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CN1306530A - 用于治疗中枢神经系统疾病的帕罗西汀10－樟脑磺酸盐 - Google Patents

用于治疗中枢神经系统疾病的帕罗西汀10－樟脑磺酸盐 Download PDF

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CN1306530A
CN1306530A CN99807798A CN99807798A CN1306530A CN 1306530 A CN1306530 A CN 1306530A CN 99807798 A CN99807798 A CN 99807798A CN 99807798 A CN99807798 A CN 99807798A CN 1306530 A CN1306530 A CN 1306530A
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camsilate
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M·乌尔屈哈特
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Abstract

帕罗西汀10－樟脑磺酸盐可用于治疗某些中枢神经系统疾病。

Description

用于治疗中枢神经系统疾病的帕罗西汀10-樟脑磺酸盐
本发明涉及一种新的化合物，涉及它的制备方法并涉及它用于治疗内科疾病的用途。
US-A-3912743和US-A-4007196中描述了具有抗抑郁和抗帕金森病性质的药品。其中公开的尤其重要的化合物是帕罗西汀，即4-(4＇-氟苯基)-3-(3＇,4＇-亚甲二氧基-苯氧甲基)-哌啶的(-)反式异构体。这种化合物作为盐酸盐用于治疗，尤其是抑郁症、强迫症(OCD)和恐慌的治疗与预防。
现在我们惊奇地发现一种帕罗西汀的新盐，它可以当作目前市面上的盐酸盐的替代物使用，或当作制备盐酸盐的中间体使用。
根据本发明，这里提供了帕罗西汀樟脑10-磺酸盐。10-樟脑磺酸以对映异构体的形式存在，本发明包括D-(+)-10-樟脑磺酸和(IR)-(-)-10-樟脑磺酸二者的盐及二种盐的外消旋混合物。
一方面，本发明的所述新盐是以非晶形提供的，它可以是固体或是油状物。所述油状物最好是吸附在固体载体上，尤其是吸附在可用作药用组合物成分的载体上。
另一方面，本发明的所述的新盐是以晶形提供的。当该晶形是以多于一种多晶型物存在时，每种多晶型物形成了本发明的另一方面。
帕罗西汀樟脑-10-磺酸盐可以通过化学计算量的酸和帕罗西汀游离碱相接触而制得。优选酸或碱二者中有一为溶液，更优选两者都为溶液。可以采用提高的温度使酸进入溶解状态，但高产量的盐是通过蒸发一些或所有的溶剂而得到的，或是通过控制冷却得到，最好是分阶段进行。最常用的溶剂适宜于使帕罗西汀游离碱活动化，如甲苯，醇如甲醇、乙醇、丙烷-2-醇，酯如乙酸乙酯，酮类如丙酮和丁酮，卤代烃如二氯代甲烷和醚如四氢呋喃和乙醚，但最好避免用樟脑-10-磺酸难溶的溶剂。樟脑-10-磺酸的适宜的溶剂包括水、醇、乙酸乙酯和乙酸。
该盐可以通过常规方法以固态形式从上述得到的溶液中分离出来。例如，可以通过沉淀、喷雾干燥和冷冻干燥所述溶液，或真空干燥所述油状物或将所述熔体固化而制得非结晶盐，所述溶液、油状物、熔体是由所述游离碱和酸反应而制得的。结晶盐可以从合适的溶剂中结晶或重结晶而制得。
当所述盐是通过与溶解其的溶剂缔合而作为溶剂合物得到时，这样的溶剂合物形成了本发明的又一个方面。溶剂合物可以通过加热作用如烘箱干燥，或用不能形成溶剂合物的取代溶剂处理而变回为不能成溶剂合物的盐。
在分所述离帕罗西汀盐之前，可以通过共沸蒸馏作用除去水，以避免形成水合物或获得无水形式的产物。这样，所述盐溶液的合适溶剂是那些与水形成共沸物的溶剂，如甲苯和丙-2-醇。同样应该认识到，也可以用溶剂混合物来帮助共沸除水。
更一般地讲，可以从允许形成所需晶体结构的任何溶剂中进行结晶，需要时采用所需结构的晶种。当有多晶型物存在时，各种多晶型物最好直接从所述盐溶液中结晶出来，尽管采用另一种多晶型物的晶种来重结晶一种多晶型物溶液也是可以进行的。
帕罗西汀游离碱可以按照美国专利号4,007,196和EP-B-O-223403所一般概述的步骤而制得。D-10-樟脑磺酸和L-10-樟脑磺酸可在市场上购得。
本发明的化合物可用于治疗和预防以下疾病：醇中毒                  焦虑抑郁症                  强迫症恐慌症                  慢性疼痛肥胖                    老年性痴呆偏头痛             贪食症厌食               社会恐怖经前综合症(PMS)    青春期抑郁拔毛癖             精神抑郁症物质滥用
这些疾病在下文称为“所述疾病”。
本发明还提供一种方法，该方法通过给予有需要的患者有效量和/或预防量的本发明的盐，治疗和/或预防所述疾病中的任何一种或更多种的方法。
本发明还提供了用于治疗和/或预防所述疾病的药用组合物，该药用组合物包含本发明的盐与药学上可接受的载体的混合物。
本发明也提供了本发明的盐用于治疗和/或预防所述疾病的用途。
本发明也提供了本发明的盐用于生产治疗和/或预防所述疾病的药物的用途。
本发明最适用于治疗抑郁、OCD和恐慌。
本发明的组合物通常适宜于口服，但溶解用于胃肠外给予的制剂也在本发明的范围内。
所述组合物通常作为包含以游离碱为基准计的1至200mg的活性成分的单位剂量组合物提供，更通常为5至100mg，如10至50mg，如对病人为10、12.5、15、20、25、30或40mg。最优选的单位剂量包含了以游离碱为基准计的20mg的活性成分。通常每天服用这种组合物1至6次，如每天2、3或4次，为的是所给予的活性药剂总量处于以游离碱为基准计的5至400mg活性成分的范围内。最优选每天服用所述单位剂量一次。
优选的单位剂型包括片剂或胶囊。
本发明的组合物可以用常规混合方法配制，如混合、填充和压片。
本发明采用的合适载体包括稀释剂、粘合剂、崩解剂、着色剂、调味剂和/或防腐剂。这些试剂可以常规方法使用，例如已经应用于市面上的抗抑郁药剂的相似的方法。
药用组合物的具体例子包括EP-B-0-223403和US4,007,196描述的那些组合物，其中本发明的制品可以作为活性成分使用。
以下实施例说明本发明：
实施例1：制备结晶帕罗西汀D-(+)-10-樟脑磺酸盐。
将帕罗西汀碱的甲苯溶液(5ml,6.38mmol)加到D(+)-10-樟脑磺酸(1.48g,6.38mmol)的甲醇(20ml)溶液中。让该混合物在室温静置20分钟，真空去除溶剂，残余物用甲苯(20ml)稀释，然后真空去除溶剂。用乙醚(c.50ml)研磨并在氮气下过滤，给出白色固体，该白色固体用乙醚(2×20ml)洗涤并在真空干燥器中干燥。
产量3.50g。
实施例2：较大规模制备结晶盐。
将帕罗西汀碱的甲苯溶液(75ml,95.7mmol)加到D(+)-l0-樟脑磺酸(22.2g,95.7mmol)甲醇(300ml)溶液中，真空去除溶剂。残余物用甲苯(100ml)稀释，真空去除溶剂。用乙醚(c.350ml)研磨，给出白色固体，该白色固体经过滤、用乙醚(2×100ml)洗涤并真空干燥。
产量54.46g。1HNMR(CDCl3)显示D(+)-10-樟脑磺酸与帕罗西汀的比率为1∶1。m.p.109℃(相变)。IR石蜡糊：谱带为1740,1501,1464,1376,1183,1034,828,768,601,515cm-1。X射线衍射图主峰(CuK2α)：
角度[°2θ] 相对丰度[％]
5.965 39.9
6.400 56.5
6.665 36.8
11.880 44.0
13.765 31.5
15.055 29.1
16.200 38.4
16.945 68.0
17.970 39.2
19.360 28.5
20.825 32.8
21.630 43.0
22.270 36.8
23.365 21.2
24.255 100.0
25.190 75.4
27.105 35.1
29.720 15.5
30.360 18.6
32.360 15.7
32.800 14.9
实施例3：制备结晶帕罗西汀(1R)-(-)-10-樟脑磺酸盐
将帕罗西汀碱的甲苯(5ml,6.38mmol)溶液加到(1R)-(-)-10-樟脑磺酸(1.48g,6.38mmol)的甲醇(20ml)溶液中，让该混合物在室温静置20分钟，然后真空去除溶剂，残余固体用甲苯(20ml)稀释，并真空去除溶剂。用乙醚(c.50ml)研磨，在氮气下过滤，给出白色固体，该白色固体用乙醚(2×20ml)洗涤并减压干燥。
产量3.18g。
实施例4：较大规模制备结晶盐
将帕罗西汀碱的甲苯溶液(66ml,84.16mmol)加到(1R)-(-)-10-樟脑磺酸(19.5g,83.94mmol)的甲醇(200ml)溶液中。让该混合物在室温静置40分钟，然后蒸发除去溶剂。残余的固体用乙醚(c.350ml)研磨，在室温下搅拌16小时，过滤，给出白色固体，该白色固体用乙醚(2×100ml)洗涤并减压干燥。
产量43.77g。1HNMR(CDCl3)显示(1R)-(-)-10-樟脑磺酸与帕罗西汀的比率为1∶1。m.p.136-139℃。IR石蜡糊：谱带为1736,1604,1503,1462,1376,1278,1194,1037,827,670,602,538cm-1。X射线衍射图主峰(CuK2α)：
角度[°2θ] 相对丰度[％]
6.105 19.0
6.645 14.2
13.615 10.0
15.715 17.0
16.785 100.0
17.175 53.2
17.735 16.7
19.205 10.5
19.550 18.9
20.050 13.6
20.430 13.0
21.200 25.5
21.760 14.3
22.270 16.4
23.350 13.2
24.345 42.7
24.905 19.8
25.160 26.1
25.925 19.4
29.015 10.8
30.860 10.6
实施例5：制备片剂
成分 20mg片剂 30mg片剂
帕罗西汀-10-樟脑磺酸盐磷酸二钙(DCP)微晶纤维素羟基乙酸淀粉钠硬脂酸镁 20.00mg(基于游离碱)83.34mg50.67mg8.34mg1.67mg 30.0mg(基于游离碱)125.0mg76.0mg12.5mg2.5mg
成分的商业来源磷酸二钙二水合物   -    Emcompress或Ditab*微晶纤维素         -    Avicel PH 102*羟基乙酸淀粉钠     -    Explotab**商品名方法
1．将DCP过筛并称重，放入行星式混合器中。
2．加入30目的帕罗西汀10-樟脑磺酸盐于筒体中。
3．加入20目的Avicel和Explotab，并将所有粉末混合10分钟。
4．加入硬脂酸镁，并混合5分钟。采用以下冲压机将片剂压成五边形片剂：30mg片剂    9.5mm     外圈20mg片剂    8.25mm    外圈
片剂令人满意地由单冲压片机或旋转式压片机制得。
实施例6：制备片剂
成分 10mg片剂 20mg片剂 30mg片剂
帕罗西汀10-樟脑磺酸盐羟基乙酸淀粉钠粒状磷酸二钙(DITAB)或Dicafos硬脂酸镁 10mg(基于游离碱)2.98mg158.88mg1.75mg 20mg(基于游离碱)5.95mg317.75mg3.50mg 30mg(基于游离碱)8.93mg476.63mg5.25mg
方法
1．将帕罗西汀10-樟脑磺酸盐、羟基乙酸淀粉钠和磷酸二钙二水合物过筛，并在适宜的混合器中混合(行星式、Cuble或高能剪切混合器)。
2．加入硬脂酸镁，并用单冲压片机或旋转式制片机将其压成片剂。

Claims (9)

1．帕罗西汀1O-樟脑磺酸盐。
2．帕罗西汀(D)-(+)-1O-樟脑磺酸盐。
3．帕罗西汀(1R)-(-)-10-樟脑磺酸盐。
4．根据权利要求1、2或3的非晶形化合物。
5．根据权利要求1、2或3的晶形化合物。
6．制备权利要求1、2、3或4中所要求保护的化合物的方法，该方法采用沉淀、喷雾干燥或冻干干燥帕罗西汀10-樟脑磺酸盐溶液，或采用真空干燥帕罗西汀10-樟脑磺酸盐油状物，或固化帕罗西汀10-樟脑磺酸盐熔体。
7．制备权利要求1、2、3或5所保护的化合物的方法，该方法采用从帕罗西汀10-樟脑磺酸盐溶液中结晶或重结晶。
8．根据权利要求6或7的方法，其中所述帕罗西汀10-樟脑磺酸盐的溶液、油状物或熔体是通过用10-樟脑磺酸处理帕罗西汀游离碱而制得的。
9．治疗和/或预防所述疾病中的任何一种或更多种的方法，该方法为给予有需要的患者有效量和/或预防量的帕罗西汀10-樟脑磺酸盐。
CN99807798A 1998-04-25 1999-04-23 用于治疗中枢神经系统疾病的帕罗西汀10－樟脑磺酸盐 Pending CN1306530A (zh)

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CA (1) CA2329913A1 (zh)
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GB (1) GB9808894D0 (zh)
HU (1) HUP0102298A2 (zh)
IL (1) IL139018A0 (zh)
NO (1) NO20005351L (zh)
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SK (1) SK15902000A3 (zh)
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NO20005351L (no) 2000-10-24
TR200003083T2 (tr) 2001-02-21
JP2002513020A (ja) 2002-05-08
BR9909878A (pt) 2000-12-26
EP1076659A1 (en) 2001-02-21
PL343596A1 (en) 2001-08-27
CA2329913A1 (en) 1999-11-04
GB9808894D0 (en) 1998-06-24
SK15902000A3 (sk) 2001-05-10
WO1999055699A1 (en) 1999-11-04
BG104973A (bg) 2001-09-28
EA200001105A1 (ru) 2001-04-23
IL139018A0 (en) 2001-11-25
HUP0102298A2 (hu) 2002-05-29

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