CN110627766B - 一种新的度洛西汀类似物及其制备方法和应用 - Google Patents
一种新的度洛西汀类似物及其制备方法和应用 Download PDFInfo
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- CN110627766B CN110627766B CN201810664555.4A CN201810664555A CN110627766B CN 110627766 B CN110627766 B CN 110627766B CN 201810664555 A CN201810664555 A CN 201810664555A CN 110627766 B CN110627766 B CN 110627766B
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- duloxetine
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- enyl
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
本发明涉及一种新的度洛西汀类似物及其制备方法和应用，其具有下述式(I)所示的结构：其中R1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。
Description
技术领域
本发明涉及一种新的度洛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
度洛西汀(Duloxetine)【化学名(R)-(-)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺(结构式如式(a)所示)】或盐酸度洛西汀(duloxetine hydrochloride/Cymbaha，也简称为度洛西汀)【化学名(R)-(-)-N-甲基-3-(1-萘氧基)-3-(2-噻吩)-丙胺盐酸盐(结构式如式(b)所示)】：
是一种5-羟色胺和去甲肾上腺素双重再摄取抑制剂。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。度洛西汀能够抑制神经元对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。度洛西汀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。度洛西汀2001年在欧洲上市，FDA于2002年9月17日批准其用于抑郁症，2004年8月首次在美国获得批准后，现已在70余个国家上市，其中，2007年在中国上市，商品名欣百达。
然而度洛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，提供一种新型的度洛西汀类似物，其具有优于度洛西汀的药物活性。
本发明的另一个目的在于提供一种上述新型的度洛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度洛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，本发明通过如下技术方案实现：
一种度洛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：
其中：
R1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。
根据本发明的优选技术方案，所述度洛西汀类似物具有下述式(II)所示的结构：
其中，R1如上所定义。
术语定义和解释
术语“C1-6烷基”应理解为优选表示具有1、2、3、4、5或6个碳原子的线性的或支化的饱和一价烃基，例如甲基、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(“C1-4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“C2-6烯基”应理解为优选表示线性的或支化的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
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”意指饱和的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所述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。
术语“C6-14芳基”应理解为优选表示具有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(“C6-14芳基”)，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。
术语“取代的”意指所指定的原子上的一个或多个氢被所列出基团取代，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选被……取代”指可以无取代或被所列出的基团取代。
环系的取代基指与芳族或非芳族环系连接的取代基，例如所述取代基代替所述环系上可用的氢。
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。
根据本发明的优选技术方案，所述度洛西汀类似物选自如下化合物：
最优选地，所述度洛西汀类似物选自如下化合物：
本发明还提供式(I)化合物的制备方法，其特征在于，所述方法包括如下步骤：
式(Ia)化合物与化合物反应得到式(I)化合物；
其中，R1具有上述定义，L为离去基团。
根据本发明，L优选1-乙氧基-1-三甲硅氧基离去基团。
上述方法中，式(Ia)化合物与的摩尔比为1:1～1:2，优选1:2。
优选地，式(Ia)化合物通过如下方法制备：
式(Ib)化合物与化合物R1-L1在碱的存在下反应得到式(Ia)化合物；
其中，R1具有上述定义，L1为离去基团。
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20-40℃，湿度为30-60％。更优选地，初始温度为25-35℃，湿度为40-50％。
上述方法可以在合适的溶剂存在下进行。所述溶剂是在反应条件下呈惰性的任何有机溶剂，包括选自例如下列的一种或多种的混合物：酮，例如丙酮和甲基乙基酮；无环醚和环醚，例如乙醚和四氢呋喃；酯，例如乙酸乙酯或者乙酸丁酯；碳氢化合物，例如苯、甲苯、二甲苯、己烷和环己烷；氯化烃，例如一氯甲烷、二氯甲烷、三氯甲烷、1,2-二氯乙烷和氯苯；醇，例如甲醇、乙醇、正-丙醇、异丙醇，正-丁醇或者叔-丁醇；或者其它的溶剂，例如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙腈或者吡啶。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(Ia)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(Ia)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℃。
上述方法中，度洛西汀衍生物是由度洛西汀衍生物盐酸盐用NaOH游离后得到的。优选地，所述NaOH的浓度为1mol/L。
上述反应具体为：
磁力搅拌装置，室温约30℃，湿度约45％下于250ml三口反应瓶中依次加入游离过的式(Ia)化合物(12.0g，0.0403mol，1eq)，甲醇(50ml)，四氢呋喃(50ml)，1-乙氧基-1-三甲硅氧基环丙烷(14.0g，0.0805mol,2eq)，醋酸(4.84g，0.0806mol，2eq)，氰基硼氢化钠(5.0g，0.0806mol，2eq)，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。
上述方法还包括下述的后处理步骤：将反应液调节为中性，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。
本发明还提供以下技术方案：
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度洛西汀类似物及其制备方法。所述类似物具有优于度洛西汀的药物活性。并且所述度洛西汀类似物制备方法的操作简便，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化合物的1H NMR(DMSO)图；
具体实施方式
下面结合附图和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B-2
磁力搅拌装置，室温约30℃，湿度约45％下于250ml三口反应瓶中依次加入游离过的度洛西汀(12.0g，0.0403mol，1eq)，甲醇(50ml)，四氢呋喃(50ml)，1-乙氧基-1-三甲硅氧基环丙烷(14.0g，0.0805mol,2eq)，醋酸(4.84g，0.0806mol，2eq)，氰基硼氢化钠(5.0g，0.0806mol，2eq)，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1mol/L的NaHCO3调节pH值至中性，用EA(200ml*2)萃取，加入50g无水硫酸钠干燥1h，50℃减压蒸馏，得粗品14.0g，粗品TLC不纯，取120g硅胶柱层析纯化，得纯品黄色油状液体9.8g，产率：75％。MS(m/z)：337.8(M+H)。
参考实施例1相同的方法制备了化合物1-102，化合物1-102的产率和表征数据如下表1所示：
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实施例2：药物活性试验
示例性的实施例化合物抗抑郁症作用
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再摄取抑制剂氟西汀和5-HT、NA双重再摄取抑制剂度洛西汀作为阳性对照品，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.方法如下：
2.1化合物对脑突触体5-羟色胺(5-HT)的抑制作用
2.1.1受体膜的制备：
大鼠断头，冰上操作，迅速取脑皮层，加入匀浆液(B0.05M的Tris-HCl NaCl120mM、KCl5mM,PH7.4)，用旋涡混合器混匀，在50000g，4℃离心10min，弃上清液，加入匀浆液匀浆于37℃孵化10min，离心后取沉淀，再加入0.05M的Tris-HCl缓冲液(PH7.4)洗涤，重复三次离心，离心完毕，弃上清液，将沉淀于-80℃储存备用。
2.1.2SERT亲和实验：
第一步：先将制备好的膜用适量的匀浆液(B)，用匀浆机分散均匀,备用。
第二步：各反应管分别加入膜制备物100μL。
第三步：总结合管(TB)加入100μL匀浆液(B)，非特异性结合管(NB)加入paroxetine100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
第四步：各反应管分别加入放射性配体3H-paroxetine10μL(各反应管均设2个平行管，加样时各管置于冰上)。
第五步：将各反应管23℃温孵60min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到2ml闪烁杯中，加入1ml的甲苯闪烁液并混匀；
第六步：将闪烁瓶放入液闪计数仪计数。
2.2化合物对脑突触体去甲肾上腺素(NA)的抑制作用。
2.2.1受体膜的制备：
大鼠断头，冰上操作，迅速取纹状体，加入匀浆液(0.05M Tris-HCl，120mM NaCl，5mM KCl，pH7.4)，用旋涡混合器混匀，在50000g，4℃离心10min，弃上清液，加入匀浆液匀浆于37℃孵化10min，离心后取沉淀，再加入0.05M的Tris-HCl缓冲液(PH7.4)洗涤，重复三次离心，离心完毕，弃上清液，将沉淀于-80℃储存备用。
2.2.2NET亲和实验：
第一步：先将制备好的膜用适量的匀浆液(C)，用匀浆机分散均匀,备用。
第二步：各反应管分别加入膜制备物100μL。
第三步：总结合管(TB)加入100μL匀浆液(C)，非特异性结合管(NB)加入desipramine100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；第四步：各反应管分别加入放射性配体3H-Nisoxetine10μL(各反应管均设2个平行管，加样时各管置于冰上)。
第五步：将各反应管4℃温孵240min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到2ml闪烁杯中，加入1ml的甲苯闪烁液并混匀；
第六步：将闪烁瓶放入液闪计数仪计数。
2.3化合物对脑突触体5-羟色胺(5-HT)、去甲肾上腺素(NA)和多巴胺(DA)的抑制作用。
2.3.1受体膜的制备：
大鼠断头，冰上操作，迅速取纹状体，加入匀浆液(25mM Na2HPO4/NaH2PO4,48mMNaCl,pH7.7，320mM蔗糖)，用旋涡混合器混匀，在50000g，4℃离心10min，弃上清液，取沉淀，再加入0.05M的Tris-HCl缓冲液(PH7.4)洗涤，重复三次离心，离心完毕，弃上清液，将沉淀于-80℃储存备用。
2.3.2DAT亲和实验：
第一步：先将制备好的膜用适量的匀浆液，用匀浆机分散均匀,备用。
第二步：各反应管分别加入膜制备物100μL。
第三步：总结合管(TB)加入100μL匀浆液，非特异性结合管(NB)加入nomifensine100μL(终浓度10-6M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；第四步：各反应管分别加入放射性配体3H-WIN35,42810μL(各反应管均设2个平行管，加样时各管置于冰上)。
第五步：将各反应管4℃温孵120min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到2ml闪烁杯中，加入1ml的甲苯闪烁液并混匀；
第六步：将闪烁瓶放入液闪计数仪计数。
表2化合物对脑突触体5-羟色胺(5-HT)、去甲肾上腺素(NA)及多巴胺(DA)再摄取的抑制作用
由上述结果可知，本发明示例性的实施例化合物相对于对三种单胺递质具有较强的抑制作用。
实施例3动物体内抗抑郁活性研究
采用“获得性绝望实验”中的小鼠悬尾实验(tail suspetion test)和小鼠强迫游泳不动实验(forced swimming test)以度洛西汀作为阳性对照药，对示例性的实施例化合物进行体内抗抑郁作用的初步研究。
3.1小鼠悬尾实验(TST)
待测化合物的药物剂量先设定为3mg/kg、10mg/kg、30mg/kg、40mg/kg,上述药物剂量若产生明显的效果(减少小鼠的不动时间)，则将剂量适量下调，若未产生效果(没有减少小鼠不动时间)则将剂量上调，或在以上3个剂量中根据受试剂量之间的比例插加受试药物剂量，根据具体情况定。盐酸度洛西汀和各待测化合物溶于50％的PEG400中，然后超声30min。
实验前1-2天筛选出体重合格的小鼠并随机分组，每组10只，设立溶媒对照组和受试药各给药组。各给药组在实验前1h采用灌胃(ig)给药，实验时间是09:00-15:00，给药完毕后，将小鼠用胶布粘贴距尾尖1cm处，然后悬挂距实验台50cm处6min，摄像头录像后，人工分析并记录小鼠后4min内的不动时间。
实验数据用表示，采用EXCEL统计软件，先进行F-test方差齐性检验，若方差齐(P>0.05)则进行T-test等方差检验；若方差不齐(P<0.05)，则进行T-test异方差检验，以P＜0.05为差异有显著性。
3.2小鼠强迫游泳实验(FST)
各待测化合物的药物剂量先设定为10mg/kg、30mg/kg,上述药物剂量若产生明显的效果(减少小鼠的不动时间)，则将剂量适量下调，若未产生效果(没有减少小鼠不动时间)则将剂量上调，或在以上2个剂量中根据受试剂量之间的比例插加受试药物剂量，根据具体情况定。盐酸度洛西汀和各待测化合物溶于50％的PEG400中，然后超声30min。
实验前几天筛选出体重合格的小鼠并随机分组，每组10只，设立溶媒对照组、阳性对照组和受试药各给药组。各给药组采用灌胃(ig)给药，每次实验前1h给药。给药完毕后，将小鼠放入透明的强迫游泳圆筒(高25cm，直径10cm)中6min，水深15cm，水温23～25℃。摄像头录像人工分析并记录小鼠后4min内的不动时间，视频分析者不知道动物的给药情况。
实验数据用表示，采用SPSS统计软件，先进行方差齐性检验，若方差齐则进行单因素方差分析，两两比较采用Dunnet-t检验，以P＜0.05为差异有显著性。
表3小鼠悬挂实验和强迫游泳不动实验结果(如下检测结果均为受试样品量为30mg/kg)
| 样品名称 | 悬尾实验(不动时间/s) | 强迫游泳实验(不动时间/s) |
| 阴性对照组 | 69.7±43.2 | 117.7±71.3 |
| 度洛西汀组 | 12.6±8.2 | 57.2±30.2 |
| 3 | 4.4±3.2 | 32.4±6.9 |
| 14 | 2.5±2.1 | 29.1±5.9 |
| 25 | 6.4±5.2 | 41.3±10.4 |
| 36 | 3.7±3.1 | 31.2±6.5 |
| 42 | 5.0±4.1 | 37.1±7.4 |
| 54 | 4.8±3.7 | 35.1±7.1 |
| 60 | 7.4±6.2 | 45.2±14.4 |
| 72 | 6.1±5.1 | 40.8±9.4 |
| 84 | 5.3±4.2 | 38.7±8.1 |
| 95 | 6.9±6.0 | 42.0±12.1 |
在如上小鼠悬挂实验和小鼠强迫游泳不动实验中，示例性的实施例化合物能明显缩短因绝望而停止不动的时间，与空白组相比有极显著差异，且明显优于度洛西汀对照组，说明本发明化合物具有较强的体内抗抑郁活性。
实施例4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 (6)
1.如下所示的度洛西汀类似物：
2.如下所示的度洛西汀类似物：
3.权利要求1或2所述度洛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。
4.一种药物组合物，包含权利要求1或2中所述的度洛西汀类似物。
5.根据权利要求4所述的药物组合物，其特征在于，还包含药学上可接受的载体。
6.一种药物组合物，其特征在于，包含权利要求1或2所述的度洛西汀类似物与已知的抗抑郁药。
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| CN1687057A (zh) * | 2003-12-11 | 2005-10-26 | 北京上地新世纪生物医药研究所 | 度洛西汀的制备方法和其重要的中间体 |
| WO2008081476A2 (en) * | 2006-12-29 | 2008-07-10 | Cadila Healthcare Limited | Process for preparing duloxetine hydrochloride |
| CN101412707A (zh) * | 2008-11-27 | 2009-04-22 | 河北工业大学 | 度洛西汀衍生物及其制备方法 |
| CN104557726A (zh) * | 2013-10-19 | 2015-04-29 | 广东东阳光药业有限公司 | 芳杂环类衍生物及其在药物上的应用 |
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| WO2008081476A2 (en) * | 2006-12-29 | 2008-07-10 | Cadila Healthcare Limited | Process for preparing duloxetine hydrochloride |
| CN101412707A (zh) * | 2008-11-27 | 2009-04-22 | 河北工业大学 | 度洛西汀衍生物及其制备方法 |
| CN104557726A (zh) * | 2013-10-19 | 2015-04-29 | 广东东阳光药业有限公司 | 芳杂环类衍生物及其在药物上的应用 |
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