CN1688307A - 4－氨基哌啶衍生物,它们的制备方法和它们作为药物的用途 - Google Patents
4－氨基哌啶衍生物,它们的制备方法和它们作为药物的用途 Download PDFInfo
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- CN1688307A CN1688307A CNA03823730XA CN03823730A CN1688307A CN 1688307 A CN1688307 A CN 1688307A CN A03823730X A CNA03823730X A CN A03823730XA CN 03823730 A CN03823730 A CN 03823730A CN 1688307 A CN1688307 A CN 1688307A
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- Prior art keywords
- carboxylic acid
- butyl ester
- acid tert
- benzyl
- piperidine carboxylic
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
本发明涉及4－氨基哌啶衍生物，涉及它们的制备方法，涉及它们在治疗中的用途，以及涉及含有它们的药物组合物。更具体地，这些化合物用于治疗中枢和/或外周神经系统疾病。特别令人感兴趣的是，这些化合物表现出有效的抗抑郁活性。
Description
本发明涉及4-氨基哌啶衍生物，涉及它们的制备方法，涉及它们在治疗中的用途，以及涉及含有它们的药物组合物。更具体地，这些化合物用于治疗中枢和/或外周神经系统疾病。特别令人感兴趣的是，这些化合物表现出有效的抗抑郁活性。
因此，这些4-氨基哌啶衍生物特别用于预防和/或治疗抑郁症、伴有焦虑的严重的抑郁症、焦虑和情感障碍。
据报道抑郁症影响至多10％的人群，而19％终生受影响并且与显著的死亡率相联系。自从引入特异靶向大脑血清素系统的药物，即广泛使用的氟西汀代表的特异血清素再摄入抑制剂(SSRI)后，传统的使用三环抗抑郁药对抑郁症的治疗方法的普及程度降低。如果SSRI与三环抗抑郁药相比具有改善的副作用是事实，则采集的数据表明这类药物不充分覆盖抑郁症固有部分的焦虑和失眠症症状。此外，这些物质本身可以诱发神经过敏，失眠症和焦虑。因此相当数量的患者需要共同施用抗焦虑/催眠药疗法，例如苯并二氮杂或抗组胺药。后面这些化合物，特别是羟嗪，可能比与SSRI共同施用苯并二氮杂更合适。SSRI的另一个副作用是似乎由血清素5-HT2受体介导的性功能障碍。
因此，为了避免多重治疗，具有SSRI功效并且具有能减轻神经过敏、焦虑和性功能障碍的加合性质的一个化学实体对于患者有较大好处。特别地，这样一种分子应该对血清素再摄入位点(SSRI作用的主要方式)；改善神经过敏、焦虑和有利于睡眠的组胺H1受体；以及预期受到阻断可防止性副作用的血清素5-HT2受体具有重要的亲和性。
我们在这个领域中的研究努力引导我们发现具有这三种性质的分子，即血清素再摄入位点的抑制，组胺能H1受体的阻断和血清素5-HT2受体的阻断。
申请人最近进行的药理学研究揭示了这里提到的新的式(I)的4-氨基哌啶衍生物不为人认识到的有效的药学性质，提示它们在例如上面提到的但不局限于上面提到的那些病症的治疗中是有用的。
美国专利5,461,066描述了4-氨基哌啶衍生物作为合成中间体。日本专利申请JP 05148234描述了下列两个化合物：N-[(4-氯苯基)甲基]-N-苯基-4-哌啶胺，N-苯基-N-(苯基甲基)-4-哌啶胺具有抗组胺和抗变应性活性。
因此，根据一个方面，本发明提供式I的4-氨基哌啶衍生物，包括其药学可接受的盐，
其中R1，R2，R3，R4独立地选自氢，氟，氯，甲基和三氟甲基，前提是，如果R1，R2和R4是氢，则R3不是氢或卤原子。
根据本发明，优选的化合物是式I的化合物，其中：
R2是氢，氟或甲基，
R4是氢，氟，氯，或三氟甲基，
R1和R3具有如上所述相同的定义，前提是，如果R1，R2和R4是氢，则R3不是氢或卤原子，
或者其药学可接受的盐。
根据本发明，更优选的化合物是式I的化合物，其中：
R1是氢，氟或氯，
R2是氢，氟或甲基，
R3是氢，氟，氯或甲基，
R4是氢，氟或氯，
前提是，如果R1，R2和R4是氢，则R3不是氢或卤原子，或者其药学可接受的盐。
根据本发明，最优选的化合物是式I的化合物，其中：
R1是氢或氟，
R2是氢或氟，
R3是氟或甲基，
R4是氢，
前提是，如果R1，R2和R4是氢，则R3不是氟，或者其药学可接受的盐。
本发明优选的化合物是：
N-苯基-N-[3-(三氟甲基)苄基]-4-哌啶胺；
N-(3-氯苄基)-N-苯基-4-哌啶胺；
N-(3，4-二氟苄基)-N-苯基-4-哌啶胺；
N-(3，4-二氯苄基)-N-苯基-4-哌啶胺；
N-(4-甲基苄基)-N-苯基-4-哌啶胺；
N-苯基-N-[4-(三氟甲基)苄基]-4-哌啶胺；
N-(3-氯苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3，4-二氯苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺；
N-(3-氟苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺；
N-(3-氯苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-(3，4-二氯苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-(3-甲基苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺；
N-苄基-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苯基)-N-[3-(三氟甲基)苄基]-4-哌啶胺；
N-(3-氯苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(3，4-二氯苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苯基)-N-[4-甲基苄基]-4-哌啶胺；
N-(4-氟苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺；
N-(4-氯苯基)-N-[4-氟苄基]-4-哌啶胺；
N-(3-氯苄基)-N-(4-甲基苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(4-甲基苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(4-甲基苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(4-甲基苯基)-4-哌啶胺；
N-(3，4-二氯苄基)-N-(4-甲基苯基)-4-哌啶胺；
N-(4-甲基苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺；
N-(4-氟苄基)-N-[4-(三氟甲基)苯基]-4-哌啶胺；
或者其药学可接受的盐。
本发明更优选的化合物是：
N-(3-氯苄基)-N-苯基-4-哌啶胺；
N-(3，4-二氟苄基)-N-苯基-4-哌啶胺；
N-(4-甲基苄基)-N-苯基-4-哌啶胺；
N-(3-氯苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺；
N-(4-氟苄基)-N-(3-甲基苯基)-4-哌啶胺；
N-苄基-N-(4-氟苯基)-4-哌啶胺；
N-(3，4-二氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氯苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苯基)-N-[4-甲基苄基]-4-哌啶胺；
N-(4-氯苯基)-N-[4-氟苄基]-4-哌啶胺；
或者其药学可接受的盐。
本发明最优选的化合物是：
N-(4-甲基苄基)-N-苯基-4-哌啶胺；
N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺；
N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苯基)-N-(4-甲基苄基)-4-哌啶胺或者其药学可接受的盐。
使用N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺和N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺或者其药学可接受的盐获得最佳结果。
根据本发明的″药学可接受的盐″包括式I的化合物能够形成的治疗活性的非毒性酸的盐形式。通过用合适的酸，如无机酸，例如氢卤酸，如盐酸或氢溴酸，硫酸，硝酸，磷酸等等；或者有机酸，如乙酸，羟基乙酸，丙酸，乳酸，丙酮酸，丙二酸，琥珀酸，马来酸，富马酸，苹果酸，酒石酸，甲磺酸，乙磺酸，苯磺酸，对甲苯磺酸，环己氨磺酸，水杨酸，对-氨基水杨酸，扑酸等等处理游离碱，能获得以其游离碱形式出现的式I的化合物的酸加成盐形式。
相反，通过用合适的碱处理，能将所述盐形式转化为游离形式。
式I的化合物和它们的盐可以是溶剂化物形式，其包括在本发明的范围内。这样的溶剂化物包括例如水合物、醇化物等等。
本发明还涉及式I的化合物的制备方法。
用与有机合成化学领域技术人员公知的常规方法相类似的方法，能制备根据本发明的式I的化合物。
下面的方法描述以详细说明的方式提出一些合成途径。其他可替代的和/或类似方法对于本领域技术人员是显而易见的。
根据一个实施方案，根据下面的反应式，通过保护式II化合物可以制备具有通式I的化合物：
其中P是保护基团，R1，R2，R3和R4具有上述相同的定义。
保护基团P可以是任何合适的胺保护基团，如，例如，氨基甲酸酯，亚磺酰衍生物，磺酰衍生物，烷基和芳基。非限制性例子是甲氧羰基，乙氧羰基，叔丁氧羰基(Boc)，9-芴基甲氧羰基(Fmoc)，9-(2-磺基)芴基甲氧羰基，9-(2，7-二溴)芴基甲氧羰基，2，2，2-三氯乙氧羰基(Troc)，2-苯基乙氧羰基，2-氯乙氧羰基，苄氧羰基，对-甲氧基苄氧羰基，苯硫基(benzensulfenyl)，2-硝基苯硫基，甲苯磺酰基，苯磺酰基，甲基，叔丁基，烯丙基，苄基，双(4-甲氧基苯基)甲基或2，4-二硝基苯基。关于去保护方法的更详细说明参见″Protective Group sin OrganicChemistry″，第2章，J.F.W.Omie，Plenum Press，London and NewYork，1973和″Protective Groups in Organic Synthesis″，第7章，Th.W.Greene，John Wiley & Sons，1999。
这种转化可以根据本领域技术人员公知的任何方法来进行。
根据下面的反应式，通过式III化合物与式IV化合物反应，可以制备式II化合物：
其中X是卤原子，优选溴，P，R1，R2，R3和R4具有上述相同的定义。
在惰性溶剂、例如乙腈或二甲基甲酰胺中，在有机或无机碱例如三乙胺或碳酸钾的存在下，在50和100℃之间，可以进行这种转化。
式IV的化合物是商业上可获得的。
根据下面的反应式，通过式V化合物与式VI酮反应，可以制备式III的化合物：
在醇性溶剂、例如甲醇中，在1-2当量的酸例如乙酸的存在下，在1-2当量的还原剂例如氰基硼氢化钠的存在下，可以进行这种转化。
式V化合物和式VI化合物是商业上可获得的。
另一方面，本发明提供用作药物的式(I)的4-氨基哌啶衍生物，包括其药学可接受的盐。
最后发现式(I)的化合物及其药学可接受盐是特别有效的抗抑郁药。
因此，这些化合物特别用于预防和/或治疗抑郁症和伴有焦虑的严重的抑郁症。
这些化合物还可以用于预防和/或治疗其他神经病，包括焦虑症，特别是一般性焦虑症(GAD)，恐慌症(PD)，创伤后紧张症(PTSD)，社交焦虑症(SAD)，强迫观念与行为障碍和广场恐怖症，双极症，狂躁，慢性疼痛，神经性疼痛，偏头痛，大脑局部缺血，心律不齐，肌强直，可卡因和酒精滥用，中风，肌阵挛，震颤，新生期脑出血，肌萎缩侧索硬化(ALS)，痉挛，帕金森氏病，和其他神经变性和运动病症。
因此，本发明的进一步方面涉及如上定义的式(I)化合物或者其药学可接受的盐用于制备用于治疗和/或预防如上文提到的神经病的药物的用途。
特别地，本发明涉及如上定义的式(I)的化合物或者其药学可接受的盐用于制备用于治疗和/或预防抑郁症的药物的用途。
本发明还涉及对需要这样治疗的哺乳动物治疗抑郁症的方法，包括对患者施用治疗剂量的至少一种式(I)的化合物和其药学可接受的盐。
本发明的方法包括对患有上述疾病的哺乳动物(优选人)施用足以减轻病症量的根据本发明的药物组合物。以任何合适的单位剂量形式方便地施用化合物，包括但不限于每单位剂量形式含有0.5至500mg，优选1至100mg活性成分的那些单位剂量形式。
申请人使用的术语″治疗″意思是治愈性治疗和预防性治疗。
所谓″治愈性″意思是式(I)在抑郁阶段目前发作的治疗中有效。
所谓″预防性″或″维持″意思是防止抑郁发作的复发。
为了治疗疾病，可以以有效日剂量使用和通过药物组合物施用式(I)的化合物或其药学可接受的盐。
因此，本发明的另一个实施方案是包括与药学可接受载体混合的有效量的式(I)的化合物或其药学可接受的盐或衍生物的用于这里描述的任何病症的药物组合物。
为了制备本发明的药物组合物，式(I)的化合物或其药学可接受的盐中的一种或几种与根据常规制药技术的药学载体充分混合，所用载体可以是各种各样的形式，取决于用于给药的期望的制剂形式，例如，口服，直肠，或肠胃外。
为了治疗和/或预防疾病，本发明需要施用有效量的化合物。根据本发明需要的剂量应该高到足以减轻疾病。含有化合物的组合物能例如口服或肠胃外给药，即静脉内，肌内或皮下，鞘内给药。
能用于口服给药的药物组合物可以是固体或液体，并且可以是例如片剂，丸剂，糖锭剂，明胶胶囊，溶液，糖浆等的形式。
为此，化合物能与惰性稀释剂或非毒性药学可接受赋形剂例如淀粉或乳糖混合。任选地，这些药物组合物还可以含有粘合剂，例如微晶纤维素，黄芪胶或明胶，崩解剂，例如藻酸，润滑剂，例如硬脂酸镁，滑移剂，例如胶态二氧化硅，增甜剂，例如蔗糖或糖精，或染色剂或调味剂，例如薄荷或水杨酸甲酯。
还包括能以控制方式释放活性物质的组合物。能用于肠胃外给药的药物组合物是已知适合这种给药方式的药物形式，并且一般是含于安瓿、一次性注射器、玻璃或塑料小瓶或输注容器中的水性或油性溶液或混悬液形式。
除了活性化合物外，这些溶液或混悬液还可以含有无菌稀释剂，例如注射用水、生理盐水、油、聚乙二醇、甘油、丙二醇或其他合成溶剂，抗细菌剂例如苄基醇，抗氧化剂例如抗坏血酸或亚硫酸氢钠，螯合剂例如乙二胺四乙酸，缓冲剂例如乙酸盐、柠檬酸盐或磷酸盐以及用于调节重量克分子渗透浓度的试剂例如氯化钠或葡萄糖。
利用药剂师通常使用的方法制备这些药物形式。
药物组合物中式(I)的化合物的百分比落在宽浓度范围内，并且取决于各种各样的因素，例如患者性别、年龄、体重和医疗情况，以及取决于给药方法。这样，用于口服给药的组合物中式(I)的化合物的量至少是组合物的0.5重量％，并且最多可以是组合物的80重量％。
在另一个实施方案中，本发明还涉及式II或III中间体的合成，其中取代基R和保护基团P如上定义。
优选的式II的化合物是：
4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{[3-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[3-氟(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{3-氟[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氟苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-{3-甲基[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-(苄基-4-氟代苯胺基)-1-哌啶羧酸叔丁酯；
4-{4-氟[3-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[4-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[4-氟(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{4-氟[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[4-氯(4-氟代苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3-氯代苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氟苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-{4-甲基[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(4-氟代苄基)-4-(三氟甲基)苯胺基]-1-哌啶羧酸叔丁酯；和
4-[(3-氯代苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯。
优选的式III的化合物是
4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯；
4-(3-甲苯氨基)-1-哌啶羧酸叔丁酯；
4-(4-甲苯氨基)-1-哌啶羧酸叔丁酯。
提供下面的实施例只是为了详细说明的目的，而不是要也不应该认为以任何方式限制本发明。本领域技术人员将理解不超出本发明的精神和范围的情况下能对下面的实施例进行常规改变和修饰。
在实施例中除非另外具体说明，根据下面的方法进行化合物表征：
在装有Aspect 3000计算机和5毫米1H/13C双探头的BRUKER AC 250Fourier Transform NMR分光计上或者在装有SG Indigo2计算机和5毫米反向几何学1H/13C/15N三探头的BRUKER DRX 400 FT NMR上记录NMR谱。在探针温度313K、浓度范围2至20mg/ml下，在DMSO-d6(或CDCl3)溶液中研究化合物。仪器锁定DMSO-d6(或CDCl3)的氘信号。化学位移是自作为内标的TMS的低磁场，单位是ppm。DMSO-d6(氘化二甲亚砜)。
如下进行LC/MS模式的质谱测定：
HPLC条件
使用安装有INERTSIL ODS 3-，DP5微米，250×4.6毫米柱子的WATERS Alliance HPLC系统进行分析。
7分钟内用100％溶剂A(乙腈，水，TFA(10/90/0.1，v/v/v))至100％溶剂B(乙腈，水，TFA(90/10/0.1，v/v/v))梯度洗脱，并且用100％B保持4分钟。流速设置为2.5毫升/分钟并且仅在API源之前使用1/10分流(split)。在30℃下进行色谱分析。
MS条件
样品溶解于乙腈/水，70/30，v/v，浓度大约是250微克/毫升。使用FINNIGAN(San Jose，CA，USA)LCQ离子阱质谱仪进行API谱(+或-)。以450℃操作APCI源并且毛细加热器是160℃。以3.5kV操作ESI源并且毛细加热器是210℃。
如下进行EI/DIP模式的质谱测定：通过在5分钟内将探头从50℃加热至250℃将样品蒸发。使用FINNIGAN(San Jose，CA，USA)TSQ700串联四极质谱仪记录EI(电子碰撞)谱。光源温度设置在150℃。
使用安装有从J & W Scientific(Folsom，CA，USA)购得的分流/无分流注射器和DB-5MS熔融硅石柱(15m×0.25mm I.D.，1微米)的3400型气相色谱(Varian，Walnut Greek，CA，USA)进行GC/MS模式的在TSQ700串联四极质谱仪(FINNIGAN MAT，San Jose，CA，USA)上进行的质谱测定。氦(纯度99.999％)用作载体气体。分别在290和250℃下操作注射器(CTC A200S自动进样器)和输送线。以非均分方式注射样品(1微升)，并且如下设定烘箱温度：50℃5分钟，升高至280℃(23℃/分钟)并且保持10分钟。以电子碰撞(EI)或化学电离(CI/CH4)方式操作TSQ700质谱仪(质量范围33-800，扫描时间1.00秒)。光源温度设置在150℃。
使用Metrohm微库仑Karl Fischer滴定器检测水含量。
使用实验室改进的Jobin Yvon-型中轴压缩柱(80毫米直径i.d.)，在粒度为15-40微米，参考值1.15111.9025的硅胶60Merck上进行制备色谱分离，流速在70和150毫升/分钟。硅胶和溶剂混合物的量如各个程序中所述。
在Buchi 535 Totoli-型熔点测定器上测定熔点，并且没有校正，或者通过在Perkin Elmer DSC 7上设置起始温度。
实施例中除非另有说明，获得的化合物是中性形式。
实施例1：式I化合物的合成
1.1 4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯1的合成
3-氟代苯胺基(40克)溶解于MeOH并且溶液冷却至0℃。接着连续向溶液加入4-氧代-1-哌啶羧酸叔丁酯(79克，1.1当量)，乙酸(26.8毫升，1.3当量)，和氰基硼氢化钠(29克，1.3当量，分部分)。反应混合物在室温下搅拌直到完全。然后将反应混合物冷却至0℃，并且将NaOH水溶液(20％)倒入混合物(pH～10)中。将沉淀过滤，用水洗涤，干燥并且用iPrOH重结晶，得到4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯1(68.5克)。
产率：63％。
MS(MH+)：295。
用类似方法能合成表1中列出的式III化合物。
表1：式III的化合物
| 编号 | IUPAC名称 | MH+(LC-MS) |
| 1 | 4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯 | 295 |
| 2 | 4-苯胺基-1-哌啶羧酸叔丁酯 | 277 |
| 4 | 4-(4-氟代苯胺基)-1-哌啶羧酸叔丁酯 | 295 |
| 5 | 4-(4-氯代苯胺基)-1-哌啶羧酸叔丁酯 | 311-313 |
| 7 | 4-[4-(三氟甲基)苯胺基]-1-哌啶羧酸叔丁酯 | 344(MH+，GC-MS) |
1.2 4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯8的合成4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯1(20克)溶解于乙腈(250毫升)。向溶液中加入碳酸钾(33.2克)和1-(溴甲基)-4-氟代苯(11毫升)。将反应混合物加热回流过夜后冷却，浓缩，残余物溶解于二氯甲烷和水。用二氯甲烷将含水层洗涤两次。合并的有机层用MgSO4干燥并浓缩。得到的白色固体用己烷研制并过滤，得到4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯8(25.5克)。
产率：89％。
MS(MH+)：403。
用类似方法能合成表2中列出的式II化合物。
表2：式II化合物
| 编号 | IUPAC名称 | MH+(LC-MS) |
| 8 | 4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 403 |
| 10 | 4-[(3-氯苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 401/403 |
| 11 | 4-[(3，4-二氟苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 403 |
| 13 | 4-[(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 381 |
| 14 | 4-{[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯 | 435 |
| 15 | 4-[(3，4-二氟苄基)-3-氟苯胺基]-1-哌啶羧酸叔丁酯 | 421 |
| 16 | 4-[(4-氯苄基)-3-氟苯胺基]-1-哌啶羧酸叔丁酯 | 419/421 |
| 18 | 4-[3-氟(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 399 |
| 26 | 4-(苄基-4-氟苯胺基)-1-哌啶羧酸叔丁酯 | 385 |
| 28 | 4-[(3-氟苄基)-4-氟苯胺基]-1-哌啶羧酸叔丁酯 | 419/421 |
| 29 | 4-[(3，4-二氟苄基)-4-氟苯胺基]-1-哌啶羧酸叔丁酯 | 421 |
| 30 | 4-[4-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯 | 403 |
| 31 | 4-[(4-氯苄基)-4-氟苯胺基]-1-哌啶羧酸叔丁酯 | 419/421 |
| 34 | 4-{4-氟[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯 | 453 |
1.3 N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺43的合成
4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯8(25.5克)溶解于二氯甲烷并且将溶液冷却至0℃。向溶液中加入TFA(30毫升)并且在室温下搅拌反应混合物。1小时30分钟之后，加入TFA(20毫升)并且将反应混合物又搅拌30分钟。真空去除溶剂，并且残余物溶解于二氯甲烷和水。通过加入NaOH将水相碱化并且用二氯甲烷洗涤。合并的有机层用MgSO4干燥并浓缩。粗产物用色谱法纯化(洗脱剂：CH2Cl2/MeOH/NH4OH 95/5/0.5)，得到N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺(18.4克)，为游离碱。
将用HCl饱和的乙醚溶液加至溶解于乙醚中的N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺。滤出沉淀，用乙醚洗涤并且在烘箱中真空干燥(50℃)，得到17.51克N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺43(2HCl，0.5H2O)，为白色固体。
产率：72％。
MS(MH+)：303。
用类似方法能合成表3中列出的式I化合物。
表3：式I的化合物
| 编号 | 盐 | IUPAC名称 | MH+(LC-MS) |
| 43 | 2HCl，0.5H2O | N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺 | 303 |
| 44 | 2CF3COOH | N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺 | 303 |
| 45 | 2CF3COOH | N-苯基-N-[3-(三氟甲基)苄基]-4-哌啶胺 | 335 |
| 46 | 2HCl，0.5H2O | N-(3-氯苄基)-N-苯基-4-哌啶胺 | 301 |
| 47 | 2CF3COOH | N-(3-氯苄基)-N-苯基-4-哌啶胺 | 301 |
| 48 | 2HCl，0.5H2O | N-(3，4-二氟苄基)-N-苯基-4-哌啶胺 | 303 |
| 49 | 2CF3COOH | N-(3，4-二氟苄基)-N-苯基-4-哌啶胺 | 303 |
| 50 | 2CF3COOH | N-(3，4-二氯苄基)-N-苯基-4-哌啶胺 | 335/337/339 |
| 51 | 2HCl，1H2O | N-(4-甲基苄基)-N-苯基-4-哌啶胺 | 281 |
| 52 | 2CF3COOH | N-(4-甲基苄基)-N-苯基-4-哌啶胺 | 281 |
| 53 | 2HCl，1H2O | N-苯基-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 335 |
| 54 | 2CF3COOH | N-苯基-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 335 |
| 55 | 2CF3COOH | N-(3-氯苄基)-N-(3-氟苯基)-4-哌啶胺 | 319/321 |
| 56 | 2CF3COOH | N-(3，4-二氟苄基)-N-(3-氟苯基)-4-哌啶胺 | 321 |
| 57 | 2HCl，0.5H2O | N-(3，4-二氟苄基)-N-(3-氟苯基)-4-哌啶胺 | 321 |
| 58 | 2CF3COOH | N-(4-氯苄基)-N-(3-氟苯基)-4-哌啶胺 | 319/321 |
| 59 | 2CF3COOH | N-(3，4-二氯苄基)-N-(3-氟苯基)-4-哌啶 | 353 |
| 胺 | |||
| 60 | 2HCl，0.5H2O | N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺 | 299 |
| 61 | 2CF3COOH | N-(3-氟苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 353 |
| 62 | 2CF3COOH | N-(3-氯苄基)-N-(3-甲基苯基)-4-哌啶胺 | 315/317 |
| 63 | 2CF3COOH | N-(3，4-二氟苄基)-N-(3-甲基苯基)-4-哌啶胺 | 317 |
| 64 | 2CF3COOH | N-(4-氟苄基)-N-(3-甲基苯基)-4-哌啶胺 | 299 |
| 65 | 2CF3COOH | N-(4-氯苄基)-N-(3-甲基苯基)-4-哌啶胺 | 315 |
| 66 | 2CF3COOH | N-(3，4-二氯苄基)-N-(3-甲基苯基)-4-哌啶胺 | 349/351/353 |
| 67 | 2CF3COOH | N-(3-甲基苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 349 |
| 68 | 2HCl，1H2O | N-苄基-N-(4-氟苯基)-4-哌啶胺 | 285 |
| 69 | 2CF3COOH | N-苄基-N-(4-氟苯基)-4-哌啶胺 | 285 |
| 70 | 2CF3COOH | N-(4-氟苯基)-N-[3-(三氟甲基)苄基]-4-哌啶胺 | 353 |
| 71 | 2HCl，0.5H2O | N-(3-氯苄基)-N-(4-氟苯基)-4-哌啶胺 | 319 |
| 72 | 2CF3COOH | N-(3-氯苄基)-N-(4-氟苯基)-4-哌啶胺 | 319 |
| 73 | 2HCl，0.5H2O | N-(3，4-二氟苄基)-N-(4-氟苯基)-4-哌啶胺 | 321 |
| 74 | 2CF3COOH | N-(3，4-二氟苄基)-N-(4-氟苯基)-4-哌啶胺 | 321 |
| 75 | 2HCl，0.5H2O | N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺 | 303 |
| 76 | 2CF3COOH | N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺 | 303 |
| 77 | 2HCl | N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺 | 303 |
| 78 | 2HCl，0.5H2O | N-(4-氯苄基)-N-(4-氟苯基)-4-哌啶胺 | 319 |
| 79 | 2CF3COOH | N-(4-氯苄基)-N-(4-氟苯基)-4-哌啶胺 | 319 |
| 80 | 2CF3COOH | N-(3，4-二氯苄基)-N-(4-氟苯基)-4-哌啶胺 | 353/355/357 |
| 81 | 2HCl，1H2O | N-(4-氟苯基)-N-(4-甲基苄基)-4-哌啶胺 | 299 |
| 82 | 2CF3COOH | N-(4-氟苯基)-N-(4-甲基苄基)-4-哌啶胺 | 299 |
| 83 | 2HCl，0.5H2O | N-(4-氟苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 353 |
| 84 | 2HCl | N-(4-氟苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 353 |
| 85 | N-(4-氯苯基)-N-(4-氟苄基)-4-哌啶胺 | 319 | |
| 86 | 2CF3COOH | N-(3-氯苄基)-N-(4-甲基苯基)-4-哌啶胺 | 315/317 |
| 87 | 2CF3COOH | N-(3，4-二氟苄基)-N-(4-甲基苯基)-4-哌 | 317 |
| 啶胺 | |||
| 88 | 2CF3COOH | N-(4-氟苄基)-N-(4-甲基苯基)-4-哌啶胺 | 299 |
| 89 | 2CF3COOH | N-(4-氯苄基)-N-(4-甲基苯基)-4-哌啶胺 | 315/317 |
| 90 | 2CF3COOH | N-(3，4-二氯苄基)-N-(4-甲基苯基)-4-哌啶胺 | 349/351/353 |
| 91 | 2CF3COOH | N-(4-甲基苯基)-N-[4-(三氟甲基)苄基]-4-哌啶胺 | 349 |
| 92 | N-(4-氟苄基)-N-[4-(三氟甲基)苯基]-4-哌啶胺 | 353 |
实施例2：结合测试
2.1 H1结合
通过[3H]-美吡拉敏结合测试评价试验化合物对人组胺H1受体的亲合力。根据Gillard等(GillardM.，Van der Perren C.，MoguilevskyN.，Massingham R，Chatelain P.，Mol.Pharmacol.(2002)，61，391-399)所述进行这项结合。
2.2 5-HT吸收
通过[3H]-帕罗西汀结合测试评价试验化合物对血清素转运蛋白的亲合力。根据Marcusson等(Marcusson J.O.，Bergstrom M.，ErikssonK.，Ross S.B.，J.Neurochem.(1988)，50，1783)所述，稍作修改，进行这项结合。将来自大鼠大脑皮层的膜蛋白(100-200微克)在25℃下在含有2mM MgCl2和0.05nM放射性配体的2毫升50mMTris-HCl(pH 7.4)缓冲液中温育120分钟。在5μM丙咪嗪存在下测定定义为残留结合的非特异性结合。
2.3 5-HT2结合
通过[3H]-酮色林结合测试评价试验化合物对5-HT2受体的亲合力。根据Leysen等(Leysen J.E.，Niemegeers C.J.，Van Nueten J.M.，Laduron P.M.，Mol.Pharmacol.(1982)，21，301-314)所述，稍作修改，进行这项结合。简要地说，将来自大鼠大脑皮层的250微克膜蛋白在25℃下在含有2mM MgCl2和0.2nM放射性配体的1毫升50mMTris-HCl(pH 7.4)缓冲液中温育60分钟。在1μM氯丙嗪存在下测定定义为残留结合的非特异性结合。
Claims (14)
1.式I的4-氨基哌啶化合物，包括其药学可接受的盐，
其中R1，R2，R3，R4独立地选自氢，氟，氯，甲基和三氟甲基，前提是，如果R1，R2和R4是氢，则R3不是氢或卤原子。
2.根据权利要求1的4-氨基哌啶化合物，其中R2是氢，氟或甲基；并且R4是氢，氟，氯或三氟甲基。
3.根据权利要求1的4-氨基哌啶化合物，其中R1是氢，氟或氯；R2是氢，氟或甲基；R3是氢，氟，氯或甲基；并且R4是氢，氟或氯。
4.根据权利要求1的4-氨基哌啶化合物，其中R1是氢或氟；R2是氢或氟；R3是氟或甲基；并且R4是氢。
5.根据权利要求1的4-氨基哌啶化合物，选自
N-(4-甲基苄基)-N-苯基-4-哌啶胺；
N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺；
N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺；
N-(4-氟苄基)-N-(4-氟苯基)-4-哌啶胺；
N-(4-氟苯基)-N-(4-甲基苄基)-4-哌啶胺或者其药学可接受的盐。
6.N-(4-氟苄基)-N-(3-氟苯基)-4-哌啶胺或者其药学可接受的盐。
7.N-(3-氟苯基)-N-(4-甲基苄基)-4-哌啶胺或者其药学可接受的盐。
8.含有治疗有效量的作为活性成分的根据权利要求1-7任一项的化合物和药学可接受的佐剂、稀释剂或载体的药物组合物。
9.权利要求1-7任一项的化合物作为药物的用途。
10.权利要求1-7任一项的化合物在制备药物中的用途。
11.权利要求1-7任一项的化合物在制备用于治疗神经病的药物中的用途。
12.式II的合成中间体，
其中R1，R2，R3，R4独立地选自氢，氟，氯，甲基和三氟甲基，前提是，如果R1，R2和R4是氢，则R3不是氢或卤原子；并且P是胺保护基团。
13.根据权利要求12的合成中间体，选自
4-[3-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{[3-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[3-氟(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{3-氟[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氟苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-3-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-{3-甲基[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-(苄基-4-氟代苯胺基)-1-哌啶羧酸叔丁酯；
4-{4-氟[3-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(3-氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[4-氟(4-氟苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-4-氟代苯胺基]-1-哌啶羧酸叔丁酯；
4-[4-氟(4-甲基苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-{4-氟[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[4-氯(4-氟代苄基)苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3-氯代苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氟苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氟苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(4-氯苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-[(3，4-二氯苄基)-4-甲基苯胺基]-1-哌啶羧酸叔丁酯；
4-{4-甲基[4-(三氟甲基)苄基]苯胺基}-1-哌啶羧酸叔丁酯；
4-[(4-氟代苄基)-4-(三氟甲基)苯胺基]-1-哌啶羧酸叔丁酯；和
4-[(3-氯代苄基)-3-氟代苯胺基]-1-哌啶羧酸叔丁酯。
14.选自4-(3-氟代苯胺基)-1-哌啶羧酸叔丁酯；4-(3-甲苯氨基)-1-哌啶羧酸叔丁酯；4-(4-甲苯氨基)-1-哌啶羧酸叔丁酯的合成中间体。
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| EP02022191 | 2002-10-04 | ||
| EP02022191.7 | 2002-10-04 |
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| US (1) | US7488741B2 (zh) |
| EP (2) | EP1693061A1 (zh) |
| JP (1) | JP2006513151A (zh) |
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| CN111233751A (zh) * | 2020-03-25 | 2020-06-05 | 丽水绿氟科技有限公司 | 一种3,3-二氟-4-氨基哌啶类化合物及其衍生物的制备方法 |
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| AU2003290735A1 (en) * | 2002-12-06 | 2004-06-30 | Eli Lilly And Company | Inhibitors of monoamine uptake |
| US7619096B2 (en) | 2003-06-11 | 2009-11-17 | Eli Lilly And Company | 3-Aminopyrrolidines as inhibitors of monoamine uptake |
| WO2005053663A2 (en) * | 2003-11-24 | 2005-06-16 | Eli Lilly And Company | Norepinephrine reuptake inhibitors useful for treatment of cognitive failure |
| US7615648B2 (en) * | 2004-06-01 | 2009-11-10 | Eli Lilly And Company | Aminomethyl-azacycle derivatives as inhibitors of monoamine uptake |
| RU2686101C2 (ru) | 2013-03-12 | 2019-04-24 | Селтакссис, Инк. | Способы ингибирования лейкотриен- а4-гидролазы |
| EP2968264A4 (en) | 2013-03-14 | 2016-11-02 | Celtaxsys Inc | INHIBITORS OF LEUCOTRIENE A4 HYDROLASE |
| WO2019232306A1 (en) | 2018-05-31 | 2019-12-05 | Celtaxsys, Inc. | Method of reducing pulmonary exacerbations in respiratory disease patients |
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| EG12406A (en) * | 1976-08-12 | 1979-03-31 | Janssen Pharmaceutica Nv | Process for preparing of novel n-aryl-n-(1-l-4-piperidinyl)-arylacetamides |
| JPH05148234A (ja) * | 1991-10-02 | 1993-06-15 | Hokuriku Seiyaku Co Ltd | アルカン酸誘導体 |
| DE4404183A1 (de) * | 1994-02-10 | 1995-08-17 | Merck Patent Gmbh | 4-Amino-1-piperidylbenzoylguanidine |
| GB0108876D0 (en) * | 2001-04-09 | 2001-05-30 | Novartis Ag | Organic Compounds |
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| EP1556045B1 (en) | 2006-08-02 |
| US7488741B2 (en) | 2009-02-10 |
| NZ539015A (en) | 2006-02-24 |
| CA2500664A1 (en) | 2004-04-15 |
| EP1693061A1 (en) | 2006-08-23 |
| DE60307308D1 (de) | 2006-09-14 |
| NO20052172D0 (no) | 2005-05-03 |
| NO20052172L (no) | 2005-06-30 |
| BR0314811A (pt) | 2005-08-02 |
| ZA200502330B (en) | 2006-05-31 |
| US20060128753A1 (en) | 2006-06-15 |
| JP2006513151A (ja) | 2006-04-20 |
| WO2004030668A1 (en) | 2004-04-15 |
| PL376368A1 (en) | 2005-12-27 |
| DE60307308T2 (de) | 2006-12-28 |
| ES2268406T3 (es) | 2007-03-16 |
| EP1556045A1 (en) | 2005-07-27 |
| AU2003270291A1 (en) | 2004-04-23 |
| ATE334680T1 (de) | 2006-08-15 |
| DK1556045T3 (da) | 2006-11-27 |
| PT1556045E (pt) | 2006-12-29 |
| MXPA05003290A (es) | 2005-07-05 |
| SI1556045T1 (sl) | 2007-02-28 |
| KR20050055748A (ko) | 2005-06-13 |
| RU2005110409A (ru) | 2005-09-10 |
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