CN1063175C - 吡咯烷基甲基吲哚盐 - Google Patents

吡咯烷基甲基吲哚盐 Download PDF

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CN1063175C
CN1063175C CN96194043A CN96194043A CN1063175C CN 1063175 C CN1063175 C CN 1063175C CN 96194043 A CN96194043 A CN 96194043A CN 96194043 A CN96194043 A CN 96194043A CN 1063175 C CN1063175 C CN 1063175C
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M·J·维希斯
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Abstract

用于治疗偏头痛的(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚的富马酸盐。

Description

吡咯烷基甲基吲哚盐
本发明涉及结构式Ⅰ(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚的富马酸盐：
Figure 9619404300031
在WO-A-92/06973实施例5A中描述了游离碱形式的化合物(Ⅰ)。尽管在WO-A-92/06973列出的适宜的可药用酸加成盐的通式中提到了富马酸盐，但并未描述过(Ⅰ)的富马酸盐。
现在，我们发现，(Ⅰ)的富马酸盐可意想不到地改善氧化降解稳定性。而且，也意外地发现，式(Ⅰ)的富马酸盐具有极好的溶解性和固体状态稳定性并且不吸湿。
因此，本发明提供(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚的富马酸盐，含有它的药物组合物及其在治疗偏头痛中的应用。
如下列实施例中所述，可通过在适宜的有机溶剂或溶剂混合物中，将化合物(Ⅰ)与大约1当量的富马酸反应来制备该盐。
式(Ⅰ)的富马酸盐可配制并给予人来治疗偏头痛和其它如WO-A-92/06973中所描述的适应症，将所述文献引入本文供参考。
实施例
(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基
甲基)-1H-吲哚
在室温下，将富马酸(5.87g，0.0506mol)一次加到(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚(16.25g，0.0506mol)的甲醇(81.25ml)悬浮液中，得到极好的悬浮液，将该悬浮液过滤并用甲醇(16ml)洗涤。在搅拌下，将溶液加热回流并用乙腈(50ml)稀释。通过在大气压下蒸馏除掉溶剂并用乙腈代替直到蒸汽温度为80℃。在蒸馏过程中，将溶液中加入(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚富马酸盐的晶种并得到淤浆。将该淤浆冷却至室温并在0℃下粒化1小时。过滤，得到产物(21.45g，97％)，为灰白色结晶，m.p.159℃(通过DSC测定)。Rf.0.2(硅胶，乙醚/乙酸乙酯/DEA/MeOH，10∶10∶1∶1)；[α]D+13.17°(c=1，H2O)。
实测值：                               C，54.94；H，6.35；N，9.60％C16H23N3O2S；C4H4O4的计算值： C，54.91；H，6.22；N，9.60％1H-NMR(300MHz，DMSO-d6):δ=1.50-1.90(m，4H)，2.50-2.54(d，3H)，2.54-2.60(s，3H)，2.62-2.74(m，1H)，2.82-2.96 (m，1H)，3.08(dd，1H)，3.20-3.30(m，1H)，4.28-4.36(s，2H)，6.48-6.54(s，2H)，6.70-6.80(q，1H)，7.02-7.12(d，1H)，7.16-7.22(s，1H)，7.28-7.36(d，1H)，7.48-7.56(s，1H)，10.86-10.94(s，1H).化合物(Ⅰ)的游离碱和富马酸盐的饱和溶解度
对于游离碱和富马酸盐来说，将大约50mg固体疏松物质精密称重并加到1.5ml塑料“Eppendort”管(Sigma)中。将0.3ml水(MilliQ)加到该管中。然后，在室温下，将该管在1，300rpm(“LKB”)转速下涡流混合16小时。通过在13，000rpm转速下离心20分钟，将上清液从未溶解的物质中分离出(“Heraeus Biofuge 13”)，然后稀释并通过HPLC测定化合物(Ⅰ)。该测定使用乙腈(20％)，水(80％)和三氟乙酸(0.1％)作为流动相，并使用150×4.2mm的“Zorbax SB CN”柱，在40℃下，用U.V.在220nm处检测。结果如下。吸湿性
在Surface Measurement System Ltd的湿度微量天平中，于30℃下分别将大约10mg的化合物(Ⅰ)的游离碱和富马酸盐暴露在相对湿度(RHs)在0-94％的8个不同环境中。让样品在各RHs下括到平衡并且计算相对于将样品放入天平中时最初值的重量变化。所得到的数据用于绘制物质的湿度吸着等温线。通过计算在90％RH下的湿度摄入量来比较物质的吸湿性，结果如下：
疏松型    溶解度(mg/ml)   在30℃和90％RH下
                          的吸湿性(％/w/w)
游离碱       0.12               0.2
富马酸盐     67.5               0.2
富马酸盐在水中的溶解度增加使得水溶液制剂简单化并且有助于固体剂型的溶出。富马酸盐的水溶解性增加并不伴随疏松物质的吸湿性增加〔这可能导致疏松稳定性降低〕。化合物(Ⅰ)的氧化稳定性
软明胶胶囊剂是具有吸引力的、化合物(Ⅰ)释放系统，因为它们可改善体内溶出性和在生产中提高成分的均匀性。化合物(Ⅰ)可配制成液体填充软明胶胶囊剂。然而，由于氧化降解，常常限制了这些制剂的贮存期限。PEG400是用于该目的的、有代表性的液体填充稀释剂。设计下列实验来测定在该制剂中，化合物(Ⅰ)是否发生氧化降解，并且富马酸盐是否可防止氧化降解。将化合物(Ⅰ)游离碱。化合物(Ⅰ)的盐酸盐，化合物(Ⅰ)的富马酸盐配制成1mg/ml的90％PEG400(BDH)和10％水(Milli-Q)溶液。将10％的水加到制剂中来模拟水从软明胶胶囊壳中进入。在该制剂中，游离碱是难溶的，这限制了该疏松型的进一步研究。然而，为了便于溶液的制备，使用盐酸盐来代替游离碱。
将过氧化氢(BDH)加到制剂中至最终浓度为0.3％w/w以便提供氧化剂。在研究中，也使用不含过氧化氢的对照制剂。将1ml各制剂密封在2mlHPLC瓶(“Cromacol”)中并放在40℃的恒温加热炉中。在1.5天和3天时取样并在测定前冷冻贮存(-20℃)。将样品稀释并用上述表明稳定性的HPLC测定法进行分析。降解情况用剩余化合物(Ⅰ)的百分数来表示。在40℃下，化合物(Ⅰ)在含或不含氧化剂的90％PEG400中的稳定性
(平均值±标准差，n=3)
稳定性研究表明，在不含氧化剂下，PEG400制剂中，化合物(Ⅰ)的两种盐形式都是较稳定的。然而，当通过加入过氧化氢，将氧化剂应用于制剂中时，可见降解作用明显提高。这表明，氧化降解可在化合物(Ⅰ)的软明胶胶囊剂中发生，这影响了制剂的贮存期限。因此，在氧化环境中稳定性提高的疏松物质对于在软明胶胶囊中的制剂是有利的。
在两个时间点，富马酸盐的降解速度均明显低于(方差分析，p＜0.001)盐酸盐。富马酸盐的抗氧化性可明显防止其在制剂中降解并且对于其在软明胶载体中的制剂来说是有利的。
就我们所知，在以前的文献中还没有关于富马酸盐氧化稳定性好的报道。
固态稳定性
分别将大约1mg化合物(Ⅰ)的游离碱。盐酸盐，氢溴酸盐和富马酸盐精密称重并加到玻璃小瓶中。分别在4℃/环境湿度，40℃/环境湿度，40℃/75％RH和50℃/环境湿度下贮存9周。然后，用下列表明稳定性的HPLC方法测定样品。将由0.05M磷酸二氢钾(用磷酸调至PH2)(90％)和乙腈(远UV)(10％)组成的流动相以1ml/分钟的流速通过“Zorbax SB-CN”150×4.6mm的柱(40℃)，在225nm进行UV检测。
除游离碱外，通过在25ml容量瓶中，将化合物(Ⅰ)的各盐溶解在流动相中来制备样品。在用流动相稀释之前，将游离碱溶解在几滴甲醇中。
通过研究贮存样品层析谱中新峰的外观并与在4℃下贮存的对照样品比较峰数的增加来确定样品的稳定性。下表显示的是通过该方法表示的、在50℃下贮存的游离碱和富马酸盐的降解情况。在较低温度贮存条件下，可观察到类似的趋势。从数据中可以看出，50℃下，富马酸盐在9周后仍没降解，而游离碱由于可见到4个新的药物相关峰表明发生降解。因此，富马酸盐是固态中最稳定的并且对于药物生产来说，具有适宜的疏松型贮存期限。
表
化合物(Ⅰ)：在50℃下，9周后的疏松稳定性数据
％降解(50℃下的％峰面积3-4℃下的峰面积3)
相对滞留时间     游离碱     富马酸盐
    0.400.590.600.640.770.850.911.00     0.05…0.010.02……0.02化合物(Ⅰ)的主谱带 …0.00…0.00………
    1.351.661.93     0.020.170.03     0.00……
％峰面积增加总数     0.32     0.00
…在该相对滞留时间不存在峰粗大并且划线的数字表示出现的新峰。
使用常规方法制备上述盐酸盐和氢溴酸盐，例如，为了制备盐酸盐，通常在65℃下，用约1当量的浓HCl来处理化合物(Ⅰ)在乙醇中的溶液并冷却。真空除掉溶剂并将剩余的泡沫从无水乙醇中重结晶，得到盐酸盐。除了使用48％HBr外，如上制备氢溴酸盐。

Claims (5)

1．(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚的富马酸盐。
2．一种药物组合物，它含有权利要求1所要求的富马酸盐和可药用稀释剂或载体。
3．权利要求1所要求的富马酸盐制备用于治疗偏头痛的药物的用途。
4．制备(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚富马酸盐的方法，其特征是将(R)-5-(甲基氨基磺酰基甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚与富马酸反应。
5．权利要求4所要求的方法，其中使用大约1当量的富马酸。
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ZA963938B (en) 1997-11-17
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AR003949A1 (es) 1998-09-30
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AP9600801A0 (en) 1996-04-30
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JP3233940B2 (ja) 2001-12-04
GB9510223D0 (en) 1995-07-19
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MA23876A1 (fr) 1996-12-31
ES2148753T3 (es) 2000-10-16
PL183142B1 (pl) 2002-05-31
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AU5500596A (en) 1996-11-29
ATE194986T1 (de) 2000-08-15
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IL118239A0 (en) 1996-09-12
LV11992A (lv) 1998-03-20
TNSN96074A1 (fr) 2005-03-15
MY132066A (en) 2007-09-28
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CA2219631A1 (en) 1996-11-21
KR100295255B1 (ko) 2001-08-07

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