CN107540710A - 肝递送抗病毒前体药物核苷环磷酸酯化合物及应用 - Google Patents
肝递送抗病毒前体药物核苷环磷酸酯化合物及应用 Download PDFInfo
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Abstract
本发明提供基于肝脏特异性递送技术(肝递送)(Liver Specific Delivery(LSD))的抗病毒前体药物核苷环磷酸酯化合物及应用,具体地,本发明提供了式II化合物及其异构体、可药用盐、水合物、溶剂化物,以及相应的药物组合物。本发明还提供了本发明化合物单独或与其它抗病毒药物联合在治疗抗乙型肝炎病毒(HBV)、丁型肝炎病毒(HDV)和人类免疫缺陷病毒(HIV)及其引起的疾病中的应用。
Description
技术领域
本发明涉及基于肝脏特异性递送技术(肝递送)(Liver Specific Delivery(LSD))的抗病毒前体药物,核苷环磷酸酯化合物的制备及应用,或其光学异构体、水合物、溶剂化物、可药用盐以及药物组合物。
背景技术
乙型肝炎病毒(HBV)、丁型肝炎病毒(HDV)、人类免疫缺陷病毒(HIV)等病毒严重威胁人类健康。以乙型肝炎病毒为例,乙型病毒性肝炎(乙型肝炎)是一种由乙型肝炎病毒引起的,以肝脏炎性病变为主,并可引起多器官损害的疾病。据世界卫生组织(WTO)调查结果显示,估计全球有2.4亿人是慢性乙型肝炎感染者,每年估计有78万人死于乙型肝炎感染,其中65万人死于慢性乙型肝炎导致的肝硬化和肝癌,13万人死于急性乙型肝炎感染,是全球健康的一个重要问题。
抗乙型肝炎病毒的药物,主要一类是核苷酸类药物,例如:阿德福韦酯、替诺福韦酯(TDF)、替诺福韦艾拉酚胺(TAF)、恩替卡韦、拉米夫定、替比夫定等,其作用机理是在细胞内活化成三磷酸代谢物,能抑制病毒的DNA或RNA聚合酶活性,阻止DNA或RNA的合成,达到抑制病毒复制的目的。
有些核苷酸类化合物,例如:阿德福韦、替诺福韦等,在生理PH下,呈高负电性。所以口服给药,跨膜能力差,生物利用度低;同时,增加了胃肠道及肾的毒副作用。然而,进行酯化改造,形成酯类前药,比如,阿德福韦酯,替诺福韦酯等,可提高生物利用度及组织分布。但酯水解酶在体内广泛分布,造成药物还没抵达肝细胞前,多数就被水解为带负电的生物活性成分(阿德福韦、替诺福韦等),该成分不容易进入肝细胞,而被主动转运至肾的近端小管,很容易造成肾毒性。
环状磷酸酯(4-芳基-2-氧代-1,3,2-二氧杂磷杂环己烷)前体结构有很好的肝脏特异性递送性能,机理非常明确,如图1所示,4-芳基取代位置被肝细胞中的细胞色素P450同功酶家族中的CYP3A特异性催化,生成羟基,然后开环生成带负电荷的磷酸中间体,该物质不易通过细胞膜而存在于细胞内,在磷酸二酯酶催化下,经过水解,β-消除反应,生成核苷单磷酸化合物,继续在核苷酸激酶作用下,生成具有生物活性的核苷酸三磷酸化合物,同时,代谢副产物芳基乙烯基酮能与肝细胞中含量丰富的抗氧化和自由基的谷胱甘肽发生1,4-加成反应而被清除,尚未发现该加成产物具有副作用的报道。
以阿德福韦为活性成分,通过芳基上取代基的改造,单取代,二取代,不同取代基等几十个组合化合物,最后发现间氯取代的芳环,Pradefovir,在CYP3A酶作用下,代谢成阿德福韦的生成速率最高,接近3,5-二氯芳基的5倍多(US200707214668B2)。
然而,目前尚缺乏活性高、肝脏特异性递送性强、且毒副作用低的病毒抑制化合物,因此,本领域迫切需要开发具有活性高、肝脏特异性递送性强、且毒副作用低等优点的新型病毒抑制化合物。
发明内容
本发明合成了抗病毒的核苷酸类药物的环状磷酸酯,然后对其芳环取代基进一步的改造,得到一类具有肝脏特异性递送(肝递送)作用的前药,使其疗效更高,毒副作用更小。
在本发明的第一方面,提供了一种如下式II所示的化合物,或其光学异构体、药学上可接受的盐、水合物或溶剂化物:
其中:
R1选自氢、氨基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基;其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
m为0、1、2、3、4、5;
各R2独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6羧基、取代或未取代的C1-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基;
其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
且式II中,各个手性中心为R型或S型。
在另一优选例中,所述的磷酸酯环结构中P2与其4位的芳香基团互为顺式,且P2为R型,C4为S型。
在另一优选例中,所述的R1选自下组:H、C1-C3烷基、和环丙基。
在另一优选例中,所述的R1选自下组:H、甲基、和环丙基。
在另一优选例中,所述的选自下组:
在另一优选例中,所述的化合物选自下组:
在另一优选例中,所述的式II化合物为式II-a化合物。
在另一优选例中,所述的化合物具有如下所示的结构:
其中,R3,R5为卤素;
n为0、1、2、3。
在另一优选例中,所述的化合物为式I-a和式III-a化合物。
在另一优选例中,R3为卤素,R5为F、Br、或I,且R3≠R5。
在另一优选例中,R3为Cl,且R5为F。
在另一优选例中,所述的化合物选自下组:
在另一优选例中,所述的式I、式II和式III所示的化合物的盐为式I、式II和式III所示的化合物与无机酸或有机酸所形成的可药用盐,或所述式I、式II和式III所示的化合物的盐为式I、式II和式III所示的化合物与碱反应所形成的可药用盐。所述的式I、式II和式III所示的化合物或其盐为无定形物或晶体。
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包括治疗有效量的如本发明第一方面中所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物;和药学上可接受的辅助剂、稀释剂或载体。
本发明的第三方面,提供了一种本发明第一方面所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物的用途,或如本发明第二方面所述的药物组合物的用途,用于制备治疗和/或预防乙型肝炎病毒(HBV)、丁型肝炎病毒(HDV)或人类免疫缺陷病毒(HIV)感染相关的急性或慢性疾病的药物组合物。
在另一优选例中,所述的乙肝病毒(HBV)、丁肝病毒(HDV)或人类免疫缺陷病毒(HIV)感染相关的急性或慢性疾病选自下组:乙型肝炎,丁型肝炎或艾滋病。
本发明的第四方面,提供了一种如本发明第一方面所述的式II化合物的制备方法,所述方法包括步骤:
i.在惰性溶剂中,将式Va化合物和式Vc化合物进行缩合反应,得到式II化合物。
在另一优选例中,在步骤i中,所述反应在缩合剂存在下进行。
在另一优选例中,所述的缩合剂选自下组:二环己基碳二亚胺(DCC)。
在另一优选例中,所述的缩合反应在60-100℃下(80℃左右)进行。
在另一优选例中,所述的缩合反应的反应时间为1-72小时,较佳地为3-48小时,更佳地为6-24小时。
在另一优选例中,所述的惰性溶剂选自下组:N,N-二甲基甲酰胺、吡啶、或其组合;优选为N,N-二甲基甲酰胺和吡啶的20:1至1:5(v/v)(较佳地10:1-至1:2(v/v))的混合溶剂。
在另一优选例中,所述的式Vc化合物(优选为手性的1,3-丙二醇衍生物)是通过以下方法制备的:
ii.在惰性溶剂(如DMF)中,在HCOOH、Et3N和(S,S)-N-(对甲苯磺酰)-1,2-二苯基乙二胺(二氯)(对甲基异丙基苯)钌(II)存在下,在40~80℃下对进行还原反应(如1-5h),从而得到
iii.在两性溶剂(如EtOH)中,用还原剂(如NaBH4)与反应(如1-5h),从而得到
在另一优选例中,所述的是通过选自下组的方法1-3中任一制备的:
方法1
i.在两性溶剂(如EtOH)中,用SOCl2与反应,得到化合物;
ii.在惰性溶剂(如THF)中,在碱(如LiHMDS)存在下,用乙酸乙酯和在-60~-20℃下反应(如10~30min),得到化合物;
方法2
i.在惰性溶剂(如DCM)中,在SnCl2存在下,在室温下用与反应,得到化合物;
方法3
i.在惰性溶剂(如THF)中,在碱(如叔丁醇钾)存在下,用和在回流温度下反应过夜,得到化合物。
应理解,在本发明范围内,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了肝递送化合物的作用机理示意图。
图2显示了各个肝递送化合物(消旋体)在CYP3A4酶作用下,代谢成活性分子的比率。化合物名称如表1,所有化合物对应的活性代谢分子为PMPA。
图3显示了肝递送化合物(S构型顺式)在CYP3A4酶作用下,代谢成活性分子的比率。化合物名称如表1。其中,化合物6-顺式对应的活性代谢分子为PMPA,化合物9(Pradefovir)对应的活性代谢分子为PMEA。
图4显示了大鼠灌胃给予30mg/kg的PA1010后,体内代谢释放活性分子PMPA在血浆、肝脏和肾脏中的浓度-时间柱状分布图。化合物名称如表1。
图5显示了大鼠灌胃给予30mg/kg的PA1007后,体内代谢释放活性分子PMPA在血浆、肝脏和肾脏中的浓度-时间柱状分布图。化合物名称如表1。
图6显示了大鼠灌胃给予30mg/kg的TAF后,体内代谢释放活性分子PMPA在血浆、肝脏和肾脏中的浓度-时间柱状分布图。
图7显示了大鼠灌胃给予30mg/kg的TDF后,体内代谢释放活性分子PMPA在血浆、肝脏和肾脏中的浓度-时间柱状分布图。
注释:
PMPA:(R)-9-(2-磷酸甲氧基丙基)-腺嘌呤
PMEA:9-[2-(膦酰甲氧基)乙基]腺嘌呤
S构型顺式:如无特殊表述,指磷酸酯环结构中C4为S构型,P2与其4位的芳香基团互为顺式
具体实施方式
本发明人经过长期而深入的研究,通过对大量化合物的筛选研究,首次发现:一类具有特定结构的式I和式III化合物(例如苯环部分的3位和5位为不同的卤素,或苯环部分的2位和5位为不同的卤素),令人意外地具有非常优异的抗病毒活性、显著提高的肝脏特异性递送性(肝递送)以及显著降低的毒副作用。基于上述发现,发明人完成了本发明。
术语
如本文所用,术语“C1-C6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,或类似基团。
如本文所用,术语“C2-C6烷酰基”指形如“具有1~6个碳原子的直链或支链烷基-羰基”结构的取代基,如乙酰基、丙酰基、丁酰基,或类似基团。
如本文所用,术语“C1-C6烷胺基”指形如“具有1~6个碳原子的直链或支链烷基-胺基”结构的取代基,如甲胺基、二甲胺基、乙胺基、丙胺基、二乙胺基,或类似基团。
术语“卤素”指F、Cl、Br和I。
本发明中,术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
本发明中,术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量,或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此,预先指定准确的有效量是没用的。然而,对于某给定的状况而言,可以用常规实验来确定该有效量,临床医师是能够判断出来的。
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基。
除非特别说明,本发明中,所有出现的化合物均意在包括所有可能的光学异构体,如单一手性的化合物,或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,术语“本发明化合物”指式II所示的化合物。该术语还包括及式II化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶,在这种情况下,可能形成各种溶剂化物。本发明的溶剂合物包括化学计量的溶剂化物如水合物等,也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。
应理解,本发明的化合物制备后可能存在各种热力学稳定的异构体,如互变异构体、构象异构体、内消旋化合物和具有对映或非对映关系的光学异构体等,上述改变形式在阅读了本发明的公开之后,对于本领域技术人员而言是显而易见的。
式I和式III化合物及其制备
为了提供一种能够通过肝脏特异性递送机制,让抗病毒的核苷酸类药物集中在肝细胞中释放的高效、低毒的前体药物,发明人制备了式II的优选化合物式I和式III化合物:
其中:
R1选自氢、氨基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基;其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
m为0、1、2、3、4、5;
各R2独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6羧基、取代或未取代的C1-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基;
其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
且式II中,各个手性中心为R型或S型。
优选的实施例中,所述的选自下组:
一类优选的式II化合物具有如下式I所示的结构:
在另一优选例中,所述的式I化合物为式I-a化合物。
在另一优选例中,所述的磷酸酯环结构中P2与4位的芳香基团互为顺式,且P2为R型,C4为S型。
在另一优选例中,所述的R1选自下组:H、C1-C3烷基、和环丙基。
在另一优选例中,所述的R1选自下组:H、甲基、和环丙基。
更优选的情况中,R3为Cl,且R5为F;或R3为Cl,且R5为Br;或R3为Cl,且R5为Cl。
在另一优选例中,所述的光学异构体包括互变异构体,顺反异构体,构象异构体,内消旋化合物和具有对映或非对映关系的光学异构体。
在另一优选例中,所述的化合物选自下组:
另一类优选的式II化合物具有如下式III所示的结构:
其中,各基团的定义如上文中所示。
在另一优选例中,所述的式III化合物为式III-a化合物。
在另一优选例中,所述的P2与磷酸酯环结构中4位的芳香基团互为顺式,且P2为R型,C4为S型。
在另一优选例中,所述的R1选自下组:H、C1-C3烷基、和环丙基。
在另一优选例中,所述的R1选自下组:H、甲基、和环丙基。
更优选的情况中,R3为Cl,且R5为F;或R3为Cl,且R5为Br;或R3为Cl,且R5为Cl。
在另一优选例中,所述的光学异构体包括互变异构体,顺反异构体,构象异构体,内消旋化合物和具有对映或非对映关系的光学异构体。
在另一优选例中,所述的化合物选自下组:
化合物的制备方法(以式III化合物为例):
在N,N-二甲基甲酰胺和吡啶(5:1)溶液中,加入单磷酸衍生物Va,1,3-丙二醇衍生物Vd和二环己基碳二亚胺,升温至80℃左右,反应16h,反应完毕,将反应液减压旋蒸,去除有机溶剂,粗产物溶于乙酸乙酯,用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析,得到通式II化合物。
其中,各个反应物可以通过市售途径购得,也可以采用市售的原料,通过本领域常规的方法制备。
在本发明的优选实施例中,所述的1,3-丙二醇衍生物Vd(优选为手性的1,3-丙二醇衍生物)是通过以下方法制备的:
i.在惰性溶剂(如DMF)中,在HCOOH、Et3N和(S,S)-N-(对甲苯磺酰)-1,2-二苯基乙二胺(二氯)(对甲基异丙基苯)钌(II)存在下,在40~80℃下对进行还原反应(如1-5h),从而得到
ii.在两性溶剂(如EtOH)中,用还原剂(如NaBH4)与反应(如1-5h),从而得到
在另一优选例中,所述的是通过选自下组的方法1-3中任一制备的:
方法1
i.在两性溶剂(如EtOH)中,用SOCl2与反应,得到化合物;
ii.在惰性溶剂(如THF)中,在碱(如LiHMDS)存在下,用乙酸乙酯和在-60~-20℃下反应(如10~30min),得到化合物;
方法2
i.在惰性溶剂(如DCM)中,在SnCl2存在下,在室温下用与反应,得到化合物;
方法3
i.在惰性溶剂(如THF)中,在碱(如叔丁醇钾)存在下,用和在回流温度下反应过夜,得到化合物。
应理解,上述制备方法仅为以式III化合物为例,本领域技术人员可以方便地替换相应的原料从而制备其他的式I和式II化合物。
药物组合物和施用方法
由于本发明化合物具有优异的对乙型肝炎病毒(乙肝病毒)的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由乙肝病毒所导致的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:HBV、HDV和HIV等感染而引起的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有0.1-1000mg本发明化合物/剂,更佳地,含有0.5-500mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如 )、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。特别优选的施用方式是口服。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为0.2~1000mg,优选0.5~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(1)肝脏特异性递送技术(肝递送)性强,化合物只能在肝细胞中的细胞色素P450同功酶家族中的CYP3A特异性催化,生成活性分子,该活性分子带高负电荷,不容易排出肝外,所以在肝中浓度更高,达到特异性递送效果。
(2)活性高,因为肝脏特异性递送性,所以更多的药物存在肝中,抗病毒活性也能大大的提高。
(3)毒副作用低:同等剂量的前药,在肝外代谢成活性分子的量很少,所以对肾脏毒性、骨毒性能大大的降低。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1(2R)-9-{2-[(4S)-4-(3-氯-2-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(84mg,0.294mmol)溶于N,N-二甲基甲酰胺(15mL)和吡啶(3mL)中,分别加入二环己基碳二亚胺(182mg,0.882mmol)和(S)-3-(3-氯-2-氟苯基)-1,3-丙二醇(60mg,0.294mmol),反应混合物加热到80度左右,反应16h,反应完毕,将反应液减压旋蒸,去除有机溶剂,粗产物溶于乙酸乙酯,用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析(二氯甲烷:甲醇=20:1到10:1),得到白色固体,收率:41%,Rf=0.4(二氯甲烷:甲醇=10:1),1H NMR(400MHz,DMSO-d6)δ:8.071-8.227(m,2H),7.202-7.661(m,5H),5.837-5.961(m,1H),4.549-4.603(m,1H),3.935-4.356(m,6H),1.914-2.119(m,2H),1.105-1.198(m,3H)ppm。
实施例2(2R)-9-{2-[(4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(84mg,0.294mmol)、二环己基碳二亚胺(182mg,0.882mmol)和(S)-3-(3-氯-5-氟苯基)-1,3-丙二醇(60mg,0.294mmol)反应完毕,得到35mg白色固体,收率:26%,Rf=0.4(二氯甲烷:甲醇=10:1),1H NMR(400MHz,DMSO-d6):δ:8.045-8.163(m,2H),7.173-7.455(m,5H),5.621-5.681(m,1H),4.228-4.271(m,1H),4.001-4.059(m,6H),1.952-2.109(m,2H),1.097-1.196(m,3H)ppm.
实施例3(2R)-9-{2-[(4S)-4-(3-氯-4-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(118mg,0.412mmol)、二环己基碳二亚胺(254.6mg,1.236mmol)和(S)-3-(3-氯-4-氟苯基)-1,3-丙二醇(84mg,0.412mmol)反应完毕,得到71mg白色固体,收率:37.8%,Rf=0.4(二氯甲烷:甲醇=10:1),1H NMR(400MHz,DMSO-d6):δ:8.056-8.151(m,2H),7.552-7.584(m,1H),7.205-7.493(m,4H),5.556-5.618(m,1H),4.427-4.502(m,1H),3.922-4.303(m,6H),1.813-2.016(m,2H),1.095-1.193(m,3H)ppm.
实施例4(2R)-9-{2-[(4S)-4-(5-氯-2-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(112mg,0.39mmol)、二环己基碳二亚胺(242mg,1.176mmol)和(S)-3-(5-氯-2-氟苯基)-1,3-丙二醇(80mg,0.39mmol)反应完毕,得到60mg白色固体,收率:38%,Rf=0.3(二氯甲烷:甲醇=10:1),1H NMR(400MHz,DMSO-d6):δ:8.048-8.225(m,2H),7.182-7.545(m,5H),5.825-5.911(m,1H),4.536-4.593(m,1H),3.971-4.339(m,6H),1.893-2.172(m,2H),1.103-1.196(m,3H)ppm.
(2R)-9-{2-[(4S)-4-(5-氯-2-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤(15.66g)通过手性柱,在以下的条件下,得到4-顺式(PA1010)异构体:(2R)-9-{2-[(2R,4S)-4-(5-氯-2-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤(9.69g),1H NMR(400MHz,Methanol-D4):δ:8.19(s,1H),8.14(s,1H),7.43–7.34(m,2H),7.19–7.11(m,1H),5.86(t,J=7.0Hz,1H),4.70–4.60(m,1H),4.46–4.26(m,3H),4.16–4.08(m,1H),4.05(t,J=7.3Hz,2H),2.16–2.08(m,2H),1.30(d,J=6.2Hz,3H).ppm
柱子:CHIRALPAK ADH
流动相:乙醇:乙腈=90:10(V/V)
波长:UV254nm
温度:25度
实施例5(2R)-9-{2-[(4S)-4-(4-吡啶)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(112mg,0.39mmol)、二环己基碳二亚胺(242mg,1.176mmol)和(S)-3-(4-吡啶)-1,3-丙二醇(80mg,0.39mmol)反应完毕,得到70mg白色固体,收率:39%,Rf=0.4(二氯甲烷:三乙胺:甲醇=10:1:0.1),1H NMR(400MHz,DMSO-d6):δ:8.595-8.629(m,1H),8.545(d,J=4.8HZ,1H),8.070-8.169(m,2H),7.213-7.350(m,4H),5.591-5.662(m,1H),4.483-4.559(m,1H),3.913-4.345(m,6H),1.913-2.114(m,2H),1.100-1.178(m,3H)ppm.
实施例6(2R)-9-{2-[(2R,4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤和(2R)-9-{2-[(2S,4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
(2R)-9-{2-[(4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤(410.7mg)通过手性柱,在以下的条件下,得到非对映异构体:(2R)-9-{2-[(2R,4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤(220.2mg),1H NMR(400MHz,CDCl3):δ:8.350(S,1H),7.930(S,1H),7.074-7.100(m,2H),6.890(d,J=8.8Hz,1H),5.735(s,2H),5.585(d,J=10.4Hz,1H),4.655-4.711(m,1H),4.343-4.429(m,2H),4.157-4.212(m,1H),3.970-4.059(m,2H),3.801-3.860(m,1H),2.014-2.108(m,2H),1.316(d,J=6.4Hz,3H)ppm.和(2R)-9-{2-[(2S,4S)-4-(3-氯-5-氟苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤(166.2mg),1H NMR(400MHz,CDCl3):δ:8.372(m,1H),7.905(s,1H),7.011-7.157(m,3H),5.899(s,2H),5.432(d,J=11.2Hz,1H),3.897-4.410(m,7H),2.141-2.249(m,1H),1.763-1.800(m,1H),1.337(d,J=6.4Hz,3H)ppm.
柱子:CHIRALPAK ADH
流动相:乙醇:乙腈=90:10(V/V)
波长:UV254nm
温度:25度
对照例7(2R)-9-{2-[(4S)-4-(3-氯苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(660mg,2.419mmol)、二环己基碳二亚胺(1.5g,7.257mmol)和(S)-3-(3-氯苯基)-1,3-丙二醇(450mg,2.419mmol)反应完毕,得到400mg白色固体,收率:38%,Rf=0.5(二氯甲烷:甲醇=10:1),1H NMR(400MHz,DMSO-d6):δ:7.872-8.296(m,2H),7.211-7.269(m,4H),6.019-6.077(m,2H),5.523-5.550(m,1H),4.261-4.357(m,1H),3.773-4.156(m,6H),1.907-1.990(m,2H),1.236-1.354(m,3H)ppm.
对照例8(2R)-9-{2-[(4S)-4-(3,5-二氯苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基丙基}腺嘌呤的制备
采用与实施例1类似的方法制备,将(R)-9-[2-(膦酰甲氧基)丙基]-腺嘌呤(84mg,0.294mmol)、二环己基碳二亚胺(182mg,0.882mmol)和(S)-3-(3,5-二氯苯基)-1,3-丙二醇(60mg,0.294mmol)反应完毕,得到62mg白色固体,收率:45%,Rf=0.4(二氯甲烷:甲醇=10:1),1H NMR(400MHz,CDCl3):δ:8.346-8.378(m,1H),7.909-7.939(m,1H),7.351-7.363(m,1H),7.265-7.268(m,1H),7.178-7.181(m,1H),5.770-5.825(m,2H),5.399-5.588(m,1H),3.808-4.428(m,7H),2.025-2.085(m,2H),1.306-1.349(m,3H)ppm.
对照例9(2R)-9-{2-[(2R,4S)-4-(3-氯苯基)-2-氧代-1,3,2-二氧杂磷杂环已烷-2-基]甲氧基乙基}腺嘌呤的制备
采用文章:J,Am,Chem,Soc,2004,126,5154-5163,公开的技术内容制备得到。1HNMR(400MHz,CDCl3):δ:8.352(s,1H),7.907(s,1H),7.285-7.354(m,3H),7.106(d,J=6.8Hz,1H),5.802(s,2H),5.591(d,J=10.8Hz,1H),4.624-4.681(m,1H),4.443-4.468(m,2H),4.235-4.321(m,1H),3.899-4.031(m,4H),1.980-2.109(m,2H)ppm.
表1各个实施例中所制备得到的化合物如下表中所示:
注释:如无特殊说明,本专利PA1010特指PA1010-顺式,PA1007特指PA1007-顺式。
实施例11体外CYP3A4酶代谢成活性分子评价
测定方法:
通过测定浓度为0.1μM的药物前体在浓度为1mg/ml的人源重组CYP3A4酶(CYPEX)作用下代谢成活性分子(PMPA或PMEA)的效率进行评价。此酶促反应在体积为500μl,浓度为0.1M pH值为7.4的Tris-HCl缓冲溶液中进行,反应体系中还含有5mM氯化镁和1mM NADPH。将反应混合物置于温度为37℃的恒温震荡水浴锅内孵育0,7,17,30分钟取样,并加入1.5倍体积的甲醇终止反应。用Eppendorf台式离心机以最大转速13,600rpm离心20分钟。取上清液,用氮吹仪吹干之后重新溶解至流动相A(含5mM乙酸铵和0.05%甲酸v/v的水溶液)。所得样品用LC-MS/MS(Waters,Acquity UPLC HSS T3column)进行分析。
表2体外CYP3A4酶代谢成活性分子的量
结果分析:化合物1、2、3、4、5、7和8为S构型消旋体结构,6和9为S-cis结构,表2为30分钟酶代谢结果,图2和图3为酶代谢动态结果。从表2所列可知:在S构型消旋体结构中,化合物2代谢成活性代谢分子PMPA的比率最多,为13.29%,对比例7和8分别为:8.67%和1.01%。
对化合物2进行拆分,得到S构型顺式(化合物6-顺式)代谢比率为:27.36%,高于其对应的S构型外消旋体(化合物2)。
从上述结果中可见,本发明的化合物2比其他结构的化合物高出约50%至1300%不等。与3位和5位皆为Cl的化合物8相比,本发明化合物2(3位和5位为不同的卤素Cl和F)的活性高出约13倍。
针对活性最好的化合物2进行拆分,得到顺式产物6-顺式,拆分后的S构型顺式化合物与目前已经进入临床研究的同类型化合物Pradefovir(化合物9,S构型顺式)相比,本发明化合物6-cis的活性也高出约57.5%。
实施例12体外由人肝微粒体代谢成活性分子评价
测定方法:
本测试使用的人肝微粒体是从In Vitro Technologies(IVT)公司购买,批号SSPX008070,是从150位捐赠者的肝组织中提取的混合肝微粒体,产品说明中记录了该批次肝微粒体的CYP3A4的代谢活性,为1.734nmol/mg/min(代谢睾酮生成6-β睾酮的速率)。测试化合物由浙江柏拉阿图医药科技有限公司合成,溶解于甲醇,制成浓度为25mM的存储液。酶促反应在100μl反应液(100mM Tris-HCl,5mM MgCl2,pH 7.4)中进行,测试化合物浓度为25μM,人肝微粒体浓度为2mg/ml,加入NADPH(终浓度2mM)启动反应。在恒温震荡水浴锅内反应5min后,迅速加入1.5倍体积的乙腈以终止反应。用Eppendorf台式离心机以最大转速13,600rpm离心20分钟。取上清液,用氮吹仪吹干之后重新溶解至流动相A(含5mM乙酸铵和v/v0.05%的水溶液)。所得样品用LC-MS/MS(Waters,Acquity UPLC HSS T3column)进行定量分析。
表3测试化合物在体外由人肝微粒体代谢为PMPA或PMEA的速率
注:HLM为人肝微粒体的英文缩写。
结果分析:化合物1、2、3、4和7为S构型消旋体结构,4-顺式,6-顺式和9为S-顺式结构,表3为5min人肝微粒体代谢产生PMPA或PMEA的平均速率。
从表3所列可知:在S构型消旋体结构中,化合物2和4代谢成活性代谢分子PMPA的速率最快,分别为46.8pmol/min/mg HLM和48.8pmol/min/mg HLM。
对化合物2进行拆分,得到S构型顺式(化合物6-顺式),其代谢生成PMPA的速率为75.8pmol/min/mg HLM,高于其对应的S构型外消旋体(化合物2)。
对化合物4进行拆分,得到S构型顺式(4-顺式),其代谢生成PMPA的速率为170pmol/min/mg HLM,高于其对应的S构型外消旋体(化合物4)。
从上述结果中可见,在人肝微粒体的催化作用下,本发明的化合物2和化合物4比其他结构的化合物更快的转化为活性代谢分子PMPA。针对活性最好的化合物2和化合物4进行拆分,得到顺式产物6-顺式和4-顺式,拆分后的S构型顺式化合物与目前已经进入临床研究的同类型化合物Pradefovir(化合物9,S构型顺式)相比,能更快的代谢为活性分子,且4-顺式显著优于6-顺式,前者代谢生成PMPA的速率是后者的2.2倍,是化合物9生成PMEA速率的8.3倍。
上述结果显示,苯环部分被5-Cl和2-F所取代的化合物4,和苯环部分被5-F和3-Cl和所取代的化合物2具有显著优于其他化合物的代谢活性,说明苯环上3,5位以及2,5具有卤素不对称取代的化合物改善了肝递送化合物被人肝微粒体活化的速率。
实施例13肝递送化合物实验
1.方法
1.1.动物实验
雄性SD大鼠,体重180~300g,上海西普尔-必凯实验动物有限公司提供。雄性动物适应环境3天以上,实验前一天晚上禁食12小时,不禁水。制备PA1010(4-顺式化合物)、PA1007(6-顺式化合物)、TAF和TDF的溶液剂(生理盐水)。给药前查看动物体重是否与实验要求相符,选取12只大鼠进行分组,每组2只大鼠,灌胃给予30mg/kg的药液。分别于0.5h、1h、3h、6h、12h和24h,用二氧化碳气体将大鼠安乐死后采集样品:通过心脏抽取血液,贮存于肝素抗凝管中,4℃下以6000rpm离心5min,取上清血浆于冰中保存;收取大鼠的肾和肝组织,并用4℃预冷的生理盐水润洗干净,吸干水分后放在冰中保存。实验后,样本保存于-80℃冰箱中。
1.2.PA1010、PA1007、TAF和TDF单磷酸代谢产物替诺福韦(PMPA)在生物样品中含量测定
样品前处理
冰浴中,肾和肝组织与5倍体积的生理盐水充分破碎混匀,获得组织匀浆样品。取100μL大鼠血浆或组织匀浆样品与100μL的内10%的三氯乙酸沉淀剂(含内标50ng/mL阿德福韦,甲醇:乙腈=50:50,v/v)混匀。在4℃下,6000rpm离心5分钟后,取全部上清液用SPE微萃取板(MCXμElution Plate 30μm,Waters)处理,最后使用5%氨水甲醇溶液洗脱,取75μL上清液于384孔样品板中,进样1.0μL进行分析。
色谱质谱条件
LC-MS/MS-AJ(Triple Quad 5500,AB SCIEX)用于样品的分析。色谱柱:AcquityUPLC HSS T3(2.1×50mm,1.8μm);柱温:40℃;流速:0.5mL/min。流动相A:0.1%甲酸水溶液,流动相B:乙腈溶液。样品分离采用梯度洗脱,程序如表4。和对应内标物的质谱条件:电喷雾离子化(ESI)正离子模式,多重反应监测(MRM)的监测离子对m/z:288/176(PMPA),274/162(PMEA);毛细管电压为3.0kV;温度为500℃;去溶剂气流1000L/h;扫描时间0.025秒;碰撞能量25V。
表4 PMPA液相洗脱梯度条件
1.3数据分析
做PMPA在血浆、肝脏和肾脏中的浓度对应时间的柱状分布图。PMPA的组织浓度-时间曲线下面积(AUC0-t),使用WinNonLin6.2.1(Pharsight,CA)的非房室模型中的对数-线性梯形法进行拟合计算。PMPA的肝肾比与肝血比为它们的AUC0-t比值。
2.结果
大鼠灌胃给予30mg/Kg的药液后,肝脏组织分布的结果显示PA1010代谢释放的活性分子PMPA显著高于对应时间点的TAF与TDF(p<0.01,图4、6和7)。用WinNonLin6.2.1拟合药时曲线下面积,根据表5,各测试药物释放的PMPA肝脏暴露量对比:PA1010>TAF>PA1007>TDF,而PA1010释放的PMPA肝脏暴露量分别为TAF的1.5倍(222692h·ng/g对148407h·ng/g)和TDF的2.9倍(222692h·ng/g对78050h·ng/g),该结果预示着更少剂量下PA1010可以达到TDF和TAF在临床上的同等疗效。同时,由PA1010和PA1007体内生成的PMPA肾脏暴露量,都显著低于由TAF和TDF释放的PMPA(表5),综合以上结果,相同剂量下,PA1010和PA1007展现出高于TAF和TDF的肝肾比率(图4-7和表5),由于TDF和TAF释放的PMPA在肾脏中的富集是导致临床阶段肾毒性的主要因素,该结果预示在同等剂量下的PA1010和PA1007都可显著降低TDF和TAF导致的临床上肾毒性问题。
表5大鼠灌胃给予30mg/kg的PA1007、PA1010、TAF和TDF后,体内代谢释放活性分子(PMPA)在血浆、肝脏和肾脏中暴露量,亦及浓度-时间曲线下面积(AUC0-t)(h*ng/g)
上述结果表明,由于本发明式I和式III化合物具有更高的活性和更高的肝递送性,这导致治疗时所需的用量更低,因此具有更高的安全性或更低的毒副作用,因而大大提高了PMPA在临床上的治疗指数。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.一种如下式II所示的化合物,或其光学异构体、药学上可接受的盐、水合物或溶剂化物:
其中:
R1选自氢、氨基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基;其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
m为0、1、2、3、4、5;
各R2独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6羧基、取代或未取代的C1-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基;
其中,所述的取代指具有一个或多个选自下组的取代基:卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基;
且式II中,各个手性中心为R型或S型。
2.如权利要求1所述的化合物,其特征在于,所述的选自下组:
3.如权利要求1所述的化合物,其特征在于,所述的化合物选自下组:
4.如权利要求3所述的化合物,其特征在于,所述的化合物具有如下所示的结构:
其中,R3,R5为卤素;
n为0、1、2、3。
5.如权利要求4所述的化合物,或其光学异构体、药学上可接受的盐、水合物或溶剂化物,其特征在于,R3为Cl,且R5为F。
6.如权利要求4所述的化合物,或其光学异构体、药学上可接受的盐、水合物或溶剂化物,其特征在于,所述的化合物选自下组:
7.如权利要求1-6所述的式I、式II和式III所示的化合物的盐为式I、式II和式III所示的化合物与无机酸或有机酸所形成的可药用盐,或所述式I、式II和式III所示的化合物的盐为式I、式II和式III所示的化合物与碱反应所形成的可药用盐;所述的式I、式II和式III所示的化合物或其盐为无定形物或晶体。
8.一种药物组合物,其特征在于,所述的药物组合物包括治疗有效量的如权利要求1-6任一项中所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物;和药学上可接受的辅助剂、稀释剂或载体。
9.如权利要求1-6所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物的用途,或如权利要求8所述的药物组合物的用途,其特征在于,用于制备治疗和/或预防乙型肝炎病毒(HBV)、丁型肝炎病毒(HDV)或人类免疫缺陷病毒(HIV)感染相关的急性或慢性疾病的药物组合物。
10.如权利要求9所述的用途,其特征在于,所述的乙肝病毒(HBV)、丁肝病毒(HDV)或人类免疫缺陷病毒(HIV)感染相关的急性或慢性疾病选自下组:乙型肝炎,丁型肝炎或艾滋病。
11.如权利要求1所述的式II化合物的制备方法,其特征在于,包括步骤:
i.在惰性溶剂中,将式Va化合物和式Vc化合物进行缩合反应,得到式II化合物。
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