CN110627664B - 一种新的氟西汀类似物及其制备方法和应用 - Google Patents

一种新的氟西汀类似物及其制备方法和应用 Download PDF

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CN110627664B
CN110627664B CN201810664565.8A CN201810664565A CN110627664B CN 110627664 B CN110627664 B CN 110627664B CN 201810664565 A CN201810664565 A CN 201810664565A CN 110627664 B CN110627664 B CN 110627664B
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CN110627664A (zh
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闫京波
王刚
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Beijing Anbo Ruida Pharmaceutical Technology Co ltd
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Abstract

本发明涉及一种新的氟西汀类似物及其制备方法和应用，属于化合物及其制备方法和应用的技术领域。本发明所述氟西汀类似物具有下述式(I)所示的结构：
Figure DDA0001707411310000011

Description

一种新的氟西汀类似物及其制备方法和应用
技术领域
本发明涉及一种新的氟西汀类似物及其制备方法和应用，属于化合物及其制备方法和应用的技术领域。
背景技术
氟西汀(Fluoxetine)【化学名(±)-N-甲基-γ-[4-三氟甲基-苯氧基]-苯丙胺(结构式如式(I-M)所示)】或盐酸氟西汀(Fluoxetine hydrochloride/Cymbaha，也简称为氟西汀)【化学名(±)-N-甲基-γ-[4-三氟甲基-苯氧基]-苯丙胺盐酸盐(结构式如式(II-M)所示)】：
Figure GDA0003654273750000011
是一种选择性5-羟色胺再摄取抑制剂。氟西汀通过抑制神经突触细胞对神经递质血清素的再吸收以增加细胞外可以和突触后受体结合的血清素水平。而对其他受体，如α-肾上腺能、β-肾上腺素能、5-羟色胺能、多巴胺能等，氟西汀则几乎没有结合力。据氟西汀生产的抗抑郁药百优解1986年在比利时首先获准上市用于抑郁症的治疗，1987年底获得美国FDA批准进入美国市场，1995年3月30日进入中国市场。氟西汀在临床上除用于成人抑郁症外，还用于强迫症和神进行贪食症的治疗，也还用于治疗具有或不具有广场恐惧症的惊恐症。
然而氟西汀的药学活性仍有待进一步改善。
发明内容
本发明的目的在于克服上述现有技术中的不足，提供一种新型的氟西汀类似物，其具有明显优于氟西汀的药物活性。
本发明的另一个目的在于提供一种上述新型的氟西汀类似物的制备方法。
本发明的再一个目的在于提供一种上述新型的氟西汀类似物在制备治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛的药物中的应用。
基于此，本发明提供一种新型的氟西汀类似物或其药学上可接受的盐，其具有下述式(I)所示的结构：
Figure GDA0003654273750000021
其中：
R1和R2分别独立地选自H、卤素、C1-6烷基，C3-8环烷基，羟基，C1-6烷氧基，C1-6卤代烷基；
R3选自C3-8环烷基；
R4选自未取代或任选被Rs取代的下列基团：C1-6烷基，羟基C1-6烷基，C3-10环烷基，C1-6烷基C3-10环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C1-6烷硫基，巯基C1-6烷硫基，C1-6烷硫基C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，二(C3-8环烷基)氨基，羟基C1-6烷基氨基，3-10元杂环烷基，C1-6烷基3-10元杂环烷基，C1-6烷氧基C1-6烷基，羟基C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基、C6-14芳基、5-14元杂芳基；
Rs选自卤素、C1-6烷基或C3-10环烷基；
X选自O、S或NH；
n为0-5的整数；
m为0-5的整数。
根据本发明，优选地R1和R2分别独立地选自H、卤素、C1-6烷基，C1-6烷氧基，C1-6卤代烷基。
根据本发明，优选地R3选自环丙烷基。
根据本发明，优选地R4选自H、C1-6烷基，羟基C1-6烷基，C3-8环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷氧基C1-6烷氧基，C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，羟基C1-6烷基氨基，C1-6烷氧基C1-6烷基，羟基C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基，以及未取代或被卤素、C1-6烷基，取代的C3-8杂环基、C6-14芳基、C6-14杂芳基；
其中C3-8杂环基更优选为吗啉基、哌啶基、哌嗪基、吡咯烷基、氮杂环丁烷基；C6-14杂芳基更优选为吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、恶唑基、苯并噻唑基、苯并咪唑基、苯并恶唑基、吲哚基、喹啉基、异喹啉基、苯并吡嗪基、苯并嘧啶基、苯并二氧六环基、1,3-苯并间二氧杂环戊烯基以及
Figure GDA0003654273750000031
根据本发明，优选地X选自O。
根据本发明，优选地n为1，2或3；更优选n为1。
根据本发明，优选地m为0，1或2；更优选m为0。
根据本发明的优选技术方案，所述氟西汀类似物选自如下化合物：
Figure GDA0003654273750000041
Figure GDA0003654273750000051
Figure GDA0003654273750000061
Figure GDA0003654273750000071
Figure GDA0003654273750000081
Figure GDA0003654273750000091
Figure GDA0003654273750000101
本发明的化合物的药学上可接受的盐包括常规无机酸、羧酸和磺酸的酸加成盐，例如盐酸、氢溴酸、硫酸、磷酸、甲烷磺酸、乙烷磺酸、苯磺酸、甲苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明的化合物的药学上可接受的盐的也包括常规的碱的盐，例如和优选，碱金属盐(例如钠和钾盐)，碱土金属盐(例如钙和镁盐)和衍生自氨或具有1-16个碳原子的有机胺，例如和优选乙胺、二乙胺、三乙胺、N,N-二异丙基乙胺、一乙醇胺、二乙醇胺、三乙醇胺、二甲氨基乙醇、二乙氨基乙醇、普鲁卡因、二环己胺、二苄胺、N-甲基哌啶、N-甲基吗啉、精氨酸、赖氨酸和1,2-乙二胺的铵盐。
根据本发明的化合物取决于它们的结构可以以不同的立体异构的形式，即以构型异构体的形式，或任选地作为构象异构体(对映异构体和/或非对映异构体，包括在阻转同分异构体情况下的那些非对映异构体)存在。本发明因此包括对映异构体和非对映异构体和它们各自的混合物。立体异构一致的组分可以由这种对映异构体和/或非对映异构体的混合物以已知的方式分离；对于这优选使用层析法，特别是在非手性或手性相上的HPLC层析。
如果根据本发明的化合物可以以互变异构形式存在，本发明包括所有的互变异构形式。
在本发明的上下文中，除非另外具体说明，所述取代基如下定义：
根据本发明，“烷基”(其本身或作为化学基团的一部分)是直链烃或支链烃，优选具有1至6个碳原子，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1，2-二甲基丙基、1，1-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1，2-二甲基丙基、1，3-二甲基丁基、1，4-二甲基丁基、2，3-二甲基丁基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基、1，1，2-三甲基丙基、1，2，2-三甲基丙基、1-乙基丁基和2-乙基丁基。还优选具有1至4个碳原子的烷基，例如尤其是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
根据本发明，“环烷基”(其本身或作为化学基团的一部分)是单环的烃，优选具有3至8个碳原子，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基。还优选具有3、4、5、6或7个碳原子的环烷基，例如尤其是环丙基或环丁基。
根据本发明，“卤素”为氟、氯、溴或碘，特别是氟、氯或溴。
根据本发明，“卤代烷基”为卤素取代的烷基，其优选具有1至9个相同或不同的卤素原子。卤代烷基的实例为三氯甲基、氯代二氟甲基、二氯氟甲基、氯甲基、溴甲基、1-氟乙基、2-氟乙基、2，2-二氟乙基、2，2，2-三氟乙基、2，2，2-三氯乙基、2-氯-2，2-二氟乙基、五氟乙基和五氟-叔丁基。优选具有1至4个碳原子以及1至9个、优选1至5个相同或不同的选自氟、氯或溴的卤素原子的卤代烷基。特别优选具有1或2个碳原子且具有1至5个相同或不同的选自氟或氯的卤素原子的卤代烷基，例如尤其是二氟甲基、三氟甲基或2，2-二氟乙基。
根据本发明，“烷氧基”为直链或支链的O-烷基，优选具有1至6个碳原子，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。还优选具有1至4个碳原子的烷氧基。
根据本发明，“烷硫基”为直链或支链的S-烷基，优选具有1至6个碳原子，例如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基和叔丁硫基。还优选具有1至4个碳原子的烷硫基。
根据本发明，“烷基氨基”是指氨基中的一个氢原子被烷基取代，为NH-烷基。其中的烷基优选具有1至6个碳原子，例如甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。还优选具有1至4个碳原子的烷氨基。
根据本发明，“二烷基氨基”是指氨基中的两个氢原子都被烷基取代，为N-(烷基)2。其中的烷基优选具有1至6个碳原子，例如二甲氨基、二乙氨基、甲基乙基氨基、二正丙氨基等。还优选具有1至4个碳原子的二烷基氨基。
根据本发明，“烷基亚磺酰基”为直链或支链的烷基亚磺酰基，优选具有1至6个碳原子，例如甲基亚磺酰基、乙基亚磺酰基、正丙基亚磺酰基、异丙基亚磺酰基、正丁基亚磺酰基、异丁基亚磺酰基、仲丁基亚磺酰基和叔丁基亚磺酰基。还优选具有1至4个碳原子的烷基亚磺酰基。根据本发明的烷基亚磺酰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“烷基磺酰基”为直链或支链的烷基磺酰基，优选具有1至6个碳原子，例如甲基磺酰基、乙基磺酰基、正丙基磺酰基、异丙基磺酰基、正丁基磺酰基、异丁基磺酰基、仲丁基磺酰基和叔丁基磺酰基。还优选具有1至4个碳原子的烷基磺酰基。根据本发明的烷基磺酰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“烷基羰基”为直链或支链的烷基-C(＝O)，优选具有2至7个碳原子，例如甲基羰基、乙基羰基、正丙基羰基、异丙基羰基、仲丁基羰基和叔丁基羰基。还优选具有1至4个碳原子的烷基羰基。根据本发明的烷基羰基可以被一个或更多个相同或不同的基团取代。
根据本发明，“环烷基羰基”为直链或支链的环烷基羰基，优选在环烷基部分具有3至8个碳原子，例如环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基-羰基、环辛基羰基。还优选在环烷基部分具有3、5或7个碳原子的环烷基羰基。
根据本发明，“烷氧羰基”(其本身或作为化学基团的一部分)是直链或支链的烷氧羰基，优选在烷氧基部分具有1至6个碳原子或具有1至4个碳原子，例如甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、仲丁氧基羰基和叔丁氧基羰基。
根据本发明，“烷氧羰基”为直链或支链的烷氧羰基，优选在烷基部分具有1至6个碳原子或具有1至4个碳原子，例如甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、仲丁氧基羰基和叔丁氧基羰基。
根据本发明，“烷基氨基羰基”为直链或支链的烷基氨基羰基，优选在烷基部分具有1至6个碳原子或具有1至4个碳原子，例如甲基氨基羰基、乙基氨基羰基、正丙基氨基羰基、异丙基氨基羰基、仲丁基氨基羰基和叔丁基氨基羰基。
根据本发明，“芳基”为优选具有6至14个、特别是6至10个环碳原子的单环、双环或多环芳族体系，例如苯基、萘基、蒽基、菲基，优选苯基。芳基也是多环体系，例如四氢萘基、茚基、茚满基、芴基、联苯基，其中键接侧在芳族体系上。
根据本发明，“杂环基”为具有至少一个环的碳环基团，其中至少一个碳原子被杂原子、优选被选自N、O、S、P、B、Si、Se的杂原子所代替并且其为饱和的或部分不饱和。所述杂环基优选含有3至8个环原子、特别是3至6个环原子，并且杂环中一个或更多个、优选1至4个、特别是1、2或3个杂原子优选选自N、O和S，但是其中两个氧原子不应当直接相邻。杂环通常含有至多4个氮原子，和/或至多2个氧原子和/或至多2个硫原子。
杂环基的实例为哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氢吡喃基、四氢吡喃基、二噁烷基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噻唑烷基、噁唑烷基、二氧戊环基、间二氧杂环戊烯基、吡唑烷基、四氢呋喃基、二氢呋喃基、氧杂环丁烷基、环氧乙烷基、氮杂环丁烷基、氮杂环丙烷基、氧氮杂环丁烷基、氧氮杂环丙烷基、氧氮杂环庚烷基、氧氮杂环己烷基、氮杂环庚烷基、氧代吡咯烷基、二氧代吡咯烷基、氧代吗啉基、氧代哌嗪基和氧杂环庚烷基。如果杂环基或杂环任选地被取代，则其可以与其他碳环或杂环稠合。在任选取代的杂环的情况下，本发明还包括多环体系，例如8-氮杂双环[3.2.1]辛基或1-氮杂双环[2.2.1]庚基。
根据本发明，“杂芳基”代表杂芳族化合物，即落在杂环的以上定义内的完全未饱和的芳族杂环化合物。优选地对于5-元到7-元环而言，具有1至3个、优选1或2个相同或不同的来自上述组的杂原子。根据本发明的杂芳基为，例如吡咯基，呋喃基，噻吩基，噻唑基，吡唑基，咪唑基，恶唑基，噻唑基，异噻唑基，吡啶基，哒嗪基，嘧啶基，吡嗪基，苯并咪唑基，苯并恶唑基，吲哚基，喹啉基，异喹啉基，苯并吡嗪基，苯并嘧啶基，苯并二氧六环基，1,3-苯并间二氧杂环戊烯基，
Figure GDA0003654273750000141
等。
本发明还涉及包含如上所述式(I)化合物或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物。
优选地，所述式(I)化合物或其药学上可接受的盐为治疗有效量。
优选地，所述组合物还包括其他能够治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛的化合物。
适宜的赋形剂一般包括粘合剂、抗粘剂、崩解剂、填充剂、稀释剂、矫味剂、着色剂、助流剂、润滑剂、防腐剂、吸附剂和甜味剂或其组合。
典型的制剂是通过本发明的化合物与载体、稀释剂或赋形剂混合制备的。适宜的载体、稀释剂和赋形剂是本领域技术人员公知的，并且包括例如碳水化合物、蜡类、水溶性和/可溶胀聚合物、亲水性或疏水性材料、明胶、油类、溶剂、水等材料。使用的具体载体、稀释剂或赋形剂将取决于本发明化合物被应用的手段和目的。溶剂一般基于本领域技术人员认为给哺乳动物施用安全(GRAS)的溶剂进行选择。一般，安全的溶剂是非毒性水性溶剂例如水和在水中溶解或混溶的其他非毒性溶剂。适宜的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如，PEG400、PEG300)等及其混合物。所述制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧剂、遮光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、矫味剂和其他已知添加剂，以提供药物的优美外观(即，本发明的化合物或其药物组合物)或在药物产品(药品)生产中的帮助。
制剂可使用传统溶解和混合的方法进行制备。例如，散装原料药(即，本发明的化合物或化合物的稳定形式(例如，与环糊精衍生物或其他复合剂)的稳定形式)在一种或多种赋形剂存在下被溶解在适宜的溶剂中。本发明的化合物一般被配制成药物剂型以提供易于控制剂量的药物，并给患者一种优美和容易处理的产品。
组合物通常被配制成选自以下的剂型：片剂、水性或油性混悬剂、软膏剂、贴剂、凝胶剂、洗剂、胶囊剂、乳剂、乳膏剂、喷雾剂、滴剂、可分散的粉末或颗粒、位于硬或软明胶胶囊中的乳剂、糖浆剂和酏剂。
用于应用的药物组合物(或制剂)可被包装成各种形式，取决于药物施用所使用的方法。一般地，用于分发的物品包括存有适当形式药物制剂的容器。适宜的容器是本领域技术人员公知的，并且包括例如瓶子(塑料和玻璃)、药袋、安瓿、塑料袋、金属圆桶等。容器还可包括防撬装置，以防不慎重地获取包装的内容物。此外，容器之上有描述容器内容物的标签。标签还可包括适当的警告。
本发明提供的新型氟西汀类似物能够治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛。
本发明还提供上述化合物的制备方法，其特征在于，所述方法包括如下步骤：
Figure GDA0003654273750000161
式(II)所示的化合物和R3-L反应得到式(I)所示化合物；
其中R1、R2、R3、R4、m、n、X具有上述定义，L为离去基团。
优选地，L为1-乙氧基-1-三甲硅氧基。
上述方法中，式(II)化合物是由式(II)所示的盐酸盐用NaOH游离后得到的。优选地，所述NaOH的浓度为1mol/L。
优选地，式(II)通过如下方法制备：
Figure GDA0003654273750000171
式(III)所示的化合物和式(III-1)所示的化合物在碱的存在下反应得到式(I)所示化合物；
其中R1、R2、R3、R4、m、n、X具有上述定义，L3为离去基团。所述L3为氯、溴或碘。
上述方法中，式(II)化合物与R3-L的摩尔比为1:1～1:2，优选1:2。
上述方法中，反应的初始温度为10-50℃，湿度为20-80％。优选地，初始温度为15-40℃，湿度为30-70％。更优选地，初始温度为20-30℃，湿度为40-60％。
上述方法中，反应在溶剂中进行。所述溶剂优选为醇类溶剂，如甲醇、四氢呋喃等或其混合物。优选地，所述溶剂使用前进行无水处理。
上述方法中，反应的催化剂为硼氢化钠或氰基硼氢化钠。所述催化剂与式(II)化合物的摩尔比为1:1～2:1，优选2:1。
优选地，所述催化剂分批少量加入。优选地，采用滴加方式加入。
上述方法中，反应体系中还加入醋酸。优选地，所述醋酸与式(II)化合物的摩尔比为1:1～2:1，优选2:1。
上述反应中，加入所有原料后升温至50-80℃回流反应。优选地，升温至60-70℃。
上述方法还包括下述的后处理步骤：将反应液调节为弱碱性，萃取，干燥，减压蒸馏得到粗品。
所述粗品再经过柱层析纯化得到最终的产品。
上述萃取采用EA进行萃取。
上述干燥是用干燥剂进行干燥。优选地，干燥剂为无水硫酸钠。干燥时间为0.5-2h，优选1h。
上述柱层析是用硅胶柱层析。
本发明还提供上述式(I)化合物或其药学上可接受的盐在制备治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛的药物中的应用。
有益效果
本发明提供了一种新型的氟西汀类似物及其制备方法。所述类似物具有明显优于氟西汀的药物活性。同时还具有制备方法的操作简便等优点。所述方法可分别以较高的产率和/或纯度，例如产率达到80％，甚至90％以上，总的产率达50％以上，制备得到所述化合物，满足药物生产的需要。
附图说明
图1是本发明实施例1化合物103的1H NMR(DMSO)图；
具体实施方式
下面结合具体实施例对本发明作进一步描述。但是，本领域技术人员了解，下列实施例仅仅是为了示例性地描述本发明的技术方案，并不旨在对本发明的保护范围进行任何限制。
实施例1：化合物103
Figure GDA0003654273750000181
磁力搅拌装置，室温约23℃，湿度约52％下于250ml三口反应瓶中依次加入游离过的氟西汀(16.8g，0.0745mol，1eq)，加入甲醇(50ml)，四氢呋喃(50ml)，作为溶剂，搅拌下滴加1-乙氧基-1-三甲硅氧基环丙烷(19.0g，0.109mol，2eq)，醋酸(6.5g，0.108mol，2eq)，搅拌十分钟，慢慢加入氰基硼氢化钠(7.0g，0.108mol，2eq)，有微热放出，反应液颜色呈无色，温度升至65℃左右回流反应，TLC监控至原料反应完毕。
将反应液用饱和的NaHCO3溶液调节pH至弱碱性，用200ml EA萃取，加入20g的无水硫酸钠干燥1h，抽滤，去滤液浓缩得到19g粗品，粗品用柱层析纯化，具体是：用200g硅胶装柱，湿法上样，淋洗剂是EA和PE，得纯品无色油状液体14.8g，产率：70％。MS(m/z)：350.1(M+H)。
参考实施例1相同的方法制备了化合物1至102，化合物1至102的产率和表征数据如下表1所示：
表1
Figure GDA0003654273750000191
Figure GDA0003654273750000201
Figure GDA0003654273750000211
Figure GDA0003654273750000221
实施例2药物活性试验
示例性的实施例化合物的抗抑郁作用采用获得性小鼠绝望模型(小鼠悬尾实验和小鼠强迫游泳实验)进行检测和验证。
受试药物为上述实施例1制备的化合物液。配制方法：用0.5％CMC-Na溶液配制成所需浓度的混悬液，临用前充分搅匀灌胃。受试物浓度：2mg/ml。受试动物为ICR小鼠，雄性，体重16-18g,SPF级，饲养条件为所有小鼠均自由觅食和饮水，在室温(23±2)℃，自然光照条件下饲养。
试验对照：阴性对照：0.5％CMC-Na溶液；阳性对照：氟西汀，剂量20mg/kg；
给药方法
给药途径：灌胃给药；给药体积：20ml/kg；给药次数：每天1次，连续7天；
小鼠悬尾实验：实验小鼠随机分为阴性对照组，阳性对照组和受试组。阴性对照组，阳性对照组分别为每组10只，受试组为每测量一种化合物，使用10只。受试组剂量为20mg/kg，氟西汀组剂量为20mg/kg，阴性对照组给予0.5％CMC-Na溶液。每天灌胃一次，灌胃量0.1ml/10g，连续给药7天。末次给药后1h，将动物尾端2厘米部位固定在一水平支撑物上，使动物成倒挂状态，支撑物放置于一敞口箱内，其头部离底面约5厘米。记录小鼠6分钟内后4分钟的不动时间，各组小鼠平行操作。
小鼠强迫游泳实验：实验小鼠随机分为阴性对照组，阳性对照组和受试组。阴性对照组，阳性对照组分别为每组10只，受试组为每测量一种化合物，使用10只。受试组剂量为20mg/kg，氟西汀组剂量为20mg/kg，阴性对照组给予0.5％CMC-Na溶液。每天灌胃一次，灌胃量0.1ml/10g，连续给药7天。末次给药后1h，将小鼠单独放入高20厘米、直径14厘米的圆柱型玻璃缸中，缸内水深10厘米，水温23-25℃。从小鼠入水后记时6分钟，记录后4分钟内的累计不动时间，各组小鼠平行操作。
统计学处理
试验数据用SPSS13.0软件进行处理，实验数据用±s表示，采用单因素方差分析(ONA-way ANOVA)检验。显著性水平a＝0.05。
试验结果
小鼠悬尾过程中出现行为绝望，表现不动状态，不动时间为109±18.2秒。与阴性对照组比较，受试组和氟西汀组均能够明显缩短小鼠悬尾不动时间，差异具有显著性意义(P<0.05，P<0.01)。受试组均强于氟西汀组，结果见表2。
小鼠强迫游泳过程中出现行为绝望，表现不动状态，不动时间为94.6±19.5秒。受试组和氟西汀组均能够明显缩短小鼠悬尾不动时间，差异具有显著性意义(P<0.05，P<0.01)。受试组均强于氟西汀组，结果见表2。
表2示例性的实施例化合物对小鼠悬尾不动时间和强迫游泳不动时间的影响(±SD，n＝10)
Figure GDA0003654273750000231
Figure GDA0003654273750000241
试验结论：由上述检测结果可知，本发明示例性的实施例化合物具有明显抗抑郁作用，且活性优于对照药物氟西汀。
实施例3示例性的实施例化合物的急性毒性研究
实验材料：
ICR小鼠，雌雄各半，体重18～22g，动物以颗粒饲料喂养，自由摄食和饮水。
表2中测试的化合物分别用0.5％CMC-Na分别配制成浓度为500mg/mL的混悬液。
实验方法
ICR小鼠按体重单次灌胃10ml/kg的表2中测试的化合物，观察给药后动物14天内的毒性反应及死亡情况。结果发现，小鼠单次灌胃给药后，小鼠活动滞缓，静卧少动，40-60分钟后即恢复正常。给药后14天内，小鼠未出现死亡，第15天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
上述急性毒性实验结果表明，灌胃给药最大耐受量MTD不低于7g/kg，说明本发明实施例化合物的急性毒性较低。

Claims (9)

1.一种氟西汀类似物或其药学上可接受的盐，其具有下述式(I)所示的结构：
Figure FDA0003654273740000011
其中：
R1选自H；
R2选自4-三氟甲基；
R3选自环丙烷基；
R4选自未取代或任选被Rs取代的下列基团：C1-6烷基，羟基C1-6烷基，C3-10环烷基，C1-6烷基C3-10环烷基，羟基，巯基，C1-6烷氧基，羟基C1-6烷氧基，C1-6烷硫基，氨基，C1-6烷基氨基，二(C1-6烷基)氨基，C3-8环烷基氨基，二(C3-8环烷基)氨基，羟基C1-6烷基氨基，3-10元杂环烷基，C1-6烷基3-10元杂环烷基，C1-6烷氧基C1-6烷基，巯基C1-6烷基，C1-6烷硫基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基C1-6烷基，二(C1-6烷基)氨基C1-6烷基，羟基C1-6烷基氨基C1-6烷基、C6-14芳基、5-14元杂芳基；
Rs选自C1-6烷基；
X选自O；
n为1；
m为0或1。
2.根据权利要求1所述的类似物，其特征在于，所述氟西汀类似物选自如下化合物：
Figure FDA0003654273740000021
Figure FDA0003654273740000031
Figure FDA0003654273740000041
Figure FDA0003654273740000051
Figure FDA0003654273740000061
Figure FDA0003654273740000071
3.权利要求1或2所述类似物的制备方法，其特征在于，包括：
Figure FDA0003654273740000081
式(II)所示的化合物和R3-L反应得到式(I)所示化合物；
其中R1、R2、R3、R4、m、n、X具有权利要求1或2所述定义，L为离去基团。
4.根据权利要求3所述的制备方法，其特征在于，L为1-乙氧基-1-三甲硅氧基。
5.根据权利要求3或4所述的制备方法，其特征在于，式(II)通过如下方法制备：
Figure FDA0003654273740000082
式(III)所示的化合物和式(III-1)所示的化合物在碱的存在下反应得到式(II)所示化合物；
其中R1、R2、R3、R4、m、n、X具有权利要求1或2所述定义，L3为离去基团。
6.根据权利要求5所述的制备方法，其特征在于，所述L3为氯、溴或碘。
7.一种包含权利要求1或2所述式(I)化合物或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物。
8.根据权利要求7所述的药物组合物，其特征在于，还包括其他能够治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛的化合物。
9.权利要求1或2所述式(I)化合物或其药学上可接受的盐在制备药物中的应用；所述药物用于治疗抑郁、焦虑、压力诱发的失禁、中枢性疼痛。
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