CN110437132B - 双并杂环核衣壳抑制剂及其药物用途 - Google Patents
双并杂环核衣壳抑制剂及其药物用途 Download PDFInfo
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- CN110437132B CN110437132B CN201810422133.6A CN201810422133A CN110437132B CN 110437132 B CN110437132 B CN 110437132B CN 201810422133 A CN201810422133 A CN 201810422133A CN 110437132 B CN110437132 B CN 110437132B
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Abstract
本发明涉及一种双并环类核衣壳抑制剂和其作为药物用于治疗乙型肝炎的用途。具体地,本发明公开了一种可作HBV抑制剂的具有化学式A所示结构的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,各基团的定义详见说明书。本发明还涉及包含上述化合物的药物组合物及其在治疗乙型肝炎中的用途。
Description
技术领域
本发明属于医药领域,具体地,本发明涉及用于治疗乙型肝炎的芳基并环酰胺类化合物及其用途。
背景技术
乙型肝炎病毒(HBV)是一种有包膜的、部分双链DNA(dsDNA)的、嗜肝病毒DNA家族(肝病毒科(Hepadnaviridae))的病毒。它的基因组包含4个重叠阅读框:前核/核基因,聚合酶基因,UM和S基因(它们编码三个包膜蛋白质),以及X基因。在感染前时,该部分双链DNA基因组在宿主细胞核中(开环DNA,rcDNA)转变为共价闭合环状DNA(cccDNA)并且该病毒mRNA进行转录。一旦被壳体化,该前基因组RNA(pgRNA)(其还为核心蛋白和Pol编码)作为模板用于逆转录,这种逆转录在核衣壳中再生该部分dsDNA基因组(rcDNA)。
HBV在亚洲和非洲的部分地区造成了流行病,并且它在中国是地方性的。HBV已经在全球感染了大约20亿人,其中大约3.5亿人发展成了慢性传染病。该病毒造成了乙型肝炎疾病并且慢性传染病与肝硬化和肝癌的发展的高增加风险相关联。
乙型肝炎病毒的传播来源于暴露于传染性的血液或体液,同时在血清中具有高效价DNA的慢性携带者的唾液、泪液以及尿液中检测到了病毒DNA。
虽然目前存在一种有效的并且具有良好耐受性的疫苗,但是直接治疗的选择目前还限于干扰素以及以下的抗病毒药;替诺福韦、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。
此外,杂芳基二氢嘧啶(HAPs)在组织培养以及动物模型中被鉴别作为一类HBV抑制剂。WO 2013/006394(公开于2013年1月10日)和WO 2013/096744(公开于2013年6月27日)还公开了涉及抗HBV活性的氨磺酰基-芳基酰胺。
然而,在这些直接的HBV抗病毒药中会遇到的是毒性、致突变性、缺乏选择性、疗效差、生物利用度差以及合成困难等问题。
因此,本领域需要开发具有如效价高、毒性更低等优点的HBV抑制剂。
发明内容
本发明的目的是提供一类效价高、毒性更低的HBV抑制剂。
本发明的第一方面,提供了一种化学式A所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,
其中,所述的B环为取代或未取代的饱和或不饱和8-20元双环并环结构;其中,所述的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、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
C环为取代或未取代的5-12元环;
R1、R2各自独立地选自下组:氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;或R1、R2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自N、S和O的杂原子的3-10元杂环基;
R4、R5和R6各自独立地为位于C环上任意位置的选自下组的取代基:氢、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
X为无、O、NR9、卤代亚C1-C4烷基(如CF2)或羟肟(=N-OH);其中,R9为氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基;其中,所述“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基;
Y为羰基(-(CO)-)或磺酰基(-SO2-),或磺酰亚胺基-SONH-;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、氨基、羧基、C6-C10芳基、卤代的C6-C10芳基、未取代或被选自下组的取代基取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基:卤素、苯基。
在另一优选例中,所述的X为无。
在另一优选例中,所述的3-10元杂环基选自下组:单环基、二环基、稠环基、桥环基、螺环基。
在另一优选例中,所述的3-10元杂环基为五元氮杂环并5、6或7元环的二环基。
在另一优选例中,所述的3-10元杂环基为五元氮杂环并5、6或7元碳环的二环基。
在另一优选例中,所述的C环为取代或未取代的苯环,或取代或未取代的5-7元杂芳环。
在另一优选例中,所述的C环为5-7元环。
在另一优选例中,所述的R4、R5和R6各自独立地为位于C环上任意位置的选自下组的取代基:氢、卤素、-CN、羟基、氨基、羧基、取代或未取代的C1-C8烷基。
本发明的第二方面,提供了一种化学式A1所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,
其中,W1选自下组:CR10R11、CR10、O、S,或NR12;
n为0、1、2或3;
虚线为化学键或无;
R10与R11为选自下组的取代基:氢、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
R12为选自下组的取代基:氢、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
R3为位于并环结构上的一个或多个(优选为1、2、3、4或5个)选自下组的取代基:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
在另一优选例中,R3为位于并环结构上的一个或多个选自下组的取代基:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C1-C4烷基、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷胺基、C1-C4烷氧基。
在另一优选例中,R12为选自下组的取代基:氢、-CN、羟基、氨基、羧基、取代或未取代的C1-C4烷基。
在另一优选例中,R10与R11为选自下组的取代基:氢、卤素、-CN、羟基、氨基、羧基、取代或未取代的C1-C4烷基。
在另一优选例中,所述的化合物具有如下式A2所示的结构:
在另一优选例中,所述的化合物具有选自下组I、II、III所示的结构:
其中,所述的R选自下组:卤素、C1-C4烷基。
在另一优选例中,所述的C环为5-7元环。
在另一优选例中,所述的C环为饱和环、部分不饱和环或芳香环。
在另一优选例中,所述的C环为苯环或吡啶环。
在另一优选例中,所述的R1为卤代或被羟基取代的C1-C4烷基,且所述的R2为H。
在另一优选例中,所述的化合物选自表1中所示的化合物。
本发明的第二方面,提供了一种药物组合物,其包含(1)本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物;和(2)药学上可接受的载体。
在另一优选例中,所述药物组合物还包含其它用于预防和/或治疗乙型肝炎病毒感染的药物。
在另一优选例中,所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组:免疫调节剂(例如干扰素-α(IFN-α)、聚乙二醇化干扰素-α)或先天免疫系统的刺激剂(如Toll样受体7和/或8激动剂)。
在另一优选例中,所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组:替诺福韦、拉米夫定、阿德福韦、恩替卡韦、替比夫定、或其组合。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如本发明第二方面所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗乙型肝炎病毒感染的药物。
本发明的第四方面,提供了一种乙型肝炎病毒抑制剂,其特征在于,所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
本发明的第五方面,提供了一种如下式所示中间体化合物:
其中,
X’选自下组:-NO2、-SO2-NR1R2、-SO2-Cl、-NH2;
其余各基团的定义如本发明第一方面中所述。
本发明的第六方面,提供了一种如本发明第五方面所述的中间体化合物的用途,用于制备本发明第一方面所述的化合物。
本发明的第七方面,提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法,所述方法包括步骤:
在惰性溶剂中,用式A-1化合物和式A-2化合物反应,得到式A化合物。
在另一优选例中,所述的式A化合物为式X-1所示的化合物,且所述的方法还包括下述步骤:
在另一优选例中,所示式A化合物为式VI-2所示的化合物,所述方法包括步骤:
在另一优选例中,所示式A化合物为式VI-3所示的化合物,所述方法包括步骤:
本发明的第八方面,提供了一种预防和/或治疗乙型肝炎的方法,包括步骤:向所需患者施用本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物。
本发明的第九方面,提供了一种体外抑制乙型肝炎病毒的方法,所述方法包括步骤:将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,与乙型肝炎病毒接触,从而抑制乙型肝炎。
应理解,在本发明范围内中,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。
具体实施方式
本发明人经过广泛而深入的研究,发现了一类对乙型肝炎具有优异的治疗效果的新型化合物。在此基础上,发明人完成了本发明。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C10环烷基”指具有3-10个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C1-C8烷胺基”是指被C1-C8烷基所取代的胺基,可以是单取代或双取代的;例如,甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用,术语“C1-C8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
活性成分
如本文所用,“本发明化合物”指式(A1)所示的化合物,并且还包括式(A1)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,“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。
在另一优选例中,所述的W1,n,R、X,Y,R1、R2、R3、R4、R5和R6各自独立地为表1中各个化合物所对应的基团。
优选的本发明化合物如表1所示:
药物组合物和施用方法
由于本发明化合物具有优异的乙型肝炎病毒(HBV)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预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒感染或用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒相关疾病(例如,乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。
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及药学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1-2000mg本发明化合物/剂,更佳地,含有10-200mg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、肠胃外(静脉内、肌肉内或皮下)。
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、矫味剂和香料。
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。
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(例如抗-HBV剂)联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物(例如抗-HBV剂)。该其他药学上可接受的化合物(例如抗-HBV剂)中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗HBV感染或HBV相关疾病。
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1~2000mg,优选20~500mg。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.本发明的化合物结构新颖且具有优异的抗乙肝病毒感染的作用。
2.本发明的化合物对正常细胞的毒性非常低。
3.本发明化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预防和/或治疗乙型肝炎病毒感染。
4.本发明化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预防和/或治疗乙型肝炎病毒相关疾病(例如,乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
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。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
以下各实施例为10类化合物的合成:
实施例1:化合物10a的合成
步骤1:
将环戊烯(30.0g)和对甲基苯亚磺酸钠(133.4g)溶于水(400ml)和二氯甲烷(400ml)的混合溶剂中,剧烈搅拌下分批加入碘单质(112g)。反应混合物室温搅拌过夜,加入二氯甲烷(400ml),分液,有机相依次用碳酸氢钠水溶液、硫代硫酸钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥后过滤,减压浓缩得化合物10-2,直接用于下步反应。
步骤2:
氮气保护下将化合物10-2(150g)溶于甲苯(1.0L)中,加入DBU(68g),室温搅拌3小时,过滤掉生成的固体,滤液依次用1M盐酸、饱和碳酸氢钠和水洗涤,有机相减压浓缩后柱层析分离得目标化合物10-3。
步骤3:
氮气保护下,冰浴冷却下将化合物10-3(25g)和异氰基乙酸乙酯(32.1g)的THF(150ml)溶液通过滴液漏斗滴入60%NaH(11.3g)的THF(150ml)悬浊液中,0℃反应1小时后升至室温反应1小时,倒入冷的1M盐酸中,用Na2CO3调pH值至8,乙酸乙酯萃取,浓缩后柱层析得化合物10-4(15g,收率75%)。
步骤4:
氮气保护下将化合物10-4(3g)溶于DMF(15ml)中,加入K2CO3(6.94g),滴加碘甲烷(2.85g),室温搅拌过夜,倒入水(60ml)中,乙酸乙酯萃取,浓缩后柱层析得化合物10-5(3.1g,收率96%)。
步骤5:
氮气保护0℃下,向化合物10-5(3.0g)的二氯甲烷(30ml)溶液中加入氯磺酸(2.17g),加完升至室温反应,待反应结束后倒入冰水中,二氯甲烷萃取,柱层析(heptane:EA=3:1)得到3.5g产物ESI-MS(M-H=272.1)。
步骤6:
将化合物10-6(3.0g)加入二氯甲烷(30ml)中,滴加氯化亚砜(3.92g),加完后加热回流3小时,浓缩后得到化合物10-7直接用于下步反应。
步骤7:
将化合物10-7(3.0g)和(R)-三氟异丙胺盐酸盐(1.85g)加入乙腈(30ml)中,氮气保护条件下加入吡啶(2.44g),40℃反应过夜,反应结束后用乙酸乙酯(3*50mL)萃取,1MHCl洗,水洗,干燥,过柱分离(heptane:EA=10:1)得到3.1g化合物10-8,ESI-MS(M+H=369)。
步骤8:
氮气保护下将化合物10-8(50mg)和3,4-二氟苯胺(35mg)溶于THF(2ml)中,冷却至0℃,加入1M NaHMDS的THF溶液(0.4ml),0℃反应30分钟后,加入氯化铵水溶液,乙酸乙酯萃取,浓缩后制备HPLC分离得化合物10a(20mg),ESI-MS(M+H=452)。
实施例2:化合物10b的合成
根据实施例1的步骤8,只需用化合物3,4,5-三氟苯胺代替化合物3,4-二氟苯胺,其他条件不变,得到目标产物10b(15mg)。ESI-MS(M+H=470)
实施例3:化合物10c的合成
根据实施例1的步骤8,只需用化合物4-氟-3-氰基苯胺代替化合物3,4-二氟苯胺,其他条件不变,得到目标产物10c(12mg)。ESI-MS(M+H=459)
实施例4:化合物10s的合成
步骤1:
将化合物10-9(Tetrahedron Lett.,29,5663-4,1988)(8.16g)溶于甲醇(50ml)中,加入盐酸羟胺(5.34g)和三水和醋酸钠(12.24g),室温搅拌过夜,过滤,滤液浓缩后加入甲醇(100ml),冷却至-10℃,加入氰基硼氢化钠(3.78g),然后加入5N盐酸使pH小于4,反应90分钟后升至0℃,加入4N氢氧化钠水溶液使反应体系变为碱性,二氯甲烷萃取,浓缩后柱层析得10-10。
步骤2:
参考实施例1中的步骤7,由化合物10-10和化合物10-7反应得到化合物10-11。
步骤3:
将化合物10-11(150mg)溶于丙酮(5ml)和水(1ml)中,加入锇酸钾(20mg)和NMO(150mg)室温搅拌过夜,乙酸乙酯萃取,依次用硫代硫酸钠溶液和饱和食盐水洗涤,干燥后浓缩,柱层析分离得到化合物10-12。
步骤4:
将化合物10-12(100mg)溶于丙酮(1ml)中,加入2,2-二甲氧基丙酮(0.5ml)和对甲苯磺酸(20mg),室温搅拌3小时,加入碳酸氢钠水溶液,乙酸乙酯萃取,干燥浓缩,柱层析分离得到化合物10-13。
步骤5:
参考实施例1中的步骤8,由化合物10-13和3,4-二氟苯胺得到化合物10-14。
步骤6:
将化合物10-14(100mg)溶于甲醇(2ml)中,加入对甲苯磺酸(50mg),室温搅拌过夜,加入碳酸氢钠,浓缩后,加入乙酸乙酯萃取,干燥浓缩后柱层析分离得到化合物10s,ESI-MS(M+1=510)。
实施例5:化合物10w的合成
步骤1:
将化合物10s(200mg)、DIPEA(185mg)和DMSO(400mg)加入到二氯甲烷(1.5ml)中,室温下加入三氧化硫吡啶复合物(180mg),搅拌5小时后用乙酸乙酯稀释,稀盐酸洗涤,饱和食盐水洗涤后,干燥过滤,浓缩后柱层析得到化合物10-15。
步骤2:
将化合物10-15(100mg)和盐酸羟胺(50mg)溶于甲醇(1ml)中,加入三水和醋酸钠(110mg),室温搅拌过夜,过滤,滤液浓缩后直接用于下步反应。
步骤3:
将化合物10-16(50mg)和苯乙炔(0.5ml)加入到甲醇(1ml)、水(0.2ml)和THF(0.5ml)中,加入二(三氟乙酰氧基)碘苯(43mg),室温搅拌3小时后,浓缩,制备HPLC分离得到化合物10w,ESI-MS(M+1=623)。
根据实施例1的合成方法又合成了如下10类系列化合物:
实施例6:化合物20a的合成
步骤1:
将环己烯(36.0g)和对甲基苯亚磺酸钠(133.4g)溶于水(400ml)和二氯甲烷(400ml)的混合溶剂中,剧烈搅拌下分批加入碘单质(112g)。反应混合物室温搅拌过夜,加入二氯甲烷(400ml),分液,有机相依次用碳酸氢钠水溶液、硫代硫酸钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥后过滤,减压浓缩得化合物20-2,直接用于下步反应。
步骤2:
氮气保护下将化合物10-2(160g)溶于甲苯(1.0L)中,加入DBU(65g),室温搅拌3小时,过滤掉生成的固体,滤液依次用1M盐酸、饱和碳酸氢钠和水洗涤,有机相减压浓缩后柱层析分离得目标化合物20-3。
步骤3:
氮气保护下,冰浴冷却下将化合物20-3(26.6g)和异氰基乙酸乙酯(32.1g)的THF(150ml)溶液通过滴液漏斗滴入60%NaH(11.3g)的THF(150ml)悬浊液中,0℃反应1小时后升至室温反应1小时,倒入冷的1M盐酸中,用Na2CO3调pH值至8,乙酸乙酯萃取,浓缩后柱层析得化合物20-4(15.2g,收率70%)。
步骤4:
氮气保护下将化合物20-4(3g)溶于DMF(15ml)中,加入K2CO3(6.94g),滴加碘甲烷(2.7g),室温搅拌过夜,倒入水(60ml)中,乙酸乙酯萃取,浓缩后柱层析得化合物20-5。
步骤5:
氮气保护0℃下,向化合物20-5(3.0g)的二氯甲烷(30ml)溶液中加入氯磺酸(2.17g),加完升至室温反应,待反应结束后倒入冰水中,二氯甲烷萃取,柱层析(heptane:EA=3:1)得到3.5g产物ESI-MS(M-H=286.1)。
步骤6:
将化合物20-6(3.0g)加入二氯甲烷(30ml)中,滴加氯化亚砜(3.7g),加完后加热回流3小时,浓缩后得到化合物20-7直接用于下步反应。
步骤7:
将化合物20-7(3.0g)和(R)-三氟异丙胺盐酸盐(1.76g)加入乙腈(30ml)中,氮气保护条件下加入吡啶(2.34g),40℃反应过夜,反应结束后用乙酸乙酯(3*50mL)萃取,1MHCl洗,水洗,干燥,过柱分离(heptane:EA=10:1)得到3.1g化合物10-8,ESI-MS(M+H=369)。
步骤8:
氮气保护下将化合物10-8(52mg)和3,4-二氟苯胺(35mg)溶于THF(2ml)中,冷却至0℃,加入1M NaHMDS的THF溶液(0.4ml),0℃反应30分钟后,加入氯化铵水溶液,乙酸乙酯萃取,浓缩后制备HPLC分离得化合物20a(26mg),ESI-MS(M+H=466)。
实施例7:化合物20b的合成
根据实施例1的步骤8,只需用化合物3,4,5-三氟苯胺代替化合物3,4-二氟苯胺,其他条件不变,得到目标产物20b(35mg)。ESI-MS(M+H=484)
实施例8:化合物20c的合成
根据实施例1的步骤8,只需用化合物4-氟-3-氰基苯胺代替化合物3,4-二氟苯胺,其他条件不变,得到目标产物20c(10mg)。ESI-MS(M+H=473)
根据实施例1、实施例4和实施例5的合成方法又合成了如下20类系列化合物:
实施例9:化合物30a的合成
参照实施例1,将环戊烯换为环庚烯,其余条件不变,合成得到化合物30a。
改变分子两端的取代氨基,相应得到化合物30b-30z。
30类系列化合物:
实施例10:化合物40a的合成
步骤1:
将化合物10-5(3g)溶于酸酐(20ml)中,冷却至-20℃,加入65%硝酸(6.0g),-20℃反应,待反应结束直接导入冰水中,EA(3*40mL)萃取,碳酸氢钠水洗,干燥,过柱分离得产物40-1(1.2g)。ESI-MS(M+H=239)
步骤2:
步骤3:
氮气保护下将32(50mg)溶于EA(5mL)中,加入10%Pd/C(20mg),置换氢气,室温反应,待反应结束,硅藻土过滤,浓缩得到40mg,直接进行下一步反应,ESI-MS(M+H)=292。
步骤4:
将化合物40-3(30mg)溶于乙腈(3ml)中,加入三乙胺(50mg)和化合物40-4(40mg),加热至80℃反应过夜。反应结束后,浓缩后过柱(heptane:EA=3:1)得到40a(10mg),ESI-MS(M+H)=467。
实施例11:化合物40c的合成
根据实施例10的合成步骤,只需用化合物3,4,5-三氟苯胺代替化合物3,4-二氟苯胺,其他条件不变,得到目标产物40c(15mg)。ESI-MS(M+H=485)
实施例12:化合物40f的合成
根据实施例10的合成步骤4,只需用化合物40-7代替化合物40-4,其他条件不变,得到目标产物40f(12mg)。ESI-MS(M+H=441)
根据实施例10的合成方法又合成了如下40类系列化合物:
实施例13:
方法a:
将氯甲酸对硝基苯酯(1.2eq)和碳酸氢钠(5.0eq)加入乙腈中,冷却至0℃加入胺(1.0eq),升至室温反应3小时,过滤,柱层析分离得到相应的氨基甲酸对硝基苯酯。
将氨基甲酸对硝基苯酯(1.3eq)和5-氨基吡咯甲酰胺类化合物(1.0eq)溶于乙腈,室温下加入三乙胺(3.0eq),搅拌反应过夜,柱层析分离得到相应的脲类化合物。
方法b:
将三光气(0.4eq)和三乙胺(3.0eq)加入二氯甲烷中,冷却至0℃加入胺(1.0eq),升至室温反应3小时,过滤,柱层析分离得到相应的异氰酸酯。
将异氰酸酯(1.3eq)和5-氨基吡咯甲酰胺类化合物(1.0eq)溶于乙腈,室温下加入三乙胺(3.0eq),搅拌反应过夜,柱层析分离得到相应的脲类化合物。
按照方法a或方法b合成得到化合物50a-50o
生物学实施例--抗-HBV活性实验
实验一:体外抗乙肝病毒核衣壳组装活性试验方法
主要试剂和原料:
C150蛋白为药明康德公司表达和纯化;
蛋白荧光标记:
向96孔板每孔加入150μL 2%w/v脱脂牛奶,室温孵育2小时。吸掉脱脂牛奶,用去离子水清洗后烘干,室温保存。将C150蛋白(每管3毫克)用5ml Hitrap脱盐柱脱盐。向每管脱盐后的C150蛋白加入50mMFL荧光染料20μl混合均匀,4℃避光孵育过夜。用Sephadex G-25凝胶过滤去除未与C150结合的荧光染料。计算C150的荧光标记效率,公式如下:
其中,
[C150Bo]表示荧光标记蛋白的浓度;
A504表示波长504nM的吸光值;
A280表示波长280nM的吸光值;
M-1表示摩尔浓度的倒数。
化合物稀释:
将化合物母液用DMSO稀释到6mM,再用50mM HEPES稀释到600μM,然后用10%DMSO/50mM HEPES进一步3倍系列稀释8个浓度。
将C150Bo用50mM HEPES稀释到2μM。取37.5μL C150Bo和2.5μL各个浓度的化合物加入到96孔反应板中混匀,室温孵育15分钟。取10μl的750mM NaCl/50mM HEPES加入到反应孔中,NaCl的终浓度为150mM。
0%蛋白组装对照孔,加入10μL的50mM HEPES,NaCl的终浓度为0mM。
100%蛋白组装对照孔,加入10μL的5M NaCl/50mM HEPES,NaCl的终浓度为1M。
DMSO终浓度为0.5%,化合物最高终浓度为30μM,C150Bo终浓度为1.5μM。室温孵育1小时。测量荧光信号(激发光485nm;发射光535nm)。
数据分析
%蛋白组装=【1-(样品荧光值–1M NaCl荧光值)/(0M NaCl荧光值-1M NaCl荧光值)】×100.
IC50值通过prism软件计算,方程如下:
Y=Bottom+(Top-Bottom)/(1+10((LogIC50-X)*HillSlope));
其中,
X表示浓度的对数值,Y表示效应值,Y从底部起始以S型拟合至顶部;
Bottom表示表示曲线的底部;
Top表示Top表示曲线的顶部;
HillSlope表示:曲线的最大斜率的绝对值。
实验二:在HepG2.2.15细胞的抗乙肝病毒活性测定
主要试剂:
QIAamp 96DNA血液试剂盒(12)(Qiagen,货号51162);
FastStart Universal Probe Master(Roche,货号04914058001);
Cell–titer Glo检测试剂(Promega,货号G7573)。
化合物稀释:体外抗HBV活性实验和细胞毒性实验所有化合物均3倍系列稀释,8个浓度。受试化合物最终起始浓度为30μM,参照化合物GLS4最终起始浓度为1μM,DMSO终浓度为0.5%。
种HepG2.2.15细胞(4×104细胞/孔)到96孔板,在37℃,5%CO2培养过夜。第二天,加入含不同浓度化合物的新鲜培养液到培养孔中。第五天,吸除培养孔中旧的培养液,加入含不同浓度化合物的新鲜培养液。
第八天,收集培养孔中的上清,用于提取上清中的HBV DNA,qPCR检测HepG2.2.15上清中的HBV DNA含量。收集上清后,再向培养孔中补加培养基和Cell-titer Glo试剂,酶标仪检测各孔的化学发光值。
活性计算公式如下:
Y=Bottom+(Top-Bottom)/(1+10((LogIC50-X)*HillSlope));
其中,
X表示浓度的对数值,Y表示效应值,Y从底部起始以S型拟合至顶部;
Bottom表示曲线的底部;
Top表示曲线的顶部;
HillSlope表示:曲线的最大斜率的绝对值。
实验三:细胞毒性测定
待测化合物的细胞毒性是使用HepG2细胞进行测试的,将这些细胞在待测化合物存在下孵育4天。使用刃天青测定来评估细胞活力。
结果表明:本发明的化合物的体外抗乙肝病毒核衣壳组装活性和抗乙肝病毒活性良好,且细胞毒性低。
实验一至实验三的活性数据见下表
表中:
“实验一”一栏中:
+++表示IC50<1μM;
++表示IC50为1~100μM;
+表示IC50为>100μM。
“实验二”一栏中:
++++表示EC50<1nM;
+++表示EC50 1~100nM;
++表示EC50为100~1000nM;
+表示EC50为>1000nM。
由此可见,本申请的化合物具有优异的抗乙肝病毒活性。
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 (10)
1.一种化学式式I,式II或式III所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐,
其中,R1、R2各自独立地选自下组:氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基;或R1、R2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自N、S和O的杂原子的3-10元杂环基;
R4、R5和R6各自独立地为位于C环上任意位置的选自下组的取代基:氢、卤素、-CN、取代或未取代的C1-C8烷基;
X为无、NR9;其中,R9为氢;
Y为-(CO)-、-SO2-;
R选自下组:卤素、C1-C4烷基;
C环为取代或未取代的苯环或吡啶环;
除非特别说明,所述的“取代”是指被选自下组的一个或多个取代基所取代:卤素、C1-C6烷基、羟基。
2.如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐,其特征在于,所述的R1为卤代或被羟基取代的C1-C4烷基,且所述的R2为H。
3.如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐,其特征在于,所述的C环为苯环。
4.如权利要求1所述的化合物,或其立体异构体或互变异构体、或其药学上可接受的盐,其特征在于,所述的R1为卤代或被羟基取代的C1-C4烷基,且所述的R2为H。
6.一种药物组合物,其包含(1)权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐;和(2)药学上可接受的载体。
7.如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐或如权利要求6所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗乙型肝炎病毒感染的药物。
8.一种乙型肝炎病毒抑制剂,其特征在于,所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐。
10.一种非诊断且非治疗性地体外抑制乙型肝炎病毒的方法,其特征在于,包括步骤:将权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐,与乙型肝炎病毒接触,从而抑制乙型肝炎。
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