CN1146565C - 结晶性氮杂双环[2,2,2]辛烷-3-胺衍生物的柠檬酸盐的多晶型物及其药物组合物 - Google Patents

结晶性氮杂双环[2,2,2]辛烷-3-胺衍生物的柠檬酸盐的多晶型物及其药物组合物 Download PDF

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CN1146565C
CN1146565C CNB008082782A CN00808278A CN1146565C CN 1146565 C CN1146565 C CN 1146565C CN B008082782 A CNB008082782 A CN B008082782A CN 00808278 A CN00808278 A CN 00808278A CN 1146565 C CN1146565 C CN 1146565C
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citrate trianion
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M·J·卡斯塔尔迪
G·J·奎里奇
L·T·温特
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    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

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Abstract

(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2，2，2]辛烷-3-胺柠檬酸盐(柠檬酸盐单水合物)的单晶性多晶型物形式及其药物组合物。柠檬酸盐单水合物的多晶型物形式的药物组合物用于治疗呕吐的制剂具有很好的稳定性。该药物组合物给药后立即释放，其可为口服剂型，优选片剂或胶囊，或可通过静脉内给药。

Description

结晶性氮杂双环[2，2，2]辛烷-3- 胺衍生物的柠檬酸盐的多晶型物及其药物组合物
技术领域
本发明涉及(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2，2，2]辛烷-3-胺柠檬酸盐及其单水合物，其单晶的多晶型物形式A，以及含有它们的药物组合物。本发明也涉及用于治疗哺乳动物包括人呕吐的CNS活性NK-1受体拮抗剂。这里定义的治疗指预防和治疗。
背景技术
被引入作为参考文献的美国专利5,393,762和美国流水号08/816,016描述了药物组合物和使用NK-1受体拮抗剂治疗呕吐。柠檬酸盐单水合物的稳定性比其它盐形式的稳定性有明显的提高，例如苯甲酸盐甚至在5℃都是不稳定的。甲磺酸盐形式容易潮解。
发明内容
本发明涉及(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2，2，2]辛烷-3-胺的柠檬酸盐及其单水合物。在本发明的一个具体方案中，该柠檬酸盐单水合物是稳定的非吸湿单晶形式。该晶体常态为片状，其特征为具有如下给出的X-射线粉末衍射花样：
                                  柠檬酸盐单水合物
 峰序号     1     2     3     4     5     6     7
 d间距     13.28     7.70     7.45     6.34     5.33     5.06     4.40
该结晶性柠檬酸盐单水合物是非吸湿的，其特征为在大约116℃丢失水分(挥发)以及在大约152.7℃开始熔化。无水柠檬酸盐在水中转变为单水合物。
具有CNS活性NK-1受体拮抗剂活性的药物组合物包含治疗呕吐有效量的多晶型物形式A和药学上可接受的载体。一种治疗呕吐的方法包含给需要治疗的对象服用止吐有效量的该化合物的多晶型物。
一种制备(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2，2，2]辛烷-3-胺柠檬酸盐单水合物多晶型物形式A的方法包含将柠檬酸加入游离碱的丙酮溶液中。固体溶解约两个小时。过滤澄清溶液并搅拌过夜。加入过滤的异丙醚，随后加入过滤的水。在环境温度搅拌所得混合物直到结晶开始，并粒化约16小时。过滤收集白色结晶并使用氮气吹扫在大约45℃真空干燥约24小时。
制备结晶性柠檬酸盐单水合物多晶型物形式A的方法包含在785gm游离碱的7.85升丙酮溶液中加入353.9gm，0.55摩尔柠檬酸(无水，99.5+％)。将固体溶解大约2小时后，过滤澄清溶液，搅拌过夜，加入7.85升过滤的异丙醚，然后加入334毫升过滤的水。在环境温度搅拌所得混合物直到结晶开始，并另外粒化16小时。通过过滤收集形成的白色结晶盐并使用氮气吹扫在45℃真空下干燥24小时，得到992gm产物(产率89.9％)。通过PLM、X射线粉末衍射、质子NMR，Karl Fisher、DSC以及元素分析鉴定所得柠檬酸盐单水合物的多晶型形式。X射线粉末衍射和PLM显示它是结晶。遇到的晶体常态为片状。X射线粉末衍射观察到的最强的反射，d间距为13.280，7.702，7.446，6.337，5.332，5.057，和4.398。该结晶在116℃显示水分丢失(挥发)，在152.7℃开始熔化并伴有分解。吸湿性测量证明在90％RH时吸收有2.52％wt./wt.的水。Karl Fisher分析显示存在2.7％的水(理论值2.66％)，证实合成了单水合物。元素分析证实了合成盐的纯净。
在水中将无水柠檬酸盐制浆得到结晶性单水合物，其在干燥条件例如45℃的真空下不丢失它的水份。
柠檬酸盐单水合物的药物组合物的有效剂量取决于给药途径、指征、待治疗的病症及其它因素例如治疗对象的年龄和体重。在下列剂量范围中，术语“mgA”指单水合物的毫克数。推荐的口服剂量范围是5-300mgA/天，优选40-200mgA/天，更优选40-80mgA/天，可以是单剂量或分剂量。以口服剂型例如药丸或药片经口服给药的推荐剂量范围是2.5mgA/天到160mgA/天，优选5-80mgA/天。它也可经静脉内给药。
具体实施方式
下列实施例说明本发明方法和化合物。然而应该理解，本发明不局限于具体的实施例。
                       实施例1
             结晶性柠檬酸盐单水合物的制备
在环境条件下，将47克游离碱悬浮在470毫升异丙醚中。在室温下，向所得稀的白色浆状物中加入21.42克无水柠檬酸。然后通过在150毫升水中悬浮18小时将浆状物转化为单水合物。过滤浆状物得到白色结晶固体。得到X射线构型结果，证实该化合物是柠檬酸盐单水合物。

Claims (7)

1.具有下式的(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2.2.2]辛烷-3-胺柠檬酸盐单水合物的晶形，
其中所述晶形为显示如下X-射线粉末衍射花样的稳定的多晶型物形式A：  峰序号     1     2     3     4     5     6     7  d间距     13.28     7.70     7.45     6.34     5.33     5.06     4.40
2.权利要求1所述的柠檬酸盐多晶型物，它的晶体常态为片状。
3.具有CNS活性NK-1受体拮抗剂活性的药物组合物，其包含治疗呕吐有效量的权利要求1所述的多晶型物的形式A和药学上可接受的载体。
4.权利要求1所述的多晶型物形式A用于制备治疗呕吐的药物的用途。
5.制备(2S，3S)-N-(2-甲氧基-5-叔丁基苯基甲基)-2-二苯甲基-1-氮杂双环[2.2.2]辛烷-3-胺柠檬酸盐单水合物结晶性多晶型物形式A的方法，其包含：
向游离碱的丙酮溶液中加入柠檬酸；将该固体溶解2小时；过滤并搅拌该澄清溶液过夜；加入过滤的异丙醚，然后加入过滤的水；在环境温度搅拌所得混合物直到结晶开始，并粒化16小时；过滤收集形成的白色结晶盐并使用氮气吹扫使之在45℃真空干燥24小时。
6.权利要求5所述的方法，其中在环境条件下进行1.5到72小时制浆，粒化在异丙醚、异丙醇和水中进行。
7.权利要求5所述的方法，其中柠檬酸是含量大于99.5％的无水柠檬酸。
CNB008082782A 1999-06-01 2000-05-18 结晶性氮杂双环[2,2,2]辛烷-3-胺衍生物的柠檬酸盐的多晶型物及其药物组合物 Expired - Lifetime CN1146565C (zh)

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JP5021318B2 (ja) * 2004-01-30 2012-09-05 ファイザー・プロダクツ・インク β−シクロデキストリンを液体投薬形態に用いて多用量製剤を達成するための抗菌性防腐剤
JP2007519702A (ja) * 2004-01-30 2007-07-19 ファイザー・プロダクツ・インク ニューロキニン受容体拮抗薬及びシクロデキストリンからなる医薬組成物、ならびに注射部位の耐容性を改善するための方法
AU2005216706B2 (en) 2004-01-30 2007-11-29 Pfizer Products Inc. NK-1 receptor antagonists anesthesia recovery
CN1914202A (zh) * 2004-02-02 2007-02-14 辉瑞产品有限公司 1－(2s,3s)－2－二苯甲基－n－(5－叔丁基－2－甲氧基苄基)奎宁环－3－胺的制备方法
JP6454323B2 (ja) * 2013-03-15 2019-01-16 パール セラピューティクス，インコーポレイテッド 粒子状結晶性材料のコンディショニングのための方法及びシステム
CN110577522B (zh) * 2018-06-07 2022-12-27 东莞市东阳光动物保健药品有限公司 马罗匹坦柠檬酸盐新晶型及其制备方法

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DE9290063U1 (de) * 1991-05-31 1994-02-24 Pfizer Inc., New York, N.Y. Chinuclidin-Derivate
US5393762A (en) * 1993-06-04 1995-02-28 Pfizer Inc. Pharmaceutical agents for treatment of emesis
US5576317A (en) * 1994-12-09 1996-11-19 Pfizer Inc. NK-1 receptor antagonists and 5HT3 receptor antagonists for the treatment of emesis

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