CN1033641C - 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-酮盐酸盐-水合物 - 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-2h-吲哚-2-酮盐酸盐-水合物 Download PDF

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CN1033641C
CN1033641C CN93117311A CN93117311A CN1033641C CN 1033641 C CN1033641 C CN 1033641C CN 93117311 A CN93117311 A CN 93117311A CN 93117311 A CN93117311 A CN 93117311A CN 1033641 C CN1033641 C CN 1033641C
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monohydrate
piperazinyl
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indol
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D·J·M·阿伦
F·R·布殊
S·A·迪罗马
D·M·戈德克
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Abstract

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-酮盐酸盐的一水合物作为精神抑制剂具有有利的制备稳定性。

Description

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－酮盐酸盐－水合物
本发明涉及新的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-酮盐酸盐一水合物，涉及含所述一水合物的药用组合物以及服用所述一水合物治疗精神疾病(neuroleptic diseases)的方法。
美国专利第4,831,031号公开了具精神抑制活性的下式5-(2-(4-(1，2-苯并异噻唑-3-基)哌嗪基)乙基)-6-氯-1，3-二氢-2H-吲哚-2-酮盐酸盐，为半水合物形式(以下称“半水合物”)：
Figure C9311731100031
式中Ar是苯并异噻唑-3-基；本文引述该文作参考。
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-酮盐酸盐一水合物(以下称“一水合物”)，该化合物具有重要的且非显而易见的性质。由于一水合物在吸湿性方面基本稳定，因此减少了在压片或制胶囊操作过程中由于活性成分的重量改变而带来的制备问题。
图1表示含水量为3.97重量％的一水合物的粉末X射线衍射。
图2表示含水量为2.55重量％的半水合物的粉末X射线衍射。
图3表示含水量为0.13重量％的无水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-酮盐酸盐(以下称“无水化合物”)的粉末X射线衍射。
图4为含水量为3.97重量％的一水合物的红外光谱。
图5为含水量为2.55重量％的半水合物的红外光谱。
图6为含水量为0.13重量％的无水化合物的红外光谱。
一水合物的理论含水量是3.85重量％。在本发明范围内，一水合物的含水量约在3.8-4.5重量％范围内。
一水合物以其含水量、其图1中的粉末X射线衍射以及其在图4中的红外光谱为特征。这三个特征与具约为0.13％含水量、图3粉末X射线衍射和图6红外光谱的无水化合物的特征不同。无水化合物可由干燥化合物的半水合物或一水合物制得。这三个特征也与具约2.55重量％的含水量、图2粉末X射线衍射和图5红外光谱的半水合物的特征不同。半水合物可按美国专利第4,831,031号的第13栏第13-17行实施例16中所述的方法制得。
一水合物可以通过无水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-酮与盐酸水溶液反应制得。该反应一般约在室温至100℃温度范围内进行，通常约为60-65℃。根据反应温度和其它条件，反应时间一般约在2-48小时内，约3-24小时为宜。
在该反应溶液中的盐酸的浓度约在0.3-3.0M之间，约0.7M为佳。
反应后形成的热淤浆可用滤纸过滤，并用水、最好是去离子的超滤水洗涤滤饼。将该滤饼在仔细监控的条件下干燥使含水量确定在约3.8-4.5％之间，以获得稳定的一水合物。
本发明一水合物可如上述美国专利第4,831,031号中所述用作精神抑制剂。该水合物可给病人单独使用，或最好按照实际的药用标准与药学上可接受的载体或稀释剂配合以药用组合物的形式给病人使用。该一水合物可以口服或经肠道外包括静脉内或肌肉内给药。适宜的药用载体包括固体稀释剂或填充剂和灭菌水溶液和各种有机溶剂。从而该药用组合物可容易地以多种剂型如片剂、粉剂、锭剂、糖浆剂和注射液来使用。如有必要，这些组合物可以含附加成分如矫味剂、粘合剂和赋形剂。因此，用于口服时，含各种赋形剂如柠檬酸钠、碳酸钙和磷酸钙的片剂可与各种崩解剂如淀粉、藻酸和某些复合硅酸盐连同粘合剂如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶一同使用。此外润滑剂如硬脂酸镁、十二烷基硫酸钠和滑石粉也常用于制片。类似的固体组合物也可用作软及硬胶囊的填充物。为此优选的材料包括乳糖及高分子量的聚乙二醇。若水性悬浮剂或酏剂需要口服，其主要的活性成分可与各种甜味剂或矫味剂、着色剂或染料混合。必要时，可加入乳化剂或助悬剂及稀释剂如水、乙醇、丙二醇、甘油及其混合物。
式I新化合物的芝麻油或花生油及含水丙二醇的溶液或悬浮液，或者其灭菌水溶液可用于肠道外给药。若有必要，这样的水溶液应适当进行缓冲，而且该液体稀释剂首先用足量的盐水或葡萄糖使之等渗。这些具体的水溶液尤其适宜于静脉内、肌内、皮下和腹膜内给药。所用的灭菌水性介质均易用本领域技术人员公知的标准技术获得。
式I化合物的有效剂量如通常所知取决于所采用的给药途径以及其它因素如患者的年龄和体重。
通过将试验样品于室温露置于相对湿度为31％、51％、71％和81％的环境中4小时和8天来测试其稳定性。测定每个样品的含水量、红外光谱和X射线衍射图。在所述的试验条件下，稳定的试样不出现实质性变化。
                  实施例1
将一只清洁的2L三颈圆底烧瓶用去离子的超滤水冲洗两遍以使之无斑迹，安装上温度计、机械搅拌器、回流冷凝器和加热罩。将750ml去离子的超滤水、250ml浓盐酸(37.3％)加到烧瓶中(制成了3M盐酸水溶液)，再加入50g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。将该反应混合物加热至60-65℃24小时。趁热(约55℃)将该淤浆用滤纸过滤并将滤饼用去离子的超滤水洗涤两次，每次200ml。于40℃-50℃在空气中干燥7小时后含水量为3.9％。其粉末X射线衍射见图1。
再于50℃继续干燥21.5小时，该物质的含水量为0.19％。其X射线衍射见图3。这样，制得了无水化合物。
                      实施例2
在洁静的150ml三颈圆底烧瓶中安装上温度计、磁性搅拌器、具氮气进口的回流冷凝器和加热浴。将5.00g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-酮游离碱以及75ml去离子水和5.0ml浓(37.3％)盐酸加至该烧瓶中，成为0.76M的HCl溶液。将该反应混合物加热至60-65℃并在该温度下保持3小时。除去加热浴并将该淤浆冷却至室温。将产物滤集在烧结玻璃滤器中。将产物滤饼用少量去离子水洗涤，然后于50℃在空气中干燥。干燥后，含水量为4.2％，其X射线衍射图见图1所示。制得一水合物，收率为96％(5.43g)。
                      实施例3
将17.4加仑去离子水和4.44L浓盐酸加至洁净并干燥的20加仑的反应器中，得0.77M溶液。将4.44kg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-酮游离碱加至该反应器中。将该淤浆温热至65℃并保持18小时。将淤浆冷至室温并取样；该样品显示成盐完全。将产物过滤并用去离子水洗涤两次，每次5加仑。然后于50℃在空气中干燥30小时。该干燥后的产品含4.4％水。相应的X射线衍射图与图1相符，从而证实得到了所需的一水合物。
用在以上实施例中的无水游离碱制备如下。
                   实验
5-(2-(4-(1，2-苯并异噻唑-3-基)哌嗪基)乙基)-6-氯-1，3-二氢-2H-吲哚-2-酮
将19L水和4.44kg碳酸钠加至洁净且干燥的20加仑的衬玻璃的罐中。待碳酸钠溶解后，加入4.29kg(17.5mol)5-(2-氯乙基)-6-氯-羟吲哚和3.62kg(16.5mol)1-(1，2-苯并异噻唑-3-基)哌嗪。将该水性淤浆加热至回流，并在该温度下保持14小时。当反应完全时，将该溶液冷至20℃并过滤。该湿产物于室温在23L异丙醇中再次制浆。2小时后，将产物滤集于2只大的布氏漏斗中，各用3.4L新鲜的异丙醇洗涤。将产物于30℃-40℃真空干燥至无异丙醇残留，得5.89kg(86.4％的收率)所需的游离碱，用高效液相色谱法(HPLC)测定，与标准样品相符。

Claims (3)

1. 5-(2-(4-(1，2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1，3-二氯-2H-吲哚-2-酮盐酸盐一水合物。
2.具有精神抑制活性的药用组合物，它含有治疗精神疾病有效量的权利要求1化合物和药学上可接受的载体。
3.权利要求1化合物的制备方法，它包括将无水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-酮与含水盐酸反应，所说盐酸盐在反应溶液中的浓度为约0.7M。
CN93117311A 1992-09-01 1993-08-31 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-酮盐酸盐-水合物 Expired - Lifetime CN1033641C (zh)

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US939,204 1992-09-01

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