CN1867322A - 结晶形式的γ-氨基丁酸类似物 - Google Patents
结晶形式的γ-氨基丁酸类似物 Download PDFInfo
- Publication number
- CN1867322A CN1867322A CNA2004800301484A CN200480030148A CN1867322A CN 1867322 A CN1867322 A CN 1867322A CN A2004800301484 A CNA2004800301484 A CN A2004800301484A CN 200480030148 A CN200480030148 A CN 200480030148A CN 1867322 A CN1867322 A CN 1867322A
- Authority
- CN
- China
- Prior art keywords
- carbonyl
- oxygen base
- amino methyl
- base oxethyl
- cyclohexaneacetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 123
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 claims description 111
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Abstract
提供了结晶形式的γ-氨基丁酸类似物及其制备方法。
Description
1.领域
本文公开的是结晶形式的γ-氨基丁酸类似物和制备其结晶形式的方法。在治疗某些疾病和障碍,包括,例如神经性疼痛和疱疹后神经痛中,这些类似物可被用作治疗剂。
2.背景
一般而言,结晶形式的药物相对于非晶形形式药物而言为优选,部分地,是因为它们的优良稳定性。例如,在许多情况下,非晶形药物在存储时转变为结晶的药物形式。由于非晶形和结晶形式的药物通常具有不同的物理/化学性质、效能和/或生物利用度,在药物施用中由于安全性原因,这样的互变是不合要求的。任何结晶药物物质的关键特性是该物质的多晶型行为。多晶型是相同分子的晶体,其具有不同的物理性质,因为晶体晶格中包含了不同的分子排列。由多晶型表现出来的不同物理性质影响重要的药物参数,例如存储、稳定性、可压缩性、密度(在制剂和产品制备中是重要的)和溶出速率(在测定生物利用度中是重要的)。稳定性差别可由化学反应性的变化(例如差别的水解作用或氧化作用,以至于剂型在包括一种多晶型时比在包括另一种多晶型时变色更快)、机械性变化(例如在动力学有利的结晶形式转变为热力学更稳定的结晶形式时,片剂在存储时破碎,)或他们两者(例如在高湿度下一种多晶型的片剂更容易分解)产生。在极端的情况下,多晶型间的溶解度差异导致向缺乏效能或有毒的结晶形式转变。另外,晶型的物理性质在药物加工中可能是重要的。例如,特殊的结晶形式可能比其它形式更容易形成溶剂化物或可更难于过滤和洗净杂质(即,一种结晶形式相对于其它形式之间的粒子形状和大小分布可能不同)。
一些机构如美国食品与药品管理局严密地规定了固体剂型中药物活性成分的多晶型含量。一般而言,对于多晶型药物(如果有什么区别的话,也只是纯度不同),管理机构要求逐批监测,将热力学优选的多晶型上市。因此,医学和商业上的原因偏爱于合成和上市热力学稳定的多晶型形式的固体药物,其基本上不含动力学有利的多晶型。
1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸(1),是GABA类似物加巴喷丁(2)的前药,当口服或直接向哺乳动物结肠内给药时,它和加巴喷丁一样具有高的生物利用度(Gallop等人,国际公布号WO 02/100347)。高生物利用度使得化合物(1)成为口服剂型(包括缓释剂型)的有价值的成分,其适用于治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红(hot flashes)、多动腿综合征、尿失禁或乙醇戒断综合征。
化合物(1),用Gallop等人在国际公布号WO 02/100347中描述的方法制备,冻干后以玻璃状固体从乙腈水溶液中分离。通过该方法获得的物质部分或全部是非晶形的,并且某些金属盐形式是吸湿性的。然而,由于低的堆密度和不令人满意的流动性质,在药物加工条件下非晶形固体和特别吸湿性固体都难以处理。而且,处理吸湿性固体需要特殊的技术和设备,以获得例如可再生量的活性化合物或固体制剂的稳定性。而且,吸湿性药物必须包装在有水蒸汽屏障的特殊容器中,因而实质上增加了这类产品的成本。
因此,存在着对具有优良理化性质的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的需求,其可被有利地用于药物加工和药物组合物中。
3.概述
提供了满足上述和其它需求的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。也提供了结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物、使用结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸及其药物组合物治疗或预防不同疾病的方法,以及制备结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的方法。
在第一方面,提供了结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,其在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处具有特征吸收峰(2θ)。
在第二方面,提供了结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物。该药物组合物包含在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处有特征吸收峰(2θ)的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,以及药学上可接受的媒介物。
在第三方面,提供了治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征的方法。该方法通常包括给需要该治疗或预防的患者施用治疗有效量的1-{[(α-异丁酰氧基乙氧基)羰基]-氨基甲基}-1-环己烷乙酸,其在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处有特征吸收峰(2θ)。
在第四方面,提供了用于治疗或预防需要该治疗或预防的患者中癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征的药物组合物。该方法通常包括给予需要该治疗或预防的患者治疗有效量的1-{[(α-异丁酰氧基乙氧基)羰基]-氨基甲基}-1-环己烷乙酸的药物组合物,其在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处有特征吸收峰(2θ)。
在第五方面,提供了制备结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的方法,其在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处有特征吸收峰(2θ)。
4.附图的简要说明
图1显示了结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的X射线粉末衍射图;以及
图2显示了结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的差示扫描量热法温谱图。
5.详细描述
5.1定义
“药学上可接受的媒介物”是指与1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸一起施用的稀释剂、助剂、赋形剂或载体。
“患者”包括人。术语“人”和“患者”在本文中可交换使用。
“预防(preventing)或(prevention)”是指患疾病或障碍的风险降低(即,使得患者中疾病的至少一种临床症状不发生,该患者可能被暴露于或者易于患该疾病但尚未经历或表现该疾病的症状)。
“前体部分(Promoiety)”是指一定形式的保护基团,当其被用于屏蔽药物分子中的官能团时,将药物转变为前体药物。通常,前体部分将通过键与药物连接,键在体内以酶或非酶方式裂解。
任何疾病或障碍的“治疗(Treating)或(treatment)”,在一个实施方案中是指改善疾病或障碍(即,停止或减缓疾病或其至少一种临床症状的发展)。在另一实施方案中“治疗”是指改善患者可能辨别不出的至少一种身体参数。在另一实施方案中,“治疗”是指在身体上(例如可辨别症状的稳定化)、生理上(例如身体参数的稳定化)或二者都抑制疾病或障碍。在又一实施方案中,“治疗”是指延缓疾病或障碍的发生。
“治疗有效量”意指当给患者施用以治疗疾病时,足以实现疾病的所述治疗的化合物的量。“治疗有效量”将根据化合物、疾病及其严重性、和被治疗患者的年龄、体重等而变化。
现在将详细介绍优选的实施方案。尽管描述了优选的实施方案,应将要理解的是,本发明不限于这些优选的实施方案。相反地,意欲涵盖如可被包含于本发明精神和范围内的可替代方案、修改形式和等价方案,正如从中提出的任何权利要求所定义的那样。
5.2结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-
1-环己烷乙酸及其制备
本文详细地公开了结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和制备结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的方法。
应当理解的是,提及1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸时,包括所有基本上外消旋的混合物、该化合物常规化学结构的所有可能的互变异构形式和该化合物的所有同位素标记的衍生物(例如2H,3H,13C,14C,15N,17O,18O,等等)。
该原料(即1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸)可以根据Gallop等人在国际公布号WO 02/100347的实施例13中公开的方法,或Gallop等人2004年8月13日申请的、标题为″合成酰氧烷基氨基甲酸酯前药的方法″的美国临时专利申请系列第60/606,637号的实施例12中公开的方法制备。
在第一方面,提供了结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。在一些实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的特征吸收峰在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在X射线粉末衍射图中的特征吸收峰在7.0°±0.2°、8.2°±0.2°、10.5°±0.2°、12.8°±0.2°、14.9°±0.2°、16.4°±0.2°、17.9°±0.2°、18.1°±0.2°、18.9°±0.2°、20.9°±0.2°、23.3°±0.2°、25.3°±0.2°和26.6°±0.2°。
在一些实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约54℃到约78℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约58℃到约70℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约62℃到约68℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约62℃到约66℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约63℃到约66℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约64℃到约66℃之间熔化。在其它实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在约63℃到约64℃之间熔化。
在一些实施方案中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸可通过首先将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸加入到溶剂中形成溶液或悬浮液而制得。正如本文使用的,术语溶液和悬浮液是互换使用的,并意指包括将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸放置于溶剂或溶剂混合物中的情况,不论溶解度。在结晶中使用的溶剂可为均质溶剂、溶剂的组合、或溶剂或溶剂组合,其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸表现出温度依赖性的溶解度。一般而言,其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在第一温度范围内溶解,并在第二温度范围内难溶的溶剂或溶剂组合可以有利地用于本文描述的方法中。“良好”溶剂和“反-溶剂”的混合物也可以被使用,具有温度依赖性增溶作用,即,在升高的温度下溶解,在室温下结晶。合适的“良好”溶剂的实例包括甲醇、乙醇、1,2-丙二醇、叔丁醇、正丁醇、异丙醇、乙酸、硝基甲烷、乙腈、二甲亚砜、二甲基甲酰胺、N-甲基吡咯烷酮、丙酮、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、甲基异丁基酮、1,2-二甲氧基乙烷、四氢呋喃、2-甲基四氢呋喃、甲苯、甲基叔丁基醚、氯苯、1,4-二噁烷、二***、异丙基苯、邻二甲苯、间二甲苯、对二甲苯、2-乙氧基乙醇、1,2-乙二醇、甲酸乙酯、2-甲氧基乙醇、1-戊醇、苯甲醚、二氯甲烷、顺式和反式1,2-二氯乙烯、氯仿、二甲基乙酰胺、乙酸丙酯及它们的混合物。合适的“反-溶剂”的实例包括烷烃类,例如戊烷、己烷、庚烷、辛烷、壬烷、癸烷、十一烷、十二烷、顺式-或反式-萘烷、环己烷、甲基环己烷及它们的混合物。
优选地,溶解过程在升高的温度下完成,直到该溶剂或溶剂组合的沸点且包括该沸点。因此,在一些实施方案中,将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在加热和任选地振荡和搅拌条件下溶解在溶剂或溶剂混合物中。加热的溶液可维持在升高的温度下,以确保1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸完全溶解。加热的溶液也可在升高的温度下过滤以除去任何不溶成分。
优选地,缓慢地冷却溶液以产生结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,其可通过过滤和/或减压干燥与残留溶剂分离。在一些实施方案中,在约0℃到约25℃之间冷却该溶液。结晶领域技术人员已知的其它方法,(例如溶剂蒸发、浸湿、化学反应、使用少量目标晶体形式的播种等)也可被用于提供结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
在一些实施方案中,在约70℃到约回流温度的温度下,将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸溶解于庚烷中。优选地,温度是约70℃,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在庚烷中的浓度为约0.07g/mL到约0.08g/mL。然后将溶液冷却至室温以产生结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
在其它实施方案中,在约50℃到约回流温度的温度下,更优选在约70℃的温度下,将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸溶解于庚烷/乙酸乙酯混合物(体积比10∶1)中。庚烷/乙酸乙酯混合物中1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的浓度为约0.18g/mL到约0.22g/mL。然后将溶液冷却到约0℃到约25℃之间,以产生结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
在其它实施方案中,在约20℃到40℃的温度下,将1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸溶解于甲基环己烷/甲基叔丁基醚的混合物(甲基环己烷与甲基叔丁基醚的体积比在约5∶1到约20∶1之间,优选地,大约10∶1)中,甲基环己烷/甲基叔丁基醚混合物中1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的浓度为约0.1g/mL到约0.25g/mL。然后将溶液冷却到约0℃到约25℃之间,以产生结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
5.3治疗用途
结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可给患者,优选人施用,其患有癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征。进一步地,在某些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物给患者,优选人施用,作为抵抗不同疾病或障碍的预防措施。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可作为预防措施给患者施用,该患者易患癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征。因此,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可被用于预防一种疾病或障碍,并同时治疗另一种疾病或障碍(例如,治疗胃肠道障碍的同时预防精神病;治疗乙醇戒断综合征的同时预防神经性疼痛)。
可通过现有技术(例如,Satzinger等人的美国专利第4,024,175号;Satzinger等人的美国专利第4,087,544号;Woodruff的美国专利第5,084,169号;Silverman等人的美国专利第5,563,175号;Singh的美国专利第6,001,876号;Horwell等人的美国专利第6,020,370号;Silverman等人的美国专利第6,028,214号;Horwell等人的美国专利第6,103,932号;Silverman等人的美国专利第6,117,906号;Silverman的国际公布号WO 92/09560;Silverman等人的国际公布号WO93/23383;Horwell等人的国际公布号WO 97/29101;Horwell等人的国际公布号WO 97/33858;Horwell等人的国际公布号WO 97/33859;Bryans等人的国际公布号WO 98/17627;Guglietta等人的国际公布号WO 99/08671;Bryans等人的国际公布号WO 99/21824;Bryans等人的国际公布号WO 99/31057;Magnus-Miller等人的国际公布号WO 99/37296;Bryans等人的国际公布号WO 99/31075;Bryans等人的国际公布号WO 99/61424;Pande的国际公布号WO 00/23067;Bellioti的国际公布号WO 00/31020;Bryans等人的国际公布号WO00/50027;和Bryans等人的国际公布号WO 02/00209)中已知的方法,测定结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物在治疗癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征中的适合性。使用现有技术(参看上文)中描述的已知方法,可将结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物用于治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征。
本文公开的化合物,可能比母体药物分子(例如加巴喷丁或其它GABA类似物)更有效地用于治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征,因为所公开的化合物在血液中达到治疗浓度可能需要更少的时间,即,当口服时,本文公开的化合物比加巴喷丁具有更短的tmax。不希望被理论所约束,认为本文公开的化合物通过不同于加巴喷丁和其它已知GABA类似物被吸收的机制从胃肠腔吸收入血。例如,加巴喷丁被认为是通过位于人小肠中的载体转运蛋白而主动转运通过肠壁的。加巴喷丁转运蛋白容易饱和,这就意味着吸收到血液中的加巴喷丁的量与口服加巴喷丁的量不成正比,因为一旦转运机制被饱和,就不会出现任何显著程度的加巴喷丁的进一步吸收。与加巴喷丁相比,本文公开的化合物,沿着胃肠道,包括结肠的更大部分穿过肠壁吸收。
因为本文公开的化合物可以制成缓释剂型,其在数小时的期间内向胃肠道内提供持续释放,特别是,在结肠中释放,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸也可能比加巴喷丁更加有效地用于治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征。本文公开的化合物用于缓释口服剂型的能力减少了用于维持血液中治疗有效药物浓度所必需的给药频率。
5.4给药方式
结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可有利地用在人类药物中。正如前面所描述的,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物适用于治疗或预防癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、疱疹后神经痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征。
当用于治疗或预防上述疾病或障碍时,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可单独给药或应用,或与其它药剂联合给药或应用。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物还可单独给药或应用或与其它药学活性剂,包括其它GABA类似物联合给药或应用。
通过给患者施用治疗有效量的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物提供了治疗和预防的方法。患者可为动物,更优选哺乳动物,最优选人。
结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物,优选口服给药。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物也可通过任何其它常规途径给药,例如,输注或单次快速推注,通过上皮或粘膜皮肤衬吸收(例如口腔粘膜、直肠和肠粘膜等)。给药可以是全身的或局部的。已知不同的递药***(例如,包囊于脂质体、微粒、微囊、胶囊等等),其可以用于施用结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物。给药方法包括但不限于,真皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬脑膜外、口腔、舌下、鼻内、脑内、***内、透皮、直肠、吸入,或局部,尤其对耳朵、鼻子或皮肤。
在一些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可以通过缓释***递送,优选口服缓释***。在一个实施方案中,可使用泵(Langer,上文;Sefton,1987,CRC Crit Ref.Biomed.Eng.14:201;Saudek等人,1989,N.Engl.J.Med.321:574)。
在其它实施方案中,可以使用聚合材料(″Medical Applications ofControlled Release,″Langer and Wise(eds.),CRC Pres.,Boca Raton,Florida(1974);″Controlled Drug Bioavailability,″Drug ProductDesign and Performance,Smolen and Ball(eds.),Wiley,New York(1984);Langer等人,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61;也参看Levy等人,1985,Science 228:190;During等人,1989,Ann.Neurol.25:351;Howard等人,1989,J.Neurosurg 71:105)。在其它实施方案中,聚合材料用于口服缓释递送。聚合物包括,例如羧甲基纤维素钠、羟丙基纤维素、羟丙甲基纤维素和羟乙基纤维素(优选羟丙甲基纤维素)。已经描述了其它纤维素醚类(Alderman,Int.J.Pharm.Tech.& Prod.Mfr.1984,5(3)1-9)。影响药物释放的因素是本领域技术人员熟知的,并且已经在本领域中描述过(Bamba等人,Int.J.Phare.1979,2,307)。
在其它实施方案中,肠溶包衣制剂可以用于口服缓释给药。包衣材料包括,例如,具有pH依赖性溶解度的聚合物(即pH-控释),具有缓慢或pH依赖性溶胀、溶出或侵蚀的聚合物(即时间-控释)、通过酶降解的聚合物(即酶-控释)和形成被压力增加所破坏的坚固层的聚合物(即压力-控释)。
在其它实施方案中,渗透递药***用于口服缓释给药(Verma 等人,Drug Dev.Ind.Pharm.2000,26:695-708)。在一些实施方案中,OROSTM渗透装置用于口服缓释递药装置(Theeuwes等人,美国专利第3,845,770号;Theeuwes等人,美国专利第3,916,899号)。
在其它实施方案中,控释***可以被放置在结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的靶点附近,这样仅需要全身剂量的一部分(例如,Goodson,in″MedicalApplications of Controlled Release,″上文,vol.2,pp.115-138(1984))。也可使用Langer,1990,Science 249:1527-1533中讨论的其它控释***。
结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物优选地在体内对患者给药后提供加巴喷丁。不希望受理论约束,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物可通过化学裂解和/或酶裂解。存在于哺乳动物的胃、肠腔、肠组织、血液、肝脏、脑或任何其它合适组织中的一种或多种酶可裂解结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物。裂解机制并不重要。优选地,从结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物裂解前体部分而形成的加巴喷丁不包含实质量的γ-内酰胺污染物(优选少于0.5%重量,更优选少于0.2%重量,最优选少于0.1%重量),它是通过γ氨基和羧基官能度的分子内环化作用形成的。从结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物形成内酰胺的程度可使用标准体外分析法评估。
不希望受理论约束,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物可在胃肠道吸收前(例如,在胃或肠腔中)和/或胃肠道吸收后(例如,在哺乳动物肠组织、血液、肝脏或其它合适的组织中)裂解。如果结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物在胃肠道吸收前裂解,加巴喷丁可通常被吸收到体循环中(例如,经由位于小肠内的大中性氨基酸转运蛋白)。如果结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物在胃肠道吸收后裂解,该GABA类似物前药可通过被动扩散、主动转运或通过被动和主动两种过程吸收到体循环中。
如果结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的前体部分和/或其药物组合物在胃肠道吸收后裂解,该GABA类似物前药可能有机会从大肠被吸收到体循环中。在这种情况下,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物优选以缓释***给药。在一些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物通过口服缓释给药进行递送。优选地,在这些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物每日给药两次(更优选,每日一次)。
5.5药物组合物
本发明药物组合物包含有治疗效量的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和合适量的药学上可接受的媒介物,以便提供对患者适当给药的形式。当对患者进行给药时,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和药学上可接受的媒介物优选是无菌的。当结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸静脉内给药时,水是优选的媒介物。盐水溶液和葡萄糖水溶液和甘油溶液也可以用做液体媒介物,尤其用于注射溶液。合适的药物媒介物也包括赋形剂,例如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,本发明组合物也可以包含少量湿润剂或乳化剂或pH缓冲剂。除此之外,可使用助剂、稳定剂、增稠剂、润滑剂和着色剂。
在一些实施方案中,结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物不含由分子内成环作用形成的内酰胺副产物。在其它实施方案中,结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物对长期存储(优选长于1年)是稳定的,没有实质的内酰胺形成(优选地,少于0.5%重量内酰胺,更优选少于0.2%重量内酰胺,最优选少于0.1%重量内酰胺)。
包含结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物可通过常规的混合、溶解、制粒、制糖衣(dragee-making)、研磨、乳化、包囊、包封(entrapping)或冻干工艺制备。药物组合物可以常规方式,使用一种或多种生理学上可接受的载体、稀释剂、赋形剂或助剂制备,其有利于将结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸加工成可以在制药上被使用的制剂。适当的制剂取决于所选择的给药途径。
本发明的药物组合物可以采用以下形式:溶液剂、混悬剂、乳剂、片剂、丸剂、小药丸、胶囊、包含液体的胶囊、散剂、持续释放剂型、栓剂、乳液、气溶胶、喷雾剂、混悬剂,或适合使用的任何其它形式。在一些实施方案中,药学上可接受的媒介物是胶囊(例如,Grosswald等人,美国专利第5,698,155号)。其它合适的药物媒介物的实例在本领域中已经描述过(参看Remington′s Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science,第19版,1995)。结晶形式1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的组合物优选被配制供口服给药,尤其是供口服缓释给药。
用于口服给药的药物组合物可为以下形式:例如,片剂、锭剂、水或油混悬剂、颗粒、散剂、乳剂、胶囊、糖浆剂、或酏剂。口服给药的组合物可包含一种或多种任选物质,例如,甜味剂,例如果糖、阿司帕坦或糖精,调味剂,如薄荷、冬青油,或樱桃着色剂和防腐剂,以提供药学上适口的制剂。而且,当呈片剂或丸剂形式时,药物组合物可被包衣以延迟在胃肠道中的崩解和吸收,从而在延长的时间期间内提供持续作用。环绕渗透活性驱动化合物的选择性渗透膜也适合于口服施用本文公开的化合物和组合物。在这后几种平台下,来自围绕胶囊的环境的流体被驱动化合物所吸进,其膨胀,以通过孔排出药剂或药剂组合物。这些递送平台与即时释放制剂的尖峰曲线相反,可以提供基本上为零级的传递曲线。也可使用诸如单硬脂酸甘油酯或硬脂酸甘油酯的时间延迟材料。口服组合物可以包含标准的媒介物,例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素和碳酸镁等。这样的媒介物优选是药物级的。
对于口服液体制剂例如混悬剂、酏剂和溶液剂来说,合适的载体、赋形剂或稀释剂包括水、盐水、烷撑二醇(例如丙二醇)、聚亚烷基二醇(例如聚乙二醇)油、醇、pH4到pH6的微酸性缓冲液(例如,约5mM到约50mM的醋酸盐、枸橼酸盐、抗坏血酸盐缓冲液)等。另外,可加入调味剂、防腐剂、着色剂、胆汁盐和酰基肉毒碱等。
也可想到通过其它途径给药的药物组合物。对于口腔含化给药来说,组合物可采用片剂和锭剂等形式,用常规方式制备。适合与雾化器和液体喷物装置和EHD气雾剂装置一起使用的液体药物制剂通常包含结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和药学上可接受的媒介物。优选地,药学上可接受的媒介物是液体,例如醇、水、聚乙二醇或全氟碳。任选地,可加入另一种物质,以改变本文公开化合物的溶液或混悬剂的气雾剂性质。优选地,该物质是液体,例如醇、乙二醇、聚乙二醇或脂肪酸。制备适用于气雾剂装置中的液体药物溶液或混悬液的其它方法是本领域技术人员已知的(参看,例如Biesalski的美国专利第5,112,598号;Biesalski的美国专利第5,556,611号)。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸也可制成直肠或***组合物,例如栓剂或保留灌肠剂,例如,包含常规的栓剂基质,如可可豆脂或其它甘油酯。除了前面所述的制剂外,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸也可制成贮库制剂。这类长效制剂可通过植入(例如皮下或肌内)或肌内注射给药。因此,例如,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸可用适当的聚合或疏水物质(例如在可接受的油中的乳剂)或离子交换树脂配制,或作为略溶的衍生物,例如作为略溶的盐。
在一些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸作为纯净的活性剂进行配制。在其它实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸作为与其它结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的混合物一起进行配制。
5.6剂量
结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物将通常以有效达到预期目的的量使用。对于用于治疗或预防疾病或障碍,例如癫痫、疼痛(尤其是神经性疼痛以及肌肉和骨骼痛)、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病(即关节炎)、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征来说,该结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物以治疗有效量给药或应用。
将在治疗本文公开的特定障碍或病况中有效的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的量将取决于障碍或病况的性质,并可通过前述本领域中已知的标准临床技术测定。除此之外,可任选采用体外或体内测定方法来帮助确定最佳剂量范围。当然,被给药的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的量将在其它因素之中取决于被治疗的对象、对象的体重、疾病的严重性、给药方式和处方医生的判断。
例如,该剂量可在药物组合物中通过单次给药、多次应用或控制释放进行递送。在一些实施方案中,该结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物通过口服缓释给药进行递送。优选地,在这些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物每日给药两次(更优选,每日一次)。剂量可间歇性重复,可单独或与其它药物联合提供,并且只要有效治疗疾病状态或障碍需要就可持续。
在一些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的剂量可调节以提供约500mg/天到约7000mg/天的前体药物(相当于约260mg/天到约3600mg/天的加巴喷丁)。剂量范围可用技术人员已知的方法轻易测定。
在用于人以前,为了期望的治疗或预防活性,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物优选在体外和体内测定。优选地,本文描述的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的治疗有效量将提供治疗益处,而不产生实质的毒性。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的毒性可使用标准药学方法测定,并且可很容易地被熟练技术人员确定。毒性和治疗效果之间的剂量比为治疗指数。本文描述的结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物的剂量将优选地在循环浓度的范围内,该循环浓度包括有效剂量而很少毒性或没有毒性。
5.7联合疗法
在某些实施方案中,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物可以与至少一种其它治疗剂用于联合治疗。结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和/或其药物组合物和其它治疗剂可以加和地起作用,更优选地,协同地起作用。在一些实施方案中,给予包含结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物的同时给予另一种治疗剂,该治疗剂可以是与结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸相同的药物组合物的一部分,或是不同药物组合物。在其它实施方案中,包含结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的药物组合物在另一种治疗剂给药之前或之后进行给药。例如,结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸可与非晶形的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸、另一种结晶形式的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸、加巴喷丁或普加巴林联合进行给药。
6.实施例
下列实施例详细描述了1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸及其晶型的制备。可在不脱离本发明的范围的情况下对材料和方法进行许多改变,这对本领域技术人员来说是显而易见的。
在下列实施例中,以下缩略语具有如下定义。如果缩略语没有被定义,则使用普遍接受的含义。
Atm = 大气
Boc = 叔丁氧羰基
Cbz = 苄酯基
DCC = 二环己基碳二亚胺
DMAP = 4-N,N-二甲氨基吡啶
DMF = N,N-二甲基甲酰胺
DMSO = 二甲亚砜
Fmoc = 9-芴甲氧羰基
g = 克
h = 小时
HPLC = 高压液相色谱法
L = 升
LC/MS = 液相色谱法/质谱法
M = 摩尔
min = 分钟
mL = 毫升
mmol = 毫摩尔
NHS = N-羟基琥珀酰亚胺
THF = 四氢呋喃
TFA = 三氟乙酸
TLC = 薄层色谱法
TMS = 三甲基甲硅烷基
μL = 微升
μM = 微摩尔
v/v = 体积比体积
6.1实施例1:经由三甲基甲硅烷基酯中间体制备
1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸
步骤A:1-{[(α-氯代乙氧基)羰基]氨基甲基}-1-环己烷乙酸
向装有二氯甲烷(1.6L)的5升三颈圆底烧瓶中加入加巴喷丁(120.4g,0.704mol),接着加入三乙胺(294mL,2.11mol)。维持反应温度低于15℃,缓慢加入氯代三甲基硅烷(178mL,1.40mol),搅拌所得混悬液30分钟。维持反应温度低于15℃,然后缓慢加入氯甲酸1-氯乙酯(100g,0.704mol)。加完以后,再加入另外的三乙胺(88mL,0.63mol),所得混悬液室温下搅拌30分钟。通过用水(2×1L),紧接着用1N HCl(2×2L),然后用盐水(2×500mL)洗涤反应混合物,经酸性处理,使所得甲硅烷基酯转变成相应的酸。用无水硫酸钠干燥后,真空除去溶剂,得到橙色油状粗产物(190g),不进行进一步纯化用于步骤B中。
1H NMR(CDCl3,400MHz):δ1.41-1.57(m,10H),1.78(d,3H),2.33(s,2H),3.27(d,2H),5.42(br.s,1H),6.55(q,1H)。
步骤B:1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸向3升三颈圆底烧瓶中加入异丁酸(254g,2.9mol),然后加入三乙胺(395ml,2.84mol)。反应混合物冷却到室温,以控制的方式加入从上个反应步骤得到的粗酸(190g,0.69mol)的二氯甲烷(80mL)溶液,同时维持温度低于30℃。搅拌所得淡黄色溶液过夜。然后用1体积的二氯甲烷稀释反应混合物,用水(6×500mL)、碳酸氢钾水溶液(3×500mL)和盐水(2×500mL)洗涤。无水硫酸钠干燥后,真空除去溶剂,得到暗红色油状粗产物(87g)。一部分(35g)该产品加载到800gBiotageTM正相硅胶急骤柱上,用40%二***的己烷溶液(6L)洗脱,真空中除去溶剂后得到无色的油状产物(13.5g)。用另一份35g的粗产物重复该步骤,得到另一13.5g的l-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。在70℃下将产物样品(25g)溶解于庚烷(325mL)中,随后缓慢冷却到室温进行重结晶。过滤分离白色结晶产物(23g)。熔点:63-64℃。
6.2实施例2:由烯丙基酯中间体制备
1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸
步骤A:1-氨基甲基-1-环己烷乙酸烯丙酯盐酸盐
用氮气冲洗装有磁性搅拌棒和500mL压力均衡添加漏斗的干燥的3L三颈圆底烧瓶。将加巴喷丁(171g,1.0mol)和烯丙醇(1L,852g,14.6mol)加入到烧瓶中,在冰水浴中将全部混合物冷却到0℃。用一小时的时间逐滴将亚硫酰氯(225mL,360g,3.0mol)加入到搅拌的溶液中。在室温下搅拌反应混合物16小时,然后用***(2L)稀释,搅拌的同时冷却到0℃。几分钟后形成白色结晶,过滤收集。从1/3(v/v)乙醇和***(2L)的混合物中将粗产物再结晶,得到白色固体产物(220g,88%)。熔点:138-142℃。1H NMR(CD3OD,400MHz):δ1.36-1.54(m,10H),2.57(s,2H),3.05(s,2H),4.61(d,J=6Hz,2H),5.22(dd,J1=10.4Hz,J2=1.2Hz,1H),5.33(dd,J1=17.2Hz,J2=1.4Hz,1H),5.90-6.00(m,1H)。MS(ESI)m/z 212.0(M-Cl)+。
步骤B:1-{[(α-氯代乙氧基)羰基]氨基甲基}-1-环己烷乙酸烯丙酯
向上述盐酸盐(220g,0.89mol)的二氯甲烷(1L)溶液中缓慢加入氯甲酸1-氯乙酯(101.7mL,132.3g,0.92mol)。将反应混合物冷却到0℃,然后维持温度低于10℃,用一小时的时间缓慢加入4-甲基吗啉(205mL,188.9g,1.87mol)。所得浑浊溶液室温下搅拌1小时。加入乙醇(150mL),反应混合物室温下搅拌1小时。然后用醚(2.5L)稀释反应混合物,用水(1L)和盐水(1L)洗涤。用硫酸钠干燥有机相,浓缩得到淡黄色粘稠液状的标题化合物(282g,100%)。1H NMR(CDCl3,400MHz):δ1.35-1.58(m,10H),1.78(d,J=5.6Hz,3H),2.32(s,2H),3.22(d,J=6.8Hz,2H),4.57(d,J=5.6Hz,2H),5.25(dd,J1=10.4Hz,J2=1Hz,1H),5.32(dd,J1=17.2Hz,J2=1.6Hz,1H),5.52(br,1H,NH),5.90-5.94(m,1H),6.54(q,J=5.6Hz,1H)。
步骤C:1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸烯丙酯
向异丁酸(432mL,391.5g,4.4mol)和4-甲基吗啉(488mL,449g,4.4mol)的混合物中加入前述步骤得到的氯代氨基甲酸酯(282g,0.88mol)的异丁酸(432mL,391.5g,4.4mol)溶液。在0℃下用30分钟的时间加完。所得浑浊溶液在室温下搅拌16小时。用醚(2.5L)稀释反应混合物,然后用水(3×500mL)、接着用10%碳酸氢钾水溶液(6×500mL)和盐水(500mL)洗涤。用硫酸钠干燥有机相,浓缩得到粘稠液状的标题化合物(328g,100%)。1H NMR(CDCl3,400MHz):δ1.15(d,J=7.2Hz,6H),1.35-1.58(m,10H),2.31(s,2H),2.51(m,1H),3.19(d,J=5.6Hz,2H),4.56(d,J=5.6Hz,2H),5.24(dd,J1=10Hz,J2=1Hz,1H),5.32(dd,J1=17Hz,J2=1.2Hz,1H),5.35(br,1H),5.84-5.94(m,1h),6.78(1,J=5.6Hz,1H)。MS(ESI)m/z 392.24(M+H)+。
步骤D:1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸烯丙酯的脱保护
在氮气氛下向搅拌的甲酸铵(112g,1.7mol)的乙醇混悬液中加入以上烯丙酯(328g,0.88mol)和10%Pd/C(15g)。6h后通过滤除催化剂,处理反应混合物。用乙醇(2×250mL)洗涤催化剂,合并滤液并蒸发。将粗产物溶于醚(2L)中,用2N HCl(2×2L)洗涤有机相,将铵盐转化成酸的形式,接着用水(1L)和盐水(1L)洗涤。用硫酸钠干燥醚层,浓缩得到粘稠液体状的粗产物(240g,82%)。
步骤E:1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的结晶
3升的圆底烧瓶装配有加热的油浴、氮气入口转接器、内部温度计、上置机械搅拌器和回流冷凝器。用氮气冲洗该烧瓶,装入1/10(v/v)的乙酸乙酯/庚烷混合物(1.2L)和前述反应的粗产物(240g)。加热烧瓶直到产物溶解,然后根据下述方案冷却:
项目 | 时间(分钟) | 温度(℃)(内部温度) | 外观 | 备注 |
1 | 0 | 18.0 | 溶剂中有固体 | 开始加热油浴 |
2 | l0 | 48 | 浑浊 | 产物缓慢溶解 |
4 | 20 | 58 | 澄清溶液 | 关闭油浴 |
5 | 25 | 60 | 澄清溶液 | 达到最高温度 |
6 | 45 | 43 | 浑浊 | 化合物结晶 |
7 | 60 | 36 | 乳状溶液 | 用纯净参照物质接种晶种 |
8 | 90 | 24 | 溶液中有固体 |
然后将烧瓶冷却到4℃搅拌过夜(冷却提高了产率)。过滤产物并用庚烷(2×100mL)洗涤,然后在30℃下减压干燥(25mmHg(0.033个大气压))18小时,生成白色结晶固体状的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸(185g)。
6.3实施例3:结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的X射线粉末衍射分析
用Bruker D8 Discover X-射线粉末衍射仪、用铜Kα辐射测量根据以上实施例1和2制备的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸结晶样品的X射线粉末衍射图(XRPD′s)。该仪器装有平行的射束镜片和二维HI-STAR区域检测器。将管电压和电流强度分别设为40kV和40mA。将准直X射线束缩小至直径为约0.5mm的斑点大小。将区域检测器放置在距角度计中心15cm的位置,角分辨率大约是0.033°/像素。检测器在一帧内覆盖了2θ的35°的范围。X射线束和水平样品托盘之间的夹角设为4°,区域检测器中心设成18°角。该几何位置可以在一帧内测量4.5°到39.5°的2θ。收集每个XRPD图像的通常平均时间是3分钟。使用刚玉样品(NIST 1976)来校准XRPD仪器。两个样品给出了相同的衍射图谱,如图1所示。
6.4实施例4:结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的熔点和差示扫描量热法分析
用Electrothermal 9200熔点装置测量以上根据实施例1和2制备的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸结晶样品的熔点,测定结果为63-64℃。
用Perkin Elmer Series 7仪器测量以上根据实施例1和2制备的1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸结晶样品的差示扫描量热法(DSC)分析,以5℃/分钟的扫描速率从25℃到250℃进行扫描。将样品的试验部分放在铝盘上,将盖子卷起,以消除盖子和盘子之间的任何看得见的接缝。以相同的方式准备一个空盘作为空白对照。将盘子放在差示扫描热量计中。以适当的温度程序(开始温度下平衡,等温,变速,最终温度)运行材料,产生如图2中所示的温谱图。DSC分析显示在58.3℃的温度点处发生吸热跃迁,ΔH是72.39J/g。在63-64℃的峰吸热处,样品可见地熔化了。
6.5实施例5:1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸
用30分钟的时间,向加巴喷丁(6.8g,0.04摩尔)的水(40mL)溶液中加入[(1-异丁酰氧基乙氧基)羰基氧基]琥珀酰亚胺(10g,0.036mol)的乙腈(40mL)溶液。反应在室温下搅拌3小时。用甲基叔丁基醚(200mL)稀释反应混合物,用水(2×100mL)和盐水(50mL)洗涤。分离有机相,用无水硫酸钠干燥,过滤并真空浓缩,得到白色固体状的标题化合物(12g,定量)。
结晶:将固体化合物(12g)混悬在甲基环己烷∶甲基叔丁基醚10∶1(60mL)中。用30分钟的时间,将混悬液缓慢加热直到50℃。然后将澄清溶液冷却到室温。向浑浊混合物中加入5mg结晶形式的标题化合物作为晶种。进一步将混合物冷却到0-4℃2小时。过滤固体产物,用甲基环己烷(2×10mL)洗涤,生成白色结晶固体状的标题化合物(10g,83%产率)。用开口毛细管熔点测定器测定,该结晶固体物质具有约64-66℃的熔点。
最后,应该注意的是,存在实现本发明的可供选择的方法。因此,本发明的实施方案应看成是说明性的而不是限制性的,本发明不限于本文给出的细节,而是可在由此提出的任意权利要求的范围内和等价方案中进行修改。本文引用的所有出版物和专利的全部内容都被引入以作参考。
Claims (28)
1、结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
2、根据权利要求1的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,它在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处具有特征吸收峰。
3、根据权利要求1的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,它具有图1显示的X射线粉末衍射图。
4、根据权利要求1的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,它具有约63℃到约64℃的熔点范围。
5、根据权利要求1的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,它具有约64℃到约66℃的熔点范围。
6、药物组合物,它包含结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸和药学上可接受的媒介物。
7、权利要求6的药物组合物,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处具有特征吸收峰。
8、权利要求6的药物组合物,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸具有图1显示的X射线粉末衍射图。
9、权利要求6的药物组合物,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的熔点范围为约63℃到约64℃。
10、权利要求6的药物组合物,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的熔点范围为约64℃到约66℃。
11、一种治疗或预防需要该治疗的患者中癫痫、疼痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征的方法,它包括给所述患者施用治疗有效量的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
12、一种治疗或预防需要该治疗的患者中神经性疼痛、肌肉疼痛、骨骼疼痛或关节炎的方法,它包括给所述患者施用治疗有效量的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
13、权利要求11或12的方法,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处具有特征吸收峰。
14、权利要求11或12的方法,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的熔点范围为约63℃到约64℃。
15、权利要求11或12的方法,其中,结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的熔点范围为约64℃到约66℃。
16、一种治疗或预防需要该治疗的患者中癫痫、疼痛、抑郁、焦虑、精神病、晕厥发作、运动减少、颅障碍、神经变性障碍、恐慌、炎性疾病、失眠、胃肠道障碍、热潮红、多动腿综合征、尿失禁或乙醇戒断综合征的方法,它包括给所述患者施用治疗有效量的权利要求5至10任一项的药物组合物。
17、一种治疗或预防需要该治疗的患者中神经性疼痛、肌肉疼痛、骨骼疼痛或关节炎的方法,它包括给所述患者施用治疗有效量的权利要求5至10任一项的药物组合物。
18、制备结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸的方法,它包括:
在溶剂或溶剂混合物中加热1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,以提供溶液;和
改变该溶液的温度。
19、权利要求18的方法,其中,所述溶剂选自甲醇、乙醇、1,2-丙二醇、叔丁醇、正丁醇、异丙醇、乙酸、硝基甲烷、乙腈、二甲亚砜、二甲基甲酰胺、N-甲基吡咯烷酮、丙酮、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯、甲基异丁基酮、1,2-二甲氧基乙烷、四氢呋喃、2-甲基四氢呋喃、甲苯、甲基叔丁基醚、氯苯、1,4-二烷、二***、异丙基苯、邻二甲苯、间二甲苯、对二甲苯、2-乙氧基乙醇、1,2-乙二醇、甲酸乙酯、2-甲氧基乙醇、1-戊醇及它们的混合物。
20、权利要求18的方法,其中,所述溶剂是由溶剂和反-溶剂组成的溶剂组合。
21、权利要求20的方法,其中,所述反-溶剂选自戊烷、己烷、庚烷、辛烷、壬烷、癸烷、十一烷、十二烷、顺式-或反式-萘烷、环己烷、甲基环己烷及它们的混合物。
22、权利要求20的方法,其中,所述溶剂组合由乙酸乙酯和庚烷组成,加热温度介于约50℃到回流温度之间。
23、权利要求22的方法,其中,所述温度为约70℃。
24、权利要求23或24的方法,其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在庚烷中的浓度为约0.18g/mL到约0.22g/mL。
25.权利要求20的方法,其中,所述溶剂组合由甲基叔丁基醚和甲基环己烷组成,加热温度在约20℃到约40℃的范围内。
26、权利要求25的方法,其中,1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸在所述溶剂组合中的浓度介于约0.1g/mL到约0.25g/mL之间。
27、权利要求26的方法,其中,通过冷却溶液改变溶液的温度到介于约0℃到约25℃之间。
28、结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸,包括在X射线粉末衍射图中在7.0°±0.3°、8.2°±0.3°、10.5°±0.3°、12.8°±0.3°、14.9°±0.3°、16.4°±0.3°、17.9°±0.3°、18.1°±0.3°、18.9°±0.3°、20.9°±0.3°、23.3°±0.3°、25.3°±0.3°和26.6°±0.3°处有特征吸收峰的结晶1-{[(α-异丁酰氧基乙氧基)羰基]氨基甲基}-1-环己烷乙酸。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102137840A (zh) * | 2008-07-02 | 2011-07-27 | 特瓦制药工业有限公司 | 加巴喷丁酯盐及其制备方法 |
WO2013008182A1 (en) * | 2011-07-10 | 2013-01-17 | Mahesh Kandula | Prodrugs of gaba analogs |
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