CN112891348A - 苯基异噁唑基亚甲基-萘-醚衍生物的用途和药物组合物 - Google Patents
苯基异噁唑基亚甲基-萘-醚衍生物的用途和药物组合物 Download PDFInfo
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- CN112891348A CN112891348A CN202011083652.8A CN202011083652A CN112891348A CN 112891348 A CN112891348 A CN 112891348A CN 202011083652 A CN202011083652 A CN 202011083652A CN 112891348 A CN112891348 A CN 112891348A
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Abstract
Description
技术领域
本发明涉及治疗或预防乙肝病毒(HBV)感染的药物领域。具体地,本发明涉及苯基异噁唑基亚甲基-萘-醚衍生物用于治疗或预防HBV感染的用途、包含苯基异噁唑基亚甲基-萘-醚衍生物和其它抗HBV剂的药物组合物,以及苯基异噁唑基亚甲基-萘-醚衍生物的制药用途。
背景技术
乙型肝炎病毒(HBV)是一种肝细胞性的包膜的有部分单链区的环状双链DNA病毒。它通常在出生时在母婴之间传播(围产期传播),也可以通过血液或体液传播。
HBV产生共价闭合的环状DNA(cccDNA),分泌HBV表面抗原以抑制免疫***,并引起难以根除的持续性(慢性)感染。HBV感染是世界上主要的公共卫生威胁,每年有超过2.57亿人被慢性感染,并造成887,000多人死亡(Revill,P.A.等人,LancetGastroenterol.Hepatol,2019,4(7),545-558)。在亚太地区,慢性乙型肝炎病毒(HBV)感染导致该地区一半以上的死亡是由肝硬化引起的,约一半是该地区肝细胞癌的病例(Sarin,SK等人,《柳叶刀胃肠病》,Hepatol,2020,5(2):167-228)。在对27项研究的汇总分析中,据报道,2013年至2017年中国普通人群中HBV感染的合并估计患病率为6.89%(Wang,H.et alBMC Infect Dis,2019,19(1),811)。
当前,针对HBV感染的治疗非常有限。批准的治疗方法包括核苷酸抑制剂,例如替诺福韦酯(Viread),替诺福韦阿拉芬酰胺(Vemlidy),恩替卡韦(Baraclude),替比夫定(Tyzeka或Sebivo),拉米夫定(Epivir-HBV,Zeffix或Heptodin)和例如聚乙二醇化干扰素(Pegasys)。因此,迫切需要新的治疗方法(Fanning,G.C,Nat.Rev.Drug Discov,2019,18(11),827-844)。
法尼酯X受体(FXR)是核受体家族的成员,该家族包含类固醇受体、类维生素A受体和甲状甲状腺激素受体(Radreau P,Porcherot M,Ramière C,et al.Reciprocalregulation of farnesoid X receptorαactivity and hepatitis B virus replicationin differentiated HepaRG cells and primary human hepatocytes.FASEB J.2016;30(9):3146-54)。FXR主要表达于肝脏、肾脏、小肠及肾上腺。HBV感染细胞后,HBV cccDNA进入细胞核开始转录多种HBV RNA,其中前基因组RNA逆转录形成HBV DNA,其余RNA翻译形成HBsAg、HBeAg、HBcAg、HBx等,这些病毒蛋白和核酸在内质网共同组装形成病毒颗粒,并释放出胞。在HBV的生活周期中,HBV cccDNA的转录可被核受体所调控,如HNF-4α和FXR等。体外实验证实,FXR激动剂通过激活FXR,抑制cccDNA与HBx形成稳定的转录复合物,进而影响cccDNA的稳定性,抑制cccDNA的转录活性,达到降低病毒DNA和HBsAg的目的(Mouzannar K,Fusil F,Lacombe B,et al.Farnesoid X receptor-αis a proviral host factor forhepatitis B virus that is inhibited by ligands in vitro and in vivo.FASEBJ.2019;33(2):2472-2483)。
发明内容
本发明的发明人发现,式(I)所示的苯基异噁唑基亚甲基-萘-醚衍生物作为高效的小分子FXR激动剂,具有抗HBV活性。体外原代人肝细胞感染试验结果表明,式(I)所示的苯基异噁唑基亚甲基-萘-醚衍生物能有效抑制HBV DNA、HBV RNA和HBsAg。
因此,本发明涉及苯基异噁唑基亚甲基-萘-醚衍生物用于治疗或预防HBV感染的用途、包含苯基异噁唑基亚甲基-萘-醚衍生物和其它抗HBV剂的药物组合物及苯基异噁唑基亚甲基-萘-醚衍生物的制药用途。
定义
为了解释本说明书的目的进行以下定义,并且在适当时,单数形式的术语也包括复数形式,反之亦然。
如本文所使用的,术语“C1-6烷基”表示具有1至6个,特别是至多4个碳原子的烷基,所述基团为直链或具有单个或多个支链的支链,例如丁基,诸如正丁基、仲丁基、异丁基、叔丁基;丙基,例如正丙基或异丙基;乙基或甲基;更特别地,甲基、异丙基或叔丁基。
如本文所使用的,“C1-6烷氧基”是指“C1-6烷基-O-”,并且特别是甲氧基、乙氧基、异丙氧基或叔丁氧基。
如本文所使用的,术语“C3-6环烷基”是指具有3至6个碳原子的环烷基,例如环丙基,环丁基,环戊基或环己基。C3-6环烷基可以任选地被C1-6烷基和/或卤素取代。
如本文所使用的,术语“C4-7烷基环烷基”是指烷基和环烷基的组合,使得碳原子总数为4至7。例如,C4烷基环烷基包括亚甲基环丙基。
如本文所使用的,术语“5-10元芳基”是指5-10元单环、双环或三环芳环体系。通常地,芳基是5或6元环体系。
如本文所使用的,术语“5-10元杂芳基”是指具有1-4个杂原子的5-10元单环、双环或三环芳环体系。通常,杂芳基是5或6元环体系。此外,本文所用的术语“杂芳基”可以包括单价或二价杂芳基。
如本文所使用的,术语“卤素”或“卤”是指氟、氯、溴和碘中的一种或多种,尤其是氟或氯。
如本文所使用的,术语“C1-6卤代烷基”是指被一个或多个卤原子取代的烷基,特别是C1-6氟代烷基或C1-6氯代烷基,例如三氟甲基和2,2,2-三氟乙基。
如本文所使用的,术语“药学上可接受的辅料”可以包括本领域技术人员已知的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如,抗菌剂和抗真菌剂)、等渗剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、颜料等及其组合。除非任何常规载体与所述活性成分不相容,否则均可考虑将其用于所述治疗组合物或药物组合物中。
如本文所使用的,术语“乙型肝炎病毒”或“HBV”是指具有约3,200个碱基对的小的双链DNA基因组和肝细胞嗜性的嗜肝DNA病毒科成员。“HBV”包括感染各种哺乳动物(例如人,非人灵长类动物等)和禽类(鸭等)宿主中的任何一种的乙型肝炎病毒。“HBV”包括任何已知的HBV基因型,例如血清型A、B、C、D、E、F和G;任何HBV血清型或HBV亚型;任何乙肝病毒分离株;HBV变异体,例如,HBeAg阴性变异体,耐药性HBV变异体(例如,拉米夫定抗性变异体、阿德福韦抗性变异体、替诺福韦抗性变异体、恩替卡韦抗性变异体等);等等。
如本文所使用的,术语“治疗有效量”是指本发明化合物或分子的量,当将其给予受试者时,(i)治疗或预防特定的疾病、病症或失调;(ii)减轻、改善或消除特定疾病、病症或障碍的一种或多种症状;或(iii)预防或延迟本文所述的特定疾病、病症或障碍的一种或多种症状的发作。治疗有效量取决于化合物、所治疗的疾病状态、所治疗疾病的严重程度、受试者的年龄和相对健康状况、给药途径和形式、主治医学或兽医的判断。
除非另有说明,术语“式(I)化合物”包括具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其前药、该化合物的盐和/或该化合物前药的盐、该化合物的水合物或溶剂化物,以及该化合物的立体异构体(包括非对映异构体和对映异构体)、互变异构体、同位素标记的化合物(包括氘取代)和多晶型物。
本发明化合物的盐可以通过本领域技术人员已知的方法制备。例如,在适当的溶剂中用适当的碱或酸处理本发明的化合物得到相应的盐。
术语“药学上可接受的盐”中所包括的盐是指本发明化合物的无毒盐。优选的是羧酸的碱金属盐,例如钠、钾、锂、钙、镁、铝、锌、N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因盐。其他药学上不可接受的盐也可用于制备本发明的化合物,并且应认为它们构成了本发明的另一方面。
用于合成本发明化合物的所有起始原料、试剂、酸、碱、溶剂和催化剂是可商购的,或者可以通过本领域技术人员已知的有机合成方法来生产。除非本文另外指出或与上下文明显矛盾,否则本文描述的所有方法可以以任何合适的顺序执行。本文提供的任何和所有示例或示例性语言(例如,诸如)的使用仅旨在更好地阐明本发明,并且不对以其他方式要求保护的本发明的范围构成限制。
一方面,本发明提供了一种治疗或预防HBV感染的方法,该方法包括向有需要的人或动物施用治疗有效量的具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体:
其中:
R1、R2和R3各自独立地选自H、卤素、未取代或卤素取代的C1-6烷基和未取代或卤素取代的C1-6烷氧基,条件是R1、R2和R3中的至少一个不是氢,R0选自未取代或卤素取代的C1-6烷基、C3-6环烷基和C4-7烷基环烷基;
X1和X2独立地选自H和卤素;
-O-Z基团连接到萘环上,其中Z选自5-10元芳基或含有一个或多个选自N、O和S的杂原子的5-10元杂芳基,其中所述5-10元芳基或5-10元杂芳基被R4取代并且任选地进一步被R5取代;
其中R4选自-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1-6烷基、-SO3H、-CONHSO2-C1-6烷基、-CONHSO2-C3-6环烷基、-CONHSO2-5-10元芳基和芳基上被C1-6烷基取代的-CONHSO2-5-10元芳基;并且其中R5选自H、C1-6烷基、卤素、C1-6卤代烷基、-O-(C1-6烷基)和-NH-(C1-6烷基)。
在本发明的优选实施方案中,R1、R2和R3各自独立地选自H、卤素和C1-3全氟烷氧基,例如H、Cl、F和-O-CF3。在本发明的一种实施方案中,R1和R2均为Cl,并且R3为H。在本发明的另一种实施方案中,R1和R2均为Cl,并且R3为F。在本发明的又一种实施方案中,R1和R2均为Cl,R3为-O-CH3。在本发明的再一种实施方案中,R1为-O-CF3,且R2和R3均为H。在本发明的再一种实施方案中,R0为异丙基或环丙基。
在本发明的一种实施方案中,Z为苯基,其被R4取代并且任选地被R5取代。在本发明的另一种实施方案中,Z是具有选自N、O和S中的一个或多个杂原子的5-10元杂芳基。在本发明的一种优选实施方案中,Z是具有选自N、O和S中的一个或多个杂原子的5-6元杂芳基。在本发明的另一种实施方案中,Z是被R4和任选地R5取代的吡啶基。
在本发明的优选实施方案中,R4选自-COOH、-CH2COOH、-CONHSO2-C1-6烷基和-CONHSO2-C3-6环烷基中的一种。在本发明的更优选的实施方案中,R4为-COOH或-CH2COOH。在本发明的最优选的实施方案中,R4为-COOH。
优选地,R5选自H、C1-3烷基和卤素中的一种。
在本发明的优选实施方案中,Z为吡啶基;R4为-COOH;R5为H或卤素。
优选地,上述取代基中的卤素是氟或氯。
具体地,在本发明的优选实施方案中,式(I)化合物具有以下结构中的一种:
制备式(I)化合物的方法可以包括以下四种通用路线(路线A、路线B、路线C和路线D),其中:
路线A:
路线B:
路线C:
路线D:
以下,具体说明上述四种通用路线。
路线A:
(a)使式(A1)的卤代化合物与二萘酚反应,得到式(A2)的醚。反应在极性溶剂中与碱反应,优选在DMF或乙腈等中与碳酸铯或碳酸钾或类似的碱进行反应。
其中:
X是卤素;
R1、R2和R3独立地选自H、卤素和未取代或卤素取代的C1-6烷基和未取代或卤素取代的C1-6烷氧基,条件是R1、R2和R3中的至少一个不是氢,R0选自未取代或卤素取代的C1-6烷基、C3-6环烷基、C4-7烷基环烷基;
(b)使所得的式(A2)的醚与卤代化合物X-Z反应,得到式(I)的化合物,
其中X是卤素,Z是具有选自N、O和S的一个或多个杂原子的5-10元杂芳基,其中Z被R4取代并且任选地被R5取代;
其中R4选自-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1-6烷基、-SO3H、-CONHSO2-C1-6烷基、-CONHSO2-C3-6环烷基、-CONHSO2-5-10元芳基和芳基上被C1-6烷基取代的-CONHSO2-5-10元芳基;并且R5选自H、C1-6烷基、卤素和C1-6卤代烷基;任选的
(c)使含有-COOH取代基的式(I)化合物与酰胺化合物反应,得到式(I)化合物的酰胺化合物;以及任选的
(d)当Z被选自-COOH和-CH2COOH的R4取代时,可以使用本领域技术人员熟知的条件通过水解将酯前体转化为游离酸,
其中式(I)化合物如上文所定义。
根据本发明提供的制备方法,X优选为溴或碘,更优选为溴。
路线B:
(a)使式(A1)的卤代化合物与取代的萘酚(B1)反应,得到式(B2)的醚。反应在极性溶剂中与碱进行反应,优选在DMF或乙腈等中与碳酸铯或碳酸钾或类似的碱进行反应;
(b)将化合物(B2)转化为硼酸酯(B3),优选在Pd催化的条件下;
(c)用氧化剂如NaClO2或H2O2将化合物(B3)氧化为萘酚(A2);
(d)使用路线A中所述的条件,将化合物(A2)转化为化合物(I),
其中,X3为卤素,优选为溴或碘,更优选为溴。
路线C:
(a)使取代的萘酚(C1)与卤代化合物X-Z反应,得到式(C2)的醚,其中反应是在极性溶剂中与碱反应,优选在DMF或乙腈等中与碳酸铯或碳酸钾或类似的碱进行反应;
(b)将化合物(C2)转化为硼酸酯(C3),优选在Pd催化的条件下;
(c)用氧化剂如NaClO2或H2O2将化合物(C3)氧化为萘酚(C4);
(d)使用路线A中所述的条件,将化合物(C4)转化为化合物(I)
其中X4为卤素,优选为溴或碘,更优选为溴。
路线D:
(a)使用路线C中所述的条件,使二萘酚与卤代化合物X-Z反应,得到式(C4)的醚;
(b)使用路线C中所述的条件,将化合物(C4)转化为化合物(I)。
根据本发明提供的治疗或预防HBV感染的方法,所述具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体(简称:式(I)化合物)可以通过适合于待治疗病症的任何途径施用。合适的途径包括口服、直肠、鼻、局部(包括颊和舌下)、透皮、***和肠胃外(包括皮下、肌内、静脉内、皮内、鞘内和硬膜外)等给药方式。应当理解,优选的给药途径可以随着例如受试者的状况而变化。
根据本发明提供的治疗或预防HBV感染的方法,可以基于医师的判断,在治疗或预防过程中调节式(I)化合物的剂量或给药频率。式(I)化合物的剂量频率将由各个患者的需求决定,并且可以是例如每天一次,或者每天两次或更多次。式(I)化合物的给药持续至治疗或预防HBV感染所需的时间。
根据本发明提供的治疗或预防HBV感染的方法,其中,可以将所述具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体与一种或多种其它抗HBV剂组合使用。其中,可以将式(I)化合物与其它抗HBV剂以混合物的形式作为一种药物组合物使用,或者可以分别作为不同的药物组合物中共同施用。当处于不同的药物组合物中时,可以按照受试者的时间表,通过相同或不同的给药途径来管理式(I)化合物与其它抗HBV剂的给药方式。共同施用包括在施用单位剂量的一种或多种其它抗HBV剂之前或之后施用单位剂量的式(I)化合物。在一些实施方式中,式(I)化合物可在施用一种或多种其它抗HBV剂的数秒、数分钟或数小时内进行施用。在另一些实施方式中,首先施用单位剂量的式(I)化合物,接着在数秒、数分钟或数小时内施用一种或多种其它抗HBV剂。
根据本发明提供的治疗或预防HBV感染的方法,其中,所述其它抗HBV剂可以是可以是除式(I)化合物外的任何抗HBV剂,本发明对此没有特别限定。例如,所述其它抗HBV剂可以选自靶向病毒mRNA的反义寡核苷酸、短干扰RNA(siRNA)、B和T淋巴细胞减毒剂抑制剂、CCR2趋化因子拮抗剂、靶向HBcAg的化合物、靶向乙肝核心抗原(HBcAg)的化合物、共价闭合环状DNA(cccDNA)抑制剂、亲环蛋白抑制剂、细胞因子、核酸内切酶调节剂、表观遗传修饰剂、基因修饰剂或编辑剂、脂肪酸合成酶(fatty acid synthase)抑制剂、乙型肝炎表面抗原(HBsAg)抑制剂、HBsAg分泌或组装抑制剂、HBV抗体、HBV DNA聚合酶抑制剂、HBV复制抑制剂、HBV RNAse抑制剂、HBV疫苗、HBV病毒进入抑制剂、HBx抑制剂、乙型肝炎结构蛋白调节剂、乙型肝炎病毒E抗原抑制剂、乙型肝炎病毒复制抑制剂、肝炎病毒结构蛋白抑制剂、IL-2激动剂、IL-7激动剂、免疫调节剂、核糖核苷酸还原酶抑制剂、干扰素激动剂、干扰素α1配体、干扰素α2配体、干扰素α5配体调节剂、干扰素α配体、干扰素α配体调节剂、干扰素α受体配体、干扰素β配体、干扰素配体、干扰素受体调节剂、白介素2配体、赖氨酸脱甲基酶抑制剂、微RNA(miRNA)基因治疗剂、B7-H3调节剂、B7-H4调节剂、CD 160调节剂、CD161调节剂、CD27调节剂、CD47调节剂、CD70调节剂、GITR调节剂、TIGIT调节剂、Tim-4调节剂、钠-牛磺胆酸盐共转运多肽(NTCP)抑制剂、天然杀伤细胞受体2B4抑制剂、NOD2基因刺激剂、核蛋白抑制剂、核蛋白调节剂、PD-1抑制剂、PD-L1抑制剂、PEG-干扰素λ、肽基脯氨酰异构酶抑制剂、视黄酸诱导型基因1激动剂、逆转录酶抑制剂、核糖核酸缓和抑制剂、RNA DNA聚合酶抑制剂、短合成发夹RNA(sshRNA)、干扰素基因激动剂(STING)的激动剂、NOD 1激动剂、T细胞表面糖蛋白CD28抑制剂、TLR-3激动剂、TLR-7激动剂、TLR-8激动剂、TLR-9激动剂、TLR9基因刺激剂、TOLL样受体(TLR)调节剂、病毒核糖核苷酸还原酶抑制剂、锌指核酸酶或合成核酸酶(TALEN)等。
在本发明优选的实施方案中,所述其它抗HBV剂选自HBV疫苗、HBV DNA聚合酶抑制剂、免疫调节剂、Toll样受体(TLR)调节剂、干扰素α受体配体、脂肪酸合成酶抑制剂、乙型肝炎表面抗原(HBsAg)抑制剂、亲环蛋白抑制剂、HBV病毒进入抑制剂、靶向病毒mRNA的反义寡核苷酸、短干扰RNA(siRNA)和ddRNAi核酸内切酶调节剂、核糖核酸核苷酸还原酶抑制剂、HBV E抗原抑制剂、共价闭合环状DNA(cccDNA)抑制剂、HBV抗体、CCR2趋化因子拮抗剂、视黄酸诱导基因1激动剂、NOD2激动剂、PD-1抑制剂、PD-L1抑制剂、KDM抑制剂和HBV复制抑制剂中的一种或多种。
在一种实施方案中,所述其它抗HBV剂是核苷酸。HBV DNA聚合酶抑制剂的实例包括阿德福韦(HEPSERA*)、安卓西他宾滨(EMTRIVA)、反丁烯二酸替诺福韦双索酯替诺福韦埃拉酚胺、替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦埃拉酚胺、替诺福韦迪皮夕(tenofovir dipivoxil)、替诺福韦阿拉福韦酯,替诺福韦十八烷氧基乙酯、CMX-157、拜斯福韦(besifovir)、恩替卡韦顺丁烯二酸恩替卡韦、替比夫定(TYZEKA)、帕拉德福韦、德威定、利巴韦林、拉米夫定迭氮膦(phosphazide)、泛昔洛韦、弗索林、美他卡韦、SNC-0 19754、FMCA、AGX-1009、AR-II-04-26、HIP-1302、天冬胺酸替诺福韦双索酯、乳清酸替诺福韦双索酯和HS-10234。HBV DNA聚合酶抑制剂的其他例子包括非洛西韦。
在一个具体的实施方案中,将本发明的式(I)化合物与恩替卡韦或替诺福韦组合。
在另一种实施方案中,所述其它抗HBV剂是免疫调节剂。所述免疫调节剂的实例包括TLR激动剂RO7020531、GS-9620、GS-9688。免疫调节剂的实例还包括PD-1抑制剂,例如纳武利尤单抗(nivolumab)、派姆单抗(pembrolizumab)、皮立珠单抗(pidilizumab)、BGB-108、SHR-1210、PDR-001、萨善利单抗(Sasanlimab)(PF-06801591)、IBI-308、测米匹单抗(cemiplimab)、坎立珠单抗(Camrelizumab)、斯迪利单抗(Sintilimab)、缇勒珠单抗(tislelizumab)(BGB-A317)、BCD-100、西利单抗(Cetrelimab)(JNJ-63723283)、Zimberelimab(GLS-010,WBP-3055),巴替利单抗(Balstilimab)(AGEN2034)、多斯利单抗(dostarlimab)(TSR-042)。免疫调节剂的实例还包括PD-L1抑制剂,例如阿特珠单抗(atezolizumab)(RG-7446)、艾维路单抗(avelumab)、BGB-A333、德瓦鲁单抗(durvalumab)、CX-072、GX-P2和恩沃利单抗(KN035、ASC022)。所述PD-L1抑制剂还可以为小分子抑制剂,例如GS-4224和INCB086550。
在一个具体的实施方案中,将式(I)化合物与恩沃利单抗组合。
在又一种实施方案中,所述其它抗HBV剂是脂肪酸合成酶抑制剂。所述脂肪酸合成酶抑制剂的实例包括TVB-2640、TVB-3150、TVB-3199、TVB-3166、TVB-3567和TVB-3664。
在一个具体的实施方案中,将本发明的式(I)化合物与脂肪酸合成酶抑制剂TVB-2640和/或TVB-3567组合。
在又一种实施方案中,所述其它抗HBV剂是普通或长效干扰素。所述干扰素的实例包括派格宾、派罗欣(Pegasys)、佩乐能(PEG-INTRON)
在一个具体的实施方案中,将式(I)化合物与派罗欣组合。
在又一种实施方案中,所述其它抗HBV剂是HBV疫苗。所述HBV疫苗包括预防和治疗疫苗。HBV预防性疫苗的实例包括Vaxelis、Hexaxim、Heplisav、Mosquirix、DTwP-HBV疫苗、Bio-Hep-B、D/T/P/F1BV7M(LBVP-0101;LBVW-0101)、DTwP-Hepb-FIib-IPV疫苗、HeberpentaL、DTwP-HepB-Hib、V-419、CVI-HBV-001、Tetrabhay、乙型肝炎预防性疫苗(Advax SuperD)、Hepatrol-07、GSK-223 192A、重组乙型肝炎疫苗(肌内注射,康泰生物制品)、重组乙型肝炎疫苗(多形汉酵母,肌内,华兰生物工程公司)、重组乙型肝炎表面抗原疫苗、Bimmugen、Euforavac、Eutravac、anrix-DTaP-IPV-Hep B、HBAI-20、Infanrix-DT aP-IPV-Hep B-Hib、Pentabio Vaksin DTP-HB-Hib、Comvac 4、Twinrix、Euvax-B、TritanrixHB、Infanrix Heb B、Comvax、DTP-Hib-HBV疫苗、DTP-HBV疫苗、Heberbiovac HB、TrivacHB、GerVax、DTwP-Hep B-Hib疫苗、倍尔来福(Bilive)、HepavaxGene、SUPERVAX、Comvac5、Shanvac-B、Hebsulin、Recombivax HB、Revac B mcf、Revac B+、Fendrix、DTwP-HepB-Hib、DNA-001、Shan5、Shan6、rhHBsAG疫苗、HBI五价疫苗、LBVD、Infanrix HeXa和DTaP-rHB-Hib疫苗。
在一个具体的实施方案中,将本发明的式(I)化合物与ABX203、AIC 649、INO-1800、HB-110、TG1050、HepTcell、VR-CHB01、VBI-2601和CAG-201中的一种或多种组合。
在再一种实施方案中,所述其它抗HBV剂是靶向病毒mRNA的反义寡核苷酸(ASO)。反义寡核苷酸的例子包括Ionis-HBVRx和Ionis-HBV-LRx。
在再一种实施方案中,所述其它抗HBV剂短干扰RNA(siRNA)。短干扰RNA的例子包括JNJ-3989(ARO-HBV),Vir-2218(ALN-HBV02)和DCR-HBVS。
在再一种实施方案中,所述其它抗HBV剂是肝炎表面抗原(HBsAg)抑制剂。HBsAg抑制剂的例子包括HBF-0259、PBHBV-001、PBHBV-2-15、PBHBV-2-1、REP-9AC、REP-9C、REP-9、REP-2139、REP-2l39-Ca、REP-2165、REP-2055、REP-2163、REP-2165、REP-2053、REP-203和REP-006、REP-9AC以及针对PAPD 57的抑制剂。
在再一种实施方案中,所述其它抗HBV剂是HB病毒进入抑制剂,例如Myrcludex B、贺普拉肽,或靶向preS的抗体。
在再一种实施方案中,所述其它抗HBV剂是衣壳抑制剂。HBsAg抑制剂的实例包括ABI-H0731、ABI-H2158、ABI-H3733、CB-HBV-001、JNJ-6379、JNJ-0440、QL-007、RG-7907和RO7049389。
在本发明最优选的实施方案中,所述其它抗HBV剂选自恩替卡韦、替诺福韦、恩沃利单抗和派罗欣中的一种或多种。
另一方面,本发明还提供了具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体在制备抗HBV药物中的应用。其中,所述具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体如前文所定义。
根据本发明提供的应用,其中,所述抗HBV药物包含作为活性成分的具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体以及一种或多种其它抗HBV剂。其中,所述其它抗HBV剂如前文所定义。
再一方面,本发明还提供了一种抗HBV药物组合物,所述药物组合物包含治疗有效量的具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体和一种或多种其它抗HBV剂,以及药学上可接受的辅料。其中,所述具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体如前文所定义。其中,所述其它抗HBV剂如前文所定义。
本发明的抗HBV药物组合物适合于口服、直肠、鼻、局部(包括颊和舌下)、透皮、***和肠胃外(包括皮下、肌内、静脉内、皮内、鞘内和硬膜外)等给药方式。具体的给药方式取决于所治疗疾病的性质和严重程度以及活性成分的性质。所述药物组合物可以方便地以单位剂型存在,并且可以通过药学领域技术人员公知的任何方法制备。
本发明的药物组合物适用于各种给药途径,包括口服给药。所述组合物可以单位剂型存在,并且可以通过药学领域公知的任何方法制备。此类方法包括使活性成分(例如,本发明的式(I)化合物或其药用盐)与一种或多种药学上可接受的赋形剂结合的步骤。可以通过将活性成分与液体赋形剂或固体赋形剂或两者均匀且紧密地结合在一起,然后,如果需要,将产品成型来制备组合物。本文描述的适合于口服施用的组合物可以以离散单位(单位剂型)的形式存在,包括但不限于分别包含预定量的活性成分的胶囊、扁囊剂或片剂。在一个实施方案中,药物组合物是片剂。
所述式(I)化合物可以有效量施用于个体。可以与非活性成分组合以产生剂型的活性成分的量可以根据预期的治疗对象和特定的给药方式而变化。例如,在一些实施方案中,用于对人口服给药的剂型可以包含约1至1000mg的活性材料,其与适当和方便量的药学上可接受的赋形剂一起配制。在某些实施方案中,药学上可接受的赋形剂为总组合物的约5%至约95%。
基于给药医师的判断,可以在治疗过程中调节本发明的式(I)化合物的剂量或给药频率。式(I)化合物的剂量频率将由各个患者的需求决定,并且可以是例如每天一次或每天两次或多次,或者更多次。化合物的给药持续至治疗HBV感染所需的时间。
附图说明
为了更清楚地说明本发明的实施例中的技术方案,下面将简要描述用于描述本发明实施例的附图。显然,以下描述中的附图仅是本发明的一些实施例。
图1为PHH细胞中抑制HBV DNA的EC50曲线;
图2为PHH细胞中HBsAg抑制的EC50曲线;
图3为PHH细胞中HBV RNA抑制的EC50曲线;
图4为化合物33对AAV/HBV小鼠血清HBV DNA的抑制作用;
图5为化合物33对AAV/HBV小鼠血清HBV RNA的抑制作用;
图6为化合物33对AAV/HBV小鼠血清HBsAg的抑制作用。
具体实施方式
参照以下实施例进一步说明本发明。需要说明的是,以下实施例仅用于举例说明,并不用于限制本发明。本领域技术人员根据本发明的教导做出的各种改变应在本发明的权利要求所述的范围内。
实施例1
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物1)
(a)参考以下反应方程式(方法A),将化合物1A-1(1.0g,2.88mmol,1当量),化合物1A-2(0.46g,2.88mmol,1当量)和碳酸铯(1.88g,5.76mmol,2当量)溶于DMF(10ml)中,在65℃下反应2小时。冷却后,加入10ml水和10ml EA(乙酸乙酯)萃取,并将有机相用水洗涤并浓缩至干,得到化合物1A,6-(((5-环丙基-3-(2,6)-二氯苯基)异噁唑-4-基)甲氧基)萘-2-醇,0.8g,产率:65.0%。LCMS(ESI):经计算为C23H17Cl2NO3;[M+H]+:426.1,实测值:426.1。
(b)参考以下反应方程式,将化合物1A(0.2g,0.47mmol,1当量),6-溴烟酸甲酯(0.1g,0.47mmol,1当量)和碳酸铯(0.306g,0.94mmol,2当量)溶于DMF(10ml)中,在65℃下反应2小时。冷却后,加入10ml水和10ml EA进行萃取,将有机相用水洗涤并浓缩至干,得到化合物1B,甲基6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸酯,0.21g,收率:80.0%。LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
(c)参考以下反应方程式,将化合物1B(100mg)溶解在甲醇(2ml)中,然后加入10%NaOH水溶液(1ml),将温度升至60℃,反应1小时。通过加入1N HCl溶液将反应溶液的pH调节至2-4,并加入10ml EA进行萃取。浓缩有机相,并在柱上纯化(PE/EA/AcOH=1/1/0.01洗脱),得到标题化合物1(36mg,产率:37.0%)。
1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.23(d,J=7.2Hz,1H),7.74(dd,J=2.0,8.8Hz,2H),7.60(d,J=7.6Hz,2H),7.56(s,1H),7.51(dd,J=8.8,7.2Hz,1H),7.33(s,1H),7.26(d,J=8.8Hz,1H),7.02(d,J=8.0Hz,1H),6.93(d,J=6.4Hz,1H),4.98(s,2H),2.57-2.50(m,1H),1.19-1.11(m,4H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例2
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)哒嗪-3-羧酸(化合物2)
按照实施例1的方法,通过用6-溴哒嗪-3-羧酸甲酯代替6-溴烟酸甲酯得到标题化合物2。
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.25(d,J=7.2Hz,1H),7.74(dd,J=2.0,8.8Hz,2H),7.61(d,J=7.6Hz,2H),7.52(dd,J=8.8,7.2Hz,1H),7.34(s,1H),7.26(d,J=8.8Hz,1H),7.00(d,J=8.0Hz,1H),6.95(d,J=6.4Hz,1H),4.98(s,2H),2.59-2.50(m,1H),1.21-1.11(m,4H).LCMS(ESI):经计算为C28H19Cl2N3O5;[M+H]+:548.1,实测值:548.1。
实施例3
制备5-氯-6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物3)
按照实施例1的方法,通过用5,6-二氯烟酸甲酯代替6-溴烟酸甲酯得到标题化合物3。
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.73(dd,J=2.0,8.8Hz,2H),7.59(d,J=7.6Hz,2H),7.51(dd,J=8.8,7.2Hz,1H),7.33(s,1H),7.26(d,J=8.8Hz,1H),7.01(d,J=8.0Hz,1H),6.95(d,J=6.4Hz,1H),5.00(s,2H),1.26-1.12(m,5H).LCMS(ESI):经计算为C29H19Cl3N2O5;[M+H]+:581.0,实测值:581.0。
实施例4
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)噻唑-5-羧酸(化合物4)
按照实施例1的方法,通过用2-溴噻唑-5-羧酸甲酯代替6-溴烟酸甲酯得到标题化合物4。
1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.69(dd,J=2.0,8.8Hz,2H),7.59(d,J=7.6Hz,2H),7.53(dd,J=8.8,7.2Hz,1H),7.32(s,1H),7.26(d,J=8.8Hz,1H),7.01(d,J=8.0Hz,1H),6.99(d,J=6.4Hz,1H),5.00(s,2H),1.25-1.12(m,5H).LCMS(ESI):经计算为C27H18Cl2N2O5S;[M+H]+:553.0,实测值:553.0。
实施例5
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)-5-甲基烟酸(化合物5)
按照实施例1的方法,通过用6-溴-5-甲基烟酸甲酯代替6-溴烟酸甲酯得到标题化合物5。
1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.35(d,J=1.5Hz,1H),8.12-7.90(m,1H),7.72-7.61(m,2H),7.54(s,3H),7.28(m,2H),7.15-7.10(m,1H),7.07(dd,J=7.5,1.5Hz,1H),6.95(dd,J=7.6,1.6Hz,1H),5.41(s,2H),2.99-2.70(m,1H),2.28(s,3H),2.12-1.56(m,4H).LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
实施例6
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)-N-(环丙基磺酰基)烟酰胺(化合物6)
将实施例1中制备的化合物1(70mg)和环丙基磺酰胺(23mg)溶于2ml DCM(二氯甲烷),然后加入40mg EDCI(1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐)和26mg DMAP(二甲基氨基吡啶)。反应完成后,加入10ml DCM和10ml水用于萃取。有机相用水洗涤并浓缩至干。粗产物通过柱纯化(PE/EA/AcOH=2/1/0.01),得到标题化合物7(8mg,产率:9.6%)。
1H NMR(400MHz,DMSO-d6)δ8.63(d,J=1.5Hz,1H),8.30(dd,J=7.5,1.5Hz,1H),7.79(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.59-7.62(m,3H),7.49-7.53(m,1H),7.35(s,1H),7.26-7.29(m,1H),7.10(d,J=8.0Hz,1H),6.93-6.96(m,1H),4.98(s,2H),1.02-1.20(m,10H).LCMS(ESI):经计算为C32H25Cl2N3O6S;[M+H]+:650.1,实测值:650.1。
实施例7
制备5-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)吡嗪-2-羧酸(化合物7)
按照实施例1的方法,通过用5-氯吡啶-2-甲酸甲酯代替6-溴烟酸甲酯得到标题化合物7。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.30(s,1H),7.79(d,J=8.8Hz,1H),7.72(d,J=9.2Hz,1H),7.58-7.63(m,4H),7.49-7.53(m,1H),7.34(d,J=2.0Hz,1H),6.94(d,J=9.2Hz,1H),4.98(s,2H),1.11-1.22(m,5H).LCMS(ESI):经计算为C28H19Cl2N3O5;[M+H]+:548.1,实测值:548.1。
实施例8
制备2-氯-6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物8)
按照实施例1的方法,通过用2,6-二氯烟酸甲酯代替6-溴烟酸甲酯得到标题化合物8。
1H NMR(400MHz,DMSO-d6)δ7.98(br s,1H),7.70-7.79(m,2H),7.60(d,J=8.0Hz,2H),7.47-7.55(m,2H),7.18-7.33(m,2H),6.90-6.95(m,2H),4.98(s,2H),1.11-1.22(m,5H).LCMS(ESI):经计算为C29H19Cl3N2O5;[M+H]+:581.0,实测值:581.0。
实施例9
制备5-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)吡啶甲酸(化合物9)
按照实施例1的方法,通过用5-溴吡啶甲酸甲酯代替6-溴烟酸甲酯得到标题化合物9。
1H NMR(400MHz,DMSO-d6)δ8.46(d,J=3.1Hz,1H),8.03(d,J=8.7Hz,1H),7.83(d,J=8.9Hz,1H),7.72(d,J=9.1Hz,1H),7.55(dt,J=28.7,8.3Hz,4H),7.43(d,J=8.6Hz,1H),7.39–7.24(m,2H),6.95(d,J=8.9Hz,1H),4.98(s,2H),1.23–1.02(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例10
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)-2-甲基烟酸(化合物10)
按照实施例1的方法,通过用6-氯-2-甲基烟酸甲酯代替6-溴烟酸甲酯得到标题化合物10。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.6Hz,1H),7.78(d,J=8.9Hz,1H),7.72(d,J=9.0Hz,1H),7.62–7.55(m,3H),7.51(dd,J=9.0,7.1Hz,1H),7.34(d,J=2.5Hz,1H),7.27(dd,J=8.8,2.4Hz,1H),6.94(dd,J=8.9,2.5Hz,1H),6.85(d,J=8.6Hz,1H),4.98(s,2H),2.52(s,3H),1.24–1.07(m,5H).LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
实施例11
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)吡啶甲酸(化合物11)
按照实施例1的方法,通过用2,6-二氯烟酸甲酯代替6-溴烟酸甲酯得到标题化合物11。
1H NMR(400MHz,DMSO-d6)δ7.99(t,J=7.9Hz,1H),7.77(d,J=8.1Hz,2H),7.71(d,J=8.9Hz,1H),7.63–7.45(m,4H),7.33(s,1H),7.29(d,J=9.0Hz,1H),7.22(d,J=8.2Hz,1H),6.94(d,J=9.0Hz,1H),4.98(s,2H),1.26–1.01(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例12
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)异烟碱酸(化合物12)
按照实施例1的方法,通过用2-氟异烟酸甲酯代替6-溴烟酸甲酯得到标题化合物12。
1H NMR(400MHz,DMSO-d6)δ8.29(d,J=5.1Hz,1H),7.78(d,J=8.8Hz,1H),7.59(t,J=7.7Hz,3H),7.52(m,2H),7.34(s,2H),7.29(s,1H),4.98(s,2H),1.31-1.06(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例13
制备3-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)吡啶甲酸(化合物13)
按照实施例1的方法,通过用3-氟吡啶甲酸甲酯代替6-溴烟酸甲酯得到标题化合物13。
1H NMR(400MHz,DMSO-d6)δ8.39(d,J=4.4Hz,1H),7.77(d,J=9.0Hz,1H),7.66(d,J=9.2Hz,1H),7.59(d,J=8.1Hz,2H),7.54–7.43(m,3H),7.30(d,J=2.8Hz,2H),7.26–7.16(m,1H),6.95–6.85(m,1H),4.95(s,2H),1.24–1.06(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例14
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)苯甲酸(化合物14)
按照实施例1的方法,通过用2-氟苯甲酸甲酯代替6-溴烟酸甲酯得到标题化合物14。
1H NMR(400MHz,DMSO-d6)δ7.82(d,J=7.8Hz,1H),7.73(d,J=8.9Hz,1H),7.66–7.57(m,3H),7.55–7.45(m,2H),7.26(d,J=10.6Hz,2H),7.21–7.11(m,2H),6.99(d,J=8.3Hz,1H),4.94(s,2H),1.27–1.06(m,5H).LCMS(ESI):经计算为C30H21Cl2NO5;[M+H]+:546.1,实测值:546.1。
实施例15
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物15)
按照实施例1的方法,通过用2-氯烟酸甲酯代替6-溴烟酸甲酯得到标题化合物15。
1H NMR(400MHz,DMSO-d6)δ8.30–8.19(m,2H),7.73(dd,J=19.2,9.0Hz,2H),7.60(d,J=7.9Hz,2H),7.55–7.47(m,2H),7.32(d,J=2.5Hz,1H),7.26–7.18(m,2H),6.92(dd,J=8.9,2.5Hz,1H),4.98(s,2H),1.23–1.10(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例16
制备3-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)异烟酸(化合物16)
按照实施例1的方法,通过用3-氟异烟酸甲酯代替6-溴烟酸甲酯得到标题化合物16。
1H NMR(400MHz,DMSO-d6)δ8.52(d,J=4.8Hz,1H),8.39(s,1H),7.76(d,J=8.9Hz,1H),7.73(d,J=4.9Hz,1H),7.64(d,J=9.0Hz,1H),7.59(d,J=7.7Hz,2H),7.50(dd,J=9.0,7.0Hz,1H),7.32–7.15(m,4H),6.89(dd,J=8.9,2.5Hz,1H),4.95(s,2H),1.27–1.09(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例17
制备6-((6-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物17)
按照实施例1的方法,通过用4-(氯甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑代替1A-1获得标题化合物17。
1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.27(d,J=8.1Hz,1H),7.75(dt,J=31.9,15.9Hz,2H),7.61(s,2H),7.56-7.43(m,2H),7.36(s,1H),7.29(d,J=8.6Hz,1H),7.11(d,J=8.2Hz,1H),7.00(d,J=8.5Hz,1H),5.03(s,2H),2.44-2.37(m,1H),1.20-1.05(m,4H).LCMS(ESI):经计算为C30H21F3N2O6;[M+H]+:563.1,实测值:563.1。
实施例18
制备6-((6-((5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物18)
按照实施例1的方法,通过用4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-氟苯基)异噁唑代替1A-1获得标题化合物18。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.27(d,J=7.9Hz,1H),7.87-7.63(m,4H),7.60(s,1H),7.40-7.24(m,2H),7.11(d,J=8.0Hz,1H),6.96(d,J=8.6Hz,1H),4.98(s,2H),2.47-2.40(m,1H),1.23-1.08(m,4H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例19
制备6-((6-((5-环丙基-3-(2,6-二氯-4-甲氧基苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物19)
按照实施例1的方法,通过用4-(氯甲基)-5-环丙基-3-(2,6-二氯-4-甲氧基苯基)异噁唑代替1A-1获得标题化合物19。
LCMS(ESI):经计算为C30H22Cl2N2O6;[M+H]+:577.1,实测值:577.1。
实施例20
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-1-氟萘-2-基)氧基)烟酸(化合物20)
(a)参考以下反应方程式(路线C),将化合物20A-1(1.0g,4.15mmol,1当量),化合物20A-2(0.90g,4.15mmol,1当量)和碳酸铯(2.70g,8.30mmol,2当量)溶于DMF(10ml)中,在65℃下反应2小时。冷却后,加入10ml水和10ml EA(乙酸乙酯)萃取,并将有机相用水洗涤并浓缩至干,得到化合物20A,甲基6-(((6-溴-1-氟萘-2-基)氧基)烟酸酯,1.2g,收率:77.0%。LCMS(ESI):经计算为C17H11BrFNO3;[M+H]+:376.0,实测值:376.0。
(b)参照以下反应方程式,将化合物20A(200mg,0.53mmol,1当量)溶解于无水THF(2ml),然后在N2下添加KOAc(104mg,1.06mmol,2当量),Pd(dppf)2Cl2(39mg,0.053mmol,0.1当量)和双(频哪醇合)二硼(135mg,0.53mmol,1当量),将反应混合物加热至回流2h。冷却后,加入10ml水和10ml EtOAc萃取,有机相用水洗涤并浓缩至干。残留物通过硅胶柱色谱法纯化(石油醚:EtOAc=3:1),得到化合物20B,6-((1-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-2-基)氧基)烟酸甲酯,151mg,收率:67.1%。LCMS(ESI):经计算为C23H23BFNO5;[M+H]+:424.2,实测值:424.2。
(c)参考以下反应方程式,将化合物20B(100mg)溶解在EtOH(2ml)中,然后加入30%H2O2水溶液(1ml)。将反应混合物在室温搅拌1h,用饱和Na2SO3水溶液淬灭,并用EA萃取。浓缩有机相,并在柱上纯化(PE/EA=3/1),得到化合物20C(36mg,收率:37.0%)。LCMS(ESI):经计算为C17H12FNO4;[M+H]+:314.1,实测值:314.1。
(d)参考以下反应方程式,将化合物20C(0.2g,0.47mmol,1当量),1A-1(0.1g,0.47mmol,1当量)和碳酸铯(0.306g,0.94mmol,2当量)溶解在DMF(10ml)中,在65℃下反应2小时。冷却后,加入10ml水和10ml EtOAc萃取,将有机相用水洗涤并浓缩至干,得到0.21g化合物20D,收率:80.0%。LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
(e)参考以下反应方程式,将化合物20D(100mg)溶解在无水THF(2ml)中,然后在N2下添加10%NaOH水溶液(1ml),并将反应混合物加热至回流1小时。通过添加1N HCl溶液将反应溶液的pH调节至3至4,并添加10ml EA用于萃取。浓缩有机相,并在柱上纯化(PE/EA/AcOH=1/1/0.01洗脱),得到标题化合物20(36mg,收率:37.0%)。
1H NMR(400MHz,DMSO-d6)δ8.63(d,J=2.4Hz,1H),8.30(dd,J=8.7,2.4Hz,1H),7.92(d,J=9.0Hz,1H),7.70(s,1H),7.64(d,J=5.3Hz,1H),7.60(d,J=6.4Hz,1H),7.57(d,J=4.3Hz,2H),7.42-7.36(m,2H),7.17(d,J=8.6Hz,1H),5.09(s,2H),1.22–1.06(m,5H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例21
制备6-((1-氯-6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物21)
按照实施例20的方法,通过用6-溴-1-氯萘-2-醇代替20A-1获得标题化合物21。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.27(d,J=7.9Hz,1H),7.87-7.63(m,4H),7.60(s,1H),7.40-7.24(m,2H),7.11(d,J=8.0Hz,1H),6.96(d,J=8.6Hz,1H),4.98(s,2H),2.47-2.40(m,1H),1.23-1.08(m,4H).LCMS(ESI):经计算为C29H19Cl3N2O5;[M+H]+:581.0,实测值:581.0。
实施例22
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)烟酸(化合物22)
(a)参照以下反应方程式(路线D),将化合物22A-1(2.0g,12.49mmol,1当量),化合物22A-2(1.71g,9.99mmol,0.8当量)和碳酸铯(6.09g,18.74mmol,1.5当量)溶于DMF(20ml)中,在65℃下反应3小时。冷却后,加入30ml水和30ml EA(乙酸乙酯)进行萃取,并将有机相用水洗涤并浓缩至干。残余物通过硅胶柱色谱法纯化(石油:AcOEt=5:1),得到化合物22A,6-((6-羟基萘-1-基)氧基)烟酸甲酯,1.1g,收率:37.3%。LCMS(ESI):经计算为C17H13NO4;[M+H]+:296.1,实测值:296.1.
(b)参考以下反应方程式,将化合物22A(0.2g,0.68mmol,1当量),22A-3(0.2g,0.68mmol,1当量)和碳酸铯(0.44g,1.36mmol,2当量)溶于DMF(5ml)中进行反应。反应在40℃下进行2小时。冷却后,加入10ml水和10ml EA进行萃取,将有机相用水洗涤并浓缩至干,得到化合物22B,6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)烟酸甲酯,0.31g,收率:81.2%。LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
(c)参考以下反应方程式,将化合物22B(100mg)溶解于甲醇(2ml)中,然后加入10%NaOH水溶液(1ml),将温度升至60℃,进行反应0.5小时。通过加入1N HCl溶液将反应溶液的pH调节至2-4,并加入10ml EA进行萃取。将有机相在柱上浓缩(PE/EA/AcOH=1/1/0.01洗脱),得到标题化合物22(42mg,收入率:43.2%)。
1H NMR(400MHz,DMSO-d6)δ13.11(br s,1H),8.56(s,1H),8.28(d,J=8.5Hz,1H),7.66(d.J=8.3Hz,1H),7.56-7.61(m,3H),7.45-7.53(m,2H),7.39(s,1H),7.15(t,J=9.6Hz,2H),6.9(d,J=9.2Hz,2H),4.98(s,2H),1.09-1.28(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例23
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)吡啶甲酸(化合物23)
按照实施例22的方法,通过用6-氟吡啶甲酸甲酯代替22A-2得到标题化合物23。
1H NMR(400MHz,DMSO-d6)δ7.99(t,J=7.8Hz,1H),7.78(d,J=7.4Hz,1H),7.73(d,J=9.2Hz,1H),7.63(d,J=8.3Hz,1H),7.60–7.55(m,2H),7.52–7.44(m,2H),7.40–7.37(m,1H),7.20(d,J=8.3Hz,1H),7.09(d,J=7.5Hz,1H),6.94–6.90(m,1H),4.99(s,2H),1.23–1.09(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例24
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)异烟酸(化合物24)
按照实施例22的方法,通过用2-氟异烟酸甲酯代替22A-2获得标题化合物24。
1H NMR(400MHz,DMSO-d6)δ8.22(d,J=5.1Hz,1H),7.67–7.62(m,2H),7.58(d,J=8.0Hz,2H),7.53–7.42(m,3H),7.38(s,2H),7.11(d,J=7.5Hz,1H),6.89(dd,J=9.2,2.4Hz,1H),4.98(s,2H),1.22–1.07(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例25
制备3-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)吡啶甲酸(化合物25)
按照实施例22的方法,通过用3-氟吡啶甲酸甲酯代替22A-2得到标题化合物25。
1H NMR(400MHz,DMSO-d6)δ8.41–8.37(m,1H),7.90(d,J=9.2Hz,1H),7.62–7.54(m,3H),7.53–7.47(m,2H),7.43–7.35(m,2H),7.35–7.30(m,1H),6.99–6.94(m,1H),6.77(d,J=7.6Hz,1H),5.00(s,2H),1.21–1.10(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例26
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)-4-氟苯甲酸(化合物26)
按照实施例22的方法,通过用2,4-二氟苯甲酸甲酯代替22A-2得到标题化合物26。
1H NMR(400MHz,DMSO-d6)δ8.22(d,J=5.1Hz,1H),7.67–7.61(m,2H),7.57(s,2H),7.52–7.43(m,3H),7.38(s,2H),7.11(d,J=7.5Hz,1H),6.90(s,0H),4.98(s,2H),1.20–1.06(m,5H).LCMS(ESI):经计算为C30H20Cl2FNO5;[M+H]+:564.1,实测值:564.1。
实施例27
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)-2-甲基烟酸(化合物27)
按照实施例22的方法,通过用6-氯-2-甲基烟酸甲酯代替22A-2得到标题化合物27。
1H NMR(400MHz,DMSO-d6)δ8.20(d,J=8.5Hz,1H),7.63(dd,J=8.8,4.5Hz,2H),7.57(s,1H),7.52–7.43(m,1H),7.38(d,J=2.7Hz,1H),7.11(d,J=7.5Hz,1H),6.90(dd,J=9.2,2.5Hz,1H),6.81(d,J=8.6Hz,1H),4.98(s,2H),2.48(s,3H),1.23–1.00(m,5H).LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1.
实施例28
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)-5-甲基烟酸(化合物28)
按照实施例22的方法,通过用6-氯-5-甲基烟酸甲酯代替22A-2得到标题化合物28。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J=2.3Hz,1H),8.19(d,J=2.3Hz,1H),7.64(d,J=8.3Hz,1H),7.61–7.55(m,3H),7.53–7.44(m,2H),7.38(d,J=2.7Hz,1H),7.11(d,J=7.5Hz,1H),6.88(dd,J=9.1,2.5Hz,1H),4.98(s,2H),2.47(s,3H),1.20–1.08(m,5H).LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
实施例29
制备6-((5-氯-6-((5-环丙基-3-(2,6-二氯苯基)-异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物29)
按照实施例32的方法,通过用6-溴-1-氯萘-2-醇代替32A-1获得标题化合物29。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.29(d,J=8.6Hz,1H),7.92(d,J=8.9Hz,1H),7.70(s,1H),7.65–7.46(m,4H),7.38(s,2H),7.17(d,J=8.5Hz,1H),5.09(s,2H),1.21–1.02(m,5H).LCMS(ESI):经计算为C29H19Cl3N2O5;[M+H]+:581.0,实测值:581.0。
实施例30
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)烟酸(化合物30)
按照实施例20的方法,通过用6-溴-2-氟萘-1-醇代替20A-1获得标题化合物30。
1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.4Hz,1H),8.31(dd,J=8.6,2.4Hz,1H),7.86(d,J=9.1Hz,1H),7.66(d,J=6.9Hz,1H),7.59(s,1H),7.56(dd,J=5.7,3.3Hz,1H),7.51(dd,J=9.0,7.1Hz,1H),7.46–7.39(m,2H),7.25(d,J=8.6Hz,1H),7.05(dd,J=9.2,2.4Hz,1H),5.02(s,2H),1.28–1.08(m,5H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例31
制备6-((7-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸(化合物31)
按照实施例1的方法,通过用萘-2,7-二醇代替1A-2获得标题化合物31。
1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.28(d,J=8.6Hz,1H),7.85(d,J=8.8Hz,1H),7.77(d,J=9.0Hz,1H),7.58(d,J=8.1Hz,2H),7.55–7.43(m,2H),7.27(s,1H),7.13(t,J=9.9Hz,2H),6.89(d,J=8.9Hz,1H),4.95(s,2H),1.29–1.06(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例32
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-5-氟萘-2-基)氧基)烟酸(化合物32)
(a)参考以下反应方程式(方法B),将化合物32A-1(1.0g,4.15mmol,1当量),化合物1A-1(1.44g,4.15mmol,1当量)和碳酸铯(2.70g,8.30mmol,2当量)溶解在DMF(10ml)中,在65℃下反应2小时。冷却后,加入10ml水和10ml EA(乙酸乙酯)萃取,有机相用水洗涤并浓缩至干,得到化合物32A,4-(((6-溴-1-氟萘-2-基)氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑,1.51g,收率:71.9%。LCMS(ESI):经计算为C23H15BrCl2FNO2;[M+H]+:506.0,实测值:506.0。
(b)参照以下反应方程式,将化合物32A(200mg,0.39mmol,1当量)溶解在无水THF(2ml)中,然后在N2下添加KOAc(76mg,0.78mmol,2当量),Pd(dppf)2Cl2(28mg,0.039mmol,0.1当量)和双(频哪醇)二硼(100mg,0.39mmol,1当量),并将反应混合物加热至回流2h。冷却后,加入10ml水和10ml EA进行萃取,有机相用水洗涤并浓缩至干。残余物通过硅胶柱色谱法纯化(石油:AcOEt=3:1),得到化合物32B,5-环丙基-3-(2,6-二氯苯基)-4-((((1-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-2-基)氧基)甲基)异噁唑137mg,收率:62.8%。LCMS(ESI):经计算为C29H27BCl2FNO4;[M+H]+:554.1,实测值:554.1。
(c)参考下面的反应方程式,将化合物32B(100mg)溶解在EtOH(2ml)中,然后加入30%H2O2水溶液(1ml)。将反应混合物在室温搅拌1h,用饱和Na2SO3水溶液淬灭,并用EA萃取。浓缩有机相,并在柱上纯化(PE/EA=3/1),得到化合物32C(61mg,收率:76.2%)。LCMS(ESI):经计算为C23H16Cl2FNO3;[M+H]+:444.1,实测值:444.1。
(d)参考以下反应方程式,将化合物32C(50mg,0.11mmol,1当量),1A-3(24.3mg,0.11mmol,1当量)和碳酸铯(71.5mg,0.22mmol,2当量)溶解在DMF(1ml)中,在65℃下反应2小时。冷却后,加入5ml水和5ml EA进行萃取,并将有机相用水洗涤并浓缩至干,得到40mg化合物32D,收率:61.5%。LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
(e)参考以下反应方程式,将化合物32D(30mg)溶于MeOH(1ml)中,然后在N2下加入10%NaOH水溶液(0.5ml),并将反应混合物加热至回流1小时。通过加入1N HCl溶液将反应溶液的pH调节至3至4,并加入5ml EA进行萃取。浓缩有机相,并在柱上纯化(PE/EA/AcOH=1/1/0.01洗脱),得到标题化合物32(21mg,收率:71.7%)。
1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.3Hz,1H),8.31(dd,J=8.6,2.4Hz,1H),7.86(d,J=9.1Hz,1H),7.62(d,J=5.3Hz,1H),7.59(s,1H),7.56(dd,J=5.7,3.3Hz,1H),7.51(dd,J=9.0,7.1Hz,1H),7.46–7.40(m,2H),7.25(d,J=8.6Hz,1H),7.06(dd,J=5.7,4.3Hz,1H),5.02(s,2H),1.26–1.09(m,5H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例33
制备6-((6-((5-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸钠
在室温下,将NaOH水溶液(30%,1.44g,1.2当量)加入到化合物1(4.99g,9.12mmol)的EtOH溶液中。将反应混合物加热回流6小时后,将其冷却至室温。过滤收集固体,用EtOH(10ml)洗涤,干燥,得到灰色固体(4.07g,收率:78.3%)。
实施例34
制备6-((6-((5-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸钙
向化合物35(1.00g,1.76mmol)的水(10ml)溶液中加入CaCl2(1.0g,20%)的水溶液,形成白色沉淀。将反应混合物在室温下搅拌。保持4小时,过滤收集固体,用水(2.0ml)洗涤,得到白色固体产物(0.80g,76.7%)。
实施例35
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)烟酸
按照实施例22的方法,根据路线D制备标题化合物35。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.29–8.24(m,1H),8.15–8.10(m,1H),7.67(d,J=9.1Hz,1H),7.64–7.56(m,3H),7.53–7.47(m,1H),7.47–7.42(m,1H),7.36(d,J=2.6Hz,1H),7.22–7.17(m,1H),7.06(d,J=7.4Hz,1H),6.92–6.87(m,1H),4.98(s,2H),1.24–1.08(m,5H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例36
制备6-((5-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)烟酸
按照实施例32的方法,根据路线B制备标题化合物36。1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),8.65(d,J=2.4Hz,1H),8.29(dd,J=8.6,2.4Hz,1H),7.77(d,J=9.1Hz,1H),7.65–7.54(m,3H),7.51–7.44(m,1H),7.44–7.34(m,2H),7.19(dd,J=9.2,2.4Hz,1H),7.14(d,J=8.7Hz,1H),7.01(d,J=7.4Hz,1H),5.09(s,2H),1.31–1.07(m,6H).LCMS(ESI):经计算为C29H20Cl2N2O5;[M+H]+:547.1,实测值:547.1。
实施例37
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-5-氟萘-2-基)氧基)-2-甲基烟酸
按照实施例32的方法,根据路线B制备标题化合物37。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),8.24(d,J=8.6Hz,1H),7.91(d,J=9.1Hz,1H),7.68(s,1H),7.62(d,J=9.1Hz,1H),7.58(d,J=7.9Hz,2H),7.55–7.51(m,1H),7.43-7.34(m,2H),6.92(d,J=8.6Hz,1H),5.09(s,2H),2.52(s,3H),1.19–1.08(m,4H).LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
实施例38
制备6-(((7-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-8-氟萘-2-基)氧基)烟酸
按照实施例32的方法,根据路线B制备标题化合物38。1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.30(dd,J=8.7,2.4Hz,1H),7.96(d,J=8.9Hz,1H),7.70(d,J=9.0Hz,1H),7.64–7.48(m,3H),7.37(t,J=8.8Hz,1H),7.27(d,J=9.2Hz,1H),7.19(d,J=8.6Hz,1H),6.85(s,1H),5.10(s,2H),2.07–1.89(m,1H),0.94–0.76(m,4H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例39
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-5-氟萘-1-基)氧基)-2-甲基烟酸
按照实施例32的方法,根据路线B制备标题化合物39。1H NMR(400MHz,CDCl3)δ7.94(dd,J=7.9,5.0Hz,1H),7.83(d,J=8.1Hz,1H),7.72–7.59(m,2H),7.58–7.49(m,2H),7.49–7.38(m,2H),7.25–6.97(m,1H),6.67(d,J=7.9Hz,1H),5.52(d,J=16.9Hz,1H),5.24(d,J=16.9Hz,1H),2.70-2.96(M,1H),2.61(s,3H),1.05–0.89(m,4H).LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
实施例40
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)-5-甲基吡啶甲酸
按照实施例22的方法,根据路线D制备标题化合物40。1H NMR(400MHz,CDCl3)δ8.34(d,J=8.5Hz,1H),7.79(d,J=8.2Hz,1H),7.65–7.55(m,2H),7.54–7.49(m,2H),7.50–7.40(m,2H),7.22(t,J=2.3Hz,1H),7.03–6.93(m,2H),5.44(s,2H),2.95–2.58(m,1H),2.22(s,3H),1.01(m,4H).LCMS(ESI):经计算为C30H22Cl2N2O5;[M+H]+:561.1,实测值:561.1。
实施例41
制备6-((2,4-二氯-6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)烟酸
按照实施例20的方法,根据路线C制备标题化合物41。1H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.66(d,J=2.4Hz,1H),8.34(dd,J=8.6,2.4Hz,1H),7.84–7.78(m,2H),7.70–7.65(m,2H),7.64–7.56(m,2H),7.38(dd,J=9.1,2.3Hz,1H),7.24(d,J=8.6Hz,1H),4.92(s,2H),2.45–2.41(m,1H),1.22–1.10(m,4H).LCMS(ESI):经计算为C29H18Cl4N2O5;[M+H]+:615.0,实测值:615.0。
实施例42
制备6-((2-氯-6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)烟酸
按照实施例20的方法,根据路线C制备标题化合物42。1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.65(d,J=2.4Hz,1H),8.31(dd,J=8.6,2.4Hz,1H),7.76(d,J=2.4Hz,1H),7.70(d,J=8.8Hz,3H),7.66–7.59(m,1H),7.51(d,J=8.8Hz,1H),7.44(d,J=9.1Hz,1H),7.22(dd,J=9.1,2.4Hz,1H),7.19(d,J=8.6Hz,1H),4.87(s,2H),2.46-2.40(m,1H),1.30–1.09(m,4H).LCMS(ESI):经计算为C29H19Cl3N2O5;[M+H]+:581.0,实测值:581.0。
实施例43
制备6-((1-氯-6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-2-基)氧基)-2-甲基烟酸
按照实施例20的方法,根据路线C制备标题化合物43。1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),8.24(d,J=8.6Hz,1H),8.00(d,J=9.2Hz,1H),7.80(d,J=8.9Hz,1H),7.60(d,J=8.0Hz,2H),7.55–7.49(m,1H),7.47(s,1H),7.43(d,J=8.8Hz,1H),7.12(dd,J=9.2,2.5Hz,1H),6.95(d,J=8.6Hz,1H),5.02(s,2H),2.47(s,3H),1.23–1.11(m,5H).LCMS(ESI):经计算为C30H21Cl3N2O5;[M+H]+:595.1,实测值:595.1。
实施例44
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)-4-氟苯甲酸
按照实施例20的方法,根据路线C制备标题化合物44。1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),7.82(t,J=8.6Hz,1H),7.71(d,J=9.2Hz,1H),7.57(d,J=7.8Hz,2H),7.52–7.46(m,1H),7.39(d,J=2.4Hz,1H),7.37–7.31(m,1H),7.15-7.10(m,1H),7.01(dd,J=9.3,2.4Hz,1H),6.88(dd,J=12.3,2.4Hz,1H),6.73(dd,J=8.7,2.3Hz,1H),5.08(s,2H),1.28–1.05(m,4H).LCMS(ESI):经计算为C30H19Cl2F2NO5;[M+H]+:582.1,实测值:582.1。
实施例45
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)-2-甲基烟酸
按照实施例20的方法,根据路线C制备标题化合物45。1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),8.21(d,J=8.6Hz,1H),7.65(dd,J=9.3,1.7Hz,1H),7.57(d,J=7.7Hz,2H),7.51–7.44(m,1H),7.37(d,J=2.5Hz,1H),7.35–7.29(m,1H),7.16–7.11(m,1H),6.98(dd,J=9.2,2.5Hz,1H),6.87(d,J=8.5Hz,1H),5.08(s,2H),1.22–1.09(m,4H).LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
实施例46
制备6-((2-氯-6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)萘-1-基)氧基)-2-甲基烟酸
按照实施例20的方法,根据路线C制备标题化合物46。1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),8.25(d,J=8.6Hz,1H),7.76(d,J=9.2Hz,1H),7.69(d,J=8.2Hz,1H),7.58(d,J=8.0Hz,2H),7.50(d,J=8.1Hz,1H),7.49–7.44(m,1H),7.18(d,J=8.2Hz,1H),7.04(dd,J=9.2,2.4Hz,1H),6.95(d,J=8.6Hz,1H),5.13(s,2H),2.59-2.54(m,1H),2.48(s,3H),1.27–1.15(m,4H).LCMS(ESI):经计算为C30H21Cl3N2O5;[M+H]+:595.1,实测值:595.1。
实施例47
制备6-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)-5-甲基烟酸
按照实施例20的方法,根据路线C制备标题化合物47。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.32(s,1H),8.21(s,1H),7.67–7.55(m,3H),7.55–7.45(m,1H),7.39(s,1H),7.37–7.30(m,1H),7.20–7.09(m,1H),7.03–6.93(m,1H),5.09(s,2H),2.48(s,3H),1.41–1.00(m,5H).LCMS(ESI):经计算为C30H21Cl2FN2O5;[M+H]+:579.1,实测值:579.1。
实施例48
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)烟酸
按照实施例20的方法,根据路线C制备标题化合物48。1H NMR(400MHz,DMSO-d6)δ8.29–8.27(m,1H),8.22(d,J=8.5Hz,1H),8.09–8.06(m,1H),7.53–7.47(m,3H),7.46–7.42(m,1H),7.30–7.25(m,2H),7.08–7.05(m,1H),6.96(dd,J=8.4,2.4Hz,1H),5.44(s,2H),2.79(p,J=6.4Hz,1H),1.20–1.09(m,5H).LCMS(ESI):经计算为C29H19Cl2FN2O5;[M+H]+:565.1,实测值:565.1。
实施例49
制备2-((6-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)-2-氟萘-1-基)氧基)-4-氟苯甲酸
按照实施例22的方法,根据路线D制备标题化合物49。1H NMR(400MHz,DMSO-d6)δ13.62(s,1H),7.84(d,J=9.2Hz,1H),7.63–7.55(m,3H),7.54–7.49(m,1H),7.42(t,J=7.9Hz,1H),7.40-7.32(m,2H),7.06(t,J=8.8Hz,1H),6.96(dd,J=9.1,2.5Hz,1H),6.90(d,J=7.5Hz,1H),6.56(d,J=8.4Hz,1H),4.99(s,2H),1.23–1.09(m,4H).LCMS(ESI):经计算为C30H20Cl2FN2O5;[M+H]+:564.1,实测值:564.1。
生物学实施例
式(I)化合物在HBV细胞中的测定
PHH(原代人肝细胞)分析:细胞系和化合物治疗
将PHH细胞以1.32×105细胞/孔的密度接种到48孔板中。将PHH细胞的接种日期定义为第0天。在第1天以1600GE/细胞的HBV(D型)感染PHH细胞。在第2、4、6和8天更新包含化合物的培养基。第9天,将细胞用CCK8处理,并培养上清液并收集细胞。
在10000.0、3000.0、1000.0、300.0、100.0、30.0和10.0nM下测试化合物,在0.2000、0.0667、0.0222、0.0074、0.0025、0.0008和0.0003nM下测试恩替卡韦(ETV)。用1%DMSO作为非治疗对照。收集第9天的上清液,并通过qPCR分析HBV DNA,通过RT-qPCR分析HBVRNA,通过ELISA分析HBsAg和HBeA。
HBV
DNA、RNA和抗原测定
根据手册,使用QIAamp 96DNA血液试剂盒分离培养上清液中的DNA,并通过qPCR进行定量。用80μl的培养上清液样品提取DNA。洗脱体积为120μl。将PCR混合物(8μl/孔)和样品(2μl/孔)或质粒标准品(2μl/孔)添加到384孔光学反应板中,并使用以下程序进行:95℃下10分钟,然后在95℃下15秒,60℃下1分钟循环40个循环。
根据手册,使用PureLinkTMPro 96病毒RNA试剂盒分离培养上清液中的RNA。将35μl的培养上清液样品提取RNA。洗脱体积为100μl。通过RT-qPCR定量HBV RNA。
对于HepG2-NTCP分析,根据手册,通过HBsAg ELISA试剂盒(Autobio)和HBeAgELISA试剂盒(Autobio)测量第9天收获的样品中的HBsAg和HBeAg。对于PHH分析,根据AntuHBsAg ELISA试剂盒手册,使用化学发光仪测量HBsAg。
在最后一天收集每个板的培养上清液后,将CCK-8工作溶液(用新鲜培养基以1:9的比例稀释)添加到细胞板上。将板在37℃,5%CO2的培养箱中孵育约30分钟。用酶标仪(OD450nm/OD630nm)测量OD。
剂量反应曲线
HBV DNA抑制百分比=(测试样品的1-HBV DNA拷贝数/平均1%DMSO对照的HBVDNA拷贝数)×100%
HBV RNA抑制百分比=(1-样品的1-HBV RNA拷贝数/1%DMSO对照的平均HBV RNA拷贝数)×100%
HBsAg抑制百分比=(1-样品的HBsAg量/1%DMSO对照的HBsAg量)×100%
细胞活力%=样品值/1%DMSO值×100%。
EC50和CC50值由GraphPad Prism使用“对数(激动剂)对响应-可变斜率”拟合的剂量-响应曲线确定。
结果分析
如图1、2、3所示,其中图1是PHH细胞中抑制HBV DNA的EC50曲线;图2是PHH细胞中HBsAg抑制的EC50曲线;图3是PHH细胞中HBV RNA抑制的EC50曲线。在PHH分析中,化合物1、22和27对细胞外HBV DNA HBsAg和HBV RNA具有剂量依赖性抑制作用。作为对照,ETV表现出对HBV DNA的显著抑制,但对HBV HBsAg和HBV RNA无显著抑制。
式(I)化合物在AAV/HBV小鼠模型中的药效
AAV/HBV小鼠模型和药物治疗
雄性C57BL/6小鼠,5周龄,无特定病原体,购于上海吉辉实验动物饲养有限公司。第-28天,小鼠(C57BL/6,雄性)经尾静脉注射rAAV8-1.3HBV病毒1×1011v.g.,用于建立HBV感染模型。
病毒注射后第14天和第21天,及给药前第-4天,实验小鼠通过颌下静脉采血。收集的血样用K2-EDTA抗凝,在4℃,7000g/分钟条件下离心10分钟并收集血浆。血浆保存于-80℃,用于HBV DNA、HBsAg检测,确定建模成功。
病毒注射后第28天,根据病毒注射后第14天和第21天,给药前第-4天血清样品的测试结果,选择40只小鼠进入给药实验,将小鼠随机分组。
病毒注射后第28天,所有小鼠开始口服给药,每天1次,持续4周;其中组1给与溶媒(0.5%CMC-Na,10ml/kg),组2给与阳性对照药物ETV 0.1mg/kg(28天),组3、组4、组5给与化合物33,分别为10mg/kg、30mg/kg和60mg/kg。
给药前所有小鼠颌下采血收集血清,用于检测HBV DNA和HBsAg。
给药后第0至21天所有小鼠颌下采血用于收集血清,每周1次。血清用于检测HBVDNA、HBV RNA和HBsAg。
第28天,心脏采血收集血浆用于检测HBV DNA、HBV RNA和HBsAg。
样品分析
定量PCR检测小鼠血浆HBV DNA含量。提取血浆中DNA,实验步骤参照QIAamp 96DNABlood Kit说明书,定量PCR检测小鼠血浆中HBV DNA的含量。反应条件:95℃,10分钟;95℃,15秒,60℃,1分钟,40个循环。
定量PCR检测小鼠血浆中HBV RNA含量。取20μl血浆样品提取血浆中核酸,实验步骤参照PureLinkTMPro 96Viral RNA/DNA Kit说明书。
ELISA检测小鼠血浆中HBsAg的含量。实验步骤参照HBsAg ELISA(安图生物,CL0310)试剂盒说明书。方法简述如下:将血浆样品稀释1200倍,加入包被板中,与酶结合物共同温育(37℃,60分钟),重复洗板5次,加入发光底物,室温避光反应10分钟,用酶标仪检测发光强度。
数据分析
数据用每组小鼠样品的平均值±标准误表示,除特别说明外,n=8。用Student’st-test进行统计分析。
结果分析
如图4所示,连续给药28天后,与溶剂组相比,化合物33高剂量组(60mg/kg)降低小鼠血浆HBV DNA平均0.77–1.12log10[拷贝/μl](p<0.05)。
如图5所示,连续给药28天后,与溶剂组相比,化合物33高剂量组(60mpk)平均降低小鼠血清HBV RNA 0.60–0.66log10[拷贝/ul](p<0.01)。ETV治疗组对HBV RNA无显著抑制作用。
如图6所示,连续给药28天后,与溶剂组相比,化合物33高剂量组(60mpk)对小鼠血清HBsAg平均降低0.38log10[IU/mL](p<0.05)。ETV治疗组对HBsAg无显著抑制作用。
Claims (13)
1.具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体在制备抗乙肝病毒药物中的应用,
其中:
R1、R2和R3各自独立地选自H、卤素、未取代或卤素取代的C1-6烷基和未取代或卤素取代的C1-6烷氧基,条件是R1、R2和R3中的至少一个不是氢,R0选自未取代或卤素取代的C1-6烷基、C3-6环烷基和C4-7烷基环烷基;
X1和X2独立地选自H和卤素;
-O-Z基团连接到萘环上,其中Z选自5-10元芳基或含有一个或多个选自N、O和S的杂原子的5-10元杂芳基,其中所述5-10元芳基或5-10元杂芳基被R4取代并且任选地进一步被R5取代;
其中R4选自-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1-6烷基、-SO3H、-CONHSO2-C1-6烷基、-CONHSO2-C3-6环烷基、-CONHSO2-5-10元芳基和芳基上被C1-6烷基取代的-CONHSO2-5-10元芳基;并且其中R5选自H、C1-6烷基、卤素、C1-6卤代烷基、-O-(C1-6烷基)和-NH-(C1-6烷基)。
2.根据权利要求1所述的应用,其中,R1、R2和R3各自独立地选自H、卤素和C1-3全氟烷氧基,并且R0为异丙基或环丙基,优选地,R1、R2和R3各自独立地选自H、Cl、F和–O–CF3;进一步优选地,R1和R2均为Cl,并且R3为H、F或–O–CF3,或者R1为–O–CF3,且R2和R3均为H;
优选地,所述卤素是氟或氯。
3.根据权利要求1所述的应用,其中,Z为苯基,其被R4取代并且任选地被R5取代;或者Z是具有选自N、O和S中的一个或多个杂原子的5-10元杂芳基,其被R4取代并且任选地被R5取代;
优选地,Z是具有选自N、O和S中的一个或多个杂原子的5-6元杂芳基,其被R4取代并且任选地被R5取代;进一步优选地,Z是被R4和任选地R5取代的吡啶基;
优选地,R4选自-COOH、-CH2COOH、-CONHSO2-C1-6烷基和-CONHSO2-C3-6环烷基中的一种,进一步优选地,R4为-COOH或-CH2COOH,进一步优选地,R4为-COOH;R5选自H、C1-3烷基和卤素中的一种;
优选地,Z为吡啶基;R4为-COOH;并且R5为H或卤素。
5.根据权利要求1所述的应用,其中,所述应用包括将所述具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物、其药学上可接受的盐、酯或立体异构体与一种或多种其它抗乙肝病毒剂组合使用。
6.根据权利要求5所述的应用,其中,所述其它抗乙肝病毒剂选自HBV疫苗、HBV DNA聚合酶抑制剂、免疫调节剂、TOLL样受体调节剂、干扰素α受体配体、乙型肝炎表面抗原抑制剂、亲环蛋白抑制剂、HBV病毒进入抑制剂、靶向病毒mRNA的反义寡核苷酸、短干扰RNA和ddRNAi核酸内切酶调节剂、核糖核酸核苷酸还原酶抑制剂、HBV E抗原抑制剂、共价闭合环状DNA抑制剂、脂肪酸合成酶抑制剂、HBV抗体、CCR2趋化因子拮抗剂、视黄酸诱导基因1激动剂、NOD2激动剂、PD-1抑制剂、PD-L1抑制剂、KDM抑制剂和HBV复制抑制剂中的一种或多种。
7.根据权利要求6所述的应用,其中,所述HBV DNA聚合酶抑制剂为恩替卡韦和/或替诺福韦;
所述PD-1抑制剂选自纳武利尤单抗、派姆单抗、皮立珠单抗、BGB-108、卡瑞利珠单抗、PDR-001、萨善利单抗、IBI-308、测米匹单抗、坎立珠单抗、斯迪利单抗、缇勒珠单抗、BCD-100、西利单抗、Zimberelimab、Balstilimab和多斯利单抗中的一种或多种;
所述PD-L1抑制剂选自阿特珠单抗、艾维路单抗、BGB-A333、德瓦鲁单抗、CX-072、GX-P2、恩沃利单抗、GS-4224和INCB086550;
所述脂肪酸合成酶抑制剂为TVB-2640和/或TVB-3567;
所述干扰素为派罗欣;
所述反义寡核苷酸为Ionis-HBVRx和/或Ionis-HBV-LRx;
所述短干扰RNA选自JNJ-3989、Vir-2218和DCR-HBVS中的一种或多种;
所述衣壳抑制剂选自ABI-H0731、ABI-H2158、ABI-H3733、CB-HBV-001、JNJ-6379、JNJ-0440、QL-007、RG-7907和RO7049389中的一种或多种,
优选地,所述其它抗HBV剂选自恩替卡韦、替诺福韦、恩沃利单抗和派罗欣中的一种或多种。
8.一种治疗或预防乙型肝炎的药物组合物,其包含治疗有效量的具有式(I)结构的苯基异噁唑基亚甲基-萘-醚衍生物或其药学上可接受的盐、酯或立体异构体和一种或多种其它抗乙肝病毒剂,以及药学上可接受的辅料,
其中:
R1、R2和R3各自独立地选自H、卤素、未取代或卤素取代的C1-6烷基和未取代或卤素取代的C1-6烷氧基,条件是R1、R2和R3中的至少一个不是氢,R0选自未取代或卤素取代的C1-6烷基、C3-6环烷基和C4-7烷基环烷基;
X1和X2独立地选自H和卤素;
-O-Z基团连接到萘环上,其中Z选自5-10元芳基或含有一个或多个选自N、O和S的杂原子的5-10元杂芳基,其中所述5-10元芳基或5-10元杂芳基被R4取代并且任选地进一步被R5取代;
其中R4选自-COOH、-CH2COOH、-NHSO2CF3、-SO2NH-C1-6烷基、-SO3H、-CONHSO2-C1-6烷基、-CONHSO2-C3-6环烷基、-CONHSO2-5-10元芳基和芳基上被C1-6烷基取代的-CONHSO2-5-10元芳基;并且其中R5选自H、C1-6烷基、卤素、C1-6卤代烷基、-O-(C1-6烷基)和-NH-(C1-6烷基)。
9.根据权利要求8所述的药物组合物,其中,R1、R2和R3各自独立地选自H、卤素和C1-3全氟烷氧基,并且R0为异丙基或环丙基,优选地,R1、R2和R3各自独立地选自H、Cl、F和–O–CF3;进一步优选地,R1和R2均为Cl,并且R3为H、F或–O–CF3,或者R1为–O–CF3,且R2和R3均为H;
优选地,所述卤素是氟或氯。
10.根据权利要求8所述的药物组合物,其中,Z为苯基,其被R4取代并且任选地被R5取代;或者Z是具有选自N、O和S中的一个或多个杂原子的5-10元杂芳基,其被R4取代并且任选地被R5取代;
优选地,Z是具有选自N、O和S中的一个或多个杂原子的5-6元杂芳基,其被R4取代并且任选地被R5取代;进一步优选地,Z是被R4和任选地R5取代的吡啶基;
优选地,R4选自-COOH、-CH2COOH、-CONHSO2-C1-6烷基和-CONHSO2-C3-6环烷基中的一种,进一步优选地,R4为-COOH或-CH2COOH,进一步优选地,R4为-COOH;R5选自H、C1-3烷基和卤素中的一种;
优选地,Z为吡啶基;R4为-COOH;并且R5为H或卤素。
12.根据权利要求8所述的药物组合物,其中,所述其它抗乙肝病毒剂选自HBV疫苗、HBVDNA聚合酶抑制剂、免疫调节剂、TOLL样受体调节剂、干扰素α受体配体、乙型肝炎表面抗原抑制剂、亲环蛋白抑制剂、HBV病毒进入抑制剂、靶向病毒mRNA的反义寡核苷酸、短干扰RNA和ddRNAi核酸内切酶调节剂、核糖核酸核苷酸还原酶抑制剂、HBV E抗原抑制剂、共价闭合环状DNA抑制剂、脂肪酸合成酶抑制剂、HBV抗体、CCR2趋化因子拮抗剂、视黄酸诱导基因1激动剂、NOD2激动剂、PD-1抑制剂、PD-L1抑制剂、KDM抑制剂和HBV复制抑制剂中的一种或多种。
13.根据权利要求12所述的药物组合物,其中,所述HBV DNA聚合酶抑制剂为恩替卡韦和/或替诺福韦;
所述PD-1抑制剂选自纳武利尤单抗、派姆单抗、皮立珠单抗、BGB-108、卡瑞利珠单抗、PDR-001、萨善利单抗、IBI-308、测米匹单抗、坎立珠单抗、斯迪利单抗、缇勒珠单抗、BCD-100、西利单抗、Zimberelimab、Balstilimab和多斯利单抗中的一种或多种;
所述PD-L1抑制剂选自阿特珠单抗、艾维路单抗、BGB-A333、德瓦鲁单抗、CX-072、GX-P2、恩沃利单抗、GS-4224和INCB086550;
所述脂肪酸合成酶抑制剂为TVB-2640和/或TVB-3567;
所述干扰素为派罗欣;
所述反义寡核苷酸为Ionis-HBVRx和/或Ionis-HBV-LRx;
所述短干扰RNA选自JNJ-3989、Vir-2218和DCR-HBVS中的一种或多种;
所述衣壳抑制剂选自ABI-H0731、ABI-H2158、ABI-H3733、CB-HBV-001、JNJ-6379、JNJ-0440、QL-007、RG-7907和RO7049389中的一种或多种,
优选地,所述其它抗HBV剂选自恩替卡韦、替诺福韦、恩沃利单抗和派罗欣中的一种或多种。
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