CN106883225A - 一种具有1,2,4‑恶二唑‑结构片段的香豆素衍生物及其应用 - Google Patents
一种具有1,2,4‑恶二唑‑结构片段的香豆素衍生物及其应用 Download PDFInfo
- Publication number
- CN106883225A CN106883225A CN201710085727.8A CN201710085727A CN106883225A CN 106883225 A CN106883225 A CN 106883225A CN 201710085727 A CN201710085727 A CN 201710085727A CN 106883225 A CN106883225 A CN 106883225A
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- CN
- China
- Prior art keywords
- cdcl
- nmr
- compound
- coumarin derivative
- oxadiazoles
- 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
- 239000012634 fragment Substances 0.000 title claims abstract description 11
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 title claims abstract description 8
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 title description 2
- -1 1,2,4-oxadiazole-coumarin Chemical compound 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 18
- 230000007423 decrease Effects 0.000 claims abstract description 5
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
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- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 239000002585 base Substances 0.000 claims 2
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- 229940122601 Esterase inhibitor Drugs 0.000 claims 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 claims 1
- 239000002329 esterase inhibitor Substances 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 claims 1
- 229960004194 lidocaine Drugs 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- FCAUTDSYVBSXNC-UHFFFAOYSA-N nitro(trifluoromethoxy)methanesulfonic acid Chemical compound FC(OC(S(=O)(=O)O)[N+](=O)[O-])(F)F FCAUTDSYVBSXNC-UHFFFAOYSA-N 0.000 claims 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 150000003235 pyrrolidines Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 57
- 229940079593 drug Drugs 0.000 abstract description 11
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- 239000007787 solid Substances 0.000 description 28
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 21
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- 108010022752 Acetylcholinesterase Proteins 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 229940022698 acetylcholinesterase Drugs 0.000 description 6
- 230000007131 anti Alzheimer effect Effects 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- HSHNITRMYYLLCV-UHFFFAOYSA-N 4-methylumbelliferone Chemical compound C1=C(O)C=CC2=C1OC(=O)C=C2C HSHNITRMYYLLCV-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 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 3
- 229940124596 AChE inhibitor Drugs 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 150000004775 coumarins Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
本发明公开了一种具有1,2,4‑恶二唑‑结构片段的香豆素衍生物及其应用。该类衍生物具有如下所示的结构通式：
Description
技术领域
本发明涉及一种具有1,2,4-恶二唑-结构片段的香豆素衍生物及其应用，属于药物领域。
背景技术
阿尔茨海默症(Alzheimer’s Disease，AD)是一种进行性发展的致死性神经退行性疾病(Noroozian M.Alzheimer’s disease:prototype of cognitive deterioration,valuable lessons to understand human cognition.Neurol.Clin.,2016,34,69-131)，临床上尚无有效对因治疗药物。在发达国家，AD已经成为继心脏病、恶性肿瘤、中风之后老年人死亡的第四位原因。目前，我国约有500万AD患者，其数目已居世界第一(廖翠红.阿尔茨海默病人的护理综述.现代养生,2015,25,215-216)。AD已成为医疗保健系统的主要负担，为社会、患者和家属带来了沉痛的精神和经济压力，是一场十分严重的“公共健康危机”。
AD病因及发病机制极其复杂，而胆碱能神经元损伤是较早被公认的AD发病机制。胆碱能学说认为，在AD病理过程中，基底前脑区的胆碱能神经元丢失以及神经递质胆碱乙酰转移酶活性下降，会导致乙酰胆碱的合成、释放和摄取减少，从而造成学习和记忆力衰退(Armstrong RA.What causes alzheimer’s disease？Folia Neuropathol.,2013,51,169-188)。根据该假说，人们认为乙酰胆碱酯酶(acetylcholinesterase,AChE)抑制剂可增加中枢神经系统的乙酰胆碱含量，有助于改善AD病人的认识和记忆能力。目前，AChE抑制剂是被研究的最多且临床上最为普遍认同的一线治疗AD药物，如他克林、多奈哌齐、雷司替明和加兰他敏。然而，这些AchE抑制剂治疗效果均不佳，例如他克林需一日服药4次且具有潜在的严重肝毒，其他三种改善AD症状药物只能在病情发展的特定阶段有限的缓解或稳定病情且伴有严重副作用。因此亟需开发新型疗效好、副作用低的AChE抑制剂。
1,2,4-恶二唑属于五元杂环结构，因杂环分子掺入供电子原子(氧、氮)，能够显著增加配体和受体间的亲和力和选择性，其衍生物在医药中应用非常广泛；香豆素是广泛存在于自然界中的内酯类化合物，具有良好的药物活性，如抗氧化、抗癌、抗HIV等，目前设计、合成高效低毒的香豆素类衍生物已经成为药物研发工作的重要方向之一。
发明内容
本发明人经过对所在实验室合成的1,2,4-恶二唑-香豆素衍生物的活性筛选，发现了一类结构相对简单、具有乙酰胆碱酯酶抑制活性的通式I所示的新化合物，由此可能对AD具有治疗作用，从而在制备抗AD药物领域具有潜在的用途。迄今为止，未见关于式I所示化合物的结构、制备方法及用途的报道。
本发明采用以下技术方案：
一种具有1,2,4-恶二唑-结构片段的香豆素衍生物，它具有如下通式I所示的结构：
其中：
A环为芳香环时，R1和R2为芳环上邻位、间位及对位取代基团，R1和R2分别为氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、羟基、巯基、甲巯基、乙巯基、氨基、二甲氨基、二乙氨基、卤素、三氟甲基、三氟甲氧基、硝基、甲磺酸基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基；所述芳香环为苯基、呋喃、噻唑、吡咯、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮；
A环为非芳香环时，R1和R2同时为氢；所述非芳香环为环己烷、吡咯烷、四氢吡喃或环戊烯基。
作为本发明的一种优选，所述的A为苯基。
上述的具有1,2,4-恶二唑-结构片段的香豆素衍生物的制备方法，它包括以下步骤：
(a)将4-甲基伞形酮(式1)与对氰基苄溴反(式2)应得到式3化合物，其中，催化剂为碳酸钾、碳酸钠、碳酸锂，氢氧化钾、氢氧化钠、氢氧化锂、三乙胺、二异丙基乙胺、二异丙胺、四丁基溴化铵或四丁基氟化铵；反应溶剂为N,N-二甲基甲酰胺、丙酮、二甲基亚砜、1,4-二氧六环、四氢呋喃、甲醇、乙醇、吡啶及水中至少一种；该反应温度为0℃～140℃；反应时间为1～12小时；
(b)将式3化合物与盐酸羟胺反应得到式4化合物，其中，催化剂为三乙胺、二异丙基乙胺、二异丙胺、碳酸钠、碳酸钾或吡啶；反应溶剂为N,N-二甲基甲酰胺、四氢呋喃、甲醇、乙醇、水及甲苯中至少一种；该反应温度为0℃～120℃；反应时间为1～12小时；
(c)将式4化合物与式5化合物反应在缩合剂催化作用下得到目标通式I化合物；所用的缩合剂为N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、1-羟基-7-偶氮苯并三氮唑、1-羟基苯并三氮唑、O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯中的一种或两种以上的组合；所用溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈、1,4-二氧六环、二氯乙烷、N,N-二异丙基乙胺和水中的一种或一种以上；反应温度为0℃～130℃；反应时间为6～12小时；
所述式5化合物结构式如下：其中：
A环为芳香环时，R1和R2为芳环上邻位、间位及对位取代基团，R1和R2分别为氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、羟基、巯基、甲巯基、乙巯基、氨基、二甲氨基、二乙氨基、卤素、三氟甲基、三氟甲氧基、硝基、甲磺酸基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基；所述芳香环为苯基、呋喃、噻唑、吡咯、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮；
A环为非芳香环时，R1和R2同时为氢；所述非芳香环为环己烷、吡咯烷、四氢吡喃或环戊烯基。
本发明提供了上述衍生物在制备治疗和/或预防胆碱能功能下降相关疾病的药物方面的应用。
本发明还提供了一种上述衍生物在制备抗AD药物中的应用。
本发明还提供了一种用于预防和/或治疗AD的药物组合物，由上述通式I所示的衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料。
本发明的有益效果：
本发明所涉及的化合物为首次合成的一类新的具有1,2,4-恶二唑-结构片段的香豆素衍生物，并首次发现该类化合物具有乙酰胆碱酯酶抑制活性，因而它们在制备抗AD药物中具有潜在的应用前景。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1：式3化合物的制备
将粉末状的7-羟基-4-甲基香豆素(式1)880mg溶解到50ml丙酮中，加入828mg碳酸钾，搅拌0.5h后加入1.5g对氰基溴苄(式2)、83mg碘化钾和156mg四丁基溴化铵，50℃搅拌5h，TLC检测反应完全，浓缩反应液。50％乙醇重结晶得到1.426g化合物式3，黄色固体，产率98％。1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.3Hz,2H),7.57(dd,J＝11.6,8.5Hz,3H),6.95(dd,J＝8.8,2.5Hz,1H),6.88(d,J＝2.5Hz,1H),6.18(s,1H),5.21(s,2H),2.43(s,3H).ESI-MS m/z:292.4[M+H]+.
实施例2：式4化合物的制备
10ml无水乙醇溶解582mg式3化合物，冰浴至0℃，加入751mg三乙胺和308mg盐酸羟胺，搅拌0.5h后，加热回流(80℃)过夜。乙酸乙酯萃取(25ml*3)，将合并的有机层用饱和氯化钠溶液洗涤3次，用无水硫酸钠干燥并减压浓缩。残余物通过硅胶色谱纯化得到395mg式4化合物，黄色固体，产率85％。1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.58–7.47(m,3H),6.99–6.93(m,1H),6.90(d,J＝2.3Hz,1H),6.17(d,J＝1.2Hz,1H),5.28–5.15(m,2H),4.89(s,2H),2.43(s,3H).ESI-MS m/z:325.2[M+H]+.
实施例3：通式I化合物的制备
5ml二氯甲烷溶解0.5mmol式5化合物，加入0.55mmol N,N-二异丙基乙胺和0.55mmol2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(HATU)，室温搅拌3h，TLC检测反应完全。向上述反应液中加入溶解于二氯甲烷中的0.5mmol式4化合物，室温搅拌三小时，TLC检测反应完全，浓缩反应液。乙酸乙酯萃取(15ml*3)，将合并的有机层用饱和氯化钠溶液洗涤3次用无水硫酸钠干燥并减压浓缩得到残渣。10ml乙醇溶解上述残渣，加入4mmol无水乙酸钠，加热回流(80℃)过夜，TLC检测反应完全，减压浓缩反应液，硅胶色谱分离纯化得到相应的通式I化合物。化合物编号、具体结构式以及原料如下表1所示。
表1化合物编号、具体结构式、所用原料以及活性结果
化合物I-1，白色固体(63mg，61.4％)。1H NMR(600MHz,CDCl3)δ8.22(dt,J＝22.0,11.2Hz,4H),7.62(dd,J＝8.3,6.4Hz,1H),7.57(dd,J＝17.3,7.8Hz,4H),7.52(d,J＝8.8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.15(s,1H),5.21(s,2H),2.40(s,3H).13C NMR(150MHz,CDCl3)δ175.83,168.58,161.42,161.21,155.22,152.47,139.04,132.83,129.14,128.19,127.93,127.74,126.98,125.68,124.23,113.98,112.87,112.25,102.00,69.94,18.70.ESI-MS m/z:4112[M+H]+.
化合物I-2，白色固体(70mg，64.5％)。1H NMR(600MHz,CDCl3)δ8.39–8.33(m,1H),8.20(dd,J＝9.9,8.4Hz,3H),7.92–7.86(m,2H),7.76(d,J＝8.4Hz,2H),7.60(d,J＝8.3Hz,1H),7.53(dt,J＝8.8,5.1Hz,2H),7.46(dd,J＝6.3,3.0Hz,1H),6.16(d,J＝1.1Hz,1H),5.25–5.18(m,2H),2.41(dd,J＝2.8,1.1Hz,3H).13C NMR(150MHz,CDCl3)δ174.04,168.96,168.52,161.38,155.20,152.58,139.49,132.93,132.22,130.49,128.68,127.97,127.88,127.81,127.42,126.08,118.08,116.42,112.93,112.26,101.97,69.87,18.71.ESI-MS m/z:435.3[M+H]+.
化合物I-3，白色固体(75mg，70％)。1H NMR(600MHz,CDCl3)δ8.29–8.17(m,3H),7.59(d,J＝8.6Hz,1H),7.53(d,J＝9.2Hz,1H),7.16(d,J＝8.2Hz,2H),7.09(d,J＝8.9Hz,1H),6.96(d,J＝9.2Hz,1H),6.91(s,1H),6.73(d,J＝9.1Hz,1H),6.16(s,1H),5.22(s,2H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ174.91,168.57,161.41,161.20,155.26,152.47,148.95,148.29,139.13,130.68,130.62,127.75,125.68,120.34,116.61,114.68,112.88,112.26,101.99,69.92,18.70.ESI-MS m/z:429.1[M+H]+.
化合物I-4，白色固体(54mg，52.6％)。1H NMR(600MHz,CDCl3)δ8.90(dd,J＝4.5,1.5Hz,2H),8.22(d,J＝8.2Hz,2H),8.07(dd,J＝4.5,1.5Hz,2H),7.61(d,J＝8.1Hz,2H),7.55(t,J＝16.4Hz,1H),6.97(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.16(s,1H),5.23(s,2H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ173.91,169.00,161.39,161.24,155.21,152.56,151.08 139.52,131.12,127.98,127.82,126.33,125.73,121.38,114.02,112.91,112.24,101.97,69.86,18.71.ESI-MS m/z:412.1[M+H]+.
化合物I-5，白色固体(66mg，52.3％)。1H NMR(600MHz,CDCl3)δ8.21(d,J＝8.0Hz,2H),8.03(d,J＝7.6Hz,1H),7.93(d,J＝8.8Hz,1H),7.60(d,J＝8.0Hz,2H),7.54(dd,J＝16.4,7.3Hz,2H),7.32(d,J＝7.7Hz,1H),6.97(d,J＝8.4Hz,1H),6.92(s,1H),6.16(s,1H),5.22(s,2H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ168.74,163.66,162.18,161.42,161.20,156.54,155.26,153.52,152.47,139.24,131.04，127.95,127.77,125.69,124.54,120.08,119.89,115.29,112.88,112.27,101.99,69.91,18.70.ESI-MS m/z:429.3[M+H]+.
化合物I-6，白色固体(85mg，65.4％)。1H NMR(600MHz,CDCl3)δ8.20(d,J＝8.3Hz,2H),8.12–8.06(m,2H),7.74–7.69(m,2H),7.59(d,J＝8.3Hz,2H),7.53(d,J＝8.8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.16(d,J＝1.1Hz,1H),5.22(s,2H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ175.03,168.70,161.42,161.25,155.21,152.54,139.21,132.54,129.58,127.94,127.76,126.74,125.70,123.11,120.34,114.00,112.90,112.24,101.99,69.91,18.71.ESI-MS m/z:491.2[M+H]+.
化合物I-7，白色固体(85mg，79.4％)。1H NMR(600MHz,CDCl3)δ8.26–8.20(m,3H),7.62(ddd,J＝8.5,4.2,2.0Hz,1H),7.59(d,J＝8.2Hz,2H),7.52(d,J＝8.8Hz,1H),7.38–7.33(m,1H),7.33–7.28(m,1H),6.96(dt,J＝6.7,3.3Hz,1H),6.91(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,1H),5.20(d,J＝13.5Hz,2H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ172.84,168.35,161.65,161.42,161.21,159.92,155.22,152.47,139.14,134.67,130.94(s),127.99,127.75,126.76,125.68,124.73,117.27,117.13,113.99,112.86,112.25,102.00,69.92,18.70.ESI-MS m/z:429.1[M+H]+.
化合物I-8，白色固体(83mg，78.3％)。1H NMR(600MHz,CDCl3)δ8.22(d,J＝8.2Hz,2H),8.05(s,1H),8.02(d,J＝7.2Hz,1H),7.58(d,J＝8.2Hz,2H),7.54–7.50(m,1H),7.47–7.41(m,2H),6.96(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,1H),5.21(s,2H),2.48(s,3H),2.40(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ176.02,168.53,161.42,161.20,155.21,152.46,139.07,139.00,133.65,129.04,128.68,127.92,127.73,127.02,125.67,125.33,124.09,113.98,112.86,112.24,101.99,69.94,21.35,18.70.ESI-MS m/z:425.4[M+H]+.
化合物I-9，白色固体(100mg，94.3％)。1H NMR(600MHz,CDCl3)δ8.26–8.21(m,2H),8.17(d,J＝8.1Hz,1H),7.59(d,J＝8.3Hz,2H),7.52(d,J＝8.8Hz,1H),7.51–7.47(m,1H),7.37(t,J＝7.8Hz,2H),6.96(dd,J＝8.8,2.5Hz,1H),6.92(t,J＝4.1Hz,1H),6.15(d,J＝1.1Hz,1H),5.22(s,2H),2.79(s,3H),2.40(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ176.46,168.20,161.43,161.22,155.22,152.48,139.18,138.98,132.28,131.94,130.22,127.93,127.74,127.13,126.31,125.67,123.38,113.98,112.88,112.25,102.01,69.95,22.00,18.70.ESI-MS m/z:425.4[M+H]+.
化合物I-10，白色固体(32mg，30.1％)。1H NMR(600MHz,CDCl3)δ8.21(d,J＝8.3Hz,2H),8.11(d,J＝8.2Hz,2H),7.58(d,J＝8.3Hz,2H),7.54–7.51(m,1H),7.36(d,J＝8.0Hz,2H),6.96(dd,J＝8.8,2.5Hz,1H),6.92(t,J＝3.9Hz,1H),6.15(d,J＝1.1Hz,1H),5.20(d,J＝7.5Hz,2H),2.46(s,3H),2.40(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ175.97,168.49,161.44,161.22,155.22,152.47,143.61,138.95,129.84,128.16,127.92,127.72,127.09,125.67,121.50,113.98,112.87,112.24,102.00,69.86,21.79,18.70.ESI-MS m/z:425.4[M+H]+.
化合物I-11，白色固体(76mg，73.1％)。1H NMR(600MHz,CDCl3)δ8.10(dd,J＝18.5,8.2Hz,2H),7.53(dd,J＝17.2,8.5Hz,2H)，7.51(d,J＝8.8Hz,1H),6.95(dd,J＝8.8,2.5Hz,1H),6.90(d,J＝2.4Hz,1H),6.15(s,1H),5.18(d,J＝9.1Hz,2H),3.09–2.97(m,1H),2.40(s,3H),2.36–2.28(m,2H),1.38–1.19(m,8H).13C NMR(150MHz,CDCl3)δ183.15,167.72,161.43,161.24,155.20,152.49,138.81,127.82,127.68,127.11,125.66,113.97,112.88,112.23,101.99,69.94,36.42,30.28,25.77,25.41,18.70.ESI-MS m/z:417.3[M+H]+.
化合物I-12，白色固体(63mg，56.7％)。1H NMR(600MHz,CDCl3)δ8.20(d,J＝8.0Hz,2H),8.17(d,J＝8.4Hz,2H),7.59(d,J＝8.1Hz,2H),7.54(dd,J＝14.2,8.8Hz,3H),6.96(d,J＝7.4Hz,1H),6.91(s,1H),6.16(s,1H),5.22(s,2H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ174.93,168.68,161.40,161.20,155.22,152.47,139.30,139.19,129.57,129.48,127.94,127.76,126.77,125.68,122.68,114.00,112.88,112.27,101.99,69.91,18.70.ESI-MS m/z:445.1[M+H]+.
化合物I-13，白色固体(18mg，15.6％)。1H NMR(600MHz,CDCl3)δ8.45–8.36(m,3H),8.14–8.06(m,1H),7.94(d,J＝8.1Hz,1H),7.91–7.83(m,2H),7.82–7.76(m,1H),7.71(t,J＝7.2Hz,1H),7.68–7.64(m,1H),7.62(t,J＝7.1Hz,1H),7.53(ddd,J＝13.2,10.6,6.2Hz,2H),6.23–6.08(m,1H),5.23(s,2H),2.45–2.35(m,3H).13C NMR(150MHz,CDCl3)δ174.64,168.99,161.43,161.20,155.24,152.46,148.13,,139.27,137.77,130.82,130.63,130.21,128.89,128.56,128.15,127.75,127.53(s),125.69(s),121.05,120.47,,112.87,112.27,102.00,69.93,18.71.ESI-MS m/z:462.2[M+H]+.
化合物I-14，白色固体(56mg，50.1％)。1H NMR(600MHz,CDCl3)δ7.96(dd,J＝7.7,1.8Hz,1H),7.82(d,J＝8.3Hz,2H),7.53–7.50(m,4H),7.10–7.02(m,2H),6.94(dd,J＝8.8,2.5Hz,1H),6.87(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,1H),5.19(s,2H),3.97(s,3H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ164.48,161.37,158.97,154.88,152.31,139.42,133.76(s),132.46,131.02,127.95,127.56,127.29,125.71,120.80,120.34,119.38,114.01,112.91(s),112.20,112.04,102.06,69.81,53.51,18.71.ESI-MS m/z:441.3[M+H]+.
化合物I-15，黄色固体(57mg，50.1％)。1H NMR(600MHz,CDCl3)δ8.43(s,3H),8.22(d,J＝8.3Hz,2H),7.61(d,J＝8.3Hz,2H),7.53(t,J＝8.4Hz,1H),7.16(d,J＝8.8Hz,1H),6.97(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.16(d,J＝1.1Hz,1H),5.30(s,2H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ173.78,169.06,161.36,161.20,155.23,152.45,150.25,139.55,129.49,129.27,128.00,127.83,126.32,125.71,124.42,114.04,112.89,112.30,101.97,69.86,18.71.ESI-MS m/z:456.2[M+H]+.
化合物I-16，黄色固体(57mg，44.0％)。1H NMR(600MHz,CDCl3)δ8.18(d,J＝8.3Hz,2H),8.07–8.01(m,2H),7.85–7.77(m,1H),7.59(d,J＝8.3Hz,2H),7.53(d,J＝8.8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.15(d,J＝1.0Hz,1H),5.22(s,2H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ172.53,168.64,165.77,161.38,161.21,155.22,152.47,139.43,133.08,132.92,131.38,128.04,127.77,126.27,125.69,124.68,119.08,114.01,112.85,112.27,102.03,69.87,18.70.ESI-MS m/z:456.2[M+H]+.
化合物I-17，黄色固体(72mg，63.3％)。1H NMR(600MHz,CDCl3)δ9.13–9.07(m,1H),8.59–8.53(m,1H),8.49(ddd,J＝8.2,2.2,1.0Hz,1H),8.23(d,J＝8.3Hz,2H),7.80(t,J＝8.0Hz,1H),7.61(d,J＝8.3Hz,2H),7.53(d,J＝8.8Hz,1H),6.97(dd,J＝8.8,2.5Hz,1H),6.92(d,J＝2.5Hz,1H),6.16(d,J＝1.1Hz,1H),5.23(s,2H),2.41(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ173.71,168.95,161.37,161.19,155.23,152.46,148.74,139.51,133.57,130.52,128.01,127.83,127.14,126.36,125.83,125.70,123.26,,114.05,112.89,112.29,101.98,69.87,18.71.ESI-MS m/z:456.2[M+H]+.
化合物I-18，白色固体(56mg，55.8％)。1H NMR(600MHz,CDCl3)δ8.12(d,J＝8.3Hz,2H),7.55(d,J＝7.9Hz,2H),7.52(d,J＝8.8Hz,1H),6.95(dt,J＝6.0,3.0Hz,1H),6.90(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,2H),5.19(s,2H),3.83(dd,J＝8.6,0.8Hz,1H),2.60–2.46(m,3H),2.40(d,J＝1.1Hz,3H),2.31(dd,J＝19.4,10.4Hz,1H),2.21–2.13(m,1H),2.12–2.05(m,1H),2.02–1.88(m,1H).13C NMR(150MHz,CDCl3)δ182.25,167.89,161.44,161.21,155.21,152.47,138.85,127.82,127.70,127.07,125.66,113.97,112.88,112.24,101.99,69.94,31.52,27.25,25.32,18.87,18.70.ESI-MS m/z:404.1[M+H]+.
化合物I-19，白色固体(52mg，47.2％)。1H NMR(600MHz,CDCl3)δ8.26–8.19(m,2H),7.86–7.79(m,1H),7.73(dt,J＝7.8,3.9Hz,1H),7.59(d,J＝8.3Hz,2H),7.53(dd,J＝8.2,4.8Hz,1H),7.49–7.45(m,1H),7.16(ddd,J＝8.3,2.6,0.8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),6.92(t,J＝4.2Hz,1H),6.15(dd,J＝4.6,1.2Hz,1H),5.21(s,2H),3.93(s，3H),2.40(dd,J＝4.1,1.2Hz,3H).13C NMR(150MHz,CDCl3)δ175.77,168.59,161.43,161.24,159.98,155.21,152.50,139.05,130.29,127.94,127.87,126.95,125.69,125.29(s),120.63,119.37,113.99,112.88,112.63,112.24,102.00,69.99,55.59,18.70.ESI-MS m/z:441.3[M+H]+.
化合物I-20，白色固体(81mg，80.4％)。1H NMR(600MHz,CDCl3)δ7.85(d,J＝8.2Hz,1H),7.66(d,J＝8.2Hz,1H),7.56–7.51(m,2H),7.48(d,J＝8.2Hz,1H),6.97–6.92(m,1H),6.90–6.84(m,1H),6.15(d,J＝1.2Hz,1H),5.20(s,1H),4.24–4.16(m,1H),3.42(dd,J＝14.6,7.3Hz,1H),2.41(s,3H),2.32(ddt,J＝14.9,11.2,7.9Hz,1H),2.12–1.88(m,6H).13CNMR(150MHz,CDCl3)δ169.93 9,166.43(s),161.379,155.14,152.78,140.15,137.91,133.06,127.86,127.63,127.39,126.24,125.78,125.71,112.98,112.12,101.96,69.69,60.55,40.29,29.71,23.35,18.71.ESI-MS m/z:404.1[M+H]+.
化合物I-21，黄色固体(52mg，47.1％)。1H NMR(600MHz,CDCl3)δ8.21(d,J＝8.2Hz,2H),8.11(d,J＝8.5Hz,2H),7.58(t,J＝8.5Hz,2H),7.54–7.49(m,3H),7.37(d,J＝8.5Hz,2H),6.15(d,J＝3.0Hz,1H),5.21(s,2H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ175.59,168.53,161.46,161.22,155.28,152.47,145.64,139.00,128.36,127.92,127.73,127.60,127.51,127.02,125.67,125.61,120.26,113.99,112.87,112.25,102.00,69.92,18.70.ESI-MS m/z:443.5[M+H]+.
化合物I-22，黄色固体(60mg，49.2％)。1H NMR(600MHz,CDCl3)δ8.48–8.42(m,2H),8.25–8.21(m,2H),8.18–8.14(m,2H),7.61(d,J＝8.3Hz,2H),7.53(dd,J＝9.5,4.3Hz,1H),6.97(dd,J＝8.8,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.16(d,J＝1.1Hz,1H),5.23(s,2H),3.14(s,3H),2.41(d,J＝1.2Hz,3H).13C NMR(150MHz,CDCl3)δ174.03,168.98,161.36,161.18,155.22,152.46,144.13,139.50,129.11,128.85,128.31,127.98,127.81,126.38,125.71,114.03,112.89,112.29,101.97,69.86,44.39,18.71.ESI-MS m/z:489.4[M+H]+.
化合物I-23，黄色固体(94mg，78.3％)。1H NMR(600MHz,CDCl3)δ8.03(d,J＝8.2Hz,2H),7.93(t,J＝5.9Hz,2H),7.51(d,J＝8.6Hz,3H),6.94(dd,J＝8.8,2.5Hz,1H),6.90(d,J＝2.5Hz,1H),6.62(dd,J＝14.1,5.6Hz,2H),6.15(d,J＝1.0Hz,1H),5.17(s,2H),3.46–3.36(m,4H),2.40(d,J＝1.0Hz,3H),1.23–1.13(m,6H).13C NMR(150MHz,CDCl3)δ171.83,171.51,168.33,161.49,161.25,155.20,152.49,151.49,,132.29,127.95,127.60,127.51,125.63,114.99,113.92,112.87,112.19,110.15,102.01,70.03,41.97,18.69,12.48.ESI-MS m/z:482.3[M+H]+.
化合物I-24，白色固体(90mg，86.1％)。1H NMR(600MHz,CDCl3)δ8.12(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,2H),7.52(d,J＝8.8Hz,1H),6.95(dd,J＝8.3,2.0Hz,1H),6.90(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,1H),5.20(s，2H),3.65–3.54(m,2H),3.50–3.39(m,2H),3.32–3.24(m,1H),2.40(d,J＝1.1Hz,3H),2.15–2.00(m,4H).13C NMR(150MHz,CDCl3)δ181.41,167.90,161.39,161.21,155.20,152.47,139.03,127.84,127.71,126.84,125.67,113.98,112.88,112.25,101.98,69.91,66.89,33.61,29.75,18.70.ESI-MS m/z:419.2[M+H]+.
化合物I-25，白色固体(81mg，81.1％)。1H NMR(600MHz,CDCl3)δ8.19–8.07(m,2H),7.59–7.49(m,3H),6.95(dd,J＝8.8,2.5Hz,1H),6.90(d,J＝2.5Hz,1H),6.15(d,J＝1.1Hz,1H),5.82–5.76(m,2H),5.19(s,2H),3.79(tt,J＝9.3,6.9Hz,1H),3.05–2.81(m,4H),2.40(d,J＝1.1Hz,3H).13C NMR(150MHz,CDCl3)δ183.22,167.85,161.42,161.21,155.21,152.46,138.88,129.01,127.83,127.68,127.00,125.66,113.97,112.87,112.24,101.98,69.93,37.80,34.89,18.70.ESI-MS m/z:401.3[M+H]+.
化合物I-26，白色固体(52mg，52.1％)。1H NMR(600MHz,CDCl3)δ8.21(d,J＝8.2Hz,2H),7.74(d,J＝1.3Hz,1H),7.57(t,J＝7.8Hz,2H),7.53(t,J＝9.2Hz,1H),7.39(d,J＝3.5Hz,1H),6.96(dt,J＝5.2,2.6Hz,1H),6.90(dd,J＝7.4,2.4Hz,1H),6.67(dd,J＝3.5,1.7Hz,1H),6.15(d,J＝0.8Hz,1H),5.20(d,J＝8.4Hz,2H),2.40(t,J＝1.6Hz,3H).13C NMR(150MHz,CDCl3)δ168.32,167.68,161.41,161.20,155.22,152.47,146.81,140.09,139.25,128.02,127.73,126.48,125.68,116.76,114.00,112.86,112.58,112.26,101.98,69.97,18.70.ESI-MS m/z:401.1[M+H]+.
实施例4：乙酰胆碱酯酶抑制活性
试剂：乙酰胆碱酯酶、作为底物的碘化硫代乙酰胆碱(ATCH)和作为显色剂的5,5-二硫双(2-硝基苯甲酸)(DTNB)均购自Sigma。
AChE抑制活性测定按照Ellan等报道的方法进行(Ellman,G.L.etal.Biochem.Pharmacol.1961,7,88.)。96孔板每孔加入20μL的磷酸缓冲液，然后将100μL的待测化合物溶液或空白对照加入到对应的空中，随后加入50μL的AChE，置于37℃摇床孵育5min。加入100μL的DTNB溶液，再置于37℃摇床孵育5min，加入10μL的底物ATCH置于37℃摇床孵育3min后，酶标仪测定415nm处的吸光度，计算待测化合物对AChE的抑制率，数据如表1所示。
从表1的结果可知，上述合成的式1-26化合物在浓度为100μM时对AChE均表现出抑制活性。其中，式I-10化合物的活性最强，它的AchE抑制率为94.8±1.7％。初步构效关系研究表明，A环为芳香环的衍生物的活性要明显优于A环为非芳香环的衍生物，且苯环上的给电子对位取代基能够使化合物的AchE抑制活性增强。初步研究结果表明，该类化合物作为一类新的乙酰胆碱抑制剂，可为新型抗AD药物的研制提供新颖的分子结构骨架。
因而，本发明所制备的一类具有AchE抑制活性的1,2,4-恶二唑-香豆素衍生物化合物在制备抗AD药物中具有广阔的应用前景。本发明所述的一系列化合物作为活性成分再添加常规药剂学辅料制备出抗AD药物，可制备成常规药剂学上的片剂、颗粒剂、胶囊剂、口服液等任一种剂型。
以上以具体的实施例来举例说明本发明化合物的制备步骤、鉴定过程和药理实验过程，但对本领域的技术人员来说可以对此作出多种修改和变化，在不背离本发明的精神和范围的情况下，所附的权利要求书覆盖本发明范围内的所有这些修改。
Claims (5)
1.一种具有1,2,4-恶二唑-结构片段的香豆素衍生物，其特征在于，具有通式I所示的结构：
；
其中：
A为芳香环时，R1和R2为芳环上邻位、间位及对位取代基团，R1和R2分别为氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、羟基、巯基、甲巯基、乙巯基、氨基、二甲氨基、二乙氨基、卤素、三氟甲基、三氟甲氧基、硝基、甲磺酸基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基；所述芳香环为苯基、呋喃、噻唑、吡咯、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮；
A为非芳香环时，R1和R2同时为氢；所述非芳香环为环己烷、吡咯烷、四氢吡喃或环戊烯基。
2.根据权利要求1所述的衍生物，其特征在于，所述的A为苯基。
3.一种权利要求1或2所述的具有1,2,4-恶二唑-结构片段的香豆素衍生物用作乙酰胆碱酯酶抑制剂，或在制备治疗和/或预防胆碱能功能下降相关疾病的药物方面的应用。
4.一种权利要求1或2所述的具有1,2,4-恶二唑-结构片段的香豆素衍生物在制备抗阿尔茨海默病药物中的应用。
5.一种用于预防和/或治疗阿尔茨海默病的药物组合物，其特征在于，以权利要求1或2所述的具有1,2,4-恶二唑-结构片段的香豆素衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料。
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| CN107382990A (zh) * | 2017-08-09 | 2017-11-24 | 济南大学 | 一种具有1,2,4‑恶二唑结构片段的化合物及其制备方法和应用 |
| CN110218183A (zh) * | 2019-06-27 | 2019-09-10 | 济南大学 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
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| CN101437510A (zh) * | 2006-03-20 | 2009-05-20 | 科学与工业研究会 | 用作乙酰胆碱酯酶抑制剂的药物组合物 |
| KR20120040596A (ko) * | 2010-10-19 | 2012-04-27 | 경희대학교 산학협력단 | 쿠마린 유도체, 그의 제조 방법 및 그를 포함하는 약제학적 조성물 |
| CN103265517A (zh) * | 2013-05-11 | 2013-08-28 | 浙江大学 | 3-取代香豆素类衍生物及其用途 |
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| CN101437510A (zh) * | 2006-03-20 | 2009-05-20 | 科学与工业研究会 | 用作乙酰胆碱酯酶抑制剂的药物组合物 |
| KR20120040596A (ko) * | 2010-10-19 | 2012-04-27 | 경희대학교 산학협력단 | 쿠마린 유도체, 그의 제조 방법 및 그를 포함하는 약제학적 조성물 |
| CN103265517A (zh) * | 2013-05-11 | 2013-08-28 | 浙江大学 | 3-取代香豆素类衍生物及其用途 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107382990A (zh) * | 2017-08-09 | 2017-11-24 | 济南大学 | 一种具有1,2,4‑恶二唑结构片段的化合物及其制备方法和应用 |
| CN107382990B (zh) * | 2017-08-09 | 2020-08-04 | 济南大学 | 一种具有1,2,4-恶二唑结构片段的化合物及其制备方法和应用 |
| CN110218183A (zh) * | 2019-06-27 | 2019-09-10 | 济南大学 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
| CN110218183B (zh) * | 2019-06-27 | 2022-02-08 | 济南大学 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
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