CN1216991A - 5－(2－(4－(1,2－苯并异噻唑－3－基)－1－哌嗪基)乙基)－6－氯－1,3－二氢－2(1h)－吲哚－2－酮(=ziprasidone)的甲磺酸盐二水合物,它的制备及其作为多巴胺d2拮抗剂的用途 - Google Patents
5－(2－(4－(1,2－苯并异噻唑－3－基)－1－哌嗪基)乙基)－6－氯－1,3－二氢－2(1h)－吲哚－2－酮(=ziprasidone)的甲磺酸盐二水合物,它的制备及其作为多巴胺d2拮抗剂的用途 Download PDFInfo
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Abstract
本发明涉及5－(2－4－(1,2－苯并异噻唑－3－基)－1－哌嗪基)乙基)－6－氯－1,3－二氢－2H－吲哚－2－酮的甲磺酸盐二水合物、含有该甲磺酸盐二水合物的药物组合物以及用该甲磺酸盐二水合物治疗精神障碍性疾病的方法。
Description
发明背景
本发明涉及5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2(1H)-吲哚-2-酮的甲磺酸盐二水合物(此后为“ziprasidone甲磺酸盐二水合物”)、含一种或两种ziprasidone甲磺酸盐二水合物的药物组合物以及用ziprasidone甲磺酸盐二水合物治疗精神病的方法。ziprasidone是一种重要的抗精神病药物，因此可有效治疗包括精神分裂症、焦虑和偏头痛在内的多种功能障碍性疾病。美国专利5,312,925公开了盐酸ziprasidone一水合物并声称该盐酸ziprasidone一水合物是极其吸湿稳定的，这样缓解了在制备胶囊和片剂时出现的活性组分重量改变的潜在问题。美国专利5,312,925全文在此引入作为参考。然而，盐酸ziprasidone一水合物水溶性较低并因此更适宜于胶囊和片剂剂型而不是注射剂型。
ziprasidone甲磺酸盐二水合物还具有吸湿稳定性。与盐酸一水合物相比，ziprasidone甲磺酸盐二水合物具有的另一优点是其显著增加的水溶性，该优越性使甲磺酸盐二水合物比其盐酸一水合物更适宜于注射剂型。
发明概述
本发明涉及5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪)乙基)-6-氯-1,3-二氢-2(1H)-吲哚-2-酮的甲磺酸盐二水合物。
本发明还涉及一种用于治疗精神障碍性疾病(例如精神分裂症、焦虑和偏头痛)的药物组合物，此组合物包含一定量的可有效治疗上述精神障碍性疾病症的5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪)乙基)-6-氯-1,3-二氢-2(1H)-吲哚-2-酮甲磺酸盐二水合物和药物可接受载体。
本发明还涉及一种治疗包括人体在内的哺乳动物精神障碍性疾病(例如精神分裂症、焦虑和偏头痛)的方法，该方法包括：将一定量的5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪)乙基)-6-氯-1,3-二氢-2(1H)-吲哚-2-酮甲磺酸盐二水合物施用于哺乳动物以治疗上述精神障碍性疾病。
附图描述
附图1．以强度(Cps)相对于衍射角(2-θ°(theta degrees))表示的ziprasidone甲磺酸盐二水合物(片型晶体)X-射线衍射光谱。
附图2．以强度(Cps)相对于衍射角(2-θ°)表示的ziprasidone甲磺酸盐二水合物(针型晶体)X-射线衍射光谱。
附图3．以强度(Cps)相对于衍射角(2-θ°)表示的无水ziprasidone甲磺酸盐(片型晶体)X-射线衍射光谱。
附图4．表示ziprasidone甲磺酸盐二水合物(片型晶体)的显微照相。
附图5．表示ziprasidone甲磺酸盐二水合物(针型晶体)的显微照相。
附图6．表示无水ziprasidone甲磺酸盐(片型晶体)的显微照相。
下表1-3通过衍射角(2-θ°)、d-间距、最大强度(max.int.)和相对强度(rel.int.)确定了选自附图1-3的峰。
表1ziprasidone甲磺酸盐二水合物(片晶)
X-射线粉末衍射数据
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 3.080 | 28.6618 | 245.00 | 4.19 |
| 3.684 | 23.9618 | 210.00 | 3.60 |
| 7.208 | 12.2538 | 626.00 | 10.71 |
| 7.931 | 11.1377 | 493.00 | 8.44 |
| 8.429 | 10.4810 | 100.00 | 1.71 |
| 9.968 | 8.8664 | 386.00 | 6.61 |
| 12.022 | 7.3558 | 1947.00 | 33.33 |
| 12.721 | 6.9527 | 620.00 | 10.61 |
| 13.394 | 6.6049 | 548.00 | 9.38 |
| 13.886 | 6.3720 | 331.00 | 5.67 |
| 14.481 | 6.1116 | 390.00 | 6.68 |
| 15.152 | 5.8426 | 194.00 | 3.32 |
| 15.949 | 5.5523 | 2462.00 | 42.15 |
| 17.048 | 5.1967 | 5841.00 | 100.00 |
| 18.111 | 4.8941 | 493.00 | 8.44 |
| 18.592 | 4.7684 | 3227.00 | 55.25 |
| 19.520 | 4.5438 | 740.00 | 12.67 |
| 19.862 | 4.4663 | 1512.00 | 25.89 |
| 20.517 | 4.3253 | 733.00 | 12.55 |
| 20.883 | 4.2503 | 872.00 | 14.93 |
| 21.372 | 4.1541 | 412.00 | 7.05 |
| 21.814 | 4.0709 | 1848.00 | 31.64 |
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 22.711 | 3.9121 | 571.00 | 9.78 |
| 23.078 | 3.8507 | 920.00 | 15.75 |
| 24.263 | 3.6652 | 2218.00 | 37.97 |
| 24.798 | 3.5874 | 1982.00 | 33.93 |
| 25.665 | 3.4681 | 1778.00 | 30.44 |
| 26.640 | 3.3434 | 204.00 | 3.49 |
| 27.162 | 3.2803 | 1232.00 | 21.09 |
| 28.728 | 3.1049 | 347.00 | 5.94 |
| 29.202 | 3.0556 | 209.00 | 3.58 |
| 30.004 | 2.9758 | 225.00 | 3.85 |
| 30.721 | 2.9079 | 366.00 | 6.27 |
| 31.610 | 2.8281 | 407.00 | 6.97 |
| 32.267 | 2.7720 | 522.00 | 8.94 |
| 32.800 | 2.7282 | 252.00 | 4.31 |
| 33.202 | 2.6960 | 743.00 | 12.72 |
| 34.549 | 2.5940 | 373.00 | 6.39 |
| 34.549 | 2.5940 | 373.00 | 6.39 |
| 35.144 | 2.5514 | 245.00 | 4.19 |
| 36.738 | 2.4443 | 220.00 | 3.77 |
| 38.910 | 2.3127 | 124.00 | 2.12 |
| 39.751 | 2.2657 | 204.00 | 3.49 |
表2ziprasidone甲磺酸盐二水合物(针晶)
X-射线粉末衍射数据
表3无水的ziprasidone甲磺酸盐二水合物(片晶)X-射线粉末衍射数据
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 7.823 | 11.2913 | 33.00 | 1.78 |
| 10.049 | 8.7946 | 504.00 | 27.20 |
| 11.502 | 7.6872 | 1095.00 | 59.09 |
| 12.660 | 6.9866 | 148.00 | 7.99 |
| 13.440 | 6.5826 | 87.00 | 4.70 |
| 14.080 | 6.2848 | 83.00 | 4.48 |
| 14.958 | 5.9178 | 791.00 | 42.69 |
| 15.762 | 5.6179 | 446.00 | 24.07 |
| 16.313 | 5.4293 | 398.00 | 21.48 |
| 16.760 | 5.2854 | 140.00 | 7.56 |
| 17.261 | 5.1330 | 71.00 | 3.83 |
| 17.696 | 5.0078 | 125.00 | 6.75 |
| 18.640 | 4.7563 | 631.00 | 3405 |
| 19.002 | 4.6665 | 1853.00 | 100.00 |
| 19.976 | 4.4411 | 294.00 | 15.87 |
| 20.726 | 4.2820 | 115.00 | 6.21 |
| 22.348 | 3.9748 | 470.00 | 25.36 |
| 22.790 | 3.8987 | 1440.00 | 77.71 |
| 24.377 | 3.6484 | 884.00 | 47.71 |
| 25.368 | 3.5080 | 192.00 | 10.36 |
| 25.861 | 3.4423 | 457.00 | 24.66 |
| 26.640 | 3.3434 | 150.00 | 8.09 |
| 27.212 | 3.2743 | 329.00 | 17.75 |
| 28.349 | 3.1456 | 309.00 | 16.68 |
| 28.930 | 3.0837 | 180.00 | 9.71 |
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 29.644 | 3.0111 | 231.00 | 12.47 |
| 30.130 | 2.9636 | 175.00 | 9.44 |
| 30.601 | 2.9190 | 236.00 | 12.74 |
| 31.704 | 2.8200 | 95.00 | 5.13 |
| 32.198 | 2.7778 | 83.00 | 4.48 |
| 33.887 | 2.6431 | 98.00 | 5.29 |
| 34.830 | 2.5737 | 124.00 | 6.69 |
| 35.519 | 2.5253 | 106.00 | 5.72 |
| 36.901 | 2.4339 | 63.00 | 3.40 |
| 37.716 | 2.3831 | 110.00 | 5.94 |
| 38.331 | 2.3463 | 113.00 | 6.10 |
| 38.732 | 2.3229 | 146.00 | 7.88 |
| 39.751 | 2.2657 | 105.00 | 5.67 |
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 3.065 | 28.8018 | 120.00 | 9.16 |
| 6.521 | 13.5424 | 63.00 | 4.81 |
| 8.737 | 10.1124 | 72.00 | 5.50 |
| 11.860 | 7.4557 | 38.00 | 2 |
| 12.776 | 6.9231 | 528.00 | 4C |
| 13.992 | 6.3241 | 386.00 | 29.47 |
| 16.307 | 5.4311 | 653.00 | 49.85 |
| 16.847 | 5.2582 | 448.00 | 34.20 |
| 17.538 | 5.0527 | 608.00 | 46.41 |
| 2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(％) |
| 18.385 | 4.8217 | 369.00 | 28.17 |
| 18.800 | 4.7162 | 169.00 | 12.90 |
| 19.712 | 4.5001 | 1310.00 | 100.00 |
| 20.722 | 4.2829 | 208.00 | 15.88 |
| 21.424 | 4.1441 | 932.00 | 71.15 |
| 22.600 | 3.9311 | 509.00 | 38.85 |
| 22.918 | 3.8772 | 658.00 | 50.23 |
| 23.690 | 3.7526 | 502.00 | 38.32 |
| 24.558 | 3.6219 | 743.00 | 56.72 |
| 25.792 | 3.4513 | 175.00 | 13.36 |
| 26.399 | 3.3734 | 612.00 | 46.72 |
| 28.185 | 3.1636 | 109.00 | 8.32 |
| 28.706 | 3.1073 | 82.00 | 6.26 |
| 29.652 | 3.0103 | 135.00 | 10.31 |
| 30.680 | 2.9117 | 104.00 | 7.94 |
| 31.034 | 2.8793 | 171.00 | 13.05 |
| 31.365 | 2.8497 | 152.00 | 11.60 |
| 32.983 | 2.7135 | 98.00 | 7.48 |
| 33.737 | 2.6545 | 101.00 | 7.71 |
| 35.533 | 2.5244 | 63.00 | 4.81 |
| 38.737 | 2.3226 | 92.00 | 7.02 |
| 39.608 | 2.2735 | 73.00 | 5.57 |
发明详述
ziprasidone甲磺酸盐存在四种不同的晶形：无水ziprasidone甲磺酸盐(片晶)、ziprasidone甲磺酸盐二水合物(片晶)，ziprasidone甲磺酸盐二水合物(针晶)和ziprasidone甲磺酸盐三水合物。每种晶形具有不同的特性，例如相异的X-射线粉末衍射图谱和从显微照片识别出的不同晶体形状。ziprasidone甲磺酸盐二水合物的片晶(附图4)和针晶(附图5)比ziprasidone甲磺酸盐三水合物棱晶相对较长和较薄。虽然无水ziprasidone甲磺酸盐(附图6)在形状上与ziprasidone甲磺酸盐二水合物的片晶相似，但它们是有区别的。附图4-6所示显微照片是利用装有卤灯、双目镜片、滤偏光器和连有Sony彩色打印机的Sony3ccd摄像机的Olympus偏光显微镜(BH-2型)拍摄的。
图1和2为ziprasidone甲磺酸盐二水合物的X-射线粉末衍射特征光谱。无水ziprasidone甲磺酸盐晶形(附图6)与二水合物的晶形(附图4)类似，无水ziprasidone甲磺酸盐的X-射线粉末衍射光谱显然区别于ziprasidone甲磺酸盐二水合物的X-射线粉末衍射光谱(附图1和2)。使用SiemensR3RA/v衍射仪测定附图1-3所示的X-射线粉末衍射光谱。ziprasidone甲磺酸盐二水合物的另一特征是由6.4±1.0的Karl Fischer(KF)值表示的含水量。ziprasidone甲磺酸盐三水合物是标题为“5-(2-(4-(1,2-苯并异噻唑-3.-基)-1-哌嗪)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐三水合物”的共同待审美国临时申请(辉瑞公司摘要号PC9277)的主题，该主题在此同时提出。上述共同待审美国临时申请的全文在此引入作为参考。
与盐酸ziprasidone一水合物室温下0.08mg/mL的水中溶解度相比，ziprasidone甲磺酸盐二水合物明显地更易溶于含水介质中。下表4列出了ziprasidone甲磺酸盐四种形式的水溶解度。
表4
ziprasidone甲磺酸盐多晶型体的水溶解度
| 多晶型体 | 在水中的溶解度 |
| 三水合物二水合物(片晶)二水合物(针晶)无水 | 0.73mg/mL1.11mg/mL1.10mg/mL1.27mg/mL |
可从(ziprasidone的)游离碱制备ziprasidone甲磺酸盐二水合物，而该游离碱的制备如上述美国专利5,312,925第4栏，第22-43行所述。游离碱也可按照美国专利5,338,846描述的方法制备，该专利公开的全文在此全文引入作为参考。当欲采用注射剂型时，优选在无热原、无微粒的条件下进行制剂。可以用0.45μm的Millipore尼龙滤器过滤得到无微粒的溶剂和试剂。
按照上文中公开的三水合物制备方法，ziprasidone甲磺酸盐二水合物针晶的制备是通过：将游离碱与水和有机溶剂的混合液进行混合，加入稀释的甲磺酸并加热回流。制备二水合物针晶时在回流条件下搅拌约30分钟后向反应溶液中加入针型多晶型体的晶种。表明晶体形成的“粉色”稠厚悬浮液开始生成。然后将该反应溶液在缓慢搅拌下冷却。当冷却至约50℃时，将水加入溶液以使悬浮液变稀。针晶经多层滤膜过滤后从组合物中分离出来，随后依次用适当体积的THF/水(65/35,v/v)溶液和水洗涤。室温至干后，针晶含水量具有6.0-6.8％KF的Karl Fisher值(三水合物的理论KF值为6.4％)。
ziprasidone二水合物片晶的制备是将游离碱与水进行混合并将所得悬浮液加热至50℃-55℃。然后加入浓缩的甲磺酸并加热混合物至回流。回流约1-6小时，优选2小时后，将溶液冷却以生成二水合物片晶。所得悬浮液在室温下搅拌约2小时，按照上述针晶的方法，将晶体从组合物中滤出并洗涤。室温下至干后，片晶的水含量具有6.0-6.8％KF的Karl Fisher值(二水合物的理论KF值为6.4％)。
据美国专利5,312,925称(上文作为参考)ziprasidone甲磺酸盐二水合物可作为精神病治疗剂给药。ziprasidone甲磺酸盐二水合物的使用优选在组合物中与药物可接受载体或稀释剂共用并依照正规医药实践进行，如上文提及的美国专利5.312.925。适宜药用载体包括本领域已知的固体稀释剂或填充剂、灭菌水溶液、多种有机溶剂和赋形剂。
ziprasidone甲磺酸盐二水合物可口服或胃肠外(包括静脉内或肌肉内给药)给药。为了肠胃外给药，当需要使用水时，优选灭菌注射用水(SWI)。优选肌肉内注射给药。肌肉内注射用的优选组合物是结合在作为载体的丁基次硫酸(sulfoxybutyl)β环糊精内的ziprasidone甲磺酸盐二水合物，并优选按二水合物与载体以1∶10(w/w)配比制备。含有有ziprasidone甲磺酸盐二水合物与次硫酸β环糊精的组合物是按照与本申请同时提出的题为“包合复合物制备方法”(辉瑞公司摘要号PC9563)和“芳基-杂环化合物的包合复合物”(辉瑞公司摘要号PC8838)的共同待审美国临时申请中记载的方法制备。这两个共同待审美国临时申请的全文都在此引入作为参考。
ziprasidone甲磺酸盐二水合物的有效剂量取决于预定给药途径、待治疗病况和患者的年龄、体重等其它因素。在以下的剂量范围中，“mgA”是指游离碱(ziprasidone)的毫克数。口服剂量的推荐范围是一次或分次的5-300mgA/天，优选40-200 mgA/天，更优选40-80 mgA/天。胃肠外用药(例如注射)的推荐剂量范围是2.5 mgA/天-160mgA/天，优选5-80mgA/天。
本发明通过下列实施例进行说明但并不局限于其中的具体内容。除非另外指出，以下实施例中的制备是在无微粒、无热原的条件下进行。在下述实施例中，以THF表示四氢呋喃，以SWI表示注射用无菌水。
实施例1
5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮的纯化
将46.8kg5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮和2816.4L THF加入到洁净干燥的搪瓷罐内。加热该悬浮液至回流并持续45分钟直至生成浑浊溶液。溶液经33英寸的滤器(sparkler)过滤至较低处的洁净干燥搪瓷罐内，其中该滤器首先用助滤剂涂布并再放上Fulflo滤膜(Parker Hannifin Corp.,Lebanon,Indaina产品)。将滤液真空蒸馏浓缩、冷却至5℃并继续搅拌2小时。用离心机过滤以收集产物并用冷的(0-5℃)THF洗涤。收集产物并且在45℃下真空干燥，得到40.5kg产物。经HPLC分析试验测定的产品纯度为101.5％(相对于标准物，介于100±2％的典型范围)。
实施例2
5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐三水合物
向装有加热罩、悬挂式机械搅拌器、冷凝器和温度探头的22升的三颈圆底烧瓶中加入1000g5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮、7500mL SWI和4000mLTHF从而得到一悬浮液。用铝箔将该瓶内容物遮盖起来以避免光照。在搅拌下加热上述悬浮液至50℃。将188mL甲磺酸与812mL SWI混合得到甲磺酸稀释液。将甲磺酸稀释液从一个滴液漏斗中缓慢滴加至反应混合液中。将反应物加热回流(约65℃)，加热中反应混合物成为暗红色溶液。该反应混合物在回流条件下搅拌约30分钟。30分钟后，关闭加热罩以使反应混合物在搅拌下缓慢冷却。将该混合物搅拌过夜(约18小时)。冷却反应混合物时结晶出大量“黄色”六方形的棱晶产物。将该混合物在室温下再搅拌1小时。产物用铺有多层滤膜的布氏漏斗进行分离。并随后用1500mL的THF/SWI(65/35)和1000mL的SWI洗涤。将结晶铺在玻璃盘中使其在室温条件下干燥直至Karl Fisher值达到约9.6％。用装有0.027H板的Mikro-Samplmill(由Pulvering Machinery Divison ofMikropul Corp.Summit,New Jersey生产)在14,000rpm碾磨产物，得到945g产物。
用NMR证实5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐三水合物的产物结构。
13C NMR(DMSO-d6):δ177.1(0),163.0(0),153.0(0),145.0(0),132.4(0),129.0(1),127.8(0),127.7(1),127.1(0),126.5(0),125.6(1),124.9 91),122.1(1),110.6(1),55.9(2),51.7(2),47.5(2),40.7(3),36.2(2),27.9(2).1H NMR(DMSO-d6):δ10.5(s,1H)；9.8(br.s,1H)；8.2(d,J=8.2Hz,1H)；8.1(d,J=8.2Hz,1H)；7.6(m,1H),7.5(m,1H)；7.3(s,1H),6.9(s,1H)；4.2(m,2H)；3.7(m,2H)；3.5(m,2H),3.4(m,2H)；3.1(m,2H)；2.4(s,3H)。
从HPLC获得的产物结果表明：该产物具有与标准物相应的保留时间峰。
HPLC条件如表5所列。
表5
| HPLC条件 | |
| 柱： | Waters-Puresil C-18 15cm长×4.6mmI.D(目录号WATO44345) |
| 流动相： | 0/05MKH2PO4 pH3.0：甲醇(60∶40.v/v) |
| 流速： | 2.0mL/分钟 |
| 检测器： | UV,229nm |
| 柱温： | 室温 |
| 样品体积： | 10μL |
实施例3
无水5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐
向装有加热罩、悬挂式机械搅拌器、冷凝器和温度探头的12升三颈圆底烧瓶中加入350g5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮、7000mL异丙醇从而得到一悬浮液。在搅拌下加热该悬浮液至50℃。将65.9mL甲磺酸从一个滴液漏斗中缓慢滴加至50℃的反应混合液中。略微加热使该悬浮液变稠并观察到悬浮液颜色变浅。常压下蒸馏上述反应液以使体积减小25％(1750mL)。冷却悬浮液至室温并用新制异丙醇洗涤。将固体铺在玻璃盘中使其在室温条件下干燥直至Karl Fisher值达到约0.5％。产物收率为420.3g。从HPLC获得的产物结果表明该产物具有与标准物相应的保留时间峰。从HPLC(如表5所示条件)测得的产物纯度为99.8％。
实施例4
5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐二水合物(针晶)
向装有加热罩、悬挂式机械搅拌器、冷凝器和温度探头的150mL三颈圆底烧瓶中加入5g5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮、37.5mL水和20mLTHF从而得到一悬浮液。用铝箔将该瓶内容物遮盖起来以避免光照。在搅拌下加热上述悬浮液至65℃。将1mL甲磺酸与4mL SWI混合得到甲磺酸稀释液。将甲磺酸稀释液从一个滴液漏斗中缓慢滴加至反应混合液中。将反应物加热回流(约65℃)，加热中反应混合物成为暗红色溶液。该反应混合物在回流条件下搅拌约30分钟。30分钟后，将针状晶形的晶种加至该反应溶液中。结晶开始形成，除去加热并在搅拌下缓慢冷却反应物。在冷却中50℃时，可观察到瓶中的悬浮液为稠状“粉红色”。向瓶中加入水(20mL)使悬浮液变稀。将产物在室温下搅拌1小时。用带有滤纸的布氏漏斗将上述产物分离并在室温下使其干燥至Karl Fischer值达到约6.6％。得到6.03g的产物。从HPLC(如表5所示条件)测得的产物纯度为99.8％。
实施例5
5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐二水合物(片晶)
向装有加热罩、悬挂式机械搅拌器、冷凝器和温度探头的500mL三颈圆底烧瓶中加入25g5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2(1H)-吲哚-2-酮、375mL水从而得到一悬浮液。用铝箔将该瓶内容物遮盖起来以避免光照。在搅拌下加热上述悬浮液至50-55℃。将甲磺酸(5mL)从一个滴液漏斗中缓慢滴加至反应混合液中。可观察到悬浮液变稠并颜色变浅。加热该混合物至回流(约100℃)并搅拌1小时。除去热源以使反应物在搅拌下缓慢冷却。将反应溶液在室温下搅拌1小时。用带有滤纸的布氏漏斗将上述产物分离并在室温下使固体干燥至Karl Fischer值达到约6.2％。得到32.11g的产物。从HPLC(如表5所示条件)测得的产物纯度为98.7％。
Claims (9)
1．5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮的甲磺酸盐二水合物。
2．权利要求1的化合物为片形晶体。
3．权利要求1的化合物为针形晶体。
4．一种用于治疗精神障碍性疾病的药物组合物，其中含有一定量的能够有效治疗所述精神障碍性疾病的权利要求1化合物和可药用载体。
5．一种治疗哺乳动物精神障碍性疾病的方法，其中包括给予该哺乳动物一定量的能够有效治疗上述精神障碍性疾病的权利要求1所述化合物。
6．权利要求5中的方法，其中该精神障碍性疾病为精神分裂症、焦虑症或偏头痛。
7．权利要求5中的方法，其中该精神障碍性疾病为精神分裂症。
8．权利要求5中的方法，其中的给药方式为肠胃外给药。
9．权利要求8中的方法，其中的给药方式为肌肉内注射。
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1997
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1998
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107595771A (zh) * | 2010-10-18 | 2018-01-19 | 大日本住友制药株式会社 | 注射用缓释制剂 |
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