CN1182845C - 用于治疗集束性头痛的抗惊厥剂衍生物 - Google Patents
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Abstract
公开了用于治疗集束性头痛的抗惊厥剂衍生物。
Description
相关申请的交叉参照
本申请要求1999年1月19日提交的序号为60/116388的美国临时申请的优先权,其内容在此引入参考。
发明背景
式I化合物
是结构新颖的抗癫痫化合物,在动物实验中具有高效抗惊厥作用(Maryanoff,B.E,Nortey,S.O.,Gardocki,J.F,Shank,R.P.和Dodgson,S.P.,药物化学杂志(J.Med.Chem.)
30,880-887,1987;Maryanoff,B.E.,Costanzo,M.J.,Shank,R.P.,Schupsky,J.J.,Ortegon,M.E.,和Vaught J.L.,生物有机化学和医用化学通讯(Bioorganic &Medicinal Chemistry Letters)3,2653-2656,1993)。美国专利4513006保护了这些化合物。化合物之一2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖氨基磺酸酯称作托吡酯,已被证实在人癫痫临床试验中作为单纯和复合局限性惊厥及继发性大发作惊厥的辅助治疗或者单药治疗是有效的(E.FAUGHT,B.J.WILDER,R.E.RAMSEY,R.A.REIFE,L D.KRAMER,G.W.PLEDGER,R.M.KARIM等,癫痫(Epilepsia)
36(S4)33,1995;S.K.SACHDEO,R.C.SACHDEO,R.A.REIFE,P.LIM和G.PLEDGER,癫痫(Epilepsia)
36(S4)33,1995),并且目前已经在包括美国在内的大约20个国家上市,而且世上还有其他数个国家正处在申请批准上市的阶段,用于治疗伴有或不伴有继发性大发作的单纯和复合局限性惊厥癫痫。
最初在经典的小鼠最大电休克惊觉(MES)试验中发现式I化合物具有抗惊厥活性(SHANK,R.P.,GARDOCKI,J.F.,VAUGHT,J.L.,DAVIS,C.B.,SCHUPSKY,J.J.,RAEEA,R.B.,DODGSON,S.J.,NORTEY,S.O.,和MARYANOFF,B.E.,癫痫(Epilepsia)
35 450-460,1994)。接下来的研究则揭示式I化合物在大鼠MES试验中也高度有效。最近发现,托吡酯在数种啮齿动物癫痫模型(J.NAKAMURA,S.TAMURA,T.KANDA,A.ISHII,K.ISHIHARA,T.SERIKAWA,J.YAMADA,和M.SASA,欧洲药理学杂志(Eur.J.Pharmacol.)
25483-89,1994),和点燃惊厥动物模型(A.WAUQUIER和S.ZHOU,癫痫研究(Epilepsy Res.)
24,73-77,1996)中能够有效阻断惊厥。
集束性头痛是与相当苦难有关的极痛苦的疼痛性病症,其具有发作严重、持续时间短暂、单侧眶-颞部疼痛的特征,同侧的自主机能障碍和进行性失调(A.Kudrow,集束性头痛的病因(The pathogenesis of a cluster headache),Curr.Opin.Neurol.7:278-282,1994;国际头痛协会头痛分类委员会,头痛、颅神经痛和面神经痛的分类和诊断标准,头痛(Cephalgia)S7:1-96,1988)。尽管治疗常常是成功的,但是有些患者具有顽固性疼痛。因而,仍存在对集束性头痛有效治疗的需要。
用托吡酯对5例病人进行治疗的研究已经揭示了未曾了解的药理特性,这些特性提示托吡酯在治疗集束性头痛中有效。
发明公开
业已发现下式I化合物适宜治疗集束性头痛:
其中,X是O或者CH2,而R1、R2、R3、R4和R5的定义见后面。
优选实施方案详述
本发明的氨基磺酸酯是下式(I)的氨基磺酸酯:
其中,
X是CH2或者氧;
R1是氢或者C1-C4烷基;和
R2、R3、R4和R5独立地是氢或C1-C3烷基,和当X是CH2时,R4和R5可以是连接形成苯环的烯基,和当X是氧时,R2与R3和/或R4与R5一起可以是下式(II)的亚甲二氧基:
其中,R6和R7相同或不同,它们是氢、C1-C3烷基或者是烷基并连接形成环戊环或环己环。
R1特别是氢或约1-4个碳的烷基,如甲基、乙基、异丙基、正丙基、正丁基、异丁基、仲丁基和叔丁基。本申请整个说明书中的烷基均包括直链和支链烷基。烷基R2、R3、R4、R5、R6和R7约1-3个碳原子,包括甲基、乙基、异丙基和正丙基。当X是CH2时,R4和R5可以结合形成与含X的六元环稠合的苯环,即R4和R5定义为链三烯基=C-CH=CH-CH=。
式(I)化合物尤其是这样一组化合物,其中X是氧以及R2与R3和R4与R5均一起形成式(II)的亚甲二氧基,其中R6和R7均是氢均是烷基或者联合形成螺环戊环或螺环己环,特别是R6和R7均是烷基如甲基。第二组化合物是那些X是CH2和R4与R5连接形成苯环的化合物。第三组式(I)化合物是R2和R3均是氢的式(I)化合物。
用于本发明方法的特别优选的化合物是称作托吡酯的2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖氨基磺酸酯。托吡酯具有如下结构式
式(I)化合物按照下述方法合成:
(a)在碱如丁氧钾或氢化钠的存在下,于约-20℃至25℃的温度,分子式为RCH2OH的乙醇与分子式为ClSO2NH2或ClSO2NHR1的氯氨基磺酸酯在溶剂如甲苯、THF或二甲基甲酰胺中进行反应,其中R是下式(III):
(b)在碱如三乙胺或吡啶的存在下,于约-40℃至25℃的温度,分子式为RCH2OH乙醇与分子式为SO2Cl2的磺酰氯在溶剂如二***或二氯甲烷中反应生成分子式为RCH2OSO2Cl的氯硫酸酯。
然后,分子式为RCH2OSO2Cl的氯硫酸酯与分子式为R1NH2的氨于约40℃至25℃的温度下,在溶剂如二氯甲烷或乙腈中进行反应,生成式(I)的化合物。此(b)步的反应条件还公开于T.Tsuchiya等在Tet.Letters第36期第3365-3368页(1978年)中。
(c)正如M.Hedayatullah在Tet.Letters第2455-2458页(1975年)中所公开的那样,氯硫酸酯RCH2OSO2Cl与金属叠氮化物如叠氮钠在溶剂如二氯甲烷或乙腈中反应产生分子式为RCH2OSO2N3的叠氮硫酸酯。然后,该叠氮硫酸酯通过催化氢化(例如通过惰性金属和H2)或者通过在金属酮在溶剂(如甲醇)中进行加热而还原为R1是氢的式(I)化合物。
分子式为RCH2OH的起始物料可以商购或者以本领域所已知的方式获得。例如,分子式为RCH2OH的起始物料,其中R2与R3和R4与R5完全相同并且均是式(II)时,可以通过R.F.Brady在烃研究(Carbohydrate Research)第14卷第35-40页(1970年)中所描述的方法获得,或者经下列反应而获得:在质子酸如盐酸或者路易斯酸如氯化锌存在下、温度为大约25℃的条件下,R6COR7酮或醛的三甲硅烷烯醇醚与果糖在溶剂如卤化烃譬如二氯甲烷中进行反应。G.L.Larson等在有机化学杂志(J.Org.Chem.)第38卷第22期第3935页(1973年)中描述了此三甲硅烷烯醇醚反应。
另外,使用标准还原技术可以将分子式为RCOOH和RCHO的羧酸和醛还原为分子式为RCH2OH的化合物,所述还原技术如H.O.House在“现代合成反应”(Modern Synthetic Reactions)第2版第45-144页(1972年)中所描述的那些,例如与氢化铝锂、硼氢化钠或硼烷-THF复合物在惰性溶剂如二甘醇二甲醚、THF或甲苯中在温度大约0℃至100℃下进行。
式I化合物也可以按照美国专利4513006、5387700和5387700中公开的方法制得,这些专利的全部内容在此引入参考。尤其是,托吡酯按照美国专利5387700实施例1至3所描述的方法来制备。
式I化合物包括各种独立的异构体及其消旋体,如各种α和β连接物,即6-元环上的R2、R3、R4和R5在环平面的上方或下方。优选地,亚甲二氧基(II)的氧附着在6-元环的同一侧。
本文所用术语“个体”是指动物,优选是哺乳动物,最优选是人,他们是治疗、观察或试验的对象。
本文所用术语“治疗有效量”,是指能够使研究者、兽医、临床医生或者其他临床工作者正在探索的组织***、动物或人出现生物或医学反应的活性化合物的量,所述反应包括正在被治疗的症状或疾病的减轻。
如同下面的实施例所显示的那样,对5名患者进行的试验性研究证实了式I化合物在治疗集束性头痛方面的活性。
为了治疗集束性头痛,对于一般成年患者而言,式(I)化合物每日给药剂量范围为约15~1000mg,优选约25mg~约400mg,最优选约25mg~约200mg,每日给药1~4次,优选每日1~2次。单位剂型通常含有约25~200mg活性组分。
本领域技术人员可以很容易地决定给药最适剂量,并且最适剂量将依据所用特定化合物、给药模式、制剂的强度、给药途径和疾病的进展状况而异。另外,与受治特定患者有关的数种因素也使得需要调整剂量,所述因素包括患者年龄、体重、饮食和给药时间。
为制备本发明药物组合物,将式(I)的一种或多种氨基磺酸酯化合物与传统药学配合技术所用的药物载体精细混合,取决于预期给药途径(如口服,栓剂,或者非胃肠道)对剂型的需要,所述载体可以是宽范围的各种形式。为了制备口服剂型的组合物,可以使用任何常用的药学介质。因此,对于液体口服制剂,例如悬浮液、酏剂和溶液,适宜的载体和添加剂包括水、二醇类、油、醇类、矫味剂、防腐剂、着色剂等等;对于固体口服制剂,如粉剂、胶囊和片剂,适宜的载体和添加剂包括淀粉、糖、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等。由于给药方便,因此片剂和胶囊是最具优势的口服剂型,此时很显然要使用固体药学载体。如果需要,可以利用标准技术而将片剂包糖衣或肠衣。可以制备栓剂,此时可以使用椰子油来作载体。对于非肠道制剂,载体将通常包括蒸馏水,尽管还可以包括其它组分,譬如为了诸如有助于溶解或防腐的目的而使用的那些组分。也可以制备注射溶液,此时要使用适宜的稳定剂。目前口服托吡酯片剂是含有25mg、100mg或200mg活性成分的圆形片剂。片剂中含有下列非活性成组分:含水乳糖、预凝胶淀粉、微晶纤维素、羟乙酸淀粉钠、硬脂酸镁、纯水、巴西棕榈蜡、羟丙基甲基纤维素、二氧化钛、聚乙二醇、合成氧化铁和吐温80。
本发明药物组合物每剂量单位如片剂、胶囊、粉针剂、一茶匙的容量、栓剂等将含有约25~约200mg活性成分。
下面给出实施例以帮助理解本发明,但并不能解释为是旨在以任何方式对本发明权利要求进行限定。
实施例1
一个50岁男性患者自14岁起即患上集束性头痛。严重的右侧眼眶-后疼痛并伴有同侧流泪、连结注射(conjunctive injection)、鼻塞和流鼻涕。发作持续30分钟~2小时,每日发生3~5次。集束性疼痛期(cluster period)通常持续2~3月,开始以25mg每日两次的始用剂量施用托吡酯并在3周内消除疼痛。接下来,患者不使用托吡酯。当再次发作时,患者每日服用25mg。控制疼痛3~4天,然后停药。
实施例2
一位42岁男性患者自10岁起即患上集束性头痛。严重的右侧眼眶-前疼痛并伴有同侧鼻塞、流鼻涕、上睑下垂、结膜充血和流泪。发作持续15~60分钟。集束性疼痛期通常持续4~8周,最后一次发作在1年半前。第一次用托吡酯治疗时集束性疼痛已经存在3个月,以每日50mg的初始剂量施用托吡酯并在1周内消除疼痛。托吡酯逐渐减量后,7个月没有复发。用维拉帕米、加巴喷丁和丙戊酰胺治疗失败。
实施例3
一位51岁男性患者自45岁患上集束性头痛。严重的左侧眶-颞疼痛并伴有同侧流鼻涕和上睑下垂。发作持续15~30分钟,每日发作1~5次。集束性疼痛期通常持续3~4个月,最后一次发作在3个月前停止。第一次使用托吡酯治疗时集束性疼痛已经存在1个月,以50mg每日两次的初始剂量施用托吡酯并在1周内消除疼痛。
实施例4
一位27岁男性患者自17岁起患上集束性头痛。严重的左侧眶-颞部疼痛并伴有同侧流泪和上睑下垂。发作持续15~180分钟并且呈散发性和群集性发作。集束性疼痛期通常持续2~4个月,最后一次发作在2年前。他每日经受1~4次疼痛。第一次使用托吡酯治疗时集束性疼痛已经存在1个月;以每日125mg的峰剂量施用,3周内消除了疼痛。用维拉帕米、丙戊酰胺、美西麦角和加巴喷丁治疗失败。
实施例5
一位72岁男性患者自59岁起患上集束性头痛。严重的右侧眼眶-颞部疼痛并伴有同侧流泪、结膜充血、眼睑水肿和鼻塞。发作持续20~90分钟,每日出现1~2次。丛集性疼痛期通常持续2~4周,一次竟长达12个月。尽管发作没有规律,但是最后一次集束性疼痛期发生在2年前。第一次托吡酯治疗时集束性疼痛已经存在10个月并且每日使用甲泼尼龙已治疗了一个月几乎控制了疼痛。每日使用托吡酯100mg保持无疼痛,而且在甲泼尼龙逐渐减量后没有复发。用维拉帕米和丙戊酰胺治疗失败。
对5个患有阵发性集束性头痛的患者进行的研究表明,托吡酯产生迅速缓解集束性疼痛和缩短集束性疼痛持续期的作用。而且,所有5个患者均对相对低剂量的药物敏感且无严重副作用的报道。
尽管为了描述的目的而在前面的说明书中用提供的实施例教导本发明原则,但是应当懂得,本发明的实践囊括所有惯常的改变、改进和/或修改,这些变改均落在本发明权利要求及其等价物的范围之内。
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Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11638899P | 1999-01-19 | 1999-01-19 | |
US60/116388 | 1999-01-19 |
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Publication Number | Publication Date |
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CN1352555A CN1352555A (zh) | 2002-06-05 |
CN1182845C true CN1182845C (zh) | 2005-01-05 |
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Application Number | Title | Priority Date | Filing Date |
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CNB008029016A Expired - Fee Related CN1182845C (zh) | 1999-01-19 | 2000-01-13 | 用于治疗集束性头痛的抗惊厥剂衍生物 |
Country Status (24)
Country | Link |
---|---|
US (1) | US6319903B1 (zh) |
EP (1) | EP1143967B1 (zh) |
JP (1) | JP2002535270A (zh) |
KR (1) | KR100653326B1 (zh) |
CN (1) | CN1182845C (zh) |
AT (1) | ATE279921T1 (zh) |
AU (1) | AU771388B2 (zh) |
BR (1) | BR0008176A (zh) |
CA (1) | CA2359541C (zh) |
CZ (1) | CZ20012620A3 (zh) |
DE (1) | DE60015070T2 (zh) |
DK (1) | DK1143967T3 (zh) |
ES (1) | ES2228465T3 (zh) |
HU (1) | HUP0105154A3 (zh) |
IL (2) | IL144406A0 (zh) |
MX (1) | MXPA01007350A (zh) |
MY (1) | MY121486A (zh) |
NO (1) | NO20013554L (zh) |
NZ (1) | NZ513115A (zh) |
PT (1) | PT1143967E (zh) |
TR (1) | TR200102711T2 (zh) |
TW (1) | TWI248360B (zh) |
WO (1) | WO2000042996A2 (zh) |
ZA (1) | ZA200106786B (zh) |
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WO2003080072A1 (en) * | 2002-03-18 | 2003-10-02 | Cady Roger K | Preemptive prophylaxis of migraine |
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JP2006500377A (ja) | 2002-06-21 | 2006-01-05 | トランスフォーム・ファーマシューティカルズ・インコーポレイテッド | 改善された溶解性を有する医薬組成物 |
US8183290B2 (en) | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
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MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
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US20110117070A1 (en) * | 2005-04-19 | 2011-05-19 | Aurora Sheena K | Compositions and methods for treating headache |
US20060233892A1 (en) * | 2005-04-19 | 2006-10-19 | Curt Hendrix | Topiramate compositions for treatment of headache |
EA200702558A1 (ru) * | 2005-05-20 | 2008-06-30 | Янссен Фармацевтика Н. В. | Способ получения производных сульфамида |
US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8716231B2 (en) | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
US8492431B2 (en) | 2005-12-19 | 2013-07-23 | Janssen Pharmaceutica, N.V. | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity |
US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
US20070155827A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression |
US20070155823A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents |
US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US20070191449A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of Benzo-Heteroaryl Sulfamide Derivatives for the Treatment of Depression |
US20070191474A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of migraine |
US20070191461A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-heteroaryl sulfamide derivatives for the treatment of migraine |
AU2007253814A1 (en) * | 2006-05-19 | 2007-11-29 | Janssen Pharmaceutica N.V. | Co-therapy for the treatment of epilepsy |
US9744137B2 (en) | 2006-08-31 | 2017-08-29 | Supernus Pharmaceuticals, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
ES2312308T3 (es) | 2006-11-17 | 2013-03-26 | Supernus Pharmaceuticals, Inc. | Formulaciones de liberación sostenida de topiramato |
CN102114002B (zh) | 2006-12-04 | 2016-05-11 | 苏佩努斯制药公司 | 托吡酯的增强的立即释放制剂 |
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US8580298B2 (en) | 2008-06-09 | 2013-11-12 | Vivus, Inc. | Low dose topiramate/phentermine composition and methods of use thereof |
EA018567B1 (ru) | 2008-06-23 | 2013-08-30 | Янссен Фармацевтика Нв | Кристаллическая форма (2s)-(-)-n-(6-хлор-2,3-дигидробензо[1,4]диоксин-2-илметил)сульфамида |
US8815939B2 (en) * | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
WO2013139292A1 (zh) | 2012-03-23 | 2013-09-26 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种含辛弗林和托吡酯的联合产品 |
CN103316026B (zh) | 2012-03-23 | 2016-05-11 | 中国人民解放军军事医学科学院毒物药物研究所 | 含芬特明和托吡酯的联合产品及其制备方法 |
CN102579367B (zh) | 2012-03-23 | 2014-03-12 | 中国人民解放军军事医学科学院毒物药物研究所 | 托吡酯缓释药物组合物、其制备方法及用途 |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
WO2020104837A1 (en) | 2018-11-21 | 2020-05-28 | Rosemont Pharmaceuticals Limited | Oral topiramate suspension formulations with extended shelf stability and enhanced bioavailability |
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US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
US5998380A (en) * | 1995-10-13 | 1999-12-07 | New England Medical Center Hospitals, Inc. | Treatment of migraine |
BR9712503A (pt) * | 1996-10-08 | 1999-10-19 | Ortho Mcneil Pharm Inc | Derivados anticonvulsivos úteis no tratamento de dor neuropática |
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2000
- 2000-01-13 AT AT00905615T patent/ATE279921T1/de not_active IP Right Cessation
- 2000-01-13 KR KR1020017009077A patent/KR100653326B1/ko not_active IP Right Cessation
- 2000-01-13 EP EP00905615A patent/EP1143967B1/en not_active Expired - Lifetime
- 2000-01-13 NZ NZ513115A patent/NZ513115A/en unknown
- 2000-01-13 WO PCT/US2000/000919 patent/WO2000042996A2/en active IP Right Grant
- 2000-01-13 ES ES00905615T patent/ES2228465T3/es not_active Expired - Lifetime
- 2000-01-13 CZ CZ20012620A patent/CZ20012620A3/cs unknown
- 2000-01-13 DK DK00905615T patent/DK1143967T3/da active
- 2000-01-13 AU AU27268/00A patent/AU771388B2/en not_active Ceased
- 2000-01-13 HU HU0105154A patent/HUP0105154A3/hu unknown
- 2000-01-13 BR BR0008176-0A patent/BR0008176A/pt not_active Application Discontinuation
- 2000-01-13 JP JP2000594453A patent/JP2002535270A/ja not_active Withdrawn
- 2000-01-13 DE DE60015070T patent/DE60015070T2/de not_active Expired - Fee Related
- 2000-01-13 TR TR2001/02711T patent/TR200102711T2/xx unknown
- 2000-01-13 IL IL14440600A patent/IL144406A0/xx active IP Right Grant
- 2000-01-13 CN CNB008029016A patent/CN1182845C/zh not_active Expired - Fee Related
- 2000-01-13 PT PT00905615T patent/PT1143967E/pt unknown
- 2000-01-13 US US09/482,801 patent/US6319903B1/en not_active Expired - Fee Related
- 2000-01-13 MX MXPA01007350A patent/MXPA01007350A/es not_active IP Right Cessation
- 2000-01-13 CA CA002359541A patent/CA2359541C/en not_active Expired - Fee Related
- 2000-01-19 MY MYPI20000156A patent/MY121486A/en unknown
- 2000-03-22 TW TW089100773A patent/TWI248360B/zh not_active IP Right Cessation
-
2001
- 2001-07-18 NO NO20013554A patent/NO20013554L/no not_active Application Discontinuation
- 2001-07-18 IL IL144406A patent/IL144406A/en not_active IP Right Cessation
- 2001-08-16 ZA ZA200106786A patent/ZA200106786B/en unknown
Also Published As
Publication number | Publication date |
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AU771388B2 (en) | 2004-03-18 |
IL144406A0 (en) | 2002-05-23 |
EP1143967A2 (en) | 2001-10-17 |
NO20013554D0 (no) | 2001-07-18 |
TWI248360B (en) | 2006-02-01 |
US6319903B1 (en) | 2001-11-20 |
IL144406A (en) | 2006-08-20 |
HUP0105154A2 (hu) | 2002-04-29 |
ES2228465T3 (es) | 2005-04-16 |
BR0008176A (pt) | 2001-11-06 |
KR100653326B1 (ko) | 2006-12-04 |
WO2000042996A2 (en) | 2000-07-27 |
CA2359541C (en) | 2005-06-21 |
CA2359541A1 (en) | 2000-07-27 |
HUP0105154A3 (en) | 2004-10-28 |
PT1143967E (pt) | 2005-01-31 |
NZ513115A (en) | 2004-11-26 |
AU2726800A (en) | 2000-08-07 |
NO20013554L (no) | 2001-07-18 |
JP2002535270A (ja) | 2002-10-22 |
EP1143967B1 (en) | 2004-10-20 |
CN1352555A (zh) | 2002-06-05 |
KR20010101595A (ko) | 2001-11-14 |
ATE279921T1 (de) | 2004-11-15 |
DE60015070D1 (de) | 2004-11-25 |
WO2000042996A3 (en) | 2000-12-07 |
TR200102711T2 (tr) | 2001-12-21 |
DK1143967T3 (da) | 2005-01-10 |
ZA200106786B (en) | 2002-11-18 |
DE60015070T2 (de) | 2006-01-05 |
CZ20012620A3 (cs) | 2002-09-11 |
MXPA01007350A (es) | 2003-06-06 |
MY121486A (en) | 2006-01-28 |
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