CN113527172B - M2乙酰胆碱受体拮抗剂及其用途 - Google Patents

M2乙酰胆碱受体拮抗剂及其用途 Download PDF

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CN113527172B
CN113527172B CN202010317072.4A CN202010317072A CN113527172B CN 113527172 B CN113527172 B CN 113527172B CN 202010317072 A CN202010317072 A CN 202010317072A CN 113527172 B CN113527172 B CN 113527172B
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dihydroquinolin
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唐德伟
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黄辰
李苗苗
吴星宇
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Abstract

本发明涉及一种M2乙酰胆碱受体拮抗剂及其用途。涉及具有如下式I的结构的化合物，这些化合物可作为新型M2乙酰胆碱受体亚型选择性拮抗剂，可用于制备治疗阿尔兹海默症药物
Figure DDA0002459948960000011

Description

M2乙酰胆碱受体拮抗剂及其用途
技术领域
本发明涉及M2乙酰胆碱受体亚型选择性拮抗剂及其在医药上的用途，尤其涉及一种新型M2乙酰胆碱受体特异性拮抗剂。
背景技术
G蛋白偶联受体(GPCRs)是已获美国食品和药物监督管理局(FDA)批准药物中数量占比最大的靶向蛋白家族。毒蕈碱型乙酰胆碱受体(mAChRs)属于A类GPCRs中的α-分支，其普遍分布在人体组织器官中并对心跳，平滑肌收缩，腺体分泌以及中枢神经系统(CNS)的许多基本功能的调节发挥着十分重要作用。mAChRs由M1到M5五个不同的亚型组成，其中M1、M3、M5主要激活Gq/11-PLC信号通路，而M2、M4偏好激活Gi/o-cAMP信号通路。目前，mAChRs的靶向药物主要用于治疗以下疾病，包括慢性阻塞性肺疾病、阿尔茨海默病、帕金森病、膀胱过度活跃综合征以及癌症、糖尿病、心血管疾病、疼痛和炎症等。
M1-M5胆碱受体各亚型在人体中具有不同的组织分布模式，例如，在脑部，M1、M2和M4是主要表达的胆碱受体亚型，M3和M5受体亚型的表达水平明显较低。M3受体主要分布于外周组织，分布范围小于M2受体。通过在啮齿动物中的结合实验和人体mRNA的表达研究中发现，M2受体亚型分布于心脏、胃肠道、颌下腺等外周组织，调节各项人体生理功能。在心脏中，激活M2受体将打开G蛋白偶联的K+内流通道(GIRK)，从而抑制心脏跳动；在平滑肌细胞中，激活M2受体将抑制腺苷酸环化酶(cAMP)活性并抵消肾上腺素能反应。在神经细胞中，M2受体是主要的轴突突触前受体，激活M2受体后可抑制神经元的兴奋性，对神经递质的释放起到负反馈的调节作用。在突触中，拮抗M2受体可使M1受体活化，增加突触前囊泡向突触间隙释放乙酰胆碱，改善海马突触后的功能，对阿尔茨海默症具有一定的治疗作用。
在人体中，M1至M5胆碱受体在跨膜区具有64-82％的序列一致性和82-92％的序列相似性，但在N端和胞外区域差异较大。尽管M2受体是阿尔茨海默症的一个极具吸引力的药物靶点，但设计新型M2胆碱受体选择性拮抗剂仍面临较大挑战。目前，已有报道一些针对M2胆碱受体的拮抗剂如SCH 57790、BIBN99、AFDX384、甲氧西林(Methoctramine)和曲比拉明(Tripitramine)等。其中SCH 57790、BIBN99、AFDX384对M2/M4受体的选择特异性仍然有限，而另两种M2胆碱受体特异性拮抗剂，甲氧西林(Methoctramine)和曲比拉明(Tripitramine)，因亲脂性差而使其通过血脑屏障(BBB)的能力较弱。因此，迫切需要开发具有较好的亚型选择性、受体亲和力、药物效力和合适亲脂性的新型的M2胆碱受体拮抗剂。
Figure BDA0002459948940000021
发明内容
针对上述问题，本发明的目的在于提供新型M2乙酰胆碱受体亚型选择性拮抗剂及其制备方法和用途。
第一方面，本申请提供一种式(I)所示的化合物或其药学上可接受的盐，
Figure BDA0002459948940000022
其中，n为1或2，a、b独立地为0或1；
R1和R2各自独立选自氢、碳原子数为1-8的烷基、环原子数为6-12的芳基、环原子数为4-7的环烷基、环原子数为4-7的杂环基，其中R1和R2不同时为氢；或者R1和R2相连形成环原子为4-7的杂环；
R3和R4各自独立选自氢、环原子数为6-12的芳基、环原子数为4-7的环烷基、环原子数为4-7的杂环基，其中R3和R4不同时为氢；或者R4和R4相连形成环原子为5-12的杂环。
优选地，
Figure BDA0002459948940000031
为
Figure BDA0002459948940000032
或者
Figure BDA0002459948940000033
其中m为1或2，X为N或者CR8，R5为氢、卤素或羟基，R6、R7、R8独立地为氢、或碳原子数为1-3的烷基。
更优选地，本发明提供下述化合物：
2-(5-溴吲哚-1-基)-1-(哌啶-1-基)乙-1-酮；
2-(2-甲基吲哚-1-基)-1-(哌啶-1-基)乙-1-酮；
2-(7-羟基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮；
2-(6-羟基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮；
2-(2-甲基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮；
2-(3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮；
2-((9-乙基-9H-咔唑-3-基)氨基)-1-(哌啶-1-基)乙-1-酮；
2-(3,4-二氢-1,6-萘啶-1(2H)-基)-1-(哌啶-1-基)乙-1-酮；
2-(2-甲基吲哚-1-基)-1-(吡咯烷-1-基)乙-1-酮；
2-(2-甲基-3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮；
2-(3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮；
2-(6-氟吲哚-1-基)-1-(吡咯烷-1-基)乙-1-酮；
2-(3,4-二氢-1,6-萘啶-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-甲基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-((2S，6R)-2,6-二甲基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-甲基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-羟基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(4-羟基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-(羟甲基)哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-N-(2-氟-4-羟基苯基)丙酰胺；
(3-(3,4-二氢喹啉-1(2H)-基)丙酰基)脯氨酸；
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-羟基吡咯烷-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)吡咯烷-1-基)丙-1-酮；
(S)-3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)吡咯烷-1-基)丙-1-酮；
1-(氮杂环丁烷-1-基)-3-(3,4-二氢喹啉-1(2H)-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-甲氧基氮杂环丁烷-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-甲基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(4-甲基哌啶-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)丙-1-酮；
3-(3,4-二氢喹啉-1(2H)-基)-N-苯基丙酰胺；
N-环己基-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺；
N-环戊基-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(噻唑-2-基)丙酰胺；
N-(4-氯苯基)-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(萘-1-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(哒嗪-3-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(1-甲基-1H-吲哚-5-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(喹啉-8-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(呋喃-2-基甲基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(噻吩-3-基甲基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(1-甲基-1H-吡唑-3-基)丙酰胺；
3-(3,4-二氢喹啉-1(2H)-基)-N-(3-氟苄基)丙酰胺。
第二方面，本申请提供一种药物组合物，其包含上述任一化合物或其药学上可接受的盐、以及药学上可接受的载体。
第三方面，本申请提供上述任一化合物或其药学上可接受的盐在制备M2胆碱受体拮抗剂中的用途。
第四方面，本申请提供上述任一化合物或其药学上可接受的盐在制备治疗阿尔兹海默症药物中的用途。
附图说明
图1、2、3分别示出实施例化合物对M2胆碱受体的结合力相对于对M1胆碱受体、M3胆碱受体、M4胆碱受体的结合力的倍数。
图4示出化合物1和化合物47的胆碱受体亚型选择性。
图5示出化合物47与M2胆碱受体结合模式。
具体实施方式
以下通过下述实施方式进一步说明本发明，应理解，下述实施方式仅用于说明本发明，而非限制本发明。
除非另外定义，本文使用的所有技术术语和科学术语均与本领域普通技术人员普遍理解的具有相同的含义。在冲突的情况下，以本文中的定义为准。
各种含碳氢结构部分的碳原子含量由该部分的标有最小和最大碳原子数目的前缀表示，即前缀Ci-Cj表示该部分的碳原子数为整数“i”至整数“j”(包括i和j)。因此，例如，C1-C4烷基是指1至4个碳原子的烷基(包括1和4)。
术语“烷基”是指直链或支链饱和烃基。除非另有说明，“烷基”含有1至10个碳原子。烷基优选理解为C1-C8烷基，如甲基、乙基、丙基、丁基、戊基、己基、庚基或辛基；优选为C1-C6烷基，如甲基、乙基、丙基、丁基、戊基或己基；更优选为C1-C4烷基，如甲基、乙基、丙基或丁基。
术语“烷氧基”是指通过氧原子与母体分子附接的烷基基团。烷氧基的代表性实例包括但不限于：甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基和叔-丁氧基。
术语“亚烷基”是指通过去掉烷基终端的一个氢原子后形成的二价基团(例如-CH2CH2-和-CH2CH2CH2-分别是-CH2CH3和-CH2CH2CH3去掉其终端氢原子后形成的)、和其类似物。
术语“芳基”是指含有6-12个环碳原子的芳族碳环基团，例如包括苯基、萘基和联苯基，优选苯基。
术语“杂环基”(杂环)是指具有1个、2个或3个环，优选地具有1-2个环并且环原子总数为4-14，优选为5-7的饱和、部分饱和以及完全不饱和的(即杂芳基)杂环基团，其中至少一个环原子是N原子、O原子或S原子。优选地，所述杂环基包含选自N、O和S的1-4个杂环原子，例如，1个或2个杂原子。适合的饱和及部分饱和的杂环基包括但不限于四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、噁唑啉基、异噁唑啉基等。适合的杂芳基包括但不限于呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、苯并吡喃基、吲哚基、喹啉基、异喹啉基、咔唑基、萘啶基(naphthyridinyl)等。适合的杂环基的其它实例是：2-喹啉基、1,3-苯并二氧杂环戊烯基(1,3-benzodioxyl)、2-噻吩基、2-苯并呋喃基、2-苯并噻吩基、3-噻吩基、2,3-二氢-5-苯并呋喃基、4-吲哚基、4-吡啶基、3-喹啉基、4-喹啉基、1,4-苯并二噁烷-6-基、3-吲哚基、2-吡咯基、苯并吡喃-6-基、5-吲哚基、1,5-苯并噁庚英-8-基(1,5-benzoxepin-8-基)、3-吡啶基、6-香豆素基(6-coumarinyl)、5-苯并呋喃基、2-异咪唑-4-基、3-吡唑基、3-咔唑基、2-噻唑基、2-噁唑基、1-咪唑基和2-咪唑基。
术语“环烷基”是指含有3至10个碳原子、0个杂原子和0个双键的碳环系统。该环烷基可以是单环的、双环的、桥联的、稠合的、或螺环的。环烷基的代表性实例包括但不限于：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、金刚烷基和二环环烷基例如双环[1.1.1]戊烷基。“环烷基”还包括碳环系统，其中环烷基基团与母体分子附接并与芳基基团(例如苯基)、杂芳基基团或杂环稠合。此类的环烷基基团的代表性实例包括但不限于：2,3-二氢-1H-茚基(例如，2,3-二氢-1H-茚-1-基和2,3-二氢-1H-茚-2-基)、6,7-二氢-5H-环戊二烯并[b]吡啶基(例如，6,7-二氢-5H-环戊二烯并[b]吡啶-6-基)、氧杂螺[3.3]庚烷基(例如2-氧杂螺[3.3]庚烷-6-基)和5,6,7,8-四氢喹啉基(例如5,6,7,8-四氢喹啉-5-基)。
术语“芳基烷基”是指被芳基取代的烷基。
术语“环烷基烷基”是指被环烷基取代的烷基。
术语“杂环基烷基”是指被杂环基取代的烷基。
术语“杂烷基”是指被含选自卤原子、N、O和S(O)n的杂原子的取代基取代的如上定义的烷基或环烷基，其中n是0至2的整数，该取代基包括羟基(OH)、C1-C4烷氧基、氨基、巯基(-SH)，或类似基团。杂烷基代表性的例子包括但不限于：2-甲氧基乙基(-CH2CH2OCH3)、2-羟乙基(-CH2CH2OH)、羟甲基(-CH2OH)、2-氨基乙基(-CH2CH2NH2)、2-甲基氨基乙基(-CH2CH2NHCH3)、苄基氧代甲基、噻吩-2-基巯基甲基，或类似基团。
术语“卤素”或“卤代”意指Cl、Br、I、或F。
术语“羟基”指-OH基团。
术语“羟烷基”意指通过亚烷基基团与母体分子部分附接的至少一个-OH基团。
术语“取代的”是指可以进一步被一个或多个非氢取代基基团取代的基团。取代基基团包括但不限于：卤基、＝O(氧代)、＝S(硫代)、氰基、异氰基、硝基、氟烷基、烷氧基氟烷基、氟烷氧基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、杂烷基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基烷基、杂芳基烷基、芳基烷基、羟基、羟烷基、烷氧基、烷氧基烷基、亚烷基、芳氧基、苯氧基、苄氧基、氨基、烷基氨基、酰基氨基、氨基烷基、芳基氨基、磺酰基氨基、亚磺酰基氨基、硫烷基、磺酰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、亚磺酰基、羧基(-COOH)、酮、酰胺、氨基甲酸酯、酯基、和酰基。例如，如果一个基团(例如烷基、烯基、炔基、芳基、杂芳基、环烷基、杂烷基、杂环或其他基团(例如R基团))被描述为是“任选地被取代的”，其可以具有0、1、2、3、4或5个取代基，该取代基独立地选自卤基、＝O(氧代)、＝S(硫代)、氰基、硝基、氟烷基、烷氧基氟烷基、氟烷氧基、烷基、烯基、炔基、卤代烷基、卤代烷氧基、杂烷基、环烷基、环烯基、芳基、杂芳基、杂环基、环烷基烷基、杂芳基烷基、芳基烷基、羟基、羟烷基、烷氧基、烷氧基烷基、亚烷基、芳氧基、苯氧基、苄氧基、氨基、烷基氨基、酰基氨基、氨基烷基、芳基氨基、磺酰基氨基、亚磺酰基氨基、磺酰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、亚磺酰基、-COOH、酮、酰胺、氨基甲酸酯、酯基、和酰基。
对于本文所述的化合物，其基团和取代基可根据原子和取代基的所允许化合价进行选择，使得选择和取代产生稳定的化合物，例如，该化合物不会自发地经历转化，例如通过重排、环化、消除等。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的异构体，例如互变异构体、对映异构体、非对映异构体、及其混合物形式。
术语“本发明化合物”指通式(I)所示的化合物。该术语还包括通式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
术语“药学上可接受的载体”表示能用于制备药物组合物的载体，它们一般是安全的、无毒性的，不是生物上或其他方面不期待的，且包括能被动物和人类药学上接受的载体。在说明书和权利要求书中使用的“药学上可接受的载体”包括一种或一种以上的这类载体。
术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
术语“预防”例如是指在可能暴露或预先处置于疾病但尚未经历或显示疾病症状的哺乳动物中使疾病临床症状不发展。
术语“治疗”可指抑制疾病，例如阻止或降低疾病或其临床症状的发展，或者缓解疾病，例如使疾病或其临床症状退化。
在此公开了式(I)所示的化合物或其药学上可接受的盐，
Figure BDA0002459948940000081
其中，n为1或2，a、b独立地为0或1。
R1和R2各自独立选自氢、碳原子数为1-8的烷基、环原子数为6-12的芳基、环原子数为4-7的环烷基、环原子数为4-7的杂环基，其中R1和R2不同时为氢；或者R1和R2相连形成环原子为4-7的杂环。
R3和R4各自独立选自氢、环原子数为6-12的芳基、环原子数为4-7的环烷基、环原子数为4-7的杂环基，其中R3和R4不同时为氢；或者R4和R4相连形成环原子为5-12的杂环。
优选地，
Figure BDA0002459948940000082
为
Figure BDA0002459948940000083
或者
Figure BDA0002459948940000084
其中m为1或2，X为N或者CR8，R5为氢、卤素或羟基，R6、R7、R8独立地为氢、或碳原子数为1-3的烷基。
在一些实施方式中，式(I)中的
Figure BDA0002459948940000085
可为哌啶或具有取代基的哌啶，例如：
Figure BDA0002459948940000086
Figure BDA0002459948940000091
在一些实施方式中，式(I)中的
Figure BDA0002459948940000092
可为吡咯或具有取代基的吡咯，例如：
Figure BDA0002459948940000093
在一些实施方式中，式(I)中的
Figure BDA0002459948940000094
可为氮杂环丁烷或具有取代基的氮杂环丁烷，例如：
Figure BDA0002459948940000095
在一些实施方式中，式(I)中的
Figure BDA0002459948940000096
可为取代亚胺基，例如
Figure BDA0002459948940000097
Figure BDA0002459948940000098
在一些实施方式中，
Figure BDA0002459948940000101
可选自以下基团：
Figure BDA0002459948940000102
合成方法
式(I)的化合物可通过合成方法或通过代谢过程制备。通过代谢过程制备化合物包括在人体或动物体(体内)发生的那些或体外发生的过程。
在一些实施方式中，式(I)的化合物通过下述合成路线1合成：
合成路线1
Figure BDA0002459948940000103
其中，各基团的定义如上所述。反应条件可为DMF，3％碳酸钾，微波反应，130℃，30分钟。
在一些实施例中，式(I)的化合物通过下述合成路线2合成：
合成路线2
Figure BDA0002459948940000104
其中各基团的定义如上所述。反应条件可为：(i)：1)DMF，1％碳酸钾，微波反应，140℃，30分钟；2)6M NaOH，微波反应，120℃，30分钟。(ii)：HATU，DIPEA，DMF，微波反应，120℃，25分钟。
在上述合成路线中，可以使用多种胺，这些胺可以是可商购的，或者可以使用本领域普通技术人员已知的方法合成。
可以通过有机合成领域技术人员熟知的方法分离和纯化化合物和中间体。用于分离和纯化化合物的常规方法的实例可以包括但不限于：在固相载体(例如硅胶，氧化铝或用烷基硅烷基团衍生的二氧化硅)上的色谱法，通过在高温或低温重结晶(任选地用活性炭进行预处理)、薄层色谱法、在各种压力下的蒸馏、在真空下升华、以及研磨。
所公开的化合物可具有至少一个碱性氮，由此可用酸处理该化合物以形成所希望的盐。例如，化合物可以在室温或高于室温与酸反应以提供所希望的盐，将该盐沉淀、并在冷却后通过过滤收集。适用于该反应的酸的实例包括但不限于：酒石酸、乳酸、琥珀酸、以及扁桃酸、阿卓乳酸、甲磺酸、乙磺酸、甲苯磺酸、萘磺酸、苯磺酸、碳酸、富马酸、马来酸、葡糖酸、乙酸、丙酸、水杨酸、盐酸、氢溴酸、磷酸、硫酸、柠檬酸、羟丁酸、樟脑磺酸、苹果酸、苯乙酸、天冬氨酸、或谷氨酸等。
每个单独步骤的反应条件和反应时间可以根据所用的特定反应物和所用反应物中存在的取代基而变化。实施例部分提供了具体的程序。可以将反应以常规方式进行处理，例如通过从残余物中消除溶剂并根据本领域通常已知的方法(例如但不限于结晶、蒸馏、提取、研磨和色谱法)进一步纯化。除非另外说明，否则起始材料和试剂是可商购的，或者可以由本领域技术人员使用化学文献中所述的方法从可商购的材料进行制备。起始材料(如果不可商购)可以通过选自标准有机化学技术的程序、与合成已知的结构类似的化合物类似的技术、或与上述方案或合成实例部分中所述的程序类似的技术来制备。
常规实验(包括反应条件、试剂、合成途径的顺序、与反应条件不相容的任何化学官能团的保护、以及在该方法的反应顺序中的适合点进行的脱保护的适当操作)包括在本发明的范围内。适合的保护基团和使用此类的适合的保护基团保护和脱保护不同取代基的方法是本领域技术人员公知的。本发明的化合物的合成可以通过类似于上文描述的合成方案和具体实例中描述的那些方法完成。
当需要所公开的化合物的光学活性形式时，它可以通过使用一种光学活性的起始材料(例如通过一个适合的反应步骤的不对称诱导而制备的)进行本文所述的程序之一、或通过使用标准程序(如色谱分离、重结晶或酶法拆分)拆分该化合物或中间体的立体异构体的混合物来获得。
类似地，当需要化合物的纯几何异构体时，它可以通过使用一种纯几何异构体作为起始材料进行以上程序之一、或通过使用标准程序如色谱分离拆分该化合物或中间体的几何异构体的混合物来获得。
式(I)化合物的应用
式(I)化合物可作为M2胆碱受体拮抗剂。
式(I)化合物可用于治疗和/或预防阿尔兹海默症、帕金森病等。
药物组合物
本发明的药物组合物包含有效量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐、及其药学上可接受的载体或赋形剂或稀释剂。
“有效量”意指本发明化合物：(i)治疗特定疾病、病症或障碍，(ii)减弱、改善或消除特定疾病、病症或障碍的一或多种症状，或(iii)预防或延迟本文所述特定疾病、病症或障碍的一或多种症状发作的量。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure BDA0002459948940000121
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
本公开的另一方面涉及一种治疗阿尔兹海默症的方法，该方法包括给予需要治疗的患者有效剂量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐或其药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，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。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
合成实施例
合成实施例所使用的试剂和溶剂购自Sigma-Aldrich和Adamas，未进行进一步纯化。通过HPLC-UV检测(254nm)和LC-MS检测，所有化合物的纯度均超过95％。微波反应采用瑞典Biotage Initiator TM Sixty微波系统进行，快速色谱分析在Teledyne IscoCombiFlash上用硅胶粉盒进行。LC-MS仪器来自Agilent。采用Gilson 500仪器进行分离纯化，乙腈/水加TFA溶液作缓冲液，通过C18反相制备型高效液相色谱柱纯化。高分辨率质谱分析在Agilent 6530Q-TOF光谱仪上进行，ESI+，直接注入模式；鞘气流速，5；毛细管温度，120℃。采用JEOL光谱仪在环境温度下测量试剂核磁共振H1谱和C13谱(400mhz)。以相对于指示溶剂中残留溶剂峰的ppm为单位测量化学位移，附带给出1H NMR光谱，多重性和赫兹偶合常数以及质子数。
用2-氯-1-(哌啶-1-基)乙-1-酮(10mg，0.062mmol)与1.0mL DMF中的相应胺(0.062mmol)和3微克K2CO3，在微波辐射130℃下反应30分钟(参见上述合成路线1)，用LC-MS监测反应过程。反应完成后，进行Gilson HPLC对反应混合物进行过滤纯化，得到如下化合物7～14，产率为20％～80％。
2-(5-溴吲哚-1-基)-1-(哌啶-1-基)乙-1-酮(2-(5-bromoindolin-1-yl)-1-(piperidin-1-yl)ethan-1-one(化合物7))
1H-NMR(CDCl3,400MHz)δ6.93(d,1H,J＝7.4Hz),6.78(d,1H,J＝7.4Hz),6.51(s,1H),3.88(s,2H),3.59(t,2H,J＝5.8Hz),3.54(t,2H,J＝7.6Hz),3.44(t,2H,J＝5.8Hz),2.98(t,2H,J＝8.0Hz),1.61(m,6H)13C-NMR(CDCl3,400MHz)δ166.64,153.16,128.97,125.59,120.96,120.53,109.59,53.92,50.79,46.31,43.06,28.13,26.53,25.63,24.47.HRMS calcd C15H19BrN2O for m/z＝323.0759(M+H)+,值323.0751。
2-(2-甲基吲哚-1-基)-1-(哌啶-1-基)乙-1-酮(2-(2-methylindolin-1-yl)-1-(piperidin-1-yl)ethan-1-one(化合物8))
1H-NMR(CDCl3,400MHz)δ7.06(m,2H),6.69(t,1H,J＝8.0Hz),6.37(d,1H,J＝8.0Hz),3.90(m,2H),3.87(m,3H),3.59(d,2H,J＝6.4Hz),3.49(s,2H),3.20(m,1H),2.66(m,1H),1.62(m,6H),1.31(d,3H,J＝6.2Hz).13C-NMR(CDCl3,400MHz)δ167.95,165.22,151.63,128.76,127.50,127.34,124.98,124.35,122.92,117.97,60.80,55.61,49.39,46.34,45.49,43.13,43.02,37.37,35.99,26.42,26.27,25.62,25.36,24.50,19.12.HRMScalcd C16H22N2O for m/z＝259.1810(M+H)+,值259.1811。
2-(7-羟基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮(2-(7-hydroxy-34-dihydroquinolin-1(2H)-yl)1-(piperidin-1-yl)ethan-1-one(化合物9))
1H-NMR(CDCl3,400MHz)δ6.81(d,1H,J＝8.4Hz),6.19(dd,1H,J＝8.4Hz,2.6Hz),6.08(d,1H,J＝2.6Hz),4.56(s,2H),3.53(t,2H,J＝5.7Hz),3.46(t,2H,J＝6.8Hz),3.25(t,2H,J＝5.5Hz),2.67(t,2H,J＝6.36Hz),1.89(m,2H),1.61(m,2H),1.55(m,4H).13C-NMR(CDCl3,400MHz)δ166.70,157.30,145.68,130.26,114.92,103.33,100.12,68.01,46.62,43.32,41.92,26.57,26.36,25.64,24.58,22.35.HRMS calcd C16H22N2O2 for m/z＝275.1760(M+H)+,值275.1764.
2-(6-羟基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮(2-(6-hydroxy-34-dihydroquinolin-1(2H)-yl)1-(piperidin-1-yl)ethan-1-one(化合物10))
1H-NMR(CDCl3,400MHz)δ6.92(m,2H),6.53(t,1H,J＝7.0Hz),6.32(d,1H,J＝8.0Hz),3.97(dd,J＝64Hz,16Hz,3.50(m,3H),3.38(s,2H),2.77(m,2H),1.97(m,1H),1.71(m,1H),1.54(m,6H),1.08(d,3H,J＝4.0Hz)13C-NMR(CDCl3,400MHz)δ167.94,144.46,128.89,127.12,122.64,116.18,110.62,52.72,51.31,46.00,43.22,28.14,26.62,25.67,24.56,24.02,18.30.HRMS calcd C17H24N2O for m/z＝273.1967(M+H)+,值273.1953.
2-(2-甲基-3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮(2-(2-methyl-34-dihydroquinolin-1(2H)-yl)1-(piperidin-1-yl)ethan-1-one(化合物11))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.5Hz),6.98(d,1H,J＝7.0Hz),6.62(t,1H,J＝7.5Hz),6.44(d,1H,J＝8.2Hz).4.05(s,2H),3.59(t,2H,J＝5.6Hz),3.46(t,2H,J＝4.8Hz),3.35(t,2H,J＝5.6Hz),2.81(t,2H,J＝6.8Hz),2.01(m,2H),1.60(m,6H).13C-NMR(CDCl3,400MHz)δ167.65,145.30,129.12,127.07,123.09,116.63,110.34,53.19,50.04,45.98,43.10,27.98,26.58,25.65,24.54,22.39.HRMS calcd C16H22N2O for m/z＝259.1810(M+H)+,值259.1850.
2-(3,4-二氢喹啉-1(2H)-基)-1-(哌啶-1-基)乙-1-酮(2-(3,4-dihydroquinolin-1(2H)-yl)1-(piperidin-1-yl)ethan-1-one(化合物12))
1H-NMR(CDCl3,400MHz)δ8.09(d,1H,J＝7.7Hz),7.43(t,1H,J＝6.4Hz),7.37(d,1H,J＝9.2Hz),7.29(m,2H),7.18(t,1H,J＝7.2Hz),6.99(d,1H,J＝8.4Hz),4.33(m,2H),3.03(s,2H),3.67(t,2H,J＝5.6Hz),3.47(t,2H,J＝5.6Hz),1.67(m,6H),1.43(t,3H,J＝7.6Hz)13C-NMR(CDCl3,400MHz)δ164.54,151.27,141.17,140.65,139.80,126.27,123.53,123.04,120.74,119.92,113.59,108.93,108.90,108.44,47.45,43.50,37.85,37.60,26.75,25.70,24.67,13.94.HRMS calcd C21H25N3O for m/z＝336.2076(M+H)+,值336.2065.
2-((9-乙基-9H-咔唑-3-基)氨基)-1-(哌啶-1-基)乙-1-酮(2-((9-ethyl-9H-carbazol-3-yl)amino)-1-(piperidin-1-yl)ethan-1-one(化合物13))
1H-NMR(CDCl3,400MHz)δ7.28(s,1H),7.00(m,2H),5.20(s,2H),3.54(t,4H,J＝5.0Hz),3.47(t,2H,J＝5.0Hz),2.70(t,2H,J＝5.6Hz),1.89(t,2H,J＝5.6Hz),1.63(m,6H).13C-NMR(CDCl3,400MHz)δ163.84,155.41,141.24,140.28,116.25,108.68,57.70,45.96,43.51,41.03,26.20,25.36,24.21,23.97,18.77.HRMS calcd C15H21N3O for m/z＝260.1763(M+H)+,found 260.1796.
2-(3,4-二氢-1,6-萘啶-1(2H)-基)-1-(哌啶-1-基)乙-1-酮(2-(3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-(piperidin-1-yl)ethan-1-one(化合物14))
1H-NMR(CDCl3,400MHz)δ6.80(t,1H,J＝8.4Hz),6.78(s,1H),6.35(d,1H,J＝8.2Hz),3.98(s,2H),3.54(t,2H,J＝5.5Hz),3.41(t,2H,J＝5.2Hz),3.27(t,2H,J＝5.8Hz),2.74(t,2H,J＝7.0Hz),2.17(s,3H),1.96(m,2H),1.60(m,6H).13C-NMR(CDCl3,400MHz)δ167.92,143.19,130.05,127.52,125.89,123.24,110.65,53.61,50.03,46.09,43.14,27.96,26.66,25.75,24.62,22.64,20.34.HRMS calcd C17H24N2O for m/z＝273.1967(M+H)+,found 273.1936.
使用2-氯-1-(吡咯烷-1-基)乙-1-酮(10mg，0.068mmol)在1.0mL DMF中与相应的胺(0.068mmol)和3微克K2CO3微波辐射下在130℃加热30分钟(参见上述合成路线1)。反应结束后，将反应混合物过滤并使用GilsonHPLC纯化，得到下列化合物15-19，产率为20％至80％。
2-(2-甲基吲哚-1-基)-1-(吡咯烷-1-基)乙-1-酮(2-(2-methylindolin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one(化合物15))
1H-NMR(CDCl3,400MHz)δ7.65(m,2H),6.98(t,2H,J＝7.6Hz),4.79(s,2H),3.53(t,2H,J＝6.8Hz),3.43(t,2H,J＝6.8Hz),3.39(m,1H),2.65(d,2H,J＝16Hz),2.00(m,2H),1.87(m,2H),1.36(d,3H,J＝6.2Hz).13C-NMR(CDCl3,400MHz)δ127.51,125.00,122.94,55.64,45.98,45.18,26.19,23.92.HRMS calcd C15H20N2O for m/z＝245.1654(M+H)+,found 245.1636.
2-(2-甲基-3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮(2-(2-methyl-3,4-dihydroquinolin-1(2H)-yl)-1-(pyrrolidin-1-yl)ethan-1-one(化合物16))
1H-NMR(CDCl3,400MHz)δ6.93(m,2H),6.53(t,1H,J＝7.4Hz),6.32(d,1H,J＝8.8Hz),3.91(dd,2H,J＝40Hz,16.6Hz),3.45(m,5H),2.76(m,1H),2.65(m,1H),1.93(m,3H),1.79(m,3H),1.08(d,3H,J＝6.0Hz).13C-NMR(CDCl3,400MHz)δ168.64,144.53,128.89,127.16,122.44,116.15,110.74,53.23,52.68,46.21,45.75,28.00 26.46,23.99,23.94,18.48.HRMS calcd C16H22N2O for m/z＝259.1810(M+H)+,found 259.1763.
2-(3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮(2-(3,4-dihydroquinolin-1(2H)-yl)-1-(pyrrolidin-1-yl)ethan-1-one(化合物17))
1H-NMR(CDCl3,400MHz)δ6.99(t,1H,J＝7.8Hz),6.94(d,1H,J＝7.6Hz),6.58(t,1H,J＝8.2Hz),6.41(d,1H,J＝8.5Hz),3.95(s,2H),3.48(m,4H),3.36(t,2H,J＝5.8Hz),2.78(t,2H,J＝5.8Hz),1.97(m,4H),1.84(m,2H).13C-NMR(CDCl3,400MHz)δ168.38,145.43,129.20,127.19,122.97,116.64,110.55,54.49,50.53,46.17,45.82,28.06,26.52,24.06,22.40.HRMS calcd C15H20N2O for m/z＝245.1654(M+H)+,found 245.1677.
2-(6-氟吲哚-1-基)-1-(吡咯烷-1-基)乙-1-酮(2-(6-fluoroindolin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one(化合物18))
1H-NMR(CDCl3,400MHz)δ7.25(s,1H),7.04(t,1H,J＝7.2Hz),6.63(t,1H,J＝8.5Hz),4.73(s,2H),4.17(t,2H,J＝8.5Hz),3.51(t,2H,J＝6.8Hz),3.41(t,2H,J＝6.8Hz),3.09(t,2H,J＝8.8Hz),1.99(m,2H),1.86(m,2H).13C-NMR(CDCl3,400MHz)δ109.34,109.11,62.51,48.47,46.12,45.24,27.04,26.26,23.98.HRMS calcd C14H17FN2O for m/z＝249.1403(M+H)+,found249.1412.
2-(3,4-二氢-1,6-萘啶-1(2H)-基)-1-(吡咯烷-1-基)乙-1-酮(2-(3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-(pyrrolidin-1-yl)ethan-1-one(化合物19))
1H-NMR(CDCl3,400MHz)δ8.72(s,1H),7.73(d,1H,J＝6.0Hz),6.87(d,1H,J＝6.0Hz),5.05(s,2H),3.50(t,2H,J＝7.2Hz),3.39(m,4H),2.60(t,2H,J＝6.4Hz),1.96(t,2H,J＝6.0Hz),1.80(m,4H).13C-NMR(CDCl3,400MHz)δ168.27,166.03,163.97,155.42,141.19,140.27,116.24,108.66,57.95,52.60,46.10,26.08,23.94,18.77.HRMS calcdC14H19N3O for m/z＝246.1606(M+H)+,found 246.1601.
3-(3,4-二氢喹啉-1(2H)-基)丙酸(3-(3,4-dihydroquinolin-1(2H)-yl)propanoic acid(化合物21))
在30mL无水DMF中加入化合物20(2.0g,15.0mmol)混合成溶液，再加入3-溴丙酸甲酯(3.76g,22.5mmol)和K2CO3(100mg,720mmol)。然后用微波将反应混合物在140℃下加热30分钟，同样采用LCMS监测反应。反应结束后，加入20毫升6M氢氧化钠混合后微波加热120度反应30分钟。反应结束后反应混合物真空处理，之后溶于ISCO CombiFlash(5％MeOH/DCM)纯化，得到2.46g黄色油性的3-(3,4-dihydroquinolin-1(2H)-yl)propanoic acid(化合物21)。产率为80％。1H NMR(CDCl3,400MHz)δ7.94(s,1H),6.99–6.89(m,1H),6.84(dd,J＝7.3,1.5Hz,1H),6.48(td,J＝7.3,1.1Hz,1H),3.62–3.51(m,2H),3.36–3.16(m,3H),2.67(t,J＝6.4Hz,2H),2.56–2.44(m,2H),2.04–1.81(m,2H).13C NMR(CDCl3,400MHz)δ171.62,162.9,144.6,140.6,130.2,129.4,127.1,116.3,114.5,110.68,49.76,47.95,43.10,33.75,27.91,22.11.
之后将相应的胺分别与3-(3,4-dihydroquinolin-1(2H)-yl)propanoic acid(化合物21)(10.0mg,0.048mmol)(0.048mmol)、HATU(18.5mg,0.048mmol)、DIPEA(12.6mg,0.097mmol)在1ml DMF中反应。然后将反应混合物在微波下加热到120℃反应25分钟，并用LCMS进行监测。反应完成后，用Gilson HPLC对反应混合物进行过滤纯化，得到相应的化合物如下。
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-甲基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(2-methylpiperidin-1-yl)propan-1-one(化合物22))
1H-NMR(CDCl3,400MHz)δ7.03(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.6(m,2H),3.64(m,3H),3.29(t,2H,J＝5.5Hz),2.73(t,2H,J＝6.3Hz),2.65(m,2H),2.55(m,2H),1.93(t,2H,J＝5.6Hz),1.60(m,6H),1.15(dd,3H,J＝11.3Hz,7.0Hz).13C-NMR(CDCl3,400MHz)δ144.79,129.38,127.31,122.52,115.74,110.41,49.58,48.30,47.71,43.69,40.83,29.70,28.19,26.36,22.28,18.82,16.80,15.63.HRMS calcd C18H26N2O for m/z＝287.2123(M+H)+,found287.2120.
3-(3,4-二氢喹啉-1(2H)-基)-1-((2S，6R)-2,6-二甲基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-((2S,6R)-2,6-dimethylpiperidin-1-yl)propan-1-one(化合物23))
1H-NMR(CDCl3,400MHz)δ7.03(t,1H,J＝7.7Hz),6.92(d,1H,J＝6.6Hz),6.55(m,2H),3.66(m,2H),3.30(t,2H,J＝5.5Hz),2.73(t,2H,J＝6.3Hz),2.62(m,2H),1.94(t,2H,J＝5.6Hz),1.94(m,2H),1.51(m,4H),1.45(m,2H),1.20(dd,6H,J＝23Hz,3.6Hz).13C-NMR(CDCl3,400MHz)δ171.07,144.82,129.36,127.30,122.46,115.67,110.40,49.61,47.83,47.51,29.29,28.20,22.29,13.91.HRMS calcd C19H28N2O for m/z＝301.2280(M+H)+,found 301.2316.
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-甲基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(2-methylpiperidin-1-yl)propan-1-one(化合物24))
1H-NMR(CDCl3,400MHz)δ7.07(t,1H,J＝7.7Hz),6.97(d,1H,J＝6.6Hz),6.60(m,2H),3.66(m,2H),3.33(t,2H,J＝5.5Hz),2.77(t,2H,J＝6.3Hz),2.62(m,2H),1.96(t,2H,J＝5.6Hz),1.96(m,4H),1.53(m,2H),0.89(dd,6H,J＝23Hz,3.6Hz),0.81(m,2H).13C-NMR(CDCl3,400MHz)δ169.79,144.66,129.32,127.22,122.48,115.73,110.31,52.88,49.58,32.14,31.00,29.28,28.11,22.21,19.10,18.96.HRMS calcd C19H28N2O for m/z＝301.2280(M+H)+,found 301.2329.
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-羟基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(3-hydroxypiperidin-1-yl)propan-1-one(化合物25))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.57(m,2H),3.86(d,1H,J＝13.3Hz),3.54(d,1H,J＝13.3Hz),3.66(m,2H),3.32(m,2H),3.28(t,2H,J＝5.5Hz),2.73(t,2H,J＝6.3Hz),2.60(m,2H),1.93(t,2H,J＝5.6Hz),1.76(m,2H),1.60(m,4H).13C-NMR(CDCl3,400MHz)δ129.44,127.34,115.93,110.40,66.53,66.03,52.44,49.62,48.60,47.62,46.10,41.98,32.86,32.20,29.26,28.15,22.94,22.25.HRMScalcd C17H24N2O2 for m/z＝289.1916(M+H)+,found 289.1922.
3-(3,4-二氢喹啉-1(2H)-基)-1-(4-羟基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(4-hydroxypiperidin-1-yl)propan-1-one(化合物26))
1H-NMR(CDCl3,400MHz)δ7.11(t,1H,J＝7.7Hz),7.01(d,1H,J＝6.6Hz),6.57(m,2H),4.03(m,1H),3.90(m,1H),3.67(m,3H),3.36(t,2H,J＝5.5Hz),3.19(t,2H,J＝5.5Hz).2.78(m,4H),2.03(m,2H),1.83(m,2H),1.47(m,2H).13C-NMR(CDCl3,400MHz)δ164.54,151.27,141.17,140.56,139.80,126.27,123.53,123.04,120.74,119.92,113.59,108.93,108.90,108.44,47.45,43,50,37.85,37.60,26.75,25.70,24.67,13.94.HRMS calcdC17H24N2O2 for m/z＝289.1916(M+H)+,found 289.1922.
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(2-(hydroxymethyl)piperidin-1-yl)propan-1-one(化合物27))
1H-NMR(CDCl3,400MHz)δ7.06(t,1H,J＝7.7Hz),6.95(d,1H,J＝6.6Hz),6.60(m,2H),4.26(m,1H),3.67(m,6H),3.30(m,2H),2.76(m,3H),2.66(m,2H),1.95(m,2H),1.65(m,6H).13C-NMR(CDCl3,400MHz)δ172.16,167.08,144.55,129.38,128.32,127.23,127.19,122.79,116.25,115.88,110.69,110.35,64.21,55.23,49.54,49.32,46.93,44.39,31.03,28.09,28.01,25.41,22.16.HRMS calcd C18H26N2O2 for m/z＝303.2073(M+H)+,found303.2097.
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-(羟甲基)哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(3-(hydroxymethyl)piperidin-1-yl)propan-1-one(化合物28))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.56(m,2H),3.65(m,2H),3.47(m,2H),3.29(m,3H),3.26(m,4H),2.72(m,2H),2.60(m,2H),1.92(m,2H),1.50(m,5H).13C-NMR(CDCl3,400MHz)δ170.49,144.70,129.44,129.37,127.35,127.32,122.65,115.93,115.76,110.49,64.88,49.98,49.65,47.92,47.66,46.97,37.58,29.20,27.23,26.61,22.22.HRMS calcd C18H26N2O2 for m/z＝303.2073(M+H)+,found303.2084.
3-(3,4-二氢喹啉-1(2H)-基)-N-(2-氟-4-羟基苯基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(2-fluoro-4-hydroxyphenyl)propanamide(化合物29))
1H-NMR(CDCl3,400MHz)δ7.91(t,1H,J＝8.3Hz),7.51(s,1H),7.07(t,1H,J＝8.2Hz),6.97(d,1H,J＝7.4Hz),6.64(m,2H),6.57(m,2H),3.68(t,2H,J＝6.6Hz),3.29(t,2H,J＝5.6Hz),2.74(t,2H,J＝6.3Hz),2.65(t,2H,J＝6.6Hz),1.94(m,2H).HRMS calcdC18H19FN2O2for m/z＝315.1509(M+H)+,found 315.1513.
(3-(3,4-二氢喹啉-1(2H)-基)丙酰基)脯氨酸((3-(3,4-dihydroquinolin-1(2H)-yl)propanoyl)proline(化合物30))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.56(m,2H),4.55(s,1H),3.67(m,2H),3.48(m,2H),3.37(m,1H),3.28(t,3H,J＝5.6),2.71(t,2H,J＝6.23),2.64(t,2H,J＝7.0),2.40(m,1H),1.92(m,5H).13C-NMR(CDCl3,400MHz)δ174.19,172.38,144.47,129.55,127.33,122.77,116.23,110.36,60.18,49.91,48.12,47.19,31.19,28.10,27.55,24.82,22.29.HRMS calcd C17H22N2O3 for m/z＝303.1709(M+H)+,found 303.1722.
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-羟基吡咯烷-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(3-hydroxypyrrolidin-1-yl)propan-1-one(化合物31))
1H-NMR(CDCl3,400MHz)δ6.98(t,1H,J＝7.7Hz),6.88(d,1H,J＝6.6Hz),6.52(m,2H),4.40(s,1H),3.60(t,2H,J＝8.0Hz),3.59(m,1H),3.50(m,2H),3.40(m,2H),3.25(t,2H,J＝6.0Hz),2.67(t,2H,J＝6.3Hz),2.49(t,2H,J＝5.6Hz),1.88(m,4H).13C-NMR(CDCl3,400MHz)δ129.44,127.34,115.93,110.40,66.53,66.03,52.44,49.62,48.60,47.62,46.10,41.98,32.86,32.20,29.26,28.15,22.94,22.25.HRMS calcd C16H22N2O2 for m/z＝275.1760(M+H)+,found 275.1792.
3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)吡咯烷-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)propan-1-one(化合物32))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.57(m,2H),4.20(m,1H),3.66(m,3H),3.56(m,1H),3.42(m,2H),3.30(m,2H),2.73(t,2H,J＝6.23),2.58(t,2H,J＝7.0),1.92(m,5H),1.55(m,1H).13C-NMR(CDCl3,400MHz)δ173.51,144.63,129.47,127.33,122.62,115.99,110.38,67.66,61.42,49.83,48.40,47.38,31.56,28.40,28.15,24.44,22.28.HRMS calcd C17H24N2O2 for m/z＝289.1916(M+H)+,found 289.1933.
(S)-3-(3,4-二氢喹啉-1(2H)-基)-1-(2-(羟甲基)吡咯烷-1-基)丙-1-酮((S)-3-(3,4-dihydroquinolin-1(2H)-yl)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)propan-1-one(化合物33))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.57(m,2H),4.20(m,1H),3.66(m,3H),3.56(m,1H),3.42(m,2H),3.30(m,2H),2.73(t,2H,J＝6.23Hz),2.58(t,2H,J＝7.0Hz),1.92(m,5H),1.55(m,1H).13C-NMR(CDCl3,400MHz)δ173.52,144.63,129.47,127.33,122.61,115.99,110.38,67.64,61.41,49.84,48.41,47.38,31.56,28.40,28.15,24.44,22.28.HRMS calcd C17H24N2O2 for m/z＝289.1916(M+H)+,found 289.1881.
1-(氮杂环丁烷-1-基)-3-(3,4-二氢喹啉-1(2H)-基)丙-1-酮(1-(azetidin-1-yl)-3-(3,4-dihydroquinolin-1(2H)-yl)propan-1-one(化合物34))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.56(m,2H),4.01(m,4H),3.61(t,2H,J＝7.2Hz),3.28(t,2H,J＝5.7Hz),2.73(t,2H,J＝6.4Hz),2.32(t,2H,J＝7.0Hz),2.19(m,2H),1.93(m,2H).13C-NMR(CDCl3,400MHz)δ171.90,144.65,129.42,127.28,122.60,115.90,110.50,50.19,49.79,47.92,47.39,28.19,27.87,22.31,15.07.HRMS calcd C15H20N2O for m/z＝245.1654(M+H)+,found 245.1661.
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-甲氧基氮杂环丁烷-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(3-methoxyazetidin-1-yl)propan-1-one(化合物35))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.56(m,2H),4.12(m,3H),3.85(m,2H),3.61(m,2H),3.28(t,2H,J＝5.7Hz),3.26(s,3H),2.73(t,2H,J＝6.4Hz),2.35(t,2H,J＝7.0Hz),1.93(m,2H).13C-NMR(CDCl3,400MHz)δ172.17,144.58,129.45,127.28,122.57,115.96,110.47,68.66,57.10,56.24,54.95,49.86,47.39,28.29,28.16,22.28.HRMS calcd C16H22N2O2 for m/z＝275.1760(M+H)+,found275.1763.
3-(3,4-二氢喹啉-1(2H)-基)-1-(3-甲基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(3-methylpiperidin-1-yl)propan-1-one(化合物36))
1H-NMR(CDCl3,400MHz)δ7.03(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.55(m,2H),4.58(m,1H),3.75(m,1H),3.64(m,2H),3.29(t,2H,J＝5.7Hz),2.92(m,1H),2.73(t,2H,J＝6.4Hz),2.57(t,3H,J＝7.6Hz),1.93(m,2H),1.61(m,3H),1.04(m,2H),0.91(dd,3H,J＝9.8Hz,6.7Hz).13C-NMR(CDCl3,400MHz)δ170.03,169.99,144.76,144.72,129.40,127.31,122.55,115.78,110.40,110.37,53.23,49.60,47.67,46.24,42.20,33.14,31.93,31.06,29.32,29.13,28.19,26.06,24.89,22.27,19.18,18.97.HRMS calcd C18H26N2O form/z＝287.2123(M+H)+,found287.2134.
3-(3,4-二氢喹啉-1(2H)-基)-1-(4-甲基哌啶-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(4-methylpiperidin-1-yl)propan-1-one(化合物37))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.56(m,2H),4.45(m,1H),3.64(m,3H),3.29(t,2H,J＝5.7Hz),2.73(t,2H,J＝6.4Hz),2.58(m,3H),1.93(m,2H),1.79(m,1H),1.65(m,1H),1.51(m,1H),1.39(m,1H),1.10(m,1H),0.86(dd,3H,J＝9.8Hz,6.7Hz).13C-NMR(CDCl3,400MHz)δ170.07,144.74,129.39,127.31,122.53,115.77,110.41,49.58,47.66,42.08,34.68,33.82,31.17,29.26,28.19,22.27,21.82.HRMS calcd C18H26N2O for m/z＝287.2123(M+H)+,found 287.2136.
3-(3,4-二氢喹啉-1(2H)-基)-1-(吡咯烷-1-基)丙-1-酮(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(pyrrolidin-1-yl)propan-1-one(化合物38))
1H-NMR(CDCl3,400MHz)δ7.03(t,1H,J＝7.7Hz),6.93(d,1H,J＝6.6Hz),6.56(m,2H),3.65(t,2H,J＝7.3Hz),3.44(t,2H,J＝6.7Hz),3.31(m,4H),2.72(t,2H,J＝6.4Hz),2.53(t,2H,J＝7.1Hz),1.87(m,6H).13C-NMR(CDCl3,400MHz)δ170.07,144.74,129.39,127.31,122.53,115.77,110.41,49.58,47.66,46.04,42.08,34.68,33.82,31.17,29.26,28.19,22.27,21.82.HRMS calcd C16H22N2O for m/z＝259.1810(M+H)+,found 259.1799.
3-(3,4-二氢喹啉-1(2H)-基)-N-苯基丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-phenylpropanamide(化合物39))
1H-NMR(CDCl3,400MHz)δ7.44(d,2H,J＝7.1Hz),7.28(d,2H,J＝8.3Hz),7.08(m,2H),6.98(d,1H,J＝6.9Hz),6.65(m,2H),3.68(t,2H,J＝6.5Hz),3.29(t,2H,J＝5.6Hz),2.73(t,2H,J＝6.3Hz),2.62(t,2H,J＝6.3Hz),1.92(m,2H).13C-NMR(CDCl3,400MHz)δ170.19,144.78,137.89,129.61,129.11,128.83,127.34,124.40,123.49,119.91,116.86,111.25,49.92,48.28,34.85,28.06,22.26.HRMS calcd C18H20N2O for m/z＝281.1654(M+H)+,found 281.1633.
N-环己基-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺(N-cyclohexyl-3-(3,4-dihydroquinolin-1(2H)-yl)propanamide(化合物40))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.58(m,2H),5.47(s,1H),3,74(m,1H),3.59(t,1H,J＝6.5Hz),3.27(t,2H,J＝5.7Hz),2.73(t,2H,J＝6.4Hz),2.38(t,2H,J＝6.5Hz),1.90(m,4H),1.67(m,2H),1.58(m,2H),1.32(m,2H),1.08(m,3H).13C-NMR(CDCl3,400MHz)δ170.80,144.82,129.45,127.23,122.92,116.19,110.71,49.93,48.32,48.14,34.25,33.25,28.14,25.57,24.97,22.32.HRMS calcd C18H26N2O form/z＝287.2123(M+H)+,found 287.2109.
N-环戊基-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺(N-cyclopentyl-3-(3,4-dihydroquinolin-1(2H)-yl)propanamide(化合物41))
1H-NMR(CDCl3,400MHz)δ7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.58(m,2H),5.56(s,1H),4.18(m,1H),3.59(t,1H,J＝6.5Hz),3.27(t,2H,J＝5.7Hz),2.73(t,2H,J＝6.4Hz),2.38(t,2H,J＝6.5Hz),1.93(m,4H),1.58(m,4H),1.29(m,2H).13C-NMR(CDCl3,400MHz)δ171.33,144.79,129.46,127.24,122.93,116.24,110.75,51.26,49.88,48.12,34.06,33.15,28.13,23.75,22.31.HRMS calcd C17H24N2O for m/z＝273.1967(M+H)+,found 273.2005.
3-(3,4-二氢喹啉-1(2H)-基)-N-(噻唑-2-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(thiazol-2-yl)propanamide(化合物42))
1H-NMR(CDCl3,400MHz)δ7.28(d,2H,J＝3.6Hz),7.04(t,1H,J＝7.7Hz),6.94(d,1H,J＝6.6Hz),6.93(t,1H,J＝3.6Hz),6.61(m,2H),3.73(t,2H,J＝3.6Hz),3.27(t,2H,J＝5.7Hz),2.75(m,4H),1.93(m,2H).13C-NMR(CDCl3,400MHz)δ136.85,129.62,127.33,116.84,113.70,110.93,49.93,47.64,33.29,27.98,22.25.HRMS calcd C15H17N3OS for m/z＝288.1171(M+H)+,found 288.1186.
N-(4-氯苯基)-3-(3,4-二氢喹啉-1(2H)-基)丙酰胺(N-(4-chlorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)propanamide(化合物43))
1H-NMR(CDCl3,400MHz)δ7.37(d,2H,J＝8.8Hz),7.24(d,2H,J＝7.6Hz),7.07(t,1H,J＝7.7Hz),6.98(d,1H,J＝6.6Hz),6.65(m,2H),3.67(t,2H,J＝6.4Hz),3.27(t,2H,J＝5.5Hz),2.73(t,2H,J＝6.4Hz),2.61(t,2H,J＝6.5Hz),1.91(m,2H).13C-NMR(CDCl3,400MHz)δ170.22,144.75,136.45,129.67,129.31,129.11,127.36,123.62,121.10,117.09,111.37,49.91,48.33,34.80,28.04,22.25.HRMS calcd C18H19ClN2O for m/z＝315.1264(M+H)+,found315.1250.
3-(3,4-二氢喹啉-1(2H)-基)-N-(萘-1-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(naphthalen-1-yl)propanamide(化合物44))
1H-NMR(CDCl3,400MHz)δ7.94(d,1H,J＝7.4Hz),7.83(d,1H,J＝8.1Hz),7.67(d,1H,J＝8.2Hz),7.59(d,1H,J＝8.5Hz),7.45(t,2H,J＝7.5Hz),7.37(m,1H),7.11(t,1H,J＝7.6Hz),7.01(d,1H,J＝7.6Hz),6.75(d,1H,J＝8.2Hz),6.67(t,1H,J＝7.2Hz),3,76(t,2H,J＝6.5Hz),3,34(t,2H,J＝5.8Hz),2.80(t,2H,J＝6.4Hz),2.73(t,2H,J＝6.3Hz),1.91(m,2H).13C-NMR(CDCl3,400MHz)δ170.69,144.90,134.14,132.34,129.66,128.80,127.41,126.83,126.28,126.05,125.84,125.78,123.78,120.64,120.58,117.11,111.47,49.90,48.33,34.75,28.04,22.26.HRMS calcd C22H22N2O for m/z＝331.1810(M+H)+,found331.1818.
3-(3,4-二氢喹啉-1(2H)-基)-N-(哒嗪-3-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(pyridazin-3-yl)propanamide(化合物45))
1H-NMR(CDCl3,400MHz)δ8.87(d,1H,J＝4.7Hz),8.52(d,1H,J＝9.2Hz),7.49(m,1H),7.03(t,1H,J＝7.8Hz),6.94(d,1H,J＝8.4Hz),6.62(m,2H),3.70(t,2H,J＝6.8Hz),3.31(t,2H,J＝5.8Hz),2.82(m,2H),2.74(m,2H),1.95(m,2H).13C-NMR(CDCl3,400MHz)δ162.73,155.42,148.41,129.50,128.76,127.25,119.21,116.69,111.04,49.88,47.89,36.64,47.89,36.64,34.81,31.56,28.02,22.28.HRMS calcd C16H18N4O for m/z＝283.1559(M+H)+,found 283.1558.
3-(3,4-二氢喹啉-1(2H)-基)-N-(1-甲基-1H-吲哚-5-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(1-methyl-1H-indol-5-yl)propanamide(化合物46))
1H-NMR(CDCl3,400MHz)δ7.77(s,1H),7.20(m,3H),7.03(d,1H,J＝3,0Hz),7.08(t,1H,J＝7.6Hz),6.97(d,1H,J＝7.1Hz),6.65(m,2H),6.41(d,1H,J＝3.0Hz),3.75(s,3H),3.71(t,2H,J＝6.6Hz),3.32(t,2H,J＝5.6Hz),2.73(t,2H,J＝6.3Hz),2.62(t,2H,J＝7.0Hz),1.92(m,2H).13C-NMR(CDCl3,400MHz)δ170.05,144.81,134.29,130.12,129.80,129.56,128.55,127.34,123.29,116.56,115.88,112.82,111.07,109.40,101.12,49.98,48.35,34.84,33.05,28.11,22.29.HRMS calcd C21H23N3O for m/z＝334.1919(M+H)+,found 334.1921.
3-(3,4-二氢喹啉-1(2H)-基)-N-(喹啉-8-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(quinolin-8-yl)propanamide(化合物47))
1H-NMR(CDCl3,400MHz)δ8.80(d,1H,J＝7.2Hz),8.76(d,1H,J＝4.4Hz),8.18(d,1H,J＝8.4Hz),7.54(m,2H),7.46(m,1H),7.12(t,1H,J＝8.4Hz),6.99(d,1H,J＝8.4Hz),6.74(d,1H,J＝8.4Hz),6.63(t,1H,J＝6.8Hz),3.83(t,2H,J＝6.8Hz),3.39(t,2H,J＝4Hz),2.87(t,2H,J＝6.8Hz),2.76(t,2H,J＝6.4Hz),1.97(m,2H).13C-NMR(CDCl3,400MHz)δ170.42,148.15,144.70,138.31,136.32,134.45,129.33,127.93,127.39,123.20,121.63,121.59,116.53,116.71,110.77,49.68,47.67,34.94,28.07,22.23.HRMS calcd C21H21N3Ofor m/z＝332.1763(M+H)+,found 332.1769.
3-(3,4-二氢喹啉-1(2H)-基)-N-(呋喃-2-基甲基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(furan-2-ylmethyl)propanamide(化合物48))
1H-NMR(CDCl3,400MHz)δ7.32(m,1H),7.03(t,1H,J＝7.1Hz),6.93(d,1H,J＝7.1Hz),6.57(m,2H),6.29(m,1H),6.19(m,1H),4.41(d,2H,J＝5.5Hz),3.60(t,2H,J＝6.7Hz),3.22(t,2H,J＝5.6Hz),2.69(t,2H,J＝6.9Hz),2.44(t,2H,J＝6.6Hz),1.86(m,2H).13C-NMR(CDCl3,400MHz)δ171.56,151.18,144.69,142.31,129.46,129.46,127,25,123.05,116.35,110.75,110.57,107.73,49.88,48.06,36.55,33.73,28.04,22.22.HRMScalcd C17H20N2O2 for m/z＝285.1603(M+H)+,found 285.1601.
3-(3,4-二氢喹啉-1(2H)-基)-N-(噻吩-3-基甲基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(thiophen-3-ylmethyl)propanamide(化合物49))
1H-NMR(CDCl3,400MHz)δ7.26(m,1H),7.08(m,1H),7.03(t,1H,J＝7.6Hz),6.95(m,2H),6.58(m,2H),4.41(d,2H,J＝5.8Hz),3.62(t,2H,J＝6.8Hz),3.22(t,2H,J＝11.4Hz),2.69(t,2H,J＝6.8Hz),2.5(t,2H,J＝6.8Hz),1.84(m,2H).13C-NMR(CDCl3,400MHz)δ171.53,144.73,138.84,129.47,127.52,127.27,126.54,123.00,122.67,116.36,110.77,49.87,48.09,38.82,33.87,28.06,22.23.HRMS calcd C17H20N2OS for m/z＝301.1375(M+H)+,found301.1381.
3-(3,4-二氢喹啉-1(2H)-基)-N-(1-甲基-1H-吡唑-3-基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide(化合物50))
1H-NMR(CDCl3,400MHz)δ7.21(d,1H,2.3Hz),7.04(t,1H,J＝7.8Hz),6.94(d,1H,J＝7.2Hz),6.62(m,3H),3.74(s,3H),3.67(t,2H,J＝6.9Hz),3.27(t,2H,J＝5.7Hz),2.72(t,2H,J＝6.4Hz),2.58(t,2H,J＝7.1Hz),1.92(m,2H).13C-NMR(CDCl3,400MHz)δ166.27,146.79,144.59,131.02,129.51,127.29,123.12,116.49,110.84,97.49,49.82,47.93,38.83,33.90,28.04,22.24.HRMS calcd C16H20N4O for m/z＝285.1715(M+H)+,found285.1718.
3-(3,4-二氢喹啉-1(2H)-基)-N-(3-氟苄基)丙酰胺(3-(3,4-dihydroquinolin-1(2H)-yl)-N-(3-fluorobenzyl)propanamide(化合物51))
1H-NMR(CDCl3,400MHz)δ7.25(m,2H),7.01(m,2H),6.93(m,3H),6.59(m,1H),4.39(d,2H,J＝6.0Hz),3.62(t,2H,J＝5.6Hz),3.23(t,2H,J＝5.8Hz),2.69(t,2H,J＝6.3Hz),2.48(t,2H,J＝6.8Hz),1.85(m,2H).13C-NMR(CDCl3,400MHz)δ171.76,164.26,161.81,144.74,140.81,140.73,130.36,130.28,129.51,127.27,123.45,123.42,123.06,116.45,114.88,114.67,114.43,110.81,49.88,48.08,43.23,33.88,28.04,22.24.HRMS calcdC19H21FN2O for m/z＝313.1716(M+H)+,found 313.1729.
生物活性实施例
除另有说明外，本文中所有数据均以3个独立实验结果的平均值±SEM表示。在放射性配体饱和结合实验中，使用GraphPad Prism 7中的非线性曲线拟合方法获得了[3H]-NMS的亲和力(KD)和最大结合量(Bmax)。在竞争结合实验中，用one-site Ki模型拟合梯度浓度的化合物与[3H]-NMS的竞争结合曲线，计算其抑制常数(Ki)。在细胞内Ca2+实验中，拮抗活性测定值IC50是由one-site IC50模型拟合产生的。所有活性参数均取对数计算。
材料
中国仓鼠卵巢细胞(CHO)包括CHO-K1/M1,CHO-K1/M2/Gα15,CHO-K1/M3,CHO-K1/M4/Gα15购自美国GenScript公司。[3H]-N-甲基莨菪碱([3H]-NMS；83.4Ci/mmol)购自美国波士顿Perkin Elmer公司。含青霉素-链霉素、博来霉素、潮霉素B、G418和HBSS缓冲液、培养基(DMEM)/F-12购自Thermo Fisher Scientific公司(美国拉斐特)。胎牛血清(FBS)购自Lonsera公司(中国苏州)。Fura-2/AM购自Dojindo(日本熊本)。对CHO-K1/M2/Gα15和CHO-K1/M4/Gα15细胞而言，将M受体与Gα15共转染至CHO-K1细胞中，从而使细胞表面高表达重组受体，且含有高水平的Gα15以连接下游钙信号通路。
细胞培养
CHO-K1细胞均在添加10％胎牛血清的DMEM/F12培养基中培养。CHO-K1/M1的培养基添加了500μg/mL的青霉素-链霉素和200μg/mL的博来霉素。CHO-K1/M3培养基包含400μg/mL的G418。CHO-K1/M2/Gα15和CHO-K1/M4/Gα15培养基中都添加了200μg/mL的博来霉素和100μg/mL潮霉素B。
膜蛋白制备
将细胞扩增至若干10cm皿中，细胞用冰冷KHB缓冲液洗两遍，加入KHB缓冲液2mL，冰面上轻轻刮下细胞，收集细胞于15mL离心管中，4℃条件下3000rpm离心5min，重悬细胞。冰水浴中利用玻璃研磨器破碎，研磨10-20次后，同样4℃条件下，12000rpm离心20min，重悬于适量KHB缓冲液中(以每皿200μL计)，得到膜蛋白后，每管1mL分装，液氮闪冻后-80℃冻存。蛋白浓度采用BCA法定量。采用Thermo Fisher Scientific公司(美国拉斐特)的microBCA试剂盒测定蛋白浓度。
细胞内Ca2+检测
细胞内Ca2+检测方法参见现有技术(Xu,J.；Tan,P.；Li,H.；Cui,Y.；Qiu,Y.；Wang,H.；Zhang,X.；Li,J.；Zhu,L.；Zhou,W.Direct SUMOylation of M1 muscarinicacetylcholine receptor increases its ligand-binding affinity and signaltransduction.The FASEB Journal 2019,33,3237-3251)。简要地说，将CHO-K1细胞接种到黑色的96孔板中，并在CO2培养箱培养约24小时。用HBSS缓冲液冲洗细胞后，并在各孔加入5μM的Fura-2/AM(日本熊本同仁化学研究所)，37℃孵育30分钟。随后从每个孔中吸出染料，用HBSS溶液洗涤细胞3次，以充分去除残留的Fura 2/AM工作液，然后加入HBSS溶液100ul，37℃培养箱孵育约20-30分钟，以确保AM体在细胞内的完全去酯化作用。利用FlexstationⅢ多功能酶标仪(Molecular Devices,USA)将不同浓度的配体溶液加入到96孔板中进行细胞内钙流检测，检测时激发波长380nm(Fura 2)和340nm(Ca2+-Fura 2)，发射波长510nm。
放射性配体结合试验
[3H]-NMS饱和结合实验采用96孔板在KHB缓冲液[3mM KCl,6mM Dextrose,113mMNaCl,2mM MgSO4,25mM HEPES,3mM CaCl2 and 1mM NaH2PO4(pH 7.4)]中进行，如前所述[35]。简要来说，为了确定[3H]-NMS对于每个亚型的亲和力，将10ug不同亚型的受体蛋白和不同浓度的[3H]-NMS(0,0.01,0.03,0.1,0.3,1,3and 10nM)混合，37℃孵育60分钟，检测[3H]-NMS非特异性结合时，体系各孔中再补加10uM阿托品。通过Whatman(美国通用电气公司)的GF/B过滤器进行过滤，终止反应，然后用冰冷的0.9％NaCl洗涤三次。通过Microbeta 2(Perkin Elmer，美国)的液体闪烁计数仪计cpm数。在进行竞争结合实验时，体系总量保持200ul不变，KHB仍为体系缓冲液，在各孔中加入10ug膜蛋白匀浆、0.5nM[3H]-NMS和一定浓度梯度的待测化合物，在37℃孵育60分钟后终止反应，放射性检测同上所述。
生物活性测试结果如表1、表2、图1-4所示。
表1化合物7-19的结构及其活性数据
Figure BDA0002459948940000251
n＝1
Figure BDA0002459948940000252
Figure BDA0002459948940000261
表2化合物22-51的结构及其活性数据
Figure BDA0002459948940000262
Figure BDA0002459948940000263
Figure BDA0002459948940000271
Figure BDA0002459948940000281
还使用ChemDraw(Perkin Elmer，美国)分析了每一种化合物的亲脂性，其cLogP示于表1、2。
从上述结果可以看出，本发明化合物具有较高的M2胆碱受体选择性、合适的亲脂性和成药性。
分子对接
化合物47采用
Figure BDA0002459948940000291
2016.1的LigPrep模块制备。在分子对接实验中，我们采用
Figure BDA0002459948940000292
2016.1标准精度(SP)方法，蛋白结构准备完成后，以共晶中的化合物配体为中心，设置默认参数生成网格。在OPLS3力场作用下，配体对接至非活性状态的M2乙酰胆碱受体亚型与QNB共晶(PDB ID:3UON)结构的正位结合位点。
化合物47对接在人体M2胆碱受体的x射线晶体结构的正构位点，该结构是非活性状态M2胆碱受体与奎宁环基苯甲酸(QNB)共晶复合体(PDB ID:3UON)。通过薛定谔软件，首先将共晶结构中QNB结合的活性区域生成网格文件，进而采用软件默认设置的标准精度(SP)方法进行分子对接。化合物47选择结合姿势和相互作用图如图5所示。化合物47与人M2胆碱受体的主要结合方式是配体的酰胺氮与M2受体蛋白的第三个跨膜螺旋区域的的保守位点Tyr104(3.33)(Ballesteros-Weinstein命名法)之间形成氢键，与典型的胺能GPCRs的正构配体类似。此外，核心酰胺基的远端芳香环与Tyr104侧链之间存在pi-pi堆积相互作用。酰胺基近端芳香环被M2受体结构中的“芳香盖”结构包围，该结构包含Tyr403、Phe181和Tyr177位点(图5A和5B)。与非选择性QNB和tiotropium的互作模式相比，与M2胆碱受体结构中的“芳香盖”相互作用可以允许容纳空间位阻更大的化合物结构，这将有利于提升化合物的亚型选择性。

Claims (4)

1.一种式(I)所示的化合物或其药学上可接受的盐，
Figure FDA0003742079580000011
其中，n为1或2；
Figure FDA0003742079580000012
为
Figure FDA0003742079580000013
Figure FDA0003742079580000014
Figure FDA0003742079580000015
为
Figure FDA0003742079580000016
R7为碳原子数为1-3的烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物为2-((9-乙基-9H-咔唑-3-基)氨基)-1-(哌啶-1-基)乙-1-酮。
3.一种药物组合物，其特征在于，包含权利要求1或2所述的化合物或其药学上可接受的盐、以及药学上可接受的载体。
4.一种权利要求1或2所述的化合物或其药学上可接受的盐在制备M2胆碱受体拮抗剂中的用途。
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