CN101268076A - 二氮杂䓬并喹啉、其合成和中间体 - Google Patents
二氮杂䓬并喹啉、其合成和中间体 Download PDFInfo
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- CN101268076A CN101268076A CNA2006800341809A CN200680034180A CN101268076A CN 101268076 A CN101268076 A CN 101268076A CN A2006800341809 A CNA2006800341809 A CN A2006800341809A CN 200680034180 A CN200680034180 A CN 200680034180A CN 101268076 A CN101268076 A CN 101268076A
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Abstract
本发明涉及合成可用作5HT<sub>2C</sub>激动剂或部分激动剂的化合物、其衍生物的方法,及其中间体。
Description
发明领域
本发明涉及合成用作5HT2c激动剂或部分激动剂的化合物、其衍生物的方法及其中间体。
发明背景
精神分裂症困扰着近500万人。目前,对于精神分裂症最普遍的治疗方法是“非典型”抗精神病药物,该药物兼具多巴胺(D2)和5-羟色胺(5-HT2A)受体拮抗作用。尽管报道表明非典型抗精神病药物在有效性和副作用易发性方面相对于典型抗精神病药物有所改善,但这些化合物显示不足以治疗所有精神分裂症症状,并伴有困扰性副作用如体重增长(Allison,D.B.等人,Am.J.Psychiatry,156:1686-1696,1999;Masand,P.S.,Exp.Opin.Pharmacother.I:377-389,2000;Whitaker,R.,Spectrum Life Sciences.Decision Resources.2:1-9,2000)。
非典型抗精神病药物还以高度亲和性结合于5-HT2c受体,并发挥5-HT2c受体拮抗剂或反相激动剂的功效。体重增长是与非典型抗精神病药物例如氯氮平和奥氮平相关的困扰性副作用,已经提出5-HT2c拮抗是造成增加体重的原因。相反,已知刺激5-HT2c受体导致食物摄入和体重降低(Walsh等人,Psychopharmacology 124;57-73,1996;Cowen,P.J.等人,Human Psychopharmacology 10:385-391,1995;Rosenzweig-Lipson,S.等人,ASPET摘要,2000)。
多种证据支持5-HT2c受体激动或部分激动作为精神分裂症治疗手段的作用。研究表明:5-HT2c拮抗剂增加多巴胺的突触水平,可有效用于帕金森病动物模型(Di Matteo,V.等人,Neuropharmacology 37:265-272,1998;Fox,S.H.等人,Experimental Neurology Hi:35-49,1998)。由于精神分裂症的阳性症状与多巴胺的水平增加有关,与5-HT2c拮抗剂作用相反的化合物例如5-HT2c激动剂和部分激动剂应当降低突触性多巴胺的水平。最近的研究已证明:5-HT2c激动剂降低额叶前皮质和伏核中多巴胺的水平(Millan,M.J.等人,Neuropharmacology 37:953-955,1998;Di Matteo,V.等人,Neuropharmacology 38:1195-1205,1999;Di Giovanni,G.等人,Synapse35:53-61,2000),这些脑部区域被认为调节药物如氯氮平的关键抗精神病作用。然而,5-HT2c激动剂不降低纹状体中的多巴胺水平,该脑部区域与锥体束外副作用极其相关。另外,最近的一项研究证明:5-HT2c激动剂降低腹侧被盖区(VTA)而不是黑质中的放电。5-HT2c激动剂在边缘叶通道中相比在黑质纹状体通道中的差别效应提示:5-HT2c激动剂具有边缘选择性,并且不太可能产生与典型抗精神病药物相关的锥体外系副作用。
发明概述
如本文所述,本发明提供了制备具有5HT2c激动剂或部分激动剂活性的化合物的方法。这些化合物可用于治疗精神分裂症、精神分裂样障碍、分裂情感性障碍、妄想性障碍、物质诱导性精神障碍、L-DOPA-诱导性精神病、与阿耳茨海默痴呆相关的精神病、与帕金森病相关的精神病、与Lewy体(Lewy body)病相关的精神病、痴呆、记忆缺失、与阿尔茨海默病相关的智力缺失、双极性精神障碍、抑郁症、心情发作(mood episodes)、焦虑症、适应障碍、饮食障碍、癫痫、睡眠障碍、偏头痛、性功能障碍、胃肠道病症、肥胖或与创伤、中风或脊髓损伤相关的中枢神经系统缺陷。这些化合物包括式I的那些化合物或其药学可接受的盐:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;
R3和R4一起形成饱和或不饱和4-8元环,其中所述环任选被1-3个独立地选自卤素、-R或OR的基团取代;
R5和R6各自独立地是-R;且
R7是氢或C1-6烷基。
本发明还提供了可用于制备这类化合物的合成中间体。
具体实施方式详述
本发明方法和中间体可用于制备例如Ramamoorthy的国际专利申请WO 03/091250所述的化合物,该专利申请的全文在此引用作为参考。在某些实施方式中,本发明化合物通常根据以下所示方案I制备:
方案I
在上述方案I中,每个n、PG1、R1、R2、R7和PG2如下文以及本文所述的类别和亚类别中所定义。
一方面,本发明提供了根据上述方案I中所述步骤制备式D手性喹啉化合物的方法。在步骤S-1中,使式G的苯胺与甲醛或其等价物以及环戊二烯在无机酸存在下反应。在某些实施方式中,N-苄基苯胺和环戊二烯在浓HCl存在下进行Diels-Alder(第尔斯-阿尔德)反应,提供环戊烯基四氢喹啉F,其中PG1是苄基。在其他实施方式中,步骤S-1以基本上类似于下文描述的方式进行:Posson等人,“亚氨基Diels-Alder反应:在各种环戊二烯并[c]喹啉衍生物合成中的应用”,Synlett 2000,No.2,209-212。
式G和F的PG1基团是适合的氨基保护基。适合的氨基保护基在本领域是已知的,包括详细描述于“有机合成中的保护基”,T.W.Greene和P.G.M.Wuts,第3版,John Wiley&Sons,1999中的那些,该文献的全文在此引用作为参考。适合的氨基保护基与其连接的-NH-部分包括但不限于芳烷基胺、氨基甲酸酯、烯丙基胺、酰胺等。式G和F的PG1基团的实例包括叔丁氧基羰基(BOC)、乙氧基羰基、甲氧基羰基、三氯乙氧基羰基、烯丙氧基羰基(Alloc)、苄基氧基羰基(CBZ)、烯丙基、苄基(Bn)、芴基甲基羰基(Fmoc)、乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基、苯基乙酰基、三氟乙酰基、苯甲酰基等。在其他实施方式中,式G和F的PG1基团是苄基。
在步骤S-2中,化合物F的烯烃部分被还原,通过除去PG1将氨基脱保护。本领域普通技术人员将意识到,根据PG1的选择,脱保护和烯烃还原可以在同一步骤中进行。例如,当式F的PG1基团是苄基时,烯烃的还原将与氨基脱保护同时发生。相应地,在某些实施方式中,本发明提供了形成式E化合物的方法,包括同时还原式F的烯烃和脱保护氨基的步骤。因此,在某些实施方式中,式F的PG1基团是通过还原、例如氢化除去的氨基保护基。例如,双键的还原和苄基的脱保护在氢气氛下使用Pd-C的同一催化还原反应中完成。在备选方法中,步骤S-2的PG1除去和烯烃还原可以利用本领域技术人员已知的方法以分步方式进行。
在步骤S-3中,用手性试剂处理外消旋化合物E,形成其非对映体混合物。在某些实施方式中,用手性酸处理外消旋化合物E,形成其非对映体盐。然后通过适合的方式分离所得非对映体混合物,得到式D化合物。这类分离非对映体混合物的适合方法为本领域普通技术人员熟知,包括但不限于本文所述的那些方法。应当理解的是,根据所使用的手性酸,可能会有一个或多个羧酸部分。在某些实施方式中,手性酸具有两个羧酸部分,例如酒石酸或其衍生物。
相应地,本领域普通技术人员应当理解,式E化合物可与所述双功能基手性酸形成半盐。如本文所使用的术语“半盐”是指每分子手性酸具有2分子式E化合物的加合物。作为替代选择,所得盐可以是手性酸和式E化合物的一比一的混合物。在某些实施方式中,本发明提供了式D化合物,其中所述式D化合物包括等摩尔量的手性酸与式E的胺。
在某些实施方式中,每个上述合成步骤可连续进行,在每个步骤后分离出每个中间体F、E和D。作为替代选择,上述方案I所述的每个步骤S-1、S-2和S-3可以以不进行中间体F和E分离的方式进行。
当X是手性酸时,在步骤S-4中用适合的碱处理式D化合物,形成游离碱化合物C。本发明的游离碱还可以例如通过使式D化合物和适合的碱在适于游离碱形成的溶剂中接触而制备。这类适合的碱包括强无机碱,即在水中完全解离形成氢氧化物阴离子的那些。在某些实施方式中,相对于式D化合物,碱的加入量为至少约1mol当量,在其他实施方式中,碱的加入量为至少约1mol当量至约10mol当量。这类碱的实例包括碱金属、碱土金属氢氧化物及其组合。在其他实施方式中,适合的碱是氢氧化钠。
适合用于步骤S-4游离碱形成期间的溶剂的实例包括极性溶剂,如烷基醇,如C1-C4醇类(例如乙醇、甲醇、2-丙醇)、水、二噁烷或THF(四氢呋喃)或其组合。在某些实施方式中,适合的溶剂是C1-C4醇,如乙醇、甲醇、2-丙醇、水或其组合。根据本发明的一个方面,在步骤S-4中使用氢氧化钠水溶液。根据本发明的另一方面,步骤S-4的游离碱形成在两相溶剂混合物中进行,其中形成的式C化合物被萃取至有机层。因此,适合的两相溶剂混合物包括水性溶剂和不可混溶的有机溶剂。这类不可混溶的有机溶剂为本领域普通技术人员所熟知,包括卤代烃溶剂(例如二氯甲烷和氯仿)、苯及其衍生物(例如甲苯)、酯类(例如乙酸乙酯和乙酸异丙酯)和醚类(例如MTBE、THF及其衍生物、甘醇二甲醚和二甘醇二甲醚)等。在某些实施方式中,步骤S-4的游离碱形成在包括水和甲苯的两相混合物中进行。在其他实施方式中,适合的碱是水溶性的,这样反应在甲苯和适合的水性碱如氢氧化钠水溶液的混合物中进行。
在步骤S-5中,手性化合物C经N-烷基化,得到式B化合物。在某些实施方式中,该N-烷基化用2-甲基-2-噁唑啉、在催化量酸存在下进行,得到N-乙酰基-N-乙二胺化合物B,其中n是1,PG2是乙酰基。
在步骤S-6中,除去式B的PG2保护基,得到式A的二胺化合物。在某些实施方式中,通过酸水解除去式B的PG2基团。应当理解的是,式B的PG2基团经酸水解,形成其盐。例如,当使用酸如三氟乙酸处理而除去式B的PG2基团时,则所得二胺化合物将形成其三氟乙酸盐。本领域普通技术人员将认识到:很多酸可用于除去对酸不稳定的氨基保护基,因此包括式A化合物的多种盐形式。
在其他实施方式中,通过碱水解除去式B的PG2基团。本领域普通技术人将认识到:有多种碱可用于除去对碱不稳定的氨基保护基。
在步骤S-7中,用甲醛或其等价物处理式A化合物,得到式II化合物。在某些实施方式中,用甲醛水溶液处理式A化合物,得到式II化合物。本领域普通技术人员应当理解:在步骤S-7中可以使用取代的甲醛,得到式IIa化合物或其药学可接受的盐:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
R7是氢或C1-6烷基。
本领域普通技术人员应当理解:通过本发明方法制备的式II化合物可以用适合的酸处理,以形成其盐。在某些实施方式中,用HCl处理式II化合物,形成其盐酸盐。
本文使用的术语“非对映体盐”是指式E手性化合物和手性酸的加合物。
本文使用的术语“对映体盐”是指经拆分的式D手性化合物的盐,其中所述式D化合物富集一种对映体。本文使用的术语“对映体富集”表示一种对映体在制备物中占到至少80%或85%。在某些实施方式中,术语对映体富集表示至少90%的制备物是一种对映体。在其他实施方式中,该术语表示至少95%的制备物是一种对映体。
根据一个方面,本发明提供了制备式II化合物或其药学可接受盐的方法:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
R7是氢或C1-6烷基。
如上文宽泛所定义,式II中的n是0、1或2。相应地,本发明提供了制备任一式IIa、IIb和IIc化合物的方法:
其中每个R1、R2、R7和n如上文和此处所定义。
根据另一方面,本发明提供了制备式II化合物或其药学可接受盐的方法:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
R7是氢或C1-6烷基,
包括下述步骤:
(a)提供式A化合物:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;和
(b)使所述式A化合物与甲醛或其等价物反应,形成式II化合物。
根据一种实施方式,上述步骤(b)使用甲醛水溶液进行。在某些实施方式中,甲醛水溶液的加入量足以消耗式A化合物。在某些实施方式中,甲醛水溶液的加入量相对于式A化合物至少为约0.90摩尔当量、约0.90摩尔当量至约1.10摩尔当量或者约1.0摩尔当量至约1.05摩尔当量。
根据另一种实施方式,步骤(b)使用甲醛等价物进行。这类甲醛等价物为本领域普通技术人员所熟知。在一些实施方式中,向反应溶剂加入固态形式的甲醛等价物,形成反应混悬液,或者将固态甲醛等价物混悬在反应溶剂中,加至反应混合物中。在其他实施方式中,低聚甲醛用作甲醛等价物,其加入的量足以消耗式A化合物。在一些实施方式中,低聚甲醛的加入量相对于式A化合物为至少约0.90摩尔当量、约0.90摩尔当量至约1.10摩尔当量,或者约1.0摩尔当量至约1.05摩尔当量。
在某些实施方式中,低聚甲醛是固态形式。适于反应的低聚甲醛可以自多个供应商以小球(或者其他颗粒形式)或粉末形式商购可得,所述供应商如Aldrich、Fluka、Celanese Chemicals、J.T.Baker、MallinckrodtLaboratory Chemicals、Miljac Inc.、Sego Int.Corp.、Spectrum ChemicalsMfg.、Total Specialty Chemicals Inc.、US Chemicals Inc.、Riedel-de Haen、Acros Organics、Pfaltz&Bauer Chemicals、Derivados、LancasterSynthesis和EM Science.。一些适合的粉末形式具有至少约10%的颗粒阻留在200目筛上。
根据另一种实施方式,本发明提供了制备式A化合物的方法:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基;
包括下述步骤:
(a)提供式C化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基,
和
(b)烷基化所述式C化合物,形成式B化合物:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基;且
PG2是适合的氨基保护基,
和
(c)脱保护所述式B化合物,形成所述式A化合物。
n是0、1或2;
PG2是适合的氨基保护基;且
L1是适合的离去基团。
如上文所定义,L1是适合的离去基团。适合的离去基团为本领域熟知,例如参见“高等有机化学”,Jerry March,第5版,351-357页,John Wileyand Sons,N.Y。这类离去基团包括但不限于卤素、烷氧基、磺酰氧基、任选取代的烷基磺酰氧基、任选取代的链烯基磺酰氧基、任选取代的芳基磺酰氧基和重氮部分。适合的离去基团的实例包括氯、碘、溴、氟、甲磺酰基、对甲苯磺酰基(tosyl)、三氟甲磺酰基(triflate)、硝基-苯基磺酰基和溴-苯基磺酰基。在某些实施方式中,L1是卤素。在其他实施方式中,L1是任选取代的烷基磺酰氧基、任选取代的链烯基磺酰氧基或任选取代的芳基磺酰氧基。
根据一种备选的实施方式,适合的离去基团可以在反应介质中原位生成。例如,L1部分自式化合物的前体原位生成,其中所述前体含有易于被L1原位替代的基团。这种原位生成适合的离去基团为本领域熟知,例如参见“高等有机化学”,Jerry March,430-431页,第5th版,John Wiley and Sons,N.Y。
在某些实施方式中,所述烷基化反应任选在适合的碱存在下进行。本领域普通技术人员可以理解,离去基团备氨基部分替代可以在适合的碱存在或不存在下实现。这类适合的碱为本领域熟知,包括有机和无机碱。
适合的介质是溶剂或溶剂混合物,其与合并的化合物一起,可促进其间的反应进程。适合的溶剂可溶解一种或多种反应成分,或者作为替代选择,适合的溶剂可促进一种或多种反应成分的悬液的激动。适合用于本发明的溶剂的实例是质子溶剂、卤代烃、醚、酯、芳烃、极性或非极性非质子溶剂或其任意混合物。适合的混合物包括例如质子和非质子溶剂的混合物,如苯/甲醇/水、苯/水、DME/水等。
这些及其他这类适合的溶剂为本领域所熟知,例如参见“高等有机化学”,Jerry March,第5版,John Wiley and Sons,N.Y。
如上文宽泛定义,式B的PG-2基团是适合的氨基保护基。适合的氨基保护基为本领域熟知,包括“有机合成中的保护基”,T.W.Greene andP.G.M.Wuts,第3版,John Wiley&Sons,1999中详述的那些,该文献在此全文引用作为参考。适合的氨基保护基与其所连接的-NH-部分一起包括但不限于芳烷基胺、氨基甲酸酯、烯丙基胺、酰胺等。PG2基团的实例包括叔丁氧基羰基(BOC)、乙氧基羰基、甲氧基羰基、三氯乙氧基羰基、烯丙氧基羰基(Alloc)、苄基氧基羰基(CBZ)、烯丙基、苄基(Bn)、芴基甲基羰基(Fmoc)、乙酰基、氯代乙酰基、二氯乙酰基、三氯乙酰基、苯基乙酰基、三氟乙酰基、苯甲酰基等。在其他实施方式中,PG2基团是乙酰基、氯代乙酰基、二氯乙酰基、三氯乙酰基、苯基乙酰基或三氟乙酰基。在其他实施方式中,氨基保护基是乙酰基。
根据另一种实施方式,一种或多种试剂可作为适合的溶剂。例如,如果在所述反应中应用,有机碱如三乙胺或二异丙乙胺除了作为碱化剂外还可用作溶剂。
在其他实施方式中,上述步骤(b)的烷基化通过使所述式C化合物与在适合的酸存在下反应而实现,形成式B化合物,其中n是1,PG2是乙酰基。这类适合的酸为本领域熟知,包括无机酸,如盐酸、氢溴酸、磷酸、硝酸、硫酸或高氯酸,或者有机酸,如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸、低级烷基磺酸或芳基磺酸。在某些实施方式中,上述步骤(b)的烷基化通式使所述式C化合物与在甲苯磺酸存在下反应而实现。
本发明的另一方面提供了制备式D化合物的方法:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
包括下述步骤:
(a)提供式E化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基;
和
(b)用手性剂处理所述式E化合物,形成式D-1化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
和
(c)通过适合的物理手段获得所述式D化合物。
术语“手性剂”是指可以通过离子或共价键连接在式E化合物氮上的对映体富集的基团。本文使用的术语“对映体富集”表示一种对映体占据制备物的至少85%。在某些实施方式中,术语对映体富集表示制备物的至少90%是一种对映体。在其他实施方式中,该术语表示制备物的至少95%是一种对映体。
以离子键连接在所述氮上的手性剂包括手性酸。当手性剂是手性酸时,该酸与氮形成非对映体盐。然后经适合的物理手段分离所得非对映体。手性酸的实例包括但不限于酒石酸和酒石酸衍生物、扁桃酸、苹果酸、樟脑磺酸和Mosher酸。在某些实施方式中,手性酸是二甲苯酰基-D-酒石酸。在其他实施方式中,手性酸是二甲苯酰基-L-酒石酸。可以以共价键连接在氮上的手性剂在本领域是已知的。
术语“通过适合的物理手段分离”是指分离对映体或非对映体混合物的方法。这类方法在本领域是已知的,包括优先结晶、蒸馏和研磨。手性剂和分离方法详细描述于“有机化合物的立体化学”,Eliel,E.L.和Wilen,S.H.,1994,John Wiley and Sons出版。
在某些实施方式中,通过优先结晶上述步骤(b)中形成的非对映体盐获得式D的手性盐。在其他实施方式中,使用质子溶剂进行结晶。在其他实施方式中,质子溶剂是醇。应当理解,结晶可以用单一的质子溶剂或者一种或多种质子溶剂的组合实现。这类溶剂和溶剂混合物对于本领域普通技术人员而言是熟知的,包括一种或多种直链或支链烷基醇。在某些实施方式中,用异丙醇实现结晶。
在某些实施方式中,式D的手性盐包括等摩尔量的手性酸和胺。在其他实施方式中,式D的手性盐包括亚化学计算量的手性酸。本文使用的术语“亚化学计量”表示相对于式E化合物,手性酸的用量小于1摩尔当量。在某些实施方式中,手性酸的用量小于0.98摩尔当量。在其他实施方式中,胺碱的用量小于0.95摩尔当量。
对于本领域技术人员显而易见的是,结晶化合物D中一种对映体的对映体富集导致母液中另一种对映体形式的对映体富集。因此,根据另一种实施方式,本发明涉及与式D-1化合物相比增加式D外消旋或对映体富集化合物%ee的方法。本文使用的术语“%ee”指的是本领域普通技术人员可以理解的对映体过量百分比。
在另一种优选的实施方式中,对结晶的化合物D任选地进行另外的结晶步骤,以引起所述对映体的结晶和进一步富集。
根据另一种实施方式,本发明提供了获得对映体富集的式D化合物的方法:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
包括下述步骤:
(a)合并式D-1化合物和适合的溶剂:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
加热,形成其溶液;和
(b)使所述溶液冷却,以引起对映体富集的式D化合物结晶。
在某些实施方式中,上述步骤(a)中使用的适合溶剂是质子溶剂。在其他实施方式中,质子溶剂是醇。应当理解,结晶可以使用单一质子溶剂或一种或多种质子溶剂的组合实现。这类溶剂和溶剂混合物对于本领域普通技术人员而言是熟知的,包括一种或多种直链或支链烷基醇。在某些实施方式中,结晶使用甲醇和异丙醇的混合物实现。
在某些实施方式中,本发明提供了式D-1化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂。
根据另一种实施方式,本发明提供了式D-1或式D-2化合物:
其中每个R1、R2和X如上文和以上和此处所定义的类别和亚类别中所定义。
根据一种实施方式,式D-1和式D-2的R1和R2基团各自独立地是R基团。根据另一种实施方式,R1和R2之一是氢。根据另一种实施方式,R1和R2都是氢。
在某些实施方式中,式D-1和式D-2的X基团是手性酸,因此形成手性盐。在另一种实施方式中,式D-1和式D-2的X基团是酒石酸衍生物。在其他实施方式中,式D-1和式D-2的X基团是二甲苯酰基-D-酒石酸。
另一种实施方式提供了式D化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂。
根据一种实施方式,式D的R1和R2基团各自独立地是R基团。根据另一种实施方式,R1和R2之一是氢。根据另一种实施方式,R1和R2都是氢。
在某些实施方式中,式D的X基团是手性酸,因此形成手性盐。在另一种实施方式中,式D的X基团是酒石酸衍生物。在其他实施方式中,式D的X基团是二甲苯酰基-D-酒石酸。
根据另一种实施方式,本发明提供了式D化合物,其中R1和R2均为氢,所述化合物为式D-3:
在某些实施方式中,式D-3化合物基本不含相应的对映体。本文使用的“基本不含”是指化合物由显著更高比例的一种对映体组成。在另一种实施方式中,存在至少约95%重量的所需对映体。在本发明另一种实施方式中,存在至少约99%重量的所需对映体。这类对映体可通过本领域技术人员已知的任何方法从外消旋混合物中分离,包括高效液相色谱法(HPLC)和手性盐拆分,或通过本文所述方法制备。
本发明的另一方面提供了如上文和此处所述的制备式D化合物的方法:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
其中所述方法还包括下述步骤:用适合的碱处理所述式D化合物,形成式C的游离碱化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基。
本文使用的适合的碱是有机或无机碱。这类适合的碱包括强无机碱,即在水中完全解离形成氢氧化物阴离子的那些。在某些实施方式中,相对于式D化合物,碱的加入量为至少约1mol当量,在其他实施方式中,加入量至少约1mol当量至约10mol当量。这类碱的实例包括碱金属、碱土金属氢氧化物及其组合。在其他实施方式中,适合的碱是氢氧化钠。
根据一种实施方式,游离碱形成在适合的溶剂存在下进行。适合用于游离碱形成期间的溶剂的实例包括极性溶剂,如烷基醇,如C1-C4醇(如乙醇、甲醇、2-丙醇)、水、二噁烷和THF(四氢呋喃)或其组合。在某些实施方式中,适合的溶剂是C1-C4醇如甲醇、乙醇、2-丙醇、水或其组合。根据本发明的一方面,适合的碱是氢氧化钠水溶液,因此溶剂是水。
根据本发明的另一方面,游离碱形成在溶剂的二相混合物中进行,其中所形成的式C化合物被萃取至有机层中。因此,适合的溶剂二相混合物包括水性溶剂和非混溶性有机溶剂。这类非混溶性有机溶剂对于本领域普通技术人员而言是熟知的,包括卤代烃溶剂(例如二氯甲烷和氯仿)、苯及其衍生物(例如甲苯)、酯(例如乙酸乙酯和乙酸异丙基酯)、醚(例如MTBE、THF及其衍生物、甘醇二甲醚和二甘醇二甲醚)等。在某些实施方式中,游离碱形成在包括水和甲苯的二相混合物中进行。在其他实施方式中,适合的碱是水溶性的,由此反应在甲苯和适合碱水溶液的混合物中进行,如氢氧化钠水溶液。
在某些实施方式中,本发明提供式III化合物或其盐:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
R3是NH2或适当保护的氨基。
在某些实施方式中,式I的R1和R2各自为R。在其他实施方式中,R1和R2之一为氢。在其他实施方式中,R1和R2均为氢。
适合的氨基保护是本领域熟知的,包括“有机合成中保护基”,T.W.Greene和P.G.M.Wuts,第3版,John Wiley&Sons,1999中详述的那些,该文献在此全文引用作为参考。R3的适当保护的氨基包括但不限于芳烷基胺、氨基甲酸酯、烯丙基胺、酰胺等。这类基团的实例包括叔丁氧基羰基(BOC)、乙氧基羰基、甲氧基羰基、三氯乙氧基羰基、烯丙氧基羰基(Alloc)、苄基氧基羰基(CBZ)、烯丙基、苄基(Bn)、芴基甲基羰基(Fmoc)、乙酰基、氯代乙酰基、二氯乙酰基、三氯乙酰基、苯基乙酰基、三氟乙酰基、苯甲酰基等。在其他实施方式中,氨基保护基是乙酰基、氯代乙酰基、二氯乙酰基、三氯乙酰基、苯基乙酰基或三氟乙酰基。在其他实施方式中,氨基保护基是乙酰基。
在某些实施方式中,本发明提供式IIa或IIc化合物或其药学可接受的盐:
其中每个R1、R2和R7如上文和此处所定义。
在某些实施方式中,本发明提供式IIa化合物,其中R1、R2和R7均为氢。
在其他实施方式中,本发明提供式IIc化合物,其中R1、R2和R7均为氢。
药学可接受的盐、包括单或二盐是衍生自有机和无机酸的那些,例如但不限于乙酸、乳酸、柠檬酸、肉桂酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、草酸、丙酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、羟乙酸、丙酮酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、苯甲酸和类似的已知可接受的酸。
本文使用的术语卤素是指氯、氟、溴或碘。C1-6烷基可以是直链或支链烷基。适合的烷基包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基。C1-6全氟代烷基可包括直链或支链烷基。适合的全氟代烷基包括三氟甲基和五氟乙基。
实施例
如本文所示,通过下述手性HPLC法获得%ee数据:
柱:Chiralcel OP 4.6×250
流动相:己烷∶IPA∶MeOH∶TEA 800∶10∶10∶0.5
流速:1mL/分钟
温度:环境温度
时间:12分钟
波长:210nm
如本文所示,通过下述HPLC方法获得%纯度数据:
柱:Chromolith Performance RP-18e(100×4.6mm)
流动相:A=95∶5∶0.1水∶CH3CN∶H3PO4
B=95∶5∶0.1CH3CN∶水∶H3PO4
梯度:8分钟内5%B-95%B
流速:1mL/分钟
温度:环境温度
时间:10分钟
波长:210nm
实施例1(方法A)
2,3,3a,4,5,9b-六氢-1H-环戊二烯并(c)喹啉:
将20mL MeOH中的N-苯基苄基胺盐酸盐(2.0g)冷却至~5℃。向溶液中加入新鲜裂解的环戊二烯(1.2g,由二环戊二烯经大气加热/蒸馏得到),然后加入甲醛水溶液(37%,1.04g)。保持反应温度为5-10℃,过夜(约18小时)。经TLC(10%乙酸乙酯/己烷)观察无原料。然后使反应物温至室温。用EtOAc稀释反应物,用0.5N NaOH溶液、然后用盐水洗涤。浓缩有机物,得到2.32g三环产物粗品,为油状物。将20mL 1∶1 EtOH∶EtOAc中的上述粗品油用0.175mL 1N HCl的EtOH溶液、然后用5%Pd-C(0.250g,50%水)处理。将混合物在40-45psi H2下振摇过夜。经过硅藻土过滤除去固体,用EtOAc漂洗过滤垫。浓缩滤液,得到桃色油,其在真空下结晶,得到1.38g(87%)脱苄基产物。
(-)2,3,3a,4,5,9b-六氢-1H-环戊二烯并(c)喹啉二-对-甲苯酰基-D-酒石酸(6):
将外消旋胺(16.0g,92.3mmol)、二-对-甲苯酰基-D-酒石酸(23.3g,60.3mmol)在IPA(160mL)中的混合物加热至70℃达10-15分钟。在此期间,固体溶解。将溶液冷却3个小时至0-5℃。过滤所得固体,用冷IPA(60mL)洗涤,在40℃干燥,得到21.0g(40%)盐,为米色固体。手性HPLC:85%ee;
1H NMR(d6-DMSO)δ7.91(d,J=6Hz,4H),7.40(d,J=6Hz,4H),6.97(d,J=6Hz,1H),6.84(t,J=6Hz,1H),6.4-6.6(m,2H),5.83(s,2H),2.9-3.1(m,2H),2.8-3.1(m,1H),2.8-2.9(m,1H),2.5-2.7(m,1H),2.5(m,1H),2.3-2.5(s,6H),2.0-2.2(m,3H),1.8-2.0(m,1H),1.2-1.7(m,4H);13C NMR(d6-DMSO)δ167.6,165.0,145.7,144.9,129.9,129.8,129.7,126.2,125.2,116.4,114.4,71.7,43.6,40.7,35.8,35.4,29.3,23.0,21.6.
实施例2(方法B)
(-)2,3,3a,4,5,9b-六氢-1H-环戊二烯并(c)喹啉二-对-甲苯酰基-D-酒石酸(6:
在备选方法中,将含N-苯基苄基胺(50g)的250mL MeOH机械搅拌,直至溶解。以单份加入29mL浓HCl。使混合物冷却至室温。胺盐酸盐逐渐从溶液中析出。将悬液在冰中冷却至约15℃,以单份加入新鲜蒸馏的环戊二烯[29.4g,经由大气短程蒸馏(罐温165-170℃,馏出物约60-70℃)热裂解二环戊二烯,得到环戊二烯。将环戊二烯收集至冰冷却的收集器中]。如果需要,在进行反应前使温度回落至15℃。滴加甲醛(37%水溶液)在150mLMeOH中的溶液,以保持内部温度为15-25℃(滴加时间为15分钟)。形成黄色溶液。一旦滴加完全,在室温、氮气下搅拌反应物过夜(12-18小时)。溶液澄清,但呈绿色。将溶液转移至2L Parr瓶中,用1.5g 10%Pd/C(50%wet)处理,在45psi氢气下振摇,直至吸收停止。完成后,以氮气清洗混合物,用碳酸氢钠(58g)处理。搅拌浆液,直至以潮湿pH试纸测试溶液为中性至弱碱性。然后将混合物经1cm硅藻土过滤,以MeOH(50mL)漂洗过滤垫。真空浓缩滤液,加入450mL IPA。将混合物搅拌过夜,过滤所得固体,用50mL IPA漂洗。向上述得到的滤液中以单份加入二-对-甲苯酰基-D-酒石酸(63.3g)。将浆液加热至约80℃,以溶解所有固体。然后使混合物逐渐冷却至室温,搅拌3小时或更长时间。然后将混合物在冰中冷却至0-5℃,在此温度搅拌1-2小时。过滤固体,用100mL冷IPA洗涤。真空干燥浅蓝绿色固体,得到标题化合物。产率:46.7g(31%)。手性纯度(HPLC):95∶5%ee。
实施例3
(-)2,3,3a,4,5,9b-六氢-1H-环戊二烯并(c)喹啉(7):
历经5分钟向二甲苯酰基-D-酒石酸盐(20.67g,37mmol)在甲苯(93mL)中的悬液中加入NaOH水溶液(12mL 30%NaOH用水稀释至100mL)。剧烈搅拌两相混合物,固体缓慢溶解。分离两层。用甲苯(46mL)萃取水层。合并有机层,浓缩,得到6.4g(100%产率)游离碱,为黄色油。
1H NMR(CDCl3)δ7.09(d,J=7.5Hz,1H),6.9-7.0(m,1H),6.6-6.7(m,1H),6.4-6.5(m,1H),3.85(bs,1NH),2.9-3.2(m,2H),2.8-3.1(m,1H),2.80(t,J=10.3Hz,1H),2.3-2.4(m,1H),2.0-2.2(m,1H),1.8-2.1(m,1H),1.3-1.8(m,4H).
实施例4
(-)[2-(1,2,3,3a,4,9b-六氢-环戊二烯并[c]喹啉-5-基)-乙基胺三氟醋酸盐(10):
将胺(6.4g,36.9mmol)和催化量的对-甲苯磺酸(0.07g,0.37mmol)的混合物加热至165℃。历经2小时向165℃的反应混合物缓慢加入2-甲基-2-噁唑啉。冷却反应混合物至60℃,然后加入稀H2SO4(6mL浓H2SO4和26mL水)。在60℃搅拌1小时。冷却至室温,加入甲苯(40mL)和30%NaOH(30mL)。滤出固体,用甲苯(2×10mL)洗涤。每次洗涤用于萃取水层。用水(25mL)洗涤合并的有机萃取物。浓缩甲苯层至20mL体积,冷却至10℃。历经15分钟加入三氟醋酸(2.4mL,31.2mmol)在甲苯(7.5mL)中的溶液。在10℃搅拌2小时。过滤,用甲苯(10mL)洗涤。在真空烘箱中于55℃干燥TFA盐,得到7.7g(产率63%)。HPLC 97.6%,手性纯度92.2∶7.8。
实施例5
历经2小时向N-乙二胺TFA盐(2.3g,7.0mmol)在水(120mL)中的60℃溶液中加入甲醛水溶液(0.72g,37%wt水溶液,8.8mmol,1.26当量)。在60℃19小时后,冷却至环境温度。向反应混合物加入氢氧化钠(0.38g)和乙酸异丙酯(20mL)。分离各层,用乙酸异丙酯(10mL)萃取水层。合并有机层,用水(10mL)洗涤。向有机层滴加浓HCl(0.82g)。过滤固体,用乙酸异丙酯(5mL)洗涤。将粗产物(2.44g)在乙醇(14mL,200标准强度,用4%乙酸乙酯变性)中加热至70℃,然后加入水(1.0ml)。历经3小时将溶液冷却至5℃。过滤产物,用冷乙醇(2.4mL)洗涤。将湿产物(1.4g)在真空烘箱中于40℃干燥20小时,得到标题化合物,为白色固体(1.1g,产率60%)。从母液分离0.34g(18%)第二批产物。HPLC(面积%):96.5%;手性纯度(HPLC):99.87∶0.13。
Claims (29)
1.制备式II化合物或其药学可接受盐的方法:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
R7是氢或C1-6烷基,
包括下述步骤:
(a)提供式E化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基,
(b)用手性剂处理所述式E化合物,形成式D-1化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
(c)通过适合的物理手段获得式D化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂;
(d)用适合的碱处理所述式D化合物,得到式C化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基,
(e)烷基化所述式C化合物,形成式B化合物:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
PG2是适合的氨基保护基,
(f)脱保护所述式B化合物,形成式A化合物:
其中:
n是0、1或2;
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基;
和
(g)使所述式A化合物与甲醛或其等价物反应,形成式II化合物。
2.根据权利要求1的方法,其中每个n均是1,R1和R2都是氢。
3.根据权利要求1或2的方法,其中所述甲醛是甲醛水溶液。
5.制备式D化合物的方法:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
包括下述步骤:
(a)提供式E化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;且
每个R独立地是氢或C1-6烷基,
和
(b)用手性剂处理所述式E化合物,形成式D-1化合物:
其中:
R1和R2各自独立地是卤素、-CN、苯基、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
每个R独立地是氢或C1-6烷基;且
X是手性剂,
和
(c)通过适合的物理手段获得所述式D化合物。
6.根据权利要求5的方法,其中X是手性酸。
7.根据权利要求6的方法,其中手性酸是二甲苯酰基-D-酒石酸,通过从质子溶剂中结晶获得式D化合物。
8.根据权利要求7的方法,其中式D化合物是对映体富集的。
10.根据权利要求9的方法,其中X是二甲苯酰基-D-酒石酸,所述适合的溶剂是质子溶剂。
11.根据权利要求10的方法,其中所述适合的溶剂包括甲醇和异丙醇的混合物。
13.根据权利要求12的方法,其中所述方法在溶剂的两相混合物中进行。
14.根据权利要求13的方法,其中所述方法在甲苯和氢氧化钠水溶液的混合物中进行。
16.根据权利要求15的化合物,其中R3是氢或乙酰基。
17.根据权利要求16的化合物,其中R1和R2各自为R。
18.根据权利要求17的化合物,其中R1和R2均为氢。
20.根据权利要求19的化合物,其中X是手性酸,R1和R2各自是氢。
21.根据权利要求20的化合物,其中X是二甲苯酰基-D-酒石酸。
22.根据权利要求21的化合物,其中所述化合物包括等摩尔量的X。
25.根据权利要求24的化合物,其中R1和R2各自独立地是R基团,X是手性酸。
26.根据权利要求25的化合物,其中R1和R2均为氢,X是二甲苯酰基-D-酒石酸。
28.根据权利要求27的化合物,其中所述化合物基本不含相应的对映体。
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AR054849A1 (es) | 2005-07-26 | 2007-07-18 | Wyeth Corp | Diazepinoquinolinas, sintesis de las mismas, e intermediarios para obtenerlas |
PE20070549A1 (es) | 2005-10-17 | 2007-06-15 | Wyeth Corp | Tetrahidroquinolinas, su sintesis e intermediarios |
TW200734334A (en) | 2006-01-13 | 2007-09-16 | Wyeth Corp | Treatment of substance abuse |
BRPI0709129A2 (pt) | 2006-03-24 | 2011-06-28 | Wyeth Corp | combinações terapêuticas para o tratamento ou prevenção de transtornos psicóticos |
US20070225279A1 (en) | 2006-03-24 | 2007-09-27 | Wyeth | Therapeutic combinations for the treatment of depression |
PE20080126A1 (es) | 2006-03-24 | 2008-04-07 | Wyeth Corp | Metodos para tratar trastornos cognitivos y otros afines |
WO2007112000A2 (en) | 2006-03-24 | 2007-10-04 | Wyeth | Treatment of pain |
CA2645099A1 (en) | 2006-03-24 | 2007-10-04 | Wyeth | Methods for modulating bladder function |
CL2008002777A1 (es) | 2007-09-21 | 2010-01-22 | Wyeth Corp | Metodo de preparacion de compuestos diazepinoquinolinicos quirales por recristalizacion en un sistema de solvente ternario. |
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2006
- 2006-07-19 AR ARP060103086A patent/AR054849A1/es unknown
- 2006-07-24 MX MX2008001030A patent/MX2008001030A/es not_active Application Discontinuation
- 2006-07-24 CN CNA2006800341809A patent/CN101268076A/zh active Pending
- 2006-07-24 TW TW095126932A patent/TW200738713A/zh unknown
- 2006-07-24 KR KR1020087004478A patent/KR20080030682A/ko not_active Application Discontinuation
- 2006-07-24 JP JP2008524026A patent/JP2009502925A/ja not_active Withdrawn
- 2006-07-24 US US11/491,590 patent/US7671196B2/en not_active Expired - Fee Related
- 2006-07-24 EP EP06788294A patent/EP1907390A2/en not_active Withdrawn
- 2006-07-24 PE PE2006000891A patent/PE20070238A1/es not_active Application Discontinuation
- 2006-07-24 RU RU2008102884/04A patent/RU2008102884A/ru not_active Application Discontinuation
- 2006-07-24 CA CA002616161A patent/CA2616161A1/en not_active Abandoned
- 2006-07-24 BR BRPI0614154-4A patent/BRPI0614154A2/pt not_active Application Discontinuation
- 2006-07-24 WO PCT/US2006/028655 patent/WO2007016029A2/en active Application Filing
- 2006-07-24 GT GT200600326A patent/GT200600326A/es unknown
- 2006-07-24 AU AU2006276010A patent/AU2006276010A1/en not_active Abandoned
- 2006-07-26 SA SA06270241A patent/SA06270241B1/ar unknown
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2008
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103204858A (zh) * | 2013-03-20 | 2013-07-17 | 广州科瑞生物技术有限公司 | 基于酒石酸拆分合成工艺制备新型手性抗焦虑症药物 |
Also Published As
Publication number | Publication date |
---|---|
CR9670A (es) | 2008-07-29 |
PE20070238A1 (es) | 2007-03-26 |
BRPI0614154A2 (pt) | 2011-03-15 |
RU2008102884A (ru) | 2009-09-10 |
SA06270241B1 (ar) | 2009-09-02 |
AU2006276010A1 (en) | 2007-02-08 |
WO2007016029A3 (en) | 2007-05-18 |
EP1907390A2 (en) | 2008-04-09 |
KR20080030682A (ko) | 2008-04-04 |
GT200600326A (es) | 2007-03-14 |
TW200738713A (en) | 2007-10-16 |
ECSP088151A (es) | 2008-02-20 |
NO20080468L (no) | 2008-02-22 |
JP2009502925A (ja) | 2009-01-29 |
MX2008001030A (es) | 2008-03-19 |
IL188896A0 (en) | 2008-04-13 |
US7671196B2 (en) | 2010-03-02 |
CA2616161A1 (en) | 2007-02-08 |
US20070027142A1 (en) | 2007-02-01 |
AR054849A1 (es) | 2007-07-18 |
WO2007016029A2 (en) | 2007-02-08 |
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