CN104119333B - Close attached amine 01 derivatives and preparation method thereof and medical usage - Google Patents
Close attached amine 01 derivatives and preparation method thereof and medical usage Download PDFInfo
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- CN104119333B CN104119333B CN201410397805.4A CN201410397805A CN104119333B CN 104119333 B CN104119333 B CN 104119333B CN 201410397805 A CN201410397805 A CN 201410397805A CN 104119333 B CN104119333 B CN 104119333B
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- ethyl acetate
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- guanfu
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- 150000001412 amines Chemical class 0.000 title abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 5
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
- 238000006243 chemical reaction Methods 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 238000001035 drying Methods 0.000 description 42
- 239000000243 solution Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 238000005303 weighing Methods 0.000 description 24
- -1 amine alcohol derivative Chemical class 0.000 description 23
- 238000004809 thin layer chromatography Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007832 Na2SO4 Substances 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- ONBIUAZBGHXJDM-UHFFFAOYSA-J bismuth;potassium;tetraiodide Chemical compound [K+].[I-].[I-].[I-].[I-].[Bi+3] ONBIUAZBGHXJDM-UHFFFAOYSA-J 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 11
- 150000001414 amino alcohols Chemical class 0.000 description 11
- 230000007935 neutral effect Effects 0.000 description 11
- 150000002431 hydrogen Chemical group 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 229930013930 alkaloid Natural products 0.000 description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 150000003797 alkaloid derivatives Chemical class 0.000 description 5
- 125000005037 alkyl phenyl group Chemical group 0.000 description 5
- OGNUSOJAYIHLNS-FODRTREWSA-N guan-fu base a Chemical compound C([C@]12C[C@@H]3N4C[C@]([C@H]53)(C)C[C@@H](C3)OC(=O)C)C(=C)[C@H]6[C@@H](OC(C)=O)[C@]2(O)C4[C@@]35[C@@H]1[C@@H]6O OGNUSOJAYIHLNS-FODRTREWSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- PIWJSAMCEMZIDO-APRJJLODSA-N Hetisine Chemical compound C([C@]12C[C@@H]3N4C[C@](C[C@H](O)C5)([C@H]63)C)C(=C)[C@@H]3[C@@H](O)[C@H]2[C@]56[C@H]4[C@H]1[C@H]3O PIWJSAMCEMZIDO-APRJJLODSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- XNFQUGPVHYJHHZ-UHFFFAOYSA-N hetisine Natural products CC12CNC3C4C(O)C5C(O)C6C4(CCC1C36CC(O)C2)CC5=C XNFQUGPVHYJHHZ-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 3
- VPMMJSPGZSFEAH-UHFFFAOYSA-N 2,4-diaminophenol;hydrochloride Chemical class [Cl-].NC1=CC=C(O)C([NH3+])=C1 VPMMJSPGZSFEAH-UHFFFAOYSA-N 0.000 description 3
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)(*)C(c1ccccc1)=O Chemical compound CC(C)(*)C(c1ccccc1)=O 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000005157 alkyl carboxy group Chemical group 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 2
- RUJYJCANMOTJMO-UHFFFAOYSA-N 3-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC(C(Cl)=O)=C1 RUJYJCANMOTJMO-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 150000004141 diterpene derivatives Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 1
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000173529 Aconitum napellus Species 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- LWQAYTWMEQUUFP-UHFFFAOYSA-K [K].I[Bi](I)I Chemical compound [K].I[Bi](I)I LWQAYTWMEQUUFP-UHFFFAOYSA-K 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000002034 butanolic fraction Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229930002995 diterpene alkaloid Natural products 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses attached amine 01 derivatives in pass and preparation method thereof and medical usage, it is the compound shown in formula (I) or its pharmaceutically acceptable salt, antitumor activity test result indicate that, the pass attached amine 01 derivatives of the present invention has antitumor action, is particularly suited for anti-lung cancer, liver cancer, breast cancer.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a guanfu amino alcohol derivative in traditional Chinese medicine Guanbaifu, a preparation method and a medical application thereof.
Background
C20The inhibition effect of diterpenoid alkaloids on various tumor cells is closely related to the structure of diterpenoid alkaloids, and the tumor cells can not be inhibited by all the substitutes at all positions, but are promoted to proliferate by some positions. Hetisine type of alkaloids is C20The diterpene alkaloids have the most complex structure and the most amount, and have wide pharmacological activities, such as arrhythmia resistance, tumor resistance, blood vessel dilation, local anesthesia, insect disinfestation and the like. The main component of the Chinese medicine Guanbaifu is Hetisine type alkaloid, except that Guanfu base A has antiarrhythmic activity, the other compounds have pharmacological activityNo systematic study was performed. Guanfu amidol is the main component of Guanbaifu medicinal materials, has the advantages of high content, high yield, simple and convenient separation and purification process and no toxicity, and is mostly discarded as waste in the industrial mass production of the guanfu base A hydrochloride injection. The Guanfu amine alcohol is also Hetisine type alkaloid, the molecule of the Guanfu amine alcohol is a double-layer rigid structure, the upper layer structure is saturated alicyclic, the lower layer structure is a combined carbon chain, and the structure has four hydroxyl groups, is high in polarity, is insoluble in dichloromethane and is soluble in acid water.
Disclosure of Invention
The invention aims to provide a series of Guanfu amino alcohol derivatives on the basis of the prior art.
The invention also provides a preparation method of the guanfu amine alcohol derivative.
The third purpose of the invention is to provide the application of the guanfu amine alcohol derivative in the aspect of medicine.
The object of the invention can be achieved by the following measures:
a compound shown in formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R1、R2、R3and R4Each independently is hydrogen, optionally substituted alkyl formyl, optionally substituted aryl vinyl formyl or optionally substituted saturated or unsaturated hydrocarbon radical, the substituents of which are selected from halogen, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, phenyl, halophenyl, alkyl phenyl, alkoxy phenyl or haloalkylphenyl;
and R is1、R2、R3And R4Not hydrogen at the same time.
The structure of the compounds of formula (I) according to the invention can also be represented by formula (II),
each dotted line in formula (II) represents a chemical bond.
In a preferred embodiment, R in the formulae (I) and (II) according to the invention1、R2、R3And R4Each independently is hydrogen, optionally substituted C1-6Alkyl formyl, optionally substituted phenyl formyl, optionally substituted styryl formyl or optionally substituted C1-6Alkyl, and R1、R2、R3And R4Not hydrogen at the same time.
In another preferred embodiment, R1、R2、R3And R4Each independently is hydrogen, optionally substituted C1-4Alkyl formyl, optionally substituted phenyl formyl, optionally substituted styryl formyl or optionally substituted C1-4Alkyl, and R1、R2、R3And R4Not hydrogen at the same time.
R1、R2、R3And R4The substituents of each group (i.e., the substituents to which the optional substitution refers) may be selected from halogen, nitro, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-6Haloalkoxy, C2-4Alkenyl, phenyl, halophenyl, C1-6Alkyl phenyl, C1-6Alkoxyphenyl or C1-6A haloalkylphenyl group; further, the substituent may be selected from chlorine, bromine, nitro, C1-2Alkyl radical, C1-2Alkoxy radical, C1-2Fluoroalkyl, C2-4Alkenyl, phenyl, halophenyl, C1-2Alkyl phenyl, C1-2Alkoxyphenyl or halo C1-2An alkyl phenyl group. Further, the substituent may be selected from chlorine, bromine, nitro, methoxy, trifluoromethyl, vinyl, and the like. When a substituent is attached to a phenyl group, each substituent is preferably located in the para or meta position of the phenyl group.
In a preferred embodiment, R1、R2、R3And R4Are all C1-4An alkyl formyl group.
In another preferred embodiment, R1Is hydrogen, optionally substituted phenylformyl or optionally substituted styrylcarbonyl, the substituents of which are selected from halogen or C1-4An alkoxy group; r2Is hydrogen, optionally substituted phenylformyl or optionally substituted styrylcarbonyl, the substituents of which are selected from halogen, nitro, C1-4Haloalkyl or C1-4An alkoxy group; r3Is hydrogen, optionally substituted phenylformyl or optionally substituted styrylcarbonyl, the substituents of which are selected from halogen, nitro, C1-4Haloalkyl or C1-4An alkoxy group; r4Is hydrogen; and R is1、R2、R3And R3Not simultaneously hydrogen, more preferably R1、R2And R3Not both being hydrogen, further, R2And R3R is not hydrogen1And R4Is hydrogen, or R1And R2R is not hydrogen3And R4Is hydrogen, or R1、R2And R3R is not hydrogen4Is hydrogen.
In one embodiment, R2And R3Each is optionally substituted phenylformyl or optionally substituted styrylcarbonyl, R1And R4Is hydrogen; or R1、R2And R3Each is optionally substituted phenylformyl or optionally substituted styrylcarbonyl, R4Is hydrogen; or R1And R2Each is optionally substituted phenylformyl or optionally substituted styrylcarbonyl, R3And R4Is hydrogen.
In another embodiment, R1And R4Is hydrogen; r2Is hydrogen or optionally substituted C1-6Alkyl, the substituents of which are selected from halogen or C2-4An alkenyl group; r3Is optionally substituted C1-6Alkyl, the substituent of which is selected from halogen and C2-4Alkenyl, phenyl, halophenyl, C1-2Alkyl phenyl, C1-2Alkoxyphenyl or C1-2A haloalkylphenyl group.
In one embodiment, R1And R4Is hydrogen; r2And R3Each being optionally substituted C1-6Alkyl, the substituent of which is selected from halogen and C2-4Alkenyl, phenyl, halophenyl, C1-2Alkyl phenyl, C1-2Alkoxyphenyl or C1-2A haloalkylphenyl group.
The invention provides specific compounds of interest selected from:
the semi-synthesis of the guanfu amine alcohol derivative comprises the preparation of the guanfu amine alcohol through conventional acylation or etherification reaction.
The guanamine alcohol derivative of the invention can be prepared by acylation of guanamine alcohol (GFAA for short).
One method is as follows: acid anhydride is used as an acylation reagent, p-toluenesulfonic acid is used as a catalyst, and the attached amino alcohol is reacted under the heating condition.
The other method is as follows: pyridine is used as a solvent and a catalyst or THF is used as a solvent and pyridine is used as a catalyst, the guanamine alcohol and the benzoylation reagent react under the heating condition,
the third method is: the guanfu amine alcohol is subjected to ether formation reaction to prepare the compound shown in the formula (I). Specifically, the reaction can be carried out under a strong alkaline condition by using a classical Williamson reaction and DMF as a solvent and halogenated hydrocarbon as a hydrocarbylating agent.
"alkyl" in the present invention means a saturated aliphatic group of 1 to 20 carbon atoms, including straight and branched chain groups (the numerical range mentioned in this application, e.g. "1 to 20" means that the group, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like.
In the present invention, "formyl" refers to HC (═ O) -group, "alkylcarboxyl" refers to "alkyl-C (═ O) -" group, "arylformyl" refers to "aryl-C (═ O) -" group. "C1-6The "alkylcarboxyl" refers to an alkylcarboxyl group and the number of carbon atoms of an alkyl substituent is 1 to 6.
The term "hydrocarbyl" as used herein refers to a functional group containing only carbon and hydrogen atoms, which may be saturated (e.g., alkyl) or unsaturated (e.g., alkenyl or alkynyl). The number of carbon atoms is generally 1 to 20, including straight and branched chains, unless otherwise specified. Under a preferable condition, the number of carbon atoms is generally 1 to 6, and further 1 to 4 or 1 to 2.
"halogen" in the present invention includes fluorine, chlorine, bromine and iodine.
"alkoxy" in the context of the present invention means an "alkyl-O-" group.
"haloalkyl" in the present invention means a group in which one or more hydrogen atoms in an alkyl group are substituted with halogen, for example, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like having one or more halogen substituents.
"haloalkoxy" in the present invention means a group in which one or more hydrogen atoms in an alkoxy group are substituted with halogen, for example, methoxy, ethoxy, propoxy, 2-propoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy and the like having one or more halogen substituents.
"alkenyl" in the present invention means an unsaturated aliphatic radical containing one or more C ═ C double bonds of 2 to 20 carbon atoms, and includes straight and branched chain radicals. Alkenyl groups having 2 to 4 or 2 to 6 carbon atoms are referred to as lower alkenyl groups, such as vinyl, propenyl, allyl, and the like.
The "halogenophenyl group, alkylphenyl group, alkoxyphenyl group or halogenoalkylphenyl group" in the present invention refers to a group having a corresponding substituent on the benzene ring, wherein the site of each substituent may be adjusted as the case may be. "C1-6The "alkylphenyl group" means an alkylphenyl group and the number of carbon atoms of the alkyl substituent is 1 to 6.
"optionally substituted" in the present invention means both "substituted" and "unsubstituted".
The compound of formula (I) or the pharmaceutically acceptable salt thereof can be applied to the preparation of antitumor drugs, and is particularly suitable for lung cancer, liver cancer or breast cancer. The experimental result of the antitumor activity of the Guanfu amidol derivative shows that: the guanfu amine alcohol derivative has an anti-tumor effect, and is particularly suitable for resisting lung cancer, liver cancer and breast cancer. AA-Ac5, 7, 13 and AA-Et5 have proper inhibition effect on the growth of three cell strains of A549, HepG-2 and MCF-7, which shows that the three cell strains may have certain broad-spectrum inhibition effect on the growth of tumor cells; the inhibition effect of AA-Ac7 on A549 is better than that of other 3 cells, the inhibition effect of AA-Ac13 on MCF-7 is better than that of other 3 cells, and the inhibition effect of most of the rest compounds, particularly AA-Ac8 and AA-Ac10, on HepG-2 is better, which indicates that the compounds may have cell selection inhibition effect.
Detailed Description
The organic solvents and chemical reagents used in the following examples were commercially available and were not further treated before use (Table 2-1), except for specific descriptions, column chromatography silica gel 100 to 200 mesh, 200 to 300 mesh, 400 mesh (product of Qingdao Katsukuyao), neutral alumina (chemical Co., Ltd., Shanghai city), diatomaceous earth (Xilonga chemical Co., Ltd., Shantou city), thin layer chromatography silica gel GF254 (Nicoti chemical Co., Ltd.), Sephadex LH-20 (Pharmacia). The guanfu amine alcohol used in the experiment is separated from a Guanbaifu medicinal material, and the purity is detected by HPLC.
Example one, preparation of raw Material Guanfu amino alcohol
1. Extracting Korean monkshood rhizome powder 8Kg with 95% ethanol by cold soaking for 3 times (10L × 3, 72h × 3). Mixing extractive solutions, concentrating to remove alcohol smell to obtain total extract (600g), kneading with 1000ml1mol/L hydrochloric acid, extracting with ethyl acetate, and concentrating the ethyl acetate extract to obtain non-alkaloid extract 4.6 g; alkalizing the acid water layer with ammonia water to pH 9, and extracting with ethyl acetate to obtain total alkaloid part 40 g; the aqueous layer was adjusted to pH 14 with sodium hydroxide and n-butanol extracted to give 103g of n-butanol fraction. Separating the total alkaloid fraction with alkalinized silica gel (400 mesh) column chromatography, gradient eluting with chloroform-methanol (20:1 → 15:1), SephadexLH-20 (chloroform-methanol) column chromatography, and ODS (methanol-water) column chromatography to obtain Guanfu base A (GFA) (47mg) and Guanfu base (GFI) (3.2 g); crystallizing the n-butanol part at room temperature, crystallizing by solvent method and recrystallization method to obtain compound Hetisine (1.7g), recovering n-butanol from the solution under reduced pressure to obtain foam, and repeatedly recrystallizing with ethanol to obtain compound Guanfu amino alcohol (GFAA) (158 mg).
2. The guanfu amine alcohol is a waste material in industrial large-scale production of the guanfu base A hydrochloride injection, and can be used for the invention after being purified by a conventional mode.
EXAMPLE two preparation of Guanfu amino alcohol derivatives
2,11,13, 14-tetraacetyl guanfu amine alcohol (AA-Ac1)
GFAA (200mg,0.58mmol) and p-toluenesulfonic acid (50mg) were weighed and added to 5mL of acetic anhydride, stirring was carried out at 65 ℃, the reaction was monitored by TLC, 1.5 hours later, the reaction was completed, 30mL of water was added to the reaction solution, stirring was carried out under heating for 30min to completely decompose excess acetic anhydride, and saturated Na was used for complete decomposition of the acetic anhydride2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl solution (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by neutral alumina column chromatography (ethyl acetate) to obtain white square crystal, drying, and weighing to obtain 116mg (39.1%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z514[ M + H ]]+And the molecular weight is 513.1HNMR(CDCl3,500MHz):0.94(3H,s,H-18),1.45(1H,s,H-5),1.96-2.10(12H,m,-OCOCH 3×4),2.43(1H,d,J＝11.7Hz,H-19β),3.10(1H,br.s,H-6),4.08(1H,s,H-20),4.76(1H,s,H-17a),4.93(1H,m,H-17b),4.97(1H,s,H-13),5.04(1H,d,J＝9.0Hz,H-11),5.10(1H,br.s,H-2)。
2,11,13, 14-tetrapropionyl guanfu amine alcohol (AA-Ac2)
Weighing GFAA (200mg,0.58mmol) and 50mg p-toluenesulfonic acid, adding into 5mL propionic anhydride, stirring at 65 deg.C, monitoring reaction by TLC, adding 30mL water into reaction solution after 3 hr, stirring for 30min to decompose excessive propionic anhydride, and dissolving with saturated Na2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl solution (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain a yellow solid, separating by neutral alumina column chromatography (ethyl acetate) to obtain a yellow powder, drying, and weighing 127mg (38.5%) of the product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z570[ M + H ]]+Molecular weight is 569.1H NMR(CDCl3,500MHz):0.90(3H,s,H-18),0.94(12H,m,-OCOCH2CH 3×4),1.49(1H,s,H-5),2.11-2.35(8H,m,-OCOCH 2CH3×4),2.48(1H,d,J＝11.7Hz,H-19β),3.09(1H,brs,H-6),4.09(1H,s,H-20),4.76(1H,s,H-17a),4.95(2H,m,H-13,H-17b),5.04(1H,d,J＝14.9Hz,H-11),5.11(1H,br.s,H-2)。
2,11,13, 14-tetraisobutyryl guanfu amine alcohol (AA-Ac3)
GFAA (200mg,0.58mmol) and 50mg of p-toluenesulfonic acid were weighed and added to 5mL of isobutyric anhydride, stirring was carried out at 75 ℃, the reaction was monitored by TLC, and after 4 hours, 30mL of water was added to the reaction solution, stirring was continued for 30 minutes to completely decompose excess isobutyric anhydride, and saturated Na was used for complete decomposition of isobutyric anhydride2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, and recovering under reduced pressureEthyl acetate was collected to give a yellow solid, which was then separated by neutral alumina column chromatography (ethyl acetate) to give a yellow powder, which was dried and weighed to give 108mg (30.4%) of the product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z626[ M + H]+And a molecular weight of 625.1H NMR(CDCl3,500MHz):0.99(3H,s,H-18),1.11(4H,m,-OCOCH(CH 3)2),1.13(8H,m,-OCOCH(CH 3)2),1.17(8H,m,-OCOCH(CH 3)2),1.19(4H,m,-OCOCH(CH 3)2),1.59(1H,s,H-5),2.54(4H,m,-OCOCH(CH3)2×4),2.87(1H,d,J＝12.1Hz,H-19β),3.19(1H,d,J＝12.9Hz,H-19α),3.45(1H,s,H-6),4.78(1H,s,H-17a),4.98(1H,s,H-17b),5.06(2H,m,H-13,H-20),5.14(2H,br.s,H-2,H-11)。
13-benzoyl-2, 11, 14-trihydroxyguanamidol (AA-Ac4)
GFAA (200mg,0.58mmol) was weighed, dissolved in 30mL of anhydrous tetrahydrofuran, added with benzoyl chloride (538. mu.L, 4.63mmol) and anhydrous pyridine (187. mu.L, 2.32mmol), reacted at 65 ℃ with stirring under reflux for 10 hours, TLC showed that GFAA had reacted completely, evaporated under reduced pressure to remove tetrahydrofuran, added with 30mL of water, and saturated Na2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (dichloromethane: methanol 20:1) to obtain white powder, drying, and weighing to obtain 59.7mg (22.6%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z450[ M + H ]]+And has a molecular weight of 449.1H NMR(CDCl3,500MHz):0.95(3H,s,H-18),1.53(1H,s,H-5),2.47(1H,d,J＝12.0Hz,H-19β),3.19(1H,br.s,H-6),4.18-4.26(3H,m,H-2,H-11,H-13),4.72(1H,s,H-17a),4.90(1H,s,H-17b),7.42(2H,t,J＝7.4Hz,Ar-H),7.54(1H,t,J＝7.1Hz,Ar-H),8.02(2H,d,J＝7.80Hz,Ar-H)。
11, 13-dibenzoyl-2, 14-dihydroxy guanfu amine alcohol (AA-Ac5)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, benzoyl chloride (269. mu.L, 2.32mmol) was added, the reaction was stirred at 75 ℃ for 4 hours, TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction solution, and saturated Na was used2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain white powder, drying, and weighing to obtain 119mg (37.1%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z554[ M + H]+And a molecular weight of 553.1H NMR(CDCl3,500MHz):0.94(3H,s,H-18),1.57(1H,s,H-5),2.01(1H,dd,J＝13.9,3.0Hz,H-15α),2.22(1H,d,J＝17.8Hz,H-19β),2.32(1H,d,J＝17.8Hz,H-19α),3.23(1H,br.s,H-6),3.93(2H,m,H-2,H-20),4.88(1H,s,H-17a),5.10(1H,s,H-17b),5.43(2H,m,H-11,H-13),7.15(2H,t,J＝7.8Hz,Ar-H),7.45(3H,t,J＝7.7Hz,Ar-H),7.61(1H,t,J＝7.4Hz,Ar-H),7.74(2H,d,J＝7.4Hz,Ar-H),8.39(2H,d,J＝7.5Hz,Ar-H)。
13-p-chlorobenzoyl-2, 11, 14-trihydroxy guanfu aminol (AA-Ac6)
GFAA (200mg,0.58mmol) was weighed out and dissolved in 30mL of anhydrous tetrahydrofuran, and 4-chlorobenzoyl chloride (565. mu.L, 4.45mmol) and anhydrous pyridine (187. mu.L, 2.32 mm) were addedol) at 65 deg.C, stirring under reflux for 10 hr, TLC to show GFAA has reacted completely, distilling off tetrahydrofuran under reduced pressure, adding 30mL purified water, adding saturated Na2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (dichloromethane: methanol 20:1) to obtain white powder, drying, and weighing to obtain 56.5mg (20.1%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z484[ M + H ]]+And has a molecular weight of 483.1H NMR(CDCl3,500MHz):0.96(3H,s,H-18),1.57(1H,s,H-5),2.01(1H,dd,J＝13.9,3.0Hz,H-15α),2.46(1H,d,J＝12.1Hz,H-19β),2.64(1H,d,J＝2.7Hz,H-12),2.86(1H,d,J＝15.2Hz,H-19α),3.17(2H,m,H-6,H-20),4.19(3H,m,H-2,H-11,H-13),4.73(1H,s,H-17a),4.91(1H,s,H-17b),5.43(2H,m,H-11,H-13),7.40(2H,dd,J＝11.0,9.2Hz,Ar-H),7.95(2H,dd,J＝10.3,8.4Hz,Ar-H)。
2, 11-di-p-chlorobenzoyl-13, 14-dihydroxy guanfu amine alcohol (AA-Ac7)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, 4-chlorobenzoyl chloride (294. mu.L, 2.32mmol) was added, the reaction was stirred at 75 ℃ for 7 hours, TLC showed that GFAA had reacted completely, 30mL of purified water was added, and saturated Na was added2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (ethyl acetate: petroleum ether: 1:2) to obtain white powder, drying, and weighing to obtain 19.4mg (5.2%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z622[ M + H]+Molecular weight of621。1H NMR(CDCl3,500MHz):1.03(3H,s,H-18),1.62(1H,s,H-5),2.16(1H,s,H-9),2.32(1H,d,J＝8.9Hz,H-15α),2.62(1H,d,J＝12.0Hz,H-19β),2.55(1H,s,H-12),3.03(1H,d,J＝12.1Hz,H-19α),3.67(1H,s,H-20),4.11(1H,br.s,H-13),4.78(1H,s,H-17a),4.93(1H,s,H-17b),5.15(1H,s,H-2),5.42(1H,d,J＝8.8Hz,H-11),7.46(2H,t,J＝8.2Hz,Ar-H),7.98(2H,t,J＝8.2Hz,Ar-H)。
2, 11-di-p-chlorobenzoyl-13, 14-dihydroxy guanfu amine alcohol (AA-Ac8)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, 4-chlorobenzoyl chloride (294. mu.L, 2.32mmol) was added, the reaction was stirred at 75 ℃ for 7 hours, TLC showed that GFAA had reacted completely, 30mL of purified water was added, and saturated Na was added2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (ethyl acetate: petroleum ether: 1:3) to obtain white powder, drying, and weighing to obtain 129mg (35.8%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z622[ M + H]+And the molecular weight is 621.1H NMR(CDCl3,500MHz):0.99(3H,s,H-18),1.58(1H,s,H-5),2.23(1H,d,J＝17.6Hz,H-15β),2.32(1H,d,J＝18.1Hz,H-15α),2.58(1H,d,J＝11.8Hz,H-19β),3.22(1H,s,H-12),3.28(1H,d,J＝11.6Hz,H-19α),3.17(2H,m,H-6,H-20),3.98(2H,m,H-2,H-20),4.89(1H,s,H-17a),5.11(1H,s,H-17b),5.40(2H,m,H-11,H-13),7.09(2H,d,J＝8.5Hz,Ar-H),7.45(2H,d,J＝8.5Hz,Ar-H),7.57(2H,d,J＝8.5Hz,Ar-H),8.40(2H,d,J＝8.5Hz,Ar-H)。
13-m-chlorobenzoyl-2, 11, 14-trihydroxy guanfu aminol (AA-Ac9)
GFAA (200mg,0.58mmol) was weighed and dissolved in 5mL of anhydrous pyridine, 149. mu.L of m-chlorobenzoyl chloride (1.16 mmol) was added, the reaction was stirred at 75 ℃ for 3 hours, TLC showed that GFAA had reacted completely, tetrahydrofuran was removed under reduced pressure, 30mL of water was added, saturated Na was used2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (ethyl acetate: methanol: 5:1) to obtain white powder, drying, and weighing to obtain 65.8mg (23.2%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z484[ M + H ]]+And has a molecular weight of 483.1H NMR(CDCl3,500MHz):0.97(3H,s,H-18),1.56(1H,s,H-5),2.57(1H,d,J＝11.6Hz,H-19β),2.68(1H,s,H-12),3.21(1H,br.s,H-6),3.30(1H,d,J＝11.7Hz,H-19α),3.93(1H,s,H-20),4.00(1H,br.s,H-2),4.14(1H,br.s,H-13),4.78(1H,s,H-17a),4.94(1H,s,H-17b),5.36(1H,d,J＝8.9Hz,H-11),7.40(1H,d,J＝7.8Hz,Ar-H),7.53(1H,d,J＝7.9Hz,Ar-H),7.97(1H,d,J＝7.7Hz,Ar-H),8.04(1H,s,Ar-H)。
11, 13-di-p-bromobenzoyl-2, 14-dihydroxy guanfu amine alcohol (AA-Ac10)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, p-bromobenzoyl chloride (508mg,2.32mmol) was added, the reaction was stirred at 75 ℃ for 10 hours, after TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction mixture, and saturated Na was used2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, and recovering ethyl acetate under reduced pressure to obtain white solidThen, the resulting extract was separated by neutral alumina column chromatography (acetone: petroleum ether: 1:4) to obtain a white powder, which was dried and weighed to obtain 79.3mg (19.2%) of a product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z712[ M + H]+The molecular weight is 711.1H NMR(CDCl3,500MHz):1.00(3H,s,H-18),1.58(1H,s,H-5),1.99(1H,dd,J＝13.8,3.3Hz,H-15α),2.59(1H,d,J＝12.1Hz,H-19β),2.97(1H,d,J＝2.2Hz,H-12),3.22(1H,s,H-6),3.28(1H,d,J＝15.2Hz,H-19α),3.96(1H,s,H-20),4.00(1H,br.s,H-2),4.90(1H,s,H-17a),5.11(1H,s,H-17b),5.40(2H,m,H-11,H-13),7.26(2H,d,J＝7.5Hz,Ar-H),7.48(2H,d,J＝8.5Hz,Ar-H),7.61(2H,d,J＝8.5Hz,Ar-H),8.33(2H,d,J＝8.5Hz,Ar-H)。
11, 13-di-p-nitrobenzoyl-2, 14-dihydroxy guanfu amine alcohol (AA-Ac11)
GFAA (200mg,0.58mmol) was weighed and dissolved in 5mL of anhydrous pyridine, paranitrobenzoyl chloride (210mg,1.16mmol) was added, the reaction was stirred at 75 ℃ for 9 hours, after TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction solution, and saturated Na was used2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by neutral alumina column chromatography (acetone: petroleum ether: 1:2) to obtain white powder, drying, and weighing to obtain 61.7mg (21.6%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z644[ M + H ]]+Molecular weight 643.1H NMR(CDCl3,500MHz):1.00(3H,s,H-18),1.59(1H,s,H-5),2.01(1H,m,H-15α),2.60(1H,d,J＝12.2Hz,H-19β),2.83(1H,d,J＝13.2Hz,H-19α),3.01(1H,s,H-12),3.27(1H,s,H-6),3.96(1H,s,H-20),4.01(2H,br.s,H-2,H-20),4.91(1H,s,H-17a),5.12(1H,s,H-17b),5.42(2H,m,H-11,H-13),7.78(2H,d,J＝8.6Hz,Ar-H),7.90(2H,d,J＝8.5Hz,Ar-H),8.28(2H,d,J＝8.6Hz,Ar-H),8.65(2H,d,J＝8.6Hz,Ar-H)。
2,11, 13-Tri-p-methoxybenzoyl-14-hydroxy guanfu amine alcohol (AA-Ac12)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, p-methoxybenzoyl chloride (392. mu.L, 2.89mmol) was added, the reaction was stirred at 75 ℃ for 10 hours, after TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction solution, and saturated Na was added2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain yellow solid, separating by neutral alumina column chromatography (ethyl acetate: petroleum ether: 2:3) to obtain yellow powder, drying, and weighing to obtain 83.2mg (23.4%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z748[ M + H ]]+Molecular weight 747.1H NMR(CDCl3,500MHz):0.95(3H,s,H-18),2.04(1H,s,H-9),2.70(1H,s,H-12),3.20(1H,s,H-6),3.31(1H,d,J＝11.9Hz,H-19α),3.87(3H,s,Ar-OCH 3),3.93(6H,d,J＝2.5Hz,Ar-OCH 3×2),4.14(1H,br.s,H-20),4.47(1H,s,H-13),4.78(1H,s,H-17a),4.93(1H,s,H-17b),5.24(1H,br.s,H-2),5.41(1H,d,J＝8.8Hz,H-11),6.95(4H,t,J＝8.9Hz,Ar-H),7.07(2H,d,J＝7.6Hz,Ar-H),8.03(4H,m,Ar-H),8.12(2H,d,J＝7.9Hz,Ar-H)。
11, 13-di-p-methoxybenzoyl-2, 14-dihydroxy guanfu amine alcohol (AA-Ac13)
GFAA (200mg,0.58mmol) was weighed out and dissolved in 5mL of anhydrous pyridine, and p-methoxybenzene was addedAcid chloride (392. mu.L, 2.89mmol), stirred at 75 ℃ for 10 hours, after TLC showed complete reaction of GFAA, 30mL of water was added to the reaction mixture, saturated Na was added2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain yellow solid, separating by neutral alumina column chromatography (ethyl acetate: petroleum ether: 2:3) to obtain yellow powder, drying, and weighing to obtain 51.1mg (14.3%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z614[ M + H]+And the molecular weight is 613.1H NMR(CDCl3,500MHz):1.01(3H,s,H-18),2.03(1H,s,H-9),2.57(1H,s,H-12),2.60(1H,d,J＝12.1Hz,H-19β),3.10(1H,d,J＝12.0Hz,H-19α),3.22(1H,s,H-6),3.85(6H,d,J＝4.6Hz,-OCH 3×2),3.88(1H,s,H-20),4.12(1H,br.s,H-13),4.74(1H,s,H-17a),4.91(1H,s,H-17b),5.14(1H,br.s,H-2),5.39(1H,d,J＝8.9Hz,H-11),6.95(4H,m,Ar-H),8.00(4H,dd,J＝8.7,7.0Hz,Ar-H)。
13-m-trifluoromethane benzyl-2, 11, 14-trihydroxy guanfu aminol (AA-Ac14)
GFAA (100mg,0.29mmol) was weighed, dissolved in 5mL of anhydrous pyridine, 3-trifluoromethylbenzoyl chloride (85. mu.L, 0.58mmol) was added thereto, the reaction was stirred at 75 ℃ for 2 hours, after TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction mixture, and saturated Na was added thereto2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (ethyl acetate: petroleum ether: 1) to obtain white powder, drying, and weighing to obtain 69.7mg (46.1%).
The potassium bismuth iodide reacts to form positiveSex; ESI-MS: m/z688[ M + H]+And the molecular weight is 687.1H NMR(CDCl3,500MHz):1.07(3H,s,H-18),1.64(1H,s,H-5),2.51(1H,s,H-12),2.62(1H,d,J＝12.1Hz,H-19β),3.00(1H,d,J＝12.0Hz,H-19α),3.19(1H,s,H-6),3.70(1H,s,H-20),4.14(1H,d,J＝8.9Hz,H-11),4.30(1H,br.s,H-2),4.69(1H,s,H-17a),4.89(1H,s,H-17b),5.41(1H,br.s,H-13),7.64(1H,t,J＝7.7Hz,Ar-H),7.81(1H,d,J＝7.5Hz,Ar-H),8.20(1H,d,J＝7.6Hz,Ar-H),8.32(1H,s,Ar-H)。
11, 13-bis-trifluoromethane benzyl-2, 14-dihydroxy guanamidol (AA-Ac15)
GFAA (200mg,0.58mmol) was weighed, dissolved in 5mL of anhydrous pyridine, 3-trifluoromethylbenzoyl chloride (856. mu.L, 5.79mmol) was added, the reaction was stirred at 75 ℃ for 6 hours, after TLC showed that GFAA had reacted completely, 30mL of water was added to the reaction mixture, and saturated Na was added2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating with neutral alumina column chromatography (ethyl acetate: petroleum ether: 1) to obtain white powder, drying, and weighing to obtain 76.9mg (19.3%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z688[ M + H]+And the molecular weight is 687.1H NMR(CDCl3,500MHz):1.07(3H,s,H-18),1.64(1H,s,H-5),2.94(1H,d,J＝14.5Hz,H-19β),2.99(1H,s,H-12),3.21(1H,s,H-6),3.31(1H,d,J＝11.9Hz,H-19α),4.02(2H,br.s,H-2,H-20),4.91(1H,s,H-17a),5.12(1H,s,H-17b),5.41(1H,d,J＝9.0Hz,H-11),5.49(1H,br.s,H-13),7.19(1H,t,J＝7.8Hz,Ar-H),7.58(1H,t,J＝7.8Hz,Ar-H),7.69(1H,d,J＝7.6Hz,Ar-H),7.78(1H,d,J＝7.7Hz,Ar-H),7.85(1H,d,J＝7.6Hz,Ar-H),8.06(1H,s,Ar-H),8.57(1H,d,J＝7.9Hz,Ar-H),8.73(1H,s,Ar-H)。
13-cinnamoyl-2, 11, 14-trihydroxyguanfu amine alcohol (AA-Ac16)
GFAA (200mg,0.58mmol) was weighed and dissolved in 5mL pyridine, cinnamoyl chloride (482.31mg,2.89mmol) was added, the reaction was stirred at 75 ℃ for 6 hours, after TLC showed that GFAA had reacted completely, 30mL water was added to the reaction solution, and saturated Na was used2CO3The solution was adjusted to pH 9, extracted with ethyl acetate (30mL × 3), the ethyl acetate layers combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by neutral alumina column chromatography (ethyl acetate: petroleum ether: 1:2) to obtain white powder, drying, and weighing to obtain 66.3mg (23.9%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z736[ M + H]+Molecular weight is 735.1H NMR(CDCl3,500MHz):0.97(3H,s,H-18),1.56(1H,s,H-5),2.69(1H,m,H-12),2.92(1H,d,J＝11.9Hz,H-19β),3.21(1H,d,J＝14.7Hz,H-19α),4.17(1H,br.s,H-6),4.26(2H,m,H-2,H-20),4.69(1H,s,H-13)4.76(1H,s,H-17a),4.90(1H,s,H-17b),5.29(1H,d,J＝8.7Hz,H-11),6.56(1H,d,J＝16.0Hz,ArCHCHCO-),6.44(1H,d,J＝15.9Hz,ArCHCHCO-),6.56(1H,d,J＝16.0Hz,ArCHCHCO-),7.31(3H,m,Ar-H),7.37(6H,m,Ar-H),7.41(3H,m,Ar-H),7.43(3H,m,Ar-H),7.52(3H,m,Ar-H),7.58(1H,m,ArCHCHCO-),7.70(1H,d,J＝16.0Hz,ArCHCHCO-),7.80(1H,d,J＝16.0Hz,ArCHCHCO-)。
11, 13-diethyl ether-2, 14-dihydroxyguanamidol (AA-Et1)
GFAA (300mg,0.87mmol) and 30mg tetrabutylammonium bromide (TBAB) were weighed out and dissolved in 30mL anhydrous DMF, and NaH (139mg,3.47mmol) was added with stirring in an ice bathAfter 1 hour, bromoethane (164. mu.L, 2.17mmol) was slowly added dropwise, the reaction was stirred at room temperature for 6 hours, TLC showed that GFAA had reacted completely, the reaction was quenched by pouring into 15mL of ice water, extracted with ethyl acetate (40mL × 3), the ethyl acetate layers were combined, washed with water (50mL × 2), washed with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to obtain white powder, drying, and weighing to obtain 84.6mg (24.1%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z402[ M + H]+The molecular weight is 401.1H NMR(CDCl3,500MHz):0.97(3H,s,H-18),1.15(3H,t,J＝6.9Hz,-OCH2CH 3),1.21(3H,t,J＝6.9Hz,-OCH2CH 3),2.51(1H,d,J＝11.7Hz,H-19β),3.04(1H,br.d,J＝15.8Hz,H-12),3.09(1H,br.s,H-6),3.20(1H,d,J＝11.7Hz,H-19α),3.38(1H,m,H-2),3.45(1H,m,-OCH 2CH3),3.68(1H,m,-OCH 2CH3),3.72(1H,s,H-20),3.74(1H,s,H-11),4.17(1H,s,H-13),4.68(1H,s,H-17a),4.84(1H,s,H-17b)。
11-propyl ether-2, 13, 14-trihydroxyguanamine (AA-Et2)
Weighing GFAA (200mg,0.58mmol) and 20mg TBAB, dissolving in 20mL of anhydrous DMF, adding NaH (139mg,3.47mmol) under stirring in ice bath, slowly adding bromoethane (117. mu.L, 1.45mmol) dropwise after 1 hour, stirring at room temperature for 5 hours, heating at 60 ℃ and stirring for 5 hours, TLC showing that GFAA has reacted completely, pouring the reaction solution into 15mL of ice water for quenching, extracting with ethyl acetate (30mL × 3), combining ethyl acetate layers, washing with water (50mL × 2), washing with saturated NaCl (50mL × 2), and washing with anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkaline silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain white powder, drying, and weighing to obtain product 28.7mg(12.9％)。
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z388[ M + H ]]+And has a molecular weight of 387.1H NMR(CDCl3,500MHz):0.94(3H,t,J＝7.4Hz,-OCH2CH2CH 3),1.00(3H,s,H-18),1.48(1H,s,H-5),1.65(2H,m,-OCH2CH 2CH3),2.56(1H,d,J＝11.7,H-19α),2.90(1H,d,J＝15.6,H-19β),3.16(1H,br.s,H-12),3.49(1H,s,H-20),3.31(2H,m,-OCH 2CH2CH3),3.46(1H,m,H-6),3.84(2H,m,H-2,H-11),4.01(1H,d,H-20),4.18(1H,br.s,H-11),4.69(1H,s,H-17a),4.89(1H,s,H-17b)。
13-propyl ether-2, 11, 14-trihydroxyguanamine (AA-Et3)
Weighing GFAA (200mg,0.58mmol) and 20mg TBAB, dissolving in 20mL of anhydrous DMF, adding NaH (139mg,3.47mmol) under stirring in ice bath, slowly adding bromoethane (117. mu.L, 1.45mmol) dropwise after 1 hour, stirring at room temperature for 5 hours, heating at 60 ℃ and stirring for 5 hours, TLC showing that GFAA has reacted completely, pouring the reaction solution into 15mL of ice water for quenching, extracting with ethyl acetate (30mL × 3), combining ethyl acetate layers, washing with water (50mL × 2), washing with saturated NaCl (50mL × 2), and washing with anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain white powder, drying, and weighing to obtain 62.6mg (28.7%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z388[ M + H ]]+And has a molecular weight of 387.1H-NMR(CDCl3,500MHz):0.94(3H,t,J＝7.4Hz,-OCH2CH2CH 3),1.00(3H,s,H-18),1.48(1H,s,H-5),1.65(2H,m,-OCH2CH 2CH3),2.43(1H,d,J＝11.8,H-19α),2.54(1H,d,J＝10.3,H-19β),2.65(1H,d,J＝2.7,H-12),3.11(1H,br.s,H-6),3.49(1H,s,H-20),3.63(2H,m,-OCH 2CH2CH3),3.73(1H,d,J＝2.2Hz,H-11),3.83(1H,d,H-11),4.19(1H,br.s,H-13),4.69(1H,s,H-17a),4.88(1H,s,H-17b)。
11, 13-Dipropyleneether-2, 14-dihydroxyguanamidol (AA-Et4)
Weighing GFAA (100mg,0.29mmol) and 10mg TBAB, dissolving in 20mL of anhydrous DMF, adding NaH (46.3mg,1.16mmol) under stirring in ice bath, slowly adding 3-bromopropylene (49 uL, 0.58mmol) dropwise after 1 hour, reacting for 6 hours under stirring at room temperature, TLC showing that GFAA has reacted completely, pouring the reaction solution into 15mL of ice water for quenching, extracting with ethyl acetate (30mL × 3), combining ethyl acetate layers, washing with water (50mL × 2), washing with saturated NaCl (50mL × 2), and anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to obtain white powder, drying, and weighing to obtain 24.4mg (19.5%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z426[ M + H]+And a molecular weight of 425.1H NMR(CDCl3,500MHz):0.99(3H,s,H-18),1.49(1H,s,H-5),2.12(1H,brd,J＝17.7Hz,H-15α),2.57(1H,d,J＝11.7Hz,H-19β),2.77(1H,d,J＝2.7Hz,H-12),3.20(1H,br.s,H-6),3.28(1H,d,J＝11.7Hz,H-19α),3.77(1H,s,H-20),4.69(1H,s,H-17a),4.86(1H,s,H-17b),5.13(1H,dd,J＝10.5,1.5Hz,-OCHCH＝CH 2),5.17(1H,dd,J＝10.4Hz,1.4Hz,-OCHCH＝CH 2),5.26(1H,dd,J＝17.3,1.7Hz,-OCHCH＝CH 2),5.36(1H,dd,J＝17.3,1.7Hz,-OCHCH＝CH 2),5.87(1H,ddd,J＝22.4,10.4,5.2Hz,-OCHCH＝CH2),5.98(1H,ddd,J＝22.4,10.4,5.2Hz,-OCHCH＝CH2)。
11, 13-dibutyl ether-2, 14-dihydroxy guanfu amine alcohol (AA-Et5)
Weighing GFAA (150mg,0.43mmol) and 15mg TBAB, dissolving in 20mL of anhydrous DMF, adding NaH (46.3mg,1.16mmol) under stirring in ice bath, slowly adding n-butyl bromide (117. mu.L, 1.09mmol) dropwise after 1 hour, stirring at room temperature for reaction for 5 hours, TLC showing that GFAA has reacted completely, pouring the reaction solution into 15mL of ice water for quenching, extracting with ethyl acetate (30mL × 3), combining ethyl acetate layers, washing with water (50mL × 2), washing with saturated NaCl (50mL × 2), and anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by alkalified silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain white powder, drying, and weighing to obtain 64.1mg (32.2%).
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z458[ M + H]+And the molecular weight is 457.1H NMR(CDCl3,500MHz):0.91(6H,td,J＝7.4,2.8Hz,-OCH2CH2CH2CH 3×2),0.99(3H,s,H-18),1.38(4H,m,-OCH2CH2CH 2CH3×2),1.51(4H,m,-OCH2CH 2CH2CH3×2),2.12(1H,br.d,J＝17.8Hz,H-15β),2.56(1H,d,J＝11.7Hz,H-19β),2.78(1H,d,J＝2.6Hz,H-12),3.18(1H,br.s,H-6),3.28(2H,m,-OCH 2CH2CH2CH3),3.39(2H,m,-OCH 2CH2CH2CH3),3.72(1H,d,J＝8.7Hz,H-11),3.80(1H,s,H-20),4.17(1H,br.s,H-2),4.68(1H,s,H-17a),4.84(1H,s,H-17b)。
13-anisole-2, 11, 14-trihydroxyguanfu amine alcohol (AA-Et6)
GFAA (200mg,0.58mmol) and 20mg TBAB were weighed out and dissolved in 20mL of anhydrous DMF, NaH (69.47mg,1.74mmol) was added with stirring in an ice bath, and after 1 hour bromine was slowly added dropwiseBenzyl (103.15. mu.L, 0.87mmol), stirring at room temperature for 6 hours, TLC to show that GFAA had reacted completely, pouring the reaction solution into 15mL ice water for quenching, extracting with ethyl acetate (25mL × 3), combining ethyl acetate layers, washing with water (50mL × 2), washing with saturated NaCl (50mL × 2), anhydrous Na2SO4Drying, filtering, recovering ethyl acetate under reduced pressure to obtain white solid, separating by neutral alumina column chromatography (ethyl acetate: methanol 20:1) to obtain white powder, and drying to obtain 78.9mg (30.9%) of product.
The reaction of bismuth potassium iodide is positive; ESI-MS: m/z436[ M + H]+The molecular weight is 435.1H NMR(CDCl3,500MHz):0.99(3H,s,H-18),1.49(1H,s,H-5),2.55(1H,d,J＝11.7Hz,H-19β),2.76(1H,s,H-12),3.16(1H,br.s,H-6),3.23(1H,d,J＝11.7Hz,H-19α),3.66(1H,s,H-20),3.95(2H,m,H-2,H-11),4.20(1H,d,J＝8.8Hz,H-13),4.67(1H,d,J＝10.5Hz,Ar-CH 2),4.74(1H,d,J＝10.6Hz,Ar-CH 2),4.74(1H,s,H-17a),4.93(1H,s,H-17b),7.38(5H,m,Ar-H)。
EXAMPLE III pharmacological experiments on Guanfu amino alcohol derivatives
Cell lines: a549 (human lung cancer cell), MCF-7 (human breast cancer cell), and HepG-2 (human liver cancer cell). Cell culture: a549 and MCF-7 in RPMI1640 complete culture solution containing 10% fetal calf serum, and HepG-2 in DMEM complete culture solution containing 10% fetal calf serum, at 37 deg.C and 5% CO2Cultured in an incubator. And (4) digesting and centrifuging the cells in the logarithmic growth phase, and counting for later use.
MTT method for determining the cytotoxic activity of the test substance: the cell suspension was seeded in 96-well plates, 5000-. After 12 hours of incubation, samples were added at various concentrations, 100. mu.l per well. The negative control is the complete culture solution with the same volume, and each drug adding group and the control group are provided with 5 parallel holes.
Administration concentration of a 549: the concentration of the tested Guanfu amino alcohol derivatives was 200. mu.M/L, 100. mu.M/L, 80. mu.M/L, 50. mu.M/L, 20. mu.M/L, 10. mu.M/L, 5. mu.M/L, 2.5. mu.M/L, 1. mu.M/L, 0.5. mu.M/L.
Dosing concentrations of MCF-7 and HepG-2: the concentration of the tested Guanfu amino alcohol derivatives was 200. mu.M/L, 100. mu.M/L, 50. mu.M/L, 10. mu.M/L, 1. mu.M/L.
Cells were incubated at 37 ℃ with 5% CO2After 24 hours of incubation in the incubator, MTT5mg/mL and 20. mu.L/well were added. After incubation at 37 ℃ for 4h, the supernatant was aspirated, DMSO was added, 100. mu.L/well was shaken, OD was measured at 570nm using a microplate reader, and IC was calculated using SPSS19.0 software50The value is obtained.
The tested guanfu amine alcohol derivatives have the following structure:
the experimental result of the antitumor activity of the tested Guanfu amino alcohol derivative shows that: AA-Ac5, 7, 13 and AA-Et5 have inhibition effect on the growth of three cell strains of A549, HepG-2 and MCF-7, which shows that the three cell strains may have certain broad-spectrum inhibition effect on the growth of tumor cells; the AA-Ac7 has better inhibition effect on A549 than other 2 cells, the AA-Ac13 has better inhibition effect on MCF-7 than other 2 cells, and the rest compounds have IC of 6-55 mu M on HepG-250Particularly, AA-Ac8 and AA-Ac10 have better inhibition effect on HepG-2, which indicates that the compounds may have cell selection inhibition effect. IC in Table 3-150Values are selected from the results representative of the subject amine alcohol derivatives tested in this experimental section.
TABLE 3-1 part of the tested Guanfu Aminoalcohol derivatives have antitumor Activity
Claims (3)
1. A compound shown in formula (I) or pharmaceutically acceptable salt thereof,
wherein,
R1and R4Is hydrogen;
R2is hydrogen or optionally substituted C1-6Alkyl, the substituents of which are selected from halogen or C2-4An alkenyl group;
R3is optionally substituted C1-6Alkyl, the substituent of which is selected from halogen and C2-4Alkenyl, phenyl, halophenyl, C1-2Alkyl phenyl, C1-2Alkoxyphenyl or C1-2A haloalkylphenyl group.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
3. use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of lung, liver or breast cancer.
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| CN102697774A (en) * | 2012-06-19 | 2012-10-03 | 中国药科大学 | New application of Korean mondshood root total alkaloids and guanfu base VIIII |
| CN103463080A (en) * | 2013-09-26 | 2013-12-25 | 刘静涵 | Use of Guanfu Base S as arrhythmia treatment drug |
| CN103494814A (en) * | 2012-04-17 | 2014-01-08 | 中国药科大学 | Novel applications of Guanfu base A and Guanfu base G |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103494814A (en) * | 2012-04-17 | 2014-01-08 | 中国药科大学 | Novel applications of Guanfu base A and Guanfu base G |
| CN102697774A (en) * | 2012-06-19 | 2012-10-03 | 中国药科大学 | New application of Korean mondshood root total alkaloids and guanfu base VIIII |
| CN103463080A (en) * | 2013-09-26 | 2013-12-25 | 刘静涵 | Use of Guanfu Base S as arrhythmia treatment drug |
Non-Patent Citations (2)
| Title |
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| Tangutisine, a new diterpenoid alkaloid from Aconitum tanguticum (Maxim.) Stapf, W. T. Wang;Balawant S. Joshi et al.;《Heterocycles》;19911231;第32卷(第9期);第1793-1804页 * |
| 抗心律失常药物的研究III.关附甲素酯类化合物的合成及心律失常活性研究;王如斌 等;《山东医科大学学报》;19951231;第33卷(第4期);第342-345页 * |
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