CN115417887B - 一种9-烷基双去氢骆驼蓬碱衍生物及其制备方法和应用 - Google Patents
一种9-烷基双去氢骆驼蓬碱衍生物及其制备方法和应用 Download PDFInfo
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- CN115417887B CN115417887B CN202211137128.3A CN202211137128A CN115417887B CN 115417887 B CN115417887 B CN 115417887B CN 202211137128 A CN202211137128 A CN 202211137128A CN 115417887 B CN115417887 B CN 115417887B
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- methyl
- carboline
- beta
- reaction
- harmine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- RAYHOJDYVGUYQQ-UHFFFAOYSA-N 7-methoxy-1-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-8-amine;hydrochloride Chemical compound [Cl-].C1CNC(C)C2=C1C1=CC=C(OC)C([NH3+])=C1N2 RAYHOJDYVGUYQQ-UHFFFAOYSA-N 0.000 title abstract description 8
- 229940022698 acetylcholinesterase Drugs 0.000 claims abstract description 13
- 102000012440 Acetylcholinesterase Human genes 0.000 claims abstract description 12
- 108010022752 Acetylcholinesterase Proteins 0.000 claims abstract description 12
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 7
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- COQBVMMHNCHDSD-UHFFFAOYSA-N C1(=CC=C2C(=C1)N(C1=C2C=CN=C1C)C)O Chemical compound C1(=CC=C2C(=C1)N(C1=C2C=CN=C1C)C)O COQBVMMHNCHDSD-UHFFFAOYSA-N 0.000 claims description 16
- RERZNCLIYCABFS-UHFFFAOYSA-N Harmaline hydrochloride Natural products C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 claims description 14
- VJHLDRVYTQNASM-UHFFFAOYSA-N harmine Natural products CC1=CN=CC=2NC3=CC(=CC=C3C=21)OC VJHLDRVYTQNASM-UHFFFAOYSA-N 0.000 claims description 14
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- LJQLTQRHIJBENP-UHFFFAOYSA-N 7-methoxy-1,9-dimethylpyrido[3,4-b]indole Chemical compound N1=CC=C2C3=CC=C(OC)C=C3N(C)C2=C1C LJQLTQRHIJBENP-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LVWSZGCVEZRFBT-UHFFFAOYSA-N 1,7-dibromoheptane Chemical compound BrCCCCCCCBr LVWSZGCVEZRFBT-UHFFFAOYSA-N 0.000 claims description 10
- 239000012154 double-distilled water Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims 2
- 230000029936 alkylation Effects 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 240000005523 Peganum harmala Species 0.000 abstract 2
- 235000005126 Peganum harmala Nutrition 0.000 abstract 2
- 208000024827 Alzheimer disease Diseases 0.000 description 16
- YIICVSCAKJMMDJ-SNVBAGLBSA-N Peganine Chemical class C1=CC=C2N=C3[C@H](O)CCN3CC2=C1 YIICVSCAKJMMDJ-SNVBAGLBSA-N 0.000 description 10
- PFFOZZWZWUMENS-UHFFFAOYSA-N chembl1199731 Chemical compound C1=NC(C)=C2N(CC)C3=CC(O)=CC=C3C2=C1 PFFOZZWZWUMENS-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IPKUPGYEVPMEEL-UHFFFAOYSA-N N-ethylharmine Chemical compound C1=NC(C)=C2N(CC)C3=CC(OC)=CC=C3C2=C1 IPKUPGYEVPMEEL-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- SZMVXHRECFRCKQ-UHFFFAOYSA-M 2-ethanethioyloxyethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=S)OCC[N+](C)(C)C SZMVXHRECFRCKQ-UHFFFAOYSA-M 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- FLPIWPOVBBNOCS-UHFFFAOYSA-N [C].[Pr] Chemical compound [C].[Pr] FLPIWPOVBBNOCS-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940125645 monoclonal antibody drug Drugs 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000019581 neuron apoptotic process Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims (8)
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CN202211137128.3A CN115417887B (zh) | 2022-09-19 | 2022-09-19 | 一种9-烷基双去氢骆驼蓬碱衍生物及其制备方法和应用 |
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CN202211137128.3A CN115417887B (zh) | 2022-09-19 | 2022-09-19 | 一种9-烷基双去氢骆驼蓬碱衍生物及其制备方法和应用 |
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CN115417887A CN115417887A (zh) | 2022-12-02 |
CN115417887B true CN115417887B (zh) | 2024-02-13 |
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CN116496272B (zh) * | 2023-04-26 | 2024-08-13 | 延安大学 | 7-苄基哌嗪基-9-烯丙基去氢骆驼蓬碱衍生物及其制备方法和应用 |
CN116514858A (zh) * | 2023-05-06 | 2023-08-01 | 苏州大学 | 一种去氢骆驼蓬生物碱衍生物、制备方法及其应用 |
Citations (5)
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---|---|---|---|---|
CN101139347A (zh) * | 2007-10-15 | 2008-03-12 | 新疆华世丹药物研究有限责任公司 | 去氢骆驼蓬碱衍生物类化合物及其应用 |
WO2009047298A2 (en) * | 2007-10-12 | 2009-04-16 | Bioalliance Pharma | Dimers of harmol or of its derivatives and uses thereof |
CN101433565A (zh) * | 2008-11-26 | 2009-05-20 | 上海中医药大学 | 骆驼蓬属种子总生物碱提取物及其有效单体成分和它们的制备与应用 |
CN102636612A (zh) * | 2012-05-14 | 2012-08-15 | 上海中医药大学 | 一种分析骆驼蓬草中有效成分的方法 |
CN104744494A (zh) * | 2013-12-27 | 2015-07-01 | 新疆华世丹药物研究有限责任公司 | 7位双β-咔啉碱类化合物、其制法和其药物组合物与用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2953410B1 (fr) * | 2009-12-09 | 2012-02-24 | Univ Claude Bernard Lyon | Compositions antivirales pharmaceutiques ou veterinaires |
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2022
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Patent Citations (5)
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WO2009047298A2 (en) * | 2007-10-12 | 2009-04-16 | Bioalliance Pharma | Dimers of harmol or of its derivatives and uses thereof |
CN101139347A (zh) * | 2007-10-15 | 2008-03-12 | 新疆华世丹药物研究有限责任公司 | 去氢骆驼蓬碱衍生物类化合物及其应用 |
CN101433565A (zh) * | 2008-11-26 | 2009-05-20 | 上海中医药大学 | 骆驼蓬属种子总生物碱提取物及其有效单体成分和它们的制备与应用 |
CN102636612A (zh) * | 2012-05-14 | 2012-08-15 | 上海中医药大学 | 一种分析骆驼蓬草中有效成分的方法 |
CN104744494A (zh) * | 2013-12-27 | 2015-07-01 | 新疆华世丹药物研究有限责任公司 | 7位双β-咔啉碱类化合物、其制法和其药物组合物与用途 |
Non-Patent Citations (3)
Title |
---|
Bivalent β-Carbolines as Potential Multitarget Anti-Alzheimer Agents;Yvonne Rook et al.;《J. Med. Chem.》;第3611-3617页 * |
Synthesis and biological evaluation of novel N9-heterobivalent b-carbolines as angiogenesis inhibitors;Liang Guo et al.;《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》;第375-387页 * |
Yifan Zhao et al..Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease.《Bioorganic & Medicinal Chemistry》.2018,第3812-3824页. * |
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