CN1529596A - 苯并二氢吡喃的应用 - Google Patents
苯并二氢吡喃的应用 Download PDFInfo
- Publication number
- CN1529596A CN1529596A CNA028063554A CN02806355A CN1529596A CN 1529596 A CN1529596 A CN 1529596A CN A028063554 A CNA028063554 A CN A028063554A CN 02806355 A CN02806355 A CN 02806355A CN 1529596 A CN1529596 A CN 1529596A
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- Prior art keywords
- benzodihydropyran
- acid
- isopropoxy
- methyl
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,其生理上可接受的盐,水合物和/或溶剂化物,尤其是其盐酸盐,在生产预防和/或治疗帕金森病药物中的应用。
Description
本发明涉及2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,其生理上可接受的盐,水合物和/或溶剂化物,尤其是其盐酸盐,在生产预防和/或治疗帕金森病药物中的应用。
帕金森病是一种慢性进行性中枢神经系统疾病。这种疾病由黑质中多巴胺能神经元的变性引起,其中的黑质合成和释放神经递质多巴胺。多巴胺能神经递质的减少,会导致控制运动的神经锥体外系功能严重失调。这些紊乱不仅与基底神经中枢有关,而且也与大脑其它邻近相联区域有关。
先天帕金森病的病因在很大程度上仍然未知。但越来越多的事实证明,黑质中多巴胺能神经元细胞发生死亡的原因是,线粒体功能紊乱导致的细胞程序性死亡。除了可能的遗传性紊乱外,作为线粒体机能障碍的原因,人们也讨论谷氨酸酯水平的提高和/或亲神经因子的供应缺乏。
由此出发,有望通过对神经退化过程的神经保护性药理学作用阻止神经元细胞死亡的进一步发展。由此这一疾病进展过程不需要与病因上的病生理机制发生相互影响就能够被终止。
已有显示,以不同方式在体内和体外系统中对神经元5-HT1A受体的刺激,都会产生神经元保护、抗细胞凋亡和亲神经作用。刺激5-HT1A受体也能相应的预防帕金森病中多巴胺神经元的进一步变性,进而最终延缓疾病的进程。
目前临床上对帕金森病的治疗大多采用单纯征候疗法。这些治疗的目的或是通过提供多巴胺前体分子(L-DOPA)来直接替代多巴胺缺乏,这种前体分子在体内经代谢生成多巴胺,或是通过多巴胺受体激动剂,或通过减少多巴胺的破坏(MAO抑制剂,COMT抑制剂)对缺乏多巴胺能神经传递过程进行其它的刺激。然而,目前所有治疗的特点均是会产生严重的副作用(例如,运动障碍、精神病、睡眠紊乱)或长期的运动失调。
苯并二氢吡喃衍生物,尤其是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物盐酸盐及其对5-HT1A受体的激动作用,作为一种治疗中枢神经系统疾病的方法,在EP-A-0352613和EP-A-0749970中是已知的。
WO99/26621中描述了苯并二氢吡喃衍生物,尤其是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物盐酸盐(通用名:瑞匹诺坦盐酸盐),其作为一种促进神经病学疾病(例如帕金森病)中神经再生的药物。
令人惊奇的是,现已发现2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,是一种5-HT1A受体激动剂,不仅具有神经保护作用,而且还具有缓解症状的活性,其以双重方式对帕金森病的进程发挥着积极的作用。
因此,本发明涉及2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,其生理上可接受的盐,水合物和/或溶剂化物,尤其是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物盐酸盐,在生产预防和/或治疗帕金森病药物中的应用。
2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物的结构如下:
本发明所用化合物的生理上可接受的盐,是该化合物与无机酸、羧酸或磺酸形成的盐。优选的盐为,例如与盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、酒石酸、草酸、柠檬酸、富马酸、马来酸或苯甲酸生成的盐。
本发明水合物的含义是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物或其盐与水的化学计量的组合物。
本发明溶剂化物的含义是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物或其盐与溶剂的化学计量的组合物。
本发明所用的化合物可通过EP-A-0749970中给出的方法制备。例如:2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物盐酸盐(在下述称为实施例11)的制备对应于EP-A-0749970中的实施例7。
2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物的盐,可以在适宜溶剂中由化学计量或超化学计量的基于所述盐的酸与游离碱反应得到,该反应于0℃到溶剂沸点的温度范围内进行。适宜的溶剂例如有水,脂肪醇例如甲醇、乙醇或2-丙醇,开链或环状脂肪醚例如二甲醚、叔丁基甲基醚、二噁烷、四氢呋喃,或是脂肪酮例如2-丙酮、2-丁酮及其混合物。任选在部分或全部蒸馏以去除溶剂后,作为固体而直接从混合物中得到所述盐。它们可通过例如在上述溶剂或其混合物中重结晶或再沉淀得以纯化。
该活性化合物能够在全身和/或局部发挥作用。为此目的,该化合物可以一种适宜的方式给药,例如口服、胃肠外、肺部、鼻腔、舌下、向舌、向颊、直肠、经皮、结膜、耳部给药,或是植入给药。优选口服给药。
对于这些给药方式,活性化合物可以适宜的形式给药。
适宜的口服给药方式均是已知的给药形式,其能快速和/或以改良的形式释放活性化合物,该形式例如为片剂(非包衣或包衣片,例如耐胃液包衣)、胶囊、糖衣片、颗粒剂、丸剂、粉剂、乳剂、混悬剂和溶液剂。
胃肠外给药能够通过避免吸收步骤(静脉内、动脉内、心内、脊柱内或腰内给药),或通过包埋吸收(肌肉、皮下、皮内、经皮或腹膜内给药)而实施。适宜的胃肠外给药形式特别是以溶液剂、混悬剂、乳剂、冻干剂和无菌粉末的形式存在的注射剂和输液剂。
适宜其它途径的给药形式为,例如,吸入药剂形式(特别是粉末吸入器,喷雾器),滴鼻剂/溶液,喷雾剂;可通过向舌、舌下或向颊给药的片剂或胶囊、栓剂、眼耳制剂、阴道胶囊、水性混悬液(洗剂、振摇混合物)、亲脂性混悬液、软膏、霜、乳、糊剂、扑粉或植入片给药。
所述活性化合物可经已知的常规方法制成上述给药形式。其通过使用惰性无毒的、药剂学上适宜的赋形剂来制备。赋形剂特别包括载体(例如微晶纤维素)、溶剂(例如液态聚乙二醇)、乳化剂(例如十二烷基硫酸钠)、分散剂(例如聚乙烯吡咯烷酮)、合成或天然的生物聚合物(例如白蛋白)、稳定剂(例如抗氧化剂,如抗坏血酸)、着色剂(例如无机颜料,如铁氧化物)或口味和/或气味矫正剂。
通常,就胃肠外给药来说,已证明给药量约为0.001到30mg/kg,优选约0.01到10mg/kg体重对于实现有效的疗效是有利的。就口服给药来说,剂量约为0.01到100mg/kg,优选约0.1到30mg/kg体重。
尽管如此,如果适宜的话,有必要偏离上述剂量并取决于体重、给药途径、对活性化合物的个体行为差异、制剂类型和定时或间隔给药。
人重组5-HT 1A 受体激动活性的测定
在人重组5-HT1A受体信号转导研究中,使用了鸟苷-5’-O-(3-[S-35]硫代)-三磷酸酯(GTPγ[S-35])结合技术(根据Elliott和Reynolds,Europ J.Pharmacol 1999,386,313-315,以及Sim等人,J.Neurosci.1996,16,8057-8066进行改进)。
在这个试验中得到瑞匹诺坦盐酸盐和实施例11化合物的EC50值分别为0.51nM和0.19nM,就是说,这两种物质均是5-HT1A激动剂,其中实施例11化合物的效力大约是瑞匹诺坦盐酸盐的两倍。
MPTP猴模型
瑞匹诺坦盐酸盐和实施例11化合物的体内活性在帕金森病猴模型中测定。该模型为“慢性MPTP猴模型”(Bézard等人,Brain Res.1997,766,107-112)。MPTP(=1-甲基-4-苯基-1,2,3,6-四氢吡啶)是神经毒素,其在人类和动物中能够引起黑质中多巴胺神经元变性,这是典型的帕金森病。此外,人体和猴子中的MPTP能产生典型帕金森病的运动症状。这些症状作为对猴子帕金森病级别的评定。
对于这个实验来讲,每天给予罗猴(Macaca fascicularis)MPTP(0.2mg/kg,静脉注射),直到它们达到帕金森病级别的8分。首次帕金森症状出现在给予MPTP后的5-10天中。由于神经毒素的长期作用,动物的临床症状进一步发展为完全的帕金森病(分数>15)。共研究了五组动物:第一组只给予MPTP,第二组给予MPTP加瑞匹诺坦盐酸盐(2mg/kg,口服,每日两次),第三组给予实施例11化合物(1mg/kg,口服,每日两次)。用瑞匹诺坦盐酸盐和实施例11化合物进行治疗的组,从动物首次出现临床症状起的那天开始给药。口服给药后,瑞匹诺坦盐酸盐和实施例11化合物均表现出神经保护活性,即,两种物质均能延缓该猴模型帕金森病症状的发生。然而十分令人意外地观察到,实施例11化合物还能够降低这一症状的严重程度,即对症状具有作用(与对照组相比降低了22%)。相反,用瑞匹诺坦盐酸盐进行治疗的组没有观察到这样的症状作用(见表1)。
表1:MPTP猴模型中瑞匹诺坦盐酸盐和化合物11的治疗效果
组 | MPTP | MPTP+瑞匹诺坦盐酸盐2.0mg/kg | MPTP+实施例11化合物1.0mg/kg |
减缓帕金森病的发展1) | 0 | + | + |
最后3天的症状学 | 100% | 100% | 78% |
1)0=没有减缓帕金森病的发展
+=统计学上显著延缓达到8分的症状
制备实施例
实施例1
2-羟基-3-甲氧基-苯基氰
在搅拌下将6375g(41.94mol)邻-香草醛,3823g(55mol)羟胺盐酸盐和6375g(93.75mol)甲酸钠在14升甲酸中的混悬液加热到约90到95℃。在这个温度范围内产生气泡的量增加并放热(停止加热)。放热反应持续大约10到15分钟(温度升高到约115℃)。然后将混合物在回流状态下继续搅拌45分钟。此反应完成后,将混合物冷却到约6℃,并在搅拌下加入到6kg冰和25升水的混合物中。1小时后,抽滤固体,用约12升水洗涤。然后在室温下于新鲜空气干燥箱内干燥24小时,并在真空干燥箱中于P2O5上干燥120小时(室温)。
产物:4816g(77%)晶体,熔点:54℃,Rf:0.34(甲苯-乙酸乙酯3∶1)
实施例2
2-羟基-3-甲氧基-乙酰苯
将750g(30.8mol)镁屑和3g碘放入充满氮气的干燥反应容器中。加入10升甲氧基苯,缓慢搅拌下将混合物加热到40℃。停止搅拌,将25ml甲基碘化物和初始混合物1)直接加入到镁屑中。反应开始后继续搅拌,并加入2.5升含有1916ml甲基碘化物的甲氧基苯溶液,适度冷却以使温度保持在40到43℃之间(1.5小时)。然后将混合物在40℃进一步搅拌5小时,并于室温下搅拌15小时。将其冷却到5℃,在1.5小时内注入6.5升含有1840g(12.3mol)2-羟基-3-甲氧基-苯基氰的甲氧基苯溶液,将得到的混合物在40℃下搅拌1.5小时。反应完成后(TLC检测/甲苯-乙酸乙酯3∶1),将反应混合物冷却到10℃,并在搅拌下加入到24kg冰和8升水的混合物中。然后加入12升6N盐酸酸化,对此温度不能超过0到5℃的范围。分离有机相并用2.5升6N盐酸洗涤。合并的水相用甲苯萃取3次,每次使用4升。然后在内部温度为98℃的条件下搅拌水相1.5小时。停止加热,加入6kg氯化钠,在室温下将混合物搅拌过夜。
在缓慢冷却到5℃以后,即可得到赭色晶体沉淀物。将其抽滤,经4升冰水洗涤(2次),并在真空干燥箱内于P2O5和NaOH小片上干燥5天(120小时)。
产物:1587g(78%),熔点:53℃,Rf:0.33(甲苯∶乙酸乙酯9∶1)
1)所用的“初始混合物”是以1mol的相同反应
实施例3:
8-甲氧基-色酮-2-甲酸乙酯
于50℃将1140g(6.86mol)2-羟基-3-甲氧基-乙酰苯,2升(14.86mol)草酸二乙酯和7升乙醇的大部分溶解的混合物加入到20升含有1024g(15.04mol)乙醇钠的乙醇冷却的溶液中。加热混合物回流3小时。冷却到50℃,加入2升浓盐酸,并将混合物加热回流30分钟。然后冷却到50℃,抽滤,过滤残余物,用乙醇洗涤,滤液经旋转蒸发器浓缩。
将黄色晶体残余物溶解在15升二氯甲烷中,与14升10%浓度的NaHCO3溶液充分搅拌30分钟。分离有机相,用2升10%浓度的NaHCO3溶液洗涤,于2kg Na2SO4和1kg Tonsil混合物上干燥。然后将固体通过硅藻土抽滤,用二氯甲烷洗涤,滤液经旋转蒸发器浓缩。残余物在旋转蒸发器中经2.5升石油醚处理,在室温下搅拌混合物15分钟,冷却到5℃,抽滤。将淡黄色晶体于新鲜空气干燥箱内干燥2小时,并在真空干燥箱中于P2O5上干燥24小时。
产物:1304g(76%)晶体,熔点:129-130℃,Rf:0.53(甲苯∶乙酸乙酯=85∶15)
实施例4
8-甲氧基-苯并二氢吡喃-2-甲酸乙酯
在500g 10%的Pd/C存在下,将含有5.30kg(22.45mol)8-甲氧基-色酮-2-甲酸乙酯的100升乙酸乙酯和50升冰醋酸的混合物于50℃、3巴氢气压力下氢化24小时。对于后处理,将反应液通过硅藻土抽滤,滤液于旋转蒸发器内浓缩。为了经共沸除去残余冰醋酸,将烧瓶内容物用6升甲苯处理2次并浓缩。将残余物于蒸汽-喷射真空装置(8h/8mm)中干燥,得到深色油状产物。
产量:5.002kg(94%)油状物,沸点:110-114℃/0.04mm,Rf:0.42(甲苯∶乙酸乙酯3∶1)
实施例5
(R)-2-羟甲基-8-甲氧基-苯并二氢吡喃
将在甲苯中的235g(R)-8-甲氧基-苯并二氢吡喃-2-甲酸乙酯(由(R,S)-8-甲氧基-苯并二氢吡喃-2-甲酸乙酯,按照DE-A 4430089中记载的方法制备)缓慢滴加到540g 65%的RedA1甲苯溶液中,共用1.5升甲苯。于室温下搅拌18小时后,首先将混合物于50℃加热1小时,然后进一步于80℃加热一小时。冷却到室温后,加入100g冰进行外部冷却,随后加入600ml 15%的酒石酸钾钠溶液。用500ml甲苯和500ml乙酸乙酯稀释混合物。分离有机相,通过硫酸镁干燥,并加入Tonsil使其澄清。浓缩至体积约为500ml,然后加入1升环己烷,将混合物在室温下搅拌30分钟。抽滤固体沉淀物,洗涤并干燥。得到135.5g目标产物。
熔点:77-78℃
实施例6
(R)-8-羟基-2-羟甲基苯并二氢吡喃
在0.7升48%的HBr水溶液中,加热135.5g(0.7mol)(-)-2-羟甲基-8-甲氧基苯并二氢吡喃20小时。冷却后用1.2升冰水稀释,将混合物搅拌30分钟,抽滤滤出沉淀物。用冰水洗涤并通过五氧化磷干燥,得到109.5g(87%)标题化合物,熔点131-132℃。
α20 289=-133.8(c=0.7甲醇)
实施例7
(R)-2-羟甲基-8-异丙氧基-苯并二氢吡喃
将4.5g(25mmol)(R)-8-羟基-2-羟甲基-苯并二氢吡喃、4.6g(27mmol)2-碘丙烷和5.2g(37.5mmol)碳酸钾粉末的50ml二甲基甲酰胺溶液于60℃下加热40小时。再加入0.9g碘丙烷,于80℃下将混合物加热24小时,然后在95℃下进一步加热24小时。冷却后,在甲苯/水中分配,经Celite过滤。干燥有机相(硫酸镁)并浓缩。经闪式色谱纯化(硅胶;用甲苯/乙酸乙酯洗脱,梯度3∶1-2∶1),得到7g粗品,用硅胶色谱纯化(梯度甲苯/乙酸乙酯1∶0-8∶1),得到2.9g(52%)产物,为油状物。
RF(硅胶,甲苯/乙酸乙酯1∶1):0.4
[α]20 289=-85[c=0.5,CHCl3]
实施例8
(R)-8-异丙氧基-2-甲磺酰氧基甲基-苯并二氢吡喃
在室温下将68g(0.6mol)甲基磺酰氯滴加到含有114g(0.51mol)实施例7化合物的95g吡啶中。室温下搅拌18小时后,用700ml水稀释混合物,并用二氯甲烷萃取。经硅胶过滤并浓缩后,得到150g粗品,将其在1.5升环己烷/甲苯3∶1混合物中结晶纯化。在母液浓缩后用环己烷重结晶,得到112g无色固体状标题产物,熔点77-78℃。
[α]20 289=-56.2[c=0.9,CH3OH]
实施例9
(R)-2-苄胺甲基-8-异丙氧基-苯并二氢吡喃
将112g(0.37mol)实施例8的化合物,200g(1.87mol)苄胺和3.0g(0.02mol)碘化钠于100℃下加热5小时。冷却后分出固体物质,有机相用水洗涤2次,每次2.5升。剩余油状物用1升乙酸乙酯处理。乙酸乙酯相用水和饱和氯化钠溶液洗涤,继而干燥、浓缩,得到114.5g(定量)油状标题化合物(HPLC纯度:93%),供下一步使用。
[α]20 289=-104[c=0.5,CH3OH]
实施例10
(R)-2-(N-苄基-N-(4-(1,1-二氧代-3-氧代-2,3-二氢-苯并异噻唑-2-基)-2-丁炔基)-氨基甲基)-8-异丙氧基-苯并二氢吡喃盐酸盐
将1升含有114g(0.37mol)实施例9化合物和13.5g(0.45mol)低聚甲醛的二噁烷溶液,用4g醋酸铜(II)处理,并温热到50℃。在此温度下加入81g(0.37mol)丙炔基糖精。80℃下搅拌2小时后,浓缩混合物,在加有Tonsil的甲苯/水体系中分配残余物。混合物经Celite过滤后,分离有机相,通过闪式色谱在硅胶上纯化(甲苯/乙酸乙酯10∶1)。用盐酸乙醚溶液沉淀出盐酸盐,得到226g粗品。用碳酸氢钠析出游离碱后,将该产物用硅胶(用甲苯/乙酸乙酯20∶1洗脱)色谱纯化。产物级分用盐酸乙醚溶液处理。得到139g(65%)固体标题化合物,熔点106-109℃。
[α]20 289=-64.1[c=0.8,CH3OH]
实施例11
2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,结构如下:
将1.4升含有120g(0.21mmol)实施例10化合物的甲醇溶液,用400ml浓盐酸和20g 10%钯/活性碳处理。常压下于20℃氢化4小时后,滤去催化剂,浓缩滤液。残余物用甲苯浓缩2次,然后用400ml乙酸乙酯溶解。加入800ml乙醚,室温下搅拌18小时,抽滤并真空干燥,得到90.5g固体物。在1升乙腈中重结晶后,用乙醚洗涤晶体,得到70.8g(69%)无色晶体标题化合物,熔点153-154℃。
[α]20 289=-65.9[c=0.6,CH3OH]
元素分析:C24H30N2O5SxHCl
计算值 C:58.2 H:6.3 N:5.7 O:16.2 C1:7.2 S:6.5
实测值:C:58.0 H:6.3 N:5.7 O:16.2 C1:7.1 S:6.3
Claims (4)
1.2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,其生理上可接受的盐,水合物和/或溶剂化物在制备预防和/或治疗帕金森病药物中的应用。
2.如权利要求1所述的应用,其中活性化合物是2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物的盐酸盐。
3.用于预防和/或治疗帕金森病的2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物,其生理上可接受的盐,水合物和/或溶剂化物。
4.用于预防和/或治疗帕金森病的2-[4-({[(2R)-8-异丙氧基-苯并二氢吡喃-2-基]甲基}氨基)丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物盐酸盐。
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GT200200002A (es) | 2002-09-02 |
EP1353670A2 (de) | 2003-10-22 |
SV2003000843A (es) | 2003-01-13 |
AR032070A1 (es) | 2003-10-22 |
PE20020841A1 (es) | 2002-10-02 |
DE10101917A1 (de) | 2002-07-18 |
PL362869A1 (en) | 2004-11-02 |
KR20040025885A (ko) | 2004-03-26 |
MXPA03006333A (es) | 2004-04-20 |
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JP2004520342A (ja) | 2004-07-08 |
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