyl chloride, chlorpromazine chloride, the bromo propionyl chloro etc.
Further concrete preparation method and process to above-mentioned intermediate (III), can be with reference to such as Banks, M.B.et.:Enantiospecific preparation of[(2,6)-endo]-5-aza-1,10,10-trimethyl-3-oxatricyclo[5.2.1.02,6] decan-4-one by a nitrene-mediated route from[(1)-endo]-(Tetrahedron 1992 for (-)-borneol and its utility as a chiralauxiliary in some asymmetric transformations, 48, (37), 7979-8006) etc. the mode of existing bibliographical information is carried out.
The reaction that above-mentioned the 2nd ' step prepares intermediate (IV) by said intermediate (III) and formula (V) compound, usually can be chosen in the multiple reaction medium that comprises dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), acetone, chloroform, methylene dichloride or DMF (DMF) etc. and carry out.This step reaction for example under the condition of room temperature～100 ℃, can successfully be carried out and be finished in very wide temperature range.Such as needs, after reaction is finished, can also be further reaction soln be washed with water, after the ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, can obtain intermediate (IV) product of purifying.This step preparation intermediate (IV) more specifically operates, all right reference is such as Palazzo, G.et.:Synthesis and Pharmacological Properties of 1-Substituted 3-Dimethylaminoalkoxy-1H-indazoles (Journal Of Medicinal Chemistry 1966,9, (1), the content of bibliographical information such as 38-41).
In this step reaction said for the YA of formula (V) compound structure of intermediate (III) reaction, can for-ONa ,-SNa, when being corresponding phenol sodium or thiophenol sodium structure, its preparation can be adopted the method for knowing, corresponding p-phenol derivatives or p-thiophenol derivative are dissolved in tetrahydrofuran (THF) (THF), N, in dinethylformamide (DMF), toluene, ethyl acetate, methylene dichloride or the chloroform, with NaH, LiAlH
4, NaBH
4, NaOH or KOH prepare.
In above-mentioned preparation method, said 5-amino-triazole ring derivative raw material (II) prepares by following mode:
1 ': formaldehyde derivatives and cyanamide are added in the methyl alcohol, slowly add successively the reaction of sodium tert-butoxide and N-bromo-succinimide and obtain corresponding cyanogen imines ester intermediate.Concrete preparation process can be with reference to such as Yin, and (OrganicLetters 2009,11, (23), the content of bibliographical information such as 5482-5485) for P.et.:Highly efficientcyanoimidation of aldehydes.
2 ': with cyanogen imines ester intermediate and the hydrazine in upper step, fully reaction namely obtains said 5-amino-triazole derivative raw material (II) in methyl alcohol, ethanol, DMF, toluene or DMSO reaction medium.Concrete preparation method can be with reference to comprising such as Barluenga, J.et.:Developments in Pd Catalysis:Synthesis of 1H-1,2,3-Triazoles from SodiumAzide and Alkenyl Bromides (Angewandte Chemie International Edition 2006,45, (41), 6893-6896), Lipshutz, B.H.et.:Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry (Angewandte Chemie International Edition 2006,45, (48), 8235-8238), and Zarguil, A.et.:Easy access to triazoles, triazolopyrimidines, benzimidazoles and imidazoles from imidates (Tetrahedron Letters 2008,49, (41), the content of each bibliographical information such as 5883-5886).
The present invention can form triazole connection helicene ketone derivatives in high regioselectivity ground, and preparation process is simple by the shift reaction of above-mentioned transition metal-catalyzed nitrene, and reaction conditions is gentle, and adaptability is wide.
Experimental result shows that many nitrogen azoles connection helicene ketone compounds of the above-mentioned formula of the present invention (I) structure all demonstrates significant anti-tumor activity to multiple cancer cells, has the using value that can be used as antitumor drug.
Embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away from the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
Embodiment 1
4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-dione compounds (LHDYX-1)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying, namely obtain corresponding 1,3-phenylbenzene-5-amino-triazole.Yield 65-85%.
3) with 1,3-phenylbenzene-5-amino-triazole adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) ethanamide.Yield 70-85%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-95%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-and 1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 85-99%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
4.56(s，2H)，6.14(d，J＝10.0Hz，2H)，6.56(d，J＝10.0Hz，2H)，7.42-7.45(m，3H)，7.50-7.56(m，5H)，8.05-8.07(m，2H)
13C-NMR(CDCl
3，100MHz)δ(ppm)：
66.0，88.1，124.8，126.4，128.6，129.6，129.8，129.9，129.9，131.1，136.3，141.7，142.2，161.8，170.3，183.5
HRMS(ESI)m/z(％)for C
22H
17N
4O
3(M+H)：
Calcd.385.1301Found.385.1293。The structure of product is:
Embodiment 2
4-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-2)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, methyl hydrazine are added in the methyl alcohol, 20 ℃～50 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-methyl-3-phenyl-5-amino-triazole.Yield 50-65%.
3) 1-methyl-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 80-95%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.88(s，3H)，4.64(s，2H)，6.35(d，J＝10.0Hz，2H)，6.90(d，J＝10.0Hz，2H)，7.39(br，3H)，7.90-7.91(m，2H)
13C-NMR(CDCl
3，100MHz)δ(ppm)：
36.1，65.8，88.0，125.9，128.5，139.5，130.1，131.4，141.7，143.0，160.6，168.9，183.6HRMS(ESI)m/z(％)for C
17H
14N
4O
3Na(M+Na)：
Calcd.345.0964Found.345.0988。The structure of product is:
Embodiment 3
4-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-3)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, methyl hydrazine are added in the methyl alcohol, 50 ℃～90 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-methyl-5-phenyl-3-amino-triazole.Yield 35-50%.
3) 1-methyl-5-phenyl-3-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl) 2-(4-anisole oxygen) ethanamide.Yield 75-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 70-80%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.96(s，3H)，4.61(s，2H)，6.31(d，J＝10.0Hz，2H)，6.90(d，J＝10.0Hz，2H)，7.49-7.50(m，3H)，7.57-7.59(m，2H)
HRMS(ESI)m/z(％)for C
17H
14N
4O
3Na(M+Na)：
Calcd.345.0964.Found.345.0965。The structure of product is:
Embodiment 4
4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-6-methoxyl group-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-4)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 65-85%.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying, namely obtain corresponding 1,3-phenylbenzene-5-amino-triazole.Yield 65-80%.
3) with 1,3-phenylbenzene-5-amino-triazole adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) hydroxyanisole is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 75-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-and 6-methoxyl group-1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 80-95%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.69(s，3H)，4.51(d，J＝14.4Hz，1H)，4.70(d，J＝14.4Hz，1H)，5.47(d，J＝1.6Hz，1H)，
6.10(dd，J＝10.0Hz，1.6Hz，1H)，6.30(d，J＝10Hz，1H)，7.41-7.44(m，3H)，
7.51-7.55(m，5H)，8.02-8.05(m，2H)。The structure of product is:
Embodiment 5
4-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively paranitrobenzaldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-amine.
3) with 3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-amine adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours are carried out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
4.58(s，2H)，6.16(d，J＝10.0Hz，2H)，6.57(d，J＝10.0Hz，2H)，7.51-7.52(m，2H)，
7.57-7.59(m，3H)，8.24(d，J＝8.8Hz，2H)，8.30(d，J＝8.8Hz，2H)。The structure of product is:
Embodiment 6
4-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-80%.
2) cyanogen imines ester, ethyl hydrazine are added in the methyl alcohol, 50 ℃～90 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-ethyl-5-phenyl-3-amino-triazole.Yield 35-45%.
3) 1-ethyl-5-phenyl-3-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-80%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 65-75%.The structure of product is:
Embodiment 7
4-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, ethyl hydrazine are added in the methyl alcohol, 20 ℃～50 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-ethyl-3-phenyl-5-amino-triazole.Yield 50-65%.
3) 1-ethyl-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-80%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 80-95%.The structure of product is:
Embodiment 8
4-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) with cyanogen imines ester, the methoxyl group phenylhydrazine is added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole.Yield 65-75%.
3) 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-90%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 70-85%.The structure of product is:
Embodiment 9
4-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, 2,4 dichloro benzene hydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole.Yield 60-75%.
3) with 1-(2, the 4-dichlorophenyl)-3-phenyl-5-amino-triazole adding is new steams in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-90%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1-(2,4 dichloro benzene base) 3-phenyl-1H-1,2,4-triazole-5-yl)-and 1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 65-80%.The structure of product is:
Embodiment 10
The CCK-8 method is measured tumor cell in vitro and is suppressed experiment
1. experiment material
BALB/c nu/nu nude mouse [animal conformity certification SCXK (river) 09-2006] is provided by West China Center of Medical Sciences of Sichuan University animal center, and is male, SPF level, 6～8 ages in week.
2. experimental technique
1) cancer cells is cultivated
Cancer cells X1 and X2 grow in the RPMI-1640 substratum that contains 10% deactivation calf serum, in 37 ℃, 5%CO
2, cultivate under the saturated humidity condition.Went down to posterity with 0.25% trysinization in every 2-3 days.
2) CCK-8 experiment
Skin carcinoma A431 cell, colorectal carcinoma HCT116 cell, cancer of the stomach MKN45 cell, ovarian cancer SKOV-3 cell that the phase of taking the logarithm grows, be inoculated in 96 well culture plates by 5 * 104/mL, 200 μ L are inoculated in every hole, behind the DMEM high glycoform nutrient solution cultivation 24h that contains 10% calf serum, change nutrient solution, give respectively following processing to above-mentioned cell: 1) control group: every hole adds DMEM high glycoform nutrient solution 200 μ L, establishes altogether 6 multiple holes; 2) administration group: the experimental concentration scope is 50 μ M, 5 μ M, 2.5 μ M, 0.5 μ M, 0.05 μ M and 0.005 μ M, each concentration is established 6 multiple holes, the every hole of 24h, 48h and 72h adds 20 μ L CCK-8 solution (being purchased from green skies biotechnology research institute) after the administration, and 37 ℃ are continued to cultivate 3h.On microplate reader, choose the 450nm wavelength and measure every hole light absorption value.Each time point and each concentration all repeat to test three times.
Inhibiting rate=(1-administration group light absorption value/control group light absorption value) * 100%.
Experimental result is as shown in table 1.
Table 1LHDYX-1 cell experiment result (IC
50)
Table 1 result shows, the compound L HDYX-1 of the embodiment of the invention 1 has inhibition in various degree active to cancer cells, and the restraining effect of cancer cells is higher than has been widely used antitumor drug Zorubicin (Doxorubicin) at present clinical.
Embodiment 11
The CCK-8 method is measured tumor cell in vitro and is suppressed experiment
Experiment material and method
Take human breast carcinoma MDA-MB-231 cell as experimental cell.Compound D YX-2, DYX-5, DYX-6, DYX-7 is mixed with 5mM solution after dissolving with analytical pure dimethyl sulfoxide (DMSO) (DMSO), add the DMEM high glycoform substratum that contains 10% calf serum and be diluted to 500 μ M, filtration sterilization, redilution becomes the serial solution of six concentration.Get 96 well culture plates, every hole is inoculated 200 μ L and is contained 10000 cells.Continue to cultivate 24 hours, suck old substratum, dosing, Experimental agents is respectively LHDYX-1, LHDYX-2, LHDYX-3, LHDYX-4.Every kind of medicine is established 6 parallel holes, and the blank group does not add medicine, also establishes 6 parallel holes.Final administration concentration is 50 μ M, 5 μ M, 2.5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M.Continue to cultivate after 24 hours, 48 hours, 72 hours, every hole adds 20 μ LCCK-8 solution, continues to cultivate after 3.5 hours again, and with the absorbance (OD value) of microplate reader measurement enchylema, the measurement wavelength is 450nM, calculates inhibitory rate of cell growth.Every group of experiment triplicate.The inhibiting rate calculation formula:
Inhibiting rate %=(1-administration group OD value/cell control group OD value) * 100%
Whether experimental result is shown in table 2～table 4.
Table 2LHDYX-1, LHDYX-3 is to the IC50 value of human breast carcinoma MDA-MB-231 cell
| 24h | 48h | 72h | |
| LHDYX-1 | 26.03uM | 2.88uM | 0.34uM |
| LHDYX-3 | 2.96uM | 1.46uM |
Table 3LHDYX-2 is to the inhibiting rate of human breast carcinoma MDA-MB-231 cell
| 50μM | 5μM | 0.5μM | 0.05μM | |
| 24h | 100％ | 39.92％ | 17.12％ | 19.11％ |
| 48h | 93.49％ | 94.70％ | 76.38％ | 19.02％ |
| 72h | 96.39％ | 96.25％ | 95.27％ | 39.44％ |
Table 4LHDYX-4 is to the inhibiting rate of human breast carcinoma MDA-MB-231 cell
| 50μM | 5μM | |
| 24h | 42.02％ | - |
| 48h | 98.39％ | 4.30％ |
| 72h | 100％ | 17.23％ |
Annotate: "-" expression unrestraint effect.
The experimental result of table 2～table 4 shows that compound of the present invention is active to the inhibition that human breast carcinoma MDA-MB-231 cell all has in various degree.Wherein compound L HDYX-1 reaches 0.34uM in 72 hours IC50 values to the MDA-MB-231 cell; Compound L HDYX-2 concentration 5 μ M, inhibiting rate reached 96.25% in 72 hours; Compound L HDYX-4 concentration 50 μ M, inhibiting rate reached 100% in 72 hours.
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