CN110627665B - 一种新的文拉法辛衍生物及其制备方法和应用 - Google Patents

一种新的文拉法辛衍生物及其制备方法和应用 Download PDF

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CN110627665B
CN110627665B CN201810661693.7A CN201810661693A CN110627665B CN 110627665 B CN110627665 B CN 110627665B CN 201810661693 A CN201810661693 A CN 201810661693A CN 110627665 B CN110627665 B CN 110627665B
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CN110627665A (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

本发明属于化学药物及其制备方法和应用的技术领域，具体涉及一种新的文拉法辛衍生物及其制备方法和应用。本发明的化合物具有优于文拉法辛的药学活性，并且制备方法简单。
Figure DDA0001706923920000011

Description

一种新的文拉法辛衍生物及其制备方法和应用
技术领域
本发明涉及一种新的文拉法辛衍生物及其制备方法和应用，属于化学药物及其制备方法和应用的技术领域。
背景技术
文拉法辛(Venlafaxine，结构如下式所示)，化学名为(R/S)-1-[2-二甲基氨基-1-(4-甲氧基苯基)乙基]环己醇，为三种生物源性胺类：5-羟色胺、去甲肾上腺素和多巴胺的再摄取抑制剂。该化合物亦可以其盐酸盐形式，即盐酸文拉法辛给药。
Figure GDA0003578550420000011
5-羟色胺和去甲肾上腺素均属中枢神经递质，在调控情感和对疼痛的敏度方面起着重要作用。文拉法辛能够抑制神经元对5-羟色胺和去甲肾上腺素的再摄取，由此提高这两种中枢神经递质在大脑和脊髓中的浓度，故可用于治疗某些心境疾病如抑郁症和焦虑症以及缓解中枢性疼痛如糖尿病外周神经病性疼痛和妇女纤维肌痛等。文拉法辛也能作用于尿道中的5-羟色胺和去甲肾上腺素受体，从而增强尿道括约肌的神经性紧张程度和收缩能力，所以对妇女应激性尿失禁症治疗也有效。
然而文拉法辛的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，提供一种式(1)所示的化合物或其药学上可接受的盐：
Figure GDA0003578550420000021
其中，n为0、1、2、3、4、5或6；
X选自H、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。
在本发明中“取代”是指一个基团中任选一个或多个H被其它基团取代。作为实例，取代基选自卤素(F、Cl、Br或I)，-OH，-NH2，-SH，C1-C6的烷基，C3-C6的环烷基，4-7元杂环烷基，芳基或杂芳基，其中所述取代基任选被进一步取代。
术语“C1-6烷基”是指碳原子数为1、2、3、4、5或6的烷基基团，其中所述烷基可以是直链烷基，也可以是支链烷基，包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基或它们的异构体。特别地，所述基团具有1、2、3或4个碳原子(“C1- 44烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基，更特别地，所述基团具有1、2或3个碳原子(“C1-3烷基”)，例如甲基、乙基、正丙基或异丙基。
术语“C3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5、6、7、8、9或10个碳原子。
所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环；
术语“3-10元杂环烷基”意指由3、4、5、6、7、8、9或10个成环原子构成的饱和一价单环或双环烃环，其包含1、2、3或4个选自N、O和S杂原子。所述杂环烷基可以通过碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环烷基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基环。任选地，所述杂环烷基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。所述含氮原子环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基环，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基环。“4-8元杂环烷基”是指4-8元的，其中任选1-3个碳原子被杂原子取代的基团，其中所述杂原子独立选自N，O或S。作为实例，所述基团可包括但不限于
Figure GDA0003578550420000031
术语“C6-14芳基”应理解为表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或1-萘基、2-萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。
术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系，其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1、2、3或4个选自N、O和S杂原子，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明，所述杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，术语吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；或者，术语噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
作为实例，所述基团可包括但不限于
Figure GDA0003578550420000041
Figure GDA0003578550420000042
本发明各通式化合物的取代基定义中使用的术语“一个或多个”应理解为包括一个、两个、三个、四个或五个，特别是一个、两个、三个或四个，更特别是一个、两个或三个，例如一个或两个。
术语“药学上可接受的盐”是指由药学上可接受的无毒的酸(包括无机或有机酸)制成的盐。本发明的化合物可以是单盐、二盐或三盐，取决于在化合物的游离碱形式中存在的酸性官能团的数目。作为实例，所述酸包括乙酸、三氟乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烷磺酸、富马酸、葡萄糖、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、杏仁酸、甲烷磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、酒石酸、对甲苯磺酸等。
示例性地，本发明式(1)化合物包括下列化合物：
Figure GDA0003578550420000043
Figure GDA0003578550420000051
Figure GDA0003578550420000061
Figure GDA0003578550420000071
Figure GDA0003578550420000081
Figure GDA0003578550420000091
Figure GDA0003578550420000101
本发明另一个目的在于提供一种上述新型的文拉法辛类似物的制备方法，包括：
方案1
Figure GDA0003578550420000111
a1)化合物A2与A3在碱的存在下反应得到化合物A4；
a2)化合物A4与A5反应得到化合物A6；
a3)化合物A6脱保护基得到化合物103；
a4)化合物103与A1在碱的存在下反应得到化合物(I)；
或者，方案2
Figure GDA0003578550420000112
b1)化合物A2与A8反应得到化合物104；
其中，n、X具有上述定义，L1、L2、L3、L4为离去基团；
方案1中X不为环丙基，n不为0。
优选地，L1、L2、L3、L4相同或不同，彼此独立地为氯、溴、碘或1-乙氧基-1-三甲硅氧基。
优选地，所述碱为无机碱，例如为碳酸钠、碳酸钾或其混合物。
优选地，化合物A2可通过常规有机合成方法制备得到。
方案1中，
步骤a1)化合物A2与碱的摩尔比为1:1～1:2，优选1:1.1。
步骤a1)反应使用的溶剂为DMF。
步骤a1)化合物A2与A3的摩尔比为1:1～1:1.5，优选1:1.2。优选反应在0℃下进行。
步骤a2)化合物A4和A5摩尔比为1:1～1:2，优选1:1.5。
步骤a2)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。
步骤a2)反应的催化剂为硼氢化钠或氰基硼氢化钠，所述催化剂与化合物的摩尔比为1:1～1:2，优选1:2。
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。
步骤a2)反应体系中还加入醋酸。优选地，所述醋酸与化合物A4的摩尔比为1:1～1:2，优选1:1。
步骤a2)加入所有原料后升温至50-80℃回流反应。优选地，升温至60-70℃。
步骤a2)反应具体为：
在250ml两口烧瓶中加入A4(3.0g，0.0088mol，1eq)，甲醇和四氢呋喃混合溶剂(体积比1:1)50ml作溶剂，搅拌下，依次向其中加入化合物A5(2.3g，0.0132mol，1.5eq)和乙酸(0.53g，0.0088mol，1eq)，最后，向其中分批加入氰基硼氢化钠(1.1g，0.0176mol，2eq)，加入完毕后，加热回流过夜。
上述方法还包括下述的后处理步骤：将反应液萃取，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。
上述萃取采用乙酸乙酯进行萃取。
上述干燥是用干燥剂进行干燥。优选地，干燥剂为无水硫酸镁。干燥时间为0.5-2h，优选1h。
上述柱层析是用硅胶柱层析。
步骤a3)化合物A6催化加氢还原脱保护基得到化合物A7。
所述催化的催化剂是Pd/C。
步骤a4)化合物103与碱的摩尔比为1:1～1:2，优选1:2。
步骤a4)反应使用的溶剂为DMF。
步骤a4)化合物103与A1的摩尔比为1:1～1:4，优选1:2。优选反应在0℃下进行。
方案2中，
步骤b1)化合物A2和A8的摩尔比为1:1～1:2，优选1:2。
其中，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。
其中，反应的催化剂为硼氢化钠或氰基硼氢化钠。所述催化剂与化合物A2的摩尔比为1:1～1:2，优选1:2。
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。
其中，反应体系中还加入醋酸。优选地，所述醋酸与化合物A2的摩尔比为1:1～1:2，优选1:1。
其中，加入所有原料后升温至50-80℃回流反应。优选地，升温至60-70℃。
上述反应具体为：
在250ml两口烧瓶中加入化合物A2(10g，0.0401mol，1eq)，甲醇和四氢呋喃混合溶剂(体积比1:1)作溶剂，搅拌下，依次向其中加入化合物A8(14.0g，0.0802mol，2eq)和乙酸(2.4g，0.0401mol，1eq)，最后，向其中分批加入氰基硼氢化钠(5.0g，0.0802mol，2eq)，加入过程中稍放热，加入完毕后，加热回流过夜。
上述方法还包括下述的后处理步骤：将反应液萃取，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，干燥剂为无水硫酸镁。干燥时间为0.5-2h，优选1h。
上述柱层析是用硅胶柱层析。
本发明还提供以下技术方案：
本发明另一方面提供一种药物组合物，包含式(I)所示的化合物或其药学上可接受的盐。
可利用这些组合物通过向有此需要的患者给药来实现期望的药理学作用。就本发明的目的而言，患者是需要治疗具体病症或疾病的包括人在内的哺乳动物。
因此，本发明还提供这样的药物组合物，其包含治疗有效量的本发明的化合物或其药学上可接受的盐和药学上可接受的载体。
药学上可接受的载体优选是这样的载体，其在与活性成分的有效活性一致的浓度下对患者相对无毒且无害，以致于由所述载体引起的任何副作用不会破坏所述活性成分的有益作用。化合物或其药学上可接受的盐的药学有效量优选是对正在治疗的具体病况产生结果或者产生影响的量。可使用包括速释、缓释和定时释放制剂在内的任意有效的常规剂量单位形式，将本发明的化合物与本领域公知的药学上可接受的载体一起以如下方式给药：口服、肠胃外、局部、鼻腔、眼部、舌下、直肠、阴道给药等。
对于口服给药，可将所述化合物或其药学上可接受的盐配制成固体或液体制剂，例如胶囊剂、丸剂、片剂、含锭剂(troche)、锭剂(lozenge)、熔胶剂(melt)、散剂、溶液剂、混悬剂或乳剂，并且可根据本领域已知的用于制备药物组合物的方法来制备。固体单位剂型可为胶囊剂，其可为普通的硬胶囊型或软胶囊型，包含例如表面活性剂、润滑剂和惰性填充剂(例如乳糖、蔗糖、磷酸钙和玉米淀粉)。
在另一实施方案中，可将本发明的化合物或其药学上可接受的盐和常规片剂基质(例如乳糖、蔗糖和玉米淀粉)一起并与如下物质组合压制成片剂：粘合剂(例如阿拉伯胶、玉米淀粉或明胶)、用于辅助给药后片剂的分解和溶出的崩解剂(例如土豆淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍树胶、阿拉伯胶)、用于提高片剂制粒的流动性并且防止片剂材料与片剂模具和冲头的表面粘附的润滑剂(例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌)、染料、着色剂，以及用于改善片剂的感官性质并使它们更容易被患者接受的调味剂(例如薄荷油、冬青油或樱桃香精)。用于口服液体剂型的适合的赋形剂包括磷酸二钙和稀释剂，例如水和醇(例如乙醇、苯甲醇和聚乙烯醇)，添加或不添加药学上可接受的表面活性剂、助悬剂或乳化剂。可以存在各种其它物质作为包衣或者用于改变剂量单位的物理形式。例如可用虫胶、糖或二者将片剂、丸剂或胶囊剂包衣。
可分散的粉末和颗粒适合用于制备水性混悬剂。它们提供与分散剂或润湿剂、助悬剂以及一种或多种防腐剂混合的活性成分。适合的分散剂或润湿剂和助悬剂的实例为上文提及的那些。还可存在另外的赋形剂，例如上文所述的那些甜味剂、调味剂和着色剂。
本发明的药物组合物还可为水包油乳剂的形式。油相可为植物油，例如液体石蜡或植物油的混合物。适合的乳化剂可为(1)天然树胶，例如阿拉伯树胶和黄蓍树胶，(2)天然磷脂，例如大豆磷脂和卵磷脂，(3)衍生自脂肪酸和己糖醇酐的酯或偏酯，例如脱水山梨糖醇单油酸酯，(4)所述偏酯与环氧乙烷的缩合产物，例如聚氧乙烯山梨糖醇酐单油酸酯。所述乳剂还可包含甜味剂和调味剂。
可通过将所述活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)中或者悬浮在矿物油(例如液体石蜡)中来配制油性混悬剂。所述油性混悬剂可包含增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。所述混悬剂还可包含一种或多种防腐剂，例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯；一种或多种着色剂；一种或多种调味剂；以及一种或多种甜味剂，例如蔗糖或糖精。
可用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)来配制糖浆剂和酏剂。此类制剂还可包含缓和剂和防腐剂(例如尼泊金甲酯和尼泊金丙酯)以及调味剂和着色剂。
还可将本发明的化合物以所述化合物的注射剂量进行肠胃外给药，即皮下、静脉内、眼内、滑膜内、肌内或腹膜内给药，所述注射剂量优选在含有药物载体的生理学可接受的稀释剂中，所述药物载体可为无菌液体或液体的混合物，所述液体例如水，盐水，葡萄糖水溶液和相关的糖溶液，醇例如乙醇、异丙醇或十六醇，二醇例如丙二醇或聚乙二醇，甘油缩酮例如2,2-二甲基-1,1-二氧戊环-4-甲醇，醚例如聚乙二醇400(PEG400)，油，脂肪酸，脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯，所述稀释剂添加或不添加有药学上可接受的表面活性剂，例如肥皂或洗涤剂，助悬剂例如果胶、卡波姆、甲基纤维素、羟丙甲纤维素或羧甲基纤维素，或乳化剂和其它药学辅剂。
可用于本发明的肠胃外制剂中的示例性的油是那些源于石油、动物、植物或合成来源的油，例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、凡士林油和矿物油。适合的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。适合的脂肪酸酯是例如油酸乙酯和肉豆蔻酸异丙酯。适合的肥皂包括脂肪酸碱金属盐、铵盐和三乙醇胺盐，并且适合的洗涤剂包括阳离子洗涤剂，例如二甲基二烷基卤化铵、烷基卤化吡啶鎓和烷基胺乙酸盐；阴离子洗涤剂例如烷基磺酸盐、芳基磺酸盐和烯烃磺酸盐、烷基硫酸盐和烷基磺基琥珀酸盐、烯烃硫酸盐和烯烃磺基琥珀酸盐、醚硫酸盐和醚磺基琥珀酸盐以及单酸甘油酯硫酸盐和单酸甘油酯磺基琥珀酸盐；非离子型洗涤剂，例如脂肪胺氧化物、脂肪酸烷醇酰胺以及聚(氧乙烯-氧丙烯)、环氧乙烷共聚物或环氧丙烷共聚物；以及两性洗涤剂，例如烷基-β-氨基丙酸盐和2-烷基咪唑啉季铵盐，以及其混合物。
本发明的肠胃外组合物通常会在溶液中包含约0.5重量％-约25重量％的所述活性成分。还可有利地使用防腐剂和缓冲剂。为了最小化或消除对注射部位的刺激，此类组合物可包含亲水-亲脂平衡(HLB)优选为约12-约17的非离子表面活性剂。此类制剂中表面活性剂的量优选为约5重量％-约15重量％。所述表面活性剂可为具有以上HLB的单一组分，或者为两种或更多种具有期望的HLB的组分的混合物。
用于肠胃外制剂的示例性表面活性剂是聚乙烯脱水山梨糖醇脂肪酸酯类，例如脱水山梨糖醇单油酸酯，以及环氧乙烷与疏水性基质的高分子量加合物，所述疏水性基质由环氧丙烷和丙二醇缩合形成。
所述药物组合物可为注射用无菌水性混悬剂的形式。可根据已知的方法使用如下物质配制此类混悬剂：适合的分散剂或润湿剂和助悬剂，例如羧甲基纤维素钠、甲基纤维素、羟丙甲纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯树胶；分散剂或润湿剂，其可为天然磷脂(例如卵磷脂)、氧化烯与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如十七乙烯氧基鲸蜡醇)、环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚氧乙烯脱水山梨糖醇单油酸酯)。
无菌注射制剂还可为在无毒的肠胃外可接受的稀释剂或溶剂中的注射用无菌溶液剂或混悬剂。可使用的稀释剂和溶剂为例如水、林格溶液、等渗氯化钠溶液和等渗葡萄糖溶液。另外，将无菌不挥发油常规性用作溶剂或悬浮介质。就此而言，可使用任何刺激性小的不挥发油，包括合成的单酸甘油酯或甘油二酯。另外，可将脂肪酸(例如油酸)用于注射剂的制备中。
还可将本发明的组合物以用于药物的直肠给药的栓剂的形式给药。可通过将药物与在常温下为固体但是在直肠温度下为液体并且因此可在直肠中溶化而释放所述药物的适合的无刺激性的赋形剂混合来制备这些组合物。此类物质是例如可可脂和聚乙二醇。
用于肠胃外给药的控释制剂包括本领域已知的脂质体微球、聚合物微球和聚合物凝胶制剂。
可能需要或必须通过机械递送装置将所述药物组合物递送至患者。用于递送药剂的机械递送装置的构造和用途是本领域公知的。例如将药物直接给药至脑的直接技术通常涉及将药物递送导管置入患者的脑室系统以绕过血脑屏障。
可将本发明的化合物作为单一药剂给药或者与一种或多种其它药剂组合给药，其中所述组合不会引起不可接受的不良反应。本发明还涉及此类组合。例如，可将本发明的化合物或其药学上可接受的盐与已知的抗抑郁药以及与它们的混合物和组合进行组合。
一般而言，将本发明化合物或其药学上可接受的盐与已知的抗抑郁药以及与它们的混合物和组合进行组合使用会起到以下作用：
(1)与单独给药任一种药剂相比在抗抑郁方面产生更好的功效，
(2)允许给药更少量的所给药的化疗药剂，
(3)提供化疗剂治疗，其被患者良好地耐受并且具有的有害药理学并发症比在单一药剂化疗和某些其它组合疗法中所观察到的少，
(4)允许治疗范围更广的哺乳动物(特别是人)，
(5)提供受治疗患者中更高的响应，
(6)与其它抗抑郁剂组合产生拮抗效应的已知情况相比，得到至少与单独使用的药剂一样好的功效和耐受性。
本发明还提供本发明化合物或其药学上可接受的盐在制备药物中的用途。所述药物优选用于治疗抑郁、焦虑、强迫症、社交恐惧、精神创伤的药物中的应用。
有益效果
本发明提供了一种新型的文拉法辛类似物及其制备方法。所述类似物具有优于文拉法辛的药物活性。此外还具有制备方法的操作简便的优点，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是本发明的化合物103的1H NMR(DMSO)图。
图2是本发明的化合物104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：制备化合物103
Figure GDA0003578550420000171
在250ml单口烧瓶中加入化合物A2(10g，0.0401mol，1eq)，100mlDMF作溶剂，搅拌下，向其中加入碳酸钾(6.7g，0.0441mol，1.1eq)，0℃下，缓慢滴加氯化苄(5.7g，0.0481mol，1.2eq)，常温过夜反应。
反应终止判断：取样，加水EA萃取后点板。
后处理：加水停止反应，200ml*2EA萃取，有机相用饱和食盐水洗一遍，无水硫酸镁干燥，抽滤浓缩，得粗品，所得粗品过柱，得到3.0g纯品(另双苄基0.5g，原料7.0g)。得到A4无色油状3.0g。产率：22.06％
在250ml两口烧瓶中加入化合物A4(3.0g，0.0088mol，1eq)，甲醇四氢呋喃混合(体积比1:1)溶剂50ml作溶剂，搅拌下，依次向其中加入1-乙氧基-1三甲基硅基环丙烷(2.3g，0.0132mol，1.5eq)和乙酸(0.53g，0.0088mol，1eq)，最后，向其中分批加入氰基硼氢化钠(1.1g，0.0176mol，2eq)，加入完毕后，加热回流过夜。
反应终止判断：取样，加水，EA萃取后点板。
后处理：加水停止反应，250ml乙酸乙酯萃取，无水硫酸镁干燥，抽滤，浓缩，得粗品4.0g，60g硅胶装柱，湿法上样，过柱得纯品2.4g。
结果：化合物A6为无色油状2.4g。产率：72.73％。
在100ml单口烧瓶中加入化合物A6(2.4g，0.0063mol，1eq)，60ml无水甲醇作溶剂，搅拌下，加入1g Pd/C，加氢，TLC监控至反应完全。
后处理：抽滤除去Pd/C，滤液浓缩，得粗品2.4g，40g硅胶装柱，最终得纯品为白色固体0.9g。
结果：化合物103白色固体0.9g产率：50％，核磁如图1所示。
实施例2：制备化合物104
在250ml两口烧瓶中加入化合物A2(10g，0.0401mol，1eq)，甲醇和四氢呋喃混合溶剂(体积比1:1)作溶剂，搅拌下，依次向其中加入1-乙氧基-1三甲基硅基环丙烷(14.0g，0.0802mol，2eq)和乙酸(2.4g，0.0401mol，1eq)，最后，向其中分批加入氰基硼氢化钠(5.0g，0.0802mol，2eq)，加入过程中稍放热，加入完毕后，加热回流过夜。
反应终止判断：取样，加水，EA萃取后点板
后处理：冷却后，加水停止反应，200ml*2EA萃取，有机相用水洗一遍，无水硫酸镁干燥，抽滤浓缩，湿法过柱，得化合物104为白色固体8.8g，产率：66.3％。
实施例3制备化合物1
将实施例1制备的化合物103(0.578g,0.002mol,1eq)与碘乙烷(0.62g,0.004mol,2eq)溶于DMF(20mL)，加入碳酸钾(0.304g,0.0022mol,1.1eq)，在0℃下反应，监测反应反应后，水洗，EA萃取，浓缩完成后过柱得到化合物1白色固体，0.476g，产率：50.6％。MS(m/z)：318.2(M+H)。
参考实施例3相同的方法制备了化合物2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 GDA0003578550420000181
Figure GDA0003578550420000191
Figure GDA0003578550420000201
实施例4：药物活性试验
本发明示例性的实施例化合物对脑突触体再摄取5-HT、NA和DA的抑制作用：
采用脑突触体对单胺类神经递质再摄取的研究方法，是目前国际上对中枢神经药理研究的重要手段，该方法不仅可以用来研究药物的作用机制，还可以筛选作用于此类环节的新药。本发明采用脑突触体对单胺类神经递质5-HT、NA和DA再摄取的研究方法，以有效的5-HT、NA双重再摄取抑制剂文拉法辛(Venlafaxine)和6-羟DA作为阳性对照品，对所发明化合物抑制脑突触体对5-HT、NA及DA再摄取的作用进行研究。
1、大鼠脑突触体的制备
雄性SD大鼠拉颈处死后迅速断头取脑，置于冰上，分离相关脑组织([3H]5-HT、[3H]NA再摄取试验取前额皮层，[3H]DA再摄取试验取纹状体)，称重后，加入10倍(V/W)冰冷0.32mol/L蔗糖液，玻璃-teflon电动匀浆；匀浆液4℃下1000g×10min离心；取上清，4℃下17000g 20min离心；取沉淀，以30倍体积KRH Buffer(125mM NaCl，4.8mM KCl，1.2mMCaCl2，1.2mM MgSO4，1.0mM KH2PO4，22mM HaHCO3，25mMHEPES，10mM Glucose，10μMPargyline，0.2mg/ml Ascorbic Acid)悬浮，置于冰浴中备用。(其中NA再摄取试验所需皮层以20倍体积悬浮)。
2、[3H]5-HT/NA/DA再摄取试验
受试品贮备液临用前取出解冻，以KRH Buffer稀释至100μmol/L，取50μl加入500μl总反应体系中，终浓度即为10μmol/L，再加入50μl悬浮的突触体膜，混匀，37℃水浴中孵育30min；加入10nmol/L[3H]5-HT(50nmol/L[3H]DA或60nmol/L[3H]NA)，37℃水浴孵育10min后立即取出加入2ml冰冷的150mmol/LTris-HCl缓冲液终止反应，真空抽滤收集样品于圆形玻璃纤维膜上，以冰冷的Tris-HCl缓冲液3ml洗膜三次；取下滤膜，远红外烤箱中烘烤15min后置于EP管中，加入1.5ml闪烁液，过夜后液体闪烁计数仪检测。溶剂对照总结合管与非特异性结合管中不加受试物，总结合管中加入50μl溶剂。
3、结果：
以0.1mM的文拉法辛、6-羟DA对单胺再摄取的抑制率为100％，化合物的抑制强度和其进行比较，测定结果见表2。
表2化合物对脑突触体5-HT、NA、DA再摄取抑制百分率(％)
Figure GDA0003578550420000211
Figure GDA0003578550420000221
本发明示例性的实施例化合物属二重再摄取抑制剂，体外具有较强的NA、5-HT两种单胺递质再摄取剂作用。所述化合物体外二重再摄取抑制活性强于阳性对照药文拉法辛。
实施例5本发明示例性的实施例化合物动物体内抗抑郁活性研究
采用“获得性绝望实验”，中的鼠强迫游泳“不动”试验，以文拉法辛为阳性对照药，对本发明示例性的实施例化合物进行了动物体内抗抑郁作用的研究。
表3.单次口服给药对ICR小鼠游泳试验的影响(n＝12，x±SD)(剂量为50mg/kg)
Figure GDA0003578550420000222
Figure GDA0003578550420000231
单次口服给药的ICR小鼠游泳试验结果表明：本发明示例性的实施例化合物的体内抗抑郁活性优于文拉法辛，与空白对照组相比具有显著差异。
实施例6本发明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40ml/kg的表3中测试的化合物，观察给药后动物15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28g/kg，说明本发明实施例化合物的急性毒性较低。

Claims (10)

1.一种式(I)所示的化合物或其药学上可接受的盐：
Figure FDA0003578550410000011
其中，n为0、1、2、3、4、5或6；
X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，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。
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C3-10环烷基选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者十氢化萘环；
所述3-10元杂环烷基选自由3、4、5、6、7、8、9或10个成环原子构成的饱和一价单环或双环烃环，其包含1、2、3或4个选自N、O和S杂原子；
所述C6-14芳基选自苯基、联苯基、茚满基、茚基、四氢化萘基、二氢萘基或1-萘基、2-萘基、芴基、蒽基；
所述5-14元杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐选自单盐、二盐或三盐。
4.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，所述化合物选自下列化合物：
Figure FDA0003578550410000021
Figure FDA0003578550410000031
Figure FDA0003578550410000041
Figure FDA0003578550410000051
Figure FDA0003578550410000061
Figure FDA0003578550410000071
Figure FDA0003578550410000081
5.根据权利要求1-4任一项的化合物或其药学上可接受的盐的制备方法，其特征在于，包括：
方案1
Figure FDA0003578550410000082
a1)化合物A2与A3在碱的存在下反应得到化合物A4；
a2)化合物A4与A5反应得到化合物A6；
a3)化合物A6脱保护基得到化合物103；
a4)化合物103与A1在碱的存在下反应得到化合物(I)；
或者，方案2
Figure FDA0003578550410000083
b1)化合物A2与A8反应得到化合物104；
其中，n、X具有权利要求1-4任一项所述的定义，L1、L2、L3、L4为离去基团；
方案1中X不为环丙基，n不为0。
6.根据权利要求5所述的制备方法，其特征在于，L1、L2、L3、L4相同或不同，彼此独立地为氯、溴、碘或1-乙氧基-1-三甲硅氧基。
7.根据权利要求5或6所述的制备方法，其特征在于，所述碱为无机碱。
8.权利要求1-4任一项的化合物或其药学上可接受的盐在制备治疗抑郁、焦虑、强迫症、社交恐惧、精神创伤的药物中的应用。
9.一种药物组合物，包含权利要求1-4任一项的式(I)所示的化合物或其药学上可接受的盐。
10.一种药物组合物，其特征在于，包含权利要求1-4任一项的式(I)所示的化合物或其药学上可接受的盐，与已知的抗抑郁药以及与它们的混合物。
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