CN110526854A - A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug - Google Patents
A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug Download PDFInfo
- Publication number
- CN110526854A CN110526854A CN201910679937.9A CN201910679937A CN110526854A CN 110526854 A CN110526854 A CN 110526854A CN 201910679937 A CN201910679937 A CN 201910679937A CN 110526854 A CN110526854 A CN 110526854A
- Authority
- CN
- China
- Prior art keywords
- ketone
- methyl
- propyl
- alkene
- trimethoxyphenyl
- 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
- 150000002576 ketones Chemical class 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 229940079593 drug Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 86
- -1 mono-substituted methoxyl group Chemical group 0.000 claims description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N 4-methyl-1h-indole Chemical compound CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 13
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N 3-methoxypyridine Chemical compound COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 230000036457 multidrug resistance Effects 0.000 claims description 5
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 231100000782 microtubule inhibitor Toxicity 0.000 claims description 3
- ICBPURKUPVLVCM-UHFFFAOYSA-N 1,5-dimethyl-2-phenylpyrazol-3-one;2-hydroxy-2-phenylacetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1.CN1C(C)=CC(=O)N1C1=CC=CC=C1 ICBPURKUPVLVCM-UHFFFAOYSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 claims description 2
- KGWPHCDTOLQQEP-UHFFFAOYSA-N 7-methylindole Chemical compound CC1=CC=CC2=C1NC=C2 KGWPHCDTOLQQEP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004838 phosphoric acid Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229940032330 sulfuric acid Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims 2
- 239000002243 precursor Substances 0.000 claims 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
- 241000720974 Protium Species 0.000 claims 1
- 229940107700 pyruvic acid Drugs 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 102000004243 Tubulin Human genes 0.000 abstract description 2
- 108090000704 Tubulin Proteins 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 230000004069 differentiation Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 85
- 235000019441 ethanol Nutrition 0.000 description 45
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000012043 crude product Substances 0.000 description 22
- 238000001953 recrystallisation Methods 0.000 description 20
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 19
- 150000003053 piperidines Chemical class 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 230000000259 anti-tumor effect Effects 0.000 description 13
- 206010009944 Colon cancer Diseases 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 208000029742 colonic neoplasm Diseases 0.000 description 10
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 206010059866 Drug resistance Diseases 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 3
- OXMKZTMGJSTKPG-UHFFFAOYSA-N 4-methyl-1h-indole-3-carbaldehyde Chemical compound CC1=CC=CC2=C1C(C=O)=CN2 OXMKZTMGJSTKPG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 235000005513 chalcones Nutrition 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical group C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- SKSALLCFIHDSMG-UHFFFAOYSA-N 1-bromoindole-3-carbaldehyde Chemical compound C1=CC=C2N(Br)C=C(C=O)C2=C1 SKSALLCFIHDSMG-UHFFFAOYSA-N 0.000 description 1
- DQPAVYYQFNXYHC-UHFFFAOYSA-N 1-chloroindole-3-carbaldehyde Chemical compound ClN1C=C(C2=CC=CC=C12)C=O DQPAVYYQFNXYHC-UHFFFAOYSA-N 0.000 description 1
- OHGRDCDSBYWPEL-UHFFFAOYSA-N 1-fluoroindole Chemical class C1=CC=C2N(F)C=CC2=C1 OHGRDCDSBYWPEL-UHFFFAOYSA-N 0.000 description 1
- QYJRWOIMQWHBIS-UHFFFAOYSA-N 1-fluoroindole-3-carbaldehyde Chemical compound C1=CC=C2N(F)C=C(C=O)C2=C1 QYJRWOIMQWHBIS-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- KAIWRKYDYWYFIT-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=N1 KAIWRKYDYWYFIT-UHFFFAOYSA-N 0.000 description 1
- IAMJYHYPXUQXGI-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine-3-carbaldehyde Chemical compound N1=CC=C2C(C=O)=CNC2=C1 IAMJYHYPXUQXGI-UHFFFAOYSA-N 0.000 description 1
- JDIWXZAFVHTGBQ-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine-3-carbaldehyde Chemical compound C1=CN=C2C(C=O)=CNC2=C1 JDIWXZAFVHTGBQ-UHFFFAOYSA-N 0.000 description 1
- DYWWWDIUNPDQLM-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine-3-carbaldehyde Chemical compound C1=NC=C2C(C=O)=CNC2=C1 DYWWWDIUNPDQLM-UHFFFAOYSA-N 0.000 description 1
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 1
- ZTNQWTPWKNDRNF-UHFFFAOYSA-N 5-methyl-1h-indole-3-carbaldehyde Chemical compound CC1=CC=C2NC=C(C=O)C2=C1 ZTNQWTPWKNDRNF-UHFFFAOYSA-N 0.000 description 1
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical class [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
- PHKYMSLVWLYDKP-UHFFFAOYSA-N 5-nitro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=C2NC=C(C=O)C2=C1 PHKYMSLVWLYDKP-UHFFFAOYSA-N 0.000 description 1
- LZERQSJGPXFAKB-UHFFFAOYSA-N 6-methyl-1h-indole-3-carbaldehyde Chemical compound CC1=CC=C2C(C=O)=CNC2=C1 LZERQSJGPXFAKB-UHFFFAOYSA-N 0.000 description 1
- ADGKBVRTGVODMM-UHFFFAOYSA-N 7-nitro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC=C2C=O ADGKBVRTGVODMM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 102000004855 Multi drug resistance-associated proteins Human genes 0.000 description 1
- 108090001099 Multi drug resistance-associated proteins Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical group S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- KBJMYBSEFSJJNV-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-3-carbaldehyde Chemical compound C1=CC=CC2=C(C=O)C=NN21 KBJMYBSEFSJJNV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- RYGIHSLRMNXWCN-UHFFFAOYSA-N quinoline-3-carbaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CN=C21 RYGIHSLRMNXWCN-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
-
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to pharmaceutical technology fields, it is proposed a kind of ɑ, alpha, beta-unsaturated ketone derivative and preparation method thereof, general structure is as shown in I, each substituent group is defined in the specification, the compound of the present invention can target tubulin, all have a strong inhibitory effect to kinds of tumors parental generation and persister, can prepare the drug for treating malignant tumour and with differentiation and proliferation related disease.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of active ɑ of micro-pipe targeting anti-tumor, alpha, beta-unsaturated ketone spread out
Biology and the preparation method and application thereof.
Background technique
Currently, cancer has become a kind of disease for seriously threatening human health life.Clinical treatment is pernicious swollen at present
The method that tumor still mainly uses chemotherapy, but the tumour of more than half has generated significant drug resistance to classic chemotherapy drug.According to U.S.'s cancer
The estimation of disease association, 90% or more tumor patient die of different degrees of drug resistance, and tumor drug resistance has become clinical chemotherapy failure
Main cause.Therefore, develop a kind of selectively targeting multidrug resistance new antitumoral chemotherapeutics have become there is an urgent need to.
In recent years, micro-pipe targeting preparation has become a pith of anti-tumor drug research and development.Micro-pipe is by α, and β is micro-
The dynamic cellular skeleton of tubulin composition, they play an important role in various cell functions, including mitosis.Micro-pipe exists
The different phase of cell cycle shows different dynamic behaviours, inhibits microtubule dynamics, arresting cell cycle, and inducing cell withers
It dies, is the critical treatment target in tumour cell.It is a variety of that the Antitubulins such as taxol, vincaleukoblastinum are widely used in treatment
Cancer.However, they show narrow therapeutic window, poor selectivity and multidrug resistance problem, be often as p- glycoprotein or
The high expression of multidrug resistance associated protein.Therefore, developing a kind of novel targeted micro-pipe, selectivity, good, less toxic small molecule still has
Very big demand (Pharm Res (2012) 29:2943-2971).
Chalcone derivative is a kind of important compound in flavonoids, and molecular structure is simple, with 1,3- diphenyl propylene
Ketone is basic framework, has extensive biological activity, such as antitumor, antibacterial, anti-inflammatory, treating tuberculosis.New indole chalcone
It is the novel chalcone derivative of one kind of the present inventor's early-stage study discovery, its anti-tumor activity can be made to significantly improve, further
Ground finds that such chalcone derivative acts on 'beta '-tubulin to antitumor action Mechanism Study, effectively induction tumour cell
Apoptosis, the blocks tumor cells period is in the G2/M phase；Wherein, the indoles chalcone that representation compound Alpha-Methyl replaces shows excellent
Different inhibition parental tumor cell and multidrug resistance tumor cells growth activity (Mol.Pharmaceutics 2018,15,
3892-3900)。
Summary of the invention
The object of the present invention is to provide a kind of active ɑ of micro-pipe targeting anti-tumor, alpha, beta-unsaturated ketone derivatives；Of the invention
Another object is to provide such ɑ, the preparation method of alpha, beta-unsaturated ketone derivative；The third object of the present invention is to provide such ɑ, β-
The application of beta-unsaturated ketone derivative.
To achieve the goals above, the present invention proposes a kind of ɑ, alpha, beta-unsaturated ketone derivative and its isomers, salt or solvent
Close the pro-drug of object.
It there is a need to propose that the compound of logical formula (I) described in one kind is preparing the application in microtubule inhibitors.
It there is a need to propose that the compound of the logical formula (I) is treating the application in tumour, including to tumour cell
Lethal effect, and the application in the tumor disease that treatment has multidrug resistance.
The first aspect of the invention provides a kind of ɑ, alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate
Pro-drug, structure is as shown in general formula I:
Wherein A, B are respectively selected from saturated rings, aromatic ring and heteroaromatic, saturated rings or aromatic ring and heteroaromatic and ring；
R1It is respectively selected from hydrogen, 1~7 identical or different C1-C10 alkoxy；
R2It is respectively selected from hydrogen, 1~7 identical or different C1-C10 alkyl, C1-C10 alkoxy, halogen, nitrogen protium group
At substituent group, hydrocarbon oxygen element composition substituent group, nitrogen oxygen element composition substituent group；
R3It is respectively selected from hydrogen, C1-C10 alkyl；And with A form polynary ring-(CH2)n, (n=1~10)；
Preferably, wherein A, B are respectively selected from saturated rings, aromatic ring and heteroaromatic, saturated rings or aromatic ring and heteroaromatic and ring；
R1Be respectively selected from trimethoxy, dimethoxy, mono methoxy that the upper different location of hydrogen, A replaces,
R2Be respectively selected from the mono-substituted methoxyl group of the upper different location of hydrogen, B, methyl, fluorine, chlorine, bromine, nitro, amido, carboxyl,
R3Be respectively selected from hydrogen, methyl, ethyl and with A form polynary ring-(CH2)n, (n=1~10)；
Preferably,
A is selected from
B is selected from
R1Be respectively selected from trimethoxy, dimethoxy, mono methoxy that the upper different location of hydrogen, A replaces,
R2Be respectively selected from the mono-substituted methoxyl group of the upper different location of hydrogen, B, methyl, fluorine, chlorine, bromine, nitro, amido, carboxyl,
R3It is respectively selected from hydrogen, methyl, ethyl and the-CH with A composition hexatomic ring2CH2-。
Preferably, the pharmaceutically acceptable salt includes the acid-addition salts that generalformulaⅰcompound and following acid are formed: salt
Acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, acetone
Acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.
Preferably, the ɑ, alpha, beta-unsaturated ketone derivative are selected from one of flowering structure:
(E) -2- methyl -3- (4- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (1),
(E) -2- methyl -3- (5- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (2),
(E) -2- methyl -3- (6- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (3),
(E) -2- methyl -3- (7- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (4),
(E)-3- (benzo [b] thiene-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(5)、
(E)-3- (the fluoro- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(6)、
(E)-3- (the fluoro- 1H- indol-3-yl of 6-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(7)、
(E)-3- (the chloro- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(8)、
(E)-3- (the bromo- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(9)、
(E) -1- (3,5- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone (10),
(E) -3- (1H- indol-3-yl) -1- (5- methoxypyridine -3- base) -2- methyl propyl- 2- alkene -1- ketone (11),
(E)-3- (6- methoxyl group-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-
1- ketone (12),
(E) -2- methyl -3- (5- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (13),
(E) -2- methyl -3- (6- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (14),
(E) -2- methyl -3- (7- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (15),
(E)-3- (6- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1-
Ketone (16),
(E) -2- ((1H- indol-3-yl) methylene) -1- (3,4,5- trimethoxyphenyl) butyl- 1- ketone (17),
(E) -1- (3,4- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone (18),
(E) -3- (1H- indol-3-yl) -1- (3- methoxyphenyl) -2- methyl propyl- 2- alkene -1- ketone (19),
(E)-3- (1H- indol-3-yl)-2- methyl-1-phenyl propyl- 2- alkene-1- ketone (20),
(E) -3- (1H- indol-3-yl) -1- phenyl propyl- 2- alkene -1- ketone (21),
(E) -2- methyl -3- (1H- pyrrolo- [2,3-b] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2-
Alkene -1- ketone (22),
(E) -2- methyl -3- (1H- pyrrolo- [3,2-c] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2-
Alkene -1- ketone (23),
(E) -2- methyl -3- (1H- pyrrolo- [3,2-b] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2-
Alkene -1- ketone (24),
(E) -2- methyl -3- (1H- pyrrolo- [2,3-c] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2-
Alkene -1- ketone (25),
(E) -3- (2- methyl -3- oxo -3- (3,4,5- trimethoxyphenyl) propyl- 1- alkene -1- base) -1H- indoles -6-
Carboxylate methyl ester (26),
(E) -3- (1H- indol-3-yl) -1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) -2- first
Base propyl- 2- alkene -1- ketone (27),
(E)-3- (imidazo [1,2-a] pyridin-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-
1- ketone (28),
(E) -2- methyl -3- (pyrazolo [1,5-a] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
1- ketone (29),
(E) -1 (2H) -one (30) of -2- ((1H- indol-3-yl) methylene) -5- methoxyl group -3,4- dihydronaphthalene,
(E) -3- (2- methyl -3- oxo -3- (3,4,5- trimethoxyphenyl) propyl- 1- alkene -1- base) -1H- indoles -6-
Carboxylic acid (31),
(E) -2- methyl -3- (1H- pyrazole-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (32),
(E) -2- methyl -3- (1H- pyrroles -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (33),
(E) -2- methyl -3- (quinoline -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (34),
(E)-3- (1H- indoles-2- base)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (35),
(E) -2- (4- (3- (1H- indol-3-yl) -2- methylacryloyl) -2,6- dimethyl phenoxy) ethyl acetate
(36)、
(E)-3- (7- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1-
Ketone (37),
(E)-3- (5- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1-
Ketone (38),
The second aspect of the invention provides the answering in treatment tumor disease of compound shown in above structure general formula (I)
With.
The third aspect of the invention provides the application, particular as microtubule inhibitors anti-tumor drug to swollen
The lethal effect of oncocyte.The tumour is HCT-116 (colon cancer cell), (drug resistance colon cancer is thin by HCT-116/OXA
Born of the same parents).
The third aspect of the invention provides such ɑ, alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate
Pro-drug preparation method.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine generation；" alkyl " refers to the alkyl of linear chain or branched chain；" heterocyclic base "
Refer to that containing one or more be armaticity selected from the heteroatomic monocycle of N, O, S or polycyclic cyclic annular system, cyclic annular system, such as
Pyrrole radicals, pyrazolyl, imidazole radicals, indyl, quinolyl, benzothienyl, pyrrolopyridinyl etc.；" heterocycle " refer to containing
One or more is selected from the heteroatomic monocycle of N, O, S or polycyclic cyclic annular system, such as piperazinyl, piperidyl, pyrrolidinyl, pyrazoles
Alkyl etc..
Due to the adoption of the above technical scheme, the beneficial effects of the present invention are embodied in following several respects:
The pro-drug of ɑ of the invention, alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate has preferable
The activity for inhibiting tumor cell proliferation can effectively inhibit the kinds of tumor such as colon cancer, lung cancer, leukaemia cell and drug resistance swollen
The proliferation of oncocyte；Present invention synthesis is simple, is not directed to tedious steps, synthesis cost is low.
Specific embodiment
The reagents and materials used in the present invention are commercially available or can prepare by literature method.
In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to manufacturer
Proposed condition.All raw materials are not specified being purchased from for synthetic method and explore the factories such as platform, Aladdin, Sigma-Aldrich
Family is that analysis is pure.
Embodiment 1:(E) -2- methyl -3- (4- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl-
The preparation of 2- alkene -1- ketone (1)
The synthesis of step a:1- (3,4,5- trimethoxyphenyl) propyl- 1- alcohol.
At 0 DEG C, 3,4,5-Trimethoxybenzaldehyde (2g, 10.19mmol) is added in reaction vessel, after vacuum processing
THF (20mL) and ethylmagnesium bromide (15mL) is added, reacts 4h under anaerobic, TLC monitoring is dilute with water and ethyl acetate
It releases, and is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and is spin-dried for organic phase, and remaining crude product passes through silicagel column color
Spectrum purifying (eluant, eluent: ethyl acetate/n-hexane=1:4), obtains compound 1- (3,4,5- trimethoxyphenyl) propyl- 1- alcohol
2.13g, yield 94%.
The synthesis of step b:1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone.
At room temperature, 1- (3,4,5- trimethoxyphenyl) propyl- 1- alcohol (746.6mg, 3.30mmol) is dissolved in CH2Cl2
(10mL) is added PCC (1068mg, 4.96mmol), N2Then the lower reaction of protection, the monitoring of TLC contact plate are diluted with water, CH2Cl2Extraction
It takes, and is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and is spin-dried for organic phase, and remaining crude product passes through silicagel column color
Spectrum purifying (eluant, eluent: petrol ether/ethyl acetate=5:1) obtains compound 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone
690mg, yield 93.2%.
Step c:(E) -2- methyl -3- (4- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2-
The synthesis of alkene -1- ketone.
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (448mg, 2mmol) is dissolved in piperidines (0.1 mL)
It in toluene (6mL) solution, is added 4- Methyl-1H-indole -3- formaldehyde (156.8mg, 0.8mmol), 130 DEG C of reaction 4h are spin-dried for
Organic phase, remaining crude product obtain target compound (E) -2- methyl -3- (4- Methyl-1H-indole -3- base)-through ethyl alcohol recrystallization
1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (1) 230mg, yield 51.3%.1H NMR(300MHz,CDCl3)δ
8.69 (s, 1H), 7.97 (s, 1H), 7.60 (d, 1H, J=1.2Hz), 7.26-7.29 (m, 1H), 7.10-7.16 (m, 1H),
6.89-6.95(m,3H),3.89-3.91(m,9H), 2.47(s,3H),2.29(s,3H).MS(ESI):m/z[M+H]+:
366.17。
The raw material products such as 4- Methyl-1H-indole -3- formaldehyde can be directly commercially available in biological producer, subsequent raw material
Access approaches are also known.
The preparation of compound 2-4 is referring to embodiment 1.In step c, when prepare compound 2,3,4, by " 4- methyl-1 H-
Indole -3-formaldehyde " replaces with " 5- Methyl-1H-indole -3- formaldehyde ", " 6- methyl-1 H- indole -3-formaldehyde ", " 7- first respectively
Base -1H- indole -3-formaldehyde ", and dosage is constant.
Embodiment 2:(E)-3- (benzo [b] thiene-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2-
The preparation of alkene -1- ketone (5)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (448mg, 2mmol) and benzo [b] thiophene -3- first
Aldehyde (162.2mg, 1mmol) is dissolved in ethyl alcohol (8mL) solution, and 30min is stirred at room temperature, and sodium hydroxide (3mL) is then added to anti-
CH should be used completely2Cl2Extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate dry, filter, and are spin-dried for organic phase, remaining crude product
Target compound (E)-3- (benzo [b] thiene-3-yl)-2- methyl-1-(3,4,5- trimethoxy is obtained through ethyl alcohol recrystallization
Phenyl) 206.1 mg of propyl- 2- alkene -1- ketone, yield 56%.1H NMR(300MHz,CDCl3)δ7.91(s,1H),7.70(d,2H,J
=13.2Hz), 7.44 (d, 3H, J=14.1Hz), 7.09 (s, 2H), 3.91-3.96 (m, 9H), 2.35 (s, 3H) .MS
(ESI):m/z [M+H]+:369.12.
Embodiment 3:(E)-3- (the fluoro- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2-
The preparation of alkene -1- ketone (6)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and the fluoro- 1H- indoles-of 5-
3- formaldehyde (81.6mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h have been spin-dried for
Machine phase, remaining crude product obtain target compound (E)-3- (the fluoro- 1H- indol-3-yl of 5-)-2- methyl-1-through ethyl alcohol recrystallization
(3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone 94.1mg, yield 51%1H NMR(300MHz,CDCl3)δ8.62(s,
1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.36 (dd, 1H, J=4.5,8.7Hz), 7.20-7.26 (m, 1H), 7.02 (s,
3H),3.90-3.96(m,9H),2.31(s,3H). MS(ESI):m/z[M+H]+:370.14。
The preparation of compound 7-8 is referring to embodiment 3.That is: when producing compound 7,8, " the fluoro- 1H- indoles -3- of 6- is used respectively
Formaldehyde ", " the chloro- 1H- indole -3-formaldehyde of 5- " substitution " the fluoro- 1H- indole -3-formaldehyde of 5- " can be realized, and dosage is identical.
Embodiment 4:(E)-3- (the bromo- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2-
The preparation of alkene -1- ketone (9)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (448mg, 2mmol) is dissolved in PhCH3(6 mL), piperazine
In pyridine (0.12mL), the bromo- 1H- indole -3-formaldehyde (149.2mg, 0.66mmol) of 5- is added, 110 DEG C of reaction 4h are spin-dried for organic
Phase, remaining crude product obtain compound (E)-3- (the bromo- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- tri- through ethyl alcohol recrystallization
Methoxyphenyl) propyl- 2- alkene -1- ketone 154.7mg, yield 54%.1H NMR(300MHz,CDCl3)δ8.61(s,1H),7.70
(s,1H),7.62(s,1H),7.53(s,1H), 7.33-7.38(m,2H),7.03(s,2H),3.91-3.97(m,9H),2.30
(s,3H)。
Embodiment 5:(E) -1- (3,5- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone
(10) preparation
Intermediate 1- (3,5- Dimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,5- Dimethoxyphenyl) propyl- 1- ketone (200mg, 1.03mmol) and 1H- indole -3-formaldehyde
(49.8mg, 0.323mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic
Phase, remaining crude product obtain target compound (E) -1- (3,5- Dimethoxyphenyl) -3- (1H- indoles -3- through ethyl alcohol recrystallization
Base) -2- methyl propyl- 2- alkene -1- ketone 56.1mg, yield 51%.1H NMR(300MHz,CDCl3)δ8.73(s,1H),7.70(s,
1H), 7.63 (s, 1H), 7.56 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.8Hz), 7.16-7.21 (m, 1H), 6.86
(s,3H),6.64(s,1H),3.83(s,6H), 2.31(s,3H).MS(ESI):m/z[M+H]+:322.14。
Embodiment 6:(E) -3- (1H- indol-3-yl) -1- (5- methoxypyridine -3- base) -2- methyl propyl- 2- alkene -1-
The preparation of ketone (11)
Intermediate 1- (5- methoxypyridine -3- base) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (5- methoxypyridine -3- base) propyl- 1- ketone (200mg, 1.21mmol) and 1H- indole -3-formaldehyde
(58.5mg, 0.403mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic
Phase, remaining crude product obtain target compound (E) -3- (1H- indol-3-yl) -1- (5- methoxypyridine -3- through ethyl alcohol recrystallization
Base) -2- methyl propyl- 2- alkene -1- ketone 54.3mg, yield 46%.1H NMR(300MHz,CDCl3)δ8.93(s,1H),8.51(d,
2H, J=18.0Hz), 7.67 (s, 2H), 7.53 (d, 2H, J=9.0Hz), 7.44 (d, 1H, J=9.0Hz), 7.30 (s, 1H),
7.15-7.20(m,1H),3.93(s,3H), 2.32(s,3H).MS(ESI):m/z[M+H]+:293.13。
Embodiment 7:(E)-3- (6- methoxyl group-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl)
The preparation of propyl- 2- alkene -1- ketone (12)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and 6- methoxyl group -1H- Yin
Diindyl -3- formaldehyde (87.5mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3 mL), 95 DEG C of stirring 48h, rotation
Dry organic phase, remaining crude product obtain target compound (E) -3- (6- methoxyl group -1H- indol-3-yl) -2- through ethyl alcohol recrystallization
120 mg of methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone, yield 63%.1H NMR(600MHz,CDCl3)δ
8.47 (s, 1H), 7.62 (s, 1H), 7.52 (d, 1H, J=2.4Hz), 7.45 (s, 1H), 7.43 (s, 1H), 7.02 (s, 1H),
6.91 (d, 1H, J=2.4Hz), 6.85-6.86 (dd, 1H, J=2.4,9.0Hz), 3.95 (s, 3H), 3.89 (s, 6H), 3.86
(s, 3H), 2.30 (d, 3H, J=0.6Hz) MS (ESI): m/z [M+H]+:382.16。
The preparation of compound 26,31 is referring to embodiment 7.That is: the identical reaction item of ingredient proportion same as Example 7
Part, " 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " react to obtain chemical combination with " 3- formoxyl -1H- indole -6-carboxylic methyl ester "
Object 26；" 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " and " 3- formoxyl -1H- Indole-6-carboxylic acid " obtains compound 31.
Embodiment 8:(E) -2- methyl -3- (5- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl-
The preparation of 2- alkene -1- ketone (13)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and 5- nitro -1H- Yin
Diindyl -3- formaldehyde (102.9mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), 95 DEG C of stirring 48h, rotation
Dry organic phase, remaining crude product obtain target compound (E) -2- methyl -3- (5- nitro -1H- indoles -3- through ethyl alcohol recrystallization
Base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone 84.5mg, yield 41%.1H NMR(300MHz,DMSO-d6)δ
12.50 (s, 1H), 8.49 (s, 1H), 8.07-8.13 (d, 2H), 7.65 (d, 2H, J=9.0Hz), 7.04 (s, 2H), 3.78-
3.84(m,9H),2.23(s,3H).13C NMR (150MHz,DMSO-d6)δ162.66,159.45,156.50,149.49,
146.64,138.11,137.52, 134.69,133.86,128.68,128.47,128.24,123.98,121.33,
120.19,117.82,116.06, 114.97,74.44,67.77,46.02.MS(ESI):m/z[M+H]+:367.17。
The preparation of compound 14-15 is referring to embodiment 8.That is: when producing compound 14,15, " 6- nitro -1H- is used respectively
Indole -3-formaldehyde ", " 7- nitro -1H- indole -3-formaldehyde " substitution " 5- nitro -1H- indole -3-formaldehyde " can be realized, dosage
It is identical.
Embodiment 9:(E)-3- (6- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl-
The preparation of 2- alkene -1- ketone (16)
(E) -2- methyl -3- (6- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxy-benzene is prepared referring to embodiment 8
Base) propyl- 2- alkene -1- ketone.
By (E) -2- methyl -3- (6- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
1- ketone (100mg, 0.25mmol) is dissolved in ethanol/water (5:1), and NH is added4Cl (53.9mg, 1mmol), is added with stirring iron powder
(56mg, 1mmol) is warming up to 55 DEG C, and TLC contact plate is monitored to fully reacting.It is filtered with diatomite, CH2Cl2Extraction, and be saturated
NaCl, anhydrous sodium sulfate dry, filter, and are spin-dried for organic phase, obtain target compound (E) -3- (6- amino -1H- Yin
Diindyl-3- base)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone 56.6mg, yield 62%.1H NMR
(300MHz,CDCl3) δ 11.35 (s, 1H), 7.54 (s, 2H), 7.08 (d, 1H, J=3.0Hz), 6.92 (s, 2H), 6.60 (d,
2H, J=3.0Hz), 6.47-6.48 (m, 1H), 4.89 (s, 1H), 3.77-3.80 (m, 9H), 2.16 (s, 3H) .MS (ESI):
m/z[M+H]+: 367.16。
The preparation of compound 37-38 is referring to embodiment 9.That is: the identical reaction item of ingredient proportion same as Example 9
Part, " (E) -2- methyl -3- (7- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone " with
“NH4Cl, iron powder " reaction obtains compound 37；" (E) -2- methyl -3- (5- nitro -1H- indol-3-yl) -1- (3,4,5- tri-
Methoxyphenyl) propyl- 2- alkene -1- ketone " and " NH4Cl, iron powder " reaction obtains compound 38.
Example 10:(E) -2- ((1H- indol-3-yl) methylene) -1- (3,4,5- trimethoxyphenyl) butyl- 1- ketone
(17) preparation
Intermediate 1- (3,4,5- trimethoxyphenyl) butyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) butyl- 1- ketone (200mg, 0.84mmol) and 1H- indole -3-formaldehyde
(40.6mg, 0.28mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic phase,
Remaining crude product obtains target compound (E) -2- ((1H- indol-3-yl) methylene) -1- (3,4,5- front three through ethyl alcohol recrystallization
Phenyl) butyl- 1- ketone 43.9mg, yield 43%.1H NMR(300MHz,CDCl3)δ8.60(s,1H),7.64(s,1H),
7.54-7.57 (m, 2H), 7.44 (d, 1H, J=8.1Hz), 7.30 (s, 1H), 7.16-7.21 (m, 1H), 7.03 (s, 2H),
3.89-3.95 (m, 9H), 2.83 (d, 2H, J=7.5Hz), 1.59 (s, 3H) .MS (ESI): m/z [M+H]+: 366.17.
Example 11:(E) -1- (3,4- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone
(18) preparation
Intermediate 1- (3,4- Dimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4- Dimethoxyphenyl) propyl- 1- ketone (200mg, 1.03mmol) and 1H- indole -3-formaldehyde
(49.82mg, 0.34mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic
Phase, remaining crude product obtain target compound (E) -1- (3,4- Dimethoxyphenyl) -3- (1H- indoles -3- through ethyl alcohol recrystallization
Base) -2- methyl propyl- 2- alkene -1- ketone 57.4mg, yield 52%.1H NMR(300MHz,CDCl3)δ8.72(s,1H),7.57-
7.62 (m, 3H), 7.40-7.45 (m, 3H), 7.30 (s, 1H), 7.16-7.21 (m, 1H), 6.93 (d, 1H, J=8.1Hz),
3.96 (d, 6H, J=13.2Hz), 2.32 (s, 3H) MS (ESI): m/z [M+H]+: 322.14.
Example 12:(E) -3- (1H- indol-3-yl) -1- (3- methoxyphenyl) -2- methyl propyl- 2- alkene -1- ketone (19)
Preparation
Intermediate 1- (3- methoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3- methoxyphenyl) propyl- 1- ketone (200mg, 1.22mmol) and 1H- indoles -3- formaldehyde
(58.94mg, 0.41mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic phase,
Remaining crude product obtains target compound (E) -1- (E) -3- (1H- indol-3-yl) -1- (3- methoxybenzene through ethyl alcohol recrystallization
Base) -2- methyl propyl- 2- alkene -1- ketone 54.4mg, yield 46%.1H NMR(300MHz,CDCl3)δ8.72(s,1H),7.65(d,
2H, J=12.3Hz), 7.53 (d, 1H, J=7.8Hz), 7.36-7.44 (m, 2H), 7.26-7.31 (m, 3H, J=15.0Hz),
7.08-7.20(m,2H),3.86(s, 3H),2.31(s,3H).MS(ESI):m/z[M+H]+:292.13。
Example 13:(E) preparation of-3- (1H- indol-3-yl)-2- methyl-1-phenyl propyl- 2- alkene-1- ketone (20)
Intermediate propiophenone is prepared referring to embodiment 1.
Intermediate propiophenone (200mg, 1.49mmol) and 1H- indole -3-formaldehyde (72.12mg, 0.50 mmol) is dissolved in
It in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), 95 DEG C of stirring 48h are spin-dried for organic phase, remaining crude product is obtained through ethyl alcohol recrystallization
To target compound (E)-3- (1H- indol-3-yl)-2- methyl-1-phenyl propyl- 2- alkene-1- ketone 74.0mg, yield 57%.1H
NMR(600MHz,CDCl3)δ8.76(s,1H), 7.73-7.75(m,2H),7.62-7.64(m,2H),7.55-7.57(m,
1H), 7.47-7.52 (m, 3H), 7.42 (d, 1H, J=7.8Hz), 7.25-7.28 (m, 1H), 7.15-7.18 (m, 1H), 2.33
(s,3H).MS(ESI):m/z [M+H]+:262.12。
Example 14:(E) -3- (1H- indol-3-yl) -1- phenyl propyl- 2- alkene -1- ketone (21) preparation
Acetophenone (200mg, 1.66mmol) and 1H- indole -3-formaldehyde (72.12mg, 0.55mmol) is dissolved in ethyl alcohol
It in (5mL) solution, is added piperidines (0.3mL), 95 DEG C of stirring 48h are spin-dried for organic phase, remaining crude product obtains mesh through ethyl alcohol recrystallization
Mark compound (E) -3- (1H- indol-3-yl) -1- phenyl propyl- 2- alkene -1- ketone 75.5mg, yield 55%.1H NMR
(300MHz,CDCl3)δ8.54(s,1H),8.03-8.14(m, 4H),7.45-7.63(m,6H),7.31-7.34(m,2H).MS
(ESI):m/z[M+H]+:248.11。
Embodiment 15:(E) -2- methyl -3- (1H- pyrrolo- [2,3-b] pyridin-3-yl) -1- (3,4,5- trimethoxy-benzene
Base) propyl- 2- alkene -1- ketone (22) preparation
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (448mg, 2mmol) is dissolved in toluene (6 mL), piperidines
In (0.12mL), 1H- pyrrolo- [2,3-b] pyridine -3- formaldehyde (97.32mg, 0.66mmol), 110 DEG C of reaction 4h, mistake is added
Filter, obtains compound (E) -2- methyl -3- (1H- pyrrolo- [2,3-b] pyridin-3-yl) -1- (3,4,5- tri- through ethyl alcohol recrystallization
Methoxyphenyl) propyl- 2- alkene -1- ketone 96.2mg, yield 41%.
The preparation of compound 23-25 is referring to embodiment 15.That is: identical with the identical ingredient proportion of embodiment 15 to react item
Part, " 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " and " 1H- pyrrolo- [3,2-c] pyridine -3- formaldehyde " reactionization
Close object 23；" 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " is reacted with " 1H- pyrrolo- [3,2-b] pyridine -3- formaldehyde "
To compound 24；" 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " and " 1H- pyrrolo- [2,3-c] pyridine -3- formaldehyde " is anti-
It should obtain compound 25.
Embodiment 16:(E) -3- (1H- indol-3-yl) -1- (7- methoxyl group benzo [d] [1,3] dioxole -5-
Base) -2- methyl propyl- 2- alkene -1- ketone (27) preparation
Intermediate 1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) propyl- 1- is prepared referring to embodiment 1
Ketone.
By intermediate 1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) propyl- 1- ketone (200mg, 0.96
Mmol it) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), 95 with 1H- indole -3-formaldehyde (46.48mg, 0.32mmol)
DEG C stirring 48h, be spin-dried for organic phase, remaining crude product obtains target compound (E) -3- (1H- indol-3-yl)-through ethyl alcohol recrystallization
1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) -2- methyl propyl- 2- alkene -1- ketone 54.8mg, yield 51%.1H
NMR(300MHz,CDCl3) δ 8.66 (s, 1H), 7.59-7.62 (m, 3H), 7.44 (d, 1H, J=7.8Hz), 7.28-7.31
(m,1H),7.17-7.22(m,1H),7.06 (s,1H),6.99(s,1H),6.09(s,2H),3.93(s,3H),2.30(s,
3H).MS(ESI):m/z [M+H]+:336.12。
Embodiment 17:(E)-3- (imidazo [1,2-a] pyridin-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl)
The preparation of propyl- 2- alkene -1- ketone (28)
Intermediate 1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) propyl- 1- is prepared referring to embodiment 1
Ketone.
By intermediate 1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) propyl- 1- ketone (200mg, 0.89
Mmol) simultaneously [1,2-a] pyridine -3- formaldehyde (44.05mg, 0.30mmol) is dissolved in ethyl alcohol (5mL) solution with 1,8a glyoxalidine
In, it is added piperidines (0.3mL), 95 DEG C of stirring 48h are spin-dried for organic phase, remaining crude product obtains target compound through ethyl alcohol recrystallization
(E)-3- (imidazo [1,2-a] pyridin-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
53.7mg, yield 51%.1H NMR(300MHz,CDCl3) δ 8.09 (s, 1H), 7.99 (d, 1H, J=6.6Hz), 7.74 (d, 1H,
), J=9.0Hz 7.32-7.38 (m, 2H), 7.26 (s, 1H), 6.93-6.99 (m, 2H), 3.89-3.95 (m, 9H), 2.39 (s,
3H).MS(ESI):m/z [M+H]+:353.15。
The preparation of compound 29 is referring to embodiment 17.That is: the identical reaction condition of ingredient proportion identical with embodiment 17,
" 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone " reacts to obtain compound 29 with " pyrazolo [1,5-a] pyridine -3- formaldehyde ".
Embodiment 18:(E) -1 (2H) -one of -2- ((1H- indol-3-yl) methylene) -5- methoxyl group -3,4- dihydronaphthalene
(30) preparation
By -1 (2H) -one (200mg, 1.13mmol) of 5- methoxyl group -3,4- dihydronaphthalene and 1H- indole -3-formaldehyde
(54.92mg, 0.38mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic phase,
Remaining crude product obtains target compound (E) -2- ((1H- indol-3-yl) methylene) -5- methoxyl group -3,4- through ethyl alcohol recrystallization
Dihydronaphthalene -1 (2H) -one (30) 59.7mg, yield 52%.1H NMR(300MHz,CDCl3)δ8.55(s,1H),8.25(s,1H),
7.89 (d, 1H, J=7.5Hz), 7.78 (d, 1H, J=7.8Hz), 7.55 (s, 1H), 7.43 (d, 2H, J=7.5Hz), 7.30-
7.35 (m, 2H), 7.04 (d, 1H, J=8.1Hz), 3.89 (s, 3H) 2.97-3.13 (m, 4H) .MS (ESI): m/z [M+H]+:
304.13。
Embodiment 19:(E) -2- methyl -3- (1H- pyrazole-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
The preparation of 1- ketone (32)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and 1H- pyrazoles -3- formaldehyde
(48.0mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for, through ethyl alcohol weight
Crystallization obtains target compound (E) -2- methyl -3- (1H- pyrazole-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
1- ketone 66.4mg, yield 44%.1H NMR(300MHz,CDCl3) δ8.11(s,1H),7.66(s,1H),7.18(s,1H),
6.98(s,2H),6.63(s,1H),3.88-3.92(m,9H), 2.34(s,3H)。
Embodiment 20:(E) -2- methyl -3- (1H- pyrroles -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
The preparation of 1- ketone (33)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and 1H- pyrroles -3- formaldehyde
(47.5mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for, through ethyl alcohol weight
Crystallization obtains target compound (E) -2- methyl -3- (1H- pyrroles -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -
1- ketone 64.5mg, yield 43%.1H NMR(300MHz,CDCl3) δ8.56(s,1H),7.23(s,1H),7.09(s,1H),
6.88-6.92(m,3H),6.52(s,1H),3.88-3.96 (m,9H),2.25(s,3H)。
Embodiment 21:(E) -2- methyl -3- (quinoline -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
(34) preparation
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (448mg, 2mmol) and quinoline-3-formaldehyde
(47.5mg, 1mmol) is dissolved in ethyl alcohol (8mL), and 30min is stirred at room temperature, then addition sodium hydroxide (3mL) to fully reacting,
Use CH2Cl2Extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate dry, filter, are spin-dried for organic phase, obtain through ethyl alcohol recrystallization
To target compound (E) -2- methyl -3- (quinoline -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
85.1mg, yield 47%.1H NMR(300MHz, CDCl3)δ8.97(s,1H),8.29(s,1H),8.18-8.21(m,1H),
7.90 (d, 1H, J=8.1Hz), 7.78-7.83 (m, 1H), 7.61-7.66 (m, 1H), 7.28 (s, 1H), 7.07 (s, 2H),
3.91-3.95(m,9H), 2.38(s,3H).MS(ESI):m/z[M+H]+:364.15。
Embodiment 22:(E)-3- (1H- indoles-2- base)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-
The preparation of 1- ketone (35)
Intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone is prepared referring to embodiment 1.
By intermediate 1- (3,4,5- trimethoxyphenyl) propyl- 1- ketone (336mg, 1.5mmol) and 1H- indoles -2- formaldehyde
(72.5mg, 0.5mmol) is dissolved in ethyl alcohol (5mL) solution, is added piperidines (0.3mL), and 95 DEG C of stirring 48h are spin-dried for organic phase, is remained
Remaining crude product obtains target compound (E)-3- (1H- indoles-2- base)-2- methyl-1-(3,4,5- trimethoxy through ethyl alcohol recrystallization
Base phenyl) propyl- 2- alkene -1- ketone 82.5mg, yield 47%.1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.66(d,1H,J
=7.2Hz), 7.38 (s, 2H), 7.20 (s, 2H), 6.97 (s, 2H), 6.89 (s, 1H), 3.89-3.94 (m, 9H), 2.43 (s,
3H)。
Embodiment 23:(E) -2- (4- (3- (1H- indol-3-yl) -2- methylacryloyl) -2,6- dimethyl phenoxy)
The preparation of ethyl acetate (36)
Synthetic route is as follows:
The synthesis of step a:4- ((t-butyldimethylsilyi) oxygroup) -3,5- dimethoxy benzaldehyde.
4- hydroxyl -3,5- dimethoxy benzaldehyde (10g, 54.89mmol) and imidazoles (14.95g, 219.6 mmol) is molten
In DMF (100mL), TBSCl (16.55g, 109.8mmol) is added at 0 DEG C, TLC is monitored to fully reacting, sudden with water
It goes out, ethyl acetate extraction, saturated sodium chloride solution is washed, and anhydrous sodium sulfate dries, filters, and is spin-dried for organic phase, and remaining crude product is logical
Silica gel chromatography (eluant, eluent: petrol ether/ethyl acetate=10:1) is crossed, compound 4- ((t-butyldimethyl silane is obtained
Base) oxygroup) -3,5- dimethoxy benzaldehyde 11.37g, yield 70%.
Step b, c is referring to step a, b in embodiment 1.
The synthesis of step d:1- (4- hydroxyl -3,5- Dimethoxyphenyl) propyl- 1- ketone.
By 1- (4- ((t-butyldimethylsilyi) oxygroup) -3,5- Dimethoxyphenyl) propyl- 1- ketone (2.32g,
It 7.15mmol) is dissolved in THF (30mL), TBAF (7.5mL) is added at 0 DEG C, N2Protection is lower to react 2h, and TLC is monitored to having reacted
Entirely, it is quenched with water, ethyl acetate extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate dries, filters, and is spin-dried for organic phase, remains
Remaining crude product obtains compound 1- (4- hydroxyl -3,5- by silica gel chromatography (eluant, eluent: petrol ether/ethyl acetate=1:1)
Dimethoxyphenyl) propyl- 1- ketone 1.34g, yield 89%.
The synthesis of step e:2- (2,6- dimethoxy-4 '-propionyl phenoxyl) ethyl acetate.
By 1- (4- hydroxyl -3,5- Dimethoxyphenyl) propyl- 1- ketone (266mg, 1.27mmol), potassium carbonate (351.9 mg,
2.55mmol), 2- bromoacetate (425.1mg, 2.55mmol) is dissolved in DMF (6mL), and TLC is monitored to fully reacting, is used
Water quenching, ethyl acetate extraction, NaCl, anhydrous sodium sulfate is dry, passes through silica gel chromatography (eluant, eluent: petroleum
Ether/ethyl acetate=10:1), compound 2- (2,6- dimethoxy-4 's-propionyl phenoxyl) ethyl acetate 296.2mg is obtained, is received
Rate 79%.
Step f:(E) -2- (4- (3- (1H- indol-3-yl) -2- methylacryloyl) -2,6- dimethyl phenoxy) second
The synthesis of acetoacetic ester.
By intermediate 2- (2,6- dimethoxy-4 '-propionyl phenoxyl) ethyl acetate (460mg, 1.55mmol) and 1H-
Indole -3-formaldehyde (75.1mg, 0.5mmol) is dissolved in ethyl alcohol (10mL) solution, is added piperidines (0.6 mL), 95 DEG C of stirring 48h,
It is spin-dried for organic phase, remaining crude product obtains target compound (E) -2- (4- (3- (1H- indol-3-yl) -2- first through ethyl alcohol recrystallization
Base acryloyl group) -2,6- dimethyl phenoxy) 100.7 mg of ethyl acetate, yield 46%.1H NMR(300MHz,CDCl3)δ
8.61(s,1H),7.66(s,2H),7.57(s,1H), 7.43(s,1H),7.21(s,2H),7.01(s,1H),4.70-4.74
(m, 2H), 4.30 (d, 2H, J=7.2Hz), 3.87-3.90 (m, 6H), 2.31 (s, 3H), 1.25 (s, 3H).
Embodiment 24: the anti tumor activity in vitro test of the compounds of this invention
Using CellTiter-Blue method, the extracorporeal anti-tumor of present invention synthesis compound and moiety intermediate is tested
Activity.
Experimental method: HCT-116 (colon cancer cell), HCT-116/OXA (drug resistance colon cancer cell) use RPMI+10%
The dual anti-culture of FBS+1%.
Sample liquid is prepared: being dissolved with DMSO, is made into the mother liquor that concentration is 50 μM.Then dilute with the culture medium containing 1%DMSO
(three times or five times of dilutions) are released, graded series strength solution is finally made into.
The every hole of 96 orifice plates adds 4000-8000 cell, is placed in 37 DEG C, 5%CO2After being incubated for 24 hours in incubator, respectively
Sample liquid and reference substance liquid is added, 200 holes μ L/, 37 DEG C act on 72 hours.CellTiter-Blue (the fluorescent blue that every hole is added
Cell activity kit) 20 μ L of solution, with full-automatic microplate reader (production firm Labsystems after effect 0.5-1 hours
Dragon 570/590nm OD value, calculation of half inhibitory concentration IC) are surveyed50。
Using GraphPad Prism software analyzing and processing data, compound IC is finally measured50Value.
Anti tumor activity in vitro is carried out to the compound of the present invention according to above anti tumor activity in vitro test method to grind
Study carefully:
Have chosen the anti tumor activity in vitro of 2 kinds of tumor cell line goal in research compounds: (colon cancer is thin by HCT-116
Born of the same parents), HCT-116/OXA (drug resistance colon cancer cell).CellTiter-Blue method is selected to carry out active testing, the results show that changing
It closes object and preferable anti-tumor activity is shown to colon cancer and its drug-resistant cell strain, especially drug-resistant leukemia cells show is gone out
Better anti-tumor activity.Wherein active best derivative mainly has 2: compound 6 and 7, IC50Value is all in 10nM or less.
But significantly reduced on phenyl ring without methoxy-substituted compound activity, such as compound 20 and 21；Bromine substitution on indole ring, carboxylic
After base replaces, activity is significantly reduced, such as compound 9,31.
IC of 1. target compound of table to colon cancer (HCT-116) and drug resistance colon cancer (HCT-116/OXA) cell50Value
To sum up, therefore the compounds of this invention and its esters can be used for preparing anti-anti-tumor drug.
The preferred embodiment of the present invention has been described in detail above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make various equivalent on the premise of not violating the inventive spirit of the present invention
Variation or replacement, these equivalent variation or replacement are all included in the scope defined by the claims of the present application.
Claims (7)
1. one kind ɑ, the pro-drug of alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate, it is characterised in that structure
As shown in general formula I:
Wherein A, B are respectively selected from saturated rings, aromatic ring and heteroaromatic, saturated rings or aromatic ring and heteroaromatic and ring；
R1It is respectively selected from hydrogen, 1~7 identical or different C1-C10 alkoxy；
R2Be respectively selected from hydrogen, 1~7 identical or different C1-C10 alkyl, C1-C10 alkoxy, halogen, nitrogen protium composition take
The substituent group that Dai Ji, the substituent group of hydrocarbon oxygen element composition, nitrogen oxygen element form；
R3It is respectively selected from hydrogen, C1-C10 alkyl；And with A form polynary ring-(CH2)n, (n=1~10).
2. one kind ɑ as described in claim 1, the precursor medicine of alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate
Object, it is characterised in that:
Wherein A, B are respectively selected from saturated rings, aromatic ring and heteroaromatic, saturated rings or aromatic ring and heteroaromatic and ring；
R1Be respectively selected from trimethoxy, dimethoxy, mono methoxy that the upper different location of hydrogen, A replaces,
R2Be respectively selected from the mono-substituted methoxyl group of the upper different location of hydrogen, B, methyl, fluorine, chlorine, bromine, nitro, amido, carboxyl,
R3Be respectively selected from hydrogen, methyl, ethyl and with A form polynary ring-(CH2)n, (n=1~10).
3. one kind ɑ as described in claim 1, the precursor medicine of alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate
Object, it is characterised in that:
A is selected from
B is selected from
R1Be respectively selected from trimethoxy, dimethoxy, mono methoxy that the upper different location of hydrogen, A replaces,
R2Be respectively selected from the mono-substituted methoxyl group of the upper different location of hydrogen, B, methyl, fluorine, chlorine, bromine, nitro, amido, carboxyl,
R3It is respectively selected from hydrogen, methyl, ethyl and the-CH with A composition hexatomic ring2CH2-。
4. ɑ as claimed in claim 3, the pro-drug of alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate, feature
Be: compound shown in the general structure (I), pharmaceutically acceptable salt include that compound of Formula I and following acid are formed
Acid-addition salts: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, winestone
Acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.
5. ɑ according to claim 4, the pro-drug of alpha, beta-unsaturated ketone derivative and its isomers, salt or solvate,
It is characterized by: the ɑ, alpha, beta-unsaturated ketone derivative is selected from one of flowering structure:
(E) -2- methyl -3- (4- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (1),
(E) -2- methyl -3- (5- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (2),
(E) -2- methyl -3- (6- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (3),
(E) -2- methyl -3- (7- Methyl-1H-indole -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (4),
(E)-3- (benzo [b] thiene-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (5),
(E)-3- (the fluoro- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (6),
(E)-3- (the fluoro- 1H- indol-3-yl of 6-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (7),
(E)-3- (the chloro- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (8),
(E)-3- (the bromo- 1H- indol-3-yl of 5-)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (9),
(E) -1- (3,5- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone (10),
(E) -3- (1H- indol-3-yl) -1- (5- methoxypyridine -3- base) -2- methyl propyl- 2- alkene -1- ketone (11),
(E)-3- (6- methoxyl group-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(12)、
(E) -2- methyl -3- (5- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
(13)、
(E) -2- methyl -3- (6- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
(14)、
(E) -2- methyl -3- (7- nitro -1H- indol-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
(15)、
(E)-3- (6- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(16)、
(E) -2- ((1H- indol-3-yl) methylene) -1- (3,4,5- trimethoxyphenyl) butyl- 1- ketone (17),
(E) -1- (3,4- Dimethoxyphenyl) -3- (1H- indol-3-yl) -2- methyl propyl- 2- alkene -1- ketone (18),
(E) -3- (1H- indol-3-yl) -1- (3- methoxyphenyl) -2- methyl propyl- 2- alkene -1- ketone (19),
(E)-3- (1H- indol-3-yl)-2- methyl-1-phenyl propyl- 2- alkene-1- ketone (20),
(E) -3- (1H- indol-3-yl) -1- phenyl propyl- 2- alkene -1- ketone (21),
(E) -2- methyl -3- (1H- pyrrolo- [2,3-b] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (22),
(E) -2- methyl -3- (1H- pyrrolo- [3,2-c] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (23),
(E) -2- methyl -3- (1H- pyrrolo- [3,2-b] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (24),
(E) -2- methyl -3- (1H- pyrrolo- [2,3-c] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1-
Ketone (25),
(E) -3- (2- methyl -3- oxo -3- (3,4,5- trimethoxyphenyl) propyl- 1- alkene -1- base) -1H- Indole-6-carboxylic acid's first
Ester (26),
(E) -3- (1H- indol-3-yl) -1- (7- methoxyl group benzo [d] [1,3] dioxole -5- base) -2- methyl propyl-
2- alkene -1- ketone (27),
(E)-3- (imidazo [1,2-a] pyridin-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(28)、
(E) -2- methyl -3- (pyrazolo [1,5-a] pyridin-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone
(29)、
(E) -1 (2H) -one (30) of -2- ((1H- indol-3-yl) methylene) -5- methoxyl group -3,4- dihydronaphthalene,
(E) -3- (2- methyl -3- oxo -3- (3,4,5- trimethoxyphenyl) propyl- 1- alkene -1- base) -1H- Indole-6-carboxylic acid
(31)、
(E) -2- methyl -3- (1H- pyrazole-3-yl) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (32),
(E) -2- methyl -3- (1H- pyrroles -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (33),
(E) -2- methyl -3- (quinoline -3- base) -1- (3,4,5- trimethoxyphenyl) propyl- 2- alkene -1- ketone (34),
(E)-3- (1H- indoles-2- base)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone (35),
(E) -2- (4- (3- (1H- indol-3-yl) -2- methylacryloyl) -2,6- dimethyl phenoxy) ethyl acetate (36),
(E)-3- (7- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(37)、
(E)-3- (5- amino-1H- indol-3-yl)-2- methyl-1-(3,4,5- trimethoxyphenyl) propyl- 2- alkene-1- ketone
(38)。
6. the compound of logical formula (I) is preparing the application in microtubule inhibitors as described in claim 1.
7. application of the compound of logical formula (I) in treatment tumour as described in claim 1, including the killing to tumour cell
Effect, and the application in the tumor disease that treatment has multidrug resistance.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910679937.9A CN110526854B (en) | 2019-07-26 | 2019-07-26 | Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine |
| PCT/CN2020/101590 WO2021017795A1 (en) | 2019-07-26 | 2020-07-13 | α,β-UNSATURATED KETONE DERIVATIVE, PREPARATION METHOD AND USE AS MEDICINE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910679937.9A CN110526854B (en) | 2019-07-26 | 2019-07-26 | Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110526854A true CN110526854A (en) | 2019-12-03 |
| CN110526854B CN110526854B (en) | 2023-12-15 |
Family
ID=68661841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910679937.9A Active CN110526854B (en) | 2019-07-26 | 2019-07-26 | Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110526854B (en) |
| WO (1) | WO2021017795A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11731939B1 (en) | 2023-03-07 | 2023-08-22 | King Faisal University | Indole-based chalcone compounds as antibacterial agents |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995014003A1 (en) * | 1993-11-17 | 1995-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivative |
| CN1172476A (en) * | 1995-12-01 | 1998-02-04 | 协和发酵工业株式会社 | Propenone derivatives |
| US5952355A (en) * | 1993-11-17 | 1999-09-14 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivatives |
| CN101288402A (en) * | 2008-06-18 | 2008-10-22 | 四川大学 | New use of aza chalcones compound as agricultural bactericidal agent |
| CN109535068A (en) * | 2018-12-26 | 2019-03-29 | 中国药科大学 | Pyridine replaces chalcone compounds or its pharmaceutical salt and its preparation method and application |
-
2019
- 2019-07-26 CN CN201910679937.9A patent/CN110526854B/en active Active
-
2020
- 2020-07-13 WO PCT/CN2020/101590 patent/WO2021017795A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995014003A1 (en) * | 1993-11-17 | 1995-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivative |
| US5952355A (en) * | 1993-11-17 | 1999-09-14 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivatives |
| CN1172476A (en) * | 1995-12-01 | 1998-02-04 | 协和发酵工业株式会社 | Propenone derivatives |
| CN101288402A (en) * | 2008-06-18 | 2008-10-22 | 四川大学 | New use of aza chalcones compound as agricultural bactericidal agent |
| CN109535068A (en) * | 2018-12-26 | 2019-03-29 | 中国药科大学 | Pyridine replaces chalcone compounds or its pharmaceutical salt and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| JUN YAN等: "Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo" * |
| YASUAKI TATSUMI等: "Enhancement of in vivo Antitumor Activity of a Novel Antimitotic 1-Phenylpropenone Derivative, AM-132, by Tumor Necrosis Factor-α or Interleukin-6" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11731939B1 (en) | 2023-03-07 | 2023-08-22 | King Faisal University | Indole-based chalcone compounds as antibacterial agents |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021017795A1 (en) | 2021-02-04 |
| CN110526854B (en) | 2023-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Scaffold diversity inspired by the natural product evodiamine: discovery of highly potent and multitargeting antitumor agents | |
| Singh et al. | 1, 2, 3-Triazole tethered β-lactam-chalcone bifunctional hybrids: synthesis and anticancer evaluation | |
| CN105566276B (en) | Benzo-hexatomic ring derivative as DPP-4 inhibitor and application thereof | |
| CN109134586B (en) | Tripterine derivative and application thereof | |
| Wang et al. | Synthesis and biological evaluation of new 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin derivatives as potential antitumor agents | |
| Kowalski et al. | Ferrocenyl derivatives of pterocarpene and coumestan: Synthesis, structure and anticancer activity studies | |
| CN102746281B (en) | 4-1,2,3-triazole-coumarin derivative and its preparation method and application | |
| CN106673988A (en) | Benzyl cyclohexenone derivative and preparation method and medical application thereof | |
| CN110526854A (en) | A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug | |
| CN111253339B (en) | Synthetic preparation method of curcumin derivatives and application of curcumin derivatives in cancer treatment | |
| CN111646974A (en) | N-methyl gatifloxacin propenone derivative and preparation method and application thereof | |
| CN108530436B (en) | Pyrazole compound and preparation method and application thereof | |
| CN111303027A (en) | Fluroxacin acrylketone derivative and preparation method and application thereof | |
| CN106117182A (en) | Quinazoline N phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN107573336B (en) | Benzoheterocycle-formamide-pyridone derivative and preparation method and application thereof | |
| CN104098457B (en) | Tetrahydrocurcumin analogue, preparation and application thereof | |
| CN115124531A (en) | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof | |
| CN111646975B (en) | N-methyl lomefloxacin allyl ketone derivative and preparation method and application thereof | |
| CN111646937B (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| Reddy et al. | Design, synthesis and docking studies of new indazole derivatives as potent cytotoxic and antibacterial agents | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN114736202A (en) | Preparation and application of berberine derivative with IDO1/TDO inhibitory activity | |
| WO2018014368A1 (en) | Water-soluble isatin derivative, and manufacturing method and application thereof | |
| EP4215521A1 (en) | Fused ring diimide derivative, preparation method therefor and use thereof | |
| CN108358858B (en) | Deuterium labeled 1-substituted phenyl-4-substituted aniline methyl-1, 2, 3-triazole derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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 |