CN106146487A - 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 - Google Patents
吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN106146487A CN106146487A CN201510204696.4A CN201510204696A CN106146487A CN 106146487 A CN106146487 A CN 106146487A CN 201510204696 A CN201510204696 A CN 201510204696A CN 106146487 A CN106146487 A CN 106146487A
- Authority
- CN
- China
- Prior art keywords
- oxadiazol
- ethyl
- group
- ethyl ester
- pyridinemethylcarbamodithioate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 alkyl esters compound Chemical class 0.000 title claims description 122
- 238000002360 preparation method Methods 0.000 claims abstract description 82
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 239000002994 raw material Substances 0.000 claims description 20
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 125000005605 benzo group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 4
- 125000003441 thioacyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 3
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000006085 pyrrolopyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 132
- 239000007787 solid Substances 0.000 description 58
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- 238000002844 melting Methods 0.000 description 31
- 230000008018 melting Effects 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000007429 general method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZMYPIWFZVPAPMI-UHFFFAOYSA-N 2-(2-chloroethyl)-5-phenyl-1,3,4-oxadiazole Chemical compound O1C(CCCl)=NN=C1C1=CC=CC=C1 ZMYPIWFZVPAPMI-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LQLLMANMSANOMV-UHFFFAOYSA-N 2-(2-bromoethyl)-1,3-benzothiazole Chemical compound BrCCC=1SC2=C(N=1)C=CC=C2 LQLLMANMSANOMV-UHFFFAOYSA-N 0.000 description 3
- ZASRXDBNOYEUEI-UHFFFAOYSA-N 2-(2-bromoethyl)benzotriazole Chemical compound C1=CC=CC2=NN(CCBr)N=C21 ZASRXDBNOYEUEI-UHFFFAOYSA-N 0.000 description 3
- IUORGRIVAYGYGM-UHFFFAOYSA-N 5-(2-bromoethyl)-2h-tetrazole Chemical compound BrCCC=1N=NNN=1 IUORGRIVAYGYGM-UHFFFAOYSA-N 0.000 description 3
- MHULESLKHQPIIX-UHFFFAOYSA-N 5-(2-chloroethyl)-3-phenyl-1,2,4-oxadiazole Chemical compound O1C(CCCl)=NC(C=2C=CC=CC=2)=N1 MHULESLKHQPIIX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CYZNULBBTVATTF-UHFFFAOYSA-N BrCCC=1OC2=C(N=1)C=CC=C2 Chemical compound BrCCC=1OC2=C(N=1)C=CC=C2 CYZNULBBTVATTF-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- DLQUPFQENKHKLJ-UHFFFAOYSA-N 2-(2-bromoethyl)-5-phenyl-1,3,4-oxadiazole Chemical compound BrCCC=1OC(=NN=1)C1=CC=CC=C1 DLQUPFQENKHKLJ-UHFFFAOYSA-N 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- PYNYHMRMZOGVML-UHFFFAOYSA-N 2-bromopropanenitrile Chemical compound CC(Br)C#N PYNYHMRMZOGVML-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- NAHHNSMHYCLMON-UHFFFAOYSA-N 2-pyridin-3-ylethanamine Chemical compound NCCC1=CC=CN=C1 NAHHNSMHYCLMON-UHFFFAOYSA-N 0.000 description 2
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 2
- PKBGHORNUFQAAW-UHFFFAOYSA-N 4-chlorobenzohydrazide Chemical compound NNC(=O)C1=CC=C(Cl)C=C1 PKBGHORNUFQAAW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CCC[C@@]1[C@@](C)(C[C@@](C)*C2CC2)CC(C)(C)C1 Chemical compound CCC[C@@]1[C@@](C)(C[C@@](C)*C2CC2)CC(C)(C)C1 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- OANQELUUJGCUOQ-UHFFFAOYSA-N hexaphenylene Chemical group C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 OANQELUUJGCUOQ-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- SJZLOWYUGKIWAK-UHFFFAOYSA-N n-(2-hydroxyethyl)pyridine-3-carboxamide Chemical compound OCCNC(=O)C1=CC=CN=C1 SJZLOWYUGKIWAK-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 2
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical compound OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ITKBAOSPYUIRMP-UHFFFAOYSA-N (2-methoxypyridin-3-yl)methanamine Chemical compound COC1=NC=CC=C1CN ITKBAOSPYUIRMP-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZXKPFIRPUUAAPQ-UHFFFAOYSA-N 1-benzothiophene-2-carbohydrazide Chemical compound C1=CC=C2SC(C(=O)NN)=CC2=C1 ZXKPFIRPUUAAPQ-UHFFFAOYSA-N 0.000 description 1
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- YJCCKQQVXNNAAR-UHFFFAOYSA-N 2-fluorobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1F YJCCKQQVXNNAAR-UHFFFAOYSA-N 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- CQZIEDXCLQOOEH-UHFFFAOYSA-N 3-bromopropanenitrile Chemical compound BrCCC#N CQZIEDXCLQOOEH-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- REKQLYUAUXYJSZ-UHFFFAOYSA-N 4-methoxybenzohydrazide Chemical compound COC1=CC=C(C(=O)NN)C=C1 REKQLYUAUXYJSZ-UHFFFAOYSA-N 0.000 description 1
- FKZXYJYTUSGIQE-UHFFFAOYSA-N 4-nitrobenzohydrazide Chemical compound NNC(=O)C1=CC=C([N+]([O-])=O)C=C1 FKZXYJYTUSGIQE-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- MKVLYUIHTXXSHQ-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carbohydrazide Chemical compound CC1=CC(C(=O)NN)=NO1 MKVLYUIHTXXSHQ-UHFFFAOYSA-N 0.000 description 1
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 1
- BIECNFYNFQQRRP-UHFFFAOYSA-N 6-chloropyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=C(Cl)N=C1 BIECNFYNFQQRRP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- COAXWQGZPUFCJR-UHFFFAOYSA-N CCCCCCCC[O] Chemical compound CCCCCCCC[O] COAXWQGZPUFCJR-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010061825 Duodenal neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical class CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Nc1ccccc1 Chemical compound Nc1ccccc1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- BBEAQIROQSPTKN-UHFFFAOYSA-N antipyrene Natural products C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical compound O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- MXOQNVMDKHLYCZ-UHFFFAOYSA-N benzamidoxime Chemical compound ON=C(N)C1=CC=CC=C1 MXOQNVMDKHLYCZ-UHFFFAOYSA-N 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 201000000312 duodenum cancer Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OCCIGHIQVMLYBZ-UHFFFAOYSA-N ethyl 5-methyl-1,2-oxazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(C)ON=1 OCCIGHIQVMLYBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- SKTSVWWOAIAIKI-UHFFFAOYSA-N furan-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CO1 SKTSVWWOAIAIKI-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000011061 large intestine cancer Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006610 n-decyloxy group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000006609 n-nonyloxy group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- HTISDHGSRIQJEV-UHFFFAOYSA-N octacyclo[36.4.0.02,7.08,13.014,19.020,25.026,31.032,37]dotetraconta-1(42),2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40-henicosaene Chemical group C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 HTISDHGSRIQJEV-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- MHAUGLFOVCQYNR-UHFFFAOYSA-N pentaphenylene Chemical group C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C3=CC=CC=C3C2=C1 MHAUGLFOVCQYNR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 230000009013 pigment accumulation Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OHFIJHDYYOCZME-UHFFFAOYSA-N pyrazine-2-carbohydrazide Chemical compound NNC(=O)C1=CN=CC=N1 OHFIJHDYYOCZME-UHFFFAOYSA-N 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- JTDPJYXDDYUJBS-UHFFFAOYSA-N quinoline-2-carbohydrazide Chemical compound C1=CC=CC2=NC(C(=O)NN)=CC=C21 JTDPJYXDDYUJBS-UHFFFAOYSA-N 0.000 description 1
- ODFBQWDWMOXDDW-UHFFFAOYSA-N quinoline-6-carbohydrazide Chemical compound N1=CC=CC2=CC(C(=O)NN)=CC=C21 ODFBQWDWMOXDDW-UHFFFAOYSA-N 0.000 description 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 201000011453 reproductive organ cancer Diseases 0.000 description 1
- 208000015608 reproductive system cancer Diseases 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005750 substituted cyclic group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 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
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- SOGBOGBTIKMGFS-UHFFFAOYSA-N thiophene-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CS1 SOGBOGBTIKMGFS-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- AMOWAJLALKAYKL-UHFFFAOYSA-N thiophene-3-carbohydrazide Chemical compound NNC(=O)C=1C=CSC=1 AMOWAJLALKAYKL-UHFFFAOYSA-N 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及通式(I)所示的化合物或其药学上可接受的盐或溶剂化物，还涉及上述化合物的制备方法及其在制备用于抗肿瘤的药物方面的用途。
Description
技术领域
本发明涉及一种具有抗肿瘤活性的化合物。具体而言，本发明涉及通式(I)化合物及其制备方法，还涉及通式(I)化合物在抗肿瘤方面的用途。
背景技术
氨基二硫代甲酸酯类化合物具有广泛的生物活性，特别是抗肿瘤活性。例如李润涛等人在中国发明专利申请CN200410054686.9中公开了此类化合物的通式：
其中，R2选自-(CH2)n-R3、-CH2-R4、-(CH2)m-COR5或-(CH2)m-COCO2R6。
本发明的发明人经过大量的实验研究，在上述通式的基础之上进行不断的优化和改造，发现了一类具有抗肿瘤活性的新型氨基二硫代甲酸乙酯类化合物。
发明内容
在本发明的第一方面，提供了通式(I)所示的化合物或其药学上可接受的盐或溶剂化物：
其中，n为1-4的整数；
Y1、Y2、Y3、Y4和Y5中的至少两个为选自于O、N和S的杂原子，其余为C原子，且Y1不为O或S；
R1表示吡啶环上任选存在的取代基，p表示取代基R1的数量，为0-4的整数，上述任选存在的取代基R1为烷氧基；
R表示五元杂芳环上任选存在的取代基，m表示取代基R的数量，为0-3的整数，上述任选存在的取代基R各自独立地选自于由芳基、杂芳基、苯并、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、酰基、硫代酰基、酰基氧基、卤代烷基、硝基、亚硝基、硫烷基和甲硅烷基所组成的组，并且任选被独立选自于下组中的一个或多个基团R2进一步取代：烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。
在优选的实施方式中，通式(I)的定义满足以下限定条件(1)至(6)中的一项或多项：
(1)n为1-3的整数，优选n为1或2；
(2)任选存在的取代基R1为C1-C4烷氧基，优选甲氧基；
(3)p为0-3的整数，优选p为0-2的整数，更优选p为0或1；
(4)m为0-2的整数，更优选m为0或1；
(5)连接于吡啶环的2位、3位或4位；和/或
(6)Y1、Y2、Y3、Y4和Y5构成的五元杂芳环含有2-4个选自于O、N和S的杂原子，优选所述五元杂芳环含有1-4个N原子以及0-1个O或S原子，更优选所述五元杂芳环选自于由噁唑、异噁唑、咪唑、噻唑、三唑、噁二唑、噻二唑和四唑所组成的组。
在优选的实施方式中，任选存在的取代基R选自于由苯基、苯并和包含5-12个环原子的杂芳基所组成的组，并且任选被独立选自于下组中的一个或多个基团R2进一步取代：C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、卤素、硝基。
在优选的实施方式中，所述包含5-12个环原子的杂芳基选自于由噁 唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基。
在优选的实施方式中，所述一个或多个基团R2各自独立地选自于氟、氯、溴、碘、甲基、甲氧基、三氟甲基、三氟甲氧基、硝基。
在本发明的第二方面，提供了一种药物组合物，所述药物组合物包含：本发明第一方面所述化合物或其药学上可接受的盐或溶剂化物；以及药学上可接受的载体。
在本发明的第三方面，提供了制备本发明第一方面所述化合物的方法，所述方法包括如下将原料A、二硫化碳和原料B在有机碱、优选三乙胺的存在下发生偶联反应：
其中各取代基如本发明第一方面所定义，X表示卤素原子。
在本发明的第四方面，提供了本发明第一方面所述的化合物及其药学上可接受的盐或溶剂化物在制备用于抗肿瘤的药物方面的用途。
在优选的实施方式中，所述肿瘤选自于由肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌和上皮癌所组成的组。
具体实施方式
本发明中使用的术语“烷基”是指仅由碳原子和氢原子组成、且不具有不饱和度(例如双键、三键或环)的基团，其涵盖了各种可能的几何异构基团与立体异构基团。该基团通过单键与分子的其余部分相连。 作为烷基的非限制性实例，可以列举以下直链或支链的基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体、正庚基及其各种异构体、正辛基及其各种异构体、正壬基及其各种异构体、正癸基及其各种异构体。
本发明中使用的术语“环烷基”是指由至少3个碳原子组成的饱和非芳香环系，该环系可以是单环、双环、多环，也可以是稠环、桥环、螺环。作为环烷基的非限制性实例，可以列举以下基团：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基；以及由两个或多个上述单环通过公共边和公共碳原子形成的稠环、桥环或螺环基团。
本发明中使用的术语“烯基”是指在上述烷基基团中(除甲基外)存在一个或多个双键的情况下所形成的基团。
本发明中使用的术语“环烯基”是指在上述环烷基基团中存在一个或多个双键的情况下所形成的基团。
本发明中使用的术语“炔基”是指在上述烷基基团中(除甲基外)存在一个或多个叁键的情况下所形成的基团。
本发明中使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举以下直链或支链的基团：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基及其另外七种异构体、正己氧基及其另外十六种异构体、正庚氧基及其各种异构体、正辛氧基及其各种异构体、正壬氧基及其各种异构体、正癸氧基及其各种异构体。
本发明中使用的术语“芳基”是指由至少6个碳原子组成的芳香环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为芳基的非限制性实例，可以列举以下基团：苯基、萘基、蒽基、菲基、茚基、芘基、苝基、薁基、戊搭烯基、庚搭烯基、苊基、芴基、非那烯基、萤蒽基、醋菲烯基、苯并苊基、三亚苯基、基、并四苯基、苉基、戊芬基、并五苯基、四邻亚苯基、 己芬基、并六苯基、蔻基、三亚萘基、庚芬基、并七苯基、吡蒽基、卵苯基、联苯基、联萘基。
本发明中使用的术语“杂芳基”是指具有一个或多个独立地选自N、O或S的杂原子的5-14元芳香族杂环环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的非限制性实例，可以列举以下基团：噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基；以及由上述杂芳基通过单键连接方式或稠合方式形成的基团。
本发明中使用的术语“杂环基”是指由碳原子和独立选自N、O或S的杂原子组成的非芳香族3-15元环系，该环系可以是单环、双环或多环，也可以是稠环、桥环、螺环，并且可以任选地包含一个或多个双键。作为杂环基的非限制性实例，可以列举以下基团：氮杂基、吖啶基、苯并间二氧杂环戊烯基、苯并二氧杂环己基、苯并二氢吡喃基、二氧戊环基、二氧磷杂环戊基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、异噻唑烷基、异噁唑烷基、吗啉基、噁唑啉基、噁唑烷基、噁二唑基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、八氢吲哚基、八氢异吲哚基、全氢化氮杂基、哌嗪基、4-哌啶酮基、哌啶基、吩噻嗪基、吩噁嗪基、奎宁环基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、四氢吡咯基、噻唑啉基、噻唑烷基、硫代吗啉基、硫代吗啉基亚砜和硫代吗啉基砜。
本发明中使用的术语“芳基烷基”是指一个或多个氢原子被芳基独立取代的烷基，其中所述的芳基和烷基如上文所定义。
本发明中使用的术语“杂芳基烷基”是指一个或多个氢原子被杂芳基独立取代的烷基，其中所述的杂芳基和烷基如上文所定义。
本发明中使用的术语“卤素”或“卤代”是指氟、氯、溴或碘。
本发明中使用的术语“苯并”是指苯环以两个相邻碳原子稠合至被取代的环状基团的两个相邻碳原子的情况。
在本发明中对取代基加以描述时，所使用的“任选”一词表示取代基可以存在，也可以不存在。例如，“五元杂芳环上任选存在的取代基”表示该五元杂芳环既可以是取代的，也可以是未取代的。
本发明中的药物组合物含有本发明第一方面所述的化合物作为活性成分。此外，该药物组合物还可包含药学上可接受的载体，包括但不限于：水、盐溶液、醇、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。该药物组合物还可包含一种或多种药学上可接受的辅助剂、润湿剂、乳化剂、悬浮剂、防腐剂、渗透压调节剂、缓冲剂、甜味剂、矫味剂、着色剂或上述的任意组合。
本发明的药物组合物可以制成任何形式的制剂，例如胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、软膏剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂、泡沫剂。根据给药途径，本发明的药物可以制成口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制剂、皮下给药制剂、皮内给药制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、鼻内给药制剂、眼部给药制剂、硬膜外给药制剂或局部给药制剂。
本发明中的“癌症”包括本领域中已知的各种癌症，包括但不限于：肺癌、肝癌、胃癌、宫颈癌、结肠癌、乳腺癌、白血病、非小细胞癌、前列腺癌或累色素瘤、脑癌、皮肤癌、骨癌、淋巴癌、鼻咽癌、喉癌、食道癌、十二指肠癌、小肠癌、大肠癌、胰腺癌、肾癌、生殖器官癌、甲状腺癌。
实施例
接下来，通过实施例对本发明进行进一步详细地说明，但本发明不仅限于这些实施例。
在一个示例性的实施方式中，本发明的化合物通过以下通用方法进行合成，其中各取代基如通式(I)中所定义，X表示卤素原子，有机碱为三乙胺(TEA)。
本领域技术人员在阅读本文后，能够容易地得知此类偶联反应所需的条件。在一个示例性的化合物合成中，上述偶联反应的过程如下所述。
[合成示例]3-吡啶甲氨基二硫代甲酸-(3-羟基)丙酯的合成
将3-吡啶甲胺(108mg,1mmol)、三乙胺(100mg,1mmol)加入10ml水中，室温下搅拌5分钟后，逐滴加入二硫化碳(91mg,1.2mmol)，室温下搅拌5分钟后，加入3-溴丙醇(138mg,1mmol)，反应2小时，用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离，得白色固体191mg，收率79％，熔点：70-71℃。
在上述合成示例以及以下实施例中，所有原料试剂均为市售化学纯或分析纯试剂，不经处理直接使用。其它相关实验仪器条件如下：
柱层析：青岛海洋化工厂硅胶200-300目。
熔点仪：X-4型显微熔点仪。
质谱仪：APEX IV型傅立叶变换高分辨质谱。
核磁共振仪：Bruker-400MHz
显色：碘、紫外。
实施例1：3-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噻二唑-2-基))乙酯
N’-(3-氯丙酰基)苯甲酰肼的制备：将苯甲酰肼(0.68g,5mmol)溶于50mL TEA中，室温搅拌下，逐滴加入氯丙酰氯(0.76g，6mmol)的乙酸乙酯溶液，滴加完毕后，加热回流3小时，反应完全，冷却至室温，蒸除溶剂，得到N’-(3-氯丙酰基)苯甲酰肼为白色固体0.49g，收率44％。
2-氯乙基-5-苯基-1,3,4-噻二唑的制备：将N’-(3-氯丙酰基)苯甲酰肼(0.45g,2mmol)加入至40mL甲苯中，抽排空气，回充氮气，加入劳森试剂(1.21g,3mmol)，115℃下反应4小时，蒸除溶剂，经硅胶柱层析分离，得淡绿色固体，0.36g，收率54％。
目标化合物的制备：该目标化合物以2-氯乙基-5-苯基-1,3,4-噻二唑为通用方法中的原料B，参照[合成示例]的合成方法制备，得到白色固体，收率32％，熔点138-142℃。
1H NMR(400MHz,CDCl3):δ3.56-3.60(t,J＝6.8Hz,2H),3.77-3.81(t,J＝6.8Hz,2H),4.97(s,2H),7.27-7.30(m,1H),7.48-7.49(m,3H),7.70-7.73(m,2H),7.94-7.95(m,2H),8.56-8.60(m,2H).
HRMS(ESI+)m/z calcd for C17H16N4S3(M+H)+,373.0537,found373.0637.
实施例2：3-吡啶甲氨基二硫代甲酸(2-(苯并噁唑-2-基))乙酯
3-溴丙亚胺酸甲酯盐酸盐的制备：将溴丙腈(2.66g,20mmol)和甲醇(1.28g,40mmol)加入至100mL乙醚中，室温搅拌下，缓慢通入干燥盐酸气，6小时后，有大量白色晶体产生，停止反应，过滤，固体用无水乙醚洗涤两次，烘干，得白色晶体2.08g，收率63％。
2-(2-溴乙基)苯并噁唑的制备：将3-溴丙亚胺酸甲酯盐酸盐(0.16g,1mmol)和邻氨基苯酚(0.15g,1.3mmol)加入至20mL乙醇中，于80℃下反应6小时，停止反应，过滤，滤液浓缩得2-(2-溴乙基)苯并噁唑粗品，黄色油状物，收率定量。
目标化合物的制备：该目标化合物以2-(2-溴乙基)苯并噁唑为通用方法中的原料B，参照[合成示例]的合成方法制备，得到白色固体，收率57％，熔点116-117℃。
1H NMR(400MHz,CDCl3):δ3.38-3.41(t,J＝6.8Hz,2H),3.80-3.84(t,J＝6.8Hz,2H),4.95(s,2H),7.25-7.33(m,3H),7.48-7.70(m,3H),8.17(bs,1H),8.50-8.53(m,2H).
13C NMR(100MHz,CDCl3):δ28.96,31.81,48.16,110.46,119.63,123.68,124.29,124.84,136.05,149.19,149.37,150.86,164.88,197.75.
Anal.Cald for C16H15N3OS2:C,58.33；H,4.59；N,12.76；Found:C,58.08；H,4.69；N,12.50.
实施例3：3-吡啶甲氨基二硫代甲酸(2-(苯并三唑-2-基))乙酯
2-(2-溴乙基)-2H-苯并[1,2,3]三唑的制备：将苯并三唑(1.19g, 10mmol)、1,2-二溴乙烷(1.86g,10mmol)、氢氧化钾(1.12g,20mmol)和四丁基碘化铵(0.37g,1mmol)加入至40mL DMF中，90℃下反应过夜。冷却至室温，加入40mL水，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离得2-(2-溴乙基)-2H-苯并[1,2,3]三唑0.72g，白色固体，收率23％。
目标化合物的制备：该目标化合物以2-(2-溴乙基)-2H-苯并[1,2,3]三唑为原料，参照[合成示例]的合成方法制备，得到白色固体，收率63％，熔点147-148℃。
1H NMR(400MHz,DMSO):δ3.78-3.81(t,J＝6.8Hz,2H),3.82-3.84(t,J＝6.8Hz,2H),4.95(m,2H),7.34-7.55(m,4H),7.64-7.83(m,2H),8.48-8.50(m,2H),10.58(bs,1H).
13C NMR(100MHz,DMSO):δ34.09,46.97,47.77,110.99,119.59,123.95,124.43,127.74,133.18,135.93,148.95,196.41.
HRMS(ESI+)m/z calcd for C15H15N5S2(M+H)+,330.0769,found330.0847.
实施例4：3-吡啶甲氨基二硫代甲酸(2-(3-苯基-1,2,4-噁二唑-5-基))乙酯
N-羟基苯甲亚胺酰胺的制备：将苯甲腈(1.03g,10mmol)、三乙胺(4.0g,40mmol)和盐酸羟胺(1.39g,20mmol)加入至60mL乙醇中，90℃下反应12小时，冷却，蒸除溶剂，加入20mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离得氮-羟基苯甲亚胺酰胺1.31g，黄色油状物，收率96％。
N-[(氯丙酰基)氧基]苯甲亚胺酰胺的制备：将N-羟基苯甲亚胺酰胺 (0.63g,5mmol)和三乙胺(0.5g,5mmol)加入至30mL乙酸乙酯中，室温搅拌下，缓慢滴入氯丙酰氯(0.63g,5mmol)，加毕，室温下继续反应2小时，反应完全，加入20mL水，萃取，收集酯层，无水硫酸钠干燥，过滤，浓缩得N-[(氯丙酰基)氧基]苯甲亚胺酰胺粗品，黄色油状物，收率定量。
5-氯乙基-3-苯基-1,2,4-噁二唑的制备：将N-[(氯丙酰基)氧基]苯甲亚胺酰胺(0.23g,1mmol)和碳酸钾(0.28g,2mmol)加入至10mL 1,4-二氧六环中，回流6小时，冷却，蒸除溶剂，加入20mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得5-氯乙基-3-苯基-1,2,4-噁二唑粗品，黄色油状物，收率定量。
目标化合物的制备：该目标化合物以5-氯乙基-3-苯基-1,2,4-噁二唑为原料，参照[合成示例]的合成方法制备，得到白色固体，收率43％，熔点118-120℃。
1H NMR(400MHz,CDCl3):δ3.40-3.43(t,J＝6.8Hz,2H),3.80-3.84(t,J＝6.8Hz,2H),4.95(m,2H),7.25-7.28(m,1H),7.45-7.51(m,3H),7.68-7.70(m,1H),8.06-8.08(m,2H),8.53(m,2H).
13C NMR(100MHz,CDCl3):δ27.09,31.65,48.26,123.68,127.44,128.83,131.19,136.01,149.42,168.36,177.74,197.32.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.28；H,4.68；N,15.24.
实施例5：3-吡啶甲氨基二硫代甲酸-(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯
2-溴乙基-5-苯基-1,3,4-噁二唑的制备：将3-溴丙亚胺酸甲酯盐酸盐(0.16g,1mmol)加入至20mL二氯甲烷中，冰浴下，分批加入苯甲酰肼(0.16g,1.3mmol)，加毕，回流6小时，冷却，过滤，浓缩得2-溴乙基-5-苯基-1,3,4-噁二唑粗品，黄色油状物，收率定量。
目标化合物的制备：该目标化合物以2-溴乙基-5-苯基-1,3,4-噁二唑作为通用方法中的原料B，参照[合成示例]的合成方法制备，得到白色固体，收率62％，熔点134-136℃。
1H NMR(400MHz,CDCl3):δ3.35-3.38(t,J＝6.8Hz,2H),3.76-3.79(t,J＝6.8Hz,2H),4.95(d,J＝5.2Hz,2H),7.19-7.21(m,1H),7.45-7.51(m,3H),7.68-7.70(m,1H),7.98-8.00(m,2H),8.39-8.49(m,2H),9.11(bs,1H).
13C NMR(100MHz,CDCl3):δ26.08,31.43,48.18,123.62,126.85,129.04,131.75,132.45,136.24,148.85,149.40,165.02,165.07,197.39.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.32；H,4.64；N,15.66.
实施例6：3-吡啶甲氨基二硫代甲酸(2-(苯并咪唑-2-基))乙酯
2-(2-溴乙基)苯并咪唑的制备：将邻苯二胺(0.22g,2mmol)和β-溴丙酸(0.61g,4mmol)加入至15mL浓盐酸中，回流6小时，冷却，缓慢加入饱和碳酸钠溶液中和至pH＝7，用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得2-(2-溴乙基)苯并咪唑粗品，黄色油状物，收率定量。
目标化合物的制备：该目标化合物以2-(2-溴乙基)苯并咪唑作为通用方法中的原料B，参照[合成示例]的合成方法制备，得到白色固体，收率33％，熔点149-151℃。
1H NMR(400MHz,DMSO):δ3.20-3.24(t,J＝6.8Hz,2H),3.67-3.71(t,J＝6.8Hz,2H),4.85(d,J＝5.2Hz,2H),7.13-7.15(m,2H),7.35-7.38(m,1H),7.48-7.50(m,2H),7.68-7.70(m,1H),8.47-8.52(m,2H),10.54(bs,1H).
13C NMR(100MHz,DMSO):δ23.71,29.00,47.56,122.02,123.98,148.88,149.52,153.44,197.41.
Anal.Cald for C16H16N4S2:C,58.51；H,4.91；N,17.06；Found:C,58.64； H,4.58；N,16.69.
实施例7：3-吡啶甲氨基二硫代甲酸(2-(1H-四唑-5-基))乙酯
5-(2-溴乙基)-1H-四唑的制备：β-溴丙腈(0.27g,2mmol)、叠氮化钠(0.16g,2.5mmol)和氯化铵(0.13g,2.5mmol)加入至20mL干燥DMF中，100℃下反应6小时，冷却至室温，将反应液倾入至20mL冰水混合物中，用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离，得5-(2-溴乙基)-1H-四唑0.13g，淡黄色油状物，收率37％。
目标化合物的制备：该目标化合物以5-(2-溴乙基)-1H-四唑作为通用方法中的原料B，参照[合成示例]的合成方法制备，得到淡黄色固体，收率49％，熔点121-124℃。
1H NMR(400MHz,MeOD):δ3.32-3.43(t,J＝6.8Hz,2H),3.69-3.72(t,J＝6.8Hz,2H),4.94(s,2H),7.41-7.44(m,1H),7.82-7.84(m,1H),8.45-8.53(m,2H).
13C NMR(100MHz,MeOD):δ23.77,31.81,47.01,123.88,134.01,136.77,147.40,148.19,155.64,197.56.
HRMS(ESI+)m/z calcd for C10H12N6S2(M+H)+,281.0565,found281.0640.
实施例8：3-吡啶甲氨基二硫代甲酸(2-(苯并噻唑-2-基))乙酯
2-(2-溴乙基)苯并噻唑的制备：将邻氨基苯硫酚(0.25g,2mmol)和三乙胺(0.20g,2mmol)加入至30mL乙酸乙酯中，室温下，逐滴滴入溴丙腈(0.26g，2mmol)，滴加完毕后，室温反应6小时，冷却，浓缩得2-(2-溴乙基)苯并噻唑粗品，未经纯化，直接用于下步反应。
目标化合物的制备：该目标化合物以2-(2-溴乙基)苯并噻唑作为通用方法中的原料B，参照[合成示例]的合成方法制备，得到白色固体，收率19％，熔点96-99℃。
1H NMR(400MHz,DMSO):δ3.60-3.72(m,4H)4.85(s,2H),7.32-7.69(m,4H),8.48-8.53(m,2H),10.61(bs,1H).
13C NMR(100MHz,DMSO):δ32.04,34.12,47.78,110.70,118.78,123.99,124.80,125.10,133.24,141.72,148.95,149.56,151.77,164.16,196.49.
HRMS(ESI+)m/z calcd for C16H15N3S3(M+H)+,346.0428,found346.0522.
实施例9：4-吡啶甲氨基二硫代甲酸(2-(苯并噁唑-2-基))乙酯
该目标化合物以4-吡啶甲胺为原料，参照实施例2的合成路线制备，得到白色固体，收率58％，熔点89-90℃。
1H NMR(400MHz,DMSO):δ3.33-3.37(t,J＝6.8Hz,2H),3.70-3.73(t,J＝6.8Hz,2H),4.85(s,2H),7.22-7.383(m,4H),7.66-7.71(m,2H),8.49-8.50(m,2H).
13C NMR(100MHz,DMSO):δ28.70,31.37,48.63,110.06,119.81,122.72,124.88,125.40,141.16,146.71,150.02,150.70,165.42,197.58.
Anal.Cald for C16H15N3OS2:C,58.33；H,4.59；N,12.76；Found:C,58.09；H,4.61；N,12.47.
实施例10：4-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯
该目标化合物以4-吡啶甲胺为原料，参照实施例5的合成路线制备， 得到白色固体，收率65％，熔点131-132℃。
1H NMR(400MHz,DMSO):δ3.33-3.36(t,J＝6.8Hz,2H),3.69-3.73(t,J＝6.8Hz,2H),4.85(s,2H),7.21-7.23(m,2H),7.59-7.61(m,3H),7.97-7.99(m,2H),8.47-8.49(m,2H).
13C NMR(100MHz,CDCl3):δ25.89,31.14,48.68,122.70,123.87,126.90,129.89,132.39,146.67,149.99,164.60,165.58,197.46.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.27；H,4.65；N,15.48.
实施例11：3-吡啶乙氨基二硫代甲酸(2-(2-苯并噁唑-2-基))乙酯
该目标化合物以3-吡啶乙胺为原料，参照实施例2的合成路线制备，得到白色固体，收率59％，熔点123-124℃。
1H NMR(400MHz,DMSO):δ2.90-2.93(t,J＝7.2Hz,2H),3.29-3.32(t,J＝6.8Hz,2H),3.65-3.69(t,J＝6.8Hz,2H),3.79-3.82(t,J＝7.2Hz,2H),7.31-7.37(m,3H),7.66-7.71(m,3H),8.43(m,2H).
13C NMR(100MHz,DMSO):δ28.78,30.81,31.09,47.73,111.06,119.79,124.03,124.86,125.38,134.89,141.17,147.90,150.06,150.69,165.46,195.99.
Anal.Cald for C17H17N3OS2:C,59.45；H,4.99；N,12.23；Found:C,59.17；H,4.94；N,12.47.
实施例12：3-吡啶乙氨基二硫代甲酸-(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯
该目标化合物以3-吡啶乙胺为原料，参照实施例5的合成路线制备，得到白色固体，收率59％，熔点124-126℃。
1H NMR(400MHz,DMSO):δ2.89-2.92(t,J＝6.8Hz,2H),3.30-3.32 (t,J＝6.8Hz,2H),3.65-3.69(t,J＝6.8Hz,2H),3.77-3.81(t,J＝6.8Hz,2H),7.29-7.32(m,1H),7.57-7.63(m,3H),7.97-7.99(m,2H),8.43(m,2H).
13C NMR(100MHz,CDCl3):δ25.97,30.79,30.85,47.78,123.86,123.97,126.90,129.87,132.36,134.81,136.70,147.99,150.17,164.58,165.60,195.85.
Anal.Cald for C18H18N4OS2:C,58.35；H,4.90；N,15.12；Found:C,58.17；H,5.01；N,14.87.
实施例13：2-甲氧基-3-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯
该目标化合物以(2-甲氧基吡啶-3-基)甲胺和2-氯乙基-5-苯基-1,3,4-噁二唑为原料，参照[合成示例]的合成方法制备，得到白色固体，收率31％，熔点109-113℃。
1H NMR(400MHz,CDCl3):δ3.71-3.80(m,4H),4.01(s,3H),4.92(d,J＝5.6Hz,2H),7.19-7.21(m,1H),6.87-6.90(m,1H),7.50-7.57(m,4H),8.04-8.09(m,3H).
13C NMR(100MHz,CDCl3):δ26.12,31.51,46.24,53.65,116.91,123.87,126.87,129.03,131.67,138.81,146.57,165.05,196.72.
HRMS(ESI+)m/z calcd for C18H18N4O2S2(M+H)+,387.0871,found387.0955.
实施例14：3-吡啶甲氨基二硫代甲酸(2-(5-(2-氟苯基)-1,3,4-噁二唑-2-基))乙酯
2-溴乙基-5-(2-氟苯基)-1,3,4-噁二唑的制备：将3-溴丙亚胺酸甲酯盐 酸盐(0.16g,1mmol)加入至20mL二氯甲烷中，冰浴下，分批加入2-氟苯甲酰肼(0.18g,1.3mmol)，加毕，回流6小时，冷却，过滤，浓缩得2-溴乙基-5-(2-氟苯基)-1,3,4-噁二唑粗品，黄色油状物，收率定量。
目标化合物的制备：该目标化合物以3-吡啶甲胺和2-氯乙基-5-苯基-1,3,4-噁二唑作为通用方法中的原料A和B，参照[合成示例]的合成方法制备，得到白色固体，收率67％，熔点108-110℃。
1H NMR(400MHz,DMSO):δ3.35-3.38(t,J＝6.8Hz,2H),3.67-3.71(t,J＝6.8Hz,2H),4.85(d,J＝5.2Hz,2H),7.36-8.00(m,6H),8.47-8.52(m,2H),10.62(bs,1H).
13C NMR(100MHz,DMSO):δ25.88,31.06,47.70,110.00,117.76,124.03,125.81,130.03,133.31,134.55,134.63,136.10,148.80,149.41,161.14,165.80,196.84.
Anal.Cald for C17H15FN4OS2:C,54.53；H,4.04；N,14.96；Found:C,54.26；H,4.11；N,14.69.
实施例15：3-吡啶甲氨基二硫代甲酸{2-[5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基]}乙酯
该目标化合物以4-甲氧基苯甲酰肼和2-氯乙基-5-苯基-1,3,4-噁二唑为原料，参照实施例14的合成路线制备，得到白色固体，收率70％，熔点149-151℃。
1H NMR(400MHz,DMSO):δ3.30-3.33(t,J＝6.8Hz,2H),3.67-3.71(t,J＝6.8Hz,2H),3.85(s,3H),4.85(d,J＝5.2Hz,2H),7.13-7.37(m,3H),7.67-7.69(m,1H),7.90-7.93(m,2H),8.47-8.52(m,2H),10.59(bs,1H).
13C NMR(100MHz,DMSO):δ25.88,31.10,47.70,55.98,115.32,116.27,123.98,128.73,133.26,135.96,148.92,149.53,162.40,164.46,164.99,196.85.
Anal.Cald for C18H18N4O2S2:C,55.94；H,4.69；N,14.50；Found:C, 56.20；H,4.71；N,14.94.
实施例16：3-吡啶甲氨基二硫代甲酸{2-[5-(4-三氟甲基苯基)-1,3,4-噁二唑-2-基]}乙酯
该目标化合物以4-三氟甲基苯甲酰肼和2-氯乙基-5-苯基-1,3,4-噁二唑作为原料，参照实施例14的合成路线制备，得到白色固体，收率65％，熔点145-146℃。
1H NMR(400MHz,DMSO):δ3.36-3.39(t,J＝6.8Hz,2H),3.69-3.73(t,J＝6.8Hz,2H),4.85(d,J＝5.2Hz,2H),7.33-7.37(m,1H),7.67-7.69(m,1H),7.90-7.93(m,2H),8.18-8.20(m,2H),8.47-8.51(m,2H),10.60(bs,1H).
13C NMR(100MHz,DMSO):δ26.00,31.01,47.72,123.95,126.91,127.78,133.23,135.94,148.92,149.54,163.57,166.26,196.83.
Anal.Cald for C18H15F3N4OS2:C,50.93；H,3.56；N,13.20；Found:C,50.81；H,4.01；N,12.91.
实施例17：3-吡啶甲氨基二硫代甲酸{2-[5-(4-氯苯基)-1,3,4-噁二唑-2-基]}乙酯
4-氯苯甲酰肼的制备：将4-氯苯甲酸(3.2g，20mmol)溶于30mL甲醇中，冰浴下缓慢滴加二氯亚砜2mL，滴毕，加热50℃反应4h，冷却，蒸除过量甲醇，加入适量饱和碳酸氢钠溶液，用乙酸乙酯萃取(15mL×3)，旋干备用；将上一步粗产物溶于30mL乙醇中，加入80％水合肼4mL，加热回流反应4h，冷却，析出白色固体，抽滤烘干，得白色固体2.5g，收率74％。
2-溴乙基-5-(4-氯苯基)-1,3,4-噁二唑的制备：将3-溴丙酸(0.46g，3mmol)溶于5mL三氯氧磷中，加入4-氯苯甲酰肼(0.47g，3mmol)油 浴80℃加热6h，冷却，将反应液缓慢倒入冰水中，加氢氧化钠溶液调节至pH 7-8，二氯甲烷萃取(20mL×3)，合并有机层，无水硫酸钠干燥，旋干溶剂得黄色固体0.31g，粗品收率36％。
目标化合物的制备：将3-氨甲基吡啶(0.1mL，1mmol)溶于20mL丙酮中，加入无水磷酸钾(0.43g，2mmol)、5mL水、二硫化碳(0.15mL，2mmol)，常温搅拌30min后加入2-溴乙基-5(4-氯苯基)-1,3,4-噁二唑(0.29g，1mmol)，加热50℃反应6h，冷却，反应液分层，分离出有机层，硅胶柱层析(石油醚：乙酸乙酯＝1:1)，得白色固体0.25g，收率64％，熔点126-127℃。
1H NMR(400MHz,DMSO)δ:10.59(t,J＝5.3Hz,1H),8.52(d,J＝1.6Hz,1H),8.48(dd,J＝4.7,1.4Hz,1H),8.07–8.01(m,2H),7.69(d,J＝7.8Hz,1H),7.45(t,J＝8.9Hz,2H),7.36(dd,J＝7.7,4.8Hz,1H),4.85(d,J＝5.5Hz,2H),3.70(t,J＝6.9Hz,2H),3.34(t,J＝6.9Hz,2H).
13C NMR(101MHz,DMSO)δ:196.84,165.60,163.82,149.55,148.93,135.93,133.24,129.63,129.54,123.95,120.57,117.24,117.01,47.72,31.06,25.92.
HRMS：Calcd for C17H16ClN4OS2(M++H)：391.91020，Found：391.91023.
实施例18：3-吡啶甲氨基二硫代甲酸{2-[5-(4-硝基苯基)-1,3,4-噁二唑-2-基]}乙酯
4-硝基苯甲酰肼的制备：除采用4-硝基苯甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率64％。
2-溴乙基-5-(4-硝基苯基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率58％。
目标化合物的制备：参照实施例17，得白色固体，收率37％，熔点157-158℃。
1H NMR(400MHz,DMSO)δ:10.62(s,1H),8.48(dd,J＝15.4,11.6Hz,2H),8.40(t,J＝7.7Hz,2H),8.24–8.19(m,2H),7.69(d,J＝7.3Hz,1H),7.43–7.32(m,1H),4.84(d,J＝5.1Hz,2H),3.72(t,J＝6.6Hz,2H),3.39(t,J＝6.6Hz,2H).
13C NMR(101MHz,DMSO)δ:196.80,166.57,163.26,149.44,148.82,136.06,133.27,129.36,128.24,128.18,125.06,123.98,47.71,31.00,26.04.
HRMS：Calcd for C17H16N5O3S2(M++H)：402.06891，Found：402.06957.
实施例19：3-吡啶甲氨基二硫代甲酸{2-[5-(吡咯-3-基)-1,3,4-噁二唑-2-基]}乙酯
吡咯-3-甲酰肼的制备：除采用吡咯-3-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率60％。
2-溴乙基-5-(3-吡咯基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率25％。
目标化合物的制备：参照实施例17，得白色固体，收率73％，熔点167-168℃。
1H NMR(400MHz,DMSO)δ:12.16(s,1H),10.60(t,J＝5.5Hz,1H),8.53(d,J＝1.6Hz,1H),8.48(dd,J＝4.7,1.3Hz,1H),7.69(d,J＝7.9Hz,1H),7.37(dd,J＝7.8,4.8Hz,1H),7.07(dd,J＝3.9,2.6Hz,1H),6.78(d,J＝3.5Hz,1H),6.25(dd,J＝5.8,2.4Hz,1H),4.86(d,J＝5.5Hz,2H),3.66(t,J＝6.9Hz,2H),3.28(t,J＝6.9Hz,2H).
13C NMR(101MHz,DMSO)δ:196.83,163.61,159.77,149.55,148.93,135.98,133.26,123.99,123.90,115.79,112.25,110.32,47.71,31.14,25.73.
HRMS：Calcd for C15H16N5OS2(M++H)：346.07908，Found：346.07884.
实施例20：3-吡啶甲氨基二硫代甲酸{2-[5-(呋喃-2-基)-1,3,4-噁二唑 -2-基]}乙酯
呋喃-2-甲酰肼的制备：除采用呋喃-2-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率65％。
2-溴乙基-5-(2-呋喃基)-1,3,4-噁二唑的制备：参照实施例17，得淡黄色油状物，收率49％。
目标化合物的制备：参照实施例17，得白色固体，收率85％，熔点155-156℃。
1H NMR(400MHz,DMSO)δ:10.58(t,J＝5.3Hz,1H),8.52(d,J＝1.5Hz,1H),8.48(dd,J＝4.7,1.2Hz,1H),8.04(d,J＝1.0Hz,1H),7.68(d,J＝7.8Hz,1H),7.37(dd,J＝7.7,4.8Hz,1H),7.31(d,J＝3.5Hz,1H),6.79(dd,J＝3.5,1.7Hz,1H),4.85(d,J＝5.5Hz,2H),3.67(t,J＝6.9Hz,2H),3.32(t,J＝6.9Hz,2H).
13C NMR(101MHz,DMSO)δ:196.79,164.85,157.52,149.55,148.93,147.28,139.10,135.93,133.23,123.96,114.73,113.01,47.72,31.05,25.76.
HRMS：Calcd for C15H15N4O2S2(M++H)：347.06309，Found：347.06367.
实施例21：3-吡啶甲氨基二硫代甲酸{2-[5-(噻吩-3-基)-1,3,4-噁二唑-2-基]}乙酯
噻吩-3-甲酰肼的制备：除采用噻吩-3-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率61％。
2-溴乙基-5-(3-噻吩基)-1,3,4-噁二唑的制备：参照实施例17，得黄色油状物，收率30％。
LP-05目标化合物的制备：参照实施例17，得白色固体，收率89％，熔点141-142℃。
1H NMR(400MHz,DMSO)δ:10.60(s,1H),8.52(s,1H),8.48(d,J＝4.5Hz,1H),8.31(s,1H),7.81(s,1H),7.68(d,J＝7.6Hz,1H),7.60(d,J＝4.9Hz,1H),7.40–7.33(m,1H),4.85(d,J＝5.2Hz,2H),3.68(t,J＝6.7Hz,2H),3.32(t,J＝6.8Hz,2H).
13C NMR(101MHz,DMSO)δ:196.81,164.85,161.48,149.54,148.93,135.95,133.25,129.48,128.93,125.99,124.97,123.98,47.71,31.08,25.84.
HRMS：Calcd for C15H15N4OS3(M++H)：363.04025，Found：363.03961.
实施例22：3-吡啶甲氨基二硫代甲酸{2-[5-(噻吩-2-基)-1,3,4-噁二唑-2-基]}乙酯
噻吩-2-甲酰肼的制备：除采用噻吩-2-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率60％。
2-溴乙基-5-(2-噻吩基)-1,3,4-噁二唑的制备：参照实施例17，得黄色油状物，收率23％。
目标化合物的制备：参照实施例17，得白色固体，收率92％，熔点145-146℃。
1H NMR(400MHz,DMSO)δ:10.59(t,J＝5.4Hz,1H),8.52(d,J＝1.7Hz,1H),8.48(dd,J＝4.7,1.5Hz,1H),7.92(dd,J＝5.0,1.2Hz,1H),7.78(dt,J＝6.4,3.2Hz,1H),7.71–7.66(m,1H),7.38–7.34(m,1H),7.28(dd,J＝5.0,3.7Hz,1H),4.85(d,J＝5.6Hz,2H),3.68(t,J＝6.9Hz,2H),3.32(t,J＝6.9Hz,2H).
13C NMR(101MHz,DMSO)δ:196.82,165.00,160.87,149.55,148.93,135.94,133.24,131.81,130.51,129.15,124.83,123.96,47.73,31.07,25.84.
HRMS：Calcd for C15H15N4OS3(M++H)：363.04025，Found：363.04064.
实施例23：3-吡啶甲氨基二硫代甲酸{2-[5-(5-甲基异噁唑-3-基)-1,3,4-噁二唑-2-基]}乙酯
5-甲基-异噁唑-3-甲酰肼的制备：将5-甲基-异噁唑-3-甲酸乙酯(3.1g，20mmol)溶于30mL乙醇中，加入80％水合肼4mL，加热回流反应24h，冷却，析出白色固体，抽滤烘干，得白色固体2.1g，收率75％。
2-溴乙基-5-[3-(5-甲基异噁唑基)]-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率36％。
目标化合物的制备：参照实施例17，得白色固体，收率75％，熔点149-150℃。
1H NMR(400MHz,DMSO)δ:10.56(s,1H),8.47(s,1H),8.43(d,J＝3.4Hz,1H),7.64(d,J＝7.2Hz,1H),7.37–7.28(m,1H),6.84(s,1H),4.80(d,J＝4.7Hz,2H),3.63(t,J＝6.4Hz,2H),3.33(t,J＝6.3Hz,2H),2.49(s,3H).
13C NMR(101MHz,DMSO)δ:196.74,172.78,166.61,157.39,150.44,149.55,148.92,135.95,133.22,123.96,101.59,47.74,30.96,25.90,12.27.
HRMS：Calcd for C15H16N5O2S2(M++H)：362.07399，Found：362.07377.
实施例24：3-吡啶甲氨基二硫代甲酸{2-[5-(吡啶-3-基)-1,3,4-噁二唑-2-基]}乙酯
吡啶-3-甲酰肼的制备：除采用吡啶-3-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率74％。
2-溴乙基-5-(3-吡啶基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率20％。
目标化合物的制备：参照实施例17，得白色固体，收率75％，熔点151-152℃。
1H NMR(400MHz,DMSO):δ10.64(s,1H),9.17(s,1H),8.81(d,J＝3.7Hz,1H),8.54(s,1H),8.50(d,J＝3.7Hz,1H),8.35(d,J＝7.8Hz,1H),7.71(d,J＝7.5Hz,1H),7.64(dd,J＝7.7,4.8Hz,1H),7.37(dd,J＝7.4,4.8Hz,1H),4.87(d,J＝5.2Hz,2H),3.74(t,J＝6.7Hz,2H),3.39(t,J＝6.6Hz,2H).
13C NMR(101MHz,DMSO):δ196.82,166.02,162.81,152.87,149.53,148.90,147.57,135.97,134.48,133.23,124.78,123.95,120.44,47.74,31.04,25.98.
HRMS：Calcd for C16H16N5OS2(M++H)：358.07908，Found：358.07826.
实施例25：3-吡啶甲氨基二硫代甲酸{2-[5-(6-氯吡啶-3-基)-1,3,4-噁二唑-2-基]}乙酯
6-氯吡啶-3-甲酰肼的制备：除采用6-氯吡啶-3-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率73％。
2-溴乙基-5-[3-(6-氯吡啶基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率15％。
目标化合物的制备：参照实施例17，得白色固体，收率75％。
HRMS：Calcd for C16H15ClN5OS2(M++H)：392.04011，Found：392.04021.
实施例26：3-吡啶甲氨基二硫代甲酸{2-[5-(吡嗪-2-基)-1,3,4-噁二唑-2-基]}乙酯
吡嗪-2-甲酰肼的制备：除采用吡嗪-2-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率64％。
2-溴乙基-5-(2-吡嗪基)-1,3,4-噁二唑的制备：参照实施例17，得黄色油状物。
目标化合物的制备：参照实施例17，得白色固体，收率88％，熔点143-144℃。
1H NMR(400MHz,DMSO)δ:10.60(s,1H),9.35(s,1H),8.88(d,J＝5.8Hz,2H),8.52(s,1H),8.48(d,J＝3.6Hz,1H),7.69(d,J＝7.6Hz,1H),7.37(dd,J＝7.3,4.9Hz,1H),4.85(d,J＝5.3Hz,2H),3.71(t,J＝6.8Hz,2H),3.41(t,J＝6.8Hz,2H).
13C NMR(101MHz,DMSO)δ:196.77,166.87,162.55,149.54,148.92,147.43,145.49,143.96,139.51,135.96,133.23,123.97,47.73,31.03,26.00.
HRMS：Calcd for C15H16N6OS2(M++H)：359.07433，Found：359.07482.
实施例27：3-吡啶甲氨基二硫代甲酸{2-[5-(喹啉-6-基)-1,3,4-噁二唑-2-基]}乙酯
喹啉-6-甲酰肼的制备：除采用喹啉-6-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率67％。
2-溴乙基-5-(6-喹啉基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率43％。
目标化合物的制备：参照实施例17，得白色固体，收率54％，熔点165-166℃。
1H NMR(400MHz,DMSO):δ10.63(s,1H),9.01(d,J＝3.6Hz,1H),8.65(s,1H),8.58(d,J＝8.2Hz,1H),8.52(s,1H),8.47(d,J＝4.4Hz,1H),8.29(d,J＝8.8Hz,1H),8.18(d,J＝8.8Hz,1H),7.73–7.61(m,2H),7.35(dd,J＝7.6,4.8Hz,1H),4.85(s,2H),3.74(t,J＝6.7Hz,2H),3.40(t,J＝ 6.8Hz,2H).
13C NMR(101MHz,DMSO):δ196.81,165.93,164.29,152.92,149.55,149.07,148.92,137.48,135.95,133.24,130.82,128.17,127.61,126.87,123.95,123.11,121.70,47.73,31.09,26.02.
HRMS：Calcd for C20H18N5OS2(M++H)：408.09473，Found：408.09520.
实施例28：3-吡啶甲氨基二硫代甲酸-{2-[5-(喹啉-2-基)-1,3,4-噁二唑-2-基]}乙酯
喹啉-2-甲酰肼的制备：除采用喹啉-2-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率75％。
2-溴乙基-5-(2-喹啉基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率21％。
目标化合物的制备：参照实施例17，得白色固体，收率81％，熔点139-140℃。
1H NMR(400MHz,DMSO)δ:10.63(s,1H),8.63(d,J＝8.5Hz,1H),8.53(s,1H),8.48(d,J＝4.4Hz,1H),8.27(d,J＝8.5Hz,1H),8.18(d,J＝8.4Hz,1H),8.12(d,J＝7.8Hz,1H),7.90(t,J＝7.5Hz,1H),7.75(t,J＝7.5Hz,1H),7.71(d,J＝7.6Hz,1H),7.41–7.34(m,1H),4.86(d,J＝5.3Hz,2H),3.73(t,J＝6.8Hz,2H),3.44(t,J＝6.8Hz,2H).
13C NMR(101MHz,DMSO)δ:196.81,166.84,164.39,149.52,148.88,147.62,143.36,138.52,136.02,133.27,131.37,129.77,128.85,128.78,128.68,123.98,119.93,47.74,31.12,26.07.
HRMS：Calcd for C20H18N5OS2(M++H)：408.09473，Found：408.09504.
实施例29：3-吡啶甲氨基二硫代甲酸{2-[5-(苯并噻吩-2-基)-1,3,4-噁二唑-2-基]}乙酯
苯并噻吩-2-甲酰肼的制备：除采用苯并噻吩-2-甲酸代替4-氯苯甲酸外，参照实施例17，得白色固体，收率52％。
2-溴乙基-5-(2-喹啉基)-1,3,4-噁二唑的制备：参照实施例17，得白色固体，收率48％。
目标化合物的制备：参照实施例17，得白色固体，收率53％，熔点249-250℃。
1H NMR(400MHz,DMSO)δ:10.66(s,1H),8.52(d,J＝1.7Hz,1H),8.47(dd,J＝4.7,1.5Hz,1H),8.12(d,J＝7.8Hz,1H),8.04(dd,J＝6.9,1.8Hz,1H),7.71–7.67(m,1H),7.52(dd,J＝7.2,5.6Hz,2H),7.36(dd,J＝7.8,4.8Hz,1H),4.85(s,2H),3.70(t,J＝6.9Hz,2H),3.40–3.31(m,2H).
13C NMR(101MHz,DMSO)δ:196.67,165.71,160.98,149.57,148.88,140.39,139.28,135.96,133.29,127.35,125.89,125.74,124.67,123.93,123.35,47.71,31.03,25.96.
HRMS：Calcd for C19H17N4OS3(M++H)：413.05590，Found：413.05648
试验例1
采用贴壁细胞MTT法测定本发明实施例中的化合物的活性，具体步骤如下所述。
体外培养乳腺癌细胞株SKBr-3、乳腺癌细胞株MDA-MB-468、结肠癌细胞株HCT116和肝癌细胞株Bel7402。细胞生长至对数生长期后，收集细胞，1000rpm离心5分钟，弃去上清液，用适量培养基进行悬浮，调整细胞浓度至3×104/ml。将细胞悬液接种到96孔细胞培养板中，每孔100μl，放入细胞培养箱(37℃，5％CO2)中培养24h后，加入待测药物(从10-4～102μM中选定八个浓度，为别为：1×10-4μM、1×10-3μM、1×10-2μM、1×10-1μM、1μM、10μM、1×101 . 5μM、1×102μM)。阴性对照组加入DMSO(终浓度为0.5％)，各组均设3个复孔。培养箱中培养72h后，每孔加入5mg/ml的MTT 20μl，于37℃放置3h。每孔加入150μl DMSO，37℃摇床振荡5min，492nm/620nm测吸光度(OD)。运用Prism Graphpad统计软件计算IC50值(以μM计)。所得结果汇总于下述表1中。
表1
| 化合物 | SKBr-3 | MDA-MB-468 | HCT116 | Bel7402 |
| 实施例1 | 1.005 | 5.861 | 9.969 | 13.48 |
| 实施例2 | 0.828 | 4.307 | 4.167 | 2.887 |
| 实施例3 | 0.989 | 11.61 | 11.33 | 2.664 |
| 实施例4 | 1.294 | 10.06 | 12.44 | 2.808 |
| 实施例5 | 0.584 | 4.299 | 8.207 | 1.233 |
| 实施例6 | 1.691 | 11.53 | 11.71 | 9.300 |
| 实施例7 | >100 | >100 | >100 | 57.67 |
| 实施例8 | 1.397 | 9.711 | 10.19 | 2.567 |
| 实施例9 | 5.227 | 3.849 | 17.89 | 3.863 |
| 实施例10 | 8.248 | 5.013 | 26.39 | 5.209 |
| 实施例11 | 1.878 | 3.997 | 4.621 | 6.842 |
| 实施例12 | 3.408 | 4.684 | 5.355 | 2.613 |
| 实施例13 | 0.3825 | 9.447 | 13.65 | 3.293 |
试验例2：除额外采用前列腺癌细胞株KB以外，采用与试验例1相同的方法对其余实施例中的化合物的活性进行测试(以Lapatinib为阳性对照)。所得结果汇总于下述表2中。
表2
| 化合物 | SKBr-3 | MDA-MB-468 | HCT116 | Bel7402 | KB |
| 实施例14 | 5.541 | 1.667 | 5.382 | 3.427 | 4.699 |
| 实施例15 | 1.545 | 5.228 | 15.10 | 6.341 | 2.968 |
| 实施例16 | 1.222 | 5.492 | 12.96 | 4.089 | 2.408 |
| 实施例17 | 1.265 | 3.783 | 10.22 | 1.978 | 0.8699 |
| 实施例18 | 1.844 | 3.134 | 9.050 | 4.601 | 1.546 |
| 实施例19 | 1.173 | 5.074 | 9.478 | 2.047 | 0.8257 |
| 实施例20 | 1.596 | 3.586 | 7.293 | 3.329 | 0.8100 |
| 实施例21 | 1.237 | 5.868 | 10.24 | 3.263 | 1.037 |
| 实施例22 | 1.346 | 5.443 | 11.15 | 3.414 | 1.071 |
| 实施例23 | 1.687 | 3.356 | 9.114 | 6.149 | 1.738 |
| 实施例24 | 1.377 | 2.597 | 9.012 | 3.168 | 0.8012 |
| 实施例25 | 1.250 | 4.732 | 10.35 | 1.550 | 0.9424 |
| 实施例26 | 1.439 | 3.881 | 7.588 | 1.716 | 1.290 |
| 实施例27 | 1.791 | 4.205 | 8.299 | 1.696 | 0.8563 |
| 实施例28 | 1.953 | 13.21 | 13.35 | 3.500 | 0.7932 |
| 实施例29 | 6.892 | 3.345 | 44.50 | 6.772 | 5.329 |
| Lapatinib | 126.4 | 17.97 | 4.714 | 7.884 | 3.502 |
Claims (10)
1.通式(I)所示的化合物或其药学上可接受的盐或溶剂化物：
其中，n为1-4的整数；
Y1、Y2、Y3、Y4和Y5中的至少两个为选自于O、N和S的杂原子，其余为C原子，且Y1不为O或S；
R1表示吡啶环上任选存在的取代基，p表示取代基R1的数量，为0-4的整数，上述任选存在的取代基R1为烷氧基；
R表示五元杂芳环上任选存在的取代基，m表示取代基R的数量，为0-3的整数，上述任选存在的取代基R各自独立地选自于由芳基、杂芳基、苯并、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、酰基、硫代酰基、酰基氧基、卤代烷基、硝基、亚硝基、硫烷基和甲硅烷基所组成的组，并且任选被独立选自于下组中的一个或多个基团R2进一步取代：烷基、环烷基、烯基、环烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环基、杂环基烷基、烷氧基、环烷氧基、芳基氧基、烷基硫基、环烷基硫基、芳基硫基、烷氧基羰基、芳基氧基羰基、酰基、硫代酰基、酰基氧基、酰胺基、脲基、亚硫酰基、烷基磺酰基、芳基磺酰基、卤代烷基、氨甲酰基、卤素、氰基、异氰基、硝基、亚硝基、硫氰基、异硫氰基、酰肼基、硫烷基、磺基和甲硅烷基所组成的组。
2.如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中，通式(I)的定义满足以下限定条件(1)至(6)中的一项或多项：
(1)n为1-3的整数，优选n为1或2；
(2)任选存在的取代基R1为C1-C4烷氧基，优选甲氧基；
(3)p为0-3的整数，优选p为0-2的整数，更优选p为0或1；
(4)m为0-2的整数，更优选m为0或1；
(5)连接于吡啶环的2位、3位或4位；和/或
(6)Y1、Y2、Y3、Y4和Y5构成的五元杂芳环含有2-4个选自于O、N和S的杂原子，优选所述五元杂芳环含有1-4个N原子以及0-1个O或S原子，更优选所述五元杂芳环选自于由噁唑、异噁唑、咪唑、噻唑、三唑、噁二唑、噻二唑和四唑所组成的组。
3.如权利要求1或2所述的化合物或其药学上可接受的盐或溶剂化物，其中，任选存在的取代基R选自于由苯基、苯并和包含5-12个环原子的杂芳基所组成的组，并且任选被独立选自于下组中的一个或多个基团R2进一步取代：C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基、卤素、硝基。
4.如权利要求3所述的化合物或其药学上可接受的盐或溶剂化物，其中，所述包含5-12个环原子的杂芳基选自于由噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基。
5.如权利要求3或4所述的化合物或其药学上可接受的盐或溶剂化物，其中，所述一个或多个基团R2各自独立地选自于氟、氯、溴、碘、甲基、甲氧基、三氟甲基、三氟甲氧基、硝基。
6.如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中，所述化合物选自于由下述化合物(1)至(29)所组成的组：
(1)3-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噻二唑-2-基))乙酯；
(2)3-吡啶甲氨基二硫代甲酸(2-(苯并噁唑-2-基))乙酯；
(3)3-吡啶甲氨基二硫代甲酸(2-(苯并三唑-2-基))乙酯；
(4)3-吡啶甲氨基二硫代甲酸(2-(3-苯基-1,2,4-噁二唑-5-基))乙酯；
(5)3-吡啶甲氨基二硫代甲酸-(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯；
(6)3-吡啶甲氨基二硫代甲酸(2-(苯并咪唑-2-基))乙酯；
(7)3-吡啶甲氨基二硫代甲酸(2-(1H-四唑-5-基))乙酯；
(8)3-吡啶甲氨基二硫代甲酸(2-(苯并噻唑-2-基))乙酯；
(9)4-吡啶甲氨基二硫代甲酸(2-(苯并噁唑-2-基))乙酯；
(10)4-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯；
(11)3-吡啶乙氨基二硫代甲酸(2-(2-苯并噁唑-2-基))乙酯；
(12)3-吡啶乙氨基二硫代甲酸-(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯；
(13)2-甲氧基-3-吡啶甲氨基二硫代甲酸(2-(5-苯基-1,3,4-噁二唑-2-基))乙酯；
(14)3-吡啶甲氨基二硫代甲酸(2-(5-(2-氟苯基)-1,3,4-噁二唑-2-基))乙酯；
(15)3-吡啶甲氨基二硫代甲酸{2-[5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基]}乙酯；
(16)3-吡啶甲氨基二硫代甲酸{2-[5-(4-三氟甲基苯基)-1,3,4-噁二唑-2-基]}乙酯；
(17)3-吡啶甲氨基二硫代甲酸{2-[5-(4-氯苯基)-1,3,4-噁二唑-2-基]}乙酯；
(18)3-吡啶甲氨基二硫代甲酸{2-[5-(4-硝基苯基)-1,3,4-噁二唑-2-基]}乙酯；
(19)3-吡啶甲氨基二硫代甲酸{2-[5-(吡咯-3-基)-1,3,4-噁二唑-2-基]}乙酯；
(20)3-吡啶甲氨基二硫代甲酸{2-[5-(呋喃-2-基)-1,3,4-噁二唑-2-基]}乙酯；
(21)3-吡啶甲氨基二硫代甲酸{2-[5-(噻吩-3-基)-1,3,4-噁二唑-2-基]}乙酯；
(22)3-吡啶甲氨基二硫代甲酸{2-[5-(噻吩-2-基)-1,3,4-噁二唑-2-基]}乙酯；
(23)3-吡啶甲氨基二硫代甲酸{2-[5-(5-甲基异噁唑-3-基)-1,3,4-噁二唑-2-基]}乙酯；
(24)3-吡啶甲氨基二硫代甲酸{2-[5-(吡啶-3-基)-1,3,4-噁二唑-2-基]}乙酯；
(25)3-吡啶甲氨基二硫代甲酸{2-[5-(6-氯吡啶-3-基)-1,3,4-噁二唑-2-基]}乙酯；
(26)3-吡啶甲氨基二硫代甲酸{2-[5-(吡嗪-2-基)-1,3,4-噁二唑-2-基]}乙酯；
(27)3-吡啶甲氨基二硫代甲酸{2-[5-(喹啉-6-基)-1,3,4-噁二唑-2-基]}乙酯；
(28)3-吡啶甲氨基二硫代甲酸-{2-[5-(喹啉-2-基)-1,3,4-噁二唑-2-基]}乙酯；
(29)3-吡啶甲氨基二硫代甲酸{2-[5-(苯并噻吩-2-基)-1,3,4-噁二唑-2-基]}乙酯。
7.一种药物组合物，所述药物组合物包含：权利要求1-6中任一项所述化合物或其药学上可接受的盐或溶剂化物；以及药学上可接受的载体。
8.制备权利要求1-6中任一项所述化合物的方法，所述方法包括如下将原料A、二硫化碳和原料B在有机碱、优选三乙胺的存在下发生偶联反应：
其中各取代基如通式(I)中所定义，X表示卤素原子。
9.权利要求1-6中任一项所述的化合物及其药学上可接受的盐或溶剂化物在制备用于抗肿瘤的药物方面的用途。
10.如权利要求9所述的用途，所述肿瘤选自于由肺癌、乳腺癌、肝癌、胃癌、宫颈癌、结肠癌和上皮癌所组成的组。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510204696.4A CN106146487B (zh) | 2015-04-27 | 2015-04-27 | 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510204696.4A CN106146487B (zh) | 2015-04-27 | 2015-04-27 | 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106146487A true CN106146487A (zh) | 2016-11-23 |
| CN106146487B CN106146487B (zh) | 2019-05-10 |
Family
ID=57347751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510204696.4A Active CN106146487B (zh) | 2015-04-27 | 2015-04-27 | 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106146487B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966978A (zh) * | 2017-03-05 | 2017-07-21 | 北京化工大学 | 一种酰胺类化合物及其制备方法和用途 |
| CN113024514A (zh) * | 2021-03-26 | 2021-06-25 | 北京大学 | 氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用 |
| CN116693540A (zh) * | 2023-05-23 | 2023-09-05 | 江苏八巨药业有限公司 | 一种西他列汀中间体的合成方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1683344A (zh) * | 2005-03-09 | 2005-10-19 | 首都师范大学 | 4－喹唑啉酮衍生物及其在抗肿瘤药物中的应用 |
| CN1727332A (zh) * | 2004-07-27 | 2006-02-01 | 北京大学 | 芳甲氨基二硫代甲酸酯类化合物及其制备方法和应用 |
| CN101899011A (zh) * | 2009-05-26 | 2010-12-01 | 北京大学 | 氨基二硫代甲酸酯类化合物、其制备方法和应用 |
| CN102234271A (zh) * | 2010-04-21 | 2011-11-09 | 北京大学 | 芳杂(烷基)氨基二硫代甲酸酯类化合物、其制备方法和应用 |
-
2015
- 2015-04-27 CN CN201510204696.4A patent/CN106146487B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1727332A (zh) * | 2004-07-27 | 2006-02-01 | 北京大学 | 芳甲氨基二硫代甲酸酯类化合物及其制备方法和应用 |
| CN1683344A (zh) * | 2005-03-09 | 2005-10-19 | 首都师范大学 | 4－喹唑啉酮衍生物及其在抗肿瘤药物中的应用 |
| CN101899011A (zh) * | 2009-05-26 | 2010-12-01 | 北京大学 | 氨基二硫代甲酸酯类化合物、其制备方法和应用 |
| CN102234271A (zh) * | 2010-04-21 | 2011-11-09 | 北京大学 | 芳杂(烷基)氨基二硫代甲酸酯类化合物、其制备方法和应用 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966978A (zh) * | 2017-03-05 | 2017-07-21 | 北京化工大学 | 一种酰胺类化合物及其制备方法和用途 |
| WO2018161476A1 (zh) * | 2017-03-05 | 2018-09-13 | 北京化工大学 | 一种酰胺类化合物及其制备方法和用途 |
| CN106966978B (zh) * | 2017-03-05 | 2020-06-26 | 北京化工大学 | 一种酰胺类化合物及其制备方法和用途 |
| CN113024514A (zh) * | 2021-03-26 | 2021-06-25 | 北京大学 | 氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用 |
| WO2022199367A1 (zh) * | 2021-03-26 | 2022-09-29 | 北京大学 | 氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用 |
| CN116693540A (zh) * | 2023-05-23 | 2023-09-05 | 江苏八巨药业有限公司 | 一种西他列汀中间体的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106146487B (zh) | 2019-05-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2785679C (en) | 1,3,4-oxadiazole-2-carboxamide compound | |
| RU2428420C2 (ru) | Новое производное кумарина, обладающее противоопухолевой активностью | |
| CN101636397B (zh) | 脲类化合物、其制备方法及其医药用途 | |
| AU2003265348B2 (en) | Thiophene compounds | |
| TWI643854B (zh) | 可做為ａｔｒ酶抑制劑之化合物 | |
| CN104470902B (zh) | N‑(3‑杂芳基芳基)‑4‑芳基芳基甲酰胺和类似物作为Hedgehog通路抑制剂及其应用 | |
| TWI851921B (zh) | 吡嗪類衍生物及其在抑制shp2中的應用 | |
| WO2002088110A1 (fr) | Derives de quinoline ayant un groupe azolyle et derives de quinazoline | |
| KR20100042623A (ko) | ｐ27 단백질 유도제 | |
| WO2008008059A1 (en) | Anti-cancer agents ans uses thereof | |
| CN102015678A (zh) | 作为c-Met抑制剂的稠合吡啶活性物质 | |
| WO2007036131A1 (fr) | Dérivés de carzole sulfamide et leur procédé de préparation | |
| CA2685389A1 (en) | Tricyclic compounds as matrix metalloproteinase inhibitors | |
| CA2983721A1 (en) | 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same | |
| BR112015030399B1 (pt) | Derivados heterocíclicos, uso dos referidos derivados e composição farmacêutica para a prevenção ou tratamento de doenças associadas com a ativação da proteína stat3 | |
| CA3071900A1 (en) | Substituted penta- fused hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof | |
| KR102214225B1 (ko) | 5원 헤테로시클릭 아미드계 wnt 경로 억제제 | |
| BRPI0713401A2 (pt) | composto, composição farmacêutica, uso de um composto, e, método de tratamento de um distúrbio de agregação plaquetária | |
| CN101723890B (zh) | 芳基硫脲及其制备方法和用途 | |
| CN107098846A (zh) | N-酰基磺酰胺类FBPase抑制剂、其制备方法、药物组合物及用途 | |
| WO2019144764A1 (zh) | 芳香杂环化合物、其中间体、制备方法、药物组合物和应用 | |
| CN109942505A (zh) | 异噻唑啉酮类化合物及相应用途 | |
| CN106146487A (zh) | 吡啶甲氨基二硫代甲酸杂芳环烷基酯类化合物及其制备方法和用途 | |
| CN104168958B (zh) | 可用于治疗炎症和癌症的二芳基磺酰胺 | |
| WO2019144765A1 (zh) | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |