CN101080251B - 制备莰佛胺及其盐的方法和中间体、含中间体的药物组合物,及其作为抗癌药的应用 - Google Patents
制备莰佛胺及其盐的方法和中间体、含中间体的药物组合物,及其作为抗癌药的应用 Download PDFInfo
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- CN101080251B CN101080251B CN2005800428600A CN200580042860A CN101080251B CN 101080251 B CN101080251 B CN 101080251B CN 2005800428600 A CN2005800428600 A CN 2005800428600A CN 200580042860 A CN200580042860 A CN 200580042860A CN 101080251 B CN101080251 B CN 101080251B
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Abstract
制备莰佛胺及其盐的方法和制备过程中的中间体,包含一些中间体的药物组合物,以及它们作为抗癌药的用途。
Description
技术领域
本发明涉及莰佛胺(canfosfamide)及其盐,并且尤其涉及其制备方法和在其制备过程中的中间体,含一些中间体的药物组合物,以及它们作为抗癌药的应用。
背景技术
美国专利第5,556,942号和PCT国际公开号WO95/09866披露了结构式
的化合物和其酰胺、酯及其盐,以及它们的合成方法,其中:L为吸电子离去基团;
SX为-S(=O)-、-S(=O)2-、-S(=NH)-、-S(=O)(=NH)-、-S+(C1-C6烷基)-、-Se(=O)-、-Se(=O)2-、-Se(=NH)-、或-Se(=O)(=NH)-,或为-O-C(=O)-、或-HN-C(=O)-;
每一R1、R2和R3独立地为H或非干扰取代基;
n为0、1或2;
Y选自由以下构成的组:
其中m为1或2;以及
AAc是通过肽键连接到该化合物的其余部分的氨基酸。
据称这些化合物是选择性治疗含有相容GST同功酶的靶组织的有用药物,同时提高骨髓中GM祖细胞的水平。所披露的关于L的具体实施方式包括对不需要细胞产生毒性药物的化合物,包括二氨基磷酸酯和二氨基磷酸酯芥。
其中一个化合物中是TLK286,在那些公开中被称为TER286,其化学名为γ-谷氨酰基-α-氨基-β-((2-乙基-N,N,N,N-四(2′-氯)乙基氨基磷酸酯基)磺酰基)丙酰基-(R)-(-)-苯基甘氨酸。TLK286是以下化学式的化合物:
TLK286本身被提议的国际非专利药名(pINN)为莰佛胺,而作为盐酸加合盐,其美国采用名(USAN)TLK286为莰佛胺盐酸盐。
Lyttle等人在J.Med.Chem.,37:1501-1507(1994)上公开了莰佛胺和两种类似物、它们的合成,以及它们与三种GST同功酶的相互作用。这些合成方法涉及未保护的三肽[在莰佛胺的情况下,L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸]与2-溴乙基二氨基磷酸酯[在莰佛胺情况下,N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-溴乙基酯]的反应,接着用过氧化氢和过乙酸对生成的硫醚进行氧化。
莰佛胺是一种抗癌化合物,通过GST P1-1的作用和并通过GSTA1-1被激活,而释放出细胞毒性的二氨基磷酸酯部分。莰佛胺经过GST P1-1的激活之后,随着MKK4、JNK、p38MAP激酶,和caspase3的激活,通过应激反应信号传导路径来诱导细胞凋亡。在体外测试中,莰佛胺已经被证实,在选择性对阿霉素有耐药性的M6709人体克隆癌细胞系中,以及在选择性对环磷酰胺有耐药性的MCF-7人体乳腺癌细胞系中(两者都过表达GST P1-1),比在它们的亲代细胞系中为有效;并且在设计以具有高、中和低水平的GST P1-1的M7609的鼠异种移植物中,莰佛胺的效能与GST P1-1的水平为正相关(Morgan等人,Cancer Res.,58:2568-2575(1998))。
莰佛胺盐酸盐,作为单一药剂和与其它抗癌药剂组合使用,目前正在进行治疗卵巢癌、乳腺癌、非小细胞肺癌以及直肠癌方面的多种临床试验评价。已经在患非小细胞肺癌和卵巢癌的患者中显示显著的单药剂抗肿瘤活性和的存活率的提高,以及在结肠癌和乳腺癌中的单药抗肿瘤活性。来自体外细胞培养和肿瘤活组织检查的证据表明,莰佛胺对铂类、红豆杉醇和阿霉素(Rosario等人,Mol.Pharmacol.,58:167-174(2000))是非交叉耐药性的,以及对吉西他滨(gemcitabine)也是非交叉耐药性的。用莰佛胺盐酸盐治疗的患者表现出非常低的临床明显血液毒性发生率。
Herr等人,Org.Proc.Res.Dev.,5:442-444(2001),披露了从未保护三肽L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸和N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(芳磺酰氧基)乙酯的莰佛胺的逆合成方法;以及从POCl3分三步,经过N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-羟乙基酯,合成N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(芳磺酰氧基)乙酯的方法。美国专利第6,506,739号和PCT国际公开号WO01/83496公开了N,N,N′,N′-四(2-卤代乙基)二氨基磷酸2-(取代)乙基酯,包括N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-羟基乙酯和N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(芳磺酰氧基)乙酯,例如,N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(4-溴苯磺酰氧基)乙酯。
开发一种经济有效的莰佛胺及其盐的合成方法是合乎需要的。
发明内容
在第一方面,本发明是以下化学式的化合物及其盐:
其中R1是氨基保护基团。
在第二方面,本发明是以下结构式的化合物及其盐:
其中R1是氨基保护基团。
在第三方面,本发明是以下化学式的化合物及其盐:
其中R1是氨基保护基团。
在第四方面,本发明是以下化学式的化合物及其盐:
其中R1是氨基保护基团,而R2是硫保护基团。
在第五方面,本发明是制备莰佛胺或其盐的方法,包括对本发明第一方面的化合物去保护,可选地随后生成莰佛胺的盐。
在第六方面,本发明是制备本发明第一方面化合物的方法,包括氧化本发明第二方面的化合物。
在第七方面,本发明是制备本发明第二方面的化合物的方法,包括在碱性条件下使本发明第三方面的化合物与N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(A-磺酰氧基)乙酯反应。
在第八方面,本发明是制备本发明第三方面的化合物的方法,包括对本发明第四方面的化合物中的硫原子去保护。
在第九方面,本发明是包括本发明第一方面化合物的药物组合物,用于治疗癌症和生产治疗癌症药物的本发明第一方面的化合物,以及通过给予本发明第一方面的化合物治疗癌症的方法。
本发明的优选具体实施方式由提交的本申请的说明书和权利要求2~4、6~8、10~12、14~18、20、21、23~27、29~35、37~42和44~46所描述内容加以特征化。
具体实施方式
定义
“莰佛胺”(Canfosfamide)是以下结构式的化合物:
其CAS命名为L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]乙基]-磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸。
莰佛胺和本发明的化合物合适的盐[参见Berge等人,J.Pharm.Sci.,66:1(1971),非穷举]是,当无机碱(例如,氢氧化钠、氢氧化钾和氢氧化钙)或有机碱(例如,乙醇胺、二乙醇胺、三乙醇胺、乙二胺、缓血酸胺、N-甲基葡糖胺)与莰佛胺和所述化合物的羧基反应时生成的那些盐,以及当无机酸(例如,盐酸、氢溴酸、硫酸、硝酸和氯磺酸)或有机酸(例如,乙酸、丙酸、草酸、苹果酸、马来酸、丙二酸、富马酸、或酒石酸,以及烷基磺酸或芳基磺酸如甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸如氯苯磺酸和甲苯磺酸、萘磺酸和取代的萘磺酸、萘二磺酸和取代的萘二磺酸,以及樟脑磺酸)反应时生成莰佛胺和所述化合物的氨基基团的酸加成盐。这些盐优选由药用酸和碱形成。莰佛胺的合适盐是酸加成盐,尤其是盐酸盐。
“氨基保护基团”是能够在氨基保护的莰佛胺合成期间保护L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸的谷酰基α-氨基,并随后在不影响莰佛胺分子其余部分的情况下可移除的基团。“可催化除去的氨基保护基团”是能够通过催化还原或催化异构化除去的氨基保护基团。常用的这种基团是含有苄基碳原子或烯丙基碳原子的形成尿烷的基团。适合用于本发明的可催化除去的氨基保护基团的实例是通过催化氢解很方便除去的(可选取代的苄基)氧羰基,以及通过催化异构化很方便除去的(可选取代的烯丙基)氧羰基。特别合适的可催化除去的氨基保护基是苄氧羰基。
“(可选取代的苄基)氧羰基”包括苄氧羰基和在苯环上用一个或两个(一般是一个)吸电子取代基如卤素(典型地是氯或溴)、硝基、氰基和三氟甲基取代的苄氧羰基。(可选取代的苄基)氧羰基的实例包括苄氧羰基、卤代苄氧羰基如2-和4-溴代苄氧羰基,2-,3-和4-氯代苄氧羰基,和2,4-二氯代苄氧羰基、2-,3-和4-硝基苄氧羰基、4-氰基苄氧羰基等。
“(可选取代的烯丙基)氧羰基”包括烯丙氧羰基和用吸电子取代基(如可选地用一个或两个(一般是一个)吸电子取代基如卤素(典型地为氯或溴)、硝基、氰基和三氟甲基取代的苯基,或吡啶基)在烯丙基的3-位取代的烯丙氧羰基,和1-异丙基烯丙氧羰基。(可选取代的烯丙基)氧羰基的实例包括烯丙氧羰基、肉桂氧羰基、4-硝基肉桂氧羰基、3-(3′-吡啶基)烯丙氧羰基,以及1-异丙基烯丙氧羰基。
“硫保护基”是能够在合成本发明第四方面的化合物过程中保护L-γ-谷酰基-L-半胱氨酰基-2(R)-苯基甘氨酸的硫原子并随后在不影响本发明第三方面相应化合物的分子其余部分(包括氨基保护基)的情况下可除去的基团。“可酸解除去的硫保护基”是能够通过酸解反应除去的硫保护基团。常用的这种基团是(可选取代的苯基)-取代的甲基。适合用于本发明的可酸解除去的硫保护基的实例是三苯甲基,其中一个或多个苯环被一个或多个(一般为一个)供电子取代基如甲氧基可选取代,例如,三苯基甲基、(4-甲氧基苯基)二苯基甲基和二(4-甲氧基苯基)苯基甲基;二苯基甲基,其中一个或多个苯环被一个或多个(一般为一个)供电子取代基如甲氧基可选取代,例如,二苯甲基、(4-甲氧基苯基)苯基甲基和二(4-甲氧基苯基)甲基;二苯基甲基类似物如9H-氧杂蒽-9-基、2-甲氧基-9H-氧杂蒽-9-基、5H-二苯并[a,d]环庚-5-基,以及10,11-二氢-5H-二苯并[a,d]环庚-5-基;以及用两个或多个供电子取代基如甲氧基取代的苄基,例如,2,4-二甲氧基苄基和2,4,6-三甲氧基苄基。特别适合的可酸解除去的硫保护基是三苯甲基。
氨基保护基(包括可催化除去的氨基保护基)和硫保护基(包括可酸解除去的硫保护基)在有机合成领域,尤其是肽合成中是众所周知的。合适的这种基团及其除去条件,描述于一些书籍中,如Synthesis of Peptides and Peptidomimetics,Workbench edition,M.Goodman,ed.,Georg Thieme Verlag,Stuttgart,Germany,2004,和Protective groups in organic synthesis,3 ed.,T.W.Greene和P.G.M.Wuts,eds.,John Wiley & Sons,Inc.,New York,New York,U.S.A.,1999,并且对于本领域普通技术员来说是众所周知的。
因为本发明第四方面的化合物既含有氨基保护基,尤其是催化可除去的氨基保护基,和硫保护基,尤其是可酸解除去的硫保护基,而且本发明第八方面涉及这些化合物中硫原子的去保护,而同时保持氨基保护基不受影响,所以本领域普通技术人员将会理解到“氨基保护基”和“硫保护基”并不是独立选择的,其定义应该根据本申请的说明和反应图解1和2的反应顺序来理解;氨基保护基和硫保护基的选择要使得在保持氨基保护基不受影响的条件下,可以除去硫保护基。考虑本申请中的这些信息以及本领域的普通技术,本领域普通技术人员在选择合适的氨基保护基和硫保护基以及除去条件方面并不困难。
“N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(A-磺酰氧基)乙酯”是以下结构式的化合物:
其中A是可选取代的烷基、可选取代的芳基、可选取代的杂芳基、可选取代的芳烷基,或可选取代的杂芳烷基。因此,A包括C1~4烷基,可选地用1至3个卤原子取代和进一步可选地用硝基或氰基取代;C6~10芳基如苯基和萘基,尤其是苯基,可选地用1至3个选自卤素、硝基、氰基、以及可选地被1至3个卤原子取代的C1~2烷基(例如,三氟甲基)取代;C5~10杂芳基,如呋喃基、噻吩基、吡咯基、吡啶基、吡嗪基和嘧啶基,可选地用1至3个选自卤素、硝基、氰基和可选地被1至3个卤原子取代的C1~2烷基的基团所取代;和C6~10芳基-C1~2烷基和C5~10杂芳基-C1~2烷基,每一个可选地在芳基或杂芳基上用1至3个选自卤素、硝基、氰基以及可选地被1至3个卤原子取代的C1~2烷基的基团取代,并可选地在烷基上用1至3个卤原子取代。A基团的实例包括甲基、三氟甲基、苯基、4-甲苯基、4-硝基苯基和4-卤代苯基如4-氯苯基和4-溴苯基。
“对溴苯磺酰基”是指4-溴苯磺酰基。
“治疗有效量”是指,当向哺乳动物尤其是人给药以治疗癌症时,足以达到治疗癌症的量。对哺乳动物癌症的“治疗”包括下列中的一种或多种:
(1)抑制癌症增长,即阻止其发展,
(2)阻止癌症的扩散,即阻止其转移,
(3)使癌症减轻,即使癌变消退,
(4)防止癌症复发,以及
(5)减轻癌症症状。
如果本发明第一方面的化合物作为具有一种或多种其它抗癌药或放射疗法的联合疗法的部分进行给药,则“治疗有效量”可以比该化合物单独给药的治疗有效量更低。
“含有”和“包括”及其语法变化词是包括和不限制的表达,意思是指定有所述特征的存在而不排除其他特征的存在或加入。本发明的化合物及其制备
本发明第一方面的化合物是以下结构式的化合物及其盐(化合物4):
其中R1是氨基保护基,尤其是可催化除去的氨基保护基。
本发明第一方面的具体化合物是其中R1是(可选取代的苄基)氧羰基或(可选取代的烯丙基)氧羰基的化合物。特别有用的化合物是这些化合物,其中R1是苄氧羰基,即N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸,及其盐,特别是药用盐。
本发明第二方面的化合物是以下结构式的化合物及其盐(化合物3):
其中R1是氨基保护基,尤其是可催化除去的氨基保护基。
本发明第二方面的具体化合物是其中R1是(可选取代的苄基)氧羰基或(可选取代的烯丙基)氧羰基的化合物。特别有用的化合物是这些化合物,其中R1是苄氧羰基,即N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸,及其盐。
本发明第三方面的化合物是以下结构式的化合物及其盐(化合物2):
其中R1是氨基保护基,尤其是可催化除去的氨基保护基。
本发明的第三方面的具体化合物是其中R1是(可选取代的苄基)氧羰基或(可选取代的烯丙基)氧羰基的化合物。特别有用的化合物是这些化合物,其中R1是苄氧羰基,即N-α-(苄氧羰基)-L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸,及其盐。
本发明第四方面的化合物是以下结构式的化合物及其盐(化合物1):
其中R1是氨基保护基,尤其是可催化除去的氨基保护基,而R2是硫保护基,尤其是可酸解除去的硫保护基。
本发明第四方面的具体化合物是其中R1是(可选取代的苄基)氧羰基或(可选取代的烯丙基)氧羰基的化合物。特别有用的化合物是R1为苄氧羰基的那些化合物。
本发明第四方面的其它具体化合物是其中R2是(可选取代的苯基)-取代的甲基的化合物。特别有用的化合物是其中R2为三苯甲基的化合物。
本发明第四方面的特别有用的化合物是其中R1是苄氧羰基而R2是三苯甲基的化合物,即N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸,及其盐。
通过本发明的方法制备本发明的化合物和莰佛胺及其盐如反应图解1所示。
本申请描述的和权利要求主张的制备方法中,在方法步骤中溶剂的命名并不指溶剂必须是单独使用的:溶剂可以与一种或多种共溶剂一起使用,条件是任何溶剂混合物的性质主要由所指定的溶剂决定。
反应图解1
在第一步中,对化合物1的硫原子进行去保护以给出化合物2。
可以通过任何适于去除硫保护基而不会除去氨基保护基的方法对化合物1进行去保护。当硫保护基是可酸解除去的硫保护基时,通过酸解可以很方便地对化合物1进行去保护。
典型地,可选地在清除剂存在的情况下,将化合物1溶解于强度足以除去可酸解除去的硫保护基但不足以除去可催化除去的氨基保护基的酸中。合适的这样的酸包括三氟乙酸和其他强酸如三氟甲磺酸,可选地存在共溶剂如二氯甲烷;合适的清除剂包括芳香族醚和硫化物如茴香醚和茴香硫醚,酚如甲酚,和最有效的硅烷,包括三烷基硅烷如三乙基硅烷和三异丙基硅烷和硅烷聚合物如聚(甲基氢硅氧烷);以及在聚(甲基氢硅氧烷)存在的情况下,特别适合的去保护剂是三氟乙酸。化合物2可以通过加入抗溶剂,例如质子非极性溶剂如烃或醚从反应混合物中分离出来;并且特别适合的抗溶剂是庚烷和甲基叔丁基醚的混合物。
在第二步中,用N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(A-磺酰氧基)乙酯对化合物2的硫醇阴离子进行烷基化以制备化合物3。
典型地,将化合物2溶解于强碱(例如,碱金属或碱土金属氢氧化物、碳酸盐、磷酸盐或醇盐,或氢氧化铵;或有机胺碱如四甲基胍、DBU(1,8-二氮杂二环[5.4.0]十一-7-烯),等;尤其是碱金属氢氧化物)的合适溶剂(例如,C1~6烷醇、二醇如1,2-乙二醇或1,3-丙二醇、醚如2-甲氧基乙醇,1,2-二甲氧基乙烷,或四氢呋喃等;尤其是C1~3烷醇如甲醇)的溶液中,以生成硫醇阴离子,加入二氨基磷酸酯(典型地是过量的,例如对化合物2至少过量1.5倍,尤其是至少2倍,例如约2.5倍),使反应混合物在合适的温度下保持一定时间直至反应完成。如果二氨基磷酸酯是以非极性非质子溶剂(例如,芳烃如甲苯)的溶液使用,那么一旦生成化合物3的反应完成,就对反应混合物进行中和,对水相和非水相进行分离,以除去未反应的二氨基磷酸酯起始原料。然后从水相中除去溶剂(例如,C1~6烷醇),并用非极性非质子溶剂(例如,酯如乙酸异丙酯)萃取水相,以除去更多未反应的二氨基磷酸酯起始原料。然后使水相的pH值进一步降低,化合物3就被萃取到非极性非质子溶剂中。化合物3可以通过除去溶剂而从溶液中分离出来;但是,如果溶剂是适合于该方法第三步的溶剂,那么化合物3可以在溶液中带入第三步中。
在第三步中,化合物3的硫原子被氧化,以制备化合物4。
典型地,将化合物3溶解于合适的溶剂中,加入氧化剂,然后将反应混合物保持足够的时间和足够的温度直至氧化反应完成。合适的溶剂/氧化剂组合包括C2~3烷酸/过氧化氢/过氧烷酸组合如乙酸/过氧乙酸和乙酸/过氧化氢/过氧乙酸,以及使用C2~3过氧烷酸或过氧三氟乙酸既作为溶剂又作为氧化剂。在有必要用试剂如甲硫醚淬灭过量的氧化剂之后,通过简单地浓缩来分离化合物4。特别合适的溶剂/氧化剂组合包括氧化作用在两相***中发生的组合,其中将化合物3溶解于非极性非质子溶剂如酯(例如,乙酸异丙酯)中,而氧化剂处于水溶液中。对于这些两相氧化作用的合适氧化剂包括硼酸盐和过氧化物如过硼酸盐和过硫酸盐,如过硫酸铵、过硫酸钠或过硫酸钾,特别适合的氧化剂是单过硫酸氢钾,如OXONETM(2KHSO5·KHSO4·K2SO4)。水相和非水相分离后,可选地洗涤非水相,以确保除去任何氧化剂,化合物4通过浓缩从非水相中分离出来。
在第四步中,对化合物4的氨基进行去保护,以制备莰佛胺,可选地接着生成莰佛胺的酸加成盐。
化合物4可以通过任何适合于除去氨基保护基而又不会影响莰佛胺分子其余部分的方法来实现去保护。当氨基保护基是可催化除去的氨基保护基时,化合物4通过催化还原或异构化可以很方便地去保护。
对于催化还原,典型地,将化合物4溶解于合适的溶剂如C1~4烷醇,或极性质子溶剂,或在非极性非质子溶剂中,尤其是在存在水时,例如在水存在时的乙酸异丙酯中,然后在还原催化剂(典型地为钯催化剂如钯黑、硫酸钡载钯和碳载钯)存在的情况下,与氢或氢供体如环己烯或1,4-环己二烯接触。在除去催化剂之后,莰佛胺可以通过加入将成为盐的抗溶剂的溶剂如非质子溶剂例如烃或卤代烃如二氯甲烷很方便地作为酸加成盐分离出来,接着加入选择的酸以生成盐,尤其是单独以无水酸的形式或在非质子溶剂中存在的酸,例如氯化氢气体。如果必要或需要,可以加入盐的其它抗溶剂例如醚如***、甲基叔丁基醚和四氢呋喃,尤其是甲基叔丁基醚。对于催化异构化,典型地在亲核烯丙基清除剂如仲胺存在下,可以使用零价钯络合物如四(三苯基膦)钯(O)。以合适的方式分离莰佛胺,通常得到酸加成盐。
化合物的用途和方法
本发明第一、第二、第三和第四方面的化合物(分别是结构式4、3、2和1的化合物)和本发明第五、第六、第七和第八方面的方法步骤,在已知的抗癌剂莰佛胺及其盐的制备中是很有用的。
另外,本发明第一方面的化合物也是活性的细胞毒性剂。因此,他们可以用于治疗癌症,尤其是可以用莰佛胺及其盐治疗的癌症类型。这些癌症包括哺乳动物的癌症,尤其是人类的癌症。特别是可治疗的癌症是对细胞凋亡诱导剂敏感的癌症,更具体地是那些表达或尤其过表达GST P1-1的癌症。当用其它抗癌疗法(即不是本发明第一方面的化合物)治疗时,表达或过表达GST P1-1的那些癌症,当与其它抗癌疗法组合使用时也尤其适合用本发明第一方面的化合物进行治疗。对于莰佛胺及其类似物的这种类型的组合化疗描述于美国专利申请公开号US2004/0138140和PCT国际公开号WO2004/045593中。这样的癌症包括脑癌、乳腺癌、膀胱癌、子宫癌、结肠直肠癌、食道癌、头颈癌、肾脏癌、肺癌、肝癌、卵巢癌、胰腺癌、***癌以及胃癌;白血病如ALL、AML、AMML、CLL、CML、CMML以及毛细胞白血病;霍奇金和非霍奇金淋巴瘤;间皮瘤、多发性骨髓瘤;以及骨骼和软组织的恶性瘤(肉瘤)。本发明第一具体实施方式的化合物可特别治疗的癌症包括乳腺癌、卵巢癌、结肠直肠癌和非小细胞肺癌。
本发明第九方面是含有本发明第一方面化合物的药物组合物,这些化合物用于治疗癌症和用于制备治疗癌症药物的应用,以及通过一般以治疗有效量给予这些化合物来治疗癌症的方法。
这些化合物可以采用任何适合于受治疗的主体以及主体疾病的特征的途径进行给药。给药的途径包括但不限于通过注射给药,包括静脉内、腹膜内、肌内、以及皮下注射,通过跨粘膜或经皮递送、采取局部施药、鼻内喷雾、栓剂等,或者可以口服给药。含有这些化合物的药物组合物可以可选地是脂质体制剂、乳剂、设计用来通过粘膜给药的剂型或经皮给药的剂型。对于这些给药方法中的每一个的合适剂型都可以在,例如,Remington:The Science andPractice of Pharmacy,20 ed.,A.Gennaro,ed.,Iippincott Williams &Wilkins,Philadelphia,Pennsylvania,U.S.A.,2003中找到。典型的组合物要么是口服的,要么是用于静脉输注的溶液,而其将含有所述化合物,并一般也含有一种或多种药用赋形剂。典型的制剂形式是片剂、用于静脉输注的溶液以及用于重配成溶液以便静脉输注的冻干粉末。
本发明第一方面化合物的治疗有效量为约50~3000mg/m2身体表面积,尤其是500~1500mg/m2。可以以1~35天的时间间隔进行给药;例如,以1~5周的时间间隔,尤其是1、2、3或4周的时间间隔以约500~1000mg/m2的量,或者以更高的频率,包括达在数天内(如5或7天)以1次/天的频率进行给药,每2、3或4周重复这种给药,或连续输注6~72h的时间段,也每2、3或4周重复这种给药;这样的给药灵活性将能够容易地与其它抗癌疗法实现组合治疗。
实施例
以下实施例将说明通过本发明的方法制备本发明化合物的方法和制备莰佛胺盐酸盐的方法,以及本发明第一方面的化合物作为抗癌剂的应用。
反应图解2表示通过本发明的方法制备本发明优选化合物的方法和制备莰佛胺盐酸盐的方法。N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸(化合物1A)的制备方法并未显示在反应图解2中,因为其将取决于其前体化合物的保护性质,但是从O-α-苄基-N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸进行制备的方法将在以下的实施例1中进行描述。
O-α-苄基-N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸可以通过肽合成的标准方法制备。使用容易获得的N-α-(苄氧羰基)-L-γ-谷氨酸α-苄基酯、S-三苯甲基-L-半胱氨酸和D-苯基甘氨酸为起始原料的方便的合成如下:通过与N-羟基琥珀酰亚胺和二环己基碳二酰亚胺在无水1,4-二氧杂环己烷中反应而作为N-羟基琥珀酰亚胺酯来活化N-α-(苄氧羰基)-L-γ-谷氨酸α-苄基酯。将N-α-(苄氧羰基)-L-γ-谷氨酸α-苄基酯的γ-N-羟基琥珀酰亚胺酯溶解于无水四氢呋喃中,并加入到S-三苯甲基-L-半胱氨酸和三乙胺的水溶液中,以给出O-α-苄基-N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酸。其作为N-羟基琥珀酰亚胺酯被活化,并与D-苯基甘氨酸偶联,以给出所需的O-α-苄基-N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸,偶联方式与γ-谷氨酸和半胱氨酸之间的偶联方式相同。
也可以使用类似的方法但使用不同的活化基团或方法来活化谷氨酸的γ-羧基和/或用于偶联的半胱氨酸羧基;正如可以使用以下方法:首先进行半胱氨酸-苯基甘氨酸的偶联,接着使所得的S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸与N-α-(苄氧羰基)-L-γ-谷氨酸α-苄基酯的偶联。也可以使用N-α-(苄氧羰基)-L-γ-谷氨酸的α-羧基的其它保护,条件是最终可以对α-羧基进行去保护,同时保持N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R))-苯基甘氨酸分子的其余部分不受影响。
反应图解2
实施例1.莰佛胺盐酸盐的制备
N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸,1A。
向装有过顶机械搅拌器、温度计和2L恒压滴液漏斗的5L三口圆底烧瓶中加入O-α-苄基-N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸(500g,590mmol)和甲醇(1L)。搅拌器设置成中速搅拌,以获得清澈琥珀色溶液,并在20min内加入NaOH水溶液(1.2L,1M,1.2mol)。在这段时间内,加入试剂使反应混合物放热,使内部反应温度升高到35℃,该温度在整个添加过程中被维持。开始沉淀出固体但是到添加结束时固体发生再溶解。然后将反应混合物冷却至室温并搅拌90min,随后在旋转蒸发器上减压除去甲醇(40mbar,最终浴温35℃),以获得N-α-(苯氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸的二钠盐水溶液。将混合物加入到装备有过顶机械搅拌器、温度计和2L恒压滴液漏斗的5L三口圆底烧瓶中,然后用水(1L)稀释。将混合物用冰/水浴冷却至0℃,然后在20min内加入盐酸水溶液(1.3L,1M,1.3mol)。在这段时间中,加入导致固体沉淀,混合物达到的最终pH值为4。将所得的淤浆在0℃下搅拌30min,通过真空过滤收集沉淀,并用水(1L)洗涤。将沉淀溶解于二氯甲烷(3L)中,然后将所得溶液转移到5L分液漏斗中。除去水溶液部分,有机相用水(2×1L)和饱和氯化钠溶液(1L)洗涤,然后用无水硫酸钠干燥(100g)。澄清后,在旋转蒸发器上并在减压(40mbar,35℃)下除去溶剂,得到琥珀色泡沫。固体产物进一步干燥过夜(40mbar,40℃),以给出作为白色粉末的N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸,1A(400g,89%的产率)。TLC分析显示为单点(Rf=0.50,硅胶,1:4甲醇/氯仿)。质子NMR谱(DMSO-d6)与所提出的结构一致。HPLC分析显示一个主峰(RT=22.1min;在30min内,20:80乙腈/0.1M NH4H2PO4水溶液至80:20乙腈/0.1M NH4H2PO4水溶液;流速=1.0mL/min;检测波长220nm;25℃)。
N-α-(苄氧羰基)-L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸,2A。
在吹氮气下向装有过顶机械搅拌器、温度计和恒压滴液漏斗的12L带夹套的三口圆底烧瓶中加入N-α-(苄氧羰基)-L-γ-谷氨酰基-S-三苯甲基-L-半胱氨酰基-2(R)-苯基甘氨酸(900g×93.7%纯度,843.3g,1.11mol)和甲苯(3.6L)。在吹氮气之后进行搅拌,并加入三氟乙酸(TFA,824mL,11.1mol)。在1h内加入聚(甲基氢硅氧烷)(PMHS,270g),维持25℃的温度,然后使反应混合物再搅拌17h。然后,反应通过在1.5h内加入1:1庚烷/甲基叔丁基醚(5.4L)而停止,沉淀出N-α-(苄氧羰基)-L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸。再搅拌2h后,过滤混合物,用庚烷(3.6L)洗涤沉淀,然后在40℃并在真空下干燥该沉淀。
N-α-(苄氧羰基)-L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸。精确分子量:517.15;MS(API-ES+):m/z518(M+H+);1H NMR(400MHz,DMSO-d6):δ8.78(1H,d,J=7.2Hz,NH),8.09(1H,d,J=8.0Hz,NH),7.62(IH,d,J=8.0Hz,NH),7.36(8H,m),7.21(2H,m),5.35(1H,d,J=7.6Hz),5.03(2H,s),4.56(1H,m),3.98(1H,m),2.68(1H,m),2.61(1H,m),2.26(2H,m),2.02(1H,m),1.78(1H,m)。
N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸,3A。
在吹氮气下向装有过顶机械搅拌器、温度计和恒压滴液漏斗的12L带夹套的三口圆底烧瓶中加入NaOH(49.46g,1.24mol)和甲醇(1.99L),在氮气氛下搅拌直至溶解,然后冷却至约5℃。加入N-α-(苄氧羰基)-L-γ-谷氨酰基-L-半胱氨酰基-2(R)-苯基甘氨酸(398.5g×80.3%纯度,320g,0.62mol),随后加入N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(4-溴苯磺酰氧基)乙酯(1487.5g×63.3%纯度,941.6g,1.55mol)在甲苯中的约1M溶液。在氮气氛下,在5h内加入NaOH(56.88g,1.42mol)甲醇(1.99L)溶液,同时将反应混合物的温度维持在5℃,然后使反应混合物在此温度下再搅拌17h。一边保持冷却,一边加入水(1.12L),用1M的磷酸调节反应混合物的pH值至6.9,加入甲苯(1.92L),并加入水(2.72L)。搅拌反应混合物,然后进行相分离,并除去甲苯相(含有过量的N,N,N′,N′-四(2-氯乙基)二氨基磷酸2-(4-溴苯磺酰氧基)乙酯)。用甲苯(1.92L)洗涤水层,进行相分离后,除去甲苯相。然后在真空下蒸馏水层,以除去甲醇,维持该批料温度(batch temperature)低于35℃。然后加入乙酸异丙酯(iPAc,1.6L),将pH值调节至6.9,进行相分离,随后除去乙酸异丙酯相(含有N,N,N′,N′-四(2-氯乙基)二氨基磷酸2(4-溴苯磺酰氧基)乙酯)。加入乙酸异丙酯(3.2L),并将pH值调节至4.8~4.85,进行相分离,留下乙酸异丙酯相(含有N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸)。将乙酸异丙酯(0.64L)加入到水相中,将pH值调节至4.8~4.85,进行相分离,然后将该乙酸异丙酯相与先前pH为4.8~4.85的乙酸异丙酯相合并。向合并的乙酸异丙酯相中加入水(1.6L),将pH值调节至5.25~5.3,进行相分离,然后除去水相。反复进行水洗,分离出水相后,在真空下蒸馏乙酸异丙酯相,以在进一步处理之前将批量体积降低至约3.15L。N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸就可以通过除去溶剂而从溶液中分离出来。
N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸。精确分子量:887.15;MS(API-ES+):m/z890,888(M+H+);1H NMR(400MHz,DMSO-d6):δ 8.93(1H,d,J=7.8Hz,NH),8.13(1H,d,J=8.6Hz,NH),7.60(1H,d,J=8.2Hz,NH),7.36(10H,m),5.35(1H,d,J=7.8Hz),5.03(2H,s),4.66(1H,m),3.97(3H,m),3.68(8H,m),3.30(8H,m),2.76(3H,m),2.57(1H,m),2.25(2H,tn),1.99(1H,m),1.76(1H,m)。
N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸,4A。
在吹氮气下向装有过顶机械搅拌器、温度计和恒压滴液漏斗的12L夹套的三口圆底烧瓶中加入来自前面步骤的N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]硫代]-L-丙氨酰基-2(R)-苯基甘氨酸(442.6g,0.50mol)的乙酸异丙酯(2.65L)溶液。在搅拌和氮气氛下,加入在水(2.66L)中的2KHSO5·KHSO4·K2SO4(OXONETM)(663.9g,1.08mol)溶液,维持温度为20~30℃,然后将反应混合物搅拌过夜以完成氧化过程。分离并除去水相,用水(885L)洗涤乙酸异丙酯相三次,每次洗涤后用淀粉/K1试纸检测过硫酸盐的存在。将乙酸异丙酯(2.65L)加入到乙酸异丙酯相中,然后,蒸馏合并后的溶液,以将体积减少到约1.77L。然后加入乙酸异丙酯(1.77L),溶液通过Karl Fischer滴定进行测试,以确保水含量不超过0.2%。使混合物搅拌过夜,过滤出的N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸,然后在35℃下进行干燥。
N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸。精确分子量:919.14;MS(API-ES+):m/z924,922,920(M+H+);1H NMR(400MHz,DMSO-d6):δ 8.81(1H,d,J=7.4Hz,NH),8.41(1H,d,J=8.2Hz,NH),7.61(1H,d,J=8.2Hz,NH),7.36(10H,m),5.30(1H,d,J=7.4Hz),5.03(2H,s),4.94(1H,m),4.25(2H,m),3.98(1H,m),3.68(8H,m),3.54(3H,m),3.33(9H,m),2.25(2H,m),1.99(1H,m),1.78(1H,m)。
莰佛胺盐酸盐
在2L高压釜中,通过以下方法对在乙酸异丙酯(350mL)中的碳载钯(5%,26.25g)进行预还原:进行三循环的氮气吹扫(真空、氮气、释放),接着三循环的氢气充入(3.4bar)和释放,在最后一次氢气充入后将混合物搅拌30min,接着进行另一次吹氮气。将N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[二[二(2-氯乙基)氨基]氧膦基]氧代]-乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸(190.6g×91.89%纯度,175g,190mmol)溶解于乙酸异丙酯(700mL)和水(53.9mL)中,并将溶液加入到高压釜内。重复进行三个循环氮气吹扫,接着进行两循环的氢气充入和释放,然后用氢气将高压釜加压至3.4bar,加热到30℃,并在此温下保持7.7h,通过HPLC监控反应的完成。通过硅藻土(CELITETM)来过滤反应混合物,以除去催化剂,过滤器用乙酸异丙酯(2×175mL)洗涤。合并的滤液和冲洗液通过真空蒸馏和再次加入乙酸异丙酯使脱水,然后,将溶液再浓缩到最终溶液质量为485.7g。向溶液中加入二氯甲烷(350mL),接着通入氯化氢气体(8.37g),并用甲基叔丁基醚(858mL)稀释。搅拌2.5h后,过滤反应混合物;并用甲基叔丁基醚(2×576mL)洗涤莰佛胺盐酸盐残留物,然后在55℃并在真空下干燥。
莰佛胺盐酸盐。精确分子量:785.10;MS(API-ES+):m/z800,788,786(M+H+);1H NMR(300MHz,DMSC-d6):δ8.81(1H,d,J=7Hz,NH),8.62(1H,d,J=7Hz,NH),8.4(2H,bs),7.35(5H,m),5.31(1H,d,J=7Hz),4.95(1H,m),4.36(2H,J=6Hz,q),3.87(1H,J=6Hz,t),3.66(8H,m),3.57(3H,m),3.31(9H,m),2.50(1H,s),2.35(1H,m),2.02(2H,m)。
实施例2.N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸,4A,的细胞毒性活性。
该实施例举例说明了N-α-(苄氧羰基)-L-γ-谷氨酰基-3-[[2-[[二[二(2-氯乙基)氨基]氧膦基]氧代]乙基]磺酰基]-L-丙氨酰基-2(R)-苯基甘氨酸,化合物4A,对体外人体癌细胞系的有益效果。这些结果被认为预示着在人体癌症化疗中的效果,因为在这些分析中试验的其它抗癌剂如莰佛胺已经显示出在人体中的抗癌活性。
人体癌细胞系HL-60(前髓细胞性白血病)和MX-1(乳腺癌)获自美国马里兰州贝塞斯达的国家癌症研究所。CellTiter-Glo分析试剂盒获自美国威斯康星州麦迪逊Promega公司,并根据制造商的指示说明使用。所有分析在三个相同的孔中进行,同时用二甲亚砜(DMSO)溶剂对照。细胞生长的程度被表达为来自溶剂对照孔(solvent control well)的信号的百分数。
Log-阶段细胞被胰蛋白酶化,通过离心收集,再悬浮于小体积的新鲜介质中,在锥虫蓝染色后测定活细胞的密度。细胞被稀释在新鲜介质(对于HL-60为5×103细胞/mL而对于MX-1细胞为3×103细胞/mL)中,在稀释使最终的DMSO浓度为0.5%之后,立即加入化合物4A(浓度为0.1至200μM之间,溶解于DMSO中,50μL),然后以150μL/孔向96-孔板加入悬浮液,培养数小时,以允许在粘附细胞的情况下粘连。培养细胞大约三个倍增时间(3天)。然后通过离心收集细胞,用CellTiter-Glo剂代替100μL的培养基上清液。在室温下培养15min之后,孔板用光度计解读。以对细胞系的IC50表示的化合物4A的活性为:HL-60,2.2μM,和MX-1,34.6μM。化合物在这种分析中与莰佛胺大约具有一样的效力。
实施例3.制剂和治疗实施例
用于口服给药的固体制剂通过组合以下物质而制备:
化合物4A 25.0%w/w
硬脂酸镁 0.5%w/w
淀粉 2.0%w/w
羟丙基甲基纤维素 1.0%w/w
微晶纤维素 71.5%w/w
将该混合物压成片剂或填充到硬明胶胶囊中,例如含有250mg的化合物4A。如果有必要,则可以通过施加成膜剂(例如,羟丙基甲基纤维素)、颜料(例如,二氧化钛)、以及增塑剂(例如,邻苯二甲酸二乙酯)的悬浮液对片剂进行涂敷,并通过蒸发溶剂来干燥该膜。
用于IV给药的制剂是通过在磷酸盐缓冲盐水中将化合物4A(例如以药用盐形式)溶解至1%w/v的浓度;并将该溶液消毒杀菌(例如通过灭菌过滤),然后密封在无菌容器中,其中容纳例如250mg的本发明化合物。
可替换地,通过将化合物4A(又例如以药用盐形式)溶解在合适的缓冲液(例如上述磷酸盐-缓冲盐水的磷酸盐缓冲液)中,对该溶液进行灭菌,然后将其分配到合适的无菌小瓶中,冻干该溶液以除去水,并密封该小瓶而制得冻干制剂。可通过加入消毒水重配该冻干制剂,并且该重配的溶液可以进一步用例如0.9%的氯化钠静脉注射液或5%的葡萄糖静脉注射液的溶液加以稀释以用于给药。
将稀释在5%的葡萄糖静脉注射液中的化合物4A,在30min内以100mg/m2的初始剂量静脉注射给药至患有代谢卵巢癌的患者;并将该剂量增大至250mg/m2、500mg/m2、750mg/m2、以及1000mg/m2。以1周的间隔期给予该化合物。以2周和3周的间隔期将相同的剂量增加给药至患有同样癌症的其他患者。
虽然已结合具体实施方式和实施例描述了本发明,但对参考了该技能和本披露内容的本领域普通技术人员来说是显而易见的:具体披露的物质和方法的等同替换也可用于本发明;并且这些等同替换包括在所附权利要求书的范围内。
Claims (3)
1.一种以下结构式的化合物或其盐:
2.一种含有权利要求1的化合物或其盐的药物组合物。
3.权利要求1的化合物或其盐在用于制备治疗癌症的药物中的应用,其中所述癌症是前髓细胞性白血病或乳腺癌。
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US11/018,391 | 2004-12-21 | ||
US11/018,391 US8198247B2 (en) | 2004-12-21 | 2004-12-21 | Process for and intermediates in the preparation of canfosfamide and its salts |
PCT/US2005/042693 WO2006068769A1 (en) | 2004-12-21 | 2005-11-23 | Process for and intermediates in the preparation of canfosfamide and its salts, pharmaceutical compositions containing some intermediates, and their use as anticancer agents |
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US8324426B2 (en) | 2008-08-28 | 2012-12-04 | Telik, Inc. | Formulations of canfosfamide and their preparation |
US20100056825A1 (en) * | 2008-08-28 | 2010-03-04 | Telik, Inc. | Formulations of canfosfamide and their preparation |
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US6417397B1 (en) * | 1999-10-04 | 2002-07-09 | The Regents Of The University Of California, San Diego | N-substituted alkylamino acids for use as amino-protecting groups |
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CN101080251A (zh) | 2007-11-28 |
EA016052B1 (ru) | 2012-01-30 |
BRPI0519141A2 (pt) | 2008-12-30 |
CA2587088A1 (en) | 2006-06-29 |
KR20070089795A (ko) | 2007-09-03 |
EA200701180A1 (ru) | 2008-04-28 |
AU2005319579B2 (en) | 2011-07-21 |
TW200633717A (en) | 2006-10-01 |
US20120238772A1 (en) | 2012-09-20 |
AU2005319579A1 (en) | 2006-06-29 |
EP1827605B1 (en) | 2014-03-26 |
US8198247B2 (en) | 2012-06-12 |
EP1827605A1 (en) | 2007-09-05 |
MX2007007215A (es) | 2007-08-14 |
JP2008524327A (ja) | 2008-07-10 |
WO2006068769A1 (en) | 2006-06-29 |
US8334266B2 (en) | 2012-12-18 |
AR052167A1 (es) | 2007-03-07 |
IL182835A0 (en) | 2007-08-19 |
JP5060306B2 (ja) | 2012-10-31 |
ZA200704318B (en) | 2008-09-25 |
US20060135409A1 (en) | 2006-06-22 |
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