CN101974046A - 一种新的天然对映贝壳杉烷衍生物及其制备方法和用途 - Google Patents
一种新的天然对映贝壳杉烷衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN101974046A CN101974046A CN2010105155994A CN201010515599A CN101974046A CN 101974046 A CN101974046 A CN 101974046A CN 2010105155994 A CN2010105155994 A CN 2010105155994A CN 201010515599 A CN201010515599 A CN 201010515599A CN 101974046 A CN101974046 A CN 101974046A
- Authority
- CN
- China
- Prior art keywords
- preparation
- compound
- column chromatography
- solvent
- extract
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000004545 kaurane derivatives Chemical class 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000004440 column chromatography Methods 0.000 claims abstract description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000000284 extract Substances 0.000 claims description 25
- 238000010828 elution Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- -1 butyryl radicals Chemical class 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000000178 monomer Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000012059 conventional drug carrier Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 244000050510 Cunninghamia lanceolata Species 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract 2
- 239000012453 solvate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 102100033639 Acetylcholinesterase Human genes 0.000 description 8
- 108010022752 Acetylcholinesterase Proteins 0.000 description 8
- 229940022698 acetylcholinesterase Drugs 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000012530 fluid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 102100032404 Cholinesterase Human genes 0.000 description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000013507 mapping Methods 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 2
- 101710083761 Cholinesterase Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 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
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 244000101724 Apium graveolens Dulce Group Species 0.000 description 1
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 description 1
- 235000010591 Appio Nutrition 0.000 description 1
- YRHWUYVCCPXYMB-UHFFFAOYSA-N Atractyligenin Natural products C1CC2(C(C3=C)O)CC3CCC2C2(C)C1C(C(O)=O)CC(O)C2 YRHWUYVCCPXYMB-UHFFFAOYSA-N 0.000 description 1
- IUCNQFHEWLYECJ-FNAJZLPOSA-L Atractyloside Chemical compound [K+].[K+].O1[C@H](CO)[C@@H](OS([O-])(=O)=O)[C@H](OS([O-])(=O)=O)[C@@H](OC(=O)CC(C)C)[C@@H]1O[C@H]1C[C@@]2(C)[C@@H]3CC[C@@H](C(=C)[C@@H]4O)C[C@]34CC[C@@H]2[C@H](C(O)=O)C1 IUCNQFHEWLYECJ-FNAJZLPOSA-L 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 208000034423 Delivery Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- OKIBNKKYNPBDRS-UHFFFAOYSA-N Mefluidide Chemical compound CC(=O)NC1=CC(NS(=O)(=O)C(F)(F)F)=C(C)C=C1C OKIBNKKYNPBDRS-UHFFFAOYSA-N 0.000 description 1
- 241001529246 Platymiscium Species 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 241000123886 Sigesbeckia pubescens Species 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000007792 alzheimer disease pathology Effects 0.000 description 1
- FYQXODZRNSCOTR-UHFFFAOYSA-N atractyloside Natural products O1C(CO)C(OS(O)(=O)=O)C(OS(O)(=O)=O)C(OC(=O)CC(C)C)C1OC1CC2(C)C3CCC(C(=C)C4O)CC34CCC2C(C(O)=O)C1 FYQXODZRNSCOTR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种新的天然对映贝壳杉烷衍生物及其组合物的制备方法和用途。该类衍生物是式(I)所示的化合物、组合物、光学异构体、药用盐、溶剂合物。该类化合物的制备方法包括采用溶剂提取，采用柱层析分离纯化而得。该类化合物及其光学异构体、组合物、药用盐、溶剂合物可用于制备治疗阿尔茨海默病(Alzheimer disease，AD)的药物。该类化合物是一种新的对映贝壳杉烷衍生物，制备方法简单、易行。
Description
技术领域
本发明涉及一种新的天然对映贝壳杉烷衍生物及其制备方法和该类化合物在制备治疗阿尔茨海默病(Alzheimer disease，AD)的药物中的用途。
背景技术
阿尔茨海默病(Alzheimer disease，AD)，是一种以慢性、进行性认知障碍和记忆力损害为主的中枢神经系统退行性疾病，主要病理特征表现为老年斑、神经元纤维缠结和神经元丢失，严重影响患者的认知、记忆、语言功能、及个人生活能力和情感人格等(NEJM1999，341，1670-1679)。
目前，世界上较为接受的AD病理为“胆碱能缺失学说”。学说认为老年性痴呆症患者大脑内神经递质-乙酸胆碱的缺失是导致AD疾病的关键原因。(Ann Neurol 1990，27，457-464；Ann Neurol 1991，30，572-580)。
乙酰胆碱的缺失导致AD患者认知功能下降，记忆能力丧失。胆碱酯酶(ChE)是生物神经传导中的一种关键性的酶，在胆碱能突触间，该酶降解乙酰胆碱，终止神经递质对突触后膜的兴奋作用，保证神经信号在生物体内的正常传递。胆碱酯酶依其催化底物的特异性分为乙酰胆碱酯酶(AchE)和丁酰胆碱酯酶(BuChE)。乙酰胆碱酯酶(AchE)会催化乙酰胆碱的裂解反应，导致乙酰胆碱的缺失、神经信号传递失败，目前对老年痴呆的药物治疗主要是通过抑制ChE来提高患者体内的乙酰胆碱水平。医学治疗上多采用乙酰胆碱酯酶抑制剂(AchEI)抑制AchE活性，延缓Ach水解的速度，提高突触间隙Ach的水平，从而发挥对AD的治疗作用(Br Med J1999，318，633-638)。
从自然界寻找具有抑制胆碱酯酶活性的化合物，将为新药的设计提供更多的功能模版，为药物合成研究和药物作用机理研究提供很好的先导化合物。腺梗豨莶(Siegesbeckiapubescens)是菊科豨莶属一年生草本植物，广布于热带和温带地区，该属植物全世界共有五种，我国有三种。《本草述》：有云，豨莶制法，大益气血，四肢不遂，大有功。近代研究也表明腺梗豨莶提取物在治疗神经疾病方面有较好的疗效。(Acta Pharm.Sin1989，24，833-836)。
发明内容
本发明的目的是提供一种新的天然对映贝壳杉烷衍生物。
本发明的另一个目的是提供该类化合物的制备方法。
本发明的第三个目的是提供该类化合物在制备治疗阿尔兹海默病药物中的用途。
本发明提供了一种式(I)所示的化合物，该类化合物易溶于有机溶剂。同时，它们的组合物、药用盐也是本发明的一部分。
其中，R1为H、甲基、羧基或CH2OH；
R2为甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、异戊酰基、戊酰基、2-甲基丁酰基、苯甲酰基或苯乙酰基。
本发明还提供了该类化合物的制备方法，包括如下步骤：
(1)腺梗豨莶地上部位用溶剂提取得浸膏；
(2)将浸膏混悬于水中，用极性从低到高溶剂萃取。得到中等极性的萃取物；
(3)将萃取物与MCI微孔树脂拌样，上样于MCI微孔树脂柱上，乙醇水溶液从低到高洗脱；
(4)洗脱物以石油醚-醋酸乙酯-甲醇为洗脱系统进行硅胶层析，然后进行ODS柱层析和硅胶柱层析，得到该类化合物。
步骤(1)中所述的溶剂为甲醇、乙醇、丙酮、水中的一种或多种。
步骤(2)中所述的洗脱溶剂，低极性溶剂为石油醚、环己烷、甲苯、二氯甲烷中的一种或多种，中极性溶剂为乙醚、氯仿、醋酸乙酯、丙酮中的一种或多种，高极性溶剂为乙醇、甲醇的一种或多种。
根据本领域内技术人员熟知的成熟的筛选酶水平对乙酰胆碱酯酶活性有抑制作用的化合物的方法，研究人员发现式(I)所示的这类化合物或其药用盐对乙酰胆碱酯酶活性有一定的抑制作用。
因此，本发明涉及的式(I)所示的化合物、药用盐具有制备治疗阿尔兹海默药物的用途，它们可以以其自身的形式施用，也可以和药学上可以接受的载体组成药物组合物而应用。
采用有效剂量的本发明所述的式(I)所示的化合物、药用盐的一种或多种作为活性成分与常规药用载体制备成药物组合物，可以按常规方法制备成口服或注射用途的常规剂型。通常的，载体包括稀释剂、填充剂、崩解剂、润滑剂、着色剂、调味剂或其他常规添加剂中的一种或多种。
本发明的有益效果：
本发明公开了一种新的天然对映贝壳杉烷衍生物及其制备方法。这些化合物可用于治疗阿尔兹海默病。本发明提供的制备方法简单易行，制备的化合物纯度高。
具体实施方式
以下通过实施例对本发明做进一步的说明。
本发明中没有具体描述的提取、分离方法均为本领域普通技术人员熟知的方法，本领域普通技术人员可以根据说明书的提示采用药典规定的方法或其他操作规程限定的方法结合使用仪器的说明书进行操作，即可实现本发明。
实施例1：化合物(II)的提取分离
腺梗豨莶地上部分干燥后用95％乙醇加热回流提取，提取液减压回收乙醇，得浸膏，浸膏混悬于蒸馏水中，依次用石油醚、乙酸乙酯、正丁醇等量萃取。乙酸乙酯萃取液浓缩后得浸膏，上样于MCI微孔树脂柱上，乙醇水溶液梯度洗脱(0％乙醇-95％乙醇)，得到洗脱物，以石油醚-醋酸乙酯-甲醇为洗脱系统进行硅胶层析，然后进行ODS和硅胶柱柱层析。ODS柱层析以丙酮-水为洗脱系统，硅胶柱层析以氯仿-甲醇为洗脱系统分离得到化合物(II)。
化合物(II)，中文名2-O-(β-D-呋喃芹菜糖基-(1→3)-2-O-异戊酰基-β-D-吡喃葡萄糖)苍术苷，英文名2-O-(β-D-apiofuranosyl-(1→3)-2-O-Isovaleryl-β-D-glucopyranosyl)atractyligenin，分子式C35H54O14，分子量698，淡黄色固体。1H-NMR和13C-NMR数据见表1。
表1化合物(II)的1H-NMR和13C-NMR数据(300MHz，500/4MHz，CD3OD)
实施例2：
腺梗豨莶地上部分干燥后用70％乙醇加热回流提取，提取液减压回收乙醇，得浸膏。取浸膏混悬于蒸馏水中，依次用石油醚、氯仿、正丁醇等量萃取。氯仿萃取液浓缩后得浸膏，上样于MCI微孔树脂柱上，乙醇水溶液梯度洗脱(0％乙醇-100％乙醇)，得到洗脱物，以石油醚-醋酸乙酯-甲醇为洗脱系统进行硅胶层析，然后进行ODS和硅胶柱柱层析。ODS柱层析以甲醇-水为洗脱系统，硅胶柱层析以乙酸乙酯-甲醇为洗脱系统分离得到化合物(II)。
实施例3：
腺梗豨莶地上部分干燥后用70％乙醇加热回流提取，提取液减压回收乙醇，得浸膏。取浸膏混悬于蒸馏水中，依次用二氯甲烷、乙酸乙酯、正丁醇等量萃取。乙酸乙酯萃取液浓缩后得浸膏，上样于MCI微孔树脂柱上，乙醇水溶液梯度洗脱(0％乙醇-75％乙醇)，得到洗脱物，以石油醚-醋酸乙酯-甲醇为洗脱系统进行硅胶层析，然后进行ODS和硅胶柱柱层析。ODS柱层析以乙醇-水为洗脱系统，硅胶柱层析以氯仿-丙酮为洗脱系统分离得到化合物(II)。
实施例4：
腺梗豨莶地上部分干燥后用70％乙醇加热回流提取，提取液减压回收乙醇，得浸膏。取浸膏混悬于蒸馏水中，依次用环己烷、氯仿、正丁醇等量萃取。氯仿萃取液浓缩后得浸膏，上样于MCI微孔树脂柱上，乙醇水溶液梯度洗脱(0％乙醇-75％乙醇)，得到洗脱物，以石油醚-醋酸乙酯-甲醇为洗脱系统进行硅胶层析，然后进行ODS和硅胶柱柱层析。ODS柱层析以乙醇-水为洗脱系统，硅胶柱层析以二氯甲烷-甲醇为洗脱系统分离得到化合物(II)。
实施例5：测定化合物(II)对乙酰胆碱酯酶抑制作用
缓冲液(10×PBS，0.1M，pH 7.4)购自invitrogen公司；Triton X-100购自碧云天公司；底物Ach-S-CL(现用现配，每次用PBS配制成0.1M的储液)购自sigma公司；显色剂DTNB(用PBS配制成0.005M的储液)购自sigma公司；96孔透明板；移液枪、枪头购自corning公司；Vistar大鼠购自江苏南京青龙山养殖场。阳性药为Rivastigmine。
大鼠两只，完整取下，全脑冷PBS洗涤全脑直到将黏附的血液清洗干净。在冰袋上将全脑切成碎片，分装到8个5mL EP管中，每管加入2mL 10×PBS(含0.5％Triton)。机搅匀得到悬液，以12000rpm，4℃离心10min，小心吸取各管上清液，混合至另一新的预冷的EP管中。以每管50μL分装上清夜，保存于-20℃备用。
将0.01M储备液的化合物用DMSO稀释成100×浓度的工作液，由高到低分别为1000、250、62.5...依次以四倍倍比进行稀释，一共七个浓度梯度(单位：μM)按照体积比为1∶100的比例用PBS稀释脑匀浆上清液即得到酶工作液。将0.1M储备液的底物用PBS稀释到4mM工作液备用。
取96孔板，每孔加入48μL的PBS、2μL一系列浓度梯度的待筛化合物工作液，其中阳性对照组和阴性对照组直接加入2μL DMSO。每孔加入50μL脑匀浆工作液，用孔板震荡仪混匀，用膜封好各孔，放于37℃孵育48h。每孔加入50μL 0.005M的显色液。每孔加入50μL底物工作液，其中阴性对照组直接加入50μL 10×PBS，孔板震荡仪混匀，37℃静置1h。于Tecan M200酶标仪上测定各孔412nm吸光值。
列公式求得抑制率：
以log[给药浓度]为横坐标，抑制率为纵坐标，在origin6.0中画图，拟合出一条药理学量效关系S形曲线，求出50％抑制率时的药物浓度，即为此化合物抑制AchE活性的IC50值。化合物(II)对乙酰胆碱酯酶有一定抑制活性，其IC50值为9.69μM。RivastigmineIC50值为1.01μM。
Claims (6)
1.一种新的天然贝壳杉烷衍生物，其特征在于，该类化合物是式(I)所示的化合物或其药用盐，
其中，R1为H、甲基、羧基或CH2OH；
R2为甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、异戊酰基、戊酰基、2-甲基丁酰基、苯甲酰基或苯乙酰基。
2.一种药物组合物，其特征在于，该组合物以权利要求1所述的式(I)所示的化合物或其药用盐的一种或多种作为活性成分，并含有常规药用载体。
3.权利要求1所述的式(I)所示的化合物或其药用盐在制备治疗阿尔茨海默病的药物中的应用。
4.权利要求1所述的化合物的制备方法，其特征在于包括如下步骤：
(1)腺梗豨莶地上部位用溶剂提取得浸膏；
(2)将浸膏混悬于水中，用极性从低到高溶剂萃取，得到中等极性的萃取物；
(3)将萃取物与MCI微孔树脂拌样，上样于MCI微孔树脂柱上，乙醇水溶液从低浓度到高浓度洗脱；
(4)洗脱物以石油醚-醋酸乙酯为洗脱系统进行硅胶层析，然后进行ODS柱层析和硅胶柱层析，得到该化合物。
5.根据权利要求4所述的制备方法，其特征在于步骤(1)中所述的溶剂为甲醇、乙醇、丙酮、水中的一种或多种。
6.根据权利要求4所述的制备方法，其特征在于步骤(2)中所述的洗脱溶剂，低极性溶剂为石油醚、环己烷、甲苯、二氯甲烷中的一种或多种，中极性溶剂为乙醚、氯仿、醋酸乙酯、丙酮中的一种或多种，高极性溶剂为乙醇、甲醇的一种或多种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010515599.4A CN101974046B (zh) | 2010-10-14 | 2010-10-14 | 一种新的天然对映贝壳杉烷衍生物及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010515599.4A CN101974046B (zh) | 2010-10-14 | 2010-10-14 | 一种新的天然对映贝壳杉烷衍生物及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101974046A true CN101974046A (zh) | 2011-02-16 |
| CN101974046B CN101974046B (zh) | 2013-04-24 |
Family
ID=43573963
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010515599.4A Expired - Fee Related CN101974046B (zh) | 2010-10-14 | 2010-10-14 | 一种新的天然对映贝壳杉烷衍生物及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101974046B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113582878A (zh) * | 2021-08-31 | 2021-11-02 | 安顺市人民医院 | 一种天然产物对映-贝壳杉烷型二萜sgp-17的衍生物sgp-17-52 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1431187A (zh) * | 2003-01-17 | 2003-07-23 | 南京中医药大学 | 一种贝壳杉烷型二萜化合物及制法和在抗癌药物中的应用 |
| CN101851271A (zh) * | 2009-03-31 | 2010-10-06 | 苏州金昊药业开发有限公司 | 蓝萼丁素衍生物、制备方法及其用途 |
-
2010
- 2010-10-14 CN CN201010515599.4A patent/CN101974046B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1431187A (zh) * | 2003-01-17 | 2003-07-23 | 南京中医药大学 | 一种贝壳杉烷型二萜化合物及制法和在抗癌药物中的应用 |
| CN101851271A (zh) * | 2009-03-31 | 2010-10-06 | 苏州金昊药业开发有限公司 | 蓝萼丁素衍生物、制备方法及其用途 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113582878A (zh) * | 2021-08-31 | 2021-11-02 | 安顺市人民医院 | 一种天然产物对映-贝壳杉烷型二萜sgp-17的衍生物sgp-17-52 |
| CN113582878B (zh) * | 2021-08-31 | 2023-05-23 | 安顺市人民医院 | 一种天然产物对映-贝壳杉烷型二萜sgp-17的衍生物sgp-17-52 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101974046B (zh) | 2013-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pang et al. | Spiro-phthalides and isocoumarins isolated from the marine-sponge-derived fungus Setosphaeria sp. SCSIO41009 | |
| Liu et al. | A synthetic 7, 8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect | |
| Chen et al. | Houttuynoids A–E, anti-herpes simplex virus active flavonoids with novel skeletons from Houttuynia cordata | |
| Kikuchi et al. | Novel Spirocyclic Trichothecanes, Spirotenuipesine A and B, Isolated from Entomopathogenic Fungus, Paecilomyces t enuipes | |
| Fujiwara et al. | Antitumor-promoting naphthoquinones from Catalpa ovata | |
| Kim et al. | Four new neuroprotective iridoid glycosides from Scrophularia b uergeriana roots | |
| Wang et al. | Eryngiolide A, a cytotoxic macrocyclic diterpenoid with an unusual cyclododecane core skeleton produced by the edible mushroom Pleurotus eryngii | |
| Fu et al. | Cytotoxic and antibacterial quinone sesquiterpenes from a Myrothecium fungus | |
| Chen et al. | Cytotoxic bromine-and iodine-containing cytochalasins produced by the mangrove endophytic fungus Phomopsis sp. QYM-13 using the OSMAC approach | |
| CN103524592B (zh) | 一种雷公藤红素衍生物、该衍生物的生物盐及其制备方法与用途 | |
| Chin et al. | Potential anticancer activity of naturally occurring and semisynthetic derivatives of aculeatins A and B from Amomum aculeatum | |
| Nishikori et al. | Anti-hepatitis C virus natural product from a fungus, Penicillium herquei | |
| Huang et al. | Antcamphins A–L, ergostanoids from Antrodia camphorata | |
| Wang et al. | Racemic alkaloids from the fungus Ganoderma cochlear | |
| Bang et al. | New aromatic compounds from the fruiting body of Sparassis crispa (Wulf.) and their inhibitory activities on proprotein convertase subtilisin/kexin type 9 mRNA expression | |
| Xue et al. | Henrischinins A− C: Three new triterpenoids from Schisandra henryi | |
| Wang et al. | Lanostane-type triterpenoids from the roots of Kadsura coccinea | |
| CN105198885B (zh) | 具有抗心律失调活性的化合物communesin I及其制备方法和用途 | |
| Wang et al. | Volvalerelactones A and B, two new sesquiterpenoid lactones with an unprecedented skeleton from Valeriana officinalis var. latifolia | |
| He et al. | Tetracyclic steroids bearing a bicyclo [4.4. 1] ring system as potent antiosteoporosis agents from the deep-sea-derived fungus Rhizopus sp. W23 | |
| Liao et al. | Design, synthesis and biological evaluation of novel carboline-cinnamic acid hybrids as multifunctional agents for treatment of Alzheimer’s disease | |
| Win et al. | Picrajavanicins A–G, quassinoids from Picrasma javanica collected in Myanmar | |
| Niu et al. | Butyrolactone I derivatives from Aspergillus terreus carrying an unusual sulfate moiety | |
| Gan et al. | Staprexanthones, xanthone-type stimulators of pancreatic β-cell proliferation from a mangrove endophytic fungus | |
| Mudur et al. | Heliconols A− C: Antimicrobial Hemiketals from the Freshwater Aquatic Fungus Helicodendron g iganteum |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU SIMOVAY MEDICINE CO., LTD. Free format text: FORMER OWNER: JIANGSU SIMCERE PHARMACEUTICAL RESEARCH COMPANY LIMITED Effective date: 20140526 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140526 Address after: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Patentee after: Jiangsu Simovay Pharmaceutical Co.,Ltd. Address before: 210042 Xuanwu Avenue, Jiangsu, Nanjing, No. 699 -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130424 Termination date: 20211014 |