CN1216990A - 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(ziprasidone)的甲磺酸盐三水合物,其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)乙基)-6-氯-1,3-二氢-2(1h)-吲哚-2-酮(ziprasidone)的甲磺酸盐三水合物,其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-yl)-1-哌嗪)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐三水合物,含有所述甲磺酸盐三水合物的药物组合物,和用所述的甲磺酸盐三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)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮的甲磺酸盐三水合物(此后称ziprasidone甲磺酸盐三水合物),含ziprasidone甲磺酸盐三水合物的药物组合物和使用ziprasidone甲磺酸盐三水合物治疗精神障碍性疾病的方法。ziprasidone是有效的精神障碍性疾病药物,因此用于治疗包括精神分裂症、偏头痛和焦虑在内的各种疾病是有效的。美国专利5,312,925涉及ziprasidone盐酸盐一水合物,并指出ziprasidone盐酸盐一水合物具有充分的吸湿稳定性,可以缓解在生产胶囊或药片过程中有效成分重量改变这一潜在问题。美国专利5,312,925全文在此作为参考。但ziprasidone盐酸盐一水合物的水溶性较差,因此更适于制成胶囊或片剂,而不是用注射剂的剂型。
ziprasidone甲磺酸盐三水合物也具有吸湿稳定性。ziprasidone甲磺酸盐三水合物还具有另外的一项优点即它具有比ziprasidone盐酸盐一水合物明显增强的水溶性,这一优点使它比ziprasidone盐酸盐一水合物更适于采用注射剂的剂型。并且,在ziprasidone甲磺酸盐的四种晶体形态中,ziprasidone甲磺酸盐三水合物在室温下在水介质中热力学最稳定。这使ziprasidone甲磺酸盐三水合物更适于制备含有水介质的稳定而剂量精确的药剂。
发明概要
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-2H-吲哚-2-酮甲磺酸盐三水合物。
本发明还涉及治疗精神障碍性疾病,如精神分裂症、偏头痛或焦虑的药物组合物,此药物组合物含有一定量的治疗所述疾病有效的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和药学能接受的载体。
本发明还涉及治疗哺乳动物,包括人在内的诸如精神分裂症、偏头痛或焦虑等精神障碍性疾病的方法,此方法包括给哺乳动物使用一定量的、治疗所述疾病有效的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。
图表说明
图1用强度(Cps)对衍射角(2θ)表示的ziprasidone甲磺酸盐三水合物的X射线粉末衍射光谱。
图2用单晶X射线晶体几何学分析法确定的ziprasidone甲磺酸盐三水合物的结构。
图3是ziprasidone甲磺酸盐三水合物(柱晶)的显微照片。
表1是根据衍射角(2θ6)、d-间距(d-spacing)、最大强度(max.int.)和相对强度(rel.int.)确定的图1光谱中的选定峰。
表1 ziprasidone甲磺酸盐三水合物
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(%) |
7.680 | 11.5025 | 84.00 | 8.54 |
9.657 | 9.1515 | 216.00 | 21.95 |
10.827 | 8.1650 | 48.00 | 4.88 |
12.205 | 7.2455 | 216.00 | 21.95 |
13.203 | 6.7002 | 803.00 | 81.61 |
13.564 | 6.5227 | 329.00 | 33.43 |
15.240 | 5.8089 | 191.00 | 19.41 |
15.507 | 5.7095 | 388.00 | 39.43 |
15.923 | 5.5612 | 836.00 | 84.96 |
16.680 | 5.3106 | 100.00 | 10.16 |
17.000 | 5.2112 | 103.00 | 10.47 |
17.946 | 4.9386 | 428.00 | 43.50 |
2-θ(度) | D-间距(度) | 最大强度(计数/秒) | 相对强度(%) |
18.794 | 4.7178 | 383.00 | 38.92 |
19.881 | 4.4622 | 195.00 | 19.82 |
20.491 | 4.3306 | 93.00 | 9.45 |
21.585 | 4.1136 | 603.00 | 61.28 |
22.179 | 4.0047 | 984.00 | 100.00 |
23.472 | 3.7870 | 282.00 | 28.66 |
24.359 | 3.6511 | 240.00 | 24.39 |
24.918 | 3.5705 | 429.00 | 43.60 |
25.280 | 3.5201 | 159.00 | 16.16 |
26.034 | 3.4198 | 221.00 | 22.46 |
26.832 | 3.3199 | 196.00 | 19.92 |
27.594 | 3.2300 | 132.00 | 13.41 |
28.299 | 3.1511 | 261.00 | 26.52 |
29.151 | 3.0608 | 86.00 | 8.74 |
29.819 | 2.9938 | 197.00 | 20.02 |
30.361 | 2.9415 | 138.00 | 14.02 |
30.792 | 2.9014 | 112.00 | 11.38 |
32.448 | 2.7570 | 102.00 | 10.37 |
33.559 | 2.6682 | 73.00 | 7.42 |
34.264 | 2.6149 | 159.00 | 16.16 |
35.069 | 2.5567 | 165.00 | 16.77 |
35.742 | 2.5100 | 84.00 | 8.54 |
38.182 | 2.3551 | 158.00 | 16.06 |
发明的详细描述
ziprasidone甲磺酸盐存在四种不同的晶格形式: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(柱晶)。每种晶格形式有不同的特点,如不同的X射线粉末衍射图谱、不同的单晶X射线衍射和不同的可由显微照片观察到的晶体形状。ziprasidone甲磺酸盐二水合物的片晶、针晶和无水ziprasidone甲磺酸盐的片晶与ziprasidone甲磺酸盐三水合物的柱晶(图3)比较要相对长和薄一些。无水ziprasidone甲磺酸盐虽然形状上与ziprasidone甲磺酸盐二水合物片晶相似,实际上是不同的。图3的显微照片是用装有卤素灯、双目目镜、偏光滤镜和带有Sony彩色打印机的Sony3ccd摄象机的Olympus偏光显微镜(BH-2型)拍摄的。
图1为ziprasidone甲磺酸盐三水合物X射线粉末衍射的特征光谱。图2为用单晶X射线晶体几何分析法确定的ziprasidone甲磺酸盐三水合物的结构。图1的X射线粉末衍射光谱和图2的单晶X射线是用Siemens R3RA/v衍射仪测得的。另外ziprasidone甲磺酸盐三水合物以其含水量为特性,其含水量的Karl Fischer(KF)值为9.6±1.0。ziprasidone甲磺酸盐二水合物(片晶和针晶)是题为“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-酮甲磺酸盐二水合物”的同时待审的(co-pending)美国临时申请(Pfizer目录号PC9573)的主题,同时在此提出。此前所述的正在进行的(co-pending)美国临时申请的全文在此作为参考的。
在大气温度下的水介质中,ziprasidone甲磺酸盐三水合物是四种ziprasidone甲磺酸盐形式中热力学最为稳定的形式。因此,ziprasidone甲磺酸盐三水合物是优选的含水制剂的甲磺酸盐形式。需特别指出的是,甲磺酸盐三水合物特别适用于胃肠外给药的含水制剂。无水甲磺酸盐在暴露于空气(潮湿)中时是吸湿性的。这使得难于制成制剂,因为在制备制剂过程中有效成分重量发生变化。用使不同晶型的混合物达到平衡的一系列桥连实验可以测定三种ziprasidone甲磺酸盐水合物晶体的相对热力学稳定性。在此桥连实验中,使200mg试样在大气温度(22-25℃)下,在水(4ml)中达到平衡。测定两个各含有90/10(w/w)和10/90(w/w)两种不同的ziprasidone甲磺酸盐的多晶型物混合物的试样(柱晶对二水合物(片晶),柱晶对二水合物(针晶),二水合物(针晶)对二水合物(片晶))。平衡后(12-13天),测定固体的多晶化转变并且用HPLC检测上层清液以测定其溶解度。测定发现,晶型互变的稳定性遵循所观察到的晶型溶解性的变化趋势,如以下表2所示。ziprasidone甲磺酸盐三水合物比ziprasidone甲磺酸盐二水合物更具热力学优越性。
四种ziprasidone甲磺酸盐晶型的每一种都比ziprasidone盐酸盐一水合物有更好的溶解性,后者在大气温度下的溶解度为0.08mg/ml。四种ziprasidone甲磺酸盐晶型的溶解度列于表2。
表2
ziprasidone甲磺酸盐多晶型物的水溶性
多晶型物 | 水溶性 |
三水合物 | 0.73mg/ml |
二水合物(片晶) | 1.11mg/ml |
一水合物(针晶) | 1.10mg/ml |
无水化合物 | 1.27mg/ml |
可以从游离碱(ziprasidone)制备ziprasidone甲磺酸盐三水合物,此游离碱的制备参考上述的美国专利5,312,925第4栏,第22-43行的记载,此专利公开的内容在此全文作为参考。当欲采用注射剂型应用时,优选在无热原、无微粒的条件下制备制剂。可以用0.45μm的Millipore尼龙滤层过滤得到无微粒的溶剂和试剂。
将游离碱(ziprasidone)与水和有机溶剂的混合物混合,有机溶剂优选四氢呋喃,在有机溶剂/水的比率(v/v)约为3∶7到27∶3,温度范围从10℃到30℃,优选大气温度(大约22-25℃)的条件下混合。优选使用THF/水比率为4∶7.5(v/v每单位游离碱)。将混合物边搅拌边加热到约50℃。然后制备稀释的甲磺酸(1∶4w/w酸/水)溶液以提供1.2当量的酸,将其缓慢地,优选以在30到60分钟内加入到含游离碱的化合物中。在避光的条件下将反应混合物加热到回流(大约65℃)并持续30分钟。在将混合物加热后,再将其缓慢冷却到大气温度。在冷却过程中,ziprasidone甲磺酸盐三水合物将开始从混合物中结晶出。一旦混合物冷却到大气温度,将其搅拌至少一小时以保证完全结晶。此三水合物晶体呈现为大的淡黄色的六边棱柱晶体。将此三水合物晶体用多层滤布从混合物中过滤,然后连续地用适量的THF/水(65/35,v/v)溶液和水清洗。在大气温度下干燥后,此晶体的水含量Karl Fischer值范围为8.9-10.1%KF(三水合物的理论KF值为9.6%)。
ziprasidone甲磺酸盐三水合物可以口服或胃肠外给药,包括静脉内或肌肉内给药。对于需要使用水的胃肠外给药优选使用无菌注射用水(SWI)。优选肌肉注射给药。用于肌肉注射的组合物优选ziprasidone甲磺酸盐三水合物与丁基次硫酸β环糊精载体组合,优选按三水合物与载体以1∶10的比率制备组合物。按与本申请同时提出的题为“包合物的制备方法”(Pfizer docketnumber PC9563)和“芳香杂环化合物的包合物”(Pfizer docket number PC8838)的未决(co-pending)美国临时申请中记载的方法制备含有ziprasidone甲磺酸盐三水合物与丁基次硫酸β环糊精的组合物。这两个同时待审(co-pending)美国临时申请都在此全文作为参考。
ziprasidone甲磺酸盐三水合物的有效剂量取决于预定的给药途径、将治疗的症状和病人的年龄、体重等其它因素。在以下的剂量范围中,“mgA”指游离碱(ziprasidone)的毫克数。口服剂量的推荐范围是一次或分次按5-300mgA/天,优选40-200mgA/天,尤其优选40-80mgA/天的剂量服用。胃肠外用药,如注射的推荐剂量范围是2.5mgA/天到160mgA/天,优选5-80mgA/天。
用以下例子说明本发明,但它并不局限于实施例中的细节。除非另外指出,以下实施例中的制备在无微粒、无热原的条件下进行。在以下实施例中,用THF表示四氢呋喃,用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)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮的净化
向清洁干燥的搪瓷罐中加入46.8kg的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-酮和2816.4L的THF。将混合物浆体加热到回流并保持45分钟以形成浑浊溶液。使溶液通过33-英寸预涂以助滤剂的sparkler过滤,并通过Fulflo过滤器(Parker Hannifin Corp.生产,Indiana,Lebanon)回到位于低处的清洁干燥的搪瓷罐中。用真空蒸馏的方法将滤液浓缩,冷却到5℃并搅拌2小时。将产物用离心分离机上的过滤装置收集并用冷的(0-5℃)THF清洗。将产物收集并在真空45℃的条件下干燥,得到40.5kg产品。HPLC测量测定此产品具有101.5%的纯度(与标准相比在100±2%的典型范围内)。
实施例2
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
将1000g5-(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,7500ml SWI和4000ml THF加入到装有加热套、悬挂式机械搅拌器、冷凝器和温度探头的22升的三颈圆底长颈瓶中以得到浆状反应物。用铝箔覆盖层使长颈瓶中的内容物避光。将浆状反应物边搅拌边加热到50℃。将188ml甲磺酸与812mlSWI混合得到稀释的甲磺酸,将其通过滴液漏斗缓慢加入到反应混合物中。将反应物加热到回流(大约65℃)得到深红色的溶液。在回流状态下将反应混合物搅拌大约30分钟。30分钟后关断加热套使反应物在搅拌下缓慢冷却。反应混合物以搅拌冷却过夜(约18小时)。在冷却过程中,产物结晶成大的微黄色的六边棱柱晶体。在大气条件下将混合物搅拌1小时。用带有多层布滤的Buchner漏斗将产物分离,并连续用1500mlL THF/SWI(65/35,V/V)和1000mL SWI清洗。将晶体平铺在玻璃皿中并在大气条件下干燥至Karl Fischer值为大约9.6%。将产物用装有0.027H盘的微量样品粉碎机(Mikro-Samplmill)(Pulverizing Machinery Division ofMikropul Corp.制造,New Jersey,Summit,)在14000rpm的转速下粉碎,得到945g产物。
核磁测定产品结构为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。13CNMR(DMSO-d6):
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=8.2 Hz,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)。
HPLC对产品进行测定显示一个峰,其保留时间与标准值相对应。HPLC条件列于下表3。
表3
HPLC状态 | |
色谱柱 | Waters-Puresil C-18 15cm长×4.6mm直径(目录号(Catalog No.)WATO44345) |
流动相 | 0.05M磷酸二氢钾pH3.0:甲醇(60:40v/v) |
流速 | 2.0mL/分 |
检测器 | UV,229nm |
柱温 | 环境温度 |
样品体积 | 10μL |
实施例3
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-酮无水甲磺酸盐
将350g5-(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,7000ml异丙醇加入到装有加热套、悬挂式机械搅拌器、冷凝器和温度探头的12升的三颈圆底长颈瓶中以得到浆状反应物。将浆状反应物边搅拌边加热到50℃。65.9ml的甲磺酸通过滴液漏斗缓慢加入到50℃的反应混合物中。随着浆状反应物变浓,颜色变浅,能观察到微小温升使反应物温度变为55℃。将反应物在大气条件下蒸馏以去除25%的体积(1750ml)。将其冷却到大气温度并搅拌过夜。将产物用烧结玻璃漏斗分离并用新鲜异丙醇清洗。将晶体平铺在玻璃皿中并在大气条件下干燥至Karl Fischer值约为0.5%。得到420.3g产物。HPLC对产品进行检测显示一个与标准保留时间相对应的峰。HPLC(条件显示在表3)测定的产品纯度为99.8%。
实施例4
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-酮甲磺酸盐二水合物(针晶)
将5g5-(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,37.5ml水和20ml THF加入到装有加热套、悬挂式机械搅拌器、冷凝器和温度探头的150mL的三颈圆底长颈瓶中以得到浆状反应物。用铝箔覆盖层使长颈瓶中的内容物避光。将浆状反应物边搅拌边加热到65℃。将1ml甲磺酸与4ml SWI混合得到稀释的甲磺酸,将其通过滴液漏斗缓慢加入到反应混合物中。反应物加热到回流(大约65℃)得到深红色的溶液。在回流状态下将反应混合物搅拌大约30分钟。30分钟后,将针形多晶型物的种晶加入到反应溶液中。结晶开始后,不再加温使反应物在搅拌下缓慢冷却。在冷却到50℃的过程中,在长颈瓶中可观察到稠的微粉红的浆状反应物。加水(20ml)到长颈瓶中以稀释此浆状反应物。将其在环境条件下搅拌1小时。用带有纸滤的Buchner漏斗将产物分离,将所得固体在环境条件下干燥至Karl Fischer值约为6.6%。得到产物6.03g。HPLC(条件显示在表3)检测产物纯度为99.8%。
实施例5
5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮甲磺酸盐二水合物(片晶)
将25g5-(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,375ml水加入到装有加热套、悬挂式机械搅拌器、冷凝器和温度探头的500毫升的三颈圆底长颈瓶中以得到浆状反应物。用铝箔覆盖层使长颈瓶中的内容物避光。将浆状反应物边搅拌边加热到50-55℃。5ml的甲磺酸通过滴液漏斗缓慢加入到反应混合物中。可观察到的浆状反应物变浓,颜色变浅。将反应物加热到回流(大约100℃)并搅拌约1小时。然后停止加热,使反应物搅拌冷却。在环境条件下将反应溶液搅拌1小时。用带有纸滤的Buchner漏斗将产物分离,将所得固体在环境条件下干燥至KarlFischer值约为6.2%。得到产物32.11g。HPLC(条件显示在表3)测定产物纯度为98.7%。
Claims (7)
1、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。
2、一种用于治疗精神障碍性疾病的药物组合物,其含有一定量权利要求1所述的化合物和药学可接受的载体,此化合物对于治疗所述精神障碍性疾病是有效的。
3、治疗哺乳动物精神障碍性疾病的方法,包括给予哺乳动物一定量权利要求1所述的治疗所述精神障碍性疾病有效的化合物。
4、权利要求3的方法,其中所述精神障碍性疾病为精神分裂症、偏头痛或焦虑。
5、权利要求3的方法,其中所述精神障碍性疾病为精神分裂症。
6、权利要求3的方法,其中所述给药方式是胃肠外给药。
7、权利要求6的方法,其中所述胃肠外给药方法是肌肉内注射。
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CN102234273A (zh) * | 2010-04-21 | 2011-11-09 | 上海医药工业研究院 | 甲磺酸齐拉西酮半水合物及其制备方法 |
CN102234273B (zh) * | 2010-04-21 | 2015-08-05 | 上海医药工业研究院 | 甲磺酸齐拉西酮半水合物及其制备方法 |
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