CN108997160A - （1r-反）-n-[[2-（2,3-二氢-4-苯并呋喃基）环丙基]甲基]丙酰胺代谢物 - Google Patents

（1r-反）-n-[[2-（2,3-二氢-4-苯并呋喃基）环丙基]甲基]丙酰胺代谢物 Download PDF

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CN108997160A
CN108997160A CN201811055156.4A CN201811055156A CN108997160A CN 108997160 A CN108997160 A CN 108997160A CN 201811055156 A CN201811055156 A CN 201811055156A CN 108997160 A CN108997160 A CN 108997160A
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sleep
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metabolin
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M·M·德雷斯曼
D·哈德克
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Vanda Pharmaceuticals Inc
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Abstract

本发明涉及(1R‑反)‑N‑[[2‑(2，3‑二氢‑4‑苯并呋喃基)环丙基]甲基]丙酰胺代谢物，特别是分离的(1R‑反)‑N‑[[2‑(2，3‑二氢‑4‑苯并呋喃基)环丙基]甲基]丙酰胺代谢物及其使用方法，以及含有该代谢物的组合物。

Description

(1R-反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙 酰胺代谢物
本申请是是分案申请，其原申请的国际申请号是PCT/US2013/041573，国际申请日是2013年05月17日，中国国家申请号为201380025225.6，进入中国的日期为2014年11月13日，发明名称为“(1R-反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺代谢物”。
相关申请的交叉引用
本申请要求共同未决的2012年5月18日提交的美国临时专利申请61/649220号的权益，其在此并入本文。
技术领域
本发明涉及(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺代谢物及其用途。
背景技术
(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺是一种视交叉上核(SCN)中的MT1R和MT2R褪黑素受体的特异性强效力激动剂，其描述于美国专利5856529号，在此引入作为参考，如同完全阐述。褪黑素与MT1R和MT2R受体的接合据信会调节昼夜节律，包括睡眠/觉醒周期。(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺耐受性良好，并在急性相位偏移(phase-shifting)和慢性再引导(re-entrainment)的临床前模型中表现出强力的生物时相活性(chronobiotic activity)。
发明内容
本发明提供了(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺代谢物、它们的使用方法以及含有所述代谢物的组合物。所述代谢物包括酚-羧酸类似物(M9)和羟丙基-酚类似物(M11)。其各自于口服施用(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺后在人体内形成。
本发明的各方面包括非晶形式或结晶形式的分离的式II和III的化合物，包括其盐、溶剂化物和水合物。“分离”是指该化合物被分离自人血浆或合成得到。
虽然本文以R-反式构型进行描述，本发明还包括它们的立体异构体，即R-顺、S-反和S-顺。此外，本发明包括式II和式III化合物的前药(包括例如这些化合物的酯)以及它们以可有效治疗或预防个体的睡眠障碍的量在个体中的施用。
本发明的另一个方面包括一种药物组合物，其包含至少一种上述化合物和药学上可接受的载体。
本发明的另一个方面包括治疗或预防个体睡眠障碍的方法，该方法包括：直接向个体施用有效量的至少一种上述化合物。“直接”是指该化合物不是间接递送，例如施用(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺。
本发明的另一个方面包括治疗或预防个体昼夜节律紊乱或具有昼夜节律成分的病症的方法，该方法包括：直接向个体施用有效量的至少一种上述化合物。
本发明的示例性方面旨在解决本文描述的问题和未讨论的其他本领域技术人员可以发现的问题。
本发明的这些和其它特征可以从以下本发明各个方面的详细说明更容易地理解。
具体实施方式
如上所述，本发明涉及分离的(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺的人体代谢物及其用途。下式I中示出(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺的结构，本文中有时被称为他司美琼(Tasimelteon)。
在人体中，他司美琼可能直接代谢为M9和M11，但并非意在限于这种解释。M11可能被进一步代谢为M9。
氧化去烷基化导致(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺的呋喃环的开环，得到代谢物M11，其结构见下式II。
进一步的氧化得到代谢物M9，一种(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺的酚-羧酸衍生物，其结构见下式III。M9代谢物可以从M11代谢物形成。
本发明包括分离的式II和式III的化合物、盐、酯、溶剂化物、水合物、对映异构体、立体异构体、它们的非晶形式和晶体形式、含有这些化合物的药物组合物以及这些化合物和药物组合物的使用方法。因此，对式II或式III的化合物的引用包括盐、酯、溶剂化物、水合物、对映异构体、立体异构体以及它们的非晶形式和晶体形式。
14C-放射性标记的(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺以100μCi/100mg的剂量施用给健康男性受试者。然后在给药后预定的时间间隔(血浆为0.5h、1h、2h、8h和24h；尿为0～6h、6h～12h、12h～24h和24h～72h；粪便为0～24h、24h～48h和48h～120h)收集受试者的血浆、尿和粪便样品。血浆和粪便样品进行甲醇萃取以除去蛋白质。所有样品经离心以除去固体然后进行HPLC放射色谱分析。每个级分的放射性由PackardNXTTM微孔板闪烁和发光计数技术来确定。选出的尿、血浆和粪便的提取物通过偶联有放射性监视器的LC/MS进行分析。
(1R，反)-N-[[2-(2，3-二氢-4-苯并呋喃基)环丙基]甲基]丙酰胺与M9和M11代谢物在受试者的血浆、尿和粪便中的存在比例如下表1所示。
表1.血浆、尿和粪便中的他司美琼和选定代谢物
可以看到，M9代谢物是一种主要的循环代谢物，占总血浆放射性的近20％。在血浆样品中也检测到未发生变化的他司美琼(约8％)以及代谢物M11(约3.5％)(在其他代谢产物发现剩余血浆放射性，其未示出)。
未变的他司美琼和代谢物M11都未在0～72h尿样中发现。包括所施用剂量的近30％的放射性的代谢物M9是主要的尿代谢物。未变的他司美琼和代谢物M9仅在粪便样本中发现，均代表少量的粪便代谢物。所有粪便代谢物呈现所施用剂量的不到1％的放射性。
M9和M11代谢物也可合成。具体地，M11代谢物可以由他司美琼合成，M9代谢物可以由M11代谢物合成。M11和M9代谢物生产的合成途径分别示于下面的方程1和2中。
根据本发明的组合物通常是口服施用，但也可以使用其他施用途径，例如，肠胃外、静脉内、肌肉内、经颊、锭剂、经皮、经粘膜等。也可以使用控释形式(包括储存形式)，例如，持续式、脉冲式或延迟式。示例形式包括那些在W02003037337和W02004006886中公开的关于他司美琼的内容，其被并入本文。根据本发明的口服单位剂型通常包含约5mg至约100mg的式II和式III的化合物。
本文中使用的短语“有效量”是指含有足以产生所需的预防或治疗效果的量，无论是单独施用还是与添加剂组合施用。这样的有效量会根据例如疾病或症状的严重程度、该组合物所施用至的个体、组合物本身以及其施用途径而有所不同。在一般情况下，式II和III化合物的剂量在约1mg/天至约500mg/天，例如，约10mg/天至约100mg/天。该剂量可处于一个或多个单位剂型中。
应当理解，给药方案(包括式II和/或式III化合物的实际施用量)将由医生根据相关情况来决定，包括例如，待治疗的病症、选择的施用途径、施用该化合物的个体的年龄、体重和响应以及个体症状的严重性。
式II或III的化合物通常作为药物组合物使用标准和常规技术施用，所述药物组合物包含作为必要活性成分(或其中之一)的至少一种此类化合物与固体或液体的药学上可接受的载体(和可选的药学上可接受的助剂和赋形剂)的组合。
本发明实践中有用的药物组合物包括用于口服、肠胃外(包括皮下、肌内、皮内和静脉内)、经皮、支气管或鼻部给药的合适剂型。因此，如果使用固体载体，制剂可以制为片剂、以粉末或颗粒形式或者以糖锭剂或锭剂形式置于硬明胶胶囊中。该固体载体可含有常规的赋形剂如粘合剂、填充剂、压片润滑剂、崩解剂、润湿剂等。如果需要，所述片剂可以通过常规技术进行薄膜包衣。如果使用液体载体，该制剂可以是糖浆、乳剂、软明胶胶囊、无菌注射液、水性悬浮液或非水液体悬浮液的形式，或可以是用于在使用前用水或其它合适载剂重配的干式产品。液体制剂可含有常规的添加剂，如悬浮剂、乳化剂、润湿剂、非水性载剂(包括食用油)、防腐剂以及调味剂和/或着色剂。对于肠胃外施用，载剂通常包括无菌水(至少占大部分)，但也可以使用盐水溶液和葡萄糖溶液等。也可使用可注射的悬浮液，在这种情况下，常规的悬浮剂都可以使用。常规的防腐剂和缓冲剂等也可加入肠胃外剂型中。特别有用的是用口服剂量制剂施用式I化合物。所述药物组合物可以通过适用于含有适当量的式II或III化合物的所需制剂的常规技术来制备。参见，例如，Remington′sPharmaceutical Sciences，Mack出版公司，Easton，Pa.，第17版，1985。
在制备在本发明中使用的药物组合物时，活性成分通常与载体混合，或用载体稀释，或封入载体内，所述载体可以是胶囊、药袋、纸或其它容器的形式。当载体充当稀释剂时，它可以是固体、半固体或液体材料，其充当活性成分的载剂、赋形剂或介质。因此，该组合物可以是片剂、丸剂、散剂、锭剂、袋剂、扁囊剂、酏剂、悬浮剂、乳剂、溶液、糖浆、气雾剂(作为固体或在液体介质中)、软膏剂(其含有例如至多10重量％的活性化合物)、软明胶胶囊和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉剂的形式。
合适的载体和稀释剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯和羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油。所述制剂可以额外包括润滑剂、润湿剂、乳化剂和悬浮剂、防腐剂、甜味剂或调味剂。本发明的组合物可配制成能在施用于患者后提供快速、持续或延迟释放的活性成分。
本发明化合物可用于昼夜节律紊乱和/或具有昼夜节律成分的病症、睡眠障碍、和任何其它有褪黑素激动剂指征的病症的治疗或预防。这种昼夜节律紊乱和/或具有潜在的昼夜节律成分的病症包括：时差、倒班工作睡眠障碍(SWSD)、广泛性焦虑症、重度抑郁症、季节性情感障碍、注意力不足/过度活跃症、阿尔茨海默病、安吉尔曼综合征、双相情感障碍、精神分裂症、自闭症、癫痫、偏头痛、夜间高血压、肥胖症和/或2型糖尿病、肿瘤和睾酮不足。可被治疗或预防的睡眠障碍包括例如，失眠、总睡眠时间(快速眼动(REM)睡眠加上非快速眼动(NREM)睡眠阶段1、2、3、或4)不足，睡眠效率不良(睡眠效率＝((熟睡时间/入睡机会(*100)、入睡后觉醒(WASO，以分钟计的陷入持续睡眠后觉醒或从持续睡眠觉醒至“开灯”前的时间分数)和持续睡眠潜伏期延长(LPS；“关灯”和开始持续睡眠之间的时间)。
出于说明和描述性目的，已经呈现了上述对本发明各个方面的描述。它不旨在穷尽说明或将本发明限于所公开的精确形式，并且显然可以有许多修改和变化形式。对于本领域技术人员可能是显而易见的这些修改和变化形式也应被包括在所附权利要求书所限定的本发明范围之内。

Claims (6)

1.非晶形式或结晶形式的式II的分离的化合物或其盐、立体异构体、溶剂化物或水合物：
2.非晶形式或结晶形式的式III的分离的化合物或其盐、立体异构体、溶剂化物或水合物：
3.一种药物组合物，其包括：
选自由以下组成的组中的至少一种化合物：处于非晶形式或结晶形式的式II的化合物、式III化合物以及它们的盐、立体异构体、溶剂化物和水合物，
和药学上可接受的载体。
4.根据权利要求3所述组合物，其为单位剂型，其中1至4个所述单位剂型包括治疗有效量的用于以下病症中的至少一种的治疗的至少一种化合物：昼夜节律紊乱、具有昼夜节律成分的病症或睡眠障碍。
5.根据权利要求4所述的组合物，其中所述有效量对于选自由以下组成的组的睡眠障碍的治疗有效：失眠、总睡眠时间不足、入睡后觉醒发作(WASO)、睡眠效率不良和持续睡眠潜伏期延长(LPS)。
6.根据权利要求4所述的组合物，其中所述有效量对于选自由以下组成的组的昼夜节律紊乱或具有昼夜节律成分病症的治疗有效：时差、倒班工作睡眠障碍(SWSD)、广泛性焦虑症、重度抑郁症、季节性情感障碍、注意力不足/过度活跃症、阿尔茨海默病、安吉尔曼综合征、双相情感障碍、精神分裂症、自闭症、癫痫、偏头痛、夜间高血压、肥胖症和/或2型糖尿病和睾酮不足。
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