CN1271284A - 玻连蛋白受体拮抗剂 - Google Patents
玻连蛋白受体拮抗剂 Download PDFInfo
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- CN1271284A CN1271284A CN98809494A CN98809494A CN1271284A CN 1271284 A CN1271284 A CN 1271284A CN 98809494 A CN98809494 A CN 98809494A CN 98809494 A CN98809494 A CN 98809494A CN 1271284 A CN1271284 A CN 1271284A
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本发明公开了式(Ⅰ)化合物或其可药用盐,该化合物是玻连蛋白受体拮抗剂,可用于治疗骨质疏松。
Description
本发明的技术领域
本发明涉及能抑制玻连蛋白受体并且可用于治疗炎症、癌症和心血管疾病例如动脉粥样硬化和再狭窄、以及其中骨吸收是致病因素的疾病例如骨质疏松的药物活性化合物。
本发明的背景技术
整联蛋白是细胞粘着受体的超家族,所述细胞粘着受体是在各种细胞中表达的跨膜糖蛋白。这些细胞表面粘着受体包括gpIIb/IIIa(血纤蛋白原受体)和αVβ3(玻连蛋白受体)。血纤蛋白原受体gpIIb/IIIa是在血小板表面上表达的,并且介导血小板聚集和止血凝块在出血伤口处的形成。Philips等人,《血液》(Blood),1988,71,831。玻连蛋白受体αVβ3在包括内皮细胞、平滑肌细胞、破骨细胞和肿瘤细胞在内的多种细胞中表达,因此具有多种功能。在破骨细胞的细胞膜上表达的αVβ3受体介导破骨细胞与骨基质的粘着,而这种粘着是骨吸收过程中的关键步骤。Ross等人,《生物化学杂志》(J.Biol.Chem.),1987,262,7703。特征是发生高度骨吸收的疾病是骨质疏松。在人主动脉平滑肌细胞中表达的αVβ3受体介导这些细胞向新内膜中的迁移,这种迁移过程可导致经皮冠状血管成形术后发生再狭窄。Brown等人,《心血管研究》(Cardiovascular Res.),1994,28,1815。此外,Brooks等人在《细胞》(Cell),1994,79,1157中提出,αVβ3拮抗剂能通过诱导新生成的血管程序化死亡而促进肿瘤消退。因此,能阻断玻连蛋白受体的活性剂可用于治疗疾病例如骨质疏松、再狭窄和癌症。
现在已知玻连蛋白受体是指三种不同的整联蛋白,即αVβ1、αVβ3和αVβ5。Horton等人,《国际实验病理学杂志》(Int.J.Exp.Pathol.),1990,71,741。αVβ1结合纤连蛋白和玻连蛋白。αVβ3结合包括血纤蛋白、血纤蛋白原、层粘连蛋白、血小板反应蛋白、玻连蛋白、冯维勒布兰德氏(von Willebrand’s)因子、骨桥蛋白和骨唾液蛋白I在内的多种配体。αVβ5结合玻连蛋白。玻连蛋白受体αVβ5已被证明参与包括微血管内皮细胞在内的多种细胞的细胞粘着(Davis等人,《细胞生物学杂志》(J.Cell.Biol.),1993,51,206),其在血管生成中的作用已被证实。Brooks等人,《科学》(Science),1994,264,569。这种整联蛋白在人伤口成颗粒组织中的血管上表达,但是不在正常皮肤中的血管上表达。
已知玻连蛋白受体结合含有三肽Arg-Gly-Asp(或RGD)基序的骨基质蛋白。因此,Horton等人在《实验细胞研究》(Exp.Cell Res.),1991,195,368中指出,含有RGD的肽和抗玻连蛋白受体抗体(23C6)能抑制牙质吸收和破骨细胞导致的细胞展开。此外,Sato等人在《细胞生物学杂志》(J.Cell Biol.),1990,111,1713中公开,含有RGD序列的蛇毒肽—锯鳞血抑肽在组织培养中是骨吸收的有效抑制剂,并抑制破骨细胞与骨的粘着。
现在已经发现,一些化合物是αVβ3和αVβ5受体的有效抑制剂。尤其是,已经发现,这类化合物对玻连蛋白受体的抑制作用比对血纤蛋白原受体的抑制作用要强。
发明简述
本发明包括如下所述的式(I)化合物,所述化合物具有抑制玻连蛋白受体的药理活性,并可用于治疗炎症、癌症和心血管疾病例如动脉粥样硬化和再狭窄、以及其中骨吸收是致病因素的疾病例如骨质疏松。
本发明还涉及含有式(I)化合物和可药用载体的药物组合物。
本发明还涉及治疗由玻连蛋白受体介导的疾病的方法。特别是,本发明化合物可用于治疗动脉粥样硬化、再狭窄、炎症、癌症以及其中骨吸收是致病因素的疾病例如骨质疏松。
发明详述
本发明包括对玻连蛋白受体的抑制作用比对血纤蛋白原受体的抑制作用要强的新化合物。所述新化合物包含苯并氮杂核,其中含氮的取代基位于该苯并氮杂的芳香6元环上,含酸性部分的脂肪族取代基位于该苯并氮杂的7元环上。据信该苯并氮杂环系能与玻连蛋白受体很好地相互作用,并且将6元和7元环上的取代基侧链定向,所以这些取代基侧链也能与玻连蛋白受体很好地相互作用。在该苯并氮杂7元环的脂肪族取代基上的酸性基团与该苯并氮杂芳香6元环的含氮取代基上的氮之间,优选存在约12-14个通过最短分子内路径的中间共价键。
本发明包括式(I)化合物或其可药用盐:该化合物是(S)-8-[3-(吡啶-2-基氨基)-1-丙氧基]-3-氧代-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸。
式(I)化合物能抑制玻连蛋白和其它含RGD的肽与玻连蛋白受体结合。该化合物对破骨细胞上玻连蛋白受体的抑制作用就抑制了骨吸收,因此可用于治疗其中骨吸收是致病因素的疾病例如骨质疏松和骨关节炎。
另一方面,本发明涉及刺激骨形成的方法,包括将能使骨钙蛋白释放增加的式(I)化合物给药。对于其中矿化骨质缺乏或需要骨质重建的疾病状况,例如骨折的愈合和预防骨折,很明显增加骨生成是有利的。这种治疗对于导致骨结构损失的疾病和代谢障碍也有利。例如,甲状旁腺机能亢进、佩吉特氏病、恶性高钙血、骨转移产生的溶骨性损伤、由于固定术或性激素缺乏而导致的骨损失、贝切特氏病、软骨病、骨肥厚、和骨硬化病可通过将本发明化合物给药而得到改善。
此外,因为本发明化合物能抑制多种细胞上的玻连蛋白受体,因此能用于治疗炎症例如类风湿性关节炎和牛皮癣,和心脏病例如动脉粥样硬化和再狭窄。本发明式(I)化合物可用于治疗或预防其它疾病,这些疾病包括但不限于血栓栓塞症、哮喘、变态反应、成人呼吸窘迫综合症、移植物抗宿主疾病、器官移植排斥、脓毒性休克、湿疹、接触性皮炎、炎性肠病、和其它自身免疫性疾病。本发明化合物还可以用于伤口愈合。
本发明化合物还可用于治疗包括预防血管生成性疾病。本发明所用的术语“血管生成性疾病”包括涉及异常新血管形成的疾病。当疾病的病因是由于新血管生长所致时,抑制血管生成就将减轻该疾病的有害作用。这种疾病的实例是糖尿病性视网膜病。当有害组织的生长需要新血管的生长来支持时,抑制血管生成将减少对该有害组织的血液供应,因此就有助于减少基于所需血液供应的组织质量。实例包括肿瘤的生长,其中肿瘤生长和实体瘤转移灶的建立不断地需要新血管生成。因此,本发明化合物能抑制肿瘤组织的血管生成,从而就阻止了肿瘤转移和肿瘤生长。
因此,依据本发明的方法,用本发明化合物抑制血管生成可改善该疾病的症状,并且在一些情况下,可治愈该疾病。
本发明化合物的另一治疗适应症是特征为新血管生成的眼疾病。这种眼疾病包括角膜新血管性疾病,例如角膜移植、疱疹性角膜炎、梅毒性角膜炎、翼状胬肉和使用隐形眼镜带来的新血管性血管翳。其它眼疾病还包括老年黄斑变性、假性眼组织胞浆菌病、早熟性视网膜病和新血管性青光眼。
本发明还提供了抑制肿瘤生长的方法,包括将式(I)化合物和抗肿瘤剂例如托泊替堪和顺铂依次给药或一起同时给药。
本说明书使用在肽和化学领域中常用的缩写和符号来描述本发明化合物。通常情况下,氨基酸缩写是遵循如在《欧洲生物化学杂志》(Eur.J.Biochem.),158,9(1984)中描述的IUPAC-IUB联合委员会制定的生物化学命名原则。
本说明书所用的C1-6烷基是指,具有1-6个碳原子的选择性地被取代的烷基,包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基和己基以及其简单的脂肪族异构体。
本说明书使用了一些试剂的缩写形式。DCC是指二环己基碳二亚胺,DMAP是指二异丙基乙胺,EDC是指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐。HOBt是指1-羟基苯并三唑,THF是指四氢呋喃,DIEA是指二异丙基乙胺,DEAD是指偶氮二甲酸二乙酯,PPh3是指三苯基膦,DIAD是指偶氮二甲酸二异丙酯,DME是指二甲氧基乙烷,DMF是指二甲基甲酰胺,NBS是指N-溴琥珀酰亚胺,Pd/C是指钯碳催化剂,PPA是指多磷酸,DPPA是指联苯磷酰基叠氮化物,BOP是指六氟磷酸苯并三唑-1-氧基-三(二甲基氨基)磷,HF是指氢氟酸,TEA是指三乙胺,TFA是指三氟乙酸,PCC是指氯铬酸吡啶。
式(I)化合物一般是通过Bondinell等人在1993年1月7日公开的PCT申请WO 93/00095和Bondinell等人在PCT申请WO 94/14776中描述的方法制得的,上述文献全文引入本发明以作参考。
此外,式(I)化合物是通过在下述反应方案中详细描述的方法制得的。
方案Ia)2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物,DEAD,(Ph)3P,DMF;b)LiHMDS,2,3,4-三氟苄基溴,DMF;c)HCl/二氧杂环己烷;d)环己烯,10%Pd/C,甲醇;e)1.0N NaOH,MeOH;f)TFA。
将按照Bondinell等人在1993年1月7日公开的PCT申请WO93/00095和Bondinell等人在PCT申请WO 94/14776中描述的方法制得的化合物I-1,与2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物进行Mitsunobu型偶合反应(《有机反应》(OrganicReactions)1992,42,335-656;《合成》(Synthesis)1981,1-28)以获得I-2。该反应是由偶氮二甲酸二乙酯和三苯基膦形成的复合物介导的,并且是在非质子传递溶剂例如THF、CH2Cl2或DMF中进行的。可在本领域技术人员众所周知的标准烷基化条件下将所得产物I-2在2位(苯并氮杂上的编号)烷基化。例如,可在适当溶剂-通常是THF、DMF、DME或其混合物中,用碱例如氢化钠、LDA、或六甲基二硅烷锂处理I-2,以影响酰胺N-H的去质子化。用适当亲电试剂例如2,3,4-三氟苄基溴处理所得阴离子物质,导致N-烷基化,获得了产物I-3。可在标准酸性条件下,除去I-3上的叔丁氧基氨基甲酸酯(Boc)基,以获得I-4。该条件是本领域技术人员众所周知的,并在合适的参考文献,例如Greene的“有机合成中的保护基”(Wiley-Interscience出版)中描述过。使用钯催化剂、优选在活化碳上的钯金属,在惰性溶剂例如甲醇、乙醇或2-丙醇中,在转移氢化条件下,将I-4的吡啶-N-氧化物部分还原成相应的吡啶I-5。在该类型反应中,通常使用环己烯、1,4-环己二烯、甲酸、和甲酸盐例如甲酸钾或甲酸铵作为氢转移试剂。用碱的含水溶液,例如LiOH在含水THF中的溶液、或NaOH在含水甲醇或乙醇中的溶液,将I-5甲酯水解,用适当的酸例如TFA或HCl将羧酸盐中间体酸化,以获得羧酸I-6。或者,如果需要的话,可将羧酸盐中间体分离,或者可通过本领域众所周知的方法制备该游离羧酸的羧酸盐。
该化合物的酸加成盐是以标准方法,在适当溶剂中用该母化合物与过量的酸制得的,所述酸有例如氢氯酸、氢溴酸、氢氟酸、硫酸、磷酸、乙酸、三氟乙酸、马来酸、琥珀酸或甲磺酸。阳离子盐是通过用过量的含有适当阳离子的碱性试剂例如氢氧化物、碳酸盐或醇盐;或用合适的有机胺处理该母化合物而制得的。阳离子例如Li+、Na+、K+、Ca++、Mg++和NH4 +是存在于可药用盐中的阳离子的具体实例。
本发明还提供了含有式(I)化合物和可药用载体的药物组合物。因此,式(I)化合物可用于生产药物。如上文所述制得的式(I)化合物的药物组合物可配制成用于非胃肠道给药的溶液或冷冻干燥粉末。粉末可在使用前通过加入适当稀释剂或其它可药用载体来重新配制。所述液体制剂可以是缓冲、等渗水溶液。适当稀释剂的实例有标准等渗盐水溶液、在水或乙酸钠或乙酸铵缓冲溶液中的5%葡萄糖标准溶液。这种制剂尤其适于非胃肠道给药,但是也可用于口服给药,或者装在计量剂量吸入器或喷雾器中进行吹入给药。可能需要加入赋形剂例如聚乙烯基吡咯烷酮、明胶、羟基纤维素、阿拉伯胶、聚乙二醇、甘露糖醇、氯化钠或柠檬酸钠。
或者,可将本发明化合物制成口服胶囊、片剂、乳剂或糖浆剂。可加入可药用固体或液体载体来增强或稳定该组合物,或者协助该组合物的制备。固体载体包括淀粉、乳糖、硫酸钙二水合物、白土、硬脂酸镁或硬脂酸、滑石粉、果胶、阿拉伯胶、琼脂或明胶。液体载体包括糖浆、花生油、橄榄油、盐水和水。载体还可以包括缓释材料,例如单独使用或与蜡一起使用的甘油单硬脂酸酯、甘油二硬脂酸酯。固体载体的用量可以不同,但是每剂量单位优选用约20mg-约1g。该药物制剂是用制药领域常规技术制备的,所述技术包括碾磨、混合、制粒、和需要时例如对于片剂压片;对于硬明胶胶囊剂型,所述技术包括碾磨、混合和填充。当使用液体载体时,该制剂可以是糖浆剂、酏剂、乳剂或水悬浮液或非水悬浮液。这种液体制剂可以直接口服给药,或者填充在软明胶胶囊中。
对于直肠给药,还可以将本发明化合物与赋形剂例如椰子油、甘油、明胶或聚乙二醇混合,并模制成栓剂。
本发明化合物是玻连蛋白受体拮抗剂,并且可用于治疗其中基础病因是由于配体或细胞与玻连蛋白受体相互作用所致的疾病。例如,本发明化合物可用于治疗其中骨基质损失是致病原因的疾病。因此,本发明化合物可用于治疗骨质疏松、甲状旁腺机能亢进、佩吉特氏病、恶性高钙血、骨转移产生的溶骨性损伤、由于固定术或性激素缺乏而导致的骨损失。据信本发明化合物还能用作抗肿瘤剂、抗血管生成剂、抗炎剂和抗转移剂,并且可用于治疗动脉粥样硬化和再狭窄。
可将本发明化合物以药物浓度足以抑制骨吸收或其它适应症的方式对患者口服或非胃肠道给药。可将含有本发明化合物的药物组合物以约0.1-约50mg/kg的口服剂量以与患者的症状相一致的方式给药。口服剂量优选为约0.5-约20mg/kg。对于急性治疗,优选采用非胃肠道给药。该肽在5%葡萄糖水溶液或5%葡萄糖标准盐水溶液中的静脉输注液或与适当赋形剂配制成的类似制剂是最有效的,也可以使用肌内药团注射剂。非胃肠道给药剂量一般是约0.01-约100mg/kg;优选0.1-20mg/kg。本发明化合物以每天给药1-4次的水平给药以达到约0.4-约400mg/kg/天的总日剂量。本领域技术人员通过比较该活性剂的血液水平与达到治疗效果所需的浓度,可容易地确定出精确的给药水平和方法。
本发明还提供了治疗骨质疏松或抑制骨损失的方法,包括将式(I)化合物与其它骨吸收抑制剂例如双膦酸盐(即allendronate)、激素替代治疗剂、抗雌激素剂、或降钙素依次给药或一起同时给药。此外,本发明还提供了用本发明化合物与组成代谢剂例如骨形态形成蛋白、异丙氧黄酮(iproflavone)来阻止骨损失和/或增加骨质的治疗方法。
此外,本发明还提供了抑制肿瘤生长的方法,包括将式(I)化合物与抗肿瘤剂依次给药或一起同时给药。喜树碱的类似化合物,例如托泊替堪、伊立替康、9-氨基喜树碱、和铂配位复合物例如顺铂、奥马铂和四铂(tetraplatin)是众所周知的抗肿瘤剂。喜树碱的类似化合物描述在美国专利5004758、4604463、4473692、4545880、4342776、4513138、4399276,欧洲专利申请公开0418009和0088642,Wani等人的《药物化学杂志》(J.Med.Chem.),1986,29,2358、Wani等人的《药物化学杂志》(J.Med.Chem.),1980,23,554、Wani等人的《药物化学杂志》(J.Med.Chem.),1987,30,1774和Nitta等人的《第14界国际化学治疗会议会报》(Proc.14thInternational Congr.Chemotherapy),1985,《抗癌部分》(Anticancer Section)1,28,所述公开物都全文引入本发明以作参考。铂配位复合物顺铂可以以商品名Platinol从Bristol Myers-Squibb Corporation购得。美国专利号5562925和4310515描述了顺铂的合适制剂,这两篇公开物都全文引入本发明以作参考。
在包括将式(I)化合物和抗肿瘤剂依次给药或一起同时给药的抑制肿瘤生长的方法中,可采用缓慢地静脉内输注的方式将铂配位化合物例如顺铂给药。优选的载体是含有甘露糖醇的葡萄糖/盐水溶液。铂配位化合物的剂量可以是每疗程用约1-约500mg/平方米(mg/m2)身体表面积。铂配位化合物的输注每周可进行1-2次,周治疗可重复数次。用喜树碱的类似化合物进行非胃肠道给药时,所采用的疗程一般是约0.1-约300.0mg/m2身体表面积/天,连续进行约5天。对于托泊替堪,最优选的是,所采用的疗程一般是约1.0-约2.0mg/m2身体表面积/天,连续进行约5天。该治疗过程优选在约7天-28天的间歇重复至少1次。
对于这类药物组合物,可将式(I)化合物和抗肿瘤剂配制在同一容器内,但是优选配制在不同容器内。当这两种活性剂以溶液形式提供时,可将其装在用于同时给药的输注/注射体系中或串联排布体系中。
为了便于将式(I)化合物和抗肿瘤剂同时或在不同时间给药,可制备在单独容器例如盒子、卡纸盒或其它容器、单独瓶子、袋子、小瓶或其它容器中分别装有有效量的上述非胃肠道给药的式(I)化合物和有效量的上述非胃肠道给药的抗肿瘤剂的药盒。例如,这种药盒可在分隔的容器或同一容器中包含选择性地作为冷冻干燥填料的这两种药物活性剂,以及装有用于重新配制的溶液的容器。各种这类药盒包含用于重新配制的溶液,和装在单个容器的两个室中、可在使用前进行混合的冷冻干燥填料。采用这种排布,抗肿瘤剂和本发明化合物可分隔包装在例如两个容器中,或者作为粉末冷冻干燥在一起并装在一个容器中。
当这两种活性剂以溶液形式提供时,可将其装在用于同时给药的输注/注射体系中或串联排布体系中。例如,式(I)化合物可以在静脉注射剂型或输液袋中,通过管线与装在另一个输液袋中的抗肿瘤剂连续地连接。使用这种体系,患者可先接受式(I)化合物的药团型注射剂或输注剂,然后接受抗肿瘤剂的输注剂。
可在其中一种生物分析中测试本发明化合物,以确定达到给定药理效果所需的化合物浓度。玻连蛋白结合的抑制[3H]-SK&F-107260对αVβ3的固相结合:将在缓冲液T(含有2mM的CaCl2和1%的辛基葡糖苷)中的人胎盘或人血小板αVβ3(0.1-0.3mg/mL)用含有1mM CaCl2、1mM MnCl2、1mM MgCl2(缓冲液A)和0.05%NaN3的缓冲液T稀释,然后立即以0.1ml/孔的量加到96-孔ELISA培养皿(Corning,New York,NY)中。每孔中加入0.1-0.2μg αVβ3。将培养皿在4℃培养过夜。在本实验期间内,将孔用缓冲液A洗涤一次,并用0.1ml 3.5%牛血清白蛋白在相同缓冲液中于室温下培养1小时。培养后,将孔彻底抽吸,并用0.2mL缓冲液A洗涤两次。
将化合物溶于100%DMSO,以得到2mM的储备液,将该储备液用结合缓冲液(15mM Tris-HCl(pH7.4),100mM NaCl,1mM CaCl2,1mM MnCl2,1mM MgCl2)稀释至化合物终浓度为100μM。然后将该溶液稀释至所需的化合物终浓度。将不同浓度的未标记拮抗剂(0.001-100μM)加到孔中,每一浓度都一式三份,然后加入5.0nM[3H]-SK&F-107260(65-86Ci/mmol)。
将培养皿在室温培养1小时。培养后,将孔彻底抽吸,并用0.2ml冰冷的缓冲液A以逐孔的方式洗涤1次。用0.1ml 1%SDS将受体溶解,通过液体闪烁计数来确定与[3H]-SK&F-107260的结合,其中在Beckman LS液体闪烁计数器中加入3ml Ready Safe,并且测定效率是40%。在2μM SK&F-107260存在下测定[3H]-SK&F-107260的非特异性结合,其始终小于总放射配体输入量的1%。通过由LUNDON-2程序修正的非线性、最小二乘方曲线拟合程序确定IC50(将[3H]-SK&F-107260的结合抑制50%时拮抗剂的浓度)。依据下述公式计算Ki(拮抗剂的解离常数):Ki=IC50/(1+L/Kd),其中L和Kd分别是[3H]-SK&F-107260的浓度和解离常数。
本发明化合物在约0.003μM(micomolar)的浓度下抑制了玻连蛋白与SK&F-107260的结合。
还在用于评价骨形成抑制的标准测试中,测定本发明化合物在体外和体内对骨吸收的作用,所述测试有,例如在EP 528587中描述的凹窝形成分析,该测试也可以用人破骨细胞代替大鼠破骨细胞来进行,和Wronski等人在《细胞和材料》(Cells and Materials)1991,Sup.1,69-74中描述的卵巢切除大鼠模型。血管平滑肌细胞迁移测试
使用大鼠或人的主动脉平滑肌细胞。在Transwell细胞培养室中,通过使用具有8μM孔的聚碳酸酯膜(Costar)监视细胞迁移。该滤器的下表面上铺有玻连蛋白。将细胞以2.5-5.0×106个细胞/ml的浓度悬浮在补充有0.2%牛血清白蛋白的DMEM中,并用测试化合物在不同浓度下于20℃预处理20分钟。使用溶剂作为对照。将0.2ml该细胞悬浮液置于培养室的上隔室。下隔室含有0.6ml补充有0.2%牛血清白蛋白的DMEM。在37℃、95%空气/5%CO2气氛下培养24小时。培养后,通过轻微刮擦将滤器上表面上的非迁移细胞除去。然后把滤器固定在甲醇中,并用10%的吉姆萨染液染色。通过下述途径测定迁移:a)计数迁移到滤器下表面上的细胞的数量,或者b)用10%乙酸提取被染色的细胞,然后在600nM处测定吸收度。作过甲状腺甲状旁腺切除术的大鼠模型
每一实验组由5-6只成年雄性Sprague-Dawley大鼠(250-400g体重)组成。在使用7天前,给大鼠作甲状腺甲状旁腺切除术(由卖主Taconic Farms作切除术)。所有的大鼠每3天接受替代剂量的甲状腺素。收到大鼠后,一经通过尾部静脉穿刺术把全血抽出置于肝素化试管中后,立即测定循环离子化钙水平。如果大鼠的离子化钙水平(用Ciba-Corning 634型钙pH分析器测定)小于1.2mM/L,就使用此大鼠进行实验。给每只大鼠装上留置的静脉和动脉导管,以分别递送测试物质和采集血液样本。然后给大鼠喂养不含钙的食物和去离子水。测定基准钙水平,通过用外置注射泵经由静脉导管进行连续静脉内输注,把对照载体或人甲状旁腺激素1-34肽(hPTH1-34,剂量是1.25ug/kg/h,在盐水/0.1%牛血清白蛋白中,Bachem,Ca)或hPTH1-34和测试物质的混合物对每只大鼠给药。在6-8小时的输注期间内,每隔2小时测定一次大鼠的钙血症反应。人破骨细胞吸收和粘着测试
已经建立了窝凹吸收和粘着测试,并且用衍生自破骨细胞瘤组织的正常人破骨细胞进行标准化。测试1是通过用激光共聚焦显微镜进行检查来测定破骨细胞窝凹体积。测试2是其中通过竞争性ELISA来测定胶原碎片(在吸收期间释放的)的高通量筛选检测。测试1(用激光共聚焦显微镜进行检查)·将等分试样的衍生自人破骨细胞瘤的细胞悬浮液从液氮罐中取出,在37℃迅速温热,用RPMI-1640培养基通过离心(1000rpm,在4℃离心5分钟)洗涤1次。·将培养基抽吸出,代替以鼠抗-HLA-DR抗体,然后用RPMI-1640培养基按1∶3的比例稀释。将悬浮液在冰上培养30分钟并频频混合。·将细胞用冷的RPMI-1640洗涤2次,然后离心(1000rpm,在4℃离心5分钟),之后把细胞转移到15ml无菌离心管中。在改进的Neubauer计数室中计数单核细胞的数目。·将包着山羊抗-鼠IgG(Dynal,Great Neck,NY)的足量磁性珠子(5/单核细胞)从其储备瓶中取出,置于5ml新鲜的培养基中(洗去有毒的叠氮化物防腐剂)。通过将磁性珠子固定在磁体上来除去培养基,用新鲜的培养基替换。·把磁性珠子与细胞混合,将所得悬浮液在冰上培养30分钟。将该悬浮液频频混合。·把包有磁性珠子的细胞固定在磁体上,将剩余细胞(富含破骨细胞的碎片)倒入50ml无菌离心管中。·将新鲜培养基加到包有磁性珠子的细胞中,以逐出任一俘获的破骨细胞。把该洗涤过程重复10次。弃去包有磁性珠子的细胞。·用荧光素二乙酸酯标记活细胞,在计数室中计数存活的破骨细胞。使用大口径一次性塑料巴斯德氏吸量管将样本加到计数室中。·通过离心将破骨细胞沉积,用补充有10%胎牛血清和1.7g/升碳酸氢钠的EMEM培养基将密度调节至适当数值(不同肿瘤中破骨细胞的数目是不同的)。·将3ml等分试样的该细胞悬浮液(每次化合物处理)倒入15ml离心管中。通过离心将细胞沉积。·每个管中加入3ml适当的化合物处理的样本(用EMEM培养基稀释至50μM)。还包括合适的载体对照,阳性对照(稀释至100μg/ml的抗-玻连蛋白受体鼠单克隆抗体[87MEM1])和同种型对照(稀释至100μg/ml的IgG2α)。将样本在37℃培养30分钟。·在48-孔培养皿中,将0.5ml等分试样的细胞接种到无菌牙质切片上,在37℃培养2小时。每一处理都以一式四份进行筛选检测。·将切片用温热的PBS洗涤6次(在6-孔培养皿中,10ml/孔),然后置于含有化合物处理或对照样本的新鲜培养基中。将样本在37℃培养48小时。酒石酸盐抗酸性磷酸酶(TRAP)操作(破骨细胞系细胞的选择性染色剂)·将含有粘着的破骨细胞的骨切片在磷酸盐缓冲盐水中洗涤,并在2%戊二醛(在0.2M二甲胂酸钠中)中固定5分钟。·然后将切片在水中洗涤,并在TRAP缓冲液中于37℃培养4分钟(溶于N,N-二甲基甲酰胺的0.5mg/ml萘酚AS-BI磷酸盐,并与含有10mM酒石酸钠的0.25M柠檬酸盐缓冲液(pH4.5)混合)。·将切片在冷水中洗涤,然后将其浸泡在含有1mg/ml坚牢红石榴石的冷的乙酸盐缓冲液(0.1M,pH6.2)中,在4℃培养4分钟。·抽吸出过量的缓冲液,在水中洗涤后,将切片在空气中干燥。·通过亮视野显微镜计数TRAP阳性破骨细胞(砖红色/紫色沉淀)的数量,然后通过超声处理将其从牙质表面上除去。·用Nikon/Lasertec ILM21W共聚焦显微镜测定窝凹的体积。测试2(用ELISA读数仪)
按照测试1前9步所述操作,富集并制备人破骨细胞以进行化合物筛选。为了清楚起见,下面再重复描述这些步骤。·将等分试样的衍生自人破骨细胞瘤的细胞悬浮液从液氮罐中取出,在37℃迅速温热,用RPMI-1640培养基通过离心(1000rpm,在4℃离心5分钟)洗涤1次。·将培养基抽吸出,代替以鼠抗-HLA-DR抗体,然后用RPMI-1640培养基按1∶3的比例稀释。将悬浮液在冰上培养30分钟并频频混合。·将细胞用冷的RPMI-1640洗涤2次,然后离心(1000rpm,在4℃离心5分钟),之后把细胞转移到15ml无菌离心管中。在改进的Neubauer计数室中计数单核细胞的数目。·将包被有山羊抗-鼠IgG(Dynal,Great Neck,NY)的足量磁性珠子(5/单核细胞)从其储备瓶中取出,置于5ml新鲜的培养基中(洗去有毒的叠氮化物防腐剂)。通过将磁性珠子固定在磁体上来除去培养基,用新鲜的培养基替换。·把磁性珠子与细胞混合,将所得悬浮液在冰上培养30分钟。将该悬浮液频频混合。·把包有磁性珠子的细胞固定在磁体上,将剩余细胞(富含破骨细胞的碎片)倒入50ml无菌离心管中。·将新鲜培养基加到包有磁性珠子的细胞中,以逐出任一俘获的破骨细胞。把该洗涤过程重复10次。弃去包有磁性珠子的细胞。·用荧光素二乙酸酯标记活细胞,在计数室中计数存活的破骨细胞。使用大口径一次性塑料巴斯德氏吸量管将样本加到计数室中。·通过离心将破骨细胞沉积,用补充有10%胎牛血清和1.7g/升碳酸氢钠的EMEM培养基将密度调节至适当数值(不同肿瘤中破骨细胞的数目是不同的)。
与上面测试1中所描述的方法不同,化合物是如下所述以4剂量进行筛选检测以获得IC50的:·用测试化合物(4剂量)或对照物将破骨细胞制备物在37℃预培养30分钟。·在48-孔组织培养皿中,将该破骨细胞制备物接种到牛皮质骨切片上,在37℃再培养2小时。·将骨切片在温热的磷酸盐缓冲盐水(PBS)中洗涤6次,以除去非粘着细胞,然后再置于含有新鲜化合物或对照物的48-孔培养皿的孔中。·然后将该组织培养皿在37℃培养48小时。·将每一孔中的上层清液抽吸到各个单独的管中,在探测吸收期间释放的I型胶原c-端肽的竞争性ELISA中筛选测定。使用的是市售的ELISA(Osteometer,Denmark),其中含有能与存在于I型胶原α1链羧基-末端肽上的8-氨基酸序列(Glu-Lys-Ala-His-Asp-Gly-Gly-Arg)发生特异性反应的兔抗体。结果以与载体对照相比,吸收被抑制的%表示。人破骨细胞粘着测试
按照测试1前9步所述操作,富集并制备人破骨细胞以进行化合物筛选。为了清楚起见,下面再重复描述这些步骤。·将等分试样的衍生自人破骨细胞瘤的细胞悬浮液从液氮存储器中取出,在37℃迅速温热,用RPMI-1640培养基通过离心(1000rpm,在4℃离心5分钟)洗涤1次。·将培养基抽吸出,代替以鼠抗-HLA-DR抗体,然后用RPMI-1640培养基按1∶3的比例稀释。将悬浮液在冰上培养30分钟并频频混合。·将细胞用冷的RPMI-1640洗涤2次,然后离心(1000rpm,在4℃离心5分钟),之后把细胞转移到15ml无菌离心管中。在改进的Neubauer计数室中计数单核细胞的数目。·将包着山羊抗-鼠IgG(Dynal,Great Neck,NY)的足量磁性珠子(5/单核细胞)从其储备瓶中取出,置于5ml新鲜的培养基中(洗去有毒的叠氮化物防腐剂)。通过将磁性珠子固定在磁体上来除去培养基,用新鲜的培养基替换。·把磁性珠子与细胞混合,将所得悬浮液在冰上培养30分钟。将该悬浮液频频混合。·把包有磁性珠子的细胞固定在磁体上,将剩余细胞(富含破骨细胞的碎片)倒入50ml无菌离心管中。·将新鲜培养基加到包有磁性珠子的细胞中,以逐出任一俘获的破骨细胞。把该洗涤过程重复10次。弃去包有磁性珠子的细胞。·用荧光素二乙酸酯标记活细胞,在计数室中计数存活的破骨细胞。使用大口径一次性塑料巴斯德氏吸量管将样本加到计数室中。·通过离心将破骨细胞沉积,用补充有10%胎牛血清和1.7g/升碳酸氢钠的EMEM培养基将密度调节至适当数值(不同肿瘤中破骨细胞的数目是不同的)。·把衍生自破骨细胞瘤的破骨细胞与化合物(4剂量)或对照物在37℃预培养30分钟。·然后将细胞接种到包有骨桥蛋白的载玻片(人或大鼠骨桥蛋白,2.5μg/ml)上,并在37℃培养2小时。·通过在磷酸盐缓冲盐水中把载玻片剧烈洗涤来除去非粘着的细胞,将载玻片上剩余的细胞在丙酮中固定。·把破骨细胞用该表型细胞的选择性标记物酒石酸盐抗酸性磷酸酶(TRAP)染色(见步骤15-17),并通过光学显微镜计数。结果以与载体对照相比,粘着被抑制的%表示。细胞粘着测试细胞和细胞培养
人胚肾细胞(HEK293细胞)得自ATCC(Catalog No.CRL 1573)。将细胞在含有Earl’s盐、10%胎牛血清、1%谷氨酰胺和1%青霉素-链霉素的Earl’s极限必需培养基(EMEM)中培养。构建和转染
通过平端连接,将αV亚单位的3.2kb EcoRI-KpnI片段和β3亚单位的2.4kb XbaI-XhoI片段插入到含有CMV启动子和G418选择性标记物的pCDN载体(Aiyar等,1994)的EcoRI-EcoRV克隆位点。为了稳定地表达,使用基因脉冲发生器(Hensley等人,1994),用αV+β3构建物(200μg DNA/亚单位)将80×106个HEK293细胞电转化,并铺在100mm平板上(5×105个细胞/平板)。48小时后,给该生长培养基补充450μg/ml遗传霉素(Geneticin)(G418 Sulfate,GIBCO-BRL,Bethesda,MD)。将细胞保持在选择性培养基中,直到菌落大到足以进行测试为止。转染细胞的免疫细胞化学分析
为了确定该HEK293转染子是否表达了玻连蛋白受体,通过离心、于室温下在丙酮中固定2分钟、并在空气中干燥,将细胞固定在显微镜玻璃载玻片上。采用标准间接免疫荧光法,证实了与23C6—对该αVβ3复合物有特异性的一种单克隆抗体之间的特异反应性。细胞粘着实验
用0.1ml人玻连蛋白(在RPMI培养基中,浓度是0.2μg/ml)将Corning 96-孔ELISA培养皿在4℃预涂布。在实验开始时,用RPMI培养基将培养皿洗涤1次,并用在RPMI培养基中的3.5%BSA在室温阻断1小时。将转染的293细胞以0.5×106个细胞/ml的密度重悬在补充有20mM Hepes、pH7.4和0.1%BSA的RPMI培养基中。每一孔中加入0.1ml细胞悬浮液,并在各种αVβ3拮抗剂存在或不存在下于37℃培养1小时。培养后,加入0.025mL pH为7.4的10%甲醛溶液,将细胞在室温固定10分钟。用0.2ml RPMI培养基将培养皿洗涤3次,用0.1ml 0.5%甲苯胺蓝将粘着细胞在室温染色20分钟。用去离子水充分洗涤以除去过量的染色剂。加入0.1ml含有50mM HCl的50%乙醇,以将掺入到细胞内的甲苯胺蓝洗脱去。用微量滴定板读数器(Titertek Multiskan MC,Sterling,VA)在600nm处的光密度定量测定细胞粘着。固相αVβ5结合测定:
从人胎盘中纯化出玻连蛋白受体αVβ5。用50mM Tris-HCl(pH7.5)、100mM NaCl、1mM CaCl2、1mM MnCl2、1mM MgCl2(缓冲液A)将受体制备物稀释,并立即以0.1ml/孔的量加到96-孔ELISA培养皿中。每孔中加入0.1-0.2μgαVβ3。将培养皿在4℃培养过夜。在实验开始时,用缓冲液A将各孔洗涤1次,并用在相同缓冲液中的3.5%牛血清白蛋白于室温下培养1小时。培养后,把各孔彻底抽吸,并用0.2ml缓冲液A洗涤2次。
在[3H]-SK&F-107260竞争性分析中,将不同浓度的未标记拮抗剂(0.001-100μM)加到各孔中,然后加入5.0nM的[3H]-SK&F-107260。将培养皿在室温培养1小时。培养后,将孔彻底抽吸,并用0.2ml冰冷的缓冲液A以逐孔的方式洗涤1次。用0.1ml 1%SDS将受体溶解,通过液体闪烁计数来确定与[3H]-SK&F-107260的结合,其中在Beckman LS 6800液体闪烁计数器中加入3ml Ready Safe,并且测定效率是40%。在2μM[3H]-SK&F-107260存在下测定[3H]-SK&F-107260的非特异性结合,其始终小于总放射配体输入量的1%。通过由LUNDON-2程序修正的非线性、最小二乘方曲线拟合程序确定IC50(将[3H]-SK&F-107260的结合抑制50%时拮抗剂的浓度)。依据Cheng和Prusoff公式计算Ki(拮抗剂的解离常数):Ki=IC50/(1+L/Kd),其中L和Kd分别是[3H]-SK&F-107260的浓度和解离常数。
抑制RGD-介导的GPIIb-IIIa结合纯化GPIIb-IIIa
通过在3%辛基葡糖苷、20mM Tris-HCl(pH 7.4)、140mM NaCl、2mM CaCl2中于4℃搅拌2小时,将10单位过时的、洗涤过的人血小板(得自Red Cross)溶解。将该溶解物于100000g离心1小时。把所得上清液加到用20mM Tris-HCl(pH7.4)、100mM NaCl、2mMCaCl2、1%辛基葡糖苷(缓冲液A)预平衡的5mL兵豆凝集素琼脂糖4B柱(E.Y.Labs)上。培养2小时后,用50ml冷的缓冲液A洗涤该柱。用含有10%葡萄糖的缓冲液A洗脱保留在凝集素上的GPIIb-IIIa。所有操作都是在4℃进行的。通过SDS聚丙烯酰胺凝胶电泳证实,所得GPIIb-IIIa的纯度大于95%。将GPIIb-IIIa掺入到脂质体中
在氮气流下,将磷脂酰丝氨酸(70%)和磷脂酰胆碱(30%)的混合物(Avanti Polar Lipid)干燥到玻璃管壁上。把纯化的GPIIb-IIIa稀释至终浓度为0.5mg/ml,并与磷脂以蛋白∶磷脂为1∶3(重量比)的比例混合。把所得混合物重悬,并在水浴超声发生器中超声处理5分钟。然后用12000-14000分子量截断透析装置在过量1000倍的50mM Tris-HCl、pH7.4、100mM NaCl、2mM CaCl2中将混合物透析过夜(换2次液)。将含有GPIIb-IIIa的脂质体以12000g离心15分钟,并以约1mg/ml的蛋白终浓度重悬在透析缓冲液中。将脂质体储存在-70℃以备用。GPIIb-IIIa的竞争性结合
用[3H]-SK&F-107260作为RGD-型配体,通过间接竞争性结合方法测定与玻连蛋白受体(GPIIb-IIIa)的结合。该结合测定是用0.22μm亲水性durapore膜在96-孔过滤板装置(Millipore Corporation,Bedford,MA)中进行的。用0.2ml 10μg/ml的聚赖氨酸(SigmaChemical Co.,St.Louis,MO.)在室温下将孔预涂布1小时,以阻断非特异性结合。将不同浓度未标记的苯并氮杂加到孔中,每一浓度都是一式四份。将[3H]-SK&F-107260以4.5nM的终浓度加到各个孔中,然后加入1μg含有纯化的人血小板GPIIb-IIIa的脂质体。将混合物在室温培养1小时。用微孔多功能过滤器通过过滤将结合了GPIIb-IIIa的[3H]-SK&F-107260与未结合的部分分离开,然后用冰冷的缓冲液洗涤(洗涤2次,每次用0.2ml)。在1.5ml Ready Solve(Beckman Instrument,Fullerton,CA)中,在Beckman液体闪烁计数器上以40%的效率计数保留在滤器上的结合了GPIIb-IIIa的放射性活度。在2μM未标记的[3H]-SK&F-107260存在下测定非特异性结合,其始终小于加入到样本中总放射活度的0.14%。所有数据都是一式四份测定的平均值。
通过非线性最小二乘方曲线拟合程序来分析竞争性结合数据。该方法提供了拮抗剂的IC50(在平衡时将[3H]-SK&F-107260的特异性结合抑制50%时拮抗剂的浓度)。此IC50与基于Cheng和Prusoff公式的拮抗剂的平衡解离常数(Ki)有关:Ki=IC50/(1+L/Kd),其中L是在该竞争性结合测试中使用的[3H]-SK&F-107260的浓度(4.5nM),Kd是[3H]-SK&F-107260的解离常数,它是在4.5nM浓度下通过Scatchard分析确定的。
本发明化合物对玻连蛋白受体的亲合力比对血纤蛋白原受体要大10倍以上。本发明化合物的活性比例大于100∶1。
用几种可移植鼠肿瘤模型可确定单独或与抗肿瘤剂联合使用的式(I)化合物的效力。参见美国专利5004758和5633016对这些模型的详细描述。
下述实施例不是为了限制本发明的范围,而是为了举例说明怎样制备和使用本发明化合物。对于本领域技术人员来说,其它很多实施方案也是显而易见的。
实施例
通述
1H核磁共振(NMR)光谱是在250或400MHz记录的。化学位移是以四甲基硅烷(TMS)为内标、以ppm(δ)为单位记录的。NMR数据的缩写如下:s=单峰,d=双峰,t=三重峰,q=四重峰,m=多重峰,dd=两个双峰,dt=两个三重峰,app=尖峰,br=宽峰。J表示以赫兹(Hertz)计量的NMR偶合常数。CDCl3是氘代氯仿,DMSO-d6是六氘代二甲亚砜,CD3OD是四氘甲醇。红外(IR)光谱是以传输方式记录的,并且谱带位置是以波长的倒数(cm-1)为单位记录的。质谱是用电喷雾(ES)电离技术获得的。元素分析是通过QuantitativeTechnologies Inc.,Whitehouse NJ进行的。熔点是在Thomas-Hoover熔点测定仪上测定的,并且未校正。所有温度单位都是摄氏度。薄层色谱使用的是Analtech Silica Gel GF和E.Merck SilicaGel 60 F-254薄层板。快速和重力色谱都是用E.Merck Kieselgel60(230-400目)硅胶进行的。分析和制备HPLC是在Rainin或Beckman色谱仪上进行的。ODS是指十八烷基甲硅烷基衍生硅胶色谱载体。5μ-Apex-ODS指由Jones Chromatography,Littleton,Colorado生产的、标称粒径为5μ的十八烷基甲硅烷基衍生硅胶色谱载体。YMC ODS-AQ是ODS色谱载体,并且是YMC Co.Ltd.,Kyoto,Japan的注册商标。PRP-1是聚(苯乙烯-二乙烯基苯)色谱载体,并且是Hamilton Co.,Reno,Nevada的注册商标。Celite是由酸洗硅藻二氧化硅构成的助滤剂,并且是Manville Corp.,Denver,Colorado的注册商标。
实施例1制备(S)-3-氧代-8-[3-(吡啶-2-基氨基)-1-丙氧基]-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸
制备1制备(±)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯a)4-溴-3-溴甲基茴香醚
将2-溴-5-甲氧基甲苯(20g,0.10mol)、N-溴琥珀酰亚胺(19.6g,0.11mol)、过氧化苯甲酰(1g,4mmol)、和二氯甲烷(200ml)的混合物用泛光灯照射18小时以引起轻微回流。然后将混合物冷却至-10℃并维持几小时,将溶液倒出以与沉淀的琥珀酰亚胺分开。把溶液浓缩,用氯仿/己烷将残余物结晶,获得了本标题化合物(19.7g,70%),为浅黄色棱晶:
1HNMR(CDCl3)δ7.45(d,J=8.9Hz,1H),6.99(d,J=3Hz,1H),6.74(dd,J=8.9,3Hz,1H),4.55(s,2H)3.80(s,3H).b)3-二(叔丁氧基羰基)氨基甲基-4-溴茴香醚
将4-溴-3-溴甲基茴香醚(24g,86mmol)和亚氨基二甲酸二叔丁酯钾(24g,94mmol)在二甲基甲酰胺(200ml)中的混合物在氩气下于室温搅拌18小时。然后将反应混合物真空浓缩,把残余物在乙酸乙酯和水之间分配。把有机相用水和盐水洗涤,干燥(MgSO4),并浓缩。用己烷将残余物重结晶,获得了本标题化合物(15g,42%),为白色固体:
1HNMR(CDCl3)δ7.40(d,J=8.6Hz,1H)),6.68(m,2H),4.81(s,2H),3.74(s,3H),1.44(s,18H).c)(±)-3-甲酯基-4-[2-二(叔丁氧基羰基)氨基甲基-4-甲氧基苯基]-3-丁烯酸甲酯
将3-二(叔丁氧基羰基)氨基甲基-4-溴茴香醚(15g,36mmol)、衣康酸二甲酯(7.5g,47mmol)、三邻甲苯基膦(1g,3mmol)、乙酸钯(0.4g,2mmol)、二异丙基乙胺(12.8ml,72mmol)、和丙腈(150ml)置于500ml烧瓶中。把混合物用氩气净化(排空数次/氩气流循环),然后在氩气下加热回流1小时。将反应混合物冷却至室温,然后倒入冰冷的乙醚(500ml)中。过滤除去生成的沉淀,将滤液浓缩。通过硅胶色谱(洗脱液是在己烷中的10%-20%乙酸乙酯)纯化残余物,获得了本标题化合物(11.8g,66%),为浅黄色油状物:
1H NMR(CDCl3)δ7.94(s,1H),7.15(d,J=8.1Hz,1H)),6.77(d,J=8.1Hz,1H),6.76(s,1H),4.73(s,2H),3.81(s,3H),3.79(s,3H),3.71(s,3H),3.38(s,2H),1.45(s,18H).d)(±)-3-甲酯基-4-[2-二(叔丁氧基羰基)氨基甲基-4-甲氧基苯基]丁酸甲酯
将装有(±)-3-甲酯基-4-[2-二(叔丁氧基羰基)氨基甲基-4-甲氧基苯基]-3-丁烯酸甲酯(11.8g)、乙酸乙酯(120ml)、和10%披钯木炭(1g)的压力容器在45psi氢气下振摇18小时。然后将混合物过滤,把滤液浓缩,得到了本标题化合物(12g,100%),为无色油状物:
1H NMR(CDCl3)δ7.00(d,J=8.2Hz,1H),6.71(m,2H),4.81(s,2H),3.75(s,3H),3.66(s,3H),3.63(s,3H),3.05(m,2H),2.73(m,2H),2.42(dd,J=16.0,4.8Hz,1H),1.44(s,18H).e)(±)-3-甲酯基-4-[2-氨基甲基-4-甲氧基苯基]丁酸甲酯
将(±)-3-甲酯基-4-[2-二(叔丁氧基羰基)氨基甲基-4-甲氧基苯基]丁酸甲酯(12g)在氯仿(100ml)和三氟乙酸(50ml)中的溶液在氩气下于室温搅拌4小时。然后将溶液真空浓缩,获得了本标题化合物(10g,100%),为粘稠的油状物:MS(ES)m/e 296.2(M+H)+。f)(±)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
将(±)-3-甲酯基-4-[2-氨基甲基-4-甲氧基苯基]丁酸甲酯(10g,24mmol)和三乙胺(17ml,120mmol)在甲苯(100ml)中的溶液加热回流18小时。然后将反应混合物浓缩,把残余物在乙酸乙酯和水之间分配。用乙酸乙酯把水层萃取两次,合并有机萃取液,用盐水洗涤,干燥(MgSO4),浓缩,获得了本标题化合物(4.8g,76%),为浅黄褐色固体:MS(ES)m/e 264.2(M+H)+。g)(±)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
在0℃、氢气下,将无水氯化铝(7.6g,57mmol)分批加到(±)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(3.0g,11mmol)和乙硫醇(4.2ml,57mmol)在二氯甲烷(100ml)中的搅拌着的溶液中。把所得混合物升至室温,搅拌过夜,然后浓缩。把残余物用冰水研制,通过过滤收集所得固体,干燥,获得了本标题化合物(2.64g,91%),为米色固体:MS(ES)m/e 250.2(M+H)+。
制备2通过HPLC分离(±)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的对映体a)(R)-(+)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯和(S)-(-)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
通过采用下述条件的手性HPLC,将(±)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯拆分成其对映体:Diacel Chiralpak AS柱(21.2×250mm),流动相为乙醇,流速为7ml/分钟,在254nm进行UV检测,进样量为70mg;(R)-(+)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的tR=21.5分钟;(S)-(-)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的tR=39.1分钟。
制备3通过HPLC分离(±)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的对映体a)(R)-(+)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯和(S)-(-)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
通过采用下述条件的手性HPLC,将(±)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯拆分成其对映体:Diacel Chiralpak AS柱(21.2×250mm),流动相为CH3CN,流速为15ml/分钟,在254nm进行UV检测,进样量为500mg;(R)-(+)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的tR=10.2分钟;(S)-(-)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯的tR=19.0分钟。
制备4将(S)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯脱甲基a)(S)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
在-8℃、氩气下,用30分钟将(S)-8-甲氧基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(15.0g,0.057mol)的CHCl3(160ml)溶液滴加到三溴化硼(20.53ml,0.217mol)的CHCl3(160ml)溶液中,同时将温度维持在-5℃-0℃。将反应混合物在约-8℃搅拌30分钟,然后加入甲醇(200ml),其中在开始时甲醇是滴加,并且将温度维持在约0℃。将反应混合物浓缩以得到粘稠油状物,用甲醇(100ml)将所得油状物再次浓缩。把所得油状物溶于H2O/MeOH,通过过滤除去少量的黑色固体。用50%的氢氧化钠将滤液中和(至pH7),沉淀出白色固体。加入少量乙酸将该悬浮液的pH调节至4.5,收集固体并真空干燥,获得了本标题化合物(9.7g,68%)。通过HPLC检测产物的手性纯度:Chiralpak AS柱(4.6×50mm),流动相为100%乙醇,流速为0.5ml/分钟,在215nm进行UV检测;tR=7.5分钟(S-对映体,99%);tR=4.4分钟(R-对映体,1%)。
制备5制备2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物a)2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物
将2-氯吡啶-N-氧化物(16.6g,0.1mol)、3-氨基-1-丙醇(15.3ml,0.2mol)、NaHCO3(42g,0.5mol)、和叔戊醇(100ml)的混合物加热至回流。21小时后,将反应混合物冷却,用CH2Cl2(300ml)稀释,抽滤以除去不溶性物质。将滤液浓缩,用甲苯再浓缩,获得了黄色油状物。通过硅胶色谱纯化(20%MeOH/CHCl3),获得了本标题化合物(15.62g,93%),为黄色固体:
TLC(20%MeOH/CHCl3)Rf0.48;1H NMR(250,CDCl3)δ8.07(dd,J=6.6,1.2Hz,1H),7.34(brt,1H),7.10-7.30(m,1H),6.64(dd,J=8.5,1.4Hz,1H),6.40-6.60(m,1H),4.49(brs,1H),3.65-3.90(m,2H),3.35-3.60(m,2H),1.75-2.00(m,2H);MS(ES)m/e 169(M+H)+.b)2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物
用二碳酸二叔丁酯(11.4g,55.3mmol)处理2-[(3-羟基-1-丙基)氨基]吡啶-N-氧化物(8.0g,47.6mmol)的叔丁醇(80ml)溶液。18小时后,将溶液浓缩,用己烷将残余物研制。把所得固体真空干燥,获得了本标题化合物(12.5g,98%),为米色固体:MS(ES)m/e 269.3(M+H)+。
制备6制备(S)-3-氧代-8-[3-(吡啶-2-氨基)-1-丙氧基]-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸a)(S)-8-[3-[N-(1-氧代吡啶-2-基)-N-(叔丁氧基羰基)氨基]-1-丙氧基]-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
在室温,用10分钟将2-[N-(3-羟基-1-丙基)-N-(叔丁氧基羰基)氨基]吡啶-N-氧化物(1.8g,6.84mmol)和偶氮二甲酸二乙酯(1.19g,6.84mmol)的无水DMF(22.5ml)溶液滴加到(S)-8-羟基-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(0.65g,2.75mmol)和三苯基膦(1.94g,7.4mmol)的无水DMF(13.5ml)溶液中。16小时后,将该溶液蒸发成棕色油状物,把该油状物在乙酸乙酯(500ml)和水(100ml)之间分配。将有机层依次用水(2×100ml)和盐水(100ml)洗涤,干燥(Na2SO4),并浓缩,获得了浅棕色油状物。通过硅胶色谱纯化(5%MeOH/CH2Cl2),获得了本标题化合物(0.85g,60%)。MS(ES)m/e 500.3(M+H)+。b)(S)-8-[3-[N-(1-氧代吡啶-2-基)-N-(叔丁氧基羰基)氨基]-1-丙氧基]-2-(2,3,4-三氟苄基)-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
在-15℃、氩气下,将1.0M的二(三甲基甲硅烷基)氨基化锂(1.0ml,1.0mmol)溶液滴加到(S)-8-[3-[N-(1-氧代吡啶-2-基)-N-(叔丁氧基羰基)氨基]-1-丙氧基]-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(0.470g,0.94mmol)的无水DMF(10.0ml)溶液中。10分钟后,滴加2,3,4-三氟苄基溴(0.22g,0.96mmol)的无水THF(5.0ml)溶液。用2小时将该溶液升至室温。18小时后,把该溶液蒸发,将残余物在乙酸乙酯(200ml)和水(30ml)之间分配。将有机层依次用水(2×25ml)和盐水(30ml)洗涤,干燥(Na2SO4),并浓缩,获得了浅黄色固体。通过硅胶色谱纯化(5%MeOH/CH2Cl2),获得了本标题化合物(0.45g,75%)。MS(ES)m/e644.1(M+H)+。c)(S)-8-[3-[N-(1-氧代吡啶-2-基)氨基]-1-丙氧基]-2-(2,3,4-三氟苄基)-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
将(S)-8-[3-[N-(1-氧代吡啶-2-基)-N-(叔丁氧基羰基)氨基]-1-丙氧基]-2-(2,3,4-三氟苄基)-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(0.39g,0.61mmol)溶于4.0M的氯化氢在1,4-二氧杂环己烷中的溶液(20ml),将反应在室温保持16小时。除去溶剂,将得到的油状物用乙醚研制,油状物固化了。把该固化物溶于二氯甲烷(80ml),用饱和碳酸氢钠溶液(10ml)洗涤。将有机层干燥(Na2SO4),浓缩,获得了本标题化合物(0.33g,98%)。MS(ES)m/e 544.1(M+H)+。d)(S)-3-氧代-8-[3-(吡啶-2-氨基)-1-丙氧基]-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯
将含有10%Pd/C(0.270g)的(S)-8-[3-[N-(1-氧代吡啶-2-基)氨基]-1-丙氧基]-2-(2,3,4-三氟苄基)-3-氧代-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(0.28g,0.52mmol)和环己烯(0.28g,3.35mmol)的甲醇(15ml)溶液加热回流16小时,冷却,通过Celite过滤。将滤液浓缩,获得了本标题化合物(0.27g,99%)。MS(ES)m/e 528.1(M+H)+。e)(S)-3-氧代-8-[3-(吡啶-2-氨基)-1-丙氧基]-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸
将(S)-3-氧代-8-[3-(吡啶-2-氨基)-1-丙氧基]-2-(2,3,4-三氟苄基)-2,3,4,5-四氢-1H-2-苯并氮杂-4-乙酸甲酯(0.27g,0.52mmol)在甲醇(15ml)和0.5N氢氧化钠水溶液(3.0ml)的混合物中的溶液在50℃加热。2小时后,将该反应混合物冷却至室温,用TFA(0.50ml)处理,浓缩,获得了浅黄色固体。通过半制备HPLC纯化(YMC ODS-AQ,10um,120A,50mm×250mm,含有0.1%TFA的40%CH3CN/H2O),获得了本标题化合物(0.210g,67%)。MS(ES)m/e 514.4(M+H)+。元素分析,C27H26F3N3O4.1.3 CF3CO2H:计算值:C,53.73;H,4.16;N,6.35。实测值:C,53.64;H,4.11;N,6.14。
实施例2非胃肠道给药组合物剂量单位
按下述步骤制备作为无菌干燥粉末的、含有20mg实施例1化合物的制剂:将20mg该化合物溶于15ml蒸馏水中。在无菌条件下将该溶液过滤到25ml多剂量安瓿中并冷冻干燥。加入20ml 5%的葡萄糖水溶液(D5W)将该粉末重新配制成静脉内和肌内注射液。由此就能通过注射体积来确定剂量。之后可通过量取一定体积的该剂量单位加到另外体积的D5W中来进一步稀释以注射,或者量取一定体积的该剂量单位加到其它给药装置中,例如加到IV滴注输液瓶或袋或其它注射-输注系统中。
实施例3口服组合物剂量单位
按下述步骤制备口服给药胶囊:将50mg实施例1化合物与75mg乳糖和5mg硬脂酸镁混合并研磨。把所得粉末过筛并装入硬明胶胶囊中。
实施例4口服组合物剂量单位
按下述步骤制备口服给药片剂:将20mg蔗糖、150mg硫酸钙二水合物和50mg实施例1化合物与10%明胶溶液混合并制粒。将湿颗粒过筛,干燥,与10mg淀粉、5mg滑石粉和3mg硬脂酸混合;压制成片。
上述描述完全公开了如何制备和使用本发明。然而,本发明并不限于上述特定实施方案,而是包括在后面权利要求范围内的所有变型。本发明所引用的各参考杂志、专利和其它出版物包括了本领域的状况,本发明将其全文引入以作参考。
Claims (29)
2.药物组合物,包含权利要求1所述的化合物和可药用载体。
3.药物组合物,包含权利要求1所述的化合物、抗肿瘤剂和可药用载体。
4.权利要求3的药物组合物,其中所述抗肿瘤剂是托泊替堪。
5.权利要求3的药物组合物,其中所述抗肿瘤剂是顺铂。
6.治疗是αVβ3受体拮抗剂的适应症的疾病的方法,包括将如权利要求1所述的化合物对需要治疗的患者给药。
7.治疗是αVβ5受体拮抗剂的适应症的疾病的方法,包括将如权利要求1所述的化合物对需要治疗的患者给药。
8.治疗骨质疏松的方法,包括将如权利要求1所述的化合物对需要治疗的个体给药。
9.抑制血管生成的方法,包括将如权利要求1所述的化合物对需要治疗的个体给药。
10.抑制肿瘤生长或肿瘤转移的方法,包括将如权利要求1所述的化合物对需要治疗的患者给药。
11.治疗动脉粥样硬化或再狭窄的方法,包括将如权利要求1所述的化合物对需要治疗的患者给药。
12.治疗炎症的方法,包括将如权利要求1所述的化合物对需要治疗的患者给药。
13.抑制肿瘤生长的方法,包括将如权利要求1所述的化合物和抗肿瘤剂依次给药或一起同时给药。
14.权利要求13的方法,其中所述抗肿瘤剂是托泊替堪。
15.权利要求13的方法,其中所述抗肿瘤剂是顺铂。
17.式(III)化合物或其可药用盐:
18.权利要求1的化合物用作药物。
19.权利要求1的化合物在制备用于治疗是αVβ3受体拮抗剂的适应症的疾病的药物中的应用。
20.权利要求1的化合物在制备用于治疗是αVβ5受体拮抗剂的适应症的疾病的药物中的应用。
21.权利要求1的化合物在制备用于治疗骨质疏松的药物中的应用。
22.权利要求1的化合物在制备用于抑制血管生成的药物中的应用。
23.权利要求1的化合物在制备用于抑制肿瘤生长或肿瘤转移的药物中的应用。
24.权利要求1的化合物在制备用于治疗动脉粥样硬化或再狭窄的药物中的应用。
25.权利要求1的化合物在制备用于治疗炎症的药物中的应用。
26.权利要求1的化合物和抗肿瘤剂在制备用于一起同时给药或依次给药来抑制肿瘤生长的药物中的应用。
27.权利要求26的应用,其中所述抗肿瘤剂是托泊替堪。
28.权利要求26的应用,其中所述抗肿瘤剂是顺铂。
29.权利要求1的化合物和骨吸收抑制剂在制备用于一起同时给药或依次给药来治疗骨质疏松的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US5986797P | 1997-09-24 | 1997-09-24 | |
US60/059,867 | 1997-09-24 |
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CN1271284A true CN1271284A (zh) | 2000-10-25 |
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CN98809494A Pending CN1271284A (zh) | 1997-09-24 | 1998-09-24 | 玻连蛋白受体拮抗剂 |
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EP (1) | EP1023073A1 (zh) |
JP (1) | JP2002500162A (zh) |
KR (1) | KR20010024249A (zh) |
CN (1) | CN1271284A (zh) |
AU (1) | AU9578798A (zh) |
BR (1) | BR9813214A (zh) |
CA (1) | CA2304000A1 (zh) |
HU (1) | HUP0003931A2 (zh) |
IL (1) | IL135188A0 (zh) |
NO (1) | NO20001515D0 (zh) |
PL (1) | PL339414A1 (zh) |
TR (1) | TR200000786T2 (zh) |
WO (1) | WO1999015178A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101861319B (zh) * | 2007-11-16 | 2013-12-11 | 宇部兴产株式会社 | 苯并氮杂*酮化合物 |
Families Citing this family (17)
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WO2000046215A1 (en) | 1999-02-03 | 2000-08-10 | Merck & Co., Inc. | Benzazepine derivatives as alpha-v integrin receptor antagonists |
US6514964B1 (en) | 1999-09-27 | 2003-02-04 | Amgen Inc. | Fused cycloheptane and fused azacycloheptane compounds and their methods of use |
CN1247258C (zh) | 2001-04-24 | 2006-03-29 | 默克专利有限公司 | 使用抗血管生成剂和TNFα的联合疗法 |
CN100560131C (zh) | 2001-10-22 | 2009-11-18 | 斯克里普斯研究学院 | 抗体靶向化合物 |
JP2006522139A (ja) | 2003-04-04 | 2006-09-28 | スミスクライン・ビーチャム・コーポレイション | ベンズアゼピンの製造方法およびその中間体 |
EP1711614B1 (en) | 2004-02-02 | 2009-01-07 | Pioneer Hi-Bred International, Inc. | Ap2 domain transcription factor odp2 (ovule development protein 2) and methods of use |
UA87854C2 (en) | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
EP1973569B1 (en) | 2006-01-18 | 2013-05-22 | Merck Patent GmbH | Specific therapy using integrin ligands for treating cancer |
US20100069302A1 (en) | 2007-07-18 | 2010-03-18 | Stefan Krueger | Specific therapy and medicament using integrin ligands for treating cancer |
EP2257538B1 (en) * | 2008-03-06 | 2016-04-27 | GlaxoSmithKline LLC | Process for the preparation of benzodiazepine derivatives |
WO2010093706A2 (en) | 2009-02-10 | 2010-08-19 | The Scripps Research Institute | Chemically programmed vaccination |
CN102427816A (zh) | 2009-03-30 | 2012-04-25 | 宇部兴产株式会社 | 用于治疗或预防眼病的药物组合物 |
JP2012528079A (ja) | 2009-05-25 | 2012-11-12 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌を治療するためのインテグリンリガンドの連続投与 |
EP2529017A2 (en) | 2009-12-30 | 2012-12-05 | Pioneer Hi-Bred International, Inc. | Methods and compositions for targeted polynucleotide modification |
EP3078748B1 (en) | 2009-12-30 | 2021-08-11 | Pioneer Hi-Bred International, Inc. | Methods and compositions for the introduction and regulated expression of genes in plants |
KR20160147007A (ko) | 2014-05-30 | 2016-12-21 | 화이자 인코포레이티드 | 선택적인 안드로겐 수용체 조절제로서의 카보니트릴 유도체 |
WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
Family Cites Families (1)
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UA60311C2 (uk) * | 1996-10-02 | 2003-10-15 | Смітклайн Бічам Корпорейшн | Антагоністи рецептора вітронектину, спосіб одержання цих сполук та фармацевтична композиція |
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1998
- 1998-09-24 TR TR2000/00786T patent/TR200000786T2/xx unknown
- 1998-09-24 AU AU95787/98A patent/AU9578798A/en not_active Abandoned
- 1998-09-24 BR BR9813214-8A patent/BR9813214A/pt not_active Application Discontinuation
- 1998-09-24 PL PL98339414A patent/PL339414A1/xx unknown
- 1998-09-24 JP JP2000512547A patent/JP2002500162A/ja not_active Withdrawn
- 1998-09-24 EP EP98949471A patent/EP1023073A1/en active Pending
- 1998-09-24 WO PCT/US1998/019987 patent/WO1999015178A1/en not_active Application Discontinuation
- 1998-09-24 CN CN98809494A patent/CN1271284A/zh active Pending
- 1998-09-24 IL IL13518898A patent/IL135188A0/xx unknown
- 1998-09-24 HU HU0003931A patent/HUP0003931A2/hu unknown
- 1998-09-24 KR KR1020007003093A patent/KR20010024249A/ko not_active Application Discontinuation
- 1998-09-24 CA CA002304000A patent/CA2304000A1/en not_active Abandoned
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2000
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101861319B (zh) * | 2007-11-16 | 2013-12-11 | 宇部兴产株式会社 | 苯并氮杂*酮化合物 |
Also Published As
Publication number | Publication date |
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TR200000786T2 (tr) | 2000-08-21 |
BR9813214A (pt) | 2000-08-29 |
HUP0003931A2 (hu) | 2001-10-28 |
EP1023073A1 (en) | 2000-08-02 |
IL135188A0 (en) | 2001-05-20 |
KR20010024249A (ko) | 2001-03-26 |
AU9578798A (en) | 1999-04-12 |
NO20001515L (no) | 2000-03-23 |
JP2002500162A (ja) | 2002-01-08 |
CA2304000A1 (en) | 1999-04-01 |
WO1999015178A1 (en) | 1999-04-01 |
PL339414A1 (en) | 2000-12-18 |
NO20001515D0 (no) | 2000-03-23 |
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