CN112898289A - 调节fxr活性的化合物及其应用 - Google Patents
调节fxr活性的化合物及其应用 Download PDFInfo
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- CN112898289A CN112898289A CN202011084166.8A CN202011084166A CN112898289A CN 112898289 A CN112898289 A CN 112898289A CN 202011084166 A CN202011084166 A CN 202011084166A CN 112898289 A CN112898289 A CN 112898289A
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Abstract
Description
技术领域
本发明涉及与FXR介导的疾病相关的药物领域。具体地,本发明涉及用于调节FXR活性的化合物及其制备方法和制药用途。
背景技术
法尼醇X受体(FXR)是核激素受体超家族中的一员,主要在肝脏、肾脏和肠中表达。它以与维甲酸X受体(RXR)的异源二聚体的形式发挥作用,与靶基因启动子中的应答元件结合来调节基因转录。FXR-RXR异源二聚体以最高亲合力与反向重复-1(IR-1)应答元件结合,其中结合共有受体(consensus receptor)的六聚物被一个核苷酸分开。FXR是相互关联的过程的一部分,其中FXR被胆汁酸(胆固醇代谢的终产物)激活,所述的胆汁酸用于抑制胆固醇的分解代谢。
FXR是胆固醇动态平衡、甘油三酯合成以及脂肪生成的关键调节子(Crawley,Expert Opinion Ther.Patents(2010),20(8):1047-1057)。除了治疗血脂异常、肥胖、维生素D-相关疾病、肠道疾病、药物导致的副作用以及肝炎外,FXR相关的适应症还包括肝胆疾病、慢性肝炎、非酒精性脂肪肝(NAFLD)、非酒精性脂肪性肝炎(NASh)、胆汁淤积、肝纤维化、肝硬化、乙型肝炎、代谢性疾病、脂代谢疾病、碳水化合物代谢疾病、心血管代谢疾病、动脉粥样硬化、II型糖尿病和糖尿病并发症。
已经开发了多种能够充当FXR调节剂(或称作FXR-激动剂)的化合物,例如WO200037077、WO2003/015771、WO2004/048349、WO2007/076260、WO2007/092751、WO2007/140174、WO2007/140183、WO2008/051942、WO2008/157270、WO2009/005998、WO2009/012125、WO2009/149795、WO2008/025539、WO2008/025540、WO2012/087520、WO2012/087521、WO2012/087519、WO2013/和WO2015/036442中公开的那些小分子FXR调节剂。
虽然在开发新型FXR激动剂方面取得了进展,但仍存在很大的改进空间。
发明内容
因此,本发明的目的是提供用于调节FXR活性的新化合物及其制备方法和制药用途,其表现出优于已知的FXR激动剂的物理化学,体外和/或体内ADME(吸收、分布、代谢和***)性质和/或体内优异的药代动力学。
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“治疗有效量”是指足以达到所述治疗效果的式(I)化合物的量。因此,用于治疗由FXR介导的病症的式(I)化合物的治疗有效量将足以用于治疗由FXR介导的病症。
一方面,本发明提供了具有式(I)结构的用于调节FXR活性的化合物、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)的化合物具有以下结构中的一种:
在另一方面,本发明提供了一种制备式(I)的化合物、其药学上可接受的盐、酯或立体异构体的方法,该方法包括四种通用路线(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)。
另一方面,本发明还提供了一种药物组合物,其包含作为活性成分的至少一种式(I)化合物或其前药化合物或其药学上可接受的盐、酯或立体异构体,以及药学上可接受的辅料。
本发明的药物组合物还可以另外包含作为活性成分的一种或多种其它化合物,例如前药化合物或其它的核受体调节剂。
尽管在特定的情况下最合适的给药方法依赖于所治疗疾病的性质和严重程度以及活性成分的性质,但所述药物组合物适于经口、经直肠、经局部、经胃肠外(包括皮下、肌注和静脉内)、经眼、经肺(鼻或口腔吸入)或经鼻给药。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公知的任何方法制备。
在体外结合测定法和细胞测定法进行测试时,式(I)化合物及其药学上可接受的盐表现出有价值的药理活性,因此可用作药物。特别地,本发明的化合物是FXR激动剂,并且可用作药物来治疗FXR介导的疾病,例如非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、胆汁淤积性肝病、慢性肝病、丙型肝炎、酒精性肝病、肝纤维化、原发性硬化性胆管炎(PSC)、胆结石、胆管闭锁、下尿路症状和良性***增生(BPH)、输尿管结石、肥胖症、2型糖尿病、动脉粥样硬化、动脉粥样硬化、高胆固醇血症和高脂血症引起的肝损害。本发明的化合物还可用于降低总胆固醇、降低LDL胆固醇、降低VLDL胆固醇、提高HDL水平和/或降低甘油三酯水平。
本发明还提供了式(I)化合物的药学上可接受的盐,酯或立体异构体以及任选地与第二治疗剂组合在制备用于治疗FXR介导的疾病的药物中的用途。所述第二治疗剂用于治疗例如非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、胆汁淤积性肝病、慢性肝病、丙型肝炎感染、酒精性肝病、肝纤维化、原发性硬化性胆管炎(PSC)、胆结石、胆管闭锁、下尿路症状和良性***增生(BPH)、输尿管结石、肥胖、2型糖尿病、动脉粥样硬化、动脉粥样硬化、高胆固醇血症或高脂血症引起的肝损害。
除非另有说明,术语“本发明的化合物”是指式(I)的化合物、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。
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显示了在STZ+DEN+HFD(streptozocin+diethylnitrosamine+high fat diet)小鼠疾病模型中化合物1治疗后NAS(Nonalcoholic Fatty Liver Disease ActivityScore,非酒精性脂肪性肝病活动评分)评分的降低。
图2显示了在STZ+DEN+HFD小鼠疾病模型中化合物1治疗后肝纤维化的减少。
图3显示了在DEN+HFD+CHOL(diethylnitrosamine+high fat diet+cholesterol/cholate)大鼠中,化合物1治疗后NAS评分的降低。
图4显示在DEN+HFD+CHOL大鼠中,化合物1治疗后肝纤维化的减少。
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(路线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(路线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
实施例A:FXR激动剂结合能力
通过使用时间分辨分析技术,就FXR与其共刺激因子SRC-1的结合,评价本发明化合物的活化效果。结果列于表1。
实验材料
1.蛋白:谷胱甘肽-S-转移酶(GST)标记的人FXR蛋白(Invitrogen)
2.共激活剂:荧光素标记的类固醇受体共激活剂(SRC2-2)(Invitrogen)
3.检测试剂:LanthaScreen时间分辨荧光分析试剂盒(Invitrogen)
实验方法
1.将化合物制成10mM的DMSO储液,并在-20℃冰箱中长时间保存。
2.实验前将化合物稀释至1mM,然后用DMSO将化合物稀释3倍至10个浓度点。然后,使用转录辅助调节因子缓冲液G(Invitrogen,PV4553)将这10个浓度点稀释50倍,成为工作液。向384孔板的每个孔中加入10μl每种工作液。
3.在冷却的缓冲液G中制备人FXR蛋白溶液(终浓度20nM),并将5μl人FXR蛋白溶液添加到384孔板的每个孔中。
4.准备含有2μM荧光素标记的类固醇受体共激活剂和20nM GST抗体的缓冲液G的混合物。
5.将5μl步骤4中制备的混合物添加到384孔板中。
6.以1000g离心384孔板1分钟。
7.在黑暗中于室温下孵育1小时。
8.在Envision 2104读板器上在520和495nm处读取384孔板。
9.计算化合物活化作用的EC50值。
实施例B:FXR激动剂反式激活能力
通过使用萤光素酶报告基因表达技术来评价本发明化合物促进FXR反式激活的能力。结果列于表1。
实验材料
1.细胞系:HEK293T(Invitrogen)
2.表达质粒:pBIND-hFXR-LBD-GAL4(Promega),pGL4.35-荧光素酶(Promega)
3.细胞培养基:含10%血清和青霉素/链霉素双重抗体的DMEM培养基
4.检测试剂:Steady-Glo荧光检测***(Promega)。
5.转染试剂:TransIT-293转染试剂(MIRUS BIO)
实验方法
1.将化合物制成10mM的DMSO储液,并在-20℃冰箱中长时间保存。
2.复苏HEK293T细胞以5.5×106的浓度接种在10cm培养皿中,并在5%CO2培养箱中于37℃孵育16小时。
3.转染前,将转染试剂恢复至室温。将Trans-IT溶液滴加到Opti-MEM中,并颠倒混合5分钟。加入表达质粒,通过倒置混合,并在室温下孵育20分钟。
4.将步骤3的转染混合物添加到步骤2准备的10cm培养皿中,并在5%CO2恒温箱中孵育5-6小时。
5.使用DMSO将化合物稀释3倍至10个浓度点;使用Echo 550声波移液器在384孔板中每孔添加25nl化合物;将HEK293T细胞以15,000个细胞/孔的浓度添加到384孔板中;在37℃下在5%CO2培养箱中孵育16-20小时。
6.向每个孔中添加25μl Steady-Glo荧光试剂,并在Envision 2104读板器上读取荧光数据。
7.计算化合物活化的EC50值。
表1:FXR激动剂结合活性值,按以下范围分组:A表示EC50<50nM;B表示50<EC50<500nM;C表示EC50>500nM。
表2:细胞活性值,按以下范围分组:A表示EC50<200nM;B表示500<EC50<1000nM;C表示EC50>1000nM。
实施例C:小鼠药代动力学研究
采用典型的药代动力学(PK)研究方法。在静脉给药的药代动力学(IV PK)研究中,对一组三只禁食的雄性CD-1小鼠给药所述化合物(2.0mg/kg,在5%生理盐水中的0.50mg/ml溶液,清液),并在0.0830、0.250、0.500、1.00、2.00、4.00、8.00、24.0小时收集0.02ml血液。在口服给药的药代动力学(PO PK)研究中,对一组三只禁食的雄性CD-1小鼠给药所述化合物(10mg/kg,在5%生理盐水中的1mg/ml溶液,清液),并在0.250、0.500、1.00、2.00、4.00、6.00、8.00、24.0小时收集0.02ml血液。将血液收集到EP(eppendorf)离心管中(含EDTA-K2 0.85-1.15mg),并在4℃下以3000g或3200g离心10分钟,分离血浆并分成两个小瓶。其中一瓶用于生物分析,另一瓶作为备用。将样品保持在-60℃或更低的温度,直到进行LC MS/MS分析。使用AB SCIEX INSTRUMENTS LC-MS/MS_AU-Triple Quad 6500Plus对样品进行分析,并用Phoenix WinNonlin 6.3(IV非房室模型和PO非房室模型)处理数据。
PK结果
表3显示了小鼠的药代动力学结果。
表3:小鼠药代动力学结果
实施例D
在雄性C57BL/6小鼠的STZ+DEN+HFD诱导的非酒精性脂肪性肝炎(NASH)模型中评估FXR化合物的治疗效果。
新生雄性C57BL/6小鼠在出生后第2周接受链脲佐星(STZ)注射,以引入糖尿病,在第4周接受二乙基亚硝胺(DEN)注射,以促进肝纤维化。既不接受STZ也不接受DEN的小鼠用作阴性对照(第1组,n=12),并接受正常饮食喂养。在第6周,选60只糖尿病小鼠(禁食6小时后血糖>12mmol/L),并喂以高脂饮食(HFD,饮食中含60kcal%脂肪)。在进行HFD一周后,根据体重将动物随机分为5组:第2组(n=12),疾病模型组,不进行化合物治疗;第3组(n=10),阳性对照组,接受OCA(奥贝胆酸)(30mg/kg)治疗;第4组(n=12),用化合物1(3mg/kg)治疗;第5组(n=12),用化合物1(10mg/kg)治疗;第6组(n=12),用化合物1(30mg/kg)治疗。OCA和化合物1为PO QD(口服,每日一次),持续7周。在最后一次给药后的第二天,将所有动物安乐死,并用***固定肝组织以进行病理评估。
图1显示了在STZ+DEN+HFD小鼠疾病模型中化合物1治疗后NAS(非酒精性脂肪性肝病活动评分)评分的降低。图2显示了在STZ+DEN+HFD小鼠疾病模型中化合物1治疗后肝纤维化的减少。
如图1所示,分别以低剂量(3mg/kg)、中剂量(10mg/kg)和高剂量(30mg/kg)给药化合物1时,肝细胞脂肪变性减少(剂量依赖性)(p<0.001)。与疾病模型组(第2组)相比,30mg/kg组的NAS评分降低了46.2%。阳性对照组(第3组,OCA 30mg/kg)也显示NAS评分降低。如图2所示,给药低剂量(3mg/kg)和高剂量(30mg/kg)的化合物1显著抑制了肝纤维化的进展,并且30mg/kg剂量组(第6组)将肝硬化百分比降低了15.2%。综上,以每天30mg/kg的剂量治疗7周后,化合物1使得NAS评分和肝纤维化明显降低。
实施例E
在雄性SD大鼠的DEN+HFD+CHOL诱导的NASH模型中评估FXR化合物的治疗效果。
新生雄性大鼠在出生后第2周接受DEN注射以形成NASH模型。阴性对照组(第1组,n=10)未注射DEN。在第4周,接受DEN注射的50只大鼠开始进行HFD+CHOL饮食(60kcal%脂肪+1.25%胆固醇+0.5%胆酸盐)持续8周,而阴性对照动物仍保持正常饮食。在第5周,根据体重将DEN治疗的大鼠随机分为5组(第2-6组):疾病组(第2组,n=10),未接受治疗;OCA组(第3组,n=10)接受30mg/kg的OCA;第4-6组(各n=10)分别以低剂量(3mg/kg)、中剂量(10mg/kg)和高剂量(30mg/kg)接受化合物1。给予OCA和化合物1PO QD,持续7周。在最后一次给药后的第二天,将所有动物安乐死,并用***固定肝组织以进行病理评估。
图3显示了在DEN+HFD+CHOL大鼠中,化合物1治疗后NAS评分的降低。图4显示在DEN+HFD+CHOL大鼠中,化合物1治疗后肝纤维化的减少。
如图3所示,分别以低剂量(3mg/kg)、中剂量(10mg/kg)和高剂量(30mg/kg)给药化合物1时,NAS评分呈剂量依赖性降低(所有p<0.001)。与模型组(第2组)相比,30mg/kg组的NAS得分降低了42.9%。阳性对照(OCA 30mg/kg)也显示NAS评分降低(p<0.001)。如图4所示,低剂量(3mg/kg)、中剂量(10mg/kg)和高剂量(30mg/kg)的化合物1给药均显着抑制了肝纤维化的进展(所有p<0.01)。30mg/kg组的治疗使肝硬化百分比降低了28.0%。
Claims (25)
1.具有式(I)结构的用于调节FXR活性的化合物、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)。
2.根据权利要求1所述的化合物,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。
3.根据权利要求2所述的化合物,其中,R1、R2和R3各自独立地选自H、Cl、F和–O–CF3。
4.根据权利要求1所述的化合物,其中,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。
5.根据权利要求1所述的化合物,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。
6.根据权利要求5所述的化合物,或者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。
7.根据权利要求1所述的化合物,其中,Z是被R4和任选地R5取代的吡啶基。
8.根据权利要求1所述的化合物,其中,R4选自-COOH、-CH2COOH、-CONHSO2-C1-6烷基和-CONHSO2-C3-6环烷基中的一种。
9.根据权利要求8所述的化合物,其中,R4为-COOH或-CH2COOH,优选地,R4为-COOH。
10.根据权利要求1所述的化合物,其中,R5选自H、C1-3烷基和卤素中的一种。
11.根据权利要求1所述的化合物,其中,Z为吡啶基;R4为-COOH;并且R5为H或卤素。
12.根据权利要求1所述的化合物,其中,所述卤素是氟或氯。
22.一种药物组合物,其包含治疗有效量的权利要求1-21中任一项所述的化合物或其药学上可接受的盐、酯或立体异构体,以及药学上可接受的辅料。
23.根据权利要求22所述的药物组合物,其中所述药物组合物还包含第二治疗剂,所述第二治疗剂用于治疗非酒精性脂肪肝疾病、非酒精性脂肪性肝炎、原发性胆汁性肝硬化、胆汁淤积性肝病、慢性肝病、丙型肝炎感染、酒精性肝病、肝纤维化、原发性硬化性胆管炎、胆结石、胆管闭锁、下尿路症状和良性***增生、输尿管结石、肥胖、2型糖尿病、动脉粥样硬化、动脉粥样硬化、高胆固醇血症或高脂血症引起的肝损害。
24.权利要求1-21中任一项的化合物或其药学上可接受的盐,酯或立体异构体,或权利要求22或23所述的药物组合物在制备用于治疗由FXR介导的疾病的药物中的用途。
25.根据权利要求24所述的用途,其中所述疾病为非酒精性脂肪肝疾病、非酒精性脂肪性肝炎、原发性胆汁性肝硬化、胆汁淤积性肝病、慢性肝病、丙型肝炎感染、酒精性肝病、肝纤维化、原发性硬化性胆管炎、胆结石、胆管闭锁、下尿路症状和良性***增生、输尿管结石、肥胖、2型糖尿病、动脉粥样硬化、动脉粥样硬化、高胆固醇血症或高脂血症引起的肝损害。
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