CN101675061A - 吡咯并n杂环类衍生物、其制备方法及其在医药上的应用 - Google Patents
吡咯并n杂环类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Description
Claims (17)
- 权利要求书1. 一种由通式 (I)表示的化 -其中:X选自碳原子或氮原子;和 R2在各种情况分别独立地选自氢原子或烷基;R3 选自烷基、 三氟甲基、 芳基或芳烷基, 其中烷基、 芳基或芳烷基进一步被 一个或多个卤素所取代;¾ 选自烷基、 环烷基、 杂环烷基、 芳基、 杂芳基、 -(CHzMOCHzCH^Ru , -[CH2CH(OH)]rCH2NR9Rio或 -(CH2)nNR9Ri0, 其中烷基、 环垸基、 杂环烷基、 芳 基、 杂芳基、 杂环芳基进一步被一个或多个选自芳基、 羟基、 氨基、 酰胺基、 氨 基羰基、垸氧基、芳氧基、氨基垸基、羟基烷基、杂环垸基、羧酸、羧酸酯或 -NR9R10 的取代基所取代;当 X为氮原子时, R5不存在, R6, R7, 分别独立地选自氢原子或卤素; 当 X为碳原子时, R5, R6, R7, Rs分别独立地选自氢原子、 卤素、 羟烷基、 烷基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR9、 -0[CH2CH20]rRn, -NR9R1()、 -(C¾)nC02R9、 -(C¾)nCONR9Ri。、 -COR9、 -NR9COR1()、 -S02R9 或 -NHCO2R10, 其中芳基、 杂芳基、 环烷基、 杂环垸基进一步被一个或多个选自烷 基、 垸氧基或卤素的取代基所取代;R9 和 0 分别独立地选自氢原子、 垸基、 环烷基、 芳基、 杂环烷基或杂芳基, 其中所述烷基、 环垸基、 芳基、 杂环垸基、 杂芳基进一步被一个或多个选自烷基、 芳基、 卤代芳基、 羟基、 氨基、 氰基、 烷氧基、 芳氧基、 羟垸基、 杂环烷基、 羧 酸、 羧酸酯或 -NR9R1Q的取代基所取代;同时 R9和 Rio—起形成 4〜8元杂环基, 其中 5〜8元杂环内含有一个或多个 N、 0、 S杂原子, 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、芳基、 杂芳基、 卤代烷基、 羟基、 氰基、 烷氧基、 芳氧基、 氨烷基、 羟烷基、 杂环烷基、 羧酸、 羧酸酯或 -NR9R1()的取代基所取代;Rn选自氢原子或焼基;n是 2〜6;z是〗〜 4;r是 1〜6。
- 2. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐, 其中 R<sub>3</sub> 是甲基。 3. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐, 其中 和 R<sub>2</sub>是氢原子。
- 4. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐, 其中包 括下述通式 (IA)表示的化合其中-X选自碳原子或氮原子;Ri 和 ¾在每种情况下各自独立地选自氢原子或垸基;R3选自烷基、 三氟甲基、 芳基、 芳烷基, 其中垸基、 芳基或芳烷基进一步被 一个或多个卤素所取代;EU选自烷基、 环垸基、 杂环烷基、 芳基、 杂芳基、 -(CH2)n(OCH2CH2 Ru、 -[Οί2 ί(ΟΗ)]^Η2Ν 。或 其中所述烷基、 环烷基、 杂环烷基、 芳基、 杂芳基、 杂环芳基进一步被一个或多个选自芳基、 羟基、 氨基、 酰胺基、 氨基羰基、烷氧基、芳氧基、氨基烷基、羟基垸基、杂环烷基、羧酸、羧酸酯或 -NR9R10 的取代基所取代;当 X为氮原子时, R5不存在, R6, R7, R8分别独立地选自氢原子或卤素; 当 X为碳原子时, R5, R6, R7, R8分别独立地选自氢原子、 素、 羟烷基、 烷基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR9、 -0[CH2CH20]rR„、 -NR9R10、 -(CH2)nC02R9、 -(CH2)nCONR9R10、 -COR9、 -NR9COR10、 -S02R9或 -NHCO2R10, 其中芳基、 杂芳基、 环烷基、 杂环院基进一步被一个或多个选自垸 基、 烷氧基或卤素的取代基所取代;R9和 R1G分别选自氢原子、烷基、 环烷基、 芳基、 杂环垸基、 杂芳基、 其中 所述的烷基、 环烷基、 芳基、 杂环垸基、 杂芳基进一步被一个或多个选自烷基、 芳基、 卤代芳基、 羟基、 氨基、 氰基、 烷氧基、 芳氧基、 羟垸基、 杂环烷基、 羧 酸、 羧酸酯或 -NR9R1Q的取代基所取代;同时 R9和 R1()—起形成 4〜8元杂环基, 其中 5〜8元杂环内含有一个或多个 N、 0、 S杂原子, 并且 4〜8元杂环上进一步被一个或多个选自垸基、 卤素、芳基、 杂芳基、 卤代垸基、 羟基、 氰基、 垸氧基、 芳氧基、 氨烷基、 羟烷基、 杂环烷基、 羧酸、 羧酸酯或 -NR9R1Q的取代基所取代;选自氢原子或烷基;n是 2〜6;r是 1〜6。
- 5. 根据权利要求 1所述的化合物或其医药上可以接受的盐,其中包括下述通式 (IB) 表示的化合物或其医药上其中-X选自碳原子或 氮原子;Ri 和 R2在各种情况下分别独立地选自氢原子或烷基;¾ 选自烷基、 三氟甲基、 芳基、 芳垸基, 其中垸基、 芳基或芳烷基进一步被 一个或多个卤素所取代;¾ 选自垸基、 环烷基、 杂环垸基、 芳基、 杂芳基、-[C¾CH(OH)]rCH2NR9Rio或 -(CH2)nNR9R1Q, 其中垸基、 环垸基、 杂环垸基、 芳 基、 杂芳基、 杂环芳基进一步被一个或多个选自芳基、 羟基、 氨基、 酰胺基、 氨 基羰基、垸氧基、芳氧基、氨基垸基、羟基垸基、杂环烷基、羧酸、羧酸酯或 -NR9R10 的取代基所取代;当 X为氮原子时, R5不存在, R6, R7, R8分别独立地选自氢原子或卤素; 当 X 为碳原子时, R5, R6, R7, R8分别独立地选自氢原子、 素、 羟焼基、 垸基、环垸基、杂环垸基、芳基、杂芳基、羟基、氰基、硝基、 -OR9、 -0[CH2CH20]rRn , -NR9R10、 -(CH2)nC02R9、 -(CH^nCONRsRn)、 -COR9、 -NR9COR10 -S02R9 或 -NHCO2R10, 其中芳基、 杂芳基、 环烷基、 杂环垸基进一步被一个或多个选自垸 基、 垸氧基或卤素的取代基所取代;R9和 R1()分别选自氢原子、 烷基、 环垸基、 芳基、 杂环烷基、 杂芳基、 其中 所述的垸基、 环烷基、 芳基、 杂环垸基、 杂芳基进一歩被一个或多个选自烷基、 芳基、 卤代芳基、 羟基、 氨基、 氰基、 烷氧基、 芳氧基、 羟垸基、 杂环烷基、 羧 酸、 羧酸酯或 -NR9R1Q的取代基所取代;同时 和 0—起形成 4〜8元杂环基, 其中 5〜8元杂环内含有一个到多个 N、 0、 S杂原子, 并且 4〜8元杂环上进一步被一个或多个烷基、 卤素、 芳基、 杂 芳基、 卤代垸基、 羟基、 氰基、 烷氧基、 芳氧基、 氨垸基、 羟烷基、 杂环垸基、 羧酸、 羧酸酯或 -NR9R1D所取代; - ι选自氢原子或垸基;n是 2〜6;r是卜 6。
- 6. 根据权利要求 1或 2所述的吡咯并 N杂环衍生物或其药学上可接受的盐, 其
- 7. 一种药物组合物, 其包括药物有效剂量的如权利要求 1〜6中任何一项所述的 吡咯并 N杂环类衍生物或其药学上可接受的盐, 和药学上可接受的载体。
- 8. 根据权利要求 1所述的吡咯并 N杂环类衍生物或其药学上可接受的盐, 其中 所述的药学上可接受的盐为化合物与选自以下的酸形成的盐: 苹果酸、 乳酸、 马 来酸、 盐酸、 甲磺酸、 硫酸、 磷酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸。
- 9. 一种如下列通式 (IC)或者 (ID)所示的化合物, 其作为通式 (I)化合物合成的中 间体:(IC) (ID)其中:选自氢原子或烷基;选自焼基、 三氟甲基、 芳基、 芳烷基, 其中烷基、 芳基或芳烷基进一步被 一个或多个卤素所取代; R4选自垸基、 环烷基、 杂环烷基、 芳基、 杂芳基、 -(CHb OCitCHyrRu, -[CHbCH OHACI^NR^o或 -(CH2)nNR9R10, 其中烷基、 环烷基、 杂环烷基、 芳 基、 杂芳基、 杂环芳基进一步被一个或多个选自芳基、 羟基、 氨基、 酰胺基、 氨 基羰基、烷氧基、芳氧基、氨基烷基、羟基烷基、杂环烷基、羧酸、羧酸酯或 -NR9R10 的取代基所取代;R9和 R1Q分别选自氢原子、 烷基、 环烷基、 芳基、 杂环烷基、 杂芳基、 其中 所述的烷基、 环烷基、 芳基、 杂环烷基、 杂芳基进一步被一个或多个选自烷基、 芳基、 卤代芳基、 羟基、 氨基、 氰基、 垸氧基、 芳氧基、 羟烷基、 杂环垸基、 羧 酸、 酸酯或 -NR9R1Q的取代基所取代;同时 和 ο—起形成 4〜8元杂环基, 其中 5〜8元杂环内含有一个到多个 N、 0、 S杂原子, 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、芳基、 杂芳基、 卤代烷基、 羟基、 氰基、 垸氧基、 芳氧基、 氨烷基、 羟烷基、 杂环烷基、 羧酸、 羧酸酯或 -NR9R1Q的取代基所取代;Rii选自氢原子或烷基;n是 2〜6;z是 1〜4;r是 1〜6。
- 10.根据权利要求 9所述的中间体 (IC)的制备方法, 所述方法包括:将原料吡咯甲基羧酸二酯 IC-1在室温条件下, 在四氢呋喃溶液中,在醋酸存在 下与硝酸铈IC-1 IC-2 化合物吡咯甲醛羧酸二酯 IC-2在无水四氢呋喃中与 (乙酯基亚甲基)三苯基正 膦发生魏IC-2 IC-3钯 /碳催化下, 吡咯乙氧羰基乙烯基二羧酸酯 IC-3在无水乙醇中, 经氢气室温 还原得到吡咯乙氧羰基乙基二羧酸酯 IC-4;吡咯乙氧羰基乙基二羧酸酯 IC-4在氢氧化锂水溶液水解得到吡咯羧基乙基: 羧酸酯 I吡咯羧基乙基二羧酸酯 IC-5在无水四氢呋喃中, -20 -5°C下, 经硼烷的四氢 呋喃溶液还原成得吡咯羟丙基二羧酸酯 IC-6;IC-5 IC-6-步, 吡咯羟丙基二羧酸酯 IC-6在无水二氯甲烷中, -20〜- 5°C, 三乙胺存 甲 丙基二羧 IC-7;IC-6 IC-7接下来, 吡咯甲磺酰氧丙基二羧酸酯 IC-7与不同的胺反应得到吡咯酰胺二羧 酸酯 IC-8;IC-7 IC-8吡咯酰胺二羧酸酯 IC-8在无水甲苯中,与三甲基铝加热回流得到吡咯并七元 N 杂环酯 IC-9;
- 11. 根据权利要求 9所述的中间体 (ID)的制备方法, 所述方法包括:氩气氛下, 吡咯甲醛羧酸二酯 IC-2在室温条件下, 在无水四氢呋喃中与格氏 试剂溴化环丙吡咯环丙基羟基羧酸二酯 ID-1室温下, 在甲醇溶剂中与氢溴酸反应得到溴化 丁烯基吡咯钯 /碳催化下, 溴化丁烯基吡咯二酯 ID-2在无水乙醇中, 经氢气室温还原得到 溴化溴化丁基吡咯二酯 ID-3在二氯甲垸中, 加热回流与不同的胺反应得到吡咯酰
- 12.根据权利要求 1〜6所述的吡咯并 N杂环类衍生物的制备方法, 包括在三乙胺 或哌啶存在下, 将醛和吲哚酮反应, 反应液加热 2〜12小时, 其中所述醛为下列
- 13.一种调节蛋白激酶催化活性的方法, 其中包括将所述的蛋白激酶与权利要求 1〜6中任何一项所述的吡咯并 N杂环类衍生物或其药学上可接受的盐接触。
- 14.根据权利要求 13所述的方法, 其中所述蛋白激酶选自受体酪氨酸激酶、 非受 体酪氨酸激酶或丝氨酸-苏氨酸激酶。 15. —种根据权利要求 1所述的化合物在制备治疗与蛋白质激酶有关的疾病的药 物中的用途。
- 16.根据权利要求 15所述的用途, 其中所述与蛋白质激酶有关的疾病选自与 VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR或 Flt3相关的 疾病。
- 17. 根据权利要求 15所述的用途, 其中所述与蛋白激酶有关的疾病选自白血病, 糖尿病, 自免疫病, 过度增生病, 牛皮癣, 骨关节炎, 类风湿性关节炎, 血管生 成, 心血管病, 多发性成血管细胞瘤, 炎症或纤维变性病。
- 18.根据权利要求 15所述的用途, 其中所述与蛋白激酶有关的疾病是癌症, 选自 鳞状细胞癌, 肾细胞癌, 卡波济氏肉瘤, 非小细胞肺癌, 小细胞肺癌, 淋巴癌, 甲状腺癌, 乳腺癌, 头颈癌, 子宫癌, 食道癌, 黑素癌, 膀胱癌, 生殖泌尿癌, 胃肠癌, 神经胶质癌, 结肠直肠癌或卵巢癌。
- 19.一种调节蛋白激酶催化活性的方法, 其中包括将所述的蛋白激酶与权利要求 7 所述的组合物接触。
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WO2008138184A1 (fr) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Dérivés de pyrrolo-azacycles, leur procédé de fabrication et leur utilisation en tant qu'inhibiteurs de protéine kinases |
WO2011056985A2 (en) * | 2009-11-04 | 2011-05-12 | Gilead Sciences, Inc. | Substituted heterocyclic compounds |
CN102146082A (zh) * | 2010-02-04 | 2011-08-10 | 江苏恒瑞医药股份有限公司 | 吡咯并n杂环类衍生物的可药用的盐、其制备方法及其在医药上的应用 |
PL3205654T3 (pl) | 2010-05-20 | 2019-08-30 | Array Biopharma, Inc. | Związki makrocykliczne jako inhibitory kinazy TRK |
ES2748873T3 (es) | 2012-01-26 | 2020-03-18 | Angion Biomedica Corp | Compuestos antifibróticos y usos de los mismos |
AU2013299922B2 (en) * | 2012-08-07 | 2018-06-21 | Janssen Pharmaceutica Nv | Process for the preparation of heterocyclic ester derivatives |
CN104119321B (zh) * | 2013-04-28 | 2017-09-08 | 齐鲁制药有限公司 | 二氢吲哚酮衍生物的二马来酸盐及其多晶型物 |
KR20180041135A (ko) | 2015-07-16 | 2018-04-23 | 어레이 바이오파마 인크. | Ret 키나아제 억제제로서 치환된 피라졸로[1,5-a]피리딘 화합물 |
CN108601778A (zh) * | 2016-01-08 | 2018-09-28 | 正大天晴药业集团股份有限公司 | 喹啉衍生物用于治疗食管癌的用途及其治疗方法、药物组合物和试剂盒 |
JOP20190077A1 (ar) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret |
TWI704148B (zh) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | 作為ret激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
CN110267960B (zh) | 2017-01-18 | 2022-04-26 | 阿雷生物药品公司 | 作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡嗪化合物 |
WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
EP3628044B1 (en) * | 2017-05-15 | 2023-11-22 | The Regents of The University of Michigan | Pyrrolo[2,3-c]pyridines and related analogs as lsd-1 inhibitors |
TWI791053B (zh) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物 |
TWI812649B (zh) | 2017-10-10 | 2023-08-21 | 美商絡速藥業公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之調配物 |
US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
JP6997876B2 (ja) | 2018-01-18 | 2022-02-04 | アレイ バイオファーマ インコーポレイテッド | Retキナーゼ阻害剤としての置換ピラゾリル[4,3-c]ピリジン化合物 |
CA3087354C (en) | 2018-01-18 | 2023-01-03 | Array Biopharma Inc. | Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors |
JP7061195B2 (ja) | 2018-01-18 | 2022-04-27 | アレイ バイオファーマ インコーポレイテッド | RETキナーゼ阻害剤としての置換ピラゾロ[3,4-d]ピリミジン化合物 |
ES2922314T3 (es) | 2018-09-10 | 2022-09-13 | Array Biopharma Inc | Compuestos heterocíclicos condensados como inhibidores de cinasa RET |
CN112538086B (zh) * | 2020-12-14 | 2021-11-12 | 承德医学院 | 杂卓并三唑环同吲哚羧酸拼合物及其盐、其制备方法及医药用途 |
CN113634240B (zh) * | 2021-08-26 | 2023-10-27 | 宏葵生物(中国)股份有限公司 | 荧光磁性复合纳米纤维、其制备方法及应用 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5866702A (en) | 1996-08-02 | 1999-02-02 | Cv Therapeutics, Incorporation | Purine inhibitors of cyclin dependent kinase 2 |
EP1066257A2 (en) * | 1998-03-26 | 2001-01-10 | Sugen, Inc. | Heterocylic classes of compounds for the modulating tyrosine protein kinase |
DE60029138T2 (de) * | 1999-12-22 | 2007-06-06 | Sugen, Inc., San Francisco | Verwendung von Indolinonverbindungen zur Herstellung von Pharmazeutika für die Modulation der Funktion c-kit Proteintyrosinkinase |
SI1255752T1 (sl) | 2000-02-15 | 2007-12-31 | Pharmacia & Upjohn Co Llc | S pirolom substituirani zaviralci 2-indolinon protein kinaza |
US6465507B2 (en) * | 2000-02-28 | 2002-10-15 | Sugen, Inc. | 3-(pyrolyllactone)-2-indolinone compounds as kinase inhibitors |
JP2003535847A (ja) | 2000-06-02 | 2003-12-02 | スージェン・インコーポレーテッド | 蛋白質キナーゼ/ホスファターゼ阻害剤としてのインドリノン誘導体 |
US6635640B2 (en) * | 2000-06-30 | 2003-10-21 | Sugen, Inc. | 4-heteroaryl-3-heteroarylidenyl-2-indolinones and their use as protein kinase inhibitors |
PE20020776A1 (es) * | 2000-12-20 | 2002-08-22 | Sugen Inc | Indolinonas 4-aril sustituidas |
US6599902B2 (en) | 2001-05-30 | 2003-07-29 | Sugen, Inc. | 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors |
US6777417B2 (en) * | 2001-09-10 | 2004-08-17 | Sugen, Inc. | 3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene-2-indolinone derivatives as kinase inhibitors |
US20040186160A1 (en) * | 2002-12-13 | 2004-09-23 | Sugen, Inc. | Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors |
US8012966B2 (en) * | 2006-01-27 | 2011-09-06 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrrolo [3,2-c] pyridine-4-one 2-indolinone protein kinase inhibitors |
CN101007814A (zh) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | 吡咯并六元杂环化合物及其在医药上的用途 |
CN101007815B (zh) * | 2006-01-27 | 2010-06-23 | 江苏恒瑞医药股份有限公司 | 吡咯并六元杂环化合物及其在医药上的用途 |
WO2008138184A1 (fr) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Dérivés de pyrrolo-azacycles, leur procédé de fabrication et leur utilisation en tant qu'inhibiteurs de protéine kinases |
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JP5342547B2 (ja) | 2013-11-13 |
HK1121757A1 (en) | 2009-04-30 |
CA2685757A1 (en) | 2008-11-20 |
KR20100022003A (ko) | 2010-02-26 |
CN101307052B (zh) | 2011-08-17 |
EP2157093A4 (en) | 2012-03-07 |
MX2009011964A (es) | 2009-12-01 |
AU2008250895A1 (en) | 2008-11-20 |
JP2010526838A (ja) | 2010-08-05 |
EP2157093A1 (en) | 2010-02-24 |
UA99617C2 (ru) | 2012-09-10 |
BRPI0811865A2 (pt) | 2014-11-18 |
US8329682B2 (en) | 2012-12-11 |
TWI409263B (zh) | 2013-09-21 |
CN101307052A (zh) | 2008-11-19 |
US20100075952A1 (en) | 2010-03-25 |
CN101675061B (zh) | 2012-07-04 |
AU2008250895B2 (en) | 2012-08-02 |
RU2009141799A (ru) | 2011-06-20 |
HK1137027A1 (en) | 2010-07-16 |
WO2008138184A1 (fr) | 2008-11-20 |
TW200946530A (en) | 2009-11-16 |
US20130303518A1 (en) | 2013-11-14 |
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