CN101421242A - 二酰胺衍生物 - Google Patents
二酰胺衍生物 Download PDFInfo
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- CN101421242A CN101421242A CNA2007800135721A CN200780013572A CN101421242A CN 101421242 A CN101421242 A CN 101421242A CN A2007800135721 A CNA2007800135721 A CN A2007800135721A CN 200780013572 A CN200780013572 A CN 200780013572A CN 101421242 A CN101421242 A CN 101421242A
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- amino
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及式(I)的二酰胺衍生物及其生理上可接受的盐,其中R1、R2、R3、R4、R5和R6如说明书中所定义。这些化合物抑制凝血因子Xa,并可用作药物。
Description
本发明涉及式(I)二酰胺衍生物或者其药学上可接受的盐,
其中
R2和R3彼此独立地是氢、C1-6烷基、羧基、C1-6烷氧基羰基、氨基甲酰基、单或二取代的氨基-羰基、任选取代的芳基羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、羟基C1-6烷基、卤代C1-6烷基、氰基C1-6烷基、C1-6烷氧基C1-6烷基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、任选取代的芳基C1-6烷基、任选取代的杂环基C1-6烷基、任选取代的杂芳基C1-6烷基、任选取代的芳基C1-6烷氧基C1-6烷基、任选取代的杂芳基C1-6烷氧基C1-6烷基、任选取代的杂环基C1-6烷氧基C1-6烷基,
R1和R4彼此独立地是氢、C1-6烷基、氰基、C1-6烷氧基羰基、C2-6链烯氧基羰基、C2-6炔氧基羰基、羟基C1-6烷基、C1-6烷氧基羰基、羧基、单-或二-C1-6烷基取代的氨基-羰基、氨基羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基或者任选取代的芳基羰基,
R5和R6彼此独立地是氯、氟或溴。
R2和R3优选彼此独立地是氢、C1-6烷基、羧基、C1-6烷氧基羰基、氨基甲酰基、单或二取代的氨基-羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基、芳基、任选取代的杂芳基、任选取代的杂环基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、氨基C1-6烷基、单或二取代的氨基C1-6烷基、任选取代的杂环基C1-6烷基或任选取代的杂芳基C1-6烷基,
R1和R4优选彼此独立地是氢或C1-6烷基。
此外,本发明涉及此类化合物的制备方法、含有此类化合物的药物制剂以及这些化合物在制备药物制剂中的用途。
本发明化合物是活性化合物,它们抑制凝血因子Xa。因此这些化合物影响血液凝固。因而它们抑制血栓的形成,并能够用于治疗和/或预防血栓形成疾病,尤其例如动脉和静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病(PAOD)、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风(脑血栓形成)、炎症和动脉硬化。它们潜在地有益于治疗与溶栓疗法和再狭窄有关的急性血管闭合(例如在经腔冠状血管成形术(PTCA)或者冠状或外周动脉的旁路移植之后和在长期血液透析患者的血管通路开放的维持中)。本发明的Xa因子抑制剂可以与具有不同作用模式的抗凝剂或者与血小板聚集抑制剂或者与溶栓剂构成联合疗法的一部分。此外,这些化合物对肿瘤细胞有作用,并预防转移。它们因此也能够用作抗肿瘤剂。
其他在结构上不与本发明化合物相关的Xa因子抑制剂以前已被表明可抑制血栓的形成和治疗相关疾病(WO 03/045912)。不过,仍然需要具有改善的药理性质(例如提高针对凝血因子Xa的选择性)的新颖Xa因子抑制剂。
本发明提供为Xa因子抑制剂的新颖的化合物。本发明化合物意外地抑制凝血因子Xa,并且与本领域其他已知的化合物相比还表现出改善的药理性质。
本发明的化合物能够形成药学上可接受的酸加成盐。这类药学上可接受的盐的实例是本发明化合物与生理学上相容的无机酸或有机酸的盐,所述无机酸例如为盐酸、硫酸、亚硫酸或磷酸;所述有机酸例如为甲磺酸、对-甲苯磺酸、乙酸、乳酸、三氟乙酸、柠檬酸、富马酸、马来酸、酒石酸、琥珀酸或水杨酸。术语“药学上可接受的盐”指此类盐。上述酸加成盐是优选的。
除非另有说明,下列定义供阐述和限定用于在文中描述本发明的各种术语的含义和范围。
术语“C1-6烷基”表示具有一至六个碳原子的直链或支链的一价烷基。本术语还可以用下列基团举例说明:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基。甲基是更优选的。
术语“C2-6炔基”,单独或与其它基团组合的,表示含有叁键和2至6个碳原子的直链或支链的烃基,例如2-丙炔基。
术语“卤代C1-6烷基”表示被一个或多个相同或不同的卤原子取代的C1-6烷基,所述卤原子独立地选自氯、氟和溴。
术语“氰基C1-6烷基”表示被一个或多个氰基(优选一个氰基)取代的C1-6烷基。
术语“羟基C1-6烷基”表示被一个或多个羟基(优选一个或两个羟基)取代的C1-6烷基。
术语“C3-7环烷基”,单独或与其它基团组合的,表示具有三至七个环碳的饱和一价环烃基团,例如环丙基、环丁基、环己基。
术语“C1-6烷氧基”,单独或与其它基团组合的,表示基团R’-O-,其中R’是C1-6烷基。
术语“C2-6烯基”,单独或与其它基团组合的,表示含有二至六个碳原子的、包含烯键的直链或支链烃基,例如乙烯基、2-丙烯基。
术语“芳基”,单独或者与其他基团组合的,表示苯基或萘基,优选苯基。术语“任选取代的芳基”指任选被一至五个、优选一至三个取代基取代的上述芳基,所述取代基独立选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、硝基、氰基、酰基、氨基甲酰基、单或二取代的氨基、氨基羰基、单或二取代的氨基-羰基、氨基羰基C1-6烷氧基、单或二取代的氨基-羰基-C1-6烷氧基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基、芳基C1-6烷氧基、杂芳基C1-6烷氧基、杂环基C1-6烷氧基、C1-6烷氧基羰基C1-6烷氧基、氨基甲酰基C1-6烷氧基和羧基C1-6烷氧基,优选选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、单-C1-6烷基取代的氨基、二-C1-6烷基取代的氨基、氨基C1-6烷基、单-C1-6烷基取代的氨基-C1-6烷基、二-C1-6烷基取代的氨基-C1-6烷基、硝基和氰基。
术语“杂环基”,单独或者与其他基团组合的,表示三至八个环原子的非芳族单环基团,其中一个或两个环原子是选自N、O或S(O)n(其中n是0至2的整数)的杂原子,其余环原子是C。杂环基的一个或两个环碳原子可以被羰基代替。术语“任选取代的杂环基”指任选独立地被一个、两个或三个、优选一个或两个取代基取代的上述杂环基,所述取代基选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、硝基、氰基、酰基、氨基甲酰基、单或二取代的氨基、氨基羰基、单或二取代的氨基-羰基、氨基羰基C1-6烷氧基、单或二取代的氨基-羰基-C1-6烷氧基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基、芳基C1-6烷氧基、杂芳基C1-6烷氧基、杂环基C1-6烷氧基、C1-6烷氧基羰基C1-6烷氧基、氨基甲酰基C1-6烷氧基和羧基C1-6烷氧基,优选选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、酰基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、单-C1-6烷基取代的氨基、二-C1-6烷基取代的氨基、氨基C1-6烷基、单-C1-6烷基取代的氨基-C1-6烷基、二-C1-6烷基取代的氨基-C1-6烷基、硝基、氨基甲酰基、单或二取代的氨基-羰基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基和氰基,更优选选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、单-C1-6烷基取代的氨基、二-C1-6烷基取代的氨基、氨基C1-6烷基、单-C1-6烷基取代的氨基-C1-6烷基、二-C1-6烷基取代的氨基-C1-6烷基、硝基和氰基。
术语“杂芳基”,单独或者与其他基团组合的,表示5至12个环原子的单环或二环基团,其具有至少一个芳环,该芳环含有一个、两个或三个选自N、O和S的环杂原子,其余环原子是C,不言而喻杂芳基基团的连接点位于芳环上。杂芳基的一个或两个环碳原子可以被羰基代替。术语“任选取代的杂芳基”指任选地独立地被一个、两个或三个、优选一个或两个取代基取代的上述杂芳基,所述取代基选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、硝基、氰基、酰基、氨基甲酰基、单或二取代的氨基、氨基羰基、单或二取代的氨基-羰基、氨基羰基C1-6烷氧基、单或二取代的氨基-羰基-C1-6烷氧基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基、芳基C1-6烷氧基、杂芳基C1-6烷氧基、杂环基C1-6烷氧基、C1-6烷氧基羰基C1-6烷氧基、氨基甲酰基C1-6烷氧基和羧基C1-6烷氧基,优选选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、单-C1-6烷基取代的氨基、二-C1-6烷基取代的氨基、氨基C1-6烷基、单-C1-6烷基取代的氨基-C1-6烷基、二-C1-6烷基取代的氨基-C1-6烷基、硝基、氨基甲酰基、单或二取代的氨基-羰基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基和氰基。
术语“任选取代的苯基”指任选被一至五个、优选一至三个取代基取代的苯基,所述取代基独立地选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、硝基、氰基、酰基、氨基甲酰基、单或二取代的氨基、氨基羰基、单或二取代的氨基-羰基、氨基羰基C1-6烷氧基、单或二取代的氨基-羰基-C1-6烷氧基、羟基-C1-6烷基、羧基、C1-6烷氧基羰基、芳基C1-6烷氧基、杂芳基C1-6烷氧基、杂环基C1-6烷氧基、C1-6烷氧基羰基C1-6烷氧基、氨基甲酰基C1-6烷氧基和羧基C1-6烷氧基,优选选自:卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、氨基、单-C1-6烷基取代的氨基、二-C1-6烷基取代的氨基、氨基C1-6烷基、单-C1-6烷基取代的氨基-C1-6烷基、二-C1-6烷基取代的氨基-C1-6烷基、硝基和氰基。
术语“单取代的氨基”和“二取代的氨基”,单独或者与其他基团组合的,分别指-NHR和-NRR’,其中R和R’独立地选自:羟基、C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、氨基甲酰基C1-6烷基、卤代C1-6烷基、C3-7环烷基、C3-7环烷基C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、单-或二-C1-6烷基取代的氨基-磺酰基、单-或二-C1-6烷基取代的氨基-亚磺酰基、单-或二-C1-6烷基取代的氨基-硫基、单-或二-C1-6烷基取代的氨基-C1-6烷基、单-或二-C1-6烷基取代的氨基羰基-C1-6烷基、酰基、卤代C1-6烷基羰基和C1-6烷氧基羰基,优选选自:羟基、C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、氨基甲酰基C1-6烷基、卤代C1-6烷基、C3-7环烷基、C3-7环烷基C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、单-或二-C1-6烷基取代的氨基-磺酰基、单-或二-C1-6烷基取代的氨基-亚磺酰基、单-或二-C1-6烷基取代的氨基-硫基、单-或二-C1-6烷基取代的氨基-C1-6烷基、单-或二-C1-6烷基取代的氨基羰基-C1-6烷基、酰基和C1-6烷氧基羰基,优选选自:羟基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、C3-7环烷基、C3-7环烷基C1-6烷基、C1-6烷氧基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、单-或二-C1-6烷基取代的氨基-磺酰基、单-或二-C1-6烷基取代的氨基-亚磺酰基、单-或二-C1-6烷基取代的氨基-硫基、酰基和C1-6烷氧基羰基。
术语“酰基”,单独或者与其他基团组合的,指-C(=O)R,其中R是H或者C1-6烷基。
上文给出定义的化学基团的优选基团是在实施例中具体例证的那些。
“药学上可接受的赋形剂”指可用于制备药物组合物的赋形剂,它一般是安全、无毒的,在生物学或其他方面都不是不可取的,包括对兽用和人类药用而言是可接受的赋形剂。用在说明书和权利要求书中的“药学上可接受的赋形剂”包括一种和多种这样的赋形剂。
具有相同分子式、但是在它们的原子键合性质或顺序或者它们的原子空间排列上不同的化合物被称为“异构体”。在它们的原子空间排列上不同的异构体被称为“立体异构体”。彼此不是镜像的立体异构体被称为“非对映异构体”,彼此是不可叠加的镜像的那些立体异构体被称为“对映体”。当化合物具有不对称中心时,例如,如果碳原子与四个不同的基团键合,则可能存在一对对映体。对映体能够以不对称中心的绝对构型为特征,根据Cahn、Ingold和Prelog的R-和S-顺序规则加以描述,或者根据分子使偏振光平面旋转的方式命名为右旋或左旋(也就是分别为(+)-或(-)-异构体)。手性化合物能够以单一的对映体或者其混合物存在。含有等比例对映体的混合物被称为“外消旋混合物”。
如上所述,本发明的化合物是活性化合物,它们抑制凝血因子Xa。因此这些化合物抑制上述因子诱导的血小板激活以及血浆的血液凝固。因而它们抑制血栓的形成,并且能够用于治疗和/或预防血栓形成疾病,尤其例如动脉和静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病(PAOD)、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风(脑血栓形成)、炎症和动脉硬化。本发明化合物还可以用于治疗与溶栓疗法和再狭窄有关的急性血管闭合(例如在经腔冠状血管成形术(PTCA)或者冠状或外周动脉的旁路移植之后和在长期血液透析患者的血管通路开放的维持中)。本发明的Xa因子抑制剂可以与具有不同作用模式的抗凝剂或者与血小板聚集抑制剂或者与溶栓剂构成联合疗法的一部分。此外,这些化合物对肿瘤细胞有作用,并预防转移。它们因此也能够用作抗肿瘤剂。
血栓形成疾病、尤其是动脉或深静脉血栓形成的预防和/或治疗是优选的适应征。
因此本发明还涉及包含本发明化合物和药学上可接受的赋形剂的药物组合物。
本发明还包括本发明化合物,其用作治疗活性物质,尤其用作治疗和/或预防与凝血因子Xa有关的疾病的治疗活性物质,特别是用作治疗和/或预防血栓形成疾病、动脉血栓形成、静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风、炎症、动脉硬化、与溶栓疗法或再狭窄有关的急性血管闭合和/或肿瘤的治疗活性物质。
在另一种优选的实施方案中,本发明涉及治疗性和/或预防性治疗与凝血因子Xa有关的疾病的方法,特别治疗性和/或预防性治疗血栓形成疾病、动脉血栓形成、静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风、炎症、动脉硬化、与溶栓疗法或再狭窄有关的急性血管闭合和/或肿瘤的方法,该方法包括对人类或动物施用如上所定义的化合物。
本发明还包括如上所定义的化合物治疗性和/或预防性治疗与凝血因子Xa有关的疾病的用途,特别是治疗性和/或预防性治疗血栓形成疾病、动脉血栓形成、静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风、炎症、动脉硬化、与溶栓疗法或再狭窄有关的急性血管闭合和/或肿瘤的用途。
本发明还涉及本发明化合物在制备用于治疗性和/或预防性治疗与凝血因子Xa有关的疾病的药物中的用途,所述药物特别是用于治疗性和/或预防性治疗血栓形成疾病、动脉血栓形成、静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风、炎症、动脉硬化、与溶栓疗法或再狭窄有关的急性血管闭合和/或肿瘤的药物。这类药物包含本发明化合物。
本发明化合物对凝血因子Xa的抑制作用可以借助如下文所描述的显色肽底物测定法加以证明。
在最终体积150μl、微量滴定平板中采用下列条件用分光光度法测量Xa因子活性:使用200nM的显色底物S-2222(Chromogenix AB,Sweden)在3nM的酶浓度下测试人Xa因子(Enzyme Research Laboratories)的抑制作用。酶和底物反应的动力学与时间和酶浓度都呈线性。将抑制剂溶于DMSO中,在直至100μM的各种浓度下测试。将抑制剂用HNPT缓冲液稀释,HNPT缓冲液由HEPES 100mM、NaCl 140mM、PEG 6000 0.1%和吐温800.02%,pH7.8组成。在室温下,在405nm下跟踪人Xa因子对S-2222的裂解作用达5分钟。借助自动读数器从7个时间点(1分钟)拟合的线性回归斜率测定反应的速率。借助线性回归拟合从线性相至少4个时间点的斜率测定每种抑制剂浓度的初始速率(mOD/min2)。按照Cheng和Prusoff方法[Cheng,Y.C.;Prusoff,W.H.抑制常数(Ki)和引起酶反应的50%抑制(IC50)的抑制剂浓度之间的关系(Relationship between theinhibition constant(Ki)and the concentration of the inhibitor that causes50 percent inhibition(IC50)of an enzyme reaction).Biochem.Pharmacol.1973,22,3099-3108.],根据预先测定的IC50和各自的Km计算表观解离常数Ki(Ki=IC50/(1+S/Km))。按照Eadie所述[Eadie G.S.毒扁豆碱和新斯的明对胆碱酯酶的抑制作用(The inhibition of cholinesterase byphysostigmine and prostigmine).J.Biol.Chem.1942,146,85-93.],在采用至少5种从0.5至15倍Km的底物浓度的试验条件下测定所用底物的Km,[Lottenberg R,Hall JA,Blinder M,Binder EP,Jackson CM.,凝血酶对多肽对硝基苯胺底物的作用。在不同反应条件下的底物选择性和水解测试(The action of thrombin on peptide p-nitroanilide substrates.Substrateselectivity and examination of hydrolysis under different reactionconditions.)Biochim Biophys Acta.1983年2月15日;742(3):539-57]。S-2222的Km等于613μM。
而且,低分子量底物的活性可以在“凝血酶原时间”(PT)凝固试验中加以鉴别。将底物制备成在DMSO中的10mM溶液,然后在相同溶剂中达到所需稀释比。然后,将0.25ml人血浆(从用1/10体积的108mM柠檬酸钠抗凝的全血中得到)置于仪器专用的样品容器。然后在每种情况下将5μl的底物-稀释系列的每种稀释液与所提供的血浆混合。将这种血浆/抑制剂混合物在37℃下孵育2分钟。然后,将测量容器中的50μl血浆/抑制剂混合物吸移至半自动装置(ACL,Automated Coagulation Laboratory(Instrument Laboratory))。加入0.1ml (重组人组织因子,合并有钙缓冲液和合成磷脂,Dade Behring,Inc.,目录号B4212-50)引发凝固反应。用光学方法从ACL测定直至纤维蛋白交联的时间。通过对数据进行指数回归(XLfit),测定引起PT凝固时间加倍的抑制剂浓度。
此外,本发明化合物能够以活化部分促凝血酶原激酶时间(aPTT)为特征。这种凝血试验例如可以在ACL 300凝血系统自动分析仪(Instrumentation Laboratory)上进行。将底物制备成在DMSO中的10mM溶液,然后在相同溶剂中达到所需稀释比。使用FS活化的PTT试剂(纯化的大豆磷脂,1.0×10-4M鞣花酸,稳定剂与防腐剂,DadeBehring,Inc.,目录号B4218-100)进行试验。然后,向0.25ml等分试样的人血浆(从用1/10体积的108mM柠檬酸钠抗凝的全血中得到)加入至少6种浓度的5μl供试化合物。将4℃的含有1/50体积(vol.)抑制剂(在溶剂中)的50μl血浆与50μl FS活化的PTT试剂在37℃水中孵育3min,然后加入37℃的50μl CaCl2.2H2O 25mM水溶液。用光学方法从ACL中测定直至纤维蛋白交联的时间。通过对数据进行指数回归(XLfit),测定引起APTT凝固时间加倍的抑制剂浓度。
本发明的活性化合物的Ki值优选为约0.001至50μM,尤其约0.001至1μM。PT值优选为约0.5至100μM,尤其约0.5至10μM。aPTT值优选为约0.5至100μM,尤其约0.5至10μM。
实施例 | Ki[μM]Xa因子 |
1.4(1S,2R)对映异构体 | 0.003 |
本发明化合物和/或它们的药学上可接受的盐可以用作药物,例如药物制剂形式的用于肠内、肠胃外或局部施用的药物。它们可以例如被经口施用,例如以片剂、包衣片、糖衣剂、硬和软明胶胶囊剂、溶液剂、乳剂或混悬液形式;直肠施用,例如以栓剂形式;肠胃外施用,例如以注射溶液或混悬液或者输注溶液形式;或者局部施用,例如以软膏剂、乳膏剂或油剂形式。口服施用是优选的。
药物制剂的生产可以按照任何本领域技术人员所熟悉的方式进行:将所述本发明的化合物和/或它们的药学上可接受的盐、以及任选其他有治疗价值的物质与适当的、无毒、惰性、治疗相容性固体或液体载体材料和(如果需要的话)通常的药物辅助剂一起制成盖仑制剂施用形式。
适当的载体材料不仅有无机载体材料,而且还有有机载体材料。因而,例如,乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐可以用作片剂、包衣片、糖衣剂和硬明胶胶囊剂的载体材料。适合于软明胶胶囊剂的载体材料例如是植物油、蜡、脂肪以及半固体和液体多元醇(不过根据活性成分的性质,在软胶囊剂的情况下可不需要载体)。适于制备溶液剂和糖浆剂的载体材料例如是水、多元醇、蔗糖、转化糖等。适于注射溶液的载体材料例如是水、醇、多元醇、甘油和植物油。适于栓剂的载体材料例如是天然或硬化的油、蜡、脂肪和半液体或液体多元醇。适于局部制剂的载体材料是甘油酯、半合成与合成的甘油酯、氢化油、液体蜡、液体石蜡、液体脂肪醇、甾醇、聚乙二醇和纤维素衍生物。
常用的稳定剂、防腐剂、湿润和乳化剂、稠度改良剂、口味改良剂、改变渗透压的盐、缓冲物质、增溶剂、着色剂、掩蔽剂和抗氧化剂被认为可作药物辅助剂。
本发明的化合物的剂量可以在宽泛的限度内变化,这取决于所要控制的疾病、患者的年龄与个体状况和施用的方式,当然在每种特定情况下将与个体需要相适应。就成年患者而言,值得考虑的日剂量为约1-1000mg、尤其约1-300mg。取决于疾病的严重性和确切的药动学特性,所述化合物可以以一个或数个日剂量单位、例如1至3个剂量单位施用。
药物制剂适宜含有约1-500mg、优选1-100mg的本发明化合物。
下列实施例用于更加详细地阐述本发明。但是,它们不旨在以任何方式限制本发明的范围。
实施例
实施例1
1.1 在氩气气氛下,将3-氧杂二环[3.1.0]己烷-2,4-二酮(1.0g;CAS5617-74-3)溶于THF(30ml)中。向该溶液中加入1-(4-氨基-3-氟-苯基)-1H-吡啶-2-酮(2.0g;CAS 536747-52-1,根据C.F.Bigge等,专利申请WO2003045912制备)。将混悬液在室温下搅拌过夜,然后浓缩。将残留物混悬于1N HCl中。将固体过滤,依次用1N HCl、水和环己烷洗涤,然后干燥得到(1RS,2SR)-2-[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基氨基甲酰基]-环丙烷甲酸(1.88g),为灰白色固体。MS 317.1([M+H]+)
1.2 将(1RS,2SR)-2-[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基氨基甲酰基]-环丙烷甲酸(1.87g)的甲醇(70ml)混悬液冷却至0℃,然后用亚硫酰氯(0.55ml)处理。将溶液在0℃搅拌3小时,然后浓缩得到(1RS,2SR)-2-[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基氨基甲酰基]-环丙烷甲酸甲酯(2.1g),为淡黄色固体,其无需进一步纯化直接用于下一步反应中。MS 329.3([M-H]-)
1.3 在氩气气氛、室温下,用三甲基铝溶液(13ml;2M的庚烷溶液)处理2-氨基-5-氯吡啶(3.3g)的二噁烷(30ml)溶液。在室温下将反应混合物搅拌2小时。加入(1RS,2SR)-2-[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基氨基甲酰基]-环丙烷甲酸甲酯(2.1g)的二噁烷(30ml)溶液。将反应混合物加热至100℃过夜。然后,加入12ml水。在室温下搅拌15分钟后,加入Na2SO4。继续搅拌15分钟。滤除固体并用CH2Cl2洗涤。浓缩滤液。通过色谱法(硅胶;梯度:CH2Cl2->CH2Cl2/MeOH 95:5)纯化粗产物,得到(1RS,2SR)-环丙烷-1,2-二甲酸1-[(5-氯-吡啶-2-基)-酰胺]2-{[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基]-酰胺}(2.3g),为黄色固体。MS 425.0([M-H]-)
1.4 将(1RS,2SR)-环丙烷-1,2-二甲酸1-[(5-氯-吡啶-2-基)-酰胺]2-{[2-氟-4-(2-氧代-2-吡啶-1-基)-苯基]-酰胺}(442mg)的CH2Cl2/MeOH 2:1(得到澄清溶液所需的最小量)溶液施用于HPLC系统,采用Chiralcel OD固定相并用30%异丙醇的庚烷溶液作为洗脱剂。浓缩第一种洗脱出的对映异构体。将残留物用叔丁基-甲基醚研磨,然后过滤,干燥,得到(1S,2R)-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺}(126mg),为白色固体。对映异构体纯度:99% ee。
用类似的方法分离得到第二种洗脱出的对映异构体,得到(1R,2S)-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺}(118mg),为白色固体。对映异构体纯度:78% ee。
实施例2
2.1 用3.1g NaOH处理1-甲基-环丙烷-1,2-二甲酸二甲酯(4.5g;JACS1958,80,6568)的甲醇(20ml)和水(20ml)溶液。在50℃下将反应混合物搅拌过夜,然后浓缩。将残留的白色固体溶解于水(25ml)中,用乙醚(25ml)洗涤。用3N HCl将水层调节至pH1,然后用EtOAc萃取。将有机萃取物干燥(MgSO4)、过滤并浓缩,得到(1SR,2RS)-1-甲基-环丙烷-1,2-二甲酸(3.2g),为白色固体,其无需进一步纯化,直接用于下一步反应。
2.2 在0℃、氩气气氛下,用三氟乙酸酐处理起始原料(1SR,2RS)-1-甲基-环丙烷-1,2-二甲酸(3.2g)。在0℃将反应混合物搅拌2小时,然后浓缩,并从THF中蒸干三次,得到(1SR,5RS)-1-甲基-3-氧杂-二环[3.1.0]己烷-2,4-二酮(2.9g),为淡黄色液体,其无需进一步纯化,直接用于下一步反应。
2.3 在0℃、氩气气氛下,将(1SR,5RS)-1-甲基-3-氧杂-二环[3.1.0]己烷-2,4-二酮(2.9g)的THF(30ml)溶液用2-氨基-5-氯吡啶处理。将反应混合物(开始为溶液,后来为混悬液)在0℃搅拌1小时,然后在室温下搅拌过夜。将混合物用水溶解,然后用EtOAc萃取。将有机层干燥(MgSO4)、过滤、浓缩并用CH2Cl2重结晶两次,得到(1SR,2RS)-2-(5-氯-吡啶-2-基氨基甲酰基)-1-甲基-环丙烷甲酸(2.6g),为白色固体。MS 255.3([M-H]-)
2.4 在0℃和氩气气氛下,用亚硫酰氯(1.5ml)处理(1SR,2RS)-2-(5-氯-吡啶-2-基氨基甲酰基)-1-甲基-环丙烷甲酸(2.2g)的MeOH(50ml)溶液。将反应混合物在室温下搅拌过夜,然后浓缩。用色谱法(硅胶;梯度:CH2Cl2->CH2Cl2/MeOH 95:5)纯化粗产物,得到(1SR,2RS)-2-(5-氯-吡啶-2-基氨基甲酰基)-1-甲基-环丙烷甲酸甲酯(2.1g),为白色固体。MS 269.4([M+H]+)
2.5 在室温、氩气气氛下,用三甲基铝溶液(1.49ml;2M的庚烷溶液)处理1-(4-氨基-3-氟-苯基)-1H-吡啶-2-酮(0.61g;CAS 536747-52-1,根据C.F.Bigge等,专利申请号WO 2003045912制备)的二噁烷(4ml)溶液。将反应混合物在室温下搅拌2小时。加入(1SR,2RS)-2-(5-氯-吡啶-2-基氨基甲酰基)-1-甲基-环丙烷甲酸甲酯(0.2g)的二噁烷(4ml)溶液。将反应混合物加热至100℃过夜,然后冷却至室温,用0.8ml H2O处理。在室温下搅拌15分钟后,加入Na2SO4。继续搅拌15分钟。然后过滤固体,用CH2Cl2洗涤。用1N HCl洗涤滤液。将有机层干燥(MgSO4)并浓缩。用色谱法(硅胶;梯度:CH2Cl2->CH2Cl2/MeOH 95:5)纯化粗产物,得到(1SR,2RS)-1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-吡啶-1-基)苯基]-酰胺}(0.175g),为黄色固体。MS 439.1([M+H]+)
2.6 通过制备型HPLC,采用20% EtOH的庚烷溶液作为洗脱剂,并采用Chiralcel OD固定相,将(1SR,2RS)-1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-吡啶-1-基)苯基]-酰胺}(170mg)分离为其对映异构体1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺](1S,2R)-1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺}和(1R,2S)-1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺}。
第一种洗脱出的对映异构体:45mg,灰白色固体。MS 439.3([M-H]-)
第二种洗脱出的对映异构体:76mg,灰白色固体。MS 439.3([M-H]-)
两种对映异构体的构型都未指定。
实施例A
含有下列成分的薄膜衣片可以按照常规方式制造:
成分 | 每片 | |
片芯: | ||
本发明化合物 | 10.0mg | 200.0mg |
微晶纤维素 | 23.5mg | 43.5mg |
含水乳糖 | 60.0mg | 70.0mg |
聚维酮K30 | 12.5mg | 15.0mg |
淀粉羟乙酸钠 | 12.5mg | 17.0mg |
硬脂酸镁 | 1.5mg | 4.5mg |
(片芯重量) | 120.0mg | 350.0mg |
膜衣: | ||
羟丙基甲基纤维素 | 3.5mg | 7.0mg |
聚乙二醇6000 | 0.8mg | 1.6mg |
滑石粉 | 1.3mg | 2.6mg |
氧化铁(黄) | 0.8mg | 1.6mg |
二氧化钛 | 0.8mg | 1.6mg |
将活性成分过筛,与微晶纤维素混合,将混合物用聚乙烯吡咯烷酮的水溶液制粒。将颗粒与淀粉羟乙酸钠和硬脂酸镁混合,分别压制成120或350mg的片芯。向片芯涂以上述膜衣的水溶液/混悬液。
实施例B
可以按照常规方式制造含有下列成分的胶囊剂:
成分 每胶囊
本发明化合物 25.0mg
乳糖 150.0mg
玉米淀粉 20.0mg
滑石粉 5.0mg
将各组分过筛,混合,并填充到2号胶囊中。
实施例C
注射溶液可以具有下列组成:
本发明化合物 3.0mg
聚乙二醇400 150.0mg
乙酸 适量至pH5.0
注射用水 加至1.0ml
将活性成分溶于聚乙二醇400和注射用水(部分)的混合物中。用乙酸调节pH至5.0。加入余量水调节体积至1.0ml。将溶液过滤,适当过量灌装在小瓶中,灭菌。
实施例D
可以按照常规方式制造含有下列成分的软明胶胶囊剂:
胶囊内容物
本发明化合物 5.0mg
黄蜡 8.0mg
氢化大豆油 8.0mg
部分氢化的植物油 34.0mg
大豆油 110.0mg
胶囊内容物重量 165.0mg
明胶胶囊
明胶 75.0mg
甘油85% 32.0mg
Karion 83 8.0mg(干物质)
二氧化钛 0.4mg
氧化铁黄 1.1mg
将活性成分溶于其他成分的热熔化物中,将混合物灌装到适当大小的软明胶胶囊中。按照通常方法处理已灌装的软明胶胶囊。
实施例E
可以按照常规方式制备含有下列成分的药囊剂:
本发明化合物 50.0mg
乳糖细粉 1015.0mg
微晶纤维素(AVICEL PH 102) 1400.0mg
羧甲基纤维素钠 14.0mg
聚乙烯吡咯烷酮K30 10.0mg
硬脂酸镁 10.0mg
矫味添加剂 1.0mg
将活性成分与乳糖、微晶纤维素和羧甲基纤维素钠混合,用聚乙烯吡咯烷酮在水中的混合物制粒。将颗粒与硬脂酸镁和矫味添加剂混合,填充在药囊中。
Claims (9)
1.式(I)化合物或者其药学上可接受的盐,
其中
R2和R3彼此独立地是氢、C1-6烷基、羧基、C1-6烷氧基羰基、氨基甲酰基、单或二取代的氨基-羰基、任选取代的芳基羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、羟基C1-6烷基、卤代C1-6烷基、氰基C1-6烷基、C1-6烷氧基C1-6烷基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、任选取代的芳基C1-6烷基、任选取代的杂环基C1-6烷基、任选取代的杂芳基C1-6烷基、任选取代的芳基C1-6烷氧基C1-6烷基、任选取代的杂芳基C1-6烷氧基C1-6烷基、任选取代的杂环基C1-6烷氧基C1-6烷基,
R1和R4彼此独立地是氢、C1-6烷基、氰基、C1-6烷氧基羰基、C2-6链烯氧基羰基、C2-6炔氧基羰基、羟基C1-6烷基、C1-6烷氧基羰基、羧基、单-或二-C1-6烷基取代的氨基-羰基、氨基羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基或者任选取代的芳基羰基,
R5和R6彼此独立地是氯、氟或溴。
2.根据权利要求1的化合物,其中R2和R3彼此独立地是氢、C1-6烷基、羧基、C1-6烷氧基羰基、氨基甲酰基、单或二取代的氨基-羰基、任选取代的杂环基羰基、任选取代的杂芳基羰基、芳基、任选取代的杂芳基、任选取代的杂环基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、氨基C1-6烷基、单或二取代的氨基-C1-6烷基、任选取代的杂环基C1-6烷基或者任选取代的杂芳基C1-6烷基,
R1和R4彼此独立地是氢或者C1-6烷基。
3.根据权利要求1和2中任意一项的化合物,其中R5是氟,且R6是氯。
4.根据权利要求1-3中任意一项的化合物,所述化合物是
(1S,2R)-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺},
(1R,2S)-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺},
1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺](1S,2R)-1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺},或者
(1R,2S)-1-甲基-环丙烷-1,2-二甲酸2-[(5-氯-吡啶-2-基)-酰胺]
1-{[2-氟-4-(2-氧代-2H-吡啶-1-基)-苯基]-酰胺}。
5.药物组合物,该药物组合物包含根据权利要求1-4中任意一项的化合物和药学上可接受的赋形剂。
6.根据权利要求1-4中任意一项的化合物,其用作治疗活性物质。
7.根据权利要求1-4中任意一项的化合物,其用作治疗和/或预防与凝血因子Xa有关的疾病的治疗活性物质。
8.根据权利要求1-4中任意一项的化合物在制备治疗性和/或预防性治疗与凝血因子Xa有关的疾病的药物中的用途。
9.根据权利要求8的用途,其中所述疾病是血栓形成疾病、动脉血栓形成、静脉血栓形成、深静脉血栓形成、外周动脉阻塞性疾病、不稳定型心绞痛、心肌梗塞、冠状动脉疾病、肺栓塞、由房颤引起的中风、炎症、动脉硬化、与溶栓疗法或再狭窄有关的急性血管闭合和/或肿瘤。
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EP06112897.1 | 2006-04-21 | ||
EP06112897A EP1847537A1 (en) | 2006-04-21 | 2006-04-21 | Dicarboxamide derivatives |
PCT/EP2007/053491 WO2007122104A1 (en) | 2006-04-21 | 2007-04-11 | Dicarboxamide derivatives |
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US (2) | US20070249683A1 (zh) |
EP (2) | EP1847537A1 (zh) |
JP (1) | JP2009534347A (zh) |
KR (1) | KR20080109866A (zh) |
CN (1) | CN101421242B (zh) |
AR (1) | AR060614A1 (zh) |
AU (1) | AU2007242884A1 (zh) |
BR (1) | BRPI0710539A2 (zh) |
CA (1) | CA2649458A1 (zh) |
CL (1) | CL2007001091A1 (zh) |
IL (1) | IL194555A0 (zh) |
MX (1) | MX2008013225A (zh) |
TW (1) | TW200811136A (zh) |
WO (1) | WO2007122104A1 (zh) |
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US7550487B2 (en) * | 2004-03-26 | 2009-06-23 | Hoffmann-La Roche Inc. | Pyrrolidine-3,4-dicarboxamide derivatives |
CA2585615C (en) * | 2004-11-03 | 2013-11-26 | F. Hoffmann-La Roche Ag | Dicarboxamide derivatives and their use as factor xa inhibitors |
BRPI0710512A2 (pt) | 2006-04-20 | 2012-06-05 | Hoffmann La Roche | moduladores derivados de diazepan de receptores de quimiocinas |
EP2978425B1 (en) * | 2013-03-27 | 2017-09-27 | Merck Sharp & Dohme Corp. | Factor xia inhibitors |
EP3078378B1 (en) | 2015-04-08 | 2020-06-24 | Vaiomer | Use of factor xa inhibitors for regulating glycemia |
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US7030141B2 (en) * | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
WO2004031145A2 (en) * | 2002-10-02 | 2004-04-15 | Bristol-Myers Squibb Company | Lactam-containing diaminoalkyl, beta-aminoacids, alpha-aminoacids and derivatives thereof as factor xa inhibitors |
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CA2585615C (en) * | 2004-11-03 | 2013-11-26 | F. Hoffmann-La Roche Ag | Dicarboxamide derivatives and their use as factor xa inhibitors |
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- 2007-04-11 CA CA002649458A patent/CA2649458A1/en not_active Abandoned
- 2007-04-11 AU AU2007242884A patent/AU2007242884A1/en not_active Abandoned
- 2007-04-11 MX MX2008013225A patent/MX2008013225A/es not_active Application Discontinuation
- 2007-04-11 CN CN2007800135721A patent/CN101421242B/zh not_active Expired - Fee Related
- 2007-04-11 JP JP2009505848A patent/JP2009534347A/ja active Pending
- 2007-04-11 EP EP07727959A patent/EP2013177A1/en not_active Withdrawn
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IL194555A0 (en) | 2009-08-03 |
TW200811136A (en) | 2008-03-01 |
BRPI0710539A2 (pt) | 2011-08-16 |
KR20080109866A (ko) | 2008-12-17 |
JP2009534347A (ja) | 2009-09-24 |
CN101421242B (zh) | 2011-06-01 |
US20110195997A1 (en) | 2011-08-11 |
CA2649458A1 (en) | 2007-11-01 |
CL2007001091A1 (es) | 2008-01-04 |
EP1847537A1 (en) | 2007-10-24 |
EP2013177A1 (en) | 2009-01-14 |
WO2007122104A1 (en) | 2007-11-01 |
MX2008013225A (es) | 2008-10-21 |
AU2007242884A1 (en) | 2007-11-01 |
US20070249683A1 (en) | 2007-10-25 |
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