CN113214231A - 5ht2a受体拮抗剂及其医疗应用 - Google Patents
5ht2a受体拮抗剂及其医疗应用 Download PDFInfo
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- CN113214231A CN113214231A CN202010068325.9A CN202010068325A CN113214231A CN 113214231 A CN113214231 A CN 113214231A CN 202010068325 A CN202010068325 A CN 202010068325A CN 113214231 A CN113214231 A CN 113214231A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明提供了一种具有中枢神经系统疾病治疗作用的式I结构的化合物，其具有5‑HT2A受体拮抗剂或反向激动剂活性，并且对5‑HT2A受体的选择性高、心脏毒性低、代谢稳定性好，可以用于治疗某些精神疾病(如抑郁症、焦虑症、精神病、精神分裂症、失眠、自闭症)及与中枢神经系统退行性疾病(如阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症)相关或者并发的精神紊乱症状。
Description
技术领域
本发明属于医药技术领域，涉及一种具有中枢神经系统疾病治疗作用的5-HT2A受体拮抗剂或反向激动剂及其应用。所述化合物可以用于治疗某些精神疾病(如抑郁症，焦虑症，精神病，精神分裂症，失眠，自闭症等)及与中枢神经系统退行性疾病(如阿尔兹海默症，帕金森病，亨廷顿病，路易小体痴呆症等)相关或者并发的精神紊乱症状。
背景技术
血清素或5-羟色胺(5-HT)在人体生理功能中发挥着极为重要的作用。在中枢神经系统中，5-HT是一种重要的神经递质和神经调节剂，它在调控多种行为如睡眠、饮食、活动、学习和记忆、机体体温、血压以及病理状态(如焦虑、躁狂、精神分裂、肥胖、药物成瘾、偏头痛和高血压)方面发挥着极为重要的作用(Alenina N，et al.，(2009)ProcNatl Acad SciUSA，106，10332-10337；Filip M，et al.，(2005)Pharmacol Rep，57，685-700；Greek AR，(2006)Br J Pharmacol，147，Suppl 1：S145-S152)。5-HT通过其受体发挥作用，根据结构(氨基酸序列)、生化(信号转导的后受体机制)和药理学差异将5-HT受体分为7个家族(5-HT1～5-HT7)以及至少15个不同亚型(Barnes NM，et al.，(1999)Neuropharmacology，38，1083-1152；Hannon J，et al.，(2008)Behav Brain Res，195，198-213；Hoyer D，et al.，(2002)Pharmacol Biochem Behav，71，533-554；Pauwels PJ.(2003)Tocris Reviews，No.25)。不同亚型受体的分布、配体偏好以及相关功能各不相同。
5-HT2A亚型受体在中枢神经系统呈现广泛而离散的表达，在参与调节高级认知和情感功能的大脑皮质、边缘、海马、下丘脑和基底神经节中表达最高。5-HT2A受体在多巴胺、GABA、谷氨酸和Ach神经元上表达并起着树突状异质受体的作用(Buhot MC，(1997)CurrOpin Neurobiol，7，243-254；Leysen JE，(2004)Curr Drug Targets CNS Neuro Disord，3，11-26)。和大多数5-HT受体一样，5-HT2A受体为G-蛋白偶联受体，它通过激活鸟嘌呤核苷酸结合蛋白(G蛋白)完成信号转导，导致第二信使分子如环腺苷酸(cAMP)、肌醇磷酸酯(inositol phosphates)以及二酰甘油(diacylglycerol)水平升高或降低。这些第二信使分子调节多种胞内酶的功能(如激酶和离子通道)，最终影响细胞兴奋性和细胞功能。
5-HT传递异常与多种精神疾病的发病机制相关，如精神疾病(抑郁、惊恐发作、精神分裂症、自杀倾向等)以及神经系统退行性疾病(阿尔兹海默症、亨廷顿舞蹈症、帕金森病等)(Fioravanti et al.，(1992)Brain Cogn.18，116-124；Sinopoli VM，et al.，(2017)Neurosci Biobehav Rev，80：372-381)。近年来研究发现，5-HT2A受体与神经精神疾病的病理状态密切相关，5-HT2A受体参与了非典型抗精神病药物如氯氮平、奥氮平、利培酮的分子作用机制(Gonzalez-Maeso J，et al.，(2009)Trends Neurosci，32：225-232；Fribourg M，et al.，(2011)Cell，147：1011-1023；Kurita M，et al.，(2012)Nat Neurosci，15：1245-1254)；5-HT2A受体拮抗剂对于治疗精神分裂症阴性症状(如情感障碍、语言功能减退等)十分重要(Blier P，et al.，(2005)JClin Psychiatry 66，Suppl 8，30-40；Richtand NM，etal.，(2008)Prog Brain Res，172，141-153；Meltzer，H.Y.(2013)Annu Rev Med 64，393-406)；另有研究证实，皮质锥体神经元的5-HT2A受体调节通路对介导致幻剂引发的信号转导和行为反应至关重要(Gonzalez-Maeso J，et al.，(2009)Trends Neurosci，32：225-232)，提示5-HT2A受体在治疗多种神经退行性疾病幻觉症状方面的作用。
用于治疗精神疾病的药物，即抗精神病药物分为两大类。“典型”抗精神病药物或上一代药物由于对人体造成的机动功能副作用(锥体外系副反应、类帕金森病证等)在临床已很少应用，现行药物更多着眼于“非典型”抗精神病药物(Prim Cre Companion J ClinPsychiatry.(2007)9(6)：444-54)。但是该第二代抗精神病药物皆有广谱受体活性，这些化合物作为激动剂、竞争性拮抗剂或反向激动剂等方式调节多种单胺能受体如5-HT能、多巴胺能、肾上腺素能、毒蕈碱或组胺能受体，这种广谱调节很有可能是造成镇静异常、运动机能异常、二型糖尿病等副作用的原因。大多数抗精神病药物都具有多巴胺D2受体拮抗作用，现已证明与锥体外系副作用相关(Strange PG.(2001)Pharmacol Rev，53(1)：119-33；Tuppurainen H，et a1.，(2010)Nord J Psychiatry，64(4)：233-8；Sykes DA，et al.，(2017)Nat Commun，8(1)：763)。因此，开发选择性5-HT2A受体拮抗剂或反向激动剂，尤其是具有选择性高的，和/或无多巴胺D2受体结合活性等特性，对于推动抗神经精神疾病药物发展有至关重要的作用，这类化合物在治疗疾病同时能够避免由于无选择性受体相互作用导致的诸多副作用。
发明内容
本发明提供一种具有5-HT2A受体拮抗活性的化合物，及含有该化合物的用于治疗中枢神经系统疾病的药物组合物，并进一步提供中枢神经系统疾病的治疗方法。
具体而言，本发明提供一种具有式I结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：
其中，
n、m分别选自0-4的整数，限定所述亚烷基链的亚烷基单元数量，
X为杂原子或碳原子，所述杂原子选自O，N，S原子，优选为N原子；
环X即X原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，
环B基团选自含4-8元环烷基、4-8元杂环烷基、5-8元芳环基或5-8元杂芳环基，该环与苯环稠合；优选环B为4-8元环烷基或4-8元杂环烷基；
R1为1或多个取代基，位于所在环系的任意取代位置，R1彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R2彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R3为1或多个取代基，位于所在环的任意取代位置，R3彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2。
进一步，所述式I结构化合物，
其中，n为1，2或3；m为0，1或2；
X为杂原子，选自O，N，S原子；优选为N原子；
环B与苯环形成的环系选自以下结构基团：
其中，Y选自O，N，S原子；优选为O原子。
更进一步，一种具有式IA结构化合物，或其药物可接受的盐，溶剂化物，或立体异构体：
其中，
n为1，2或3；m为0，1或2，
X为杂原子，选自O，N，S原子，优选为N原子；
Y选自O，N，S原子；优选为O原子；
R1为1或多个取代基，位于所在环系的任意取代位置，R1彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R2彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R3为1或多个取代基，位于所在环的任意取代位置，R3彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2。
优选，式I或式IA化合物中，环X通过环碳原子与化合物主体结构连接；优选R3在X位置取代。
进一步优选，式I或式IA化合物中，环X为吖丁啶基，吡咯烷基，或哌啶基；Y为O原子。
术语“烷基”是指饱和的烃基，包括直链烷基、分支链烷基。
术语“卤素”指F、Cl、Br或I。
术语“亚烷基”是指二价烷基。“亚烷基链”是聚亚甲基，即-(CH2)x-，其中x为正整数。
术语“环烷基”，是指饱和或含有一个或一个以上不饱和单元但非芳香族的单环烃基，所述环为3-20元环，其具有单个连接点与化合物的其余部分相连接。
术语“杂环烷基”为含有1个到5个、独立的选自N，S，O等杂原子的单环状基团，所述杂环烷基可以是饱和环或不饱和环，所述环为3-20元环，包括哌啶，吡咯烷，四氢呋喃等。
术语“芳基”、“芳环基”或“芳香环基”，指单环，所述系统共具有5至10个(优选5、6或9个)环成员，环成员为环碳原子；环系中共享(4n+2)个π电子(其中n是正整数)以符合休克尔规则。
术语“杂芳基”和“杂芳环基”是指具有5到10个环原子，优选5、6或9个；环原子具有(4n+2)个π电子(其中n是正整数)以符合休克尔规则；并且除碳原子外，还具有1到5个杂原子，所述杂原子选自氮、氧或硫，并包括氮或硫的任何氧化形式和碱性氮的任何季铵化形式。
术语“彼此独立”在本申请中表示，所述取代彼此独立，不互为关联。
术语“所在环任意取代位置”、“位于所在环系任意取代位置”表示，取代基团位于环或环系中任意的可被取代的位置，包括环碳原子、环氮、环硫原子等取代位点。可举例为：所述环为苯环时，取代位置为相对于主链取代位置的邻、间和/或对位，或2，3，4，5或6位(相对于苯环连接主链位置)；所述环为含氮5元或6元环时，取代位置可能为环N位置，或环氮位置的邻、间或对位，或2，3，4或5位等。
术语“药学上可接受的盐”包括从适合的无机酸和碱以及有机酸和碱衍生而来的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸如盐酸，氢溴酸，磷酸，硫酸和高氯酸等，或者与有机酸如乙酸，草酸，马来酸、酒石酸，柠檬酸，琥珀酸或丙二酸等形成的盐，或者通过使用诸如离子交换等本领域的其他方法形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。
本发明还进一步保护如下具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：
3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基哌啶-4-基)-脲，
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，
(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，
(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，
(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，
(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，或，
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲。
本发明还保护一种制备式I化合物的方法，其特征在于：
步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，
步骤2、如果需要，再根据目标产物的需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物。
所述制备方法同样适用于式IA化合物的制备。
本发明的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体具有5HT2A受体抑制活性或反向激动活性，可以用于5HT2A受体活性介导的相关疾病的治疗。
本发明化合物对5HT2A的抑制活性是采用Flp-In-CHO-5HT2A稳定细胞系，通过IP-One实验完成检测。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。如果化合物表现出EC50≤1μM，认为在以上分析中测试的化合物具有5HT2A受体抑制活性。本发明优选的化合物具有EC50≤150nM，更优选的化合物具有EC50≤50nM，最优选化合物具有EC50≤30nM。
本发明的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体，具有好的5HT2A受体的拮抗活性。进一步的，本发明化合物还具有好的选择性，尤其是对5HT2B和/或5HT2C的选择性，降低的心脏毒性，和/或，提高的代谢稳定性。
本发明提供式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体活性介导的相关疾病的药物中的用途。
所述5HT2A受体活性介导的相关疾病包括但不限于中枢神经系统疾病。
所述中枢神经系统疾病包括但不限于：精神疾病、中枢神经系统退行性疾病、中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状。
所述精神疾病包括但不限于：抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症等。
所述中枢神经系统退行性疾病包括但不限于：阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症等。
所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状包括但不限于：情感障碍、语言功能减退、幻觉、兴趣缺失等。
本发明提供一种药物组合物，其特征在于包括式I化合物、式IA化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
所述药物组合物可以用于治疗5HT2A受体活性介导的相关疾病。所述5HT2A受体活性介导的相关疾病的定义如前文所述。
所述药物组合物进一步含有药学上可接受的载体。
所述药学上可接受的载体是制药领域中常用或已知的各种辅料，包括但不限于：稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。
所述稀释剂例如：乳糖、淀粉、纤维素衍生物、无机钙盐、山梨醇等。所述粘合剂例如：淀粉、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮等。所述抗氧化剂例如：维生素E、亚硫酸氢钠、亚硫酸钠、丁羟基茴香醚等。所述pH调节剂例如：盐酸、氢氧化钠、柠檬酸、酒石酸、Tris、乙酸、磷酸二氢钠、磷酸氢二钠等。所述防腐剂例如：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、间甲酚、苯扎氯铵等。所述润滑剂例如：硬脂酸镁、微粉硅胶、滑石粉等。所述崩解剂例如：淀粉、甲基纤维素、黄原胶、交联羧甲基纤维素钠等。
所述药物组合物中含有式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的量为0.1-1000mg，优选1-500mg，更优选为5-100mg。
所述药物组合物中式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体占药物组合物的质量百分比为10％-90％，优选为20％-80％，更优选为30％-70％。
所述药物组合物的剂型可以是口服剂的形式，例如片剂、胶囊、丸剂、粉剂、颗粒剂、悬浮剂、糖浆剂等；也可以是注射给药的剂型，例如注射液、粉针剂等，通过静脉内、腹膜内、皮下或肌肉内的途径注射给药。所有使用的剂型形式都是药学领域普通技术人员所熟知的。
所述药物组合物的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的；通过植入储库或储液器。
式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物、式IA化合物或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-100mg/kg/天，优选为0.1-10mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。
所述药物组合物可以和其他的治疗5HT2A受体活性介导的相关疾病的药物联合应用。
所述药物组合物可以进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体活性介导的相关疾病的药物。
本发明提供一种治疗5HT2A受体活性介导的相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体。
所述式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的；通过植入储库或储液器。
所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体活性介导的相关疾病的药物。
其他的治疗5HT2A受体活性介导的相关疾病的药物包括但不限于：精神疾病治疗药物、中枢神经系统退行性疾病治疗药物等。
所述精神疾病治疗药物包括但不限于：苯二氮
类(例如：甲基三唑西泮、氯氮
氯硝西泮、地西泮、舒乐安定、氟西泮、咪达唑仑等)；巴比妥类(例如：苯巴比妥、戊巴比妥等)；水合氯醛；丁螺环酮；吩噻嗪类(例如：氯丙嗪、硫利达嗪、氟奋乃静等)；硫杂蒽类(例如：替沃噻吨)；丁酰苯类(例如：氟哌啶醇)；氯氮平；利哌利酮；三环类抗抑郁药(例如：丙咪嗪、多塞平、去甲替林、阿米替林等)；杂环类抗抑郁药(例如：阿莫沙平、马普替林、曲唑酮、安非他酮、文法拉辛等)；选择性5-HT重摄取抑制剂(例如：氟西汀、帕罗西汀、舍曲林、西酞普兰、氟伏沙明等)；单胺氧化酶抑制剂(例如：苯乙肼、吗氯贝胺等)；氯胺酮；米氮平等。
所述中枢神经系统退行性疾病治疗药物包括但不限于：左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺、利血平等。
具体实施方案
实施例中使用的化学试剂均为市售化合物，其中
DMF：N，N-二甲基甲酰胺；
DIEA：N，N-二异丙基乙胺；
Et3N：三乙基胺
DCM：二氯甲烷
THF：四氢呋喃
Acetone：丙酮
Pyridine：吡啶
Pd(PPh3)4：四(三苯基膦)钯
FTA：三氟乙酸
Triphosgene：三光气
Et：乙基，Ac：乙酰基；如EtOAc为乙酸乙酯或醋酸乙酯，ETOH为乙醇。
中间体化合物制备
N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)，用5.5mmol(1-甲基吖丁啶-3-基)甲胺得到棕色油状中间体(H001-057)(500mg，44％产率)。LCMS：[M+1]+209.2。
(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)，用8.5mmol(S)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-058)(720mg，38％产率)。LCMS：[M+1]+223.2。
(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)，用8.5mmol(R)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-059)(750mg，40％产率)。LCMS：[M+1]+223.2。
N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)，用8.8mmol(1-甲基哌啶-4-基)甲胺得到棕色油状中间体(H002-070)(1.5g，75％产率)。LCMS：[M+1]+255.3。
实施例1：合成3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基-哌啶-4-基)-脲(compound#45)，ER10058
0℃下，三光气(148mg，0.500mmol)的DCM(5.0mL)溶液慢慢加入到色烷-6-基-甲胺单-盐酸(99mg，0.500mmol)和三乙胺(50mg，0.500mmol)的DCM溶液(5.0mL)中。混合物在室温下搅拌1小时。加入冰水(20毫升)，用DCM(20mL×2)提取混合物。将有机相用盐水清洗，用Na2SO4干燥，在真空下过滤和浓缩，得油状产物(45-1)(80mg，85％的产率)。
室温下，在1-甲基-哌啶-4-基胺(19g，88mmol)的500.0mL二氯甲烷溶液中添加4-氟苯甲醛(11g，90mmol)，然后分批慢慢加入三乙酰氧基氢硼化物钠(33g，180mmol)，及10ml醋酸。混合物在室温下搅拌过夜。加入冰水(500m1)，用10％(v/v)异丙醇/氯仿(500ml×4)提取混合物。有机相用Na2SO4干燥，在真空条件下过滤和浓缩，得到无色油状中间体(45-2)(12.7g，产率65％)。LCMS：[M+1]+223.4。
0℃下把色烷-6-甲基异氰酸酯(45-1)(79mg，0.42mmol)的无水THF(5ml)溶液慢慢加到(4-氟-苯甲基)-(1-甲基-哌啶-4-基)-胺(45-2)(100mg，0.45mmo1)的DCM(5.0mL)溶液中。生成的混合物在40℃加热约10分钟。在真空下去除溶剂。粗产物高效液相色谱法进行纯化。得到黄色固体compound#45(109mg，产率62％)。LCMS：[M+1]+411.9。
实施例2：合成3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-064)ER10191
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-064)ER10191合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.25mmol)得到白色固体H001-064(12mg，产率12％)。LCMS：[M+1]+398.3。
实施例3：合成(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-065)ER10192
(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-065)ER10192
合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.5mmol)得到白色固体H001-065(70mg，产率34％)。LCMS：[M+1]+412.3。
实施例4：合成(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-066)ER10193
(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-066)ER10193
合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.5mmol)得到白色固体H001-066(45mg，产率22％)。LCMS：[M+1]+412.3。
实施例5：合成3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-074)ER10216
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-074)ER10216合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-074(28mg，产率42％)。LCMS：[M+1]+ 444.3。
实施例6：合成3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-075)ER10217
N-(2，4-二氟苯甲基)-1-甲基哌啶-4-胺(H002-069)：合成方法类似于(45-2)。用1-甲基哌啶-4-基胺(8.8mmol)得到棕色油状中间体(H002-069)(0.8g，产率38％)。LCMS：[M+1]+241.3。
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-075)ER10217合成方法类似于compound#45。用0.15mmol色烷-6-甲基异氰酸酯(45-1)得到白色固体H002-075(32mg，50％产率)。1H NMR(400MHz，Chloroform-d)δ11.61(s，1H)，7.11(td，J＝8.8，8.3，6.1Hz，1H)，6.86-6.75(m，3H)，6.73(d，J＝2.1Hz，1H)，6.66(d，J＝8.3Hz，1H)，4.74(s，1H)，4.34(s，2H)，4.22(s，2H)，4.20-4.09(m，2H)，3.59(d，J＝11.6Hz，2H)，2.87(s，2H)，2.78(s，3H)，2.77-2.63(m，2H)，2.13(d，J＝13.0Hz，2H)，2.03-1.85(m，4H)。LCMS：[M+1]+430.2。
实施例7：合成(R)-3-(色烷-6-基甲基)-1-(2，4-二二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-080)ER10220
(S)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-078)：合成方法类似于(45-2)。用(S)-(1-甲基吡咯烷-3-基)甲胺(4mmol)得到棕色油状中间体(H002-078)(0.6g，产率63％)。LCMS：[M+1]+241.3。
(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-080)ER10220：合成方法类似于compound#45。用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-080(7mg，产率11％)。LCMS：[M+1]+430.2。
实施例8：合成(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-083)ER10223
(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-083)ER10223：合成方法类似于compound#45。用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-083(9mg，产率13％)。LCMS：[M+1]+430.2。
生物学活性试验
以下生物学活性试验中，使用的ER10152是阳性对照物，结构式为：
可商购，或按照US7601740B2中记载的方法合成制备。
1、5-HT2A受体拮抗剂活性筛选试验
为证实本发明化合物对5-HT2A受体的拮抗活性，选择IP-One实验完成检测。以下实验采用Flp-In-CHO-5HT2A稳定细胞系完成。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。细胞产生的IP1和试剂盒所提供的标记了d2的IP1竞争抗IP1抗体的抗原结合位点，当铽标记抗IP1抗体与d2标记的IP1结合后，会发生能量共振转移，从而产生信号，随细胞内IP1产生增多，游离的IP1与抗体结合增多，信号逐渐减小。
材料和方法：
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-InTM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择ZeocinTM抗性克隆产生Flp-InTM-CHO细胞系。Flp-InTM-CHO细胞系于加有10％FBS(Hyclone)+1×Penicilin-Streptomycin(15140-122，Gibco)的Ham's F-12K完全培养基(Hyclone)中培养，之后以人HTR2A基因(Human HTR2A，GeneBank，NM_000621)稳定转染得到Flp-In-CHO-5HT2A细胞。稳定转染的细胞系培养于加有10％FBS(Hyclone)+1×Penicilin-Streptomycin+800μg/mlHygromycin B(ant-hg-5，Invivogen)的Ham's F-12K完全培养基(Hyclone)中。为验证化合物活性，Flp-In-CHO-5HT2A稳定细胞系在37℃，5％CO2条件下，于384孔板中培养(7.5K)20小时。化合物用Ham's F-12K培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞用化合物处理30分钟后加入5-HT在37摄氏度下培养45分钟，之后顺序加入裂解检测缓冲液、IP1-d2和IP1-Ab室温培养1小时后在Envision上读板(HTRF模块)。
根据所示结果，Flp-In-CHO-5HT2A稳定细胞系的5HT2A受体活性会被化合物所抑制，提示所述化合物具有5HT2A受体拮抗活性。
| ID | 5HT2A EC50(nM) |
| ER10152 | 45 |
| ER10058 | 15 |
| ER10216 | 8 |
| ER10217 | 7.5 |
| ER10220 | 26 |
| ER10223 | 20 |
2、5-HT2B/2CvGv受体拮抗剂活性筛选试验
为证实本发明化合物对5-HT2B/2CvGv受体的拮抗活性，选择IP-One实验完成检测。以下实验采用Flp-In-CHO-5HT2B/2CvGv稳定细胞系完成。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。细胞产生的IP1和试剂盒所提供的标记了d2的IP1竞争抗IP1抗体的抗原结合位点，当铽标记抗IP1抗体与d2标记的IP1结合后，会发生能量共振转移，从而产生信号，随细胞内IP1产生增多，游离的IP1与抗体结合增多，信号逐渐减小。
材料和方法：
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-InTM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择ZeocinTM抗性克隆产生Flp-InTM-CHO细胞系。Flp-InTM-CHO细胞系于加有10％FBS(Gibco)+1×Penicilin-Streptomycin(15140122，Gibco)的Ham's F-12K完全培养基(Hyclone)中培养，之后以人HTR2B/2CvGv基因(Human HTR2B，GeneBank，NM_000867；Human HTR2C(5-HT2CvGv)，GeneBank， NM_000868)稳定转染得到Flp-In-CHO-5HT2B/2CvGv细胞。稳定转染的细胞系培养于加有10％FBS(Gibco)+1×Penicilin-Streptomycin+800μg/ml Hygromycin B(ant-hg-5，Invivogen)的Ham's F-12K完全培养基(Hyclone)中。为验证化合物活性，Flp-In-CHO-5HT2B/2CvGv稳定细胞系在37摄氏度，5％CO2条件下，于384孔板中培养(5K，7.5K)20小时。化合物用Ham's F-12K培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞用化合物处理30分钟后加入5-HT在37摄氏度下培养45分钟，之后顺序加入裂解检测缓冲液、IP1-d2和IP1-Ab室温培养1小时后在Envision上读板(HTRF模块)，计算化合物对细胞5-HT2B/2CvGv受体的抑制率。
将每个化合物对5-HT2B或5-HT2C的EC50值除以其对5-HT2A的EC50值，计算出每个化合物对5-HT2B或5-HT2C的选择性相对于5-HT2A的选择性的倍数：
| ID | 对2B选择性(倍数) | 对2C选择性(倍数) |
| ER10152 | 86× | 4× |
| ER10058 | 199× | 19× |
| ER10217 | 1000× | 28× |
3、hERG膜蛋白特异性结合实验
为检验本发明化合物对心脏的毒性，选择hERG膜蛋白特异性结合实验完成检测。该实验采用稳定表达hERG(human Ether-a-go-go Related Gene)编码钾通道的HEK293细胞系完成实验。在心肌中，hERG编码的钾通道介导一种延迟整流钾电流(IKr)，Ikr抑制是药物导致QT间期延长最重要的机制。hERG因其特殊的分子结构，其功能缺失或药物抑制都会影响心脏动作电位复极过程并会引起QT间期延长，同时可能诱发尖端扭转性室性心动过速，导致心律失常。
该实验将hERG膜蛋白、检测化合物与固定浓度的放射性配体混合，使检测化合物和放射性配体竞争性地与hERG膜蛋白结合，孵育一定时间达到平衡后，用真空过滤掉没有与膜蛋白结合的放射性配体，烘干过滤板后加入闪烁液，并在Microbeta上检测同位素信号(CPM)。信号越高代表检测化合物与hERG膜蛋白结合能力越弱。
材料和方法：
将化合物、稀释好的hERG膜蛋白以及稀释好的H3-多菲利特配体(NET1144100UC，PerkinElmer)先后加入到96孔板(3631，Corning)内，封板膜封板后，室温摇动孵育1小时，使用PerkinElmer细胞收集器将孵育后的hERG膜蛋白转移至GF/B板(600517，PerkinElmer)上，使用冲洗缓冲液(20mmol/LHEPES(PH7.4)(Sigma-H3375)；10mmol/L氯化钾(Sigma-P9333)；1mmol/L氯化镁(Sigma-449172)，4℃保存)清洗5次(4℃，每次0.4mL)。随后将GF/B板于50℃烘箱内烘烤30min，使GF/B板充分干燥后，底部封板膜(6005199，PerkinElmer)封闭GF/B板底部，向板子每孔加入50μL闪烁液20(6013621，PerkinElmer)后用顶部封板膜(6005250，PerkinElmer)封板，Microbeta上读板检测放射性信号。
测试化合物以及它们的结合率值
| ID | hERG结合率(％at 10μM) |
| ER10152 | 91 |
| ER10058 | 66 |
| ER10217 | 53 |
4、人肝微粒体代谢稳定性实验
肝脏是内源性基质及外源性药物代谢的主要器官。有几种体外工具可以帮助研究人员研究候选药物的代谢，包括分离的新鲜或冷冻保存的肝细胞、肝脏切片以及肝微粒和S9组分等亚细胞成分。这些亚细胞成分是通过一系列的均质化和超速离心的方式从肝脏中制备出来。
10,000g肝脏匀浆的初始低速离心法产生的S9组分是此离心方法得到的上清液中的组分。S9组分包含所有I相和II相酶，S9组分进一步离心100,000g得到内质网衍生微粒。微粒体富含细胞色素P450(CYP)和黄素单加氧酶(FMO)。此外，一些II相酶(如某些苷葡糖苷酸转移酶UGT亚型和环氧水解酶EH)也在微粒体中存在。微粒体可用于研究UGT的活性，然而，微粒体膜限制UGT基质和/或辅助因子的进入。通过添加MgCl2以及成孔抗生素(如丙甲菌素)可以达到最佳UGT活性。这些组件使得微粒体网络中的葡萄糖醛酸产物和辅助因子UDPGA能够有效转运。个体或组合的供者肝微粒体可用于进行代谢相关研究。组合的供者可以代表人群平均水平或特定研究因素，如年龄，BMI或特定CYP亚型的限制能力。本研究的目的是评定化合物在人肝微粒体中的代谢稳定性。
材料和方法
该测试体系用到的人肝微粒体购买自Corning(Cat No.452117)，使用前储存于低于-60℃的冰箱内。辅酶为NADPH(Chem-impex international，Cat.No.00616)和UDPGA(Sigma，Cat.No.U6751)辅因子。将称量好的NADPH粉末和UDPGA粉末溶解在MgCl2溶液中配置25mM UGPDA和10mM NADPH的工作液。准备八块96孔板(T0，T5，T10，T20，T30，T60，NFC60，BLANK)，使用Apricot自动液体工作站(PP-550DS，USA)，每孔加入10μL化合物工作液(T0，T5，T10，T20，T30，T60，NFC60)，T0板加入冷乙腈终止液，随后向八块板中加入80μL/孔人肝微粒体，37度预孵育10分钟。NCF60板加入10μL/孔100mM磷酸钾缓冲液放入37度水浴锅中孵育计时1小时。其他板在孵育结束后加入10μL/孔NADPH+UDPGA辅因子组合，按照每板设定做不同时间孵育。孵育结束后加入300μL/孔冷乙腈终止反应，封板震荡10分钟后4000rpm，4度离心20分钟。取100μL/孔离心上清液加入到已添加300μL/孔HPLC水的新板中，混匀递交LC-MS/MS生物分析。
计算化合物与内标峰面积比值转化成剩余百分比求得供试品和对照化合物体外消除速率常数ke：％剩余量＝任意时间点对照品与内标的峰面积比值/0分钟时对照品与内标的峰面积比值×100％。
CLint(mic)＝0.693/T1/2/微粒体蛋白含量(孵育时微粒体蛋白浓度mg/mL)
CLint(liver)＝CLint(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比
根据充分搅拌模型(well stir model)，肝固有清除率和肝清除率可以通过下式换算：
CL(Liver)＝(CLint(liver)×Qh)/(CLint(liver)+Qh)
化合物的肝微粒体清除率：
| ID | HLM(mL/min/Kg) |
| ER10152 | 23.6 |
| ER10058 | 21.6 |
| ER10216 | 22 |
| ER10217 | 13 |
| ER10220 | 22 |
Claims (9)
1.一种具有式I结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：
其中，
n、m分别选自0-4的整数，
X为杂原子或碳原子，所述杂原子选自O，N，S原子，优选为N原子；
环X即X原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，
环B基团选自含4-8元环烷基、4-8元杂环烷基、5-8元芳环基或5-8元杂芳环基，该环与苯环稠合；优选环B为4-8元环烷基或4-8元杂环烷基；
R1为1或多个取代基，位于所在环系的任意取代位置，R1彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R2彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R3为1或多个取代基，位于所在环的任意取代位置，R3彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2。
2.如权利要求1所述的化合物，其特征在于，所述式I结构化合物，
其中，n为1，2或3；m为0，1或2；
X为杂原子，选自O，N，S原子，优选为N原子；
环B与苯环形成的环系选自以下结构基团：
其中，Y选自O，N，S原子；优选为O原子。
3.一种具有式IA结构化合物，或其药物可接受的盐，溶剂化物，或立体异构体：
其中，
n为1，2或3；m为0，1或2，
X为杂原子，选自O，N，S原子，优选为N原子；
Y选自O，N，S原子，优选为O原子；
R1为1或多个取代基，位于所在环系的任意取代位置，R1彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R2彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2；
R3为1或多个取代基，位于所在环的任意取代位置，R3彼此独立选自H、卤素，C1-6烷基，C1-6烷氧基、羟基或NO2。
4.如权利要求1-3任一项所述的化合物，其特征在于，环X通过环碳原子与化合物主体结构连接；
优选R3在X位置取代。
5.如权利要求1-4任一项所述的化合物，其特征在于，环X为吖丁啶基，吡咯烷基，或哌啶基；Y为O原子。
6.如权利要求1-5任一项所述的化合物，其选自如下结构的具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：
3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基哌啶-4-基)-脲，
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，
(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，
(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，
(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，
(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，或，
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲。
7.如权利要求1-6任一项所述化合物的制备方法，其特征在于：
步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，
步骤2、如果需要，再根据目标产物的需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物。
8.一种药物组合物，其特征在于包含权利要求1-6任一化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
优选，所述药物组合物进一步包含药学上可接受的载体。
优选，所述药物组合物进一步包含第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体活性介导的相关疾病的药物。
优选，所述第二种治疗剂选自：苯二氮
类、巴比妥类、水合氯醛、丁螺环酮、吩噻嗪类、硫杂蒽类、丁酰苯类、氯氮平、利哌利酮、三环类抗抑郁药、杂环类抗抑郁药、选择性5-HT重摄取抑制剂、单胺氧化酶抑制剂、氯胺酮、米氮平、左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺和利血平。
9.权利要求1-6任一化合物或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体活性介导的相关疾病的药物中的应用。
优选，所述5HT2A受体活性介导的相关疾病是中枢神经系统疾病。
优选，所述中枢神经系统疾病是精神疾病、中枢神经系统退行性疾病、中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状。
优选，所述精神疾病是抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症。
优选，所述中枢神经系统退行性疾病是阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症。
优选，所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状是情感障碍、语言功能减退、幻觉、兴趣缺失。
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