CN101723813A - 一种乙氧基二苯乙烷衍生物及其制备方法和用途 - Google Patents
一种乙氧基二苯乙烷衍生物及其制备方法和用途 Download PDFInfo
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- CN101723813A CN101723813A CN200810201182A CN200810201182A CN101723813A CN 101723813 A CN101723813 A CN 101723813A CN 200810201182 A CN200810201182 A CN 200810201182A CN 200810201182 A CN200810201182 A CN 200810201182A CN 101723813 A CN101723813 A CN 101723813A
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- trimethoxy
- compound
- ethoxy diphenyl
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Abstract
本发明公开了一种乙氧基二苯乙烷衍生物及其合成方法和用途,在苯乙烷B芳环的4′位,用乙氧基进行化学修饰,同时把其的3′位羟基改造成磷酸盐等的水溶性前药,同样,在3′位氨基引入氨基酸侧链,形成氨基酸酰胺水溶性前药,结构如结构式(I)所示,乙氧基苯乙烷衍生物及其前药具有较强的抑制微管蛋白集聚能力,对肿瘤血管具有明显的靶向破坏作用,选择性地导致肿瘤血管功能紊乱和结构的破坏、诱导血管内皮细胞凋亡,使得肿瘤细胞失去营养和氧气的支持,而发挥其杀伤肿瘤细胞或抑制肿瘤转移的作用。
Description
技术领域
本发明涉及药物合成领域,尤其涉及二苯乙烷类衍生物抗癌药物的合成。
背景技术
近几年发现的一类新型的微管蛋白解聚因子能在低于MTD的剂量下就能使血管闭合(Expert Opin Investig Drugs.2004 Sep;13(9)1171-82)。LoicVincent等人在2005年提到一类具有类似属性的新型微管蛋白解聚因子,作为血管靶点因子(VTAs)能破坏微管蛋白骨架,文献数据显示血管靶点因子能选择性诱导肿瘤血管的衰退,部分通过VE-cadherin信号通道。这类微管蛋白解聚因子选择性的破坏肿瘤血管,并阻止新生肿瘤血管形成,而且对正常血管系统没有影响。同时它能抑制微管蛋白的聚合、选择性的导致肿瘤血管功能紊乱和结构的破坏、诱导血管内皮细胞调亡,使得肿瘤细胞失去营养和氧气的支持,而发挥其杀伤肿瘤细胞或抑制肿瘤转移的作用。
GillianM.Tozer等人于2005年曾在具影响力的杂志Nature Rev Cancer中报道,指出该类化合物不但影响血管内皮细胞的增殖,也影响内皮细胞的迁移,快速改变血管内皮细胞形态,引起内皮细胞调亡,打断血管中内皮细胞的连接,从而迅速导致肿瘤血管功能紊乱和结构的破坏。由于一般正常血管都是通过平滑肌细胞支撑的,这一类化合物只作用于没有平滑肌细胞支持的血管,对平滑肌支持的血管没有影响,从而迅速并有选择性的导致肿瘤血管功能紊乱和结构的破坏,进而能选择性的作用于肿瘤细胞,对正常细胞的毒性大大降低(Nat rveCanaer.2005 Jun;5(6)423-35、J.Clin.Invest.,Novenber 1,2005;115(11):2992-3006)。这类药物目前被认为是抗肿瘤最有前景的药物之一。
目前国内外同时在开展研究的的该类药物只有CombretastatinA-4二苯乙烯类化合物进入临床研究,发明专利申请“乙氧基康普立停及其前药的制备和用途”(国际公布号WO2008/031333A1)公开了CombretastatinA-4的二苯乙烯的B芳环4’位烷氧基是个活性作用位点,把二苯乙烯B芳环4’位原有的甲基改造成乙基,和3’的羟基、氨基等基团能形成活性靶点,可提高其对肿瘤血管靶向活性。但由于通过双键连接,在Combretastatin中氏类单元的最有效破坏肿瘤血管是顺式构型,而反式构型的氏类化学物对肿瘤没有抑制作用。由于存在顺反异构化反应,而反式结构没有药效,还会带来一定的毒副作用,这样分离纯化工艺要求高,要经过柱层析,原料损耗大,工艺成本高,收率低,同时二苯乙烯类化合物经紫外光照,要转变为反式结构,需低温避光保存,使得二苯乙烯类化合物在保存和实际应用中带来了很大的困难。
专利文献(Cushman,Mark等,Synthesis and evaluation of analogs of(Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane aspotential cytotoxic andantimitotic agents,Journal of MedicinalChemistry,1992,Vol.35,No.12,2293-306)公开了一种化合物,即(Z)-1-(3,4,5-三甲氧基)苯基-2-(4′-乙氧基)苯基乙烯,但3′位没有-OH、-NH2等取代基团,不能形成协同活性靶点,随4′位从4′-甲氧基,乙氧基,丙氧基…抗癌药效渐次降低;而美国专利SU6054598公开了一种把2-甲氧基雌二醇改造为2-乙氧基雌二醇的合成方法,2-乙氧基雌二醇的体外抗肿瘤活性比2-甲氧基雌二醇提高1000倍;我们经研究发现乙氧基二苯乙烷类衍生物,4′-乙氧基和3′-羟基、氨基同样有协同作用,能显著提高抗癌效果,但4′用丙氧基改造后其抗癌效果则明显大大降低。
发明内容
1、本发明提供一种乙氧基二苯乙烷衍生物,其结构如通式(I):
其中:所述的R为羟基、氨基、磷酸盐、硫酸盐、磷酸胆碱、或是氨基酸侧链及其水溶性铵盐。
所述的R优选为羟基、氨基、磷酸二钠盐、磷酸铵盐、硫酸酯盐、磷酸胆碱内式盐、天然氨基酸侧链及其水溶性铵盐、或是-NH(COCHR’NH)m-H(其中R’是氢、苯基,m表示1~3的整数)及其水溶性铵盐。
在优选例中,所述的R为-OH、-NH2、-OPO2Na2、-NHCOCH2NH2、或是-NHCOCHNH2CH2OH。
2、本发明提供了一种通式(I)化合物中羟基乙氧基二苯乙烷类衍生物的制备方法,它包括步骤:
(1)4-羟基-3-甲氧基苯甲醛II,在相转移催化下,用溴乙烷进行乙氧基化反应,形成4-乙氧基-3-甲氧基苯甲醛III;
(2)用二苯基磷锂,选择性脱去间位甲基,转化成羟基,得到4-乙氧基-3-羟基苯甲醛IV;
(3)4-乙氧基-3-羟基苯甲醛IV,用氯化苄制得4-乙氧基-3-苄氧基苯甲醛V;
(4)3,4,5-三甲氧基苄溴三苯基溴化磷四氢呋喃溶液在加入叔丁醇钾下和4一乙氧基一3一苄氧基苯甲醛进行乙烯化加成反应,合成3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯VI
(5)3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯VI,在钯-碳下加氢,使烯键氢化,脱苄基,制得3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷VII(简称代号:ECB1);
(6)3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷(VII)经磷酰化、磷酸酯化、硫酸酯化,形成乙氧基羟基二苯乙烷水溶性衍生物:磷酸二钠盐、硫酸酯盐、磷酸铵盐或磷酸胆碱内式盐。
(7)ECB1在磷酰化试剂三氯氧磷、2mol/L的NaOH的作用下,形成3,4,5-三甲氧基-4′-乙氧基二苯乙烷-3′-o-磷酸二钠盐VIII(简称代号:ECB1P)。
(8)另一优选磷酯化反应,是ECB1与二苄基亚磷酸酯反应形成磷酸苄酯,在三甲基溴硅烷(TMBS)下加甲醇钠/无水甲醇,制得3,4,5-三甲氧基-4′-乙氧基二苯乙烷-3′-o-磷酸二钠盐(简称代号:ECB1P)。
本发明制备方法的另一优选例中,提供了一种通式(I)化合物中氨基乙氧基二苯乙烷类衍生物的制备方法,它包括步骤:
(1)4-羟基一3一硝基苯甲醛IX,在相转移催化下,用溴乙烷进行乙氧基化反应,形成4一乙氧基-3一硝基苯甲醛X;
(2)溴化三甲氧基苯基亚甲基三苯磷和4一乙氧基一3一硝基苯甲醛X发生Wittig反应,生成3,4,5一三甲氧基苯基一3′一硝基一4′一乙氧基二苯乙烯XI。
(3)3,4,5一三甲氧基苯基一3′一硝基一4′一乙氧基二苯乙烯XI在钯-碳催化剂/硼氢化钠下,实现氢化还原反应,使硝基还原成氨基,烯键还原成乙烷单键,制得3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烷XII(简称代号:ECB1N)
(4)3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烷(XII)与氨基酸衍生物反应,形成乙氧基氨基二苯乙烷氨基酸酰胺衍生物,其氨基酸酰胺侧链为:天然氨基酸侧链、或-NH(COCHR’NH)m-H(其中R’是氢、苯基,m表示1一3的整数)。
(5)在二环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt)或六氟合磷氢酸苯并三唑-1-基-氧-三(二甲氨基)磷(BOP试剂)催化下,3,4,5-三甲氧基-3-氨基-4′-乙氧基二苯乙烷XII与N-a-9-芴基甲氧羰基氨基酸衍生物(FmocAA)反应,转换3′位氨基成Fmoc-氨基酸酰胺,脱去Fmoc,生成ECB1N的氨基酸酰胺,分别为3,4,5-三甲氧基-3′-甘氨酰氨基-4′-乙氧基二苯乙烷XIII(简称代号:ECB1GN),3,4,5-三甲氧基-3′-丝氨酰氨基-4′-乙氧基二苯乙烷XIV(简称代号:ECB1SN)
(6)氨基酸酰胺衍生物溶解于甲醇、乙醇或异丙醇中,加等当量的盐酸、硫酸或磷酸,加石油醚或正己烷,释出形成水溶性铵盐。
3、本发明的药物制剂,选自包括以下剂型:静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液;口服形式给药的颗粒剂、片剂、胶囊或糖浆;或是栓剂。
4、提供了一种通式(I)上化合物在制备治疗微管蛋白聚集抑制剂中的应用。
5、上述通式(I)上化合物在制备作为抗肿瘤血管破坏剂,对各种肿瘤具有血管靶向作用的药物中的应用。所述各种肿瘤主要包括有:肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、多发性骨髓瘤。
6、上述所述通式(I)上化合物在制备治疗非正常新生血管引起的疾病的药物中的应用,所述的疾病主要包括有:风湿性关节炎、糖尿病视网膜病、早熟视网膜病、视网膜静脉闭塞、牛皮癣、红斑痤疮、卡波济肉瘤、特异性反应性角膜炎、流行性角膜结膜炎、新生血管性青光眼、细菌性溃疡、真菌性溃疡、单纯性疤疹感染、带状疤疹感染、原生动物感染、分支杆菌感染、多动脉炎、肉样瘤、巩膜炎、潮红、口干眼燥关节炎综合症、全身性红斑狼疮、艾滋病综合症、梅毒。
7、上述所述通式(I)上化合物药效、安全评价,阳性对照物如下:
(Z)-3,4,5-三甲氧基-3′-羟基-4′-甲氧基二苯乙烯XV(简称代号:CA4);
(Z)-3,4,5-三甲氧基-4′-甲氧基二苯乙烯-3′-o-磷酸二钠盐XVI(简称代号:CA4P)
(Z)-3,4,5-三甲氧基-3′-氨基-4′-甲氧基二苯乙烯XVII(简称代号:CA4N);
3,4,5-三甲氧基-3′-羟基-4′-甲氧基二苯乙烷XVIII(简称代号:CB1);
3,4,5-三甲氧基-4′-甲氧基二苯乙烷-3′-o-磷酸二钠盐XIV(简称代号:CB1P);
3,4,5-三甲氧基-3′-氨基-4′-甲氧基二苯乙烷XX(简称代号:CB1N);
3,4,5-三甲氧基-3′-甘氨酰氨基-4′-甲氧基二苯乙烷XXI(简称代号:CB1GN);
(Z)-3,4,5-三甲氧基-3′-羟基-4′-乙氧基二苯乙烯XXII(简称代号:ECA4)
(Z)-3,4,5-三甲氧基-4′-乙氧基二苯乙烯-3′-o-磷酸二钠盐XXIII(简称代号:ECA4P)
(Z)-3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烯XXIV(简称代号:ECA4N)
(Z)-3,4,5-三甲氧基-3′-甘氨酰氨基-4′-乙氧基二苯乙烯XXV(简称代号:ECA4GN)
8、上述所述通式(I)上化合物药效、安全评价结果综述如下:
(1)体外培养肿瘤细胞的抗肿瘤活性评价,结果表明4′位乙氧基二苯乙烷类化合物ECB1和ECB1N,和4′位乙氧基二苯乙烯类阳性对照化合物ECA4、ECA4N相比较表明,对多种体外培养的肿瘤细胞均有明显的抗肿瘤活性,抗肿瘤活性作用基本相当,但显著强于4′位甲氧基类阳性对照化合物CA4、CB1、CB1N(强10~200倍),对于结肠癌HT-29,ECB1N较4′位甲氧基类阳性对照CB1强约200倍,ECB1较阳性对照CB1强约100倍。
(2)实体瘤依赖于血管系统而生长,一部分快速增殖的肿瘤血管内皮细胞因缺少完好的肌丝结构而更依赖于微管来保持结构的完整,增殖的人脐静脉内皮细胞(HUVEC)的快速增殖,便是更依赖于微管来保持结构的完整,故常被用作肿瘤血管内皮细胞的体外模型,以人脐静脉内皮细胞(HUVEC)为作用对象,考察乙氧基二苯乙烷衍生物的抗肿瘤血管性能,乙氧基二苯乙烷衍生物ECB1N的IC50值为6.8×10-4μmol/L、ECB1的IC50值7.5×10-4μmol/L对人脐静脉内皮细胞增殖抑制作用,显示一类很强微管蛋白聚集抑制剂,明显强于4′位甲氧基类阳性对照化合物CA4、CB1、CB1N(IC50值4.8×10-3~7.7×10-3μmol/L之间),预示着乙氧基二苯乙烷类衍生物是一类潜在的很强的肿瘤血管靶向药物。
(3)体内静脉注射受试药物对肉瘤S180小鼠移植瘤的抑瘤率实验结果表明,按给药方案,各受试化合物,均能明显抑制肉瘤S180小鼠移植瘤的生长,给药后第8天左右,可以观察到,乙氧基二苯乙烷衍生物ECB1P、ECB1GN盐酸盐、ECB1SN盐酸盐与4′位乙氧基二苯乙烯类阳性对照化合物ECA4P、ECA4GN盐酸盐比较,在给药组肿瘤都有缩小的趋势,50(mg/kg)剂量抑瘤率均达60%以上,疗效基本相当,而明显优于甲氧基类阳性对照CB1GN盐酸盐、CB1P、CA4P(100mg/kg)剂量抑瘤率为40%左右的疗效。
(4)单次小鼠腹腔注射给药急性毒性试验,高剂量注射给药40min~1hr时,有死亡,解剖未见明显的残留药液,说明药物吸收快,其余主要在给药后第1~2天死亡,第5天后即未见小鼠死亡,死亡小鼠解剖未见心、肺、肝、脾、肾等脏器异常,存活小鼠可见腹泻,但不严重,说明受试药物都主要为急性毒性反应,无明显的迟发性毒性,实验结果表明乙氧基二苯乙烷类化合物ECB1P、ECB1GN盐酸盐、ECB1SN盐酸盐毒性低于乙氧基二苯乙烯类阳性对照化合物ECA4P、ECA4GN盐酸盐给药组。
9、本发明研究发现乙氧基二苯乙烷类化合物即上述所述通式(I)类化合物在二苯乙烷的B芳环4’位原有的甲氧基改造成乙氧基,和3’的羟基、氨基能形成活性靶点,与B芳环4’位原有的甲氧基、3’的羟基、氨基的甲氧基二苯乙烷类化合物比较,可极大地提高其对肿瘤血管靶向活性;实验表明4′位乙氧基二苯乙烷类化合物ECB1、ECB1N对多种体外培养的肿瘤细胞均有明显的抗肿瘤活性,显著强于4′位甲氧基类阳性对照化合物CA4、CB1、CB1N(强10~200倍),对于结肠癌HT-29,ECB1N较阳性对照CB1强约200倍,ECB1较阳性对照CB1强约100倍。
两个苯环是通过单键连接,使得与二苯乙烯类化合物CombretastatinA-4结构不同、构象、结合力、逆反等作用都不同,不存在顺反结构差异,能极大的提高了药物的稳定性,同时能降低毒性,能使制备工艺更加简便,不需要通过柱层析分离,工艺收率明显提高,原料损耗大大降低,单位合成工艺成本也大大降低,提高了药物的稳定性,不需要避光保存,使保存和实际应用中带来了很大方便,取得意料不到的效果。
附图说明
图1:羟基乙氧基二苯乙烷类化合物及其水溶性前药的合成路线。
图2:氨基乙氧基二苯乙烷类化合物及其氨基酸酰胺衍生物的合成路线。
具体实施方式
实施例1:
制备4一乙氧基一3一甲氧基苯甲醛:
四颈烧瓶加入4-羟基-3-甲氧基苯甲醛76克(0.5mol),500mL异丙醇,搅拌20分钟,用恒压滴液漏斗缓缓滴入6.5克18-冠-6醚和133克氢氧化钠的150毫升水溶液,搅拌30分钟,将反应体系加热到60℃,在此温度下,滴入溴乙烷85克,反应5~6小时,TLC跟踪,反应完成后将体系冷却下来(15℃),加入500mL的水中止反应,产物用乙醚(3×300mL)萃取,有机相用水洗至中性,无水MgSO4干燥,蒸去部分乙醚,加入大量石油醚,沉淀出粗产品。用乙醚/石油醚重结晶得到4一乙氧基一3-甲氧基苯甲醛83克,产率92%。
实施例2
制备4一乙氧基一3-羟基苯甲醛:
步骤1,在氩气的保护之下,取4一乙氧基一3一甲氧基苯甲醛54克(0.3mol)加入到三颈瓶中,然后加入乙二醇130克(2.1mol),原甲酸二乙酯133克(0.9mol),100℃左右回流,加入1ml三氟化硼乙醚溶液,作为催化剂。反应24小时,TLC跟踪,冷却到室温,加入200ml 15%氢氧化钠水溶液,用300ml的乙醚萃取,用饱和食盐水洗涤,无水硫酸镁干燥,减压蒸去乙二醇和原甲酸三乙酯,得到黄色油状物。
步骤2,在1.28M二苯基膦锂四氢呋喃溶液200ml中,分批加入上述缩醛56克(0.25mol),室温搅拌3-4小时,TLC跟踪,加水中止反应,加入200ml 30%的氢氧化钠溶液后,用300ml乙醚进行萃取,用盐酸酸化,调节pH值3-4左右,然后用500ml乙醚萃取,合并乙醚萃取液,用水和饱和食盐水洗涤,无水硫酸镁干燥,过滤,减压除去溶剂,得到黄色固体,苯/石油醚重结晶,得浅黄色晶体31.8克,产率76%。
实施例3
4一乙氧基一3一苄氧基苯甲醛的制备:
三颈瓶中加入4一乙氧基一3一羟基苯甲醛16.6g(100mmol),200ml无水乙醇,加热到40℃溶解,加入碳酸钾9g(65.07mmol),搅拌下加入氯化苄15ml(130.13mmol),加热回流1hr,TLC检测反应完全后,冷却到50℃,趁热过滤,滤液放入冰箱中冷却过夜,晶体析出,抽滤,滤饼用30mL无水乙醇洗涤,真空干燥后,得到白色针状晶体21.5g,收率为83.9%。
实施例4
3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯的制备:
三颈瓶中,加入3,4,5-三甲氧基苄溴三苯基溴化磷20g(38.2mmol),150ml四氢呋喃,搅拌悬浮液,10.5g(41.0mmol))4一乙氧基一3一苄氧基苯甲醛溶于70ml四氢呋喃,放入100ml的滴液漏斗中。反应瓶中加入固体叔丁醇钾7.5g(66.5mmol),反应体系变为血红色,室温搅拌5min,缓慢滴加4一乙氧基一3一苄氧基苯甲醛的溶液,再室温搅拌20min,TLC检测反应完全后,倒入500ml的分液漏斗中,加入140ml去离子水后,溶液分层,加入乙醚300ml×2萃取,合并乙醚层,用无水硫酸镁干燥,过滤,滤饼用50mL乙醚洗涤,滤液旋转蒸发仪浓缩至干,得油状物25g,加入20mL无水乙醇,抽滤得淡黄色固体14.1g,放入圆底烧瓶中,加入25ml无水乙醇,加热部分固体溶解后,室温搅拌,抽滤,滤饼用10ml的无水乙醚洗涤后,红外灯干燥,得纯3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯10.6g,淡黄色粉末固体,收率为61.6%。
实施例5
3,4,5-三甲氧基-3′-羟基-4′-乙氧基二苯乙烷(简称代号:ECB1)的制备
步骤一、三颈瓶中,加入纯3,4,5-三甲氧基-3′-苄氧基-4′-乙氧基二苯乙烯10.6g(25.8mmol),溶于200ml乙酸乙酯和120ml无水乙醇中,淡黄色溶液,加入5%钯炭1.0g后,搅拌下通氢气,室温搅拌1hr,过滤,得无水溶液,旋转蒸发仪浓缩至干,得油状物8.06g,3,4,5-三甲氧基-3′-羟基-4′-乙氧基二苯乙烷粗品,收率为96.8%。
步骤二、圆底烧瓶中,加入3,4,5-三甲氧基-3′-羟基-4′-乙氧基二苯乙烷粗品8.06g(24.3mmol),用40ml无水乙醇溶解,若有不溶物,过滤除去,室温静止,有晶体析出,放置过夜,溶剂挥发完全,大量白色晶体析出。过滤,滤饼用乙醇洗涤,白色晶体6.7g,收率为83%。
实施例6
3,4,5,-三甲氧基-4′-乙氧基二苯乙烷-3′-o-磷酸二钠盐(简称代号:ECB1P)的制备(磷酯化反应1)
圆底烧瓶中,加入三氯氧磷4.4ml(47.4mmol)和二氯甲烷25ml,滴加入3,4,5-三甲氧基-3-羟基-4-乙氧基二苯乙烷5g(15.1mmol)于10ml二氯甲烷的溶液,滴完后,搅拌5分钟,滴加入三乙胺3.3ml(23.8mmol)于5ml二氯甲烷的溶液,室温搅拌3hr,TLC检测,反应完全后,加入100ml冷水淬灭。充分振荡分出有机相,再用水50mL×2洗涤,二氯甲烷萃取水层后合并有机层,用适量无水硫酸纳干燥过夜,抽滤,滤液减压蒸去溶剂的粘稠液体,在冰浴冷却下,搅拌下加入2mol/L的NaOH溶液,直到混合液pH值在8-10之间,65℃搅拌8小时,过滤除去不溶物,减压蒸去大部分溶液,冷却析晶得白色固体,为3,4,5,-三甲氧基-4′-乙氧基二苯乙烷-3-O-磷酸二钠盐粗品,粗品用乙醇加热溶解,趁热过滤除去不溶固体,滤液冷却析晶得到纯品约5.6克,为白色结晶产物,产率81.6%。
1H-NMR(ppm)δ:7.33(d,1H,2’-H);6.89(d,1H,6’-H);6.67(d,1H,5’-H);6.58(s,2H,2,6-H);4.18(2H,q;-OCH2);3.80(s,3H,4-OCH3);3.76(s,6H,3,5-OCH3);2.82(d,1H,J=13.2Hz,la-H);2.79(d,1H,J=13.3Hz,la’-H);1.52(3H,t;-CH3)
13C NMR(ppm)δ:14.9,37.8,38.2,56.1,56.3,64.7,105.3,114.3,115.2,138.4,121.6,132.2,133.8,145.0,150.1,136.7
实施例7
3,4,5,-三甲氧基-4′-乙氧基二苯乙烷-3′-O-磷酸二钠盐(ECB1P)的制备(磷酯化反应2)
步骤1:在氩气氛下,四颈烧瓶中加入4.2克3,4,5-三甲氧基-3-羟基-4-乙氧基二苯乙烷(12.6mmol)用40mL干燥乙腈溶解,冷却到-25℃,然后加入6ml四氯化碳,继续搅拌5分钟后,加入4.7ml二异丙基乙基胺和0.15克4一二甲基氨基吡啶,1分钟后,慢慢加入4ml二苄基亚磷酸酯(80%),保持温度在-10℃以下,继续反应3.5小时,TLC跟踪,当反应完全时,加入10ml0.5M的KH2P04,自然升温到室温,乙酸乙酯萃取,合并有机层,用蒸馏水、饱和食盐水依次洗涤,无水硫酸镁干燥,减压蒸去溶剂,得到混浊油状物,经乙酸乙酯一正己烷重结晶得到无色针状晶体6.6克,产率88%。
步骤2:四颈烧瓶中,加入干燥的上述得到的磷酸苄酯6.5克(10.8mmol),用25ml的干燥无水乙腈溶解,在15℃、氩气氛围下搅拌,快速滴加4.5ml三甲基溴硅烷(TMBS),5~10分钟以后,加入1.8克甲醇钠的7ml无水甲醇溶液,反应体系立即变成乳白色的悬浊液,半小时以后,加入3.6ml无水甲醇,3.6ml丙酮,搅拌过夜,抽滤,得到白色固体,用无水甲醇和丙酮洗涤,真空干燥。用水/甲醇/丙酮重结晶得到白色粉末4.1克,产率83.6%。
1H-NMR(ppm)δ:7.34(d,1H,2’-H);6.88(d,1H,6’-H);6.68(d,1H,5’-H);6.60(s,2H,2,6-H);4.20(2H,q;-OCH2);3.76(s,3H,4-OCH3);3.75(s,6H,3,5-OCH3);2.81(d,1H,J=13.6Hz,la-H);2.79(d,1H,J=13.6Hz,la’-H);1.54(3H,t;-CH3)
13C NMR(ppm)δ:14.8,37.8,38.3,56.1,56.3,64.6,105.5,114.6,115.3,138.3,121.7,132.4,133.8,145.1,150.1,136.7
实施例8
制备4一乙氧基-3一硝基苯甲醛:
四颈烧瓶加入用4-羟基一3一硝基苯甲醛83.5克(0.5mol),加入N,N-二甲基甲酰胺668mL,碳酸钾167克,十八冠六醚8.35克,搅拌,在55-65℃温度下,加溴乙烷反应5~6小时,TLC跟踪,加入溴乙烷约80克,反应完成后,降温至40℃,加入600ml纯化水,中止反应,产物用乙醚(3×300mL)萃取,有机相用水洗至中性,无水MgSO4干燥,蒸去部分乙醚,加入大量石油醚,沉淀出粗产品,用乙醚/石油醚重结晶得到,得到4一乙氧基一3一硝基苯甲醛80.9克,产率83%。
实施例9
制备3,4,5一三甲氧基苯基一3′一硝基一4′一乙氧基二苯乙烯
氩气保护下,将溴化三甲氧基苯基亚甲基三苯磷15g(28.7mmol.)悬浮于300ml THF中,冷却到-15℃左右。滴入1.6mol/L的正丁基锂环己烷溶液22ml,反应1小时。将5.7克(29mmol.)4一乙氧基一3一硝基苯甲醛24ml THF溶液,缓慢滴加入反应中,TLC跟踪,搅拌过夜,反应温度升到室温,将溶液温度降到-5℃,加入饱和食盐水中止反应,分出有机层,除去3/4溶剂,加入剩下母液的4倍无水乙醇,0~-5℃重结晶,过滤得到6.8克浅黄色物体,产率65%。
实施例10
3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烷(简称代号:ECB1N)的制备
反应瓶中加入水100ml,10%的钯/碳催化剂0.5g,再加入硼氢化钠8克溶于150ml水配成的溶液,通入氮气,搅拌下,滴加3,4,5-三甲氧基-3-硝基-4乙氧基二苯乙烯6.8g(16.6mmol)溶于2mol/L的NaOH250ml配成的溶液,约20min加完,过滤,滤液用2mol/LHCL酸化以分解过量的硼氢化钠,再用稀NaOH中和,乙醚提取(100ml×4),合并乙醚提取液,无水硫酸镁干燥,蒸出乙醚,用约9∶1正己烷/乙酸乙酯重结晶,得到无色晶体4.8克,产率83%。
1H-NMR(ppm)δ:7.14(d,1H,2’-H);6.88(d,1H,6’-H);6.68(d,1H,5’-H);6.60(s,2H,2,6-H);4.48(brs,2H,NH2);4.08(q,2H,-CH2);3.77(s,3H,4-OCH3);3.75(s,6H,3,5-OCH3);2.85(d,1H,J=12.5Hz,la-H);2.78(d,1H,J=12.5Hz,la’-H);1.56(3H,t;-CH3)。
MS(m/Z):331(M+);高分辨质谱,计算值:331.1784,实测值:331.1753。
实施例11
3,4,5-三甲氧基-3′-甘氨酰氨基-4′-乙氧基二苯乙烷(简称代号:ECB1GN)的制备
步骤1:取3,4,5一三甲氧基-3’一氨基一4’-乙氧基苯基一二苯乙烷4.8克(14.5mmol)和Fmoc一甘氨酸5.27克(17.8mmol)以及BOP试剂25克(57mmol)溶于100mlDMF,在搅拌下,将反应混合物加热到60℃,反应2小时,TLC跟踪,反应完成后,冷却,加入饱和碳酸氢钠溶液100ml,混合均匀。用二氯甲烷120mlx3萃取,有机层经无水硫酸镁干燥,减压浓缩,到白色物质6.6克,产率75%。
步骤2,取上述得到的3,4,5一三甲氧基苯基一3’一氨基一4’-乙氧基二苯乙烷一Fmoc一甘氨酰胺6.6克(10.8mmol)溶于120ml甲醇,在搅拌下,加入6ml2N氧氧化钠溶液,室温反应3小时,TLC跟踪,反应完成后,冷却,加入饱和碳酸氢钠溶液60ml,混合均匀,用二氯甲烷150mlx3萃取,有机层经无水硫酸镁干燥,过滤,减压浓缩,得到白色粉沫状物质3.2克,产率77%。
1H-NMR(CDCl3,500M)δ:9.54(brs,1H,-NH);7.04(d,1H,2’-H);6.92(d,1H,6’-H);6.78(d,1H,5’-H);6.65(s,2H,2,6-H);4.77(brs,2H,Cly-NH2);4.20(brs,2H,Gly-CH2);4.02(q,2H,-CH2);3.76(s,3H,4-OCH3);3.75(s,6H,3,5-OCH3);2.88(d,1H,J=12.8Hz,la-H);2.78(d,1H,J=12.8Hz,la’-H);1.55(3H,t;-CH3)。
MS(m/Z):338(M+);高分辨质谱:计算值:388.1998,实测值:388.1945。
实施例12
制备3,4,5-三甲氧基-3′-丝氨酰氨基-4′-乙氧基二苯乙烷(简称代号:ECB1SN)
步骤1:取3,4,5一三甲氧基-3’一氨基一4’-乙氧基苯基一二苯乙烷4.8克(14.5mmol)和Fmoc一丝氨酸6.5克(17.8mmol.)以及DCC(二环己基碳化二亚胺)3.7克(17.8mmol)和HOBt(1-羟基-苯并-三氮唑)2.7克溶于90mlDMF,在搅拌下,反应混合物室温反应5小时,TLC跟踪,反应完成后,冷却,加入乙酸乙酯60ml稀释,混合均匀,过滤,经无水硫酸镁干燥,减压浓缩,得到白色物质6.5克,产率74%。
步骤2:取上述得到的物质6.5克(10mmol)溶于70ml甲醇和70ml二氯甲烷混合溶剂中,在搅拌下,加入12ml 2N氢氧化钠溶液,室温反应24小时,TLC跟踪,反应完成后,冷却,加入饱和氯化钠溶液70ml,混合均匀,用二氯甲烷150mlx3萃取,有机层经无水硫酸镁干燥,过滤,减压浓缩,得到白色粉沫状物质3.3克,产率79%。
1H-NMR(CDCl3,500M)δ:9.65(brs,1H,-NH);7.06(d,1H,2’-H);6.90(d,1H,6’-H);6.76(d,1H,5’-H);6.66(s,2H,2,6-H);5.27(brs,2H,Ser-NH2);4.50(brs,2H,Ser-OH);4.19(q,2H,-CH2);3.93(m,1H,Ser-CH);3.86(s,3H,4-OCH3);3.80(s,6H,3,5-OCH3);2.92(d,1H,J=13.2Hz,la-H);2.85(d,1H,J=13.2Hz,la’-H);2.67(m,2H,Ser-CH2);1.54(3H,t;-CH3)。
MS(m/Z):418(M+);高分辨质谱:计算值:418.2104,实测值:418.2114。
实施例13(体外培养肿瘤细胞的抗肿瘤活性评价)
1、试验方法
细胞以含200mL/L胎牛血清的RPMI 1640培养液培养,使细胞一直处于对数生长期,接种至96孔板,密度4~8×104/ml(HUVEC密度3×104/mL),37℃,预培养24小时加药,药物设6个浓度,每种药物设3个复孔,连续作用48小时,甩去培养液风干,每孔加冰冷500g/L三氯醋酸50μL(终浓度为100g/L)固定60min后去离子水洗4~5次,干燥,每孔加4g/L SRB 100μL作用30min,10mL/L醋酸轻洗4次,甩干,每孔加10mmol Tris base 200μL摇动混匀,在平板振荡器上振荡5min,在酶联免疫检测仪测定A值,用空白对照调零,所用波长为490nm,抑瘤率(%)=(无药细胞对照孔A值平均值-用药孔A值平均值)/无药细胞对照孔A值平均值×100%,阳性对照为CA4、CB1、CB1N,根据不同浓度下药物对细胞生长的抑制率,以Logit方法计算IC50值。
2、试验结果:
4′位乙氧基二苯乙烷类化合物ECB1和ECB1N,和4′位乙氧基二苯乙烯类阳性对照化合物ECA4、ECA4N比较,对多种体外培养的肿瘤细胞均有明显的抗肿瘤活性,抗肿瘤活性作用基本相当,显著强于4′位甲氧基类阳性对照化合物CA4、CB1、CB1N(强10~200倍),对于结肠癌HT-29,ECB1N较CB1强约200倍,ECB1较CB1强约100倍。
实体瘤依赖于血管系统而生长,一部分快速增殖的肿瘤血管内皮细胞因缺少完好的肌丝结构而更依赖于微管来保持结构的完整,增殖的人脐静脉内皮细胞(HUVEC)的快速增殖,便是更依赖于微管来保持结构的完整,故常被用作肿瘤血管内皮细胞的体外模型,以人脐静脉内皮细胞(HUVEC)为作用对象,考察乙氧基二苯乙烷衍生物的抗肿瘤血管性能,乙氧基二苯乙烷衍生物ECB1N的IC50值为6.8×10-4μmol/L、乙氧基二苯乙烷衍生物ECB1的IC50值7.5×10-4μmol/L对人脐静脉内皮细胞增殖抑制作用,明显强于4′位甲氧基类阳性对照化合物CA4、CB1、CB1N(IC50值4.8×10-3~7.7×10-3μmol/L之间),预示着乙氧基二苯乙烷类衍生物是一类潜在的很强的肿瘤血管靶向药物。
体外培养肿瘤细胞的抗肿瘤活性评价测定结果
实施例14(体内静脉注射受试药物对肉瘤S180小鼠移植瘤的抑瘤率实验)
1、实验方法:
经1周适应后,皮下接种小鼠肉瘤S180瘤块组织,待肿瘤生长100-300mm3后,将动物随机分组,用药组每个化合物每组分别6只,对照组12只,给药剂量ECB1P、ECB1GN盐酸盐、ECB1SN盐酸盐、阳性对照ECA4P、ECA4GN盐酸盐均为25、50mg/kg,而阳性对照CB1GA盐酸盐、CB1P、CA4P为50mg/kg、100mg/kg,静脉给药,给药时间均为d0,d2,d4,d6,d8,d10,d12天,共7次,每周测3次瘤体积,称鼠重,记录数据,接种后第14天处死,取瘤块称重,计算抑瘤率,瘤重抑制率%=(1-治疗组平均瘤重/对照组平均瘤重)×100%。
2、实验结果:
按给药方案,上述化合物,均能明显抑制肉瘤S180小鼠移植瘤的生长,给药后第8天左右,可以观察到4′位乙氧基二苯乙烷衍生物ECB1P、ECB1GN盐酸盐、ECB1SN盐酸盐与4′位乙氧基二苯乙烯类阳性对照化合物ECA4P、ECA4GN盐酸盐比较,在给药组肿瘤都有缩小的趋势,50(mg/kg)剂量抑瘤率均达60%以上,疗效基本相当,而明显优于4′位甲氧基类阳性对照化合物CB1GN盐酸盐、CB1P、CA4P(100mg/kg)剂量抑瘤率为40%左右的疗效。
静脉注射受试药物对肉瘤S180小鼠移植瘤的抑瘤率(%)
实施例15(小鼠单次腹腔注射受试药物的急性毒性试验)
1、实验方法
昆明种小鼠(体重17~22g,雌雄各半),按体重随机分组,实验时以每10只为一剂量组,以最高剂量1500mg/kg,以0.9比例分成10个剂量组,受试药物剂量分别为1500、1350、1215、1093、984、885、797、717、645、581mg/kg单次腹腔注射给药,给药后0.25h、0.5h、1h、2h、4h、24h分别观察一次,记录死亡率,以后每天观察一次,记录死亡率,持续14天,第15天处死未死亡的小鼠,进行病理解剖。
2、实验结果
单次腹腔注射给药,高剂量注射给药40min~1hr时,有死亡,解剖未见明显的残留药液,说明药物吸收快,其余主要在给药后第1~2天死亡,第5天后即未见小鼠死亡,死亡小鼠解剖未见心、肺、肝、脾、肾等脏器异常,存活小鼠可见腹泻,但不严重,说明受试药物都主要为急性毒性反应,无明显的迟发性毒性,实验结果表明乙氧基二苯乙烷类化合物ECB1P、ECB1GN盐酸盐、ECB1SN盐酸盐毒性低于乙氧基二苯乙烯类阳性对照化合物ECA4P、ECA4GN盐酸盐给药组。
小鼠单次腹腔注射受试药物的急性毒性试验结果
ECB1P | ECB1GN盐酸盐 | ECB1SN盐酸盐 | ECA4P | ECA4GN盐酸盐 | CB1P | CA4P | |
LD50(mg/kg) | 1056 | 1012 | 1185 | 906 | 912 | 1228 | 1276 |
95%可信限 | 815~1392 | 787~1296 | 840~1338 | 714~1186 | 654~1208 | 1050~1438 | 1047~1455 |
Claims (15)
2.如权利要求1所述的化合物,其特征在于所述的R为羟基、氨基、磷酸二钠盐、磷酸铵盐、硫酸酯盐、磷酸胆碱内式盐、天然氨基酸侧链及其水溶性铵盐、或是-NH(COCHR’NH)m-H(其中R’是氢、苯基,m表示1~3的整数)及其水溶性铵盐。
3.如权利要求1所述的化合物,其特征在于所述的R为-OH、-NH2、-OPO2Na2、-NHCOCH2NH2、或-NHCOCHNH2CH2OH。
4.如权利要求1所述的化合物的的制备方法,其特征在于包括如下步骤:
(1)4-羟基-3-甲氧基苯甲醛(II),在相转移催化下,用溴乙烷进行乙氧基化反应,形成4-乙氧基-3-甲氧基苯甲醛(III);
(2)用二苯基磷锂,选择性脱去间位甲基,转化成羟基,得到4-乙氧基-3-羟基苯甲醛(IV);
(3)4-乙氧基-3-羟基苯甲醛(IV),用氯化苄制得4-乙氧基-3-苄氧基苯甲醛(V);
(4)3,4,5-三甲氧基苄溴三苯基溴化磷四氢呋喃溶液在加入叔丁醇钾下和4一乙氧基一3一苄氧基苯甲醛进行乙烯化加成反应,合成3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯(VI);
(5)3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烯(VI),在钯-碳下加氢,使烯键氢化,脱苄基,制得3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷(VII)。
5.如权利要求4所述的化合物的的制备方法,其特征在于3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷(VII)经磷酰化、磷酸酯化、硫酸酯化,形成乙氧基羟基二苯乙烷水溶性衍生物:磷酸二钠盐、硫酸酯盐、磷酸铵盐或磷酸胆碱内式盐。
6.如权利要求5所述的化合物的的制备方法,其特征在于在于3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷(VII)在磷酰化试剂三氯氧磷、2mol/L的NaOH的作用下,形成3,4,5-三甲氧基-4′-乙氧基二苯乙烷-3′-o-磷酸二钠盐(VIII)。
7.如权利要求5所述的化合物的的制备方法,其特征在于在于3,4,5-三甲氧基-3-苄氧基-4-乙氧基二苯乙烷(VII)与二苄基亚磷酸酯反应形成磷酸苄酯,在三甲基溴硅烷(TMBS)下加甲醇钠/无水甲醇,制得3,4,5-三甲氧基-4′-乙氧基二苯乙烷-3′-o-磷酸二钠盐。
8.如权利要求1所述的化合物的的制备方法,其特征在于也包括如下步骤:
(1)4-羟基-3一硝基苯甲醛(IX),在相转移催化下,用溴乙烷进行乙氧基化反应,形成4一乙氧基-3一硝基苯甲醛(X);
(2)溴化三甲氧基苯基亚甲基三苯磷和4一乙氧基一3一硝基苯甲醛(X)发生Wittig反应,生成3,4,5一三甲氧基苯基一3′一硝基一4′一乙氧基二苯乙烯(XI);
(3)3,4,5一三甲氧基苯基一3′一硝基一4′一乙氧基二苯乙烯(XI)钯-碳催化剂/硼氢化钠下,实现氢化还原反应,使硝基还原成氨基,烯键还原成乙烷单键,制得3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烷(XII)。
9.如权利要求8所述的化合物的的制备方法,其特征在于将3,4,5-三甲氧基-3′-氨基-4′-乙氧基二苯乙烷(XII)与氨基酸衍生物反应,形成乙氧基氨基二苯乙烷氨基酸酰胺衍生物,其氨基酸酰胺侧链为:天然氨基酸侧链、或-NH(COCHR’NH)m-H(其中R’是氢、苯基,m表示1一3的整数)。
10.如权利要求9所述的化合物的的制备方法,其特征在于在二环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt)或六氟合磷氢酸苯并三唑-1-基-氧-三(二甲氨基)磷(BOP试剂)催化下,3,4,5-三甲氧基-3-氨基-4′-乙氧基二苯乙烷(XII)与N-a-9-芴基甲氧羰基氨基酸衍生物(FmocAA)反应,转换3′位氨基成Fmoc-氨基酸酰胺,脱去Fmoc,生成乙氧基二苯乙烷氨基酸酰胺衍生物,分别为3,4,5-三甲氧基-3′-甘氨酰氨基-4′-乙氧基二苯乙烷(X III),3,4,5-三甲氧基-3′-丝氨酰氨基-4′-乙氧基二苯乙烷(XIV)。
11.如权利要求9或10所述的化合物的的制备方法,其特征在于氨基酸酰胺衍生物溶解于甲醇、乙醇或异丙醇中,加等当量的盐酸、硫酸或磷酸,加石油醚或正己烷,释出形成水溶性铵盐。
12.如权利要求1所述的化合物,其特征在于其药物制剂,选自包括以下剂型:静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液;口服形式给药的颗粒剂、片剂、胶囊或糖浆;或是栓剂。
13.如权利要求1所述的化合物,其特征在于通式(I)化合物在制备微管蛋白聚集抑制剂中的应用。
14.如权利要求13所述的化合物,其特征在于包括通式(I)上化合物在制备作为抗肿瘤血管破坏剂,对各种肿瘤具有血管靶向作用的药物中的应用。
15.如权利要求13所述的化合物,其特征在于包括通式(I)上化合物在制备治疗非正常新生血管引起的疾病的药物中的应用。
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CN102245560A (zh) | 2011-11-16 |
HK1160446A1 (zh) | 2012-08-17 |
WO2010043180A1 (zh) | 2010-04-22 |
EP2351730A4 (en) | 2012-03-21 |
PL2351730T3 (pl) | 2014-12-31 |
EP2351730B1 (en) | 2014-07-30 |
ES2492496T3 (es) | 2014-09-09 |
CN102245560B (zh) | 2014-04-16 |
US20120046492A1 (en) | 2012-02-23 |
JP2012505841A (ja) | 2012-03-08 |
EP2351730A1 (en) | 2011-08-03 |
US8686187B2 (en) | 2014-04-01 |
JP5735919B2 (ja) | 2015-06-17 |
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