CN111499626A - 一种表小檗碱的合成方法及应用 - Google Patents
一种表小檗碱的合成方法及应用 Download PDFInfo
- Publication number
- CN111499626A CN111499626A CN201910097678.9A CN201910097678A CN111499626A CN 111499626 A CN111499626 A CN 111499626A CN 201910097678 A CN201910097678 A CN 201910097678A CN 111499626 A CN111499626 A CN 111499626A
- Authority
- CN
- China
- Prior art keywords
- epiberberine
- acid
- reaction
- cancer
- synthesis method
- 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.)
- Pending
Links
- FPJQGFLUORYYPE-UHFFFAOYSA-N epiberberine Chemical compound C1=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C2OCOC2=C1 FPJQGFLUORYYPE-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 238000010189 synthetic method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 34
- 239000012065 filter cake Substances 0.000 claims abstract description 34
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims abstract description 28
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 20
- 235000019253 formic acid Nutrition 0.000 claims abstract description 20
- 238000010992 reflux Methods 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 229940015043 glyoxal Drugs 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 14
- 238000001308 synthesis method Methods 0.000 claims abstract description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 10
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 10
- 239000011780 sodium chloride Substances 0.000 claims abstract description 10
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 9
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 239000013078 crystal Substances 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 229940037467 helicobacter pylori Drugs 0.000 claims description 17
- 241000590002 Helicobacter pylori Species 0.000 claims description 16
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 16
- 206010017758 gastric cancer Diseases 0.000 claims description 16
- 201000011549 stomach cancer Diseases 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- -1 epiberberine halide Chemical class 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 206010019375 Helicobacter infections Diseases 0.000 claims description 2
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 208000021780 appendiceal neoplasm Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 235000013402 health food Nutrition 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 20
- 239000000706 filtrate Substances 0.000 abstract description 14
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 abstract description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 abstract description 6
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- 239000000883 anti-obesity agent Substances 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- 230000000694 effects Effects 0.000 description 17
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 13
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 11
- 229940093265 berberine Drugs 0.000 description 11
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000004321 preservation Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 238000009210 therapy by ultrasound Methods 0.000 description 7
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 6
- 241000037740 Coptis chinensis Species 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 5
- LUXPUVKJHVUJAV-UHFFFAOYSA-M coptisine, chloride Chemical compound [Cl-].C1=C2C=C(C3=C(C=C4OCOC4=C3)CC3)[N+]3=CC2=C2OCOC2=C1 LUXPUVKJHVUJAV-UHFFFAOYSA-M 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- RLQYRXCUPVKSAW-UHFFFAOYSA-M 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium;chloride Chemical compound [Cl-].COC1=C(OC)C=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=C1 RLQYRXCUPVKSAW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 229930013930 alkaloid Natural products 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000001603 reducing effect Effects 0.000 description 4
- 101150037123 APOE gene Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101100216294 Danio rerio apoeb gene Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 230000010757 Reduction Activity Effects 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940000406 drug candidate Drugs 0.000 description 3
- 239000003777 experimental drug Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000218202 Coptis Species 0.000 description 2
- 235000002991 Coptis groenlandica Nutrition 0.000 description 2
- XDVZNDLANFJOQR-UHFFFAOYSA-N Coptisine Natural products O=Cc1c2OCOc2ccc1C=C3/NCCc4cc5OCOc5cc34 XDVZNDLANFJOQR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MXTLAHSTUOXGQF-UHFFFAOYSA-O Jatrorrhizine Chemical compound COC1=CC=C2C=C3C(C=C(C(=C4)O)OC)=C4CC[N+]3=CC2=C1OC MXTLAHSTUOXGQF-UHFFFAOYSA-O 0.000 description 2
- PTPHDVKWAYIFRX-UHFFFAOYSA-N Palmatine Natural products C1C2=C(OC)C(OC)=CC=C2C=C2N1CCC1=C2C=C(OC)C(OC)=C1 PTPHDVKWAYIFRX-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- QUCQEUCGKKTEBI-UHFFFAOYSA-N palmatine Chemical compound COC1=CC=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C1OC QUCQEUCGKKTEBI-UHFFFAOYSA-N 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 229940126680 traditional chinese medicines Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000005740 tumor formation Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- ZILSBZLQGRBMOR-UHFFFAOYSA-N 1,3-benzodioxol-5-ylmethanamine Chemical compound NCC1=CC=C2OCOC2=C1 ZILSBZLQGRBMOR-UHFFFAOYSA-N 0.000 description 1
- QZMQKPGVXNSITP-UHFFFAOYSA-N 1,3-benzodioxole-4-carbaldehyde Chemical compound O=CC1=CC=CC2=C1OCO2 QZMQKPGVXNSITP-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- XKBUFTXNLBWTFP-UHFFFAOYSA-N 2-(2,3-dimethoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1OC XKBUFTXNLBWTFP-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000893536 Epimedium Species 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003836 berberines Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- TUDWMIUPYRKEFN-UHFFFAOYSA-N bromoiodomethane Chemical compound BrCI TUDWMIUPYRKEFN-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000018905 epimedium Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- AHHYEKPJZYDDFK-UHFFFAOYSA-N formic acid;phosphoric acid Chemical compound OC=O.OP(O)(O)=O AHHYEKPJZYDDFK-UHFFFAOYSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种表小檗碱卤酸盐的合成方法及其用途;表小檗碱卤酸盐的合成方法包括以下步骤:1)将甲酸和占甲酸体积0~10%的磷酸作为催化剂,加入无水硫酸铜、氯化钠及乙二醛回流搅拌反应;2)往反应体系中加入N‑(2,3‑亚甲氧基‑N‑苄基)‑β‑(3,4‑甲氧基苯基)乙胺,继续回流反应;3)反应完毕后,滤饼水洗去除反应残留物;4)将滤饼放入NaHCO3溶液中加热搅拌,然后趁热过滤,滤液中加入氢卤酸,冷却结晶。本发明将表小檗碱卤酸盐的收率从35%大幅提高到90%以上,本发明制备的表小檗碱卤酸盐可以用于制备抗癌、减肥药和防治心脑血管类疾病的药物。
Description
技术领域
本发明属于药物学技术领域,具体涉及一种表小檗碱的合成方法及应用。
背景技术
表小檗碱(epiberberine)是黄连中的主要生物碱之一,也是黄连的主要活性成分(匡艳辉,朱晶晶,王智民,张启伟。一测多评法测定黄连中小檗碱、巴马汀、表小檗碱、表小檗碱、药根碱含量。中国药学杂志,2009,44(5):390)。与黄连素的广泛研究不同,关于表小檗碱的研究相对较少:纪丽莎等研究了黄连类中成药中表小檗碱的分析监测方法(纪丽莎,张先福,喻卫武,陈安良。HPLC法测定黄连复方汤中盐酸小檗碱、表小檗碱、药根碱、盐酸巴马汀和甘草酸。中草药,42(2):285)。
关于表小檗碱的应用,目前主要是用于降糖和降血脂等方面。蒋小飞等研究了表小檗碱的提取分离技术及其体外降糖活性(蒋小飞,王立军,李学刚,赵忠启,朱家颖。黄连中药根碱和表小檗碱的分离及其体外降糖活性。贵州农业科学,2011,39(9):44~46)。王嘉陵等研究了表小檗碱对α-受体的影响(王嘉陵,方达超。表小璧碱对a受体的作用。药学学报,1990,25(4):289~292)。发现表小檗碱对细胞色素P450亚型CYP2D6较强的抑制活性、非竞争性BACE1抑制活性、抑制醛糖还原酶活性、α受体阻断作用、降血糖活性等。
关于表小檗碱的制备:专利技术(申请号:201410027042.4)发明了表小檗碱的提取方法及其在制药中的应用,包括表小檗碱用于制备降血脂药物、抗氧化药物、预防或治疗动脉粥样硬化的药物、预防或治疗肥胖症的药物等方面的应用。专利技术(申请号201210136741.3)发明了表小檗碱的全合成技术:以3,4-二甲氧基苯乙胺与2,3-亚甲二氧基苯甲醛为起始原料,经环和、缩和及闭环等反应合成了目标化合物;反应第一步的反应试剂为二氯甲烷、二溴甲烷、二碘甲烷、氯碘甲烷或溴碘甲烷,缚酸剂为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠或碳酸镁,收率达到75.0%;反应第二步,缚酸剂为三乙胺、二乙胺、氢氧化钠、碳酸钾、碳酸钠或者碳酸镁,收率达到98.7%;反应第三步的还原剂为硼氢化钾、硼氢化钠、Zn+浓盐酸或Fe+浓硫酸,收率达到98.4%;反应第四步的反应试剂为乙二醛,中和碱溶液为氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠或氨溶液,达到收率35.8%;该发明的综合收率可以达到10%以上。对比该发明与陈帅等报道的“盐酸黄连碱的全合成”(合成化学,2009,17(4):512),发现这两个合成工艺技术基本相同,只是将盐酸黄连碱全合成反应中的“胡椒乙胺”更换“2,3-二甲氧基苯乙胺”;而且两个合成工艺技术中的最后一步反应的收率均很低:盐酸黄连碱全合成工艺的最后一步收率为23.4%,表小檗碱合成方法的最后一步合成收率为35.8%。导致目标化合物的总收率很低,经济价值受到严重制约。
发明内容
本发明的目的之一是小檗碱的卤酸盐的合成方法,该方法能够大幅度提高表小檗碱卤酸盐的收率,降低生产成本。
一种表小檗碱的合成方法,其反应式如下:
其中,X=F-、Cl-、Br-、I-,溶剂为甲酸,催化剂为占甲酸体积0~10%的磷酸,反应的温度为50~100℃。
优选的,所述磷酸的体积为甲酸体积的1~5%。
优选的,所述反应式中,乙二醛与式I所示化合物的物质量之比为1-2:1。
优选的,所述反应式中,乙二醛与式I所示化合物的物质量之比为1.4:1。
优选的,所述合成方法的具体步骤为:
(1)将甲酸、磷酸、乙二醛、硫酸铜和氯化钠加入容器,50~100℃回流搅拌得到反应体系;
(2)将式I化合物(N-(2,3-亚甲氧基-N-苄基)-β-(3,4-二甲氧基苯基)乙胺)加入步骤(1)得到的反应体系中,继续在50~100℃下搅拌回流,反应完毕后加水,加热,中和剂中和,冷却过滤得滤饼为表小檗碱卤酸盐;
优选的,所述步骤(2)中,式I化合物与溶剂的重量体积比为1g:15~20mL。
优选的,所述步骤(2)中,所述滤饼还经过超声水洗、加热至80℃,冷却,过滤和洗涤得表小檗碱卤酸盐。
优选的,所述合成方法还包括将步骤(2)获得的表小檗碱卤酸盐在氢卤酸-乙醇溶液中重结晶,过滤得卤酸盐表小檗碱晶体。
优选的,所述步骤(2)中,中和剂选自氢氧化钠、氢氧化钾、碳酸钠和碳酸氢钠中的一种或多种。
优选的,所述氢卤酸-乙醇溶液中的氢卤酸选自氢氟酸、盐酸、氢溴酸或氢碘酸。
本发明的目的之二是提供一种表小檗碱的新应用,经研究发现,表小檗碱除了具备降糖和降血脂等方面的作用,表小檗碱还具备抗消化道肿瘤(特别是胃癌)、抗幽门螺杆菌和防治心脑血管疾病的作用。
一种表小檗碱的应用,所述应用是表小檗碱在制备治疗/预防消化道肿瘤的保健食品或药剂中的应用,所述述消化道肿瘤是食道癌,胃癌,肝癌,胰腺癌,胆囊癌,12指肠癌,阑尾癌,结肠癌或直肠癌;优选的,所述消化道肿瘤是胃癌。
一种表小檗碱的应用,所述应用是表小檗碱在制备抗幽门螺杆菌的药剂或保健食品中的应用。
一种表小檗碱的应用,所述应用是表小檗碱在制备/预防幽门螺杆菌感染的药剂或保健食品中的应用。
一种表小檗碱的应用,所述应用是表小檗碱在制备治疗/预防心脑血管类疾病的药剂或保健食品中的应用。优选的,所述心脑血管类疾病是动脉粥样硬化引起的心脑血管类疾病。
上述药剂可以组合物的形式通过口服、注射或外用等给药的方式用于相关疾病的患者;用于口服时,可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等,制成液体制剂如水油悬浮剂或糖浆等;用于注射给药时,可将其制成注射用溶液或油悬浮剂等;用于外用可以制成贴膏或擦剂;以上各种剂型可以按照药学领域的常规生产方法制备。施用量可根据用药途径、患者的年龄、体重、所治疗疾病的类型和严重程度等变化。
本发明所述表小檗碱如式III所示。
本发明的有益效果在于:
1.本发明提供的一种表小檗碱的新应用,其除了在抗降糖和降血脂等方面的作用,还具备抗幽门螺杆菌、胃癌和心脑血管类疾病的作用,这些新作用为防治胃病、胃癌和心脑血管疾病等开辟了一条新途径;
2.本发明提供的一种表小檗碱的合成方法,该合成方法将现有技术中的溶剂醋酸和醋酸酐,更换为甲酸-磷酸体系,表小檗碱卤酸盐的收率从35%-70%大幅提高到95%以上,大幅度提高了产品的收率,合成工艺更环保,成本更低,有利于表小檗碱的实际应用。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚,下面将对本发明的优选实施例进行详细的描述。
实施例1表小檗碱盐酸盐的合成
1)将85mL甲酸、8.35g无水硫酸铜、5.85g氯化钠及3.55mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-二甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL浓盐酸,冷却至室温,析出晶体,过滤得到表小檗碱盐酸盐晶体,烘干称重4.19g。
该产物可利用薄层层析鉴别是否为纯物质,薄层层析条件:硅胶G制板,展开剂为:苯:乙酸乙酯:异丙醇:甲醇:氨水(6:3:1.5:1.5:0.5);所用试剂均为分析纯。
提纯后的样品采用1HNMR和13CNMR核磁共振仪测定化合物的氢谱和碳谱,溶剂均为DMSO-d6,1HNMR测定的内标为TMS。
以下是实施例1的产物的表征结果:
1HNMR(DMSO-d6)δ:9.89(1H,s,H-8)8.94(1H,s,H-13)8.22(1H,d,J=8.43Hz,H-11)8.19(1H,d,J=8.4Hz H-12)7.99(1H,s,H-l)7.07(1H,s,H-4)6.55(2H,s,-OCH2O-)4.94(2H,t,J=5.6Hz,H-6)3.93(3H,s,2-OCH3)3.86(3H,s,3-OCH3)蕌3.12(2H,t,J=5.6Hz,H-5)。
上述数据表明,实施例1得到的化合物确实为表小檗碱盐酸盐。
实施例2表小檗碱溴酸盐的合成
1)将85mL甲酸、8.5mL磷酸、8.35g无水硫酸铜、5.85g氯化钠及3.55mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-二甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL氢溴酸,冷却至室温,析出晶体,过滤得到表小檗碱溴酸盐晶体,烘干称重6.29g。
实施例3表小檗碱碘酸盐的合成
1)将85mL甲酸、4.25mL磷酸、8.35g无水硫酸铜、5.85g氯化钠及3.55mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL氢碘酸,冷却至室温,析出晶体,过滤得到表小檗碱碘酸盐晶体,烘干称重7.04g。
实施例4表小檗碱氟酸盐的合成
1)将85mL甲酸、0.85mL磷酸、8.35g无水硫酸铜、5.85g氯化钠及3.55mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL氢氟酸,冷却至室温,析出晶体,过滤得到表小檗碱氟酸盐晶体,烘干称重5.45g。
实施例5表小檗碱氟酸盐的合成
1)将85mL甲酸、0.85mL磷酸、8.35g无水硫酸铜、5.85g氯化钠及2.48mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL氢氟酸,冷却至室温,析出晶体,过滤得到表小檗碱氟酸盐晶体,烘干称重5.20g。
实施例6表小檗碱氟酸盐的合成
1)将85mL甲酸、0.85mL磷酸、8.35g无水硫酸铜、5.85g氯化钠及4.96mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL氢氟酸,冷却至室温,析出晶体,过滤得到表小檗碱氟酸盐晶体,烘干称重5.46g。
比较例1:(专利技术:申请号201210136741.3)
1)将85mL乙酸、8.35g无水硫酸铜、5.85g氯化钠及3.55mL39%的乙二醛装入三口烧瓶中于50℃下回流搅拌反应30分钟;
2)往步骤1)得到的反应体系中加入N-(2,3-亚甲氧基-N-苄基)-β-(3,4-甲氧基苯基)乙胺5g(16.7mmol),90℃下继续回流反应3小时;
3)反应完毕后,体系呈红棕色,将其过滤,得滤饼,滤饼转移至烧杯加入200mL水超声处理15分钟,然后加热至80℃保持15分钟,放置冷却,过滤,滤饼用水洗涤;
4)将步骤3)得到的滤饼放入2L浓度为0.5mol/L的NaHCO3溶液中搅拌并置于80℃水浴保温2小时,趁热过滤,滤液中加入100mL浓盐酸,冷却至室温,析出晶体,过滤得到表小檗碱盐酸盐晶体,烘干称重2.07g。
比较例2:将85mL乙酸更换为85mL乙醇,其余步骤与比较例1相同,得到表小檗碱盐酸盐晶体,烘干称重1.92g。
比较例3:将85mL乙酸更换为85mL乙酸乙酯,其余步骤与比较例1相同,得到表小檗碱盐酸盐晶体,烘干称重1.73g。
比较例4:将85mL乙酸更换为85mL四氢呋喃,其余步骤与比较例1相同,得到表小檗碱盐酸盐晶体,烘干称重1.26g。
比较例5:将85mL乙酸更换为85mL盐酸,其余步骤与比较例1相同,得到表小檗碱盐酸盐晶体,烘干称重2.14g。
比较例6:将85mL乙酸更换为85mL硫酸,其余步骤与比较例1相同,得到表小檗碱盐酸盐晶体,烘干称重1.02g。
从表1的结果可以看到,将溶剂从乙酸更换为甲酸后,表小檗碱卤酸盐的收率从33%(比较例1)大幅提高到67.5%(实施例1),而在甲酸中混合少量磷酸后,表小檗碱卤酸盐的收率进一步提高(实施例2~4),并且可以得出最优选的方案是将甲酸和占甲酸体积1~5%的磷酸作为溶剂和催化剂。相反,将溶剂从乙酸更换为乙醇、乙酸乙酯、四氢呋喃、盐酸、硫酸等溶剂后,表小檗碱卤酸盐的收率更低(比较例2~6)。乙二醛的量与式I的摩尔比低于1.4:1时,产量有所下降,高于1.4以后,继续升高,产量变化不大。
表1表小檗碱卤酸盐收率对比结果
实施例7表小檗碱盐酸盐的药物片剂
取10克表小檗碱盐酸盐,加入球粒状乳糖70克、硬脂酸镁15克、微晶纤维素5克,混合均匀后压制成为0.5克一片的片剂,即为每片含药50mg。
实施例8表小檗碱盐酸盐的降血脂实验
实验药物为表小檗碱盐酸盐(含量95%以上)。
降血脂实验方法参照“天然药物(中药)新药研究指导原则”进行:将金黄地鼠分为3组,空白组(10只)给予正常饲料;另外两组给以高脂饲料,1个月后,监测血脂,造模成功者分为两组,高脂模型组(10只)继续给予高脂饲料,表小檗碱盐酸盐组(10只)给予高脂饲料同时给予药物(500mg/Kg);继续喂养4周后,监测血脂指标。
表2降血脂效果比较
从表2中可以看到,与正常对照组相比,高脂组血脂明显增加,达到显著水平,表示造模成功;与高脂组相比,表小檗碱盐酸盐组血脂明显降低,而与正常组接近,表明表小檗碱盐酸盐有显著的降血脂效果。
实施例9表小檗碱盐酸盐的减肥实验
实验药物为表小檗碱盐酸盐(含量95%以上)。
减肥实验方法参照“天然药物(中药)新药研究指导原则”进行:将金黄地鼠分为3组,空白组(10只)给予正常饲料,高脂模型组(10只)给予高脂饲料,表小檗碱盐酸盐组(10只)给予高脂饲料同时给予药物(500mg/Kg);连续喂养6周,每周监测一次体重的变化。
表3减肥效果比较
从表3中可以看到,与正常对照组相比,高脂组体重明显增加;与高脂组相比,表小檗碱盐酸盐组体重明显低,而与正常组接近,表明表小檗碱盐酸盐有显著的减肥效果。
实施例10表小檗碱盐酸盐对动脉粥样硬化等心血管疾病的作用实验
实验药物为表小檗碱盐酸盐(含量95%以上)。
实验方法参照“天然药物(中药)新药研究指导原则”进行:将Apoe小鼠分为2组,对照组(10只)给予高脂饲料,表小檗碱盐酸盐组(10只)给予高脂饲料的同时给予药物(500mg/Kg);连续喂养3个月。试验结束后,采血检测血清中氧化地密度脂蛋白(OX-LDL)和血管壁厚度,作为评价动脉粥样硬化的指标,结果见表4。
表4表小檗碱盐酸盐对Apoe小鼠血管动脉粥样硬化板块的影响
从表4中可以看到,与对照组相比,表小檗碱盐酸盐组可以明显降低血清OX-LDL浓度,减少血管壁厚度,表明表小檗碱盐酸盐具有预防和阻止血管动脉粥样硬化的作用。
实施例11表小檗碱盐酸盐体外抗胃癌实验
实验药物为表小檗碱盐酸盐(含量95%以上)、小檗碱盐酸盐(含量95%以上)、黄连碱盐酸盐(含量95%以上)、巴马亭盐酸盐(含量95%以上)。
选生长良好的胃癌细胞(BGC-823),稀释后接种到96孔板,每孔1×106个细胞;添加不同浓度的药物,培养24小时以后检测细胞量。计算一包的IC50。结果见下表:
表5黄连生物碱体外对胃癌细胞(BGC-823)的抑制率
体外实验结果表明,黄连碱抑制肿瘤的活性非常好,64μg/mL时,即可抑制胃癌细胞50%,到μg/mL时,胃癌细胞几乎全部杀死。相比较而言,黄连碱的巴马亭的活性最差,其次为小檗碱,表小檗碱的抑制胃癌的活性适中。
实施例12表小檗碱盐酸盐抗胃癌实验
实验药物为表小檗碱盐酸盐(含量95%以上)、小檗碱盐酸盐(含量95%以上)、黄连碱盐酸盐(含量95%以上)、巴马亭盐酸盐(含量95%以上)。
胃癌细胞(BGC-823),选择生长对数期的BGC-823肿瘤细胞,用0.25%胰蛋白酶液消化1~2min,倒出消化液,加入PBS洗涤,反复吹打,将细胞悬液移至离心管中,1300rpm离心5min,弃上清,加入DMEM完全培养基,调整细胞浓度为1×108个/mL,0.4%台盼蓝检测活细胞>95%,备用。
试验动物:裸小鼠(nude mice):BALB/cnu,4周龄,50只,16-20g/只。
试验方法:将80只4周龄BALB/c nu裸鼠单笼饲养,屏障隔离系统平衡3~5天,无菌饲料和水充足。将裸鼠随机分为5组,每组10只,除阴性对照组外,各组裸鼠均接种肿瘤细胞(0.1mL/只),给予实验药物饲养,按照表5给与表小檗碱,持续30天,30天后,处死老鼠,取下肿瘤块,称重,分析比较每组肿瘤组织平均重量,结果见表6。
表6抗肿瘤效果实验
试验组 | 药物剂量(mg/kg) | 肿瘤平均重量/g | 肿瘤发生率/% |
阴性对照组 | — | 0.00±0.00 | 0 |
阳性对照组 | — | 1.51±0.55 | 100 |
表小檗碱 | 50 | 1.11±0.45* | 90 |
表小檗碱 | 100 | 0.78±0.35** | 80 |
表小檗碱 | 150 | 0.58±0.35** | 60 |
小檗碱 | 150 | 0.95±0.31* | 90 |
黄连碱 | 150 | 1.25±0.45 | 100 |
巴马亭 | 150 | 1.10±0.38* | 100 |
试验结果表明,黄连生物碱均有抑制胃癌的效果;与体外试验不同,体外抗癌效果最好的黄连碱,其体内抗癌效果却叫较差,表小檗碱的抗癌效果最好,其次为小檗碱,巴马亭的体内抗癌效果一般。
实验结果还别名,与阳性对照组相比,在较低剂量下,表小檗碱也具有抑制胃癌的效果,并达到显著水平;随着表小檗碱剂量的增加,其抑制肿瘤生长的效果进一步增加。此外,模型组实验小鼠全部成瘤,而药物组的成瘤率随着药物剂量的增加而下降,表明表小檗碱对胃癌具有预防和治疗作用。
实施例13表小檗碱盐酸盐抗幽门螺杆菌实验
(1)、实验材料:表小檗碱盐酸盐(含量95%以上)。
(2)、对照药物:小檗碱盐酸盐(含量95%以上)、黄连碱盐酸盐(含量95%以上)、巴马亭盐酸盐(含量95%以上),配制为1000μg/mL。
(3)、菌种:幽门螺杆菌(HP)。
(4)、培养基:MH肉汤,MH琼脂均为售品。
(5)、MIC试验(采用液体培养基连续稀释法):用肉汤将各试验药倍半稀释为1:2、1:4、1:8、:1:16、1:32、1:64、1:128、1:256、1:512、1:1024、1:2048、1:4096、1:8192,另设不加试验药的阳性对照管;每试验管加入试验菌液0.05mL(108cfu/mL),混匀后置37℃培养24h观察结果。实验结果见表7。
表7小檗碱及其修饰化合物的抗菌结果(MIC;药物浓度:μg/mL)
表小檗碱盐 | 小檗碱盐 | 黄连碱盐 | 巴马亭盐 | |
MIC/(μg/mL) | 1.95 | 125 | 250 | 62.5 |
MBC/(μg/mL) | 1.95 | 500 | 250 | 125 |
从上述实验结果可以看到,黄连生物碱对HP都有抑制活性,其中表小檗碱的MIC最小,表明极低浓度的表小檗碱即可抑制HP的生长,其抑制HP的活性比小檗碱高64倍。从杀菌浓度(MBC)看,1.95μg/mL的表小檗碱,不仅可以抑制HP的生长,而且在该浓度下还可以杀死HP;125μg/mL的小檗碱浓度下,HP虽然停止生长,但是稀释以后HP可以继续生长,只有更高的浓度下(500μgμg/mL)才可以杀死HP;可见,表小檗碱杀死HP的能力比小檗碱高256倍。
以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (10)
2.根据权利要求1所述合成方法,其特征在于,所述磷酸的体积为甲酸体积的1~5%;优选的,所述反应式中,乙二醛与式I所示化合物的物质量之比为1-2:1,更为优选的,乙二醛与式I所示化合物的物质量之比为1.4:1。
3.根据权利要求1或2所述合成方法,其特征在于,所述合成方法的具体步骤为:
(1)将甲酸、磷酸、乙二醛、硫酸铜和氯化钠加入容器,50~100℃回流搅拌得到反应体系;
(2)将式I化合物(N-(2,3-亚甲氧基-N-苄基)-β-(3,4-二甲氧基苯基)乙胺)加入步骤(1)得到的反应体系中,继续在50~100℃下搅拌回流,反应完毕后加水,加热,中和剂中和,冷却过滤得滤饼为表小檗碱卤酸盐。
4.根据权利要求3所述合成方法,其特征在于,所述步骤(2)中,式I化合物与溶剂的重量体积比为1g:15~20mL;优选的,所述步骤(2)中,所述滤饼还经过超声水洗、加热至80℃,冷却,过滤和洗涤得表小檗碱卤酸盐;优选的,所述合成方法还包括将步骤(2)获得的表小檗碱卤酸盐在氢卤酸-乙醇溶液中重结晶,过滤得卤酸盐表小檗碱晶体。
5.根据权利要求4所述合成方法,其特征在于,所述步骤(2)中,中和剂选自氢氧化钠、氢氧化钾、碳酸钠和碳酸氢钠中的一种或多种;优选的,所述氢卤酸-乙醇溶液中的氢卤酸选自氢氟酸、盐酸、氢溴酸或氢碘酸。
6.一种表小檗碱的应用,所述应用是表小檗碱在制备治疗/预防消化道肿瘤的保健食品或药剂中的应用,所述述消化道肿瘤是食道癌,胃癌,肝癌,胰腺癌,胆囊癌,12指肠癌,阑尾癌,结肠癌或直肠癌;优选的,所述消化道肿瘤是胃癌。
7.一种表小檗碱的应用,所述应用是表小檗碱在制备抗幽门螺杆菌的药剂或保健食品中的应用。
8.一种表小檗碱的应用,所述应用是表小檗碱在制备/预防幽门螺杆菌感染的药剂或保健食品中的应用。
9.一种表小檗碱的应用,所述应用是表小檗碱在制备治疗/预防心脑血管类疾病的药剂或保健食品中的应用,优选的,所述心脑血管类疾病是动脉粥样硬化引起的心脑血管类疾病。
10.根据权利要求6-9任一项所述应用,其特征在于,所述表小檗碱的卤酸盐由权利要求1-5任一项所述合成方法合成。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910097678.9A CN111499626A (zh) | 2019-01-31 | 2019-01-31 | 一种表小檗碱的合成方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910097678.9A CN111499626A (zh) | 2019-01-31 | 2019-01-31 | 一种表小檗碱的合成方法及应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111499626A true CN111499626A (zh) | 2020-08-07 |
Family
ID=71865130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910097678.9A Pending CN111499626A (zh) | 2019-01-31 | 2019-01-31 | 一种表小檗碱的合成方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111499626A (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090048246A1 (en) * | 2007-06-22 | 2009-02-19 | Haiyan Liu | Compounds, compositions and methods for reducing lipid levels |
CN102256973A (zh) * | 2008-12-23 | 2011-11-23 | Cvi制药有限公司 | 用于降低脂类水平的紫堇碱衍生物 |
CN103387574A (zh) * | 2012-05-07 | 2013-11-13 | 北京以岭药业有限公司 | 一种表小檗碱的合成方法 |
CN104045636A (zh) * | 2014-05-12 | 2014-09-17 | 西南大学 | 黄连碱卤酸盐的合成方法及其用途 |
US20170037043A1 (en) * | 2014-07-29 | 2017-02-09 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
CN106543171A (zh) * | 2016-10-28 | 2017-03-29 | 佑华制药(乐山)有限公司 | 一种黄连素合成工艺 |
US20170135995A1 (en) * | 2015-11-13 | 2017-05-18 | Shenzhen Hightide Biopharmaceutical, Ltd. | Pharmaceutical compositions of berberine with epa and dha, and methods thereof |
CN108358912A (zh) * | 2018-02-28 | 2018-08-03 | 四川依科制药有限公司 | 一种黄连素的绿色合成工艺 |
-
2019
- 2019-01-31 CN CN201910097678.9A patent/CN111499626A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090048246A1 (en) * | 2007-06-22 | 2009-02-19 | Haiyan Liu | Compounds, compositions and methods for reducing lipid levels |
CN102256973A (zh) * | 2008-12-23 | 2011-11-23 | Cvi制药有限公司 | 用于降低脂类水平的紫堇碱衍生物 |
CN103387574A (zh) * | 2012-05-07 | 2013-11-13 | 北京以岭药业有限公司 | 一种表小檗碱的合成方法 |
CN104045636A (zh) * | 2014-05-12 | 2014-09-17 | 西南大学 | 黄连碱卤酸盐的合成方法及其用途 |
US20170037043A1 (en) * | 2014-07-29 | 2017-02-09 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
US20170135995A1 (en) * | 2015-11-13 | 2017-05-18 | Shenzhen Hightide Biopharmaceutical, Ltd. | Pharmaceutical compositions of berberine with epa and dha, and methods thereof |
CN106543171A (zh) * | 2016-10-28 | 2017-03-29 | 佑华制药(乐山)有限公司 | 一种黄连素合成工艺 |
CN108358912A (zh) * | 2018-02-28 | 2018-08-03 | 四川依科制药有限公司 | 一种黄连素的绿色合成工艺 |
Non-Patent Citations (3)
Title |
---|
LIHUA TAN,等: "Epiberberine, a natural protoberberine alkaloid, inhibits urease of Helicobacter pylori and jack bean: Susceptibility and mechanism", 《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
SHUMING KOU,等: "Synergetic cholesterol-lowering effects of main alkaloids from Rhizoma Coptidis in HepG2 cells and hypercholesterolemia hamsters", 《LIFE SCIENCES》 * |
ZI-MING LU,等: "Total synthesis of epiberberine", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105153122B (zh) | [(吲哚-3-基)嘧啶-2-基]氨基苯基丙-2-烯酰胺衍生物及盐、制备方法、应用 | |
CN111333686B (zh) | 黄芩苷衍生物及其制备方法和应用 | |
EP1774968A1 (en) | Benzylisoquinoline derivative- or bisbenzylisoquinoline derivative-containing psychotropic agent, analgesic and/or antiphlogistic, and health food | |
CN110372689B (zh) | R9与r10连接的亲水性小檗碱型衍生物及其制备药物的应用 | |
CN111943962A (zh) | 咪唑并噁嗪晶体、含有所述晶体的药物组合物和制备所述晶体的方法 | |
CN111484435A (zh) | 四氢吡咯烷类化合物或其药学上可接受的盐及其制备方法和应用 | |
CN108368115A (zh) | 吡咯并嘧啶化合物的盐 | |
CN114163453A (zh) | 一种洛普替尼晶型及其制备方法 | |
CN111499626A (zh) | 一种表小檗碱的合成方法及应用 | |
WO2018058863A1 (zh) | 聚醚类化合物用途 | |
CN106866666A (zh) | 一种帕博西尼晶型化合物及其制备方法 | |
CN108143741B (zh) | 厚朴酚糖苷在制备治疗中枢神经系统疾病药物中的应用 | |
CN107281180B (zh) | 8-烷基小檗碱盐在制备预防和治疗肺癌药物中的应用 | |
EP2695884B1 (en) | Camptothecin derivatives having anti-tumor activity | |
CN113603711B (zh) | 一种双吲哚生物碱化合物及其制备方法和应用 | |
CN102267952B (zh) | 喹唑啉类化合物、其制备方法和用途 | |
CN101845052B (zh) | 一类含氮杂环的噻吩并吡啶酮衍生物、其制备方法和用途 | |
CN111662303A (zh) | 一种aurovertin B衍生物及制备方法与应用 | |
CN114075253B (zh) | 一种含硫的化合物及其应用 | |
CN115397426B (zh) | 伊布替尼葡萄糖酸内酯共晶体及其制备方法 | |
CN114907372B (zh) | 一种用于治疗多囊卵巢综合征的药物及其制备方法 | |
CN113845533B (zh) | 双-4,5-二芳基咪唑环卡宾金配合物及其制备方法和应用 | |
CN103304556B (zh) | 含有苯并吡喃的希夫碱类化合物、其制备方法和用途 | |
CN112274539B (zh) | 竹柏籽油预防或治疗癌症的用途 | |
CN108586341B (zh) | 酰胺类化合物和其药用盐及其制备方法和药物用途 |
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 | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200807 |