CN103965188A - 含硒多奈哌齐类似物 - Google Patents
含硒多奈哌齐类似物 Download PDFInfo
- Publication number
- CN103965188A CN103965188A CN201310033667.7A CN201310033667A CN103965188A CN 103965188 A CN103965188 A CN 103965188A CN 201310033667 A CN201310033667 A CN 201310033667A CN 103965188 A CN103965188 A CN 103965188A
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- CN
- China
- Prior art keywords
- acid
- selenazoles
- benzo selenazoles
- ethyl
- benzyl
- 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.)
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- 229910052711 selenium Inorganic materials 0.000 title claims abstract description 25
- 239000011669 selenium Substances 0.000 title claims abstract description 25
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 title abstract description 10
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical class O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 15
- 150000003839 salts Chemical group 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 239000012453 solvate Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 66
- -1 selenium E2020 analogue Chemical class 0.000 claims description 25
- IESZBYHZFYGRNV-UHFFFAOYSA-N CN(C)C1=CC=CC(=C1)N2CCC(CC2)CCC3=NC4=CC(=C(C=C4[Se]3)OC)OC Chemical class CN(C)C1=CC=CC(=C1)N2CCC(CC2)CCC3=NC4=CC(=C(C=C4[Se]3)OC)OC IESZBYHZFYGRNV-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 9
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 8
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- AIGNCQCMONAWOL-UHFFFAOYSA-N 1,3-benzoselenazole Chemical class C1=CC=C2[se]C=NC2=C1 AIGNCQCMONAWOL-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical class CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000000324 neuroprotective effect Effects 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- 230000000994 depressogenic effect Effects 0.000 claims description 3
- LBKPGNUOUPTQKA-UHFFFAOYSA-N ethyl n-phenylcarbamate Chemical compound CCOC(=O)NC1=CC=CC=C1 LBKPGNUOUPTQKA-UHFFFAOYSA-N 0.000 claims description 3
- 230000006872 improvement Effects 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims description 2
- GAOGPNYSGYFOHS-UHFFFAOYSA-N 2-chloro-1,3-benzoselenazole Chemical class C1=CC=C2[se]C(Cl)=NC2=C1 GAOGPNYSGYFOHS-UHFFFAOYSA-N 0.000 claims description 2
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 claims description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 claims description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- JKCHTVORSRIIKL-UHFFFAOYSA-N FC1=NC(C=CC=C2)=C2[Se]1 Chemical class FC1=NC(C=CC=C2)=C2[Se]1 JKCHTVORSRIIKL-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
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- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
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- 230000000694 effects Effects 0.000 abstract description 29
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Abstract
本发明提供了游离形式、盐形式或溶剂化物形式的含硒多奈哌齐类似物,以及上述衍生物在治疗、改善和/或预防阿尔茨海默病的药物组合物的应用;通过体外活性测试实验表明,本发明的含硒多奈哌齐类似物式I具有优异的胆碱酯酶(乙酰胆碱酯酶和丁酰胆碱酯酶)抑制活性、清除体内过氧化氢活性、清除过氧亚硝基活性以及模拟谷胱甘肽过氧化物酶过氧化物酶活性和作为硫氧还蛋白还原酶底物参与氧化还原反应的活性。因此本发明的含硒多奈哌齐类似物式I可用于制备抗阿尔茨海默病药物。上述含硒多奈哌齐类似物结构如式I所示,其中式I中的R1、R2、R3、R4、R5、R6、R7、R6、R7如说明书所定义。
Description
技术领域
本发明属于医药技术领域,主要涉及到含硒多奈哌齐类似物的设计合成,及其在治疗、改善和/或预防抗阿尔茨海默症中的应用。
背景技术
阿尔茨海默病(Alzheimer’s disease,AD)又名老年痴呆症,以渐进性记忆障碍、认知功能障碍、人格改变以及语言障碍等神经精神症状为特征。常起病于老年或老年前期、多缓慢发病,逐渐进展,以神经退行性障碍为主要表现。随着人类寿命的不断延长,人口出现老龄化,阿尔茨海默病已成为继心脑血管疾病、恶性肿瘤、脑卒中之后的第四大老年人疾病杀手,不仅严重威胁老年人的身体健康,也给患者家属和社会带来沉重的经济负担。
阿尔茨海默病的发病机理非常复杂,是多因素相互作用的结果,科学界提出了很多导致阿尔茨海默病发病的机制,如胆碱能降低、淀粉样蛋白毒性、氧化应激及自由基损伤、tau蛋白磷酸化、遗传、炎症等学说。目前美国联邦药品管理局(FDA)批准用于临床的AD治疗药物,主要为乙酰胆碱酯酶抑制剂(他克林、多奈哌齐、加兰他敏和卡巴拉汀),对该疾病有着改善症状和延缓病情的作用。其中,多奈哌齐(临床上用其盐酸盐)是一种长效阿尔茨海默病(AD)治疗药物,其治疗作用是可逆性地抑制乙酰胆碱酯酶(AChE)引起的乙酰胆酰水解而增加受体部位的乙酰胆碱含量。它能明显抑制脑组织中的ChE,但对心脏(心肌)或小肠(平滑肌)无作用,对中枢神经毒性比他克林小。
硒是多种生物学上具有抗氧化特性酶的结构成分。大量研究说明硒化合物具有较强的生物活性,如抗氧化特性,是人和动物所必须的微量元素之一。依布硒啉是一种有机硒化合物,可通过模拟过氧化物酶的功能而显示出抗氧化活性,可作为哺乳动物硫氧还蛋白还原酶的底物,增强硫氧还原蛋白系统抗氧化能力。依布硒啉显示出神经保护作用在临床前期实验和临床研究中。
鉴于老年痴呆的发病机理复杂,病因机制还未完全阐明,因此,设计合成药物分子同时作用于疾病网络中的多个靶点,产生协同效应,达到最佳的治疗效果的多靶点药物分子,是当今药物研究的重要趋势之一。本发明以多奈哌齐为先导化合物,结合依布硒林(Ebselen)的抗氧化等功能团,设计合成了一系列新型的含硒多奈哌齐类似物,期望达到既具有多奈哌齐优良的抑制乙酰胆碱酯酶活性,又具有依布硒林的抗氧化活性,可作为硫氧还蛋白还原酶底物及神经保护作用的特点。
发明内容
本发明的目的之一是提供一类具有乙酰胆碱酯酶抑制活性,抗氧化活性作用的新型含硒多奈哌齐类似物,可用于治疗、改善和/或预防阿尔茨海默病。
本发明的目的之一是是提供所述的含硒多奈哌齐类似物在制备治疗、改善和/或预防阿尔茨海默病药物中的应用。
本发明的目的之一是提供游离形式或盐形式的下式的化合物:
式I中的R1、R2、R3、R4彼此独立的为H、OH、NO2、CN、C1-C4的烷基、被一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基、C1-C4的烷氧基、卤素;
式I中的R5、R6、R7、R8、R9彼此独立的为H、OH、NO2、CN、C1-C4的烷基、被一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基、C1-C4的烷氧基、卤素、NR10R11、COOR12、NHCOR13、NHSO2R14、NHCOOR15;其中R10、R11、R12、R13、R14、R15、彼此独立的为H、C1-C4的烷基、一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基;
式I中的n=0,1,2,3或4;
式I中的X、Y彼此独立的为C、N;
通式I的化合物能够形成酸加成盐,特别是可药用酸加成盐。通式I化合物的可药用酸加成盐包括下述酸的酸加成盐:无机酸,如氢卤酸,如盐酸,氢溴酸或氢碘酸,硝酸、硫酸、磷酸;和有机酸,如甲酸、乙酸、丙酸、丁酸、苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、对氯苯乙酸、二苯基乙酸、1-羟基萘-2-甲酸、3-羟基萘-2-甲酸,脂肪羟基酸如乳酸、柠檬酸、酒石酸或苹果酸,二元羧酸如富马酸、马来酸或琥珀酸,以及磺酸如甲磺酸或苯磺酸。这些盐可根据公知的成盐方法由通式I的化合物制备。
适宜的溶剂化为可作为药用的溶剂化物,优选水合物。
本发明的含硒多奈哌齐类似物可通过化学合成获得。通常本发明的含硒多奈哌齐类似物可通过以下反应式所得。
具体实施上,本发明主要通过先制备苯环上不同取代基的硒氯,然后与相应按文献制备的胺反应得到所设计的目标含硒多奈哌齐类似物。
本发明实施列中也描述了原料的制备。或者可通过现有技术的类似方法获得必须原料。
游离形式、盐形式的通式I的化合物可用作药物。因此本发明也提供了用做药物的游离形式、盐形的通式I的化合物。游离形式、盐形式的通式I的化合物被称为“本发明的试剂”。
本发明还提供上述“本发明的试剂”在制备治疗、改善和/或预防阿尔茨海默病药物中的应用。
本发明还提供一种用于治疗、改善和/或预防阿尔茨海默病的药物组合物;该药物组合物包含上述“本发明的试剂”,选择性地还包含药学上可接受的辅助剂,选择性的还包含乙酰胆碱酯酶抑制剂、抗氧化剂、抗炎剂或者神经保护剂。该药物可以制成注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂的形式使用。其给药途径可为口服、经皮、静脉或肌肉注射。
本发明试剂具有优异的胆碱酯酶(乙酰胆碱酯酶和丁酰胆碱酯酶)抑制活性、清除体内过氧化氢活性、清除过氧亚硝基活性以及模拟谷胱甘肽过氧化物酶过氧化物酶活性和作为硫氧还蛋白还原酶底物参与氧化还原反应的活性。本发明试剂的胆碱酯酶抑制活性采用Ellman法来测试;清除体内过氧化氢活性采用文献报道的Ferrous Oxidation-Xylenol orange Assay(FOX assay)和HorseradishPeroxidase Assay(HRPA)两种不同的方法来评估;清除过氧亚硝基活性参考Balavoineet所报道的方法;本发明试剂模拟谷胱甘肽过氧化物酶的活性测试主要参考Ray J.Butcher文献报道的方法来评估;另外本发明试剂作为硫氧还蛋白还原酶底物参与氧化还原反应的活性通过文献(Neuroscience Letters50320111-5)上报道的办法,ORAC测试参考文献J.Agric.Food Chem.2001,49,4619-4626进行。
本发明的试剂对胆碱酯酶的抑制活性很高,对乙酰胆碱酯酶的抑制活性IC50值大约在0.01-20μM范围内,对丁酰胆碱酯酶的抑制活性IC50值大约在0.4-30μM范围内,化合物17、18、20、21、23、26、28、29和30具有优异的乙酰胆碱酯酶抑制活性,分别达到了28nM、32nM、21nM、35nM、39nM、38nM、33nM、18nM和23nM。化合物15、16、17、22、23、24和30对丁酰胆碱酯酶的抑制活性分别为2.4μM、1.9μM、1.8μM、1.8μM、1.7μM、2.0μM和0.7μM,相应其他化合物的数据结果如表1所示。本发明的试剂对乙酰胆碱酯酶的Lineweaver-Burk曲线结果显示抑制乙酰胆碱酯酶的方式为混合型抑制。本发明的试剂在抗氧化活性测试中同样展现出优越的活性。在抗氧化ORAC测试中,大部分化合物展现出相当的活性,化合物23、24、25、26、31、32和34的抗氧化能力相对于水溶性维生素E分别为0.67、0.68、0.65、0.66、0.65、0.66和0.65。展现出与对照药物水溶性维生素E相比稍低的抗氧化活性。本发明的试剂在清除双氧水的作用上,展现出与对照药物依布硒林相比更加优越的活性,按照FoxAssay在100μM双氧水水平上,加入150μM化合物,作用一段时间后,化合物16、17、18、19、20、21、23、25、26清除双氧水的能力能够达到80%以上,优于相应浓度的依布硒林。同样按照HRPA方法在相同水平上得到相似的实验结果。过氧亚硝基阴离子存在于人体内皮细胞、神经细胞、巨噬细胞、嗜中性细胞,其强氧化及硝化特性可引起细胞内DNA、蛋白质及脂等大分子的损伤,使细胞的代谢发生障碍及能量耗竭,导致细胞凋亡、损伤,甚至死亡,本发明的试剂采用Balavoineet所报道的方法测得具有一定的清除过氧亚硝基阴离子活性,大部分化合物展现出与依布硒林相当甚至更高的活性,在相同过氧亚硝基浓度水平上,优选化合物之一18清除过氧亚硝基的活性kTC/kEB值为3.28,是对照药物依布硒林的1.5倍。硒作为多种生物学上具有抗氧化特性酶的结构成分,使大部分含硒化合物也具有相应的生物功能。本发明的试剂基于依布硒林可模拟谷胱甘肽过氧化物酶活性,也按照Ray J.Butcher文献报道的方法评估其模拟谷胱甘肽过氧化物酶的活性,大部分化合物展现出一定的谷胱甘肽过氧化物酶模拟活性,结果如表1所示。硫氧还蛋白还原酶同样属于硒酶家族中的一种,能够有效地调节生物体内的氧化还原反应,通过文献报道的方法测试发现,本发明的试剂可以有效的作为硫氧还蛋白还原酶的底物来参与生物体内的氧化还原反应,从而起到抗氧化的作用。本发明的试剂优选16、17、18、20、21、22、23、24和依布硒林参考文献(Neuroscience Letters2011,503,1-5)方法测得其作为硫氧还蛋白还原酶底物活性对比空白依次为1.6、1.8、3.5、3.7、3.4、3.4、3.2、3.3和3.3。大部分化合物具有依布硒林相似的活性。
具体实施方式
以下为部分优选化合物的具体实施方式,只说明本发明,但并不限制本发明。
概要
不同取代的邻氨基苯甲酸来自于商品化或经过相应的邻硝基苯甲酸还原制得。根据相关文献制得4-氨基-1-苄基哌啶(European Journal ofMedicinal Chemistry,45,2827-2840;2010)、1-(1-苄基哌啶-4-基)甲胺(Journal of Medicinal Chemistry,42,730-741;1999)、1-(1-苄基哌啶-4-基)乙胺、1-(1-苄基哌啶-4-基)丁胺(Bioorganic&Medicinal Chemistry Letters,14,4639-4642;2004)、1-(1-苄基哌啶-4-基)丙胺(European Journal of Medicinal Chemistry,46(9),4665-4668;2011)、2-(4-苄基哌嗪基)乙基-1-胺(Journal ofMedicinal Chemistry,48,792-804;2005)、2-(4-苄基哌嗪基)丙基-1-胺(Journal of Medicinal Chemistry,39(7),1514-20;1996)、2-[1-(2-甲基苄基)哌啶-4-基]乙胺、2-[1-(3-甲基苄基)哌啶-4-基]乙胺、2-[1-(4-甲基苄基)哌啶-4-基]乙胺、2-[1-(3-氯苄基)哌啶-4-基]乙胺、2-[1-(3-溴苄基)哌啶-4-基]乙胺、2-[1-(4-硝基苄基)哌啶-4-基]乙胺、3-((4-(2-氨乙基)哌啶-1-基)甲基)-N,N-二甲基苯胺(Australian Journal of Chemistry,42(7),1133-46;1989)、3-((4-(2-氨乙基)哌啶-1-基)甲基)-N,N-二甲基苯胺、甲基-3-((4-(2-氨乙基)哌啶-1-基)甲基)苯甲酸酯、N-(3-((4-(2-氨乙基)哌啶-1-基)甲基)苯基)乙酰胺、N-(3-((4-(2-氨乙基)哌啶-1-基)甲基)苯基)甲基磺酰胺和甲基-3-((4-(2-氨乙基)哌啶-1-基)甲基)苯胺基甲酸酯均由相应取代基的苄溴/氯与哌啶酮反应,然后按照(Bioorganic&MedicinalChemistry Letters,14,4639-4642;2004)制得。
实施例1 2,2’-二硒二苯甲酸
在100mL的圆底烧瓶中加入KBH4(0.89g,16.5mmol)、NaOH(3.2g,80mmol)和PEG600(0.2g)和水50mL。搅拌均匀后,加入硒粉(3.95g,50mmol),升至75℃搅拌30min,冷却后加40%NaOH38mL即制得Na2Se2溶液,待用。
另外,在100mL的圆底烧瓶中加入邻氨基苯甲酸(6.85g,50mmol)和6N HCl20mL,加一定量水溶解完全后,放置冰水浴中,,将亚硝酸钠(3.5g,50.7mmol)的水溶液缓慢滴加到上述溶液中,控制反应温度0-5℃,搅拌30min,即制得相应的重氮盐溶液,待用。
在0-5℃条件下,将制得的重氮盐溶液缓慢滴加到Na2Se2溶液中,然后缓慢升至60℃反应2.5h,冷却后抽滤,滤液调酸,析出大量固体,抽滤,固体用饱和碳酸氢钠溶液溶解,煮沸1h,抽滤,滤液再调酸,抽滤得到的固体,真空干燥后得灰褐色目标化合物8.24g,产率:82%。
实施例2 2,2’-二硒二-4-氟苯甲酸
具体实施步骤同实施例1,采用4-氟-2-氨基苯甲酸为原料。产率:86%。
实施例3 2,2’-二硒二-4-氯苯甲酸
具体实施步骤同实施例1,采用4-氯-2-氨基苯甲酸为原料。产率:80%。
实施例4 2,2’-二硒二-5-甲氧基苯甲酸
具体实施步骤同实施例1,采用5-甲氧基-2-氨基苯甲酸为原料。产率:73%。
实施例5 2,2’-二硒二-3,4,3’,4’-二甲氧基苯甲酸
具体实施步骤同实施例1,采用3,4-二甲氧基-2-氨基苯甲酸为原料。产率:68%。
实施例6 2,2’-二硒二-3,4,5,3’,4’,5’-三甲氧基苯甲酸
具体实施步骤同实施例1,采用3,4,5-三甲氧基-2-氨基苯甲酸为原料。产率:58%。
实施例7 4-苯并硒唑[d][1,2]-3(2H)-酮-1-苄基哌啶(1)
在25mL的圆底烧瓶中加入2,2’-二硒二苯甲酸(2.0g,5mmol),加入二氯亚砜10mL,加热回流2h,反应完毕,减压除去多余的二氯亚砜,即制得相应的硒氯,待用,不需纯化直接进行下一步反应。
在50mL的圆底烧瓶中加入4-氨基-1-苄基哌啶(0.95g,5mmol),干燥的二氯甲烷10mL,干燥的三乙胺(1.0g,10mmol),氩气保护,将现制备的硒氯溶于干燥的二氯甲烷中,冰水浴下,注射加入到上述溶液中,搅拌反应5h,反应完毕,加水,分液,水相用二氯甲烷洗涤2次,合并,干燥,浓缩得黄色油状物,柱层析纯化得到19a,1.4g,产率:76%。1H NMR(400MHz,CDCl3)δ8.04(d,J=7.7Hz,1H),7.63(d,J=7.9Hz,1H),7.59-7.54(m,1H),7.41(t,J=7.1Hz,1H),7.33(d,J=4.3Hz,4H),7.28(d,J=4.0Hz,1H),4.52(tt,J=11.5,4.2Hz,1H),3.54(s,2H),3.00(d,J=11.9Hz,2H),2.25-2.15(m,2H),2.08-2.01(m,2H),1.77(ddd,J=24.1,12.1,3.8Hz,2H).
实施例8 4-(4-氟-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(2)
具体实施步骤同实施例7,得目标化合物,产率:62%。1H NMR(400MHz,CDCl3)δ8.00(dd,J=8.6,5.2Hz,1H),7.32(t,J=4.3Hz,5H),7.28(d,J=3.9Hz,1H),7.12(td,J=8.6,2.1Hz,1H),4.50(tt,J=11.4,4.2Hz,1H),3.54(s,2H),2.99(d,J=11.9Hz,2H),2.19(t,J=11.0Hz,2H),2.04(d,J=9.9Hz,2H),1.75(ddd,J=23.8,11.9,3.7Hz,2H).
实施例9 4-(4-氯-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(3)
具体实施步骤同实施例7,得目标化合物,产率:70%。1H NMR(400MHz,CDCl3)δ7.94(d,J=8.4Hz,1H),7.63(s,1H),7.38(d,J=8.4Hz,1H),7.31(dd,J=19.5,4.2Hz,5H),4.55-4.45(m,1H),3.54(s,2H),2.99(d,J=12.0Hz,2H),2.19(t,J=11.3Hz,2H),2.04(d,J=10.2Hz,2H),1.75(dt,J=11.8,8.3Hz,2H).
实施例10 4-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(4)
具体实施步骤同实施例7,得目标化合物,产率:70%。1H NMR(400MHz,CDCl3)7.48(m,3H),7.31(dd,J=19.5,4.2Hz,5H),4.5(s,1H),3.82(s,3H),3.54(s,2H),2.96(d,J=12.0Hz,2H),2.19(t,J=11.3Hz,2H),2.01(d,J=10.2Hz,2H),1.72(dt,J=11.8,8.3Hz,2H).
实施例11 4-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(5)
具体实施步骤同实施例7,得目标化合物,产率:58%。1H NMR(400MHz,CDCl3)δ7.47(d,J=3.6Hz,1H),7.31(d,J=26.4Hz,5H),7.05(s,1H),4.49(s,1H),3.96(s,6H),3.55(d,J=3.5Hz,2H),3.00(d,J=10.0Hz,2H),2.21(t,J=10.8Hz,2H),2.03(s,2H),1.76(d,J=12.1Hz,2H).
实施例11 4-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(6)
具体实施步骤同实施例7,得目标化合物,产率:70%。[M+1]+=464.2+
实施例12 4-甲基-(苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(7)
具体实施步骤同实施例7,得目标化合物.产率:71%。1H NMR(400MHz,CDCl3)δ8.04(d,J=7.9Hz,1H),7.59(q,J=7.9Hz,2H),7.41(t,J=7.2Hz,1H),7.29(d,J=3.1Hz,4H),7.23(d,J=3.4Hz,1H),3.74(d,J=5.6Hz,2H),3.49(s,2H),2.87(d,J=11.2Hz,2H),1.96(t,J=11.5Hz,2H),1.81-1.66(m,3H),1.41(dd,J=22.3,11.1Hz,2H).
实施例13 4-甲基-(4-氟苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(8)
具体实施步骤同实施例7,得目标化合物,产率:66%。1H NMR(400MHz,CDCl3)δ8.00(dd,J=8.5,5.3Hz,1H),7.36-7.26(m,5H),7.25-7.20(m,1H),7.13(t,J=8.6Hz,1H),3.72(d,J=6.8Hz,2H),3.49(s,2H),2.88(d,J=11.2Hz,2H),1.96(t,J=11.5Hz,2H),1.71(d,J=11.7Hz,3H),1.40(dd,J=21.9,10.6Hz,2H).
实施例14 4-甲基-(4-氯苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(9)
具体实施步骤同实施例7,得目标化合物,产率:58%。1H NMR(400MHz,CDCl3)δ7.95(dd,J=8.2,3.6Hz,1H),7.62(d,J=1.8Hz,1H),7.43-7.36(m,1H),7.34-7.23(m,5H),3.73(d,J=2.9Hz,2H),3.49(d,J=3.3Hz,2H),2.88(d,J=9.5Hz,2H),1.96(t,J=11.3Hz,2H),1.71(d,J=13.9Hz,3H),1.40(dd,J=23.6,11.7Hz,2H).
实施例15 4-甲基-(5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(10)
具体实施步骤同实施例7,得目标化合物,产率:58%。1H NMR(400MHz,CDCl3)δ7.85(dd,J=8.2,3.6Hz,1H),7.52(d,J=1.8Hz,1H),7.40(m,1H),7.34-7.23(m,5H),3.84(s,3H),3.71(d,J=2.9Hz,2H),3.47(d,J=3.3Hz,2H),2.80(d,J=9.7Hz,2H),1.90(t,J=11.6Hz,2H),1.74(d,J=14.9Hz,3H),1.46(dd,J=22.6,11.7Hz,2H).
实施例16 4-甲基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(11)
具体实施步骤同实施例7,得化合物,产率:60%。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.30(d,J=4.4Hz,4H),7.24(d,J=3.5Hz,1H),7.03(s,1H),3.96(d,J=2.0Hz,6H),3.72(d,J=6.5Hz,2H),3.49(s,2H),2.88(d,J=11.6Hz,2H),1.97(t,J=11.4Hz,2H),1.72(d,J=13.4Hz,3H),1.41(dd,J=22.1,10.8Hz,3H).
实施例17 4-甲基-(3,4-5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(12)
具体实施步骤同实施例7,得目标化合物,产率:67%。[M+1]+=478.1+
实施例18 4-乙基-(苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(13)
具体实施步骤同实施例7,得化合物,产率:66%。1H NMR(400MHz,CDCl3)δ8.03(d,J=7.8Hz,1H),7.66-7.54(m,2H),7.42(t,J=7.4Hz,1H),7.30(d,J=4.4Hz,4H),7.24(dd,J=9.1,4.3Hz,1H),3.89(t,J=7.3Hz,2H),3.48(s,2H),2.87(d,J=11.7Hz,2H),1.94(t,J=11.1Hz,2H),1.74(d,J=10.3Hz,2H),1.66(dd,J=13.8,6.7Hz,2H),1.37-1.27(m,3H).
实施例19 4-乙基-(4-氟苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(14)
具体实施步骤同实施例7,得化合物,产率:65%。1H NMR(400MHz,CDCl3)δ8.00(dd,J=8.5,5.4Hz,1H),7.31(dd,J=15.1,2.4Hz,5H),7.14(dd,J=9.8,7.5Hz,2H),3.87(t,J=7.2Hz,2H),3.48(s,2H),2.87(d,J=10.6Hz,2H),1.94(t,J=10.9Hz,2H),1.73(d,J=10.4Hz,2H),1.66(s,2H),1.39-1.29(m,3H).
实施例20 4-乙基-(4-氯苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(15)
具体实施步骤同实施例7,得化合物,产率:64%。1H NMR(400MHz,CDCl3)δ7.94(d,J=8.1Hz,1H),7.65(d,J=22.8Hz,1H),7.39(s,1H),7.29(s,4H),7.25(s,1H),3.87(d,J=6.7Hz,2H),3.47(s,2H),2.86(s,2H),1.93(s,2H),1.71(s,2H),1.62(s,4H),1.33(s,3H).
实施例21 4-乙基-(3-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(16)
具体实施步骤同实施例7,得化合物,产率:64%。1H NMR(400MHz,CDCl3)δ7.85(d,J=8.0Hz,1H),7.75(d,J=21.8Hz,1H),7.37(s,1H),7.29(s,4H),7.25(s,1H),3.87(m,5H),3.46(s,2H),2.89(s,2H),1.90(s,2H),1.76(s,2H),1.65(s,4H),1.35(s,3H).
实施例22 4-乙基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(17)
具体实施步骤同实施例7,得目标化合物,产率:59%。1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.30(d,J=4.3Hz,4H),7.25-7.22(m,1H),7.04(s,1H),3.96(d,J=3.0Hz,6H),3.87(t,J=7.2Hz,2H),3.48(s,2H),2.87(d,J=11.7Hz,2H),1.94(t,J=11.2Hz,2H),1.74(d,J=10.4Hz,2H),1.68-1.65(m,2H),1.37-1.29(m,3H).
实施例23 4-乙基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(18)
具体实施步骤同实施例7,得目标化合物,产率:52%。[M+1]+=492.2+
实施例24 2-[2-(4-苄基哌嗪-1-基)乙基]-5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮(19)
具体实施步骤同实施例7,得目标化合物,产率:70%。[M+1]+=433.3+
实施例25 2-[2-(4-苄基哌嗪-1-基)乙基]-3,4-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮(20)
具体实施步骤同实施例7,得目标化合物,产率:66%。[M+1]+=463.3+
实施例26 2-[2-(4-苄基哌嗪-1-基)乙基]-3,4-5-三甲氧基苯并硒唑[d][1,2]-3(2H)-酮(21)
具体实施步骤同实施例7,得目标化合物,产率:60%。[M+1]+=493.2
实施例27 4-丙基-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(22)
具体实施步骤同实施例7,得目标化合物,产率:52%。[M+1]+=446.1+
实施例28 4-丙基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(23)
具体实施步骤同实施例7,得目标化合物,产率:57%。1H NMR(400MHz,CDCl3)δ7.47(d,J=3.1Hz,1H),7.30(d,J=4.2Hz,4H),7.27(d,J=3.2Hz,1H),7.04(d,J=3.1Hz,1H),3.96(d,J=2.8Hz,6H),3.81(s,2H),3.48(d,J=2.9Hz,2H),2.86(d,J=10.3Hz,2H),1.93(t,J=9.9Hz,2H),1.72(s,2H),1.65(s,4H),1.29(m,3H).
实施例29 4-丙基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(24)
具体实施步骤同实施例7,得目标化合物,产率:48%。[M+1]+=506.2+
实施例30 2-[2-(4-苄基哌嗪-1-基)丙基]-5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮(25)
具体实施步骤同实施例7,得目标化合物,产率:54%。[M+1]+=447.2+
实施例31 2-[2-(4-苄基哌嗪-1-基)丙基]-3,4-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮(26)
具体实施步骤同实施例7,得目标化合物,产率:54%。[M+1]+=477.1+
实施例32 2-[2-(4-苄基哌嗪-1-基)丙基]-3,4,5-三甲氧基苯并硒唑[d][1,2]-3(2H)-酮(27)
具体实施步骤同实施例7,得目标化合物,产率:54%。[M+1]+=507.1+
实施例33 4-丁基-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(28)
具体实施步骤同实施例7,得目标化合物,产率:50%。[M+1]+=460.2+
实施例34 4-丁基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(29)
具体实施步骤同实施例7,得目标化合物,产率:53%。1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.30(d,J=3.8Hz,4H),7.26-7.20(m,1H),7.04(s,1H),3.95(s,6H),3.82(t,J=7.0Hz,2H),3.47(s,2H),2.85(d,J=10.3Hz,2H),1.92(d,J=8.9Hz,3H),1.74-1.59(m,4H),1.39(s,3H).
实施例35 4-丁基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶(30)
具体实施步骤同实施例7,得目标化合物,产率:38%。[M+1]+=520.1+
实施例36 5,6-二甲氧基-2-{2-[1-(2-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(31)
具体实施步骤同实施例7,得目标化合物,产率:48%。[M+1]+=476.1+
实施例37 5,6-二甲氧基-2-{2-[1-(3-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(32)
具体实施步骤同实施例7,得目标化合物,产率:38%。1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.31(d,J=4.2Hz,4H),7.25-7.25(m,1H),7.01(s,1H),3.99(d,J=3.0Hz,6H),3.88(t,J=7.1Hz,2H),3.50(s,2H),2.28(s,3H),2.81(d,J=11.8Hz,2H),1.91(t,J=11.4Hz,2H),1.76(d,J=10.6Hz,2H),1.66-1.60(m,2H),1.47-1.32(m,3H).[M+1]+=476.1+
实施例38 5,6-二甲氧基-2-{2-[1-(4-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(33)
具体实施步骤同实施例7,得目标化合物,产率:40%。[M+1]+=476.1+
实施例39 5,6-二甲氧基-2-{2-[1-(3-氯苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(34)
具体实施步骤同实施例7,得目标化合物,产率:48%。[M+1]+=495.9+
实施例40 5,6-二甲氧基-2-{2-[1-(3-溴苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(35)
具体实施步骤同实施例7,得目标化合物,产率:42%。1H NMR(400MHz,CDCl3)δ7.53(s,1H),7.42(d,J=4.3Hz,4H),6.98(s,1H),3.86(d,J=3.0Hz,6H),3.81(t,J=7.1Hz,2H),3.48(s,2H),2.80(d,J=10.7Hz,2H),1.92(t,J=10.2Hz,2H),1.70(d,J=11.4Hz,2H),1.69-1.65(m,2H),1.47-1.39(m,3H).
实施例41 5,6-二甲氧基-2-{2-[1-(3-硝基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮(36)
具体实施步骤同实施例7,得目标化合物,产率:42%。1H NMR(400MHz,CDCl3)δ8.13-7.61(m,4H),7.0-6.91(m,2H),3.9(d,J=3.0Hz,2H),3.81(s,6H),3.68(s,2H),1.9(m,1H),1.78-1.71(m,4H),1.73(d,J=10.4Hz,2H),1.60-1.57(m,2H),1.33-1.21(m,2H).[M+1]+=507.1+
实施例42 2-(2-{1-[3-(二甲氨基)苯基]哌啶-4-基}乙基)-5,6-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮(37)
具体实施步骤同实施例7,得目标化合物,产率:50%。1H NMR(400MHz,CDCl3)δ7.49(s,1H),7.20(d,J=4.3Hz,4H),7.01(s,1H),3.86(d,J=3.0Hz,6H),3.87(t,J=7.2Hz,2H),3.50(s,2H),3.04(s,6H),2.87(m,2H),1.90(t,J=11.2Hz,2H),1.71(m,2H),1.68-1.65(m,2H),1.38-1.27(m,3H).[M+1]+=505.1+
实施例43 甲基-3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯氨基甲酸酯(38)
具体实施步骤同实施例7,得目标化合物,产率:54%。1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.32(d,J=4.2Hz,4H),7.08(s,1H),3.77(d,J=2.9Hz,6H),3.89(t,J=7.0Hz,2H),3.44(s,2H),2.89(m,2H),2.11(s,3H),1.88(t,J=10.2Hz,2H),1.70(m,2H),1.64-1.60(m,2H),1.35-1.27(m,3H).[M+1]+=535.1+
实施例44 N-(3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯基)甲基磺酰胺(39)
具体实施步骤同实施例7,得目标化合物,产率:47%。1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.98(d,J=4.0Hz,4H),7.18(s,1H),3.87(d,J=2.7Hz,6H),3.84(t,J=7.5Hz,2H),3.48(s,2H),3.10(m,2H),2.97(s,3H),1.89(t,J=10.2Hz,2H),1.76(m,2H),1.67-1.61(m,2H),1.45-1.37(m,3H).[M+1]+=555.1+
实施例45 N-(3-(4{-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯基)乙酰胺(40)
具体实施步骤同实施例7,得目标化合物,产率:52%。1H NMR(400MHz,CDCl3)δ7.55-7.54(m,1H),7.51-7.48(m,3H),7.12-7.08(s,1H),7.01-6.91(m,1H),3.89(t,J=7.0Hz,2H),3.82(s,6H),3.38(m,2H),2.60-2.51(m,2H),2.08(s,3H),1.88(t,J=10.2Hz,2H),1.69(m,2H),1.66-1.60(m,2H),1.33-1.25(m,3H).[M+1]+=519.1+
实施例46 甲基-3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯甲酸酯(41)
具体实施步骤同实施例7,得目标化合物,产率:38%。1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.78(d,J=3.9Hz,4H),7.19(s,1H),3.89(d,J=2.5Hz,6H),3.83(t,J=7.6Hz,2H),3.45(s,2H),3.08(m,2H),2.90(s,3H),1.87(t,J=10.8Hz,2H),1.79(m,2H),1.67-1.60(m,2H),1.48-1.35(m,3H).[M+1]+=520.1+
Claims (7)
1.游离形式、盐形式或溶剂化物形式的下列式I所示的含硒多奈哌齐类似物:
式I中的R1、R2、R3、R4彼此独立的为H、OH、NO2、CN、C1-C4的烷基、被一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基、C1-C4的烷氧基、卤素;
式I中的R5、R6、R7、R8、R9彼此独立的为H、OH、NO2、CN、C1-C4的烷基、被一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基、C1-C4的烷氧基、卤素、NR10R11、COOR12、NHCOR13、NHSO2R14、NHCOOR15;其中R10、R11、R12、R13、R14、R15、彼此独立的为H、C1-C4的烷基、一个或多个卤原子或一个或多个羟基或C1-C4的烷氧基取代的C1-C4的烷基;
式I中的n=0,1,2,3或4;
式I中的X、Y彼此独立的为C、N。
2.根据权利要求1的化合物,其为选自下述的化合物:
4-苯并硒唑[d][1,2]-3(2H)-酮-1-苄基哌啶,
4-(4-氟-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-(4-氯-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(4-氟苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(4-氯苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-甲基-(3,4-5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(4-氟苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(4-氯苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(3-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-乙基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
2-[2-(4-苄基哌嗪-1-基)乙基]-5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
2-[2-(4-苄基哌嗪-1-基)乙基]-3,4-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
2-[2-(4-苄基哌嗪-1-基)乙基]-3,4-5-三甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
4-丙基-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-丙基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-丙基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
2-[2-(4-苄基哌嗪-1-基)丙基]-5-甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
2-[2-(4-苄基哌嗪-1-基)丙基]-3,4-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
2-[2-(4-苄基哌嗪-1-基)丙基]-3,4,5-三甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
4-丁基-(5-甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-丁基-(3,4-二甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
4-丁基-(3,4,5-三甲氧基-苯并硒唑[d][1,2]-3(2H)-酮)-1-苄基哌啶,
5,6-二甲氧基-2-{2-[1-(2-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
5,6-二甲氧基-2-{2-[1-(3-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
5,6-二甲氧基-2-{2-[1-(4-甲基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
5,6-二甲氧基-2-{2-[1-(3-氯苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
5,6-二甲氧基-2-{2-[1-(3-溴苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
5,6-二甲氧基-2-{2-[1-(3-硝基苄基)哌啶-4-基]乙基}苯并硒唑[d][1,2]-3(2H)-酮,
2-(2-{1-[3-(二甲氨基)苯基]哌啶-4-基}乙基)-5,6-二甲氧基苯并硒唑[d][1,2]-3(2H)-酮,
甲基-3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯氨基甲酸酯,
N-(3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯基)甲基磺酰胺,
N-(3-(4{-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯基)乙酰胺,
甲基-3-({4-[2-(5,6-二甲氧基-3-苯并硒唑[d][1,2]-3(2H)-酮)乙基]哌啶-1-基}甲基)苯甲酸酯。
3.权利要求1所述的盐形式式I化合物,其特征在于所示盐形式为以下之一:盐酸、氢溴酸、氢碘酸,硝酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、苯甲酸、邻羟基苯甲酸、对羟基苯甲酸、对氯苯乙酸、二苯基乙酸、1-羟基萘-2-甲酸、3-羟基萘-2-甲酸、乳酸、柠檬酸、酒石酸或、苹果酸、富马酸、马来酸、琥珀酸、甲磺酸或苯磺酸。
4.权利要求1所述的化合物在制备治疗、改善和/或预防阿尔茨海默病药物中的应用。
5.一种用于治疗、改善和/或预防阿尔茨海默病的药物组合物,其包含权利要求1所述化合物,选择性地还包含药学上可接受的辅助剂。
6.权利要求5所述的药物组合物,选择性的还包含乙酰胆碱酯酶抑制剂、抗氧化剂、抗炎剂或神经保护剂。
7.权利要求5所述的药物组合物,其特征是该药物组合物为注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂。
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