CN105461738A - 一种雷帕霉素衍生物、其制备方法、其药物组合物及用途 - Google Patents
一种雷帕霉素衍生物、其制备方法、其药物组合物及用途 Download PDFInfo
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- CN105461738A CN105461738A CN201410242439.5A CN201410242439A CN105461738A CN 105461738 A CN105461738 A CN 105461738A CN 201410242439 A CN201410242439 A CN 201410242439A CN 105461738 A CN105461738 A CN 105461738A
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- Prior art keywords
- carbonylmethyl
- rapamycin
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- methyl
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- 125000003118 aryl group Chemical group 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 claims description 12
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Abstract
本发明属于医药化工领域,涉及一种式I所示的雷帕霉素衍生物、其制备方法、其药物组合物及用途。本发明的化合物改善了雷帕霉素在水溶性及代谢性质方面的缺点,而且部分化合物在体外抗肿瘤活性方面优于雷帕霉素,对正常细胞的毒性小于雷帕霉素,具有很好的成药性。
Description
技术领域
本发明属于医药化工领域,涉及一种雷帕霉素衍生物、其制备方法、其药物组合物及用途。
背景技术
雷帕霉素(rapamycin)又称为西罗莫司(sirolimus),1975年由Veniza等从吸水链霉菌(Streptomyceshygroscopicus)中,分离得到。1989年雷帕霉素作为抗移植的排斥反应的新药进入临床,1999年已上市。在上世纪90年代中期,由于雷帕霉素对T淋巴细胞增殖的抑制又引导人们将其用于抗肿瘤细胞治疗,并发现其同样具有较好的抗肿瘤活性,此药作为抗癌药已由美国惠氏公司开发即将进入临床。
雷帕霉素在人体内的作用位点为mTOR(哺乳动物雷帕霉素靶蛋白);mTOR是PI3K-Akt-mTOR信号通路的重要组成部分。PI3K-Akt-mTOR信号通路通过对肿瘤细胞增殖和凋亡相关信号传导通路的调控,一方面促进肿瘤细胞的增殖活性,进一步增强肿瘤细胞的浸润和转移的能力;另一方面,通过对肿瘤细胞凋亡相关蛋白的影响,促进内源性凋亡抑制物的激活和/或抑制凋亡相关蛋白激酶的表达和活化,抑制肿瘤细胞的凋亡。因此,PI3K-Akt-mTOR信号通路可能是肿瘤发生发展的核心调控环节,从而也使mTOR成为对肿瘤进行基因治疗的关键靶点。
雷帕霉素的抗癌活性虽强,但它有两个严重的缺点:稳定性差及水溶性差。雷帕霉素在水中的溶解度只有2.6μg/ml,几乎不溶于水。经过多年的研究发现,修饰雷帕霉素42位上的羟基是一种较可靠的改善雷帕霉素理化性质的方法,基于这一方案已产生了一些上市药物。
下面是部分已上市的42位取代雷帕霉素衍生物:
坦西莫斯(Temsirolimus),商品名Torisel,由惠氏公司(Wyeth-Ayerst)开发,为雷帕霉素42位丙酸酯类衍生物,属于雷帕霉素前药。它是雷帕霉素衍生物中最早被FDA批准的抗癌药物(2007年)。坦西莫斯是治疗晚期肾细胞癌RCC(Renalcellcarcinoma)患者的一线用药,它可将早期RCC患者的中位生存期延长3-6个月。坦西莫斯能显著抑制T细胞的增殖,其半数抑制浓度(IC50)为0.8nmol/L,并可与舒尼替尼(sunitinib)或索拉非尼(sorafenib)等激酶抑制剂合并使用。
依维莫司(Everolimus),商品名Zortress,Novartis公司开发,是第一个口服mTOR抑制剂,化学结构为42一O一(2-羟乙基)一雷帕霉素,其水溶性优于雷帕霉素,进人体内时迅速水解。实验表明依维莫司的口服生物利用度只有15%-30%,在人体半衰期为16-19h。2003年首先在瑞典上市,起初只用作免疫抑制剂,现在已被批准用于RCC,胰腺神经内分泌肿瘤(PNET)和室管膜下巨细胞星形细胞瘤(SEGA)的治疗。FDA已批准依维莫司口服片剂用于防止有低至中度免疫风险的成人肾移植患者的器官排斥反应。依维莫司与减量的环孢霉素A(cyclosporineA)及巴利昔单抗(basiliximab)和皮质类固醇同时使用。已批准的Ⅲ期试验显示,依维莫司可防止急性器官排斥并保存肾功能。
Ridaforolimus(Ariad/Merck公司),在雷帕霉素C43处作了修饰,改善了其溶解度和PK值。它的研究工作已完成了治疗转移性软组织或骨肉瘤(metastaticsoft-tissueorbonesarcomas)患者的三期临床,对安慰剂组相比,服药组的死亡风险降低了28%(NCT00538239)。Ariad和默克公司2012年已向FDA提交ridaforolimus的新药申请,但由于FDA专家组对其疗效的质疑,所以申报过程遇到了一些阻力。
Zotarolimus(Medtroni公司)2006年FDA批准Zotarolimus涂药冠脉支架系统(Endeavor)上市,相比较裸金属冠脉支架组,涂药组能有效减少支架使用者的动脉栓塞,心脏病和心梗死死亡率。
Umiroliums(Biolimus,Biosensors公司)2007年欧洲批准Biolimus涂药冠脉支架系统biolimusA9上市。它具有比雷帕霉素更强的免疫抑制及其抗炎活性,它通过使细胞周期停滞在G1而阻碍细胞迁移及增生,从而防止血管再狭窄的发生。
目前,尚需要开发新的雷帕霉素衍生物。
发明内容
本发明通过深入的研究和创造性的劳动,得到了一系列结构新颖的具有季铵盐结构的雷帕霉素羧酸酯衍生物(式I化合物),不仅极大的改善了雷帕霉素在水溶性及代谢性质方面的缺点(其中实施例14的化合物水溶性比雷帕霉素提高4万倍),而且部分化合物在体外抗肿瘤活性方面优于雷帕霉素,对正常细胞的毒性小于雷帕霉素,具有很好的成药性。由此提供了下述发明:
本发明的一个方面涉及式I所示的化合物、其可药用盐或其水合物:
其中,
R1和R2独立地选自H、A和B,并且R1,R2不同时为H;
其中,式A或式B中,
箭头表示A或B与式I母环连接的位点;
n独立地为1、2、3、4、5、6或7;
R4独立地选自氟、氯、溴、碘、硝基、氰基;
X1、X2、X3、X4、Y1、Y2、Y3、Y4、Y5各自独立选自C、S、O、N和Se原子;
X1~X2、X2~X3、X3~X4、Y1~Y2、Y2~Y3、Y3~Y4、Y4~Y5各自独立的为单键或双键;
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、醛基、羧基、氨基、氰基、卤素、C1-C6烷基、C3-C10环烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C10环烷氧基、C1-C6烷烯基、烯炔基杂环、杂环烷基、取代杂环烷基、芳香环、芳香杂环、苯并芳香杂环,其中所述的C1-C6烷基、芳香环、芳香杂环、苯并芳香杂环未被取代或者被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷硫基、C1-C6烷基、C1-C6烯基、C1-C6炔基和C1-C6烷氧基。
具体地,N原子与X1、X2、X3、X4,或与Y1、Y2、Y3、Y4、Y5组成杂环结构;具体地,为稳定的杂环结构。
根据本发明的任一项所述的式I化合物、其可药用盐或其水合物,其中:
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、醛基、羧基、氨基、氰基、卤素、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、C1-C3烷硫基、C3-C6环烷氧基、C1-C3烷烯基。
根据本发明的任一项所述的式I化合物、其可药用盐或其水合物,其中:
式A中,N原子与X1、X2、X3、X4组成噻唑环,和/或
式B中,N原子与Y1、Y2、Y3、Y4、Y5组成吡啶环。
根据本发明的任一项所述的式I化合物、其可药用盐或其水合物,其中:
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、甲基。
根据本发明的任一项所述的式I化合物、其可药用盐或其水合物,其中:
R1和R2独立地选自H、羰基甲基-(4-甲基-噻唑R4盐-3-基)、羰基甲基-(4,5-二甲基-噻唑R4盐-3-基)、羰基甲基-(吡啶R4盐-1-基)、羰基甲基-(3-羟基-吡啶R4盐-1-基)、羰基甲基-(3-甲基-吡啶R4盐-1-基)以及羰基甲基-(4-甲基-吡啶R4盐-1-基),其中R4独立地选自氟、氯、溴、碘、硝基和氰基;
并且R1,R2不同时为H。
根据本发明的任一项所述的式I化合物、其可药用盐或其水合物,其中:
R1和R2独立地选自H、羰基甲基-(4-甲基-噻唑溴盐-3-基)、羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)、羰基甲基-(吡啶溴盐-1-基)、羰基甲基-(3-羟基-吡啶溴盐-1-基)、羰基甲基-(3-甲基-吡啶溴盐-1-基)以及羰基甲基-(4-甲基-吡啶溴盐-1-基);
并且R1,R2不同时为H。
在本发明的一个实施方案中,选自下面的表1所示的化合物、其可药用盐或其水合物。
表1:本发明的部分化合物
本发明的再一方面涉及本发明中任一项所述的式I化合物的制备方法,其包括下面的(1)-(3)中任一方法所述的步骤:
方法(1):31,42位双取代式I化合物的制备方法
方法(2):42位单取代的式I化合物的制备
方法(3):31位单取代的式I化合物的制备
上述方法(1)-(3)中,
R3独立地选自F、Cl、Br和I;
其余各符号的含义独立地如前面任一项所述。
对于方法(1),雷帕霉素先与酰卤发生反应,生成31位和42位双酯化产物(中间体1),然后该产物与杂环反应生成31,42双取代的季铵盐类雷帕霉素衍生物。
对于方法(2),雷帕霉素先与足量四甲基氯硅烷反应生成中间体2,然后其31位醚键在酸的作用下水解生中间体3,然后用卤代酰卤取代该中间体的42位得中间体4,紧接着用酸脱去31位的四甲基硅烷醚,得到42位单酯化产物(中间体5);最后,中间体5与氮杂环反应生成42位单取代的季铵盐类雷帕霉素衍生物。
对于方法(3),将叔丁基二甲基氯硅烷将中间体3的42位取代,得到中间体6;随后,用酸将其31位的四甲基硅烷醚水解得到中间体7;卤代酰卤与中间体7反应得到中间体8;然后在酸性条件下将叔丁基二甲基氯硅烷醚水解得到中间体9;最后氮杂环与中间体9反应得到31位单取代的季铵盐类雷帕霉素衍生物。
本发明的再一方面涉及一种药物组合物,其包含本发明中任一项所述的化合物、其可药用盐或其水合物,以及任选的药学上可接受的辅料。
本发明所涉及的一系列化合物均将具有极好的水溶性,方便制备成为多种剂型。当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。
本发明的化合物、其可药用盐或其水合物、或者本发明的药物组合物的给药剂量取决于许多因素,例如所要治疗或辅助治疗的疾病的性质和严重程度,患者或动物的性别、年龄、体重及个体反应,所用的具体化合物,给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个,例如二、三、四个剂量形式给药。
本发明的再一方面涉及本发明中任一项所述的化合物、其可药用盐或其水合物或者本发明的药物组合物在制备免疫抑制剂、mTOR抑制剂、抑制PI3K-Akt-mTOR信号通路的药物、抑制T淋巴细胞增殖的药物、抗肿瘤药物、促进肿瘤细胞凋亡的药物、使细胞周期停滞在G1的药物、防止器官排斥反应的药物、降低动脉栓塞的药物、抗衰老药物、抗阿尔茨海默病药物、抗炎药物或抗菌药物中的用途;具体地,所述抗肿瘤药物为治疗和/或预防和/或辅助治疗肾癌、淋巴瘤、肺癌、肝癌、乳腺癌、神经内分泌癌或胃癌的药物。
本发明在再一方面涉及一种在体内或者体外抑制免疫、抑制mTOR、抑制PI3K-Akt-mTOR信号通路、抑制T淋巴细胞增殖、抗肿瘤、促进肿瘤细胞凋亡、使细胞周期停滞在G1、降低动脉栓塞、抗衰老、抗阿尔茨海默病、防止器官排斥反应、抗炎或者抗菌的方法,包括使用有效量的本发明中任一项所述的化合物、其可药用盐或其水合物或者本发明的药物组合物的步骤。
在本发明的一个实施方案中,上述“在体外”的方法是非治疗目的的。
本发明的再一方面涉及一种冠脉支架,其药物涂层包含本发明中任一项所述的化合物、其可药用盐或其水合物或者本发明的药物组合物。
本发明还涉及本发明中任一项所述的化合物、其可药用盐或其水合物或者本发明的药物组合物在制备上述的冠脉支架中的用途。
本发明还涉及一种制备上述的冠脉支架的方法,包括使用有效量的本发明中任一项所述的化合物、其可药用盐或其水合物或者本发明的药物组合物。
在本发明中,
术语“C1-C6烷基”是指具有1-4个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基等;C1-C4烷基、C1-C3烷基或C1-C2烷基也可做类似理解。具体的烷基是C1-C4烷基、C1-C3烷基或C1-C2烷基。
术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基等;C1-C4烷氧基、C1-C3烷氧基或C1-C2烷氧基也可做类似理解。具体的烷氧基是C1-C4烷氧基、C1-C3烷氧基或C1-C2烷氧基。
术语““C1-C6烷硫基””可与“C1-C6烷氧基”做类似理解,不同之处在于将氧原子替换为硫原子。
术语“C3-C10环烷基”是指具有3-10个碳原子的饱和碳环基团。该环烷基可以是单环或者多环稠合系统,而且可以稠合在芳环上。这些基团的实例包括环丙基、环丁基、环戊基和环己基。本文的环炕基可以是未取代的或者如详细说明,在一个或多个可取代的位置被各种基团取代。例如,这些环烷基可任选被以下基团取代:C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C}-C6卤代烷基、C1-C6卤代烷氧基。C3-C6环烷基也可做类似理解。
术语“C3-C10环烷氧基”是指具有3-10个碳原子的饱和碳环烷氧基基团。该环烷氧基可以是单环或者多环稠合系统,而且可以稠合在芳环上。这些基团的实例包括环丙氧基、环丁氧基、环戊氧基和环己氧基。本文的环炕基可以是未取代的或者如详细说明,在一个或多个可取代的位置被各种基团取代。例如,这些环烷氧基可任选被以下基团取代:C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C}-C6卤代烷基、C1-C6卤代烷氧基。C3-C6环烷氧基也可做类似理解。
术语“C2-C6烯基”是指具有2-6个碳原子以及至少一个双键的烯基,并且包括乙烯基、丙烯基、1-丁-3-烯基、1-戊-3-烯基、1-己-5-烯基等;C3-C5烯基也可做类似理解。优选的是C3-C5烯基。
术语“C2-C6炔基”是指具有2-6个碳原子以及至少一个叁键的烃基,并且包括乙炔基、丙炔基、丁炔基、戊炔-2-基等;C3-C5炔基也可做类似理解。优选的是C3-C5炔基。
术语“卤素”是指氟、氯、溴以及碘原子。
术语“芳香环”或“芳基”是指具有单环(如苯基)、多环(如联苯基)或其中至少一个环是芳香性的多个稠合环(如1,2,3,4-四氢萘基、萘基)的芳族碳环基,其任选被例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基和羟基单、二或三取代。
术语“芳基烷基”是指被一个或多个芳基(如上定义的)取代的烷基(如上定义的)。更优选的芳基烷基是芳基-Cl-C3烷基。实例包括苄基、苯基乙基等。
术语“芳香杂环”或“杂芳基”是指五元、六元或七元环的一个或多个芳族环系,其包括5-10个原子的稠合环系(其中至少一个环是芳香性的),所述环系含有至少一个和最多四个选自氮、氧或硫的杂原子。杂芳基的实例为吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯环、喹啉环、异喹啉环、吲哚环、苯并咪唑、苯并呋喃环、苯并噻吩环、苯并噻唑环、哒嗪环等。其任选被例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基和羟基单、二或三取代。
术语“杂环”或“杂环基”是指五元、六元或七元环的一个或者多个碳环环系,其包括4-10个原子的稠合环系,所述环系含有至少一个和最多四个选自氮、氧或硫的杂原子,条件是该基团的环不含两个相邻的O或S原子。稠合环系可以是稠合在芳组基团上的杂环。优选的杂环包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、哌啶基、吗啉环、环己环、哌嗪环等,它们可以被以下基团取代:C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C}-C6卤代烷基、C1-C6卤代烷氧基。
当用于“在体内”时,术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
化合物熔点由SRY-1型熔点仪测定,温度未经校正。1H-NMR光谱由VARIANINOVA600型核磁仪测定;质谱由API-150EXLC/MS高分辨质谱仪测定。
实施例1:31,42-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素
(化合物1)的制备
步骤1:将1g(1.09mmol)雷帕霉素溶于10ml干燥的二氯甲烷,冷却至-10℃,然后加入0.87g(11mmol)干燥的吡啶。向反应液中缓慢滴加溴乙酰溴2.2g(10mmol)的5ml二氯甲烷溶液,30min滴加完毕,继续反应10min后停止反应。用1mol/L盐酸调反应液pH至中性,20ml×3的蒸馏水洗涤,然后使用柱层析的方法提纯,得0.73g白色泡沫状产品中间体1(n=1,R3=Br,R4=Br)。
步骤2:将0.73g(0.63mmol)中间体1(n=1,R3=Br,R4=Br)溶于20ml丙酮,加入4-甲基噻唑0.94g(9.45mmol),60℃反应5h,柱分离得0.7g淡黄色颗粒状化合物1。
M.p.142-145℃;MS:1193[M-2Br-H]+,597[(M-2Br)/2]+;1H-NMR(600MHz,DMSO-d6δppm),10.18(d,2H),8.07(s,2H),6.46(s,1H),6.38(m,1H),6.24(m,1H),6.22(m,1H),5.71(s,1H),5.59(s,2H),5.46(m,1H),5.33(s,1H),4.91(m,3H),4.53(s,2H)。
实施例2:42-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素(化
合物2)的制备
步骤1:将2g(2.19mmol)雷帕霉素溶于25ml干燥的乙酸乙酯,冷却至0-5℃。向反应液中投入咪唑1.50g(22mmol),30min缓慢滴加1.2g(11mmol)三甲基氯硅烷的5ml乙酸乙酯溶液,至完全转化为中间体2。3h内向反应液中缓慢滴加0.5mol/L的H2SO4溶液10ml,待中间体2完全转化后用柱层析提取,得1.3g白色泡沫状产品中间体3。
步骤2:将1.3g(1.3mmol)中间体3溶于15ml二氯甲烷中,冷却至-10℃,然后加入1.03g(13mmol)干燥的吡啶。向反应液中缓慢滴加1.31g(6.5mmol)溴乙酰溴的5ml溶液,30min滴加完毕,继续反应10min后停止反应。用1mol/L盐酸调反应液pH至中性,20ml×3的蒸馏水洗涤,然后使用柱层析的方法提纯,得1.2g白色泡沫状产品中间体4(n=1,R3=Br,R4=Br)。
步骤3:将1.2g(1.1mmol)中间体4(n=1,R3=Br,R4=Br)溶于15ml丙酮中,滴加1mol/L的H2SO4水溶液0.7ml,1h加完,继续反应30min,反应物完全转化。柱分离提纯,得1.05g白色泡沫状产品中间体5(n=1,R3=Br,R4=Br)g。
步骤4:将1.05g(0.95mmol)中间体5(n=1,R3=Br,R4=Br)溶于20ml丙酮,加入0.94g(9.5mmol)4-甲基噻唑,60℃反应5h,柱分离得1.02g淡黄色颗粒状化合物2。
M.p.130-133℃;MS:1053.8[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),10.16(d,1H),8.06(s,1H),6.45(s,1H),6.38(m,1H),6.22(m,1H),6.15(m,1H),5.62(s,2H),5.46(M,1H),5.24(s,1H),5.08(d,1H),4.97(s,1H),4.93(s,1H),4.68(m,1H),4.00(s,2H),3.97(s,1H)。
实施例3:31-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素(化
合物3)的制备
步骤1:将2g(2mmol)中间体3溶于20ml乙酸乙酯中,冷却至0~5℃。向反应液中投入1.36g(20mmol)咪唑,30min缓慢滴加1.5g(10mmol)叔丁基二甲基氯硅烷的5ml乙酸乙酯溶液,继续反应30min,柱分离得1.3g中间体6。30min内向反应液中滴加0.5mol/L的H2SO4溶液0.5ml,1h加完,反应物完全转化。柱分离提纯,得1.05g白色泡沫状产品中间体7。
步骤2:将1.05g(1.02mmol)中间体7溶于10ml二氯甲烷中,冷却至-10℃,然后加入0.81g(10.2mmol)干燥的吡啶。向反应液中缓慢滴加1.03g(5.1mmol)溴乙酰溴的5ml溶液,30min滴加完毕。继续反应10min后停止反应。用1mol/L盐酸调反应液pH至中性,20ml×3的蒸馏水洗涤,然后使用柱层析的方法提纯,得0.73g白色泡沫状产品中间体8(n=1,R3=Br,R4=Br)。
步骤3:将0.73g(0.64mmol)中间体8(n=1,R3=Br,R4=Br)溶于10ml丙酮中,滴加2mol/L的H2SO4溶液0.5ml,30min加完,继续反应30min,反应物完全转化。柱分离提纯,得0.4g白色泡沫状产品中间体9(n=1,R3=Br,R4=Br)。
步骤4:将0.4g(0.39mmol)中间体9(n=1,R3=Br,R4=Br)溶于20ml丙酮,加入0.38g(3.90mmol)4-甲基噻唑,60℃反应5h,柱分离得0.27g(0.24mmol)淡黄色颗粒状化合物3。
M.p.130-132℃;MS:1054[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),10.16(d,1H),8.05(s,1H),6.45(s,1H),6.37(m,1H),6.25(m,1H),6.18(m,2H),5.70(s,2H),5.46(m,1H),5.35(s,1H),4.55(d2H),4.04(s,1H)。
实施例4:31,42-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷
帕霉素(化合物4)的制备
制备方法参见实施例1(n=1,R3=Br,R4=Br,R5=4,5-二甲基噻唑)。
m.p.135-139℃;MS:1220.9[M-2Br-H]+;1H-NMR(600MHz,DMSO-d6δppm),10.03(d,2H),6.46(s,1H),6.37(m,1H),6.24(m,1H),6.18(m,1H),6.12(m,1H),5.76(m,3H),5.62(s,2H),5.46(m,1H),5.32(s,1H),5.32(s,1H),4.93(s,1H),4.83(m,2H),4.61(s,1H),4.55(s,1H),4.52(s,1H)。
实施例5:42-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷帕霉
素(化合物5)的制备
制备方法参见实施例2(n=1,R3=Br,R4=Br,R5=4,5-二甲基噻唑)。
m.p.135-138℃;MS:1067.9[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),10.03(d,1H),6.49(s,1H),6.37(m,1H),6.21(m,1H),6.14(m,2H),5.62(m,2H),5.46(m,1H),5.23(s,1H),5.08(s,1H),4.97(s,1H),4.93(s,1H),4.68(s,1H),4.06(s,2H),4.01(s,1H)。
实施例6:31-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷帕霉
素(化合物6)的制备
制备方法参见实施例3(n=1,R3=Br,R4=Br,R5=4,5-二甲基噻唑)。
m.p.125-127℃;MS:1067.7[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),10.02(d,1H),6.45(s,1H),6.37(m,1H),6.25(m,1H),6.20(m,H),6.15(m,H),5.70(m,2H),5.45(m,1H),5.33(s,1H),5.08(s,1H),4.93(s,1H),4.81(m,1H),4.56(m,3H),4.03(m,1H)。
实施例7:31,42-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素(化合
物7)的制备
制备方法参见实施例1(n=1,R3=Br,R4=Br,R5=吡啶)。
m.p.140-142℃;MS:1153[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),8.96(d,4H),8.72(m,2H),8.22(m,4H),6.44(s,1H),6.40(m,1H),6.24(m,1H),6.17(m,2H),5.87(m,1H),5.79(m,1H),5.48(m,1H),5.29(s,1H),4.95(m,2H),4.81(s,1H),4.52(m,3H)。
实施例8:31,42-O-羰基甲基-(3-羟基-吡啶溴盐-1-基)-雷帕霉素
(化合物8)的制备
合成方法参见实施例1(n=1,R3=Br,R4=Br,R5=3-羟基吡啶)。
m.p.120-124℃;MS:1185.4[M-2Br-H]+;1H-NMR(600MHz,DMSO-d6δppm),12.04(s,2H),8.60(m,4H),8.00(m,4H),6.43(m,2H),6.12(m,3H),5.61(m,3H),5.56(m,1H)。
实施例9:31,42-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素
(化合物9)的制备
制备方法参见实施例1(n=1,R3=Br,R4=Br,R5=3-甲基吡啶)。
m.p.159-162℃;MS:1181.2[M-2Br-H]+;1H-NMR(600MHz,DMSO-d6δppm),9.00(s,1H),8.89(m,2H),8.81(m,1H),8.57(s,2H),8.14(m,2H),6.46(s,1H),6.38(m,1H),6.23(m,1H),6.14(m,2H),5.80(m,5H),5.46(m,1H),5.29(m,1H)。
实施例10:42-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素(化合物
10)的制备
制备方法参见实施例2(n=1,R3=Br,R4=Br,R5=吡啶)。
m.p.135-137℃;MS:1034.1[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),9.07(d,1H),9.02(m,1H),8.71(m,1H),8.24(m,2H),8.14(m,2H),6.45(s,1H),6.41(m,1H),6.22(m,1H),6.14(m,1H),5.80(m,5H),5.67(m,2H),5.44(m,1H),5.25(s,1H),5.08(m,1H)。
实施例11:42-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素(化
合物11)的制备
制备方法参见实施例2(n=1,R3=Br,R4=Br,R5=3-甲基吡啶)。
m.p.138-140℃;MS:1048[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),9.07(d,1H),9.02(m,1H),8.71(m,1H),8.24(m,2H),8.14(m,2H),6.45(s,1H),6.41(m,1H),6.22(m,1H),6.14(m,1H),5.80(m,5H),5.67(m,2H),5.44(m,1H),5.25(s,1H),5.08(m,1H)。
实施例12:42-O-羰基甲基-(3-羟基-吡啶溴盐-1-基)-雷帕霉素(化
合物12)的制备
制备方法参见实施例2(n=1,R3=Br,R4=Br,R5=3-羟基吡啶)。
m.p.146-148℃;MS:1050[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),12.08(s,1H),8.60(m,1H),8.53(m,1H),8.02(m,2H),6.45(m,2H),6.38(s,1H),6.22(m,1H),6.12(m,2H),5.60(m,2H),5.48(m,1H),5.25(m,1H),5.08(m,1H)。
实施例13:42-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉素(化
合物13)的制备
制备方法参见实施例2(n=1,R3=Br,R4=Br,R5=4-甲基吡啶)。
m.p.157-160℃;MS:1048.1[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),8.89(d,1H),8.05(m,2H),6.45(s,1H),6.41(m,1H),6.22(m,1H),6.12(m,2H),5.61(m,3H),5.46(m,1H),5.25(m,1H),5.08(d,1H),4.93(m,2H)。
实施例14:31,42-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉
素(化合物14)的制备
制备方法参见实施例1(n=1,R3=Br,R4=Br,R5=4-甲基吡啶)。
m.p.181-183℃;MS:1181.2[M-2Br-H]+;1H-NMR(600MHz,DMSO-d6δppm),8.90(d,2H),8.78(d,2H),8.06(m,4H),6.46(d,1H),6.38(m,1H),6.20(m,1H),6.14(m,2H),5.80(d,1H),5.62(m,4H),5.47(m,1H),5.29(s,1H)。
实施例15:31-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素(化
合物15)的制备
制备方法参见实施例3(n=1,R3=Br,R4=Br,R5=3-甲基吡啶)。
m.p.138-140℃;MS:1048.1[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),8.88(d,1H),8.80(d,1H),8.57(m,1H),8.12(m,1H),6.45(m,1H),6.40(m,1H),6.23(m,1H),6.17(m,2H),5.81(d,1H),5.74(m,2H),5.47(m,1H)5.28(s,1H)。
实施例16:31-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素(化合物
16)的制备
制备方法参见实施例3(n=1,R3=Br,R4=Br,R5=吡啶)。
m.p.140-142℃;MS:1034[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),8.96(d,2H),8.72(m,1H),8.22(m,2H),6.44(s,1H),6.40(m,1H),6.24(m,1H),6.17(m,2H),5.87(m,1H),5.79(m,1H),5.48(m,1H),5.29(s,1H),4.95(m,2H),4.81(s,1H),4.52(m,3H)。
实施例17:31-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉素(化
合物17)的制备
制备方法参见实施例3(n=1,R3=Br,R4=Br,R5=4-甲基吡啶)。
m.p.145-148℃;MS:1048.1[M-Br]+;1H-NMR(600MHz,DMSO-d6δppm),8.77(d,2H),8.03(d,2H),6.44(s,1H),6.40(m,1H),6.23(m,1H),6.16(m,2H),5.80(d,1H),5.70(d,1H),5.44(m,1H),5.29(m,1H),5.29(s,1H)。
实施例18:溶解度试验
取本发明所述化合物1-17,分别按中国药典2010版第二部的所述的溶解度测试方法进行试验,结果见表2:
表2:化合物1-17的水溶性一览表
由表2的数据可见,本发明的化合物的水溶性显著地高于雷帕霉素,部分化合物甚至高出3至4个数量级。
实施例19:mTOR抑制试验
利用Alphascreen技术评价实施例化合物对mTOR的抑制。
实验方法:在SH-SY5Y细胞中筛选实施例化合物浓度均为2μM时对mTOR的作用。将细胞铺板至96孔板,待细胞生长至密度达到80%-90%时加入化合物,孵育1小时,然后裂解细胞检测其mTOR水平(以雷帕霉素的抑制率为100%进行对比),结果见表3。
表3:实施例化合物浓度为2μM在SH-SY5Y细胞上的抑制率(以雷帕霉素的抑制率为100%对比)
化合物 | 抑制率(%) |
雷帕霉素 | 100 |
实施例1化合物 | 95.2931 |
实施例2化合物 | 99.5542 |
实施例3化合物 | 98.6552 |
实施例4化合物 | 102.6678 |
实施例5化合物 | 102.4485 |
实施例6化合物 | 98.4287 |
实施例7化合物 | 100.6871 |
实施例8化合物 | 53.5448 |
实施例9化合物 | 119.1639 |
实施例10化合物 | 114.2816 |
实施例11化合物 | 101.2791 |
实施例12化合物 | 111.2192 |
实施例13化合物 | 108.7926 |
实施例14化合物 | 110.6272 |
实施例15化合物 | 111.3727 |
实施例16化合物 | 110.6929 |
实施例17化合物 | 111.8624 |
由表3的数据可见,本发明的化合物能够有效地抑制mTOR。
实施例20:对大鼠原代肝细胞毒性的评价实验
实验方法:取SD大鼠肝叶置入消毒平皿内,加入适量肝细胞洗涤液(4℃预冷),撕碎肝脏并祛除纤维结缔组织,制成混合肝脏细胞悬液,200目筛网过滤入50ml离心管,500rpm离心1-2分钟;去上清,沉淀加入RPMI1640(4℃预冷)20-30ml洗涤3次;取等体积肝细胞悬液悬浮于Percoll分离液I,颠倒混匀,于4℃800rpm离心10min,弃上清,用PBS清洗肝细胞一次(800rpm,5min)。将肝细胞沉淀加入肝细胞培养液重悬定量为10ml,取适量计数并用0.4%台盼蓝染色判断存活率。活率在90%以上的肝细胞按2x103密度接种于96孔板,每孔加入100μlRPMI1640培养基,于37℃,5%CO2条件下培养24h。将化合物用DMSO稀释到所需浓度,每孔加药1μl(化合物终浓度通常为1000μM起始,10x梯度稀释,6个梯度),空白对照加入1μlDMSO。
细胞37℃,5%CO2培养24h后,加入100μlATP检测试剂,震荡孵育15分钟。于酶标仪上读取各孔荧光值。计算各实施例化合物处理后细胞存活率,计算GI50值(50%细胞生长受到抑制时加入化合物的浓度)。结果见表4。化合物的毒性明显小于雷帕霉素。
表4:部分实施例化合物浓度对大鼠原代肝细胞的GI50值
化合物 | GI50(μM) |
雷帕霉素 | 24.822 |
实施例11化合物 | 71.753 |
实施例13化合物 | 44.936 |
实施例17化合物 | 54.311 |
由表4的数据可见,本发明的化合物的毒性明显小于雷帕霉素。
实施例21:肿瘤细胞抑制实验
评价实施例化合物对肿瘤细胞A549的活性。
实验材料:DMEM高糖细胞培养基(Hyclone公司),胎牛血清(FBS)(Gibco公司),青霉素、链霉素购自华北制药股份有限公司,磷酸生理盐水缓冲液(PBS)购自Gibco公司,Cell细胞活力检测试剂购自Promega公司,胰酶以及二甲亚砜(DMSO)为Sigma公司产品。A549细胞系(人肺腺癌细胞系)购自ATCC。
实验方法:
以每孔5000个细胞的数量接种白壁底透96孔板(Costar),37℃5%CO2条件下培养24h。利用DMSO将待测化合物溶解至100mM,作为化合物母液。
利用含有2%FBS的DMEM培养液稀释化合物,浓度梯度为3,浓度范围为100μM~3nM。将各稀释度化合物加入培养好的96孔板细胞中,每孔100μl。37℃CO2条件下培养72h,弃去上清后,进行细胞活力检测实验。
将Cell的反应缓冲液以及底物进行等比混合后,加入96孔板中,每孔100μl。水平震荡4min以诱导细胞裂解。室温平衡15min,以稳定反应信号。利用化学发光检测仪检测96孔板中每孔的化学发光单位。
根据每孔的化学发光检测值,计算每个化合物各稀释度的抑制率,利用Origin8.0软件对每个化合物的不同梯度进行S型曲线拟合,计算EC50值。结果见表5。
表5:部分实施例化合物浓度对肿瘤细胞A549的EC50值
化合物 | IC50(μM) |
雷帕霉素 | 49.35 |
实施例1化合物 | 17.39 |
实施例2化合物 | 19.31 |
实施例3化合物 | 3.04 |
实施例4化合物 | 6.23 |
实施例5化合物 | 7.40 |
实施例6化合物 | 52.26 |
实施例7化合物 | 46.68 |
实施例8化合物 | 45.98 |
实施例9化合物 | 25.12 |
实施例10化合物 | 66.32 |
实施例11化合物 | 52.80 |
实施例12化合物 | 51.48 |
实施例13化合物 | 44.80 |
实施例14化合物 | 44.0 |
实施例15化合物 | 52.70 |
实施例16化合物 | 57.71 |
实施例17化合物 | 40.80 |
结果表明,本发明的化合物能够有效地肿瘤细胞,部分化合物的效果甚至优于雷帕霉素,具有用于制备抗肿瘤药物的潜力。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解:根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (10)
1.式I所示的化合物、其可药用盐或其水合物:
其中,
R1和R2独立地选自H、A和B,并且R1,R2不同时为H;
其中,式A或式B中,
箭头表示A或B与式I母环连接的位点;
n独立地为1、2、3、4、5、6或7;
R4独立地选自氟、氯、溴、碘、硝基、氰基;
X1、X2、X3、X4、Y1、Y2、Y3、Y4、Y5各自独立选自C、S、O、N和Se原子;
X1~X2、X2~X3、X3~X4、Y1~Y2、Y2~Y3、Y3~Y4、Y4~Y5各自独立的为单键或双键;
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、醛基、羧基、氨基、氰基、卤素、C1-C6烷基、C3-C10环烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C10环烷氧基、C1-C6烷烯基、烯炔基杂环、杂环烷基、取代杂环烷基、芳香环、芳香杂环、苯并芳香杂环,其中所述的C1-C6烷基、芳香环、芳香杂环、苯并芳香杂环未被取代或者被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷硫基、C1-C6烷基、C1-C6烯基、C1-C6炔基和C1-C6烷氧基。
2.根据权利要求1所述的式I化合物、其可药用盐或其水合物,其中:
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、醛基、羧基、氨基、氰基、卤素、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、C1-C3烷硫基、C3-C6环烷氧基、C1-C3烷烯基。
3.根据权利要求1或2所述的式I化合物、其可药用盐或其水合物,其满足如下的1)-3)项中的任意一项或者多项:
1)式A中,N原子与X1、X2、X3、X4组成噻唑环;
2)式B中,N原子与Y1、Y2、Y3、Y4、Y5组成吡啶环;
3)Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9独立地选自氢原子、羟基、甲基。
4.根据权利要求1所述的式I化合物、其可药用盐或其水合物,其中:
R1和R2独立地选自H、羰基甲基-(4-甲基-噻唑R4盐-3-基)、羰基甲基-(4,5-二甲基-噻唑R4盐-3-基)、羰基甲基-(吡啶R4盐-1-基)、羰基甲基-(3-羟基-吡啶R4盐-1-基)、羰基甲基-(3-甲基-吡啶R4盐-1-基)以及羰基甲基-(4-甲基-吡啶R4盐-1-基),其中R4独立地选自氟、氯、溴、碘、硝基和氰基,并且R1,R2不同时为H;或者
R1和R2独立地选自H、羰基甲基-(4-甲基-噻唑溴盐-3-基)、羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)、羰基甲基-(吡啶溴盐-1-基)、羰基甲基-(3-羟基-吡啶溴盐-1-基)、羰基甲基-(3-甲基-吡啶溴盐-1-基)以及羰基甲基-(4-甲基-吡啶溴盐-1-基),并且R1,R2不同时为H。
5.根据权利要求1所述的式I化合物、其可药用盐或其水合物,其中,所述化合物选自如下:
31,42-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素,
42-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素,
31-O-羰基甲基-(4-甲基-噻唑溴盐-3-基)-雷帕霉素,
31,42-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷帕霉素,
42-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷帕霉素,
31-O-羰基甲基-(4,5-二甲基-噻唑溴盐-3-基)-雷帕霉素,
31,42-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素,
31,42-O-羰基甲基-(3-羟基-吡啶溴盐-1-基)-雷帕霉素,
31,42-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素,
42-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素,
42-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素,
42-O-羰基甲基-(3-羟基-吡啶溴盐-1-基)-雷帕霉素,
42-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉素,
31,42-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉素,
31-O-羰基甲基-(3-甲基-吡啶溴盐-1-基)-雷帕霉素,
31-O-羰基甲基-(吡啶溴盐-1-基)-雷帕霉素,和
31-O-羰基甲基-(4-甲基-吡啶溴盐-1-基)-雷帕霉素。
6.权利要求1至5中任一项所述的式I化合物的制备方法,其包括下面的(1)-(3)中任一方法所述的步骤:
方法(1):31,42位双取代式I化合物的制备方法
方法(2):42位单取代的式I化合物的制备
方法(3):31位单取代的式I化合物的制备
上述方法(1)-(3)中,
R3独立地选自F、Cl、Br和I;
其余各符号的含义独立地如权利要求1至5中任一项所述。
7.一种药物组合物,其包含权利要求1至5中任一项所述的化合物、其可药用盐或其水合物,以及任选的药学上可接受的辅料。
8.权利要求1至5中任一项所述的化合物、其可药用盐或其水合物或者权利要求7所述的药物组合物在制备免疫抑制剂、mTOR抑制剂、抑制PI3K-Akt-mTOR信号通路的药物、抑制T淋巴细胞增殖的药物、抗肿瘤药物、促进肿瘤细胞凋亡的药物、使细胞周期停滞在G1的药物、防止器官排斥反应的药物、降低动脉栓塞的药物、抗衰老药物、抗阿尔茨海默病药物、抗炎药物或抗菌药物中的用途;具体地,所述抗肿瘤药物为治疗和/或预防和/或辅助治疗肾癌、淋巴瘤、肺癌、肝癌、乳腺癌、神经内分泌癌或胃癌的药物。
9.一种冠脉支架,其药物涂层包含权利要求1至5中任一项所述的化合物、其可药用盐或其水合物或者权利要求7所述的药物组合物。
10.一种在体内或者体外抑制免疫、抑制mTOR、抑制PI3K-Akt-mTOR信号通路、抑制T淋巴细胞增殖、抗肿瘤、促进肿瘤细胞凋亡、使细胞周期停滞在G1、降低动脉栓塞、抗衰老、抗阿尔茨海默病、防止器官排斥反应、抗炎或者抗菌的方法,包括使用有效量的权利要求1至5中任一项所述的化合物、其可药用盐或其水合物或者权利要求7所述的药物组合物的步骤。
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US10160767B2 (en) | 2018-12-25 |
US20170253606A1 (en) | 2017-09-07 |
JP6542808B2 (ja) | 2019-07-10 |
JP2017516807A (ja) | 2017-06-22 |
WO2015184983A1 (zh) | 2015-12-10 |
EP3153165B1 (en) | 2020-05-06 |
EP3153165A4 (en) | 2018-01-03 |
EP3153165A1 (en) | 2017-04-12 |
CN105461738B (zh) | 2019-03-08 |
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