CN117024326A - 5位氨基取代吲哚化合物及其制备方法和在抗乙酰胆碱酯酶药物中的应用 - Google Patents
5位氨基取代吲哚化合物及其制备方法和在抗乙酰胆碱酯酶药物中的应用 Download PDFInfo
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- CN117024326A CN117024326A CN202310924484.8A CN202310924484A CN117024326A CN 117024326 A CN117024326 A CN 117024326A CN 202310924484 A CN202310924484 A CN 202310924484A CN 117024326 A CN117024326 A CN 117024326A
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- indole
- carbaldehyde
- tosyl
- sulfonyl
- amino
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Abstract
本发明涉及生物医药技术领域,公开了5位氨基取代吲哚化合物及其制备方法和在抗乙酰胆碱酯酶药物中的应用。以4位碘代吲哚位原料,通过钯催化Catellani反应,制备得到5位氨基取代吲哚化合物;其反应收率可达到中等到优秀,反应的化学选择性和区域选择性优秀,反应条件温和,底物的适用范围广;其操作简便、成本较低、副反应少、产品纯度高、便于分离提纯和适用于较大规模的制备;所得的产物具有非常好的生物医药领域的应用前景,尤其具有较好的抗乙酰胆碱酯酶活性。
Description
技术领域
本发明涉及生物医药技术领域,更具体地,涉及5位氨基取代吲哚化合物及其制备方法和在抗乙酰胆碱酯酶药物中的应用。
背景技术
吲哚是一类重要的核心骨架,在众多天然产物和具有重要的生理和药物活性的药物分子中普遍存在(Z.K.Poulíková,S.Mani,Eur.J.Med.Chem.2021,215,113231;Y.Han,W.Dong,Q.Guo,X.Li,L.Huang,Eur.J.Med.Chem.2020,203,112506;Y.Wan,Y.Li,C.Yan,M.Yan,Z.Tang,Eur.J.Med.Chem.2019,183,111691;P.V.Thanikachalam,R.K.Maurya,V.Garg,V.Monga,Eur.J.Med.Chem.2019,180,111691;562-612;A.Kumari,R.K.Singh,Bioorganic Chemistry,2019,89,103021;N.Chadha,O.Silakari,EuropeanJournal ofMedicinal Chemistry,2017,134,159-184;A.J.Kochanowska-Karamyan,M.T.Hamann,Chem.Rev.2010,110,4489-4497;R.J.Sundberg,Indoles,AcademicPress,SanDiego,1996)。在众多的吲哚衍生物中,3,5-二取代吲哚是一类特殊的结构,构成了很多市售药物的核心组成部分(Y.Wu,Top Heterocycl.Chem.2010,26,1-29)。例如:舒马普坦,商品名英明格,是一类抗偏头痛新药,是高度选择性5-羟色胺受体(5-HT)激动剂,逆转偏头痛时颅内血管扩张,减轻血浆蛋白外渗,从而改善脑血流量,缓解偏头痛的症状。通过收缩脑血管、抑制周围神经和“三叉神经颈复合体”二级神经元的神经痛觉传递,进而发挥止痛作用。用于偏头痛急性发作(无论有无发作先兆症状)的治疗。口服起效快于麦角胺咖啡因,有效率达66%;还可用于丛集性头痛的治疗,15~30分钟的有效率达74%~77%。阿莫曲普坦,同样是一类选择性5-羟色胺受体激动剂的药物。它的作用是缩小大脑中的血管,阻止疼痛信号被送到大脑,并停止释放某些导致疼痛,恶心和偏头痛症状的天然物质,但不能预防偏头痛发作。佐米曲普坦被用于治疗真性月经期偏头痛非常有效,病人能很好耐受性。那拉曲坦表现出与舒马普坦相似的体外药理作用,但是效力更强。维拉佐酮是由美国TrovisPharmaceuticalsLLC公司开发的一种具有双重作用的选择性5-羟色胺再摄取抑制剂和5-HT1A受体部分激动剂。主要用做治疗成年人中重度抑郁症。扎鲁司特是一种口服白三烯受体拮抗剂(LTRA),用于哮喘的维持治疗,通常与吸入的类固醇和/或长效支气管扩张剂联合使用,阻断半胱氨酰白三烯对CysLT1受体的作用,从而减少气道收缩,肺部粘液积聚和呼吸道的炎症。是一种口服有效的5-羟色胺受体4(HTR4;5-HT4R)激动剂和5-HT2B受体拮抗剂。替加色罗,别名泽马可对人重组5-HT2A、5-HT2B和5-HT2C受体的pKis分别为7.5、8.4和7.0,通过激活胃肠道5-HT4受体而刺激胃肠蠕动反射和肠道分泌,用于女性便秘型肠易激综合征(IBS-C)缓解症状的短期治疗。并具有抗肿瘤活性,有效减弱PI3K/Akt/mTOR信号传导并降低S6磷酸化,导致肿瘤细胞凋亡。
鉴于3,5-二取代吲哚化合物的主要药学应用,有机合成化学家和药物合成化学家投入大量时间精力,寻求简便高效的合成方法。通常有两种办法构建3,5-二取代吲哚,其一是选择合适原料,在构建吲哚环时引入想要的取代基,但这些取代基的影响往往会导致成环效率和选择性降低;另一种是通过碳氢键直接官能化进行后期修饰,在特定位置选择性引入想要的官能团。得益于近二十年碳氢键活化的发展,反应底物不需要预活化,具有选择性好,效率高等优点。碳氢活化策略大大提高了反应的原子经济性和步骤经济性,极大地增强了在有机合成和药物化学中实际应用(P.H.Dixneuf,H.Doucet(Eds.),C–HBondActivation and Catalytic Functionalization,Topics in Current Chemistry,Springer,Heidelberg,Germany,2016;J.Q.Yu,Z.J.Shi(Eds.),C–H Activation,Topicsin Current Chemistry,Springer,Heidelberg,Germany,2010)。目前已经建立了完善的体系,通过吲哚1号位导向基可以实现2位和7位选择性官能化,通过吲哚1号位导向基可以实现2位和4位选择性官能化,吲哚3号位由于自身的电负性,导致反应活性高,易于进行衍生化反应。而相比之下,吲哚5位和6位则缺乏系统成熟的衍生化策略(J.Wen,Z.Shi,Acc.Chem.Res.2021,54,1723-1736;B.Prabagar,Youqing Yang,Z.Shi,Chem.Soc.Rev.2021,50,11249-11269;J.A.Leitch,Y.Bhonoah,C.G.Frost,ACSCatal.2017,7,5618-5627)。仅有少数几个例子实现了吲哚5位选择性官能化,例如:德国马尔堡大学李书明教授课题组采用酶催化,实现L-色氨酸及其类似物的5位苄基化(M.Liebhold,S.Li,Org.Lett.2013,15,5834-5837);南京大学史壮志教授课题组采用4位大位阻酮协助的铜催化体系,对吲哚-3-酮底物进行5位芳基化(Y.Yang,P.Gao,Y.Zhao,Z.Shi,Angew.Chem.Int.Ed.2017,56,3966-3971)。另一条曲线救国的办法是先将吲哚进行氢化变成吲哚啉,再利用苯胺对位富电子特性,进行官能化之后再重新氧化芳构化回到吲哚结构。但这些反应局限于碳碳键的生成,尚无生成碳氮键的相关报道。并且多余的氧化还原步骤,低的原子经济性,亲电反应特性的限制,无疑阻碍了该方法的实用性。因此迫切需要开发新的方法,进行吲哚环5位选择性修饰,高效合成5位氨基取代吲哚化合物。
本申请的发明人长期从事吲哚杂环化学的研究,之前发展了数个吲哚杂环高效构建方法,例如,本申请的发明人发展了铜催化邻溴苯甲醛和甘氨酸酯盐酸盐一锅法可以合成得到2-羧酸酯取代的吲哚化合物,在温和的反应条件下获得了中等到优良的产率(Z.Zhu,J.Yuan,Y.Zhou,Q.Yang,J.Xu,Y.Peng,Eur.J.Org.Chem.2014,511-514);从乙酰苯胺和三氟甲基取代苯乙炔出发,通过铑催化一步碳氢活化氧化环化,可以高效制备三氟甲基取代吲哚化合物(Y.Zhou,C.Zhang,J.Yuan,Q.Yang,Q.Xiao,Y.Peng,TetrahedronLett.2016,57,3222-3225)。此外,本申请的发明人还采用临时导向基团基团策略,通过钯催化,实现吲哚4位卤代反应,可以将氯、溴、碘三种卤素原子在统一的标准条件下成功引入吲哚苯环骨架(G.Kuang,D.Liu,X.Chen,G.Liu,Y.Fu,Y.Peng,H.Li,Y.Zhou,Org.Lett.2021,23,8402-8406)。
发明内容
基于以上前期研究工作基础,本申请的发明人进一步利用钯和降冰片烯共催化策略,通过4位碘代或者溴代吲哚和氧化胺的Catellani反应,成功合成5位氨基取代吲哚化合物。进一步生物活性测试表明上述合成的5位氨基取代吲哚化合物具有较好的抗乙酰胆碱酯酶活性,有望开发新型抗乙酰胆碱酯酶药物。
鉴于此,本发明的目的在于提供5位氨基取代吲哚化合物,并提供一种全新的5位氨基取代吲哚化合物的制备方法,以及通过活性筛选、构效关系分析、深入的作用和机制研究对5位氨基取代吲哚化合物进行抗乙酰胆碱酯酶活性评价。
本发明的一个方面提供了式I或式II所示的5位氨基取代吲哚化合物:
其中,
R1、R2独立地选自C1~C7烷基、苯基、萘基、苄基;
R3选自醛基、酰胺基、酯基、羟甲基、酯甲基;
R4选自芳基磺酰基;
A环选自吗啉、硫代吗啉、哌嗪、吡咯烷、哌啶、六亚甲基亚胺;
R5选自氢、C1~C7烷基、芳基、芳酰基、苄氧羰基、烷氧羰基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基。
优选地,R1、R2独立地选自甲基、乙基、苯基、萘基、苄基;R3选自甲醛基、N,N-二乙基甲酰胺基、乙氧羰基、羟甲基、乙酯基甲基;R4选自苯磺酰基、4-氟苯磺酰基、4-氯苯磺酰基、4-溴苯磺酰基、4-叔丁基苯磺酰基、4-甲氧基苯磺酰基、4-三氟甲基苯磺酰基、4-硝基苯磺酰基、3-氯苯磺酰基;R5选自氢、甲基、乙基、苯基、萘基、苯甲酰基、苄氧羰基、叔丁氧基羰基、乙氧羰基甲基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基。
优选地,式I或式II所示的5位氨基取代吲哚化合物具体为下列化合物之一:
其中,TJ-1为[5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-2为[5-硫代吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-3为[5-(4-苯甲酰基哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-4为[4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸苄酯];TJ-5为[4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸叔丁酯];TJ-6为[4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸乙酯];TJ-7为[5-(吡咯烷-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-8为[5-(哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-9为[5-(六亚甲基亚胺-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-10为[5-(4-甲基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];TJ-11为[5-(4-苯基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];TJ-12为[1-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌啶-4-羧酸乙酯];
TJ-13为[5-(1,4-二氧-8-氮杂螺[4.5]癸-8-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-14为[5-(3,4-二氢异喹啉-2(1H)-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-15为[5-(二乙基氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-16为[5-(苄基(甲基)氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-17为[5-(4-((双苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];TJ-18为[5-(4-(双(4-氟苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-19为[5-(4-((4-氯苯基)(苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];TJ-20为[5-(4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-21为[5-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];TJ-22为[5-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-23为[5-(4-(4-氯苯基)-4-羟基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-24为[5-(4-(嘧啶-2-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-25为[5-(4-(苯并噻吩-4-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛];
TJ-26为[5-吗啉-1-(苯基磺酰基)-1H-吲哚-3-甲醛];
TJ-27为[1-((4-氟苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-28为[1-((4-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-29为[1-((4-溴苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-30为[1-((4-(叔丁基)苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-31为[1-(4-甲氧基苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-32为[5-吗啉-1-((4-(三氟甲基)苯基)磺酰基)-1H-吲哚-3-甲醛];
TJ-33为[5-吗啉-1-((4-硝基苯基)磺酰基)-1H-吲哚-3-甲醛];
TJ-34为[1-((3-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛];
TJ-35为[N、N-二乙基-5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲酰胺];
TJ-36为[5-吗啉-1-甲苯磺酰基-1H-吲哚-3-羧酸乙酯];
TJ-37为[(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)甲醇];
TJ-38为[(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)乙酸甲酯]。
本发明的另一个方面提供了所述的5位氨基取代吲哚化合物的制备方法,该方法包括以下步骤:
在有机溶剂中,在催化剂、配体、碱和添加剂参与的条件下,使式III所示的4位卤代吲哚和式IV或式V所示的氧化胺反应,得到式I或式II所示的5位氨基取代吲哚化合物;
其中,
R1、R2独立地选自C1~C7烷基、苯基、萘基、苄基;
R3选自醛基、酰胺基、酯基、羟甲基、酯甲基;
R4选自芳基磺酰基;
A环选自吗啉、硫代吗啉、哌嗪、吡咯烷、哌啶、六亚甲基亚胺;
R5选自氢、C1~C7烷基、芳基、芳酰基、苄氧羰基、烷氧羰基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基;
X为卤素。
上述方法中,式III所示的4位卤代吲哚和式V所示的氧化胺的摩尔比例可以为1:1.2。
上述方法中,有机溶剂可以为甲苯或者二氧六环。
上述方法中,催化剂可以为醋酸钯或者氯化钯。
上述方法中,配体可以为三芳基膦和降冰片烯。
上述方法中,碱可以为碳酸铯或者碳酸钾。
上述方法中,添加剂可以为对三氟甲基苯甲醇。
上述方法中,反应温度可以为80~100℃。
上述方法中,反应时间可以为24小时。
本发明的第三方面提供了所述的5位氨基取代吲哚化合物在抗乙酰胆碱酯酶药物中的应用。5位氨基取代吲哚化合物具有抗乙酰胆碱酯酶活性,可用于制备抗乙酰胆碱酯酶药物。
与现有技术相比,本发明的优点包括:
其一,本发明首次制备了5位氨基取代吲哚化合物,成功将氨基选择性引入吲哚5位;
其二,本发明的制备方法不需要对底物进行预活化,而是直接发生Catellani反应;反应的收率可达到良好至优秀,反应的化学选择性和区域选择性非常高,没有其他位点的副反应发生,反应条件温和,底物适用范围广,官能团兼容性好,操作简便,成本较低,副产物少,产品纯度高,便于分离提纯和可适用于大规模制备;
其三,本发明的5位氨基取代吲哚化合物具有潜在的生物和药物活性,尤其具有较好的抗乙酰胆碱酯酶活性,因此可应用于生物医药领域,尤其在抗乙酰胆碱酯酶药物领域具有非常好的应用前景。
附图说明
图1为5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-1的X-单晶衍射结构图。
图2为5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-1单晶结构对应的化合物分子结构图。
图3为化合物TJ-1~TJ-38对乙酰胆碱酯酶活性抑制率柱状图。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点,下面结合附图和具体实施方式对本发明进行进一步的详细描述。在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是,本发明还可以采用其他不同于在此描述的其他方式来实施,因此,本发明并不限于下面公开的具体实施例的限制。
本发明的部分实施例提供了5位氨基取代吲哚化合物的制备方法,采用4位碘代吲哚作为反应底物,使其和氧化胺在钯催化下,发生Catellani反应,制备5位氨基取代吲哚化合物;并且,进行结构鉴定,确认为所需目标产物。
所述5位氨基取代吲哚化合物的制备方法的具体操作可以为:向反应试管中分别依次加入4位碘代吲哚、氧化胺、催化剂醋酸钯、配体三(3-氯苯基)膦和降冰片烯、碱碳酸铯、添加剂对三氟甲基苯甲醇,最后加入溶剂甲苯,用橡胶塞密封反应试管;把试管置于80~100℃油浴中搅拌加热24小时,反应过程中用TLC检测至完全反应;后处理时先将溶剂旋干,直接上硅胶柱层析分离得纯净的产物5位氨基取代吲哚化合物(式I或式II所示的化合物)。
本发明的部分实施例提供了5位氨基取代吲哚化合物对乙酰胆碱酯酶(AChE)抑制活性的实验资料。
实施例1
向反应试管中分别依次加入4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛(0.2mmol)、吗啉代苯甲酸酯(0.24mmol)、催化剂醋酸钯(5mol%)、配体三(3-氯苯基)膦(25mol%)和降冰片烯(0.2mmol),碱碳酸铯(0.4mmol)、添加剂对三氟甲基苯甲醇(0.24mmol),最后加入溶剂甲苯(4mL),用橡胶塞密封反应试管。把试管置于100℃油浴中搅拌加热24小时左右,反应过程中用TLC检测至完全反应。后处理时先将溶剂旋干,直接上硅胶柱层析分离得纯净的产物5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-1。
5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-1,产率:86%;黄色固体;熔点126-128℃;1HNMR(400MHz,CDCl3)δ10.04(s,1H),8.14(s,1H),7.84-7.81(m,3H),7.71(d,J=2.4Hz,1H),7.27(d,J=8.8Hz,2H),7.05(dd,J=9.2,2.4Hz,1H),3.89–3.81(m,4H),3.29–3.08(m,4H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ185.7,149.8,146.2,136.91,134.7,130.5,129.9,127.6,127.3,122.5,116.8,114.0,108.2,67.1,50.4,21.9;HRMS(pos.ESI):m/z[M+Na]+for C20H20N2O4NaS calcd:407.1036,found:407.1037。
仅改变相应的反应物,用与实施例1基本相同的方法得到实施例2~38。
实施例2
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和硫代吗啉苯甲酸酯,产物为5-硫代吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-2。
5-硫代吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-2,产率:65%;黄色固体;熔点154-156℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.14(s,1H),7.81(m,3H),7.71(d,J=2.4Hz,1H),7.28(d,J=8.4Hz,2H),7.02(dd,J=9.2,2.4Hz,1H),3.60-3.42(m,4H),2.91-2.66(m,4H),2.37(s,3H);13C NMR(100MHz,CDCl3)δ186.0,150.4,146.5,137.2,135.0,130.8,130.1,127.9,127.7,122.8,118.75,114.4,110.1,53.5,27.6,22.2;HRMS(pos.ESI):m/z[M+Na]+for C20H20N2O3NaS2calcd:423.0808,found:423.0803。
实施例3
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-苯甲酰基哌嗪-1-基苯甲酸酯,产物为5-(4-苯甲酰基哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-3。
5-(4-苯甲酰基哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-3,产率:61%;黄色固体;熔点93-95℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.15(s,1H),7.89-7.78(m,3H),7.74(d,J=2.4Hz,1H),7.47-7.36(m,5H),7.28(d,J=8.4Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),4.05-3.56(m,4H),3.30-3.05(m,4H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ185.7,170.6,149.5,146.3,136.9,135.7,134.6,130.5,130.2,130.1,128.7,127.5,127.3,127.3,122.4,118.0,114.1,109.3,50.8,21.8;HRMS(pos.ESI):m/z[M+Na]+forC27H25N3O4NaS calcd:510.1458,found:510.1462。
实施例4
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(苯甲酰氧基)哌嗪-1-羧酸苄酯,产物为4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸苄酯TJ-4。
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸苄酯TJ-4,产率:63%;黄色固体;熔点78-79℃;1H NMR(400MHz,CDCl3)δ9.93(s,1H),8.04(s,1H),7.78-7.67(m,3H),7.63(d,J=1.2Hz,1H),7.31-7.24(m,3H),7.24-7.12(m,4H),6.96(d,J=8.4Hz,1H),5.05(s,2H),3.62-3.42(m,4H),3.20-2.87(m,4H),2.26(s,3H);13C NMR(100MHz,CDCl3)δ185.3,155.1,146.0,136.6,136.5,134.3,130.2,129.9,128.4,128.0,127.8,127.3,127.0,122.1,117.7,113.8,109.1,67.2,50.2,43.6,21.5;HRMS(pos.ESI):m/z[M+Na]+forC28H27N3O5NaS calcd:540.1564,found:540.1564。
实施例5
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(苯甲酰氧基)哌嗪-1-羧酸叔丁酯,产物为4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸叔丁酯TJ-5。
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸叔丁酯TJ-5,产率:61%;黄色固体;熔点176-177℃;1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.11(s,1H),7.79(d,J=8.4Hz,3H),7.70(d,J=1.6Hz,1H),7.25(d,J=8.4Hz,2H),7.04(dd,J=8.8,0.8Hz,1H),3.74-3.37(m,4H),3.31-2.93(m,4H),2.34(s,3H),1.45(s,9H);13C NMR(100MHz,CDCl3)δ185.7,154.9,149.8,146.2,136.9,134.7,130.5,123.0,127.6,127.3,122.5,117.9,114.0,109.1,80.1,50.5,44.0,28.6,21.9;HRMS(pos.ESI):m/z[M+Na]+forC25H29N3O5NaScalcd:506.1720,found:506.1728。
实施例6
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(苯甲酰氧基)哌嗪-1-羧酸乙酯,产物为4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸乙酯TJ-6。
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸乙酯TJ-6,产率:62%;黄色固体;熔点119-120℃;1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.12(s,1H),7.85-7.75(m,3H),7.71(d,J=2.4Hz,1H),7.25(d,J=8.4Hz,2H),7.04(dd,J=9.2,2.0Hz,1H),4.14(q,J=7.2Hz,2H),3.82-3.46(m,4H),3.30-3.02(m,4H),2.34(s,3H),1.25(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ185.7,155.7,149.7,146.2,136.9,134.6,130.5,130.1,127.6,127.3,122.5,117.9,114.0,109.3,61.7,50.4,43.9,21.8,14.9;HRMS(pos.ESI):m/z[M+Na]+for C23H25N3O5NaS calcd:477.1407,found:477.1399。
实施例7
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和吡咯烷-1-基苯甲酸酯,产物为5-(吡咯烷-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-7。
5-(吡咯烷-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-7,产率:40%;黄色固体;熔点158-160℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.08(s,1H),7.80(d,J=8.4Hz,2H),7.76(d,J=9.2Hz,1H),7.29(d,J=2.4Hz,1H),7.25(d,J=8.0Hz,2H),6.68(dd,J=9.2,2.4Hz,1H),3.51-3.01(m,4H),2.35(s,3H),2.07-1.94(m,4H);13C NMR(100MHz,CDCl3)δ185.8,146.5,145.9,136.7,134.9,130.34,128.0,127.3,127.2,122.6,114.0,112.3,102.9,48.3,25.7,21.8;HRMS(pos.ESI):m/z[M+Na]+for C20H20N2O3NaScalcd:391.1087,found:391.1083。
实施例8
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和哌啶-1-基苯甲酸酯,产物为5-(哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-8。
5-(哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-8,产率:75%;黄色固体;熔点147-149℃;1H NMR(400MHz,CDCl3)δ10.02(s,1H),8.10(s,1H),7.87-7.74(m,3H),7.70(d,J=2.4Hz,1H),7.32-7.17(m,2H),7.07(dd,J=9.2,2.4Hz,1H),3.30-2.91(m,4H),2.34(s,3H),1.80-1.63(m,4H),1.55(m,2H);13C NMR(100MHz,CDCl3)δ185.7,150.9,146.1,136.7,134.7,130.4,129.4,127.6,127.3,122.6,118.1,113.8,108.6,51.8,26.1,24.4,21.8;HRMS(pos.ESI):m/z[M+Na]+for C21H22N2O3NaScalcd:405.1243,found:405.1237。
实施例9
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和苯甲酸氮潘-1-酯,产物为5-(六亚甲基亚胺-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-9。
5-(六亚甲基亚胺-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-9,产率:52%;黄色固体;熔点170-172℃;1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.05(s,1H),7.80(d,J=8.4Hz,2H),7.72(d,J=9.2Hz,1H),7.43(d,J=2.4Hz,1H),7.30-7.18(m,2H),6.79(dd,J=9.2,2.4Hz,1H),3.71-3.13(m,4H),2.34(s,3H),1.96-1.64(m,4H),1.60-1.36(m,4H);13CNMR(100MHz,CDCl3)δ185.8,147.6,145.9,136.6,134.9,130.4,128.2,127.3,127.1,122.6,114.0,111.9,102.7,49.8,27.9,27.3,21.8;HRMS(pos.ESI):m/z[M+Na]+forC22H24N2O3NaScalcd:419.1400,found:419.1403。
实施例10
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-甲基哌啶-1-基苯甲酸酯,产物为5-(4-甲基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-10。
5-(4-甲基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-10,产率:76%;黄色固体;熔点130-132℃;1H NMR(400MHz,CDCl3)δ10.02(s,1H),8.10(s,1H),7.85-7.74(m,3H),7.71(d,J=2.4Hz,1H),7.31-7.16(m,2H),7.08(d,J=8.4Hz,1H),3.63(d,J=12.4Hz,2H),2.77-2.59(m,2H),2.35(s,3H),1.73(d,J=13.2Hz,2H),1.56-1.43(m,1H),1.42-1.29(m,2H),0.96(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ185.4,150.2,145.8,136.4,134.4,130.1,129.2,127.3,127.0,122.3,117.8,113.5,108.4,50.8,34.0,30.5,21.7,21.5;HRMS(pos.ESI):m/z[M+Na]+for C22H24N2O3NaScalcd:419.1400,found:419.1396。
实施例11
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-苯基哌啶-1-基苯甲酸酯,产物为5-(4-苯基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-11。
5-(4-苯基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-11,产率:71%;黄色固体;熔点163-164℃;1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.13(s,1H),7.88-7.79(m,3H),7.77(d,J=2.0Hz,1H),7.38-7.17(m,7H),7.13(dd,J=9.2,2.4Hz,1H),3.99-3.55(m,2H),2.94-2.74(m,2H),2.72-2.55(m,1H),2.36(s,3H),2.10-1.78(m,4H);13C NMR(100MHz,CDCl3)δ185.7,150.4,146.2,146.1,136.8,134.7,130.4,129.6,128.7,127.6,127.4,127.0,126.5,122.6,118.1,113.9,108.8,51.6,42.6,33.6,21.8;HRMS(pos.ESI):m/z[M+Na]+for C27H26N2O3NaS calcd:481.1556,found:481.1549。
实施例12
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和1-(苯甲酰氧基)哌啶-4-羧酸乙酯,产物为1-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌啶-4-羧酸乙酯TJ-12。
1-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌啶-4-羧酸乙酯TJ-12,产率:65%;黄色固体;熔点110-112℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.13(s,1H),7.91-7.74(m,3H),7.72(d,J=2.0Hz,1H),7.27(d,J=7.6Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),4.15(q,J=7.2Hz,2H),3.70-3.59(m,2H),2.91-2.66(m,2H),2.46-2.39(m,1H),2.36(s,3H),2.08-1.97(m,2H),1.94-1.77(m,2H),1.26(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ185.7,175.0,150.2,146.1,136.8,134.7,130.4,129.6,127.6,127.3,122.6,118.1,113.9,108.9,60.6,50.3,41.1,28.3,21.8,14.4;HRMS(pos.ESI):m/z[M+Na]+forC24H26N2O5NaScalcd:477.1455,found:477.1459。
实施例13
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和1,4-二氧-8-氮杂螺[4.5]癸-8-基苯甲酸酯,产物为5-(1,4-二氧-8-氮杂螺[4.5]癸-8-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-13。
5-(1,4-二氧-8-氮杂螺[4.5]癸-8-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-13,产率:84%;黄色固体;熔点156-158℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.11(s,1H),7.86-7.76(m,3H),7.74(d,J=2.0Hz,1H),7.27(d,J=8.8Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),3.98(s,4H),3.44-3.22(m,4H),2.37(s,3H),1.93-1.79(m,4H);13C NMR(100MHz,CDCl3)δ186.0,149.9,146.5,137.1,135.0,130.8,129.8,127.9,127.7,122.9,118.1,114.2,109.3,107.6,64.9,49.1,35.1,22.2;HRMS(pos.ESI):m/z[M+Na]+forC23H24N2O5NaScalcd:463.1298,found:463.1304。
实施例14
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和3,4-二氢异喹啉-2(1H)-苯甲酸酯,产物为5-(3,4-二氢异喹啉-2(1H)-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-14。
5-(3,4-二氢异喹啉-2(1H)-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-14,产率:70%;黄色固体;熔点161-163℃;1H NMR(400MHz,CDCl3)δ10.14(s,1H),8.21(s,1H),8.04-7.75(m,4H),7.53-7.03(m,7H),4.50(s,2H),3.79-3.53(m,2H),3.25-2.90(m,2H),2.45(s,3H);13C NMR(100MHz,CDCl3)δ185.8,149.2,146.1,136.9,134.9,134.7,134.5,130.5,129.1,128.7,127.8,127.3,126.8,126.6,126.3,122.6,116.3,114.0,107.2,51.6,47.6,29.5,21.9;HRMS(pos.ESI):m/z[M+Na]+for C25H22N2O3NaScalcd:453.1243,found:453.1248。
实施例15
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和O-苯甲酰基-N,N-二乙基羟胺,产物为5-(二乙基氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-15。
5-(二乙基氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-15,产率:35%;黄色固体;熔点124-126℃;1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.05(s,1H),7.80(d,J=8.4Hz,2H),7.72(d,J=9.2Hz,1H),7.45(d,J=2.0Hz,1H),7.25(d,J=8.4Hz,2H),6.80(dd,J=9.2,2.0Hz,1H),3.36(q,J=7.2Hz,4H),2.35(s,3H),1.14(t,J=7.2Hz,6H);13C NMR(100MHz,CDCl3)δ186.1,146.9,146.2,136.9,135.2,130.7,128.5,127.7,122.9,114.4,113.4,104.2,100.5,45.4,22.2,13.0;HRMS(pos.ESI):m/z[M+Na]+for C20H22N2O3NaScalcd:393.1243,found:393.1237。
实施例16
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和O-苯甲酰基-N-苄基-N-甲基羟胺,产物为5-(苄基(甲基)氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-16。
5-(苄基(甲基)氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-16,产率:53%;黄色固体;熔点119-121℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.10(s,1H),7.88-7.77(m,2H),7.74(d,J=9.2Hz,1H),7.58(d,J=2.4Hz,1H),7.36-7.17(m,7H),6.87(dd,J=9.2,2.6Hz,1H),4.56(s,2H),3.05(s,3H),2.37(s,3H);13C NMR(100MHz,CDCl3)δ185.7,148.4,146.0,138.9,136.6,134.8,130.4,128.8,127.9,127.9,127.3,127.2,127.1,122.5,114.0,113.5,104.2,57.4,39.3,21.8;HRMS(pos.ESI):m/z[M+Na]+for C24H22N2O3NaScalcd:441.1243,found:441.1239。
实施例17
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-((双苯基)甲基)哌嗪-1-基苯甲酸酯,产物为5-(4-((双苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-17。
5-(4-((双苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-17,产率:56%;黄色固体;熔点171-173℃;1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.09(s,1H),7.85-7.73(m,3H),7.67(d,J=2.0Hz,1H),7.46-7.38(m,4H),7.30-7.21(m,6H),7.20-7.13(m,2H),7.01(dd,J=9.2,2.4Hz,1H),4.25(s,1H),3.27-3.11(m,4H),2.59-2.46(m,4H),2.34(s,3H);13C NMR(100MHz,CDCl3)δ185.7,149.9,146.1,142.8,136.7,134.7,130.4,129.6,128.8,128.1,127.6,127.3,127.2,122.6,117.2,113.9,108.2,76.3,52.1,50.3,21.8;HRMS(pos.ESI):m/z[M+H]+for C33H32N3O3Scalcd:550.2159,found:550.2157。
实施例18
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(双(4-氟苯基)甲基)哌嗪-1-基苯甲酸酯,产物为5-(4-(双(4-氟苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-18。
5-(4-(双(4-氟苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-18,产率:53%;黄色固体;熔点210-213℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.12(s,1H),7.89-7.74(m,3H),7.70(d,J=2.4Hz,1H),7.44-7.32(m,4H),7.31-7.23(m,2H),7.09-6.91(m,5H),4.27(s,1H),3.26-3.10(m,4H),2.58-2.43(m,4H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ185.67,162.1(d,JC-F=244.1Hz),149.79,146.15,138.3(d,JC-F=2.9Hz),136.78,134.71,130.43,129.66,129.5(d,JC-F=7.8Hz),127.59,127.33,122.58,117.19,115.7(d,JC-F=21.1Hz),113.90,108.27,74.60,51.94,50.30,21.83;19F NMR(565MHz,CDCl3)δ-115.51;HRMS(pos.ESI):m/z[M+H]+for C33H30F2N3O3Scalcd:589.1970,found:589.1966。
实施例19
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(双(4-氟苯基)甲基)哌嗪-1-基苯甲酸酯,产物为5-(4-((4-氯苯基)(苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-19。
5-(4-((4-氯苯基)(苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-19,产率:72%;黄色固体;熔点126-128℃;1HNMR(400MHz,CDCl3)δ10.02(s,1H),8.42(d,J=3.6Hz,1H),8.11(s,1H),7.81(m,3H),7.69(d,J=2.0Hz,1H),7.45(d,J=6.8Hz,1H),7.33-7.22(m,2H),7.21-7.01(m,5H),3.59-.46(m,2H),3.45-3.30(m,2H),3.01-2.89(m,2H),2.89-2.74(m,2H),2.72-2.42(m,4H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ185.4,157.1,149.5,146.5,145.8,139.4,138.1,137.6,137.4,136.4,134.4,133.4,133.1,132.7,130.6,130.1,129.3,128.9,127.3,127.0,126.0,122.3,122.2,117.7,113.6,108.5,51.8,51.6,31.7,31.4,30.7,30.5,21.5;HRMS(pos.ESI):m/z[M+Na]+for C35H30ClN3O3NaScalcd:630.1589,found:630.1584。
实施例20
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-((4-氯苯基)(苯基)甲基)哌嗪-1-基苯甲酸酯,产物为5-(4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-20。
5-(4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-20,产率:60%;黄色固体;熔点160-162℃;1HNMR(400MHz,CDCl3)δ10.02(s,1H),8.11(s,1H),7.88-7.73(m,3H),7.69(d,J=2.0Hz,1H),7.44-7.33(m,4H),7.34-7.16(m,7H),7.03(dd,J=9.2,2.4Hz,1H),4.25(s,1H),3.26-3.12(m,4H),2.62-2.46(m,4H),2.35(s,3H);13C NMR(100MHz,CDCl3)δ185.7,149.8,146.1,142.2,141.4,136.8,134.7,132.9,130.4,129.6,129.4,128.9,128.9,128.0,127.6,127.5,127.3,122.6,117.2,113.9,108.3,75.6,52.0,50.3,21.8;HRMS(pos.ESI):m/z[M+Na]+forC33H30ClN3O3NaScalcd:606.1589,found:606.1588。
实施例21
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基苯甲酸酯,产物为5-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-21。
5-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-21,产率:70%;黄色固体;熔点136-138℃;1H NMR(400MHz,CDCl3)δ10.02(s,1H),8.11(s,1H),7.80(d,J=8.4Hz,3H),7.76(d,J=2.0Hz,1H),7.66(dd,J=8.4,5.2Hz,1H),7.32-7.17(m,3H),7.10(dd,J=9.2,2.0Hz,1H),7.03(td,J=8.8,1.6Hz,1H),3.91-3.63(m,2H),3.33-3.09(m,1H),3.00-2.83(m,2H),2.34(s,3H),2.23-2.08(m,4H);13C NMR(100MHz,CDCl3)δ186.05,164.7(d,JC-F=249.2Hz),164.4(d,JC-F=13.4Hz),161.34,150.42,146.51,137.17,135.01,130.78,130.10,127.92,127.66,123.0(d,JC-F=11.1Hz),122.88,118.53,117.9(d,JC-F=0.9Hz),114.28,113.0(d,JC-F=25.2Hz),109.41,98.0(d,JC-F=26.6Hz),51.26,34.82,30.92,22.16;19F NMR(565MHz,CDCl3)δ-109.41;HRMS(pos.ESI):m/z[M+Na]+for C28H24FN3O4NaS calcd:540.1364,found:540.1364。
实施例22
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(苯并[d]异噻唑-3-基)哌嗪-1-基苯甲酸酯,产物为5-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-22。
5-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-22,产率:80%;黄色固体;熔点103-105℃;1HNMR(400MHz,CDCl3)δ10.06(s,1H),8.15(s,1H),7.95(d,J=8.0Hz,1H),7.89-7.76(m,5H),7.48(t,J=7.6Hz,1H),7.38(t,J=7.6Hz,1H),7.28(d,J=8.4Hz,2H),7.15(dd,J=9.2,2.0Hz,1H),3.81-3.58(m,4H),3.55-3.33(m,4H),2.37(s,3H);13CNMR(100MHz,CDCl3)δ185.7,164.0,153.0,149.8,146.2,136.9,134.7,130.5,129.9,128.2,127.9,127.6,127.3,124.2,124.0,122.6,120.8,117.6,114.0,108.7,50.3,50.2,21.8;HRMS(pos.ESI):m/z[M+Na]+for C27H24N4O3NaS2calcd:539.1182,found:539.1179。
实施例23
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(4-氯苯基)-4-羟基哌啶-1-基苯甲酸酯,产物为5-(4-(4-氯苯基)-4-羟基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-23。
5-(4-(4-氯苯基)-4-羟基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-23,产率:62%;黄色固体;熔点120-122℃;1H NMR(400MHz,CDCl3)δ9.96(s,1H),8.06(s,1H),7.83-7.68(m,4H),7.45-7.32(m,2H),7.30-7.14(m,4H),7.05(dd,J=9.2,2.4Hz,1H),3.63-3.41(m,2H),3.25-3.07(m,2H),2.30(s,3H),2.22-2.08(m,2H),1.83-1.70(m,2H),1.64(s,1H);13C NMR(100MHz,CDCl3)δ185.8,150.0,146.9,146.2,136.9,134.7,133.2,130.5,129.7,128.7,127.6,127.4,126.3,122.6,117.9,113.9,109.0,71.2,46.8,38.4,21.9;HRMS(pos.ESI):m/z[M+Na]+for C27H25ClN2O4NaScalcd:531.1116,found:531.1123。
实施例24
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(嘧啶-2-基)哌嗪-1-基苯甲酸酯,产物为5-(4-(嘧啶-2-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-24。
5-(4-(嘧啶-2-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-24,产率:60%;黄色固体;熔点138-140℃;1HNMR(400MHz,CDCl3)δ10.04(s,1H),8.33(d,J=4.8Hz,2H),8.14(s,1H),7.88-7.79(m,3H),7.77(d,J=2.4Hz,1H),7.27(d,J=8.4Hz,2H),7.12(dd,J=9.2,1.6Hz,1H),6.51(t,J=4.8Hz,1H),4.13-3.85(m,4H),3.32-3.08(m,4H),2.36(s,3H);13C NMR(100MHz,CDCl3)δ185.7,161.8,157.9,149.8,146.2,136.9,134.7,130.5,130.0127.6,127.3,122.5,117.7,114.0,110.4,109.0,50.4,43.9,21.8;HRMS(pos.ESI):m/z[M+Na]+for C24H23N5O3NaScalcd:484.1414,found:484.1410。
实施例25
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-甲醛和4-(苯并噻吩-4-基)哌嗪-1-基苯甲酸酯,产物为5-(4-(苯并噻吩-4-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-25。
5-(4-(苯并噻吩-4-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛TJ-25,产率:80%;黄色固体;熔点103-105℃;1H NMR(400MHz,CDCl3)δ10.06(s,1H),8.15(s,1H),7.95(d,J=8.0Hz,1H),7.89-7.76(m,5H),7.48(t,J=7.6Hz,1H),7.38(t,J=7.6Hz,1H),7.28(d,J=8.4Hz,2H),7.15(dd,J=9.2,2.0Hz,1H),3.81-3.58(m,4H),3.55-3.33(m,4H),2.37(s,3H);13CNMR(100MHz,CDCl3)δ185.7,164.0,153.0,149.8,146.2,136.9,134.7,130.5,129.9,128.2,127.9,127.6,127.3,124.2,124.0,122.6,120.8,117.6,114.0,108.7,50.3,50.2,21.8;HRMS(pos.ESI):m/z[M+Na]+for C27H24N4O3NaS2calcd:539.1182,found:539.1179。
实施例26
反应物为4-碘-1-(苯基磺酰基)-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为5-吗啉-1-(苯基磺酰基)-1H-吲哚-3-甲醛TJ-26。
5-吗啉-1-(苯基磺酰基)-1H-吲哚-3-甲醛TJ-26,产率:70%;黄色固体;熔点153-155℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.13(s,1H),7.92(d,J=7.6Hz,2H),7.82(d,J=9.2Hz,1H),7.71(d,J=1.2Hz,1H),7.59(t,J=7.6Hz,1H),7.54-7.43(m,2H),7.05(d,J=7.6Hz,1H),3.98-3.73(m,4H),3.26-3.06(m,4H);13C NMR(100MHz,CDCl3)δ185.7,149.8,137.7,136.8,134.8,129.9,129.9,127.6,127.3,122.7,117.0,114.0,108.2,67.1,50.4;HRMS(pos.ESI):m/z[M+Na]+for C19H18N2O4NaScalcd:393.0879,found:393.0880。
实施例27
反应物为1-((4-氟苯基)磺酰基)-4-碘-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-((4-氟苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-27。
1-((4-氟苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-27,产率:74%;黄色固体;熔点149-151℃;1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.19(s,1H),8.10-7.99(m,2H),7.88(d,J=9.2Hz,1H),7.80(d,J=2.0Hz,1H),7.29-7.19(m,2H),7.15(d,J=8.8Hz,1H),4.07-3.84(m,4H),3.37-3.16(m,4H);13C NMR(100MHz,CDCl3)δ185.65,166.3(d,JC-F=257.3Hz),149.91,136.65,133.6(d,JC-F=3.2Hz),130.2(d,JC-F=9.8Hz),129.69,127.67,122.86,117.3(d,JC-F=22.9Hz),116.97,113.85,108.29,67.06,50.29;HRMS(pos.ESI):m/z[M+Na]+for C19H17FN2O4NaS calcd:411.0785,found:411.0779。
实施例28
反应物为1-((4-氯苯基)磺酰基)-4-碘-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-((4-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-28。
1-((4-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-28,产率:68%;黄色固体;熔点126-128℃;1H NMR(400MHz,CDCl3)δ10.05(s,1H),8.11(s,1H),7.86(d,J=8.4Hz,2H),7.80(d,J=9.2Hz,1H),7.72(d,J=1.2Hz,1H),7.46(d,J=8.4Hz,2H),7.06(dd,J=8.8,1.2Hz,1H),4.09-3.64(m,4H),3.44-2.90(m,4H);13C NMR(100MHz,CDCl3)δ185.9,150.3,142.0,136.9,136.3,130.5,123.0,129.0,128.0,123.3,117.3,114.2,108.6,67.4,50.6;HRMS(pos.ESI):m/z[M+Na]+for C19H17ClN2O4NaScalcd:427.0490,found:427.0493。
实施例29
反应物为1-((4-溴苯基)磺酰基)-4-碘-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-((4-溴苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-29。
1-((4-溴苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-29;产率:58%;黄色固体;熔点110-112℃;1H NMR(400MHz,CDCl3)δ10.03(s,1H),8.09(s,1H),7.84-7.74(m,3H),7.71(d,J=2.4Hz,1H),7.64-7.57(m,2H),7.04(dd,J=9.2,2.4Hz,1H),3.91-3.76(m,4H),3.24-3.09(m,4H);13C NMR(100MHz,CDCl3)δ185.6,149.9,136.6,136.6,133.2,130.4,129.8,128.6,127.7,123.0,117.1,113.9,108.4,67.0,50.4;HRMS(pos.ESI):m/z[M+Na]+for C19H17BrN2O4NaS calcd:470.9985,found:470.9978。
实施例30
反应物为1-((4-(叔丁基)苯基)磺酰基)-4-碘-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-((4-(叔丁基)苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-30。
1-((4-(叔丁基)苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-30;产率:85%;黄色固体;熔点99-101℃;1HNMR(400MHz,DMSO)δ10.04(s,1H),8.78(s,1H),8.00(d,J=7.6Hz,2H),7.83(d,J=9.2Hz,1H),7.65(d,J=7.6Hz,2H),7.55(s,1H),7.17(d,J=8.4Hz,1H),3.88-3.51(m,4H),3.18-2.95(m,4H),1.22(s,9H);13C NMR(100MHz,DMSO)δ187.3,159.1,149.8,139.1,134.1,128.9,127.6,127.5,127.3,122.1,116.7,114.1,106.8,66.6,49.6,35.6,31.0;HRMS(pos.ESI):m/z[M+Na]+for C23H26N2O4NaScalcd:449.1505,found:449.1504。
实施例31
反应物为4-碘-1-((4-甲氧基苯基)磺酰基)-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-(4-甲氧基苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-31。
1-(4-甲氧基苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-31;产率:72%;黄色固体;熔点93-95℃;1H NMR(400MHz,CDCl3)δ10.02(s,1H),8.12(s,1H),7.86(d,J=8.8Hz,2H),7.80(d,J=9.2Hz,1H),7.71(s,1H),7.04(d,J=9.2Hz,1H),6.97-6.86(m,2H),3.95-3.81(m,4H),3.80(s,3H),3.25-3.02(m,4H);13C NMR(100MHz,CDCl3)δ185.7,164.6,149.7,136.9,129.8,129.7,128.9,127.6,122.4,116.8,115.1,114.0,108.2,67.1,56.0,50.4;HRMS(pos.ESI):m/z[M+Na]+for C20H20N2O5NaScalcd:423.0985,found:423.0990。
实施例32
反应物为4-碘-1-((4-(三氟甲基)苯基)磺酰基)-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为5-吗啉-1-((4-(三氟甲基)苯基)磺酰基)-1H-吲哚-3-甲醛TJ-32。
5-吗啉-1-((4-(三氟甲基)苯基)磺酰基)-1H-吲哚-3-甲醛TJ-32;产率:70%;黄色固体;熔点156-158℃;1H NMR(400MHz,CDCl3)δ10.07(s,1H),8.13(s,1H),8.06(d,J=8.4Hz,2H),7.83(d,J=9.2Hz,1H),7.81-7.65(m,3H),7.08(dd,J=9.2,2.0Hz,1H),3.90-3.77(m,4H),3.28-3.08(m,4H);13C NMR(100MHz,CDCl3)δ185.6,150.1,141.0,136.4((q,JC-F=33.2Hz)),136.4,129.6,127.8,127.8,127.1(q,JC-F=3.7Hz),123.3,122.9(q,JC-F=271.7Hz),117.1,113.9,108.4,67.1,50.2;HRMS(pos.ESI):m/z[M+Na]+for C20H17F3N2O4NaScalcd:461.0753,found:461.0746。
实施例33
反应物为4-碘-1-((4-硝基苯基)磺酰基)-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为5-吗啉-1-((4-硝基苯基)磺酰基)-1H-吲哚-3-甲醛TJ-33。
5-吗啉-1-((4-硝基苯基)磺酰基)-1H-吲哚-3-甲醛TJ-33;产率:50%;黄色固体;熔点83-85℃;1H NMR(400MHz,CDCl3)δ10.07(s,1H),8.37-8.26(m,2H),8.16-8.05(m,3H),7.83(d,J=9.2Hz,1H),7.72(d,J=2.4Hz,1H),7.08(dd,J=9.2,2.4Hz,1H),4.05-3.65(m,4H),3.37-2.97(m,4H);13C NMR(100MHz,CDCl3)δ185.5,151.3,150.2,142.9,136.2,129.5,128.6,127.9,125.1,123.7,117.2,113.8,108.5,67.0,50.2;HRMS(pos.ESI):m/z[M+Na]+for C19H17N3O6NaScalcd:438.0730,found:438.0720。
实施例34
反应物为1-((3-氯苯基)磺酰基)-4-碘-1H-吲哚-3-甲醛和吗啉代苯甲酸酯,产物为1-((3-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-34。
1-((3-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛TJ-34;产率:60%;黄色固体;熔点108-110℃;1H NMR(400MHz,CDCl3)δ10.07(s,1H),8.12(s,1H),7.92(t,J=1.6Hz,1H),7.85-7.78(m,2H),7.73(d,J=2.4Hz,1H),7.57(dd,J=8.0,0.8Hz,1H),7.44(t,J=8.0Hz,1H),7.09(dd,J=9.2,2.4Hz,1H),4.02-3.76(m,4H),3.40-2.97(m,4H);13C NMR(100MHz,CDCl3)δ185.6,150.0,139.3,136.6,136.2,135.0,131.1,129.7,127.7,127.3,125.3,123.1,117.1,113.9,108.3,67.1,50.3;HRMS(pos.ESI):m/z[M+Na]+for C19H17ClN2O4NaScalcd:427.0490,found:427.0498。
实施例35
反应物为N、N-二乙基-4-碘-1-甲苯磺酰基-1H-吲哚-3-甲酰胺和吗啉代苯甲酸酯,产物为N、N-二乙基-5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲酰胺TJ-35。
N、N-二乙基-5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲酰胺TJ-35;产率:30%;白色固体;熔点88-90℃;1H NMR(400MHz,CDCl3)δ7.86(d,J=8.8Hz,1H),7.74(d,J=8.4Hz,2H),7.60(s,1H),7.21(d,J=8.4Hz,2H),7.15(s,1H),7.10-7.00(m,1H),3.93-3.75(m,4H),3.50(q,J=1.2Hz,4H),3.19-3.05(m,4H),2.34(s,3H),1.22(t,J=6.8Hz,6H);13C NMR(100MHz,CDCl3)δ164.9,145.6,135.1,130.4,130.2,127.3,127.1,125.1,117.8,116.8,116.7,114.3,107.4,67.0,50.9,29.9,21.8,14.0;HRMS(pos.ESI):m/z[M+H]+forC24H29N3O4NaS calcd:478.1771,found:478.1774。
实施例36
反应物为4-碘-1-甲苯磺酰基-1H-吲哚-3-羧酸乙酯和吗啉代苯甲酸酯,产物为5-吗啉-1-甲苯磺酰基-1H-吲哚-3-羧酸乙酯TJ-36。
5-吗啉-1-甲苯磺酰基-1H-吲哚-3-羧酸乙酯TJ-36;产率:40%;白色固体;熔点92-94℃;1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.91-7.75(m,3H),7.63(s,1H),7.34-7.19(m,2H),7.04(d,J=6.4Hz,1H),4.37(q,J=7.2Hz,2H),4.00-3.79(m,4H),3.24-3.13(m,4H),2.35(s,3H),1.41(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ164.0,145.8,135.0,132.4,130.4,130.3,129.2,127.5,127.3,116.4,114.1,113.6,107.9,67.1,60.7,50.6,21.8,14.6;HRMS(pos.ESI):m/z[M+H]+for C22H24N2O5NaScalcd:451.1298,found:451.1304。
实施例37
反应物为(4-碘-1-甲苯磺酰基-1H-吲哚-3-基)甲醇和吗啉代苯甲酸酯,产物为(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)甲醇TJ-37。
(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)甲醇TJ-37;产率:45%;白色固体;熔点72-75℃;1H NMR(400MHz,CDCl3)δ7.87(d,J=9.2Hz,1H),7.73(d,J=8.4Hz,2H),7.45(s,1H),7.19(d,J=8.0Hz,2H),7.05(d,J=2.0Hz,1H),7.00(dd,J=9.2,2.4Hz,1H),4.76(s,2H),3.92–3.75(m,4H),3.17–3.03(m,4H),2.33(s,3H),1.72(s,1H).;13C NMR(100MHz,CDCl3)δ148.5,145.1,135.5,130.7,130.4,130.0,127.0,124.6,122.6,116.1,114.6,106.1,67.2,57.3,50.8,21.7;HRMS(pos.ESI):m/z[M+Na]+for C20H22N2O4NaScalcd:409.1192,found:409.1185。
实施例38
反应物为(4-碘-1-甲苯磺酰基-1H-吲哚-3-基)乙酸甲酯和吗啉代苯甲酸酯,产物为(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)乙酸甲酯TJ-38。
(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)乙酸甲酯TJ-38;产率:52%;白色固体;熔点127-129℃;1H NMR(400MHz,CDCl3)δ7.87(d,J=8.8Hz,1H),7.74(d,J=8.4Hz,2H),7.55(s,1H),7.21(d,J=8.0Hz,2H),7.07-6.89(m,2H),5.19(s,2H),4.00-3.70(m,4H),3.38-2.96(m,4H),2.33(s,3H),2.07(s,3H);13C NMR(100MHz,CDCl3)δ171.1,148.6,145.1,135.4,130.6,130.1,127.0,126.5,117.6,116.1,114.6,105.7,67.3,57.9,50.8,21.7,21.2;HRMS(pos.ESI):m/z[M+Na]+for C22H24N2O5NaScalcd:451.1298,found:451.1291。
实施例39
化合物TJ-1~TJ-38的抗乙酰胆碱酯酶活性评价。乙酰胆碱酯酶(AChE)催化乙酰胆碱的分解,直接造成神经性或传递失败,从而引发阿尔滋海默症(老年痴呆症AD)。乙酰胆碱酯酶抑制剂可以用于老年痴呆症的治疗,全世界目前在研的抗乙酰胆碱酯酶药物有40多个,已经成为阿尔滋海默症治疗的一个重要研究领域。本实验分别采用不同浓度的化合物TJ-1~TJ-38处理乙酰胆碱酯酶的PBS溶液,加入等量的TDNB,预热2min,然后加入硫代乙酰胆碱,37℃孵育0.5h后用SDS终止反应,所得溶液于412nm下检测吸光值,并根据下列公式计算吸光值。
抑制率(%)=[A对照-(A样品-A样品空白)]/A对照×100
抗乙酰胆碱酯酶活性实验结果显示,本发明的多种化合物(如TJ-6,TJ-22,TJ-24,TJ-35)相对于阳性药物小檗碱对乙酰胆碱酯酶活性具有较好的抑制活性,抑制率最高达到82%,揭示了吲哚环5位特定的氨基,以及3位酰胺基是药物起效的关键药效团。各实验数据均为平均值±标准误差,以空白溶剂对照组为参照组(抑制率0%)。
表1是化合物TJ-1~TJ-38对乙酰胆碱酯酶活性抑制率。
表1化合物TJ-1~TJ-38对乙酰胆碱酯酶活性抑制率
化合物 | 抑制率 | 化合物 | 抑制率 | 化合物 | 抑制率 |
TJ-1 | 15% | TJ-14 | 23% | TJ-27 | 45% |
TJ-2 | 24% | TJ-15 | 33% | TJ-28 | -11% |
TJ-3 | 20% | TJ-16 | 43% | TJ-29 | 27% |
TJ-4 | -12% | TJ-17 | 26% | TJ-30 | 21% |
TJ-5 | 44% | TJ-18 | 37% | TJ-31 | 35% |
TJ-6 | 62% | TJ-19 | 51% | TJ-32 | 18% |
TJ-7 | 37% | TJ-20 | 50% | TJ-33 | 26% |
TJ-8 | 28% | TJ-21 | 47% | TJ-34 | 42% |
TJ-9 | 39% | TJ-22 | 68% | TJ-35 | 82% |
TJ-10 | 30% | TJ-23 | 23% | TJ-36 | 53% |
TJ-11 | 43% | TJ-24 | 75% | TJ-37 | 55% |
TJ-12 | 18% | TJ-25 | 39% | TJ-38 | 48% |
TJ-13 | 22% | TJ-26 | 45% | 小檗碱 | 61% |
由上表和说明书附图3可以看出,所筛选的38个化合物中有4个(TJ-6,TJ-22,TJ-24,TJ-35)抑制率超过了阳性药小檗碱,其中化合物TJ-35显示出了最强的抑制活性,达到82%,有望开发成为新型抗乙酰胆碱酯酶药物。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (10)
1.式I或式II所示的5位氨基取代吲哚化合物:
其中,
R1、R2独立地选自C1~C7烷基、苯基、萘基、苄基;
R3选自醛基、酰胺基、酯基、羟甲基、酯甲基;
R4选自芳基磺酰基;
A环选自吗啉、硫代吗啉、哌嗪、吡咯烷、哌啶、六亚甲基亚胺;
R5选自氢、C1~C7烷基、芳基、芳酰基、苄氧羰基、烷氧羰基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基。
2.根据权利要求1所述的化合物,其特征在于,R1、R2独立地选自甲基、乙基、苯基、萘基、苄基;R3选自甲醛基、N,N-二乙基甲酰胺基、乙氧羰基、羟甲基、乙酯基甲基;R4选自苯磺酰基、4-氟苯磺酰基、4-氯苯磺酰基、4-溴苯磺酰基、4-叔丁基苯磺酰基、4-甲氧基苯磺酰基、4-三氟甲基苯磺酰基、4-硝基苯磺酰基、3-氯苯磺酰基;R5选自氢、甲基、乙基、苯基、萘基、苯甲酰基、苄氧羰基、叔丁氧基羰基、乙氧羰基甲基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基。
3.一种5位氨基取代吲哚化合物,其特征在于,所述5位氨基取代吲哚化合物具体为下列化合物之一:
5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-硫代吗啉-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-苯甲酰基哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸苄酯;
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸叔丁酯;
4-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌嗪-1-羧酸乙酯;
5-(吡咯烷-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(六亚甲基亚胺-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-甲基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-苯基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
1-(3-甲酰基-1-甲苯磺酰基-1H-吲哚-5-基)哌啶-4-羧酸乙酯;
5-(1,4-二氧-8-氮杂螺[4.5]癸-8-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(3,4-二氢异喹啉-2(1H)-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(二乙基氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(苄基(甲基)氨基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-((双苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(双(4-氟苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-((4-氯苯基)(苯基)甲基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(8-氯-5H-苯并[5,6]环庚[1,2-b]吡啶-11(6H)-亚基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(4-氯苯基)-4-羟基哌啶-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(嘧啶-2-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-(4-(苯并噻吩-4-基)哌嗪-1-基)-1-甲苯磺酰基-1H-吲哚-3-甲醛;
5-吗啉-1-(苯基磺酰基)-1H-吲哚-3-甲醛;
1-((4-氟苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
1-((4-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
1-((4-溴苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
1-((4-(叔丁基)苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
1-(4-甲氧基苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
5-吗啉-1-((4-(三氟甲基)苯基)磺酰基)-1H-吲哚-3-甲醛;
5-吗啉-1-((4-硝基苯基)磺酰基)-1H-吲哚-3-甲醛;
1-((3-氯苯基)磺酰基)-5-吗啉基-1H-吲哚-3-甲醛;
N、N-二乙基-5-吗啉-1-甲苯磺酰基-1H-吲哚-3-甲酰胺;
5-吗啉-1-甲苯磺酰基-1H-吲哚-3-羧酸乙酯;
(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)甲醇;
(5-吗啉-1-甲苯磺酰基-1H-吲哚-3-基)乙酸甲酯。
4.根据权利要求1所述的化合物的制备方法,包括以下步骤:
在有机溶剂中,在催化剂、配体、碱和添加剂参与的条件下,使式III所示的4位卤代吲哚和式IV或式V所示的氧化胺反应,得到式I或式II所示的5位氨基取代吲哚化合物;
其中,
R1、R2独立地选自C1~C7烷基、苯基、萘基、苄基;
R3选自醛基、酰胺基、酯基、羟甲基、酯甲基;
R4选自芳基磺酰基;
A环选自吗啉、硫代吗啉、哌嗪、吡咯烷、哌啶、六亚甲基亚胺;
R5选自氢、C1~C7烷基、芳基、芳酰基、苄氧羰基、烷氧羰基、苯并异恶唑基、苯并异噻唑基、嘧啶基、苯并噻吩基;
X为卤素。
5.根据权利要求4所述的方法,其特征在于,式III所示的4位卤代吲哚和式V所示的氧化胺的摩尔比例为1:1.2。
6.根据权利要求4所述的方法,其特征在于,有机溶剂为甲苯或者二氧六环。
7.根据权利要求4所述的方法,其特征在于,催化剂为醋酸钯或者氯化钯;配体为三芳基膦和降冰片烯;碱为碳酸铯或者碳酸钾;添加剂为对三氟甲基苯甲醇。
8.根据权利要求4所述的方法,其特征在于,反应温度为80~100℃;反应时间为24小时。
9.根据权利要求1~3任一权利要求所述的5位氨基取代吲哚化合物在制备抗乙酰胆碱酯酶药物中的应用。
10.一种抗乙酰胆碱酯酶药物,其特征在于,包括权利要求1~3任一权利要求所述的5位氨基取代吲哚化合物。
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