CN117285504A - 一种氨基苯乙酰胺类衍生物及其制备方法和应用 - Google Patents
一种氨基苯乙酰胺类衍生物及其制备方法和应用 Download PDFInfo
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- CN117285504A CN117285504A CN202311148331.5A CN202311148331A CN117285504A CN 117285504 A CN117285504 A CN 117285504A CN 202311148331 A CN202311148331 A CN 202311148331A CN 117285504 A CN117285504 A CN 117285504A
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Abstract
本发明公开一种氨基苯乙酰胺类衍生物及其制备方法，以及衍生物作为法尼醇X受体拮抗的独特用途。重点进行了体外的FXR拮抗活性研究、HepG2和L02细胞毒性研究、HepG2细胞油红O染色实验、HepG2细胞甘油三酯含量测试、体内抗非酒精性脂肪性肝炎活性研究。证实了本发明所述的化合物具有很强的法尼醇X受体拮抗活性，同时具有制备治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物的潜力。
Description
技术领域
本发明属于新药设计及合成领域，具体而言，涉及一种氨基苯乙酰胺类衍生物及其制备方法和应用。
技术背景
非酒精性脂肪性肝炎(Nonalcoholic steatohepatitis，NASH)，是一种代谢相关脂肪性肝病，是非酒精性脂肪性肝病(Nonalcoholic fatty liver disease，NAFLD)较为严重的形式，其病理表现为肝脏脂肪变性、肝细胞、气球样病变，并伴有炎症及损伤，严重者还可能出现肝纤维化等。NASH不加以控制可能进一步发展为肝硬化、肝衰竭，最终导致肝癌。目前，NAFLD在全球患病率高达25％，而NAFLD患者中约有15-20％为NASH患者。然而，目前市场上仍无有效的药物能预防和治疗NASH，因此，探索NASH的有效治疗药物具有广阔的应用前景。
法尼醇X受体(Farnesoid X receptor,FXR)也称为胆汁酸受体，属于核受体超家族的一员，主要广泛分布于肝脏、肠道、肾脏、胆囊等器官。FXR作为一种代谢的调节因子，在胆汁酸、胆固醇、脂质以及葡萄糖代谢中发挥着重要的作用，被认为是治疗NAFLD非常有潜力的靶点之一。迄今为止，FXR激动剂的研究较为成熟，多个化合物已处于临床前或临床研究阶段，其中最有代表性的是Intercept制药公司开发的甾体类FXR激动剂奥贝胆酸(Obeticholic Acid,OCA)，其于2016年5月被美国FDA 正式批准用于治疗原发性胆汁性肝管炎，也是目前唯一上市FXR激动剂。尽管目前已有多种FXR激动剂被发现，但几乎所有的FXR激动剂存在易发生瘙痒、提高低密度脂蛋白和降低高密度脂蛋白等缺点，大大的限制其在临床上的应用。近年来FXR拮抗剂的研究逐渐增多，FXR拮抗剂在改善代谢紊乱和肝脏相关疾病方面同样也表现出良好的作用(Li F，Nat Commun,2013,4:2384；Jiang CC.NatCommun,2015,6:10166.)。FXR拮抗剂不仅能够提高胆固醇7α-羟化酶(CYP7A1)的活性而降低总胆固醇含量，还能降低肝脏三酰甘油、低密度脂蛋白水平，减轻NAFLD的脂肪变性、炎症以及纤维化(Zhang,C.J Med Chem，2022，65:13452-13472；)。然而，目前已报道的大部分FXR拮抗剂都是天然产物或者内源性胆汁酸，例如没药甾酮(Gugggulsterone，GS)是第一个被发现的天然FXR拮抗剂，但它属于一个杂泛性配体，选择性较差(Urizar NL.Science,2002,296:1703-1706；Takanori Yamada.Adv Exp Med Biol,2016,929:329-361)。熊去氧胆酸(UDCA)是首个上市的FXR拮抗剂(Sun,L.Nat Med，2018，24:1919-1929)，批准的适应症为原发性胆汁性肝管炎，但作用强度较弱(IC50＝90μM)。牛磺熊去氧胆酸(TUDCA)是UDCA 的牛磺酸结合物，也是一个FXR拮抗剂，可以依赖性抑制FXR转录激活(Zangerolamo L.LifeSci,2021,272:119252)。天然来源或内源性FXR拮抗剂普遍存在来源有限，作用强度不大，选择性差，且合成困难等问题，因此，寻找高活性、高选择性的FXR拮抗剂，对研发出治疗NASH的有效药物具有重大意义。
本申请人课题组在前期的法尼醇X受体拮抗剂及其虚拟筛选方法和应用(CN116130027A)申请中通过虚拟筛选方法已筛选得到多种结构新颖的FXR受体拮抗剂，其中拥有氨基苯乙酰胺骨架的化合物V023-9340(IC50＝4.31μM，在CN116130027A编号为1号化合物)表现出强效的FXR拮抗作用。本发明旨在对筛出的氨基苯乙酰胺类FXR拮抗剂做深入的研究，对CN116130027A所公开的化合物V023-9340结构进行进一步修饰，合成一系列新型氨基苯乙酰胺类衍生物，并通过实验研究证明氨基苯乙酰胺衍生物具有很强的FXR拮抗作用以及治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎作用。
没药甾酮(GS)、牛磺熊去氧胆酸(TUDCA)和V023-9340的结构式如下：
发明内容
本发明公开了一系列新型氨基苯乙酰胺类衍生物，作为法尼醇X受体拮抗剂，用于治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物的开发。
本发明的第一方面是提供了如下式(I)所示的化合物或其药学上可接受的盐，
其中：
R1选自甲基、卤素、叔丁基；
R2选自以下任意一个基团：R3选自以下任意一个基团：/>在本发明的第一方面中，式(I)所示的衍生物具体结构式为：
本发明第二方面，提供了如式(I)所示的衍生物的制备方法，制备路线如下：
制备方法为：
步骤a、在有机溶剂下，将4-氨基苯乙酸乙酯Ⅱ与苄溴衍生物Ⅲ在碱性条件中反应得化合物Ⅳ；
步骤b、化合物Ⅳ在溶剂及碱性条件下水解，然后酸化反应制备得化合物Ⅴ；
步骤c、化合物Ⅴ与氨基衍生物Ⅵ在适当溶剂及缩合剂下发生酰胺化反应得化合物Ⅶ；
步骤d、化合物Ⅶ在碱性条件下与酰氯衍生物Ⅷ反应得到式Ⅰ所示衍生物。
进一步地，制备方法，步骤a中所述4-氨基苯乙酸乙酯Ⅱ与苄溴衍生物Ⅲ的摩尔比为1:1.1，反应温度为45～60℃；
所述有机溶剂选自无水四氢呋喃(THF)，N,N-二甲基甲酰胺(DMF)、二氯甲烷、三氯甲烷中的一种；
所述碱为碳酸钾、碳酸钠和三乙胺中的一种。
进一步地，步骤b中所述的溶剂为无水乙醇、甲醇和四氢呋喃中的一种；
所述的碱为氢氧化钠或氢氧化钾；
所述的水解反应温度为20～40℃，反应时间是12～24h；
所述的酸化反应，本领域技术人员可以对反应条件做适当选择，优先选用1mol/L盐酸溶液，调节pH＝1～2，在0～5℃下反应。
进一步地，步骤c中所述化合物Ⅴ与氨基衍生物Ⅵ的摩尔比为1:1.5，反应温度为45～50℃，反应时间是8～24h；
所述的适当溶剂选自无水四氢呋喃(THF)，N,N-二甲基甲酰胺(DMF)、二氯甲烷和三氯甲烷中的一种；
所述的酰胺化反应的缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和N,N-二异丙基乙胺(DIPEA)。
进一步地，步骤d中化合物Ⅶ与酰氯衍生物Ⅷ的摩尔比为1:1.5，反应温度为10～30℃，反应时间为8～16h；
所述的碱为三乙胺。
本发明的第三方面，提供了治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物组合物，其中包括式(Ⅰ)所示衍生物或其药学上可接受的盐以及药学上可接受的载体。
本发明的第四方面，提供了式(Ⅰ)所示衍生物或其药学上可接受的盐作为、或其药物组合物作为法尼醇X受体拮抗剂的应用。
此外，本发明提供了式(Ⅰ)所示衍生物或其药学上可接受的盐、或其药物组合物在制备治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物中的应用。
本发明公开了氨基苯乙酰胺类衍生物在作为法尼醇X受体拮抗的独特用途。重点进行了体外的FXR拮抗活性研究、HepG2和L02细胞毒性研究、HepG2细胞油红O染色实验、HepG2细胞甘油三酯含量测试、体内抗非酒精性脂肪性肝炎活性研究。证实了本发明所述的化合物具有很强的法尼醇X受体拮抗活性，同时具有制备治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物的潜力。
附图说明
图1是化合物8的HepG2细胞甘油三酯含量测试结果图；
图2是化合物8的HepG2细胞油红O染色实验结果图；
图3是化合物8对NASH小鼠血清甘油三酯影响示意图；
图4是化合物8对NASH小鼠血清胆固醇影响示意图；
图5是化合物8对NASH小鼠血清低密度脂蛋白影响示意图；
图6是化合物8对NASH小鼠血清高密度脂蛋白影响示意图；
图7是化合物8对NASH小鼠谷丙转氨酶影响示意图；
图8是化合物8对NASH小鼠谷草转氨酶影响示意图。
具体实施方式
以下将通过实施例和附图进一步阐述本发明，但并不用于限制本发明的保护范围。
实施例1：化合物Ⅳ-1～3的制备
2-(4-((3-甲基苄基)氨基)苯基)乙酸乙酯(Ⅳ-1)的制备
将化合物4-氨基苯乙酸乙酯(II，27.89mmol)加入反应烧瓶中，依次加入无水四氢呋喃(THF)(50mL)、碳酸钾(30.69mmol)，常温下搅拌10min后，加入化合物3-甲基苄溴(30.69mmol)。反应液升温至45～60℃，反应时间为8～16h。TLC监控(石油醚:乙酸乙酯＝3:1，v/v)反应完全后，将反应液静置至常温，倾倒于100mL冷水中，用乙酸乙酯(60mL×3)萃取，合并有机相，饱和NaCl(60mL)洗涤，无水MgSO4干燥，抽滤，减压蒸除溶剂，石油醚/乙酸乙酯为洗脱剂，柱层析得到化合物Ⅳ-1。黄色固体，产率76.4％，1H NMR(600MHz,DMSO-d6)δ7.20–7.12(m,3H),7.02(d,J＝7.4Hz,1H),6.92(d,J＝8.4Hz,2H),6.51(d,J＝8.4Hz,2H),6.14(t,J＝5.9Hz,1H),4.19(d,J＝6.0Hz,2H),4.03(q,J＝7.1Hz,2H),3.41(s,2H),2.28(s,3H),1.16(t,J＝7.1Hz,3H)。
2-(4-((3-氯苄基)氨基)苯基)乙酸乙酯(IV-2)的制备
按照化合物IV-1的制备方法，将3-甲基苄溴换成3-氯苄溴，其余条件相同。化合物IV-2：黄色固体，产率71.8％，1H NMR(600MHz,DMSO-d6)δ7.39(s,1H),7.36–7.30(m,2H),7.27(d,J＝7.5Hz,1H),6.93(d,J＝8.4Hz,2H),6.51(d,J＝8.5Hz,2H),6.26(t,J＝6.2Hz,1H),4.26(d,J＝6.2Hz,2H),4.03(q,J＝7.1Hz,2H),3.42(s,2H),1.15(t,J＝7.1Hz,3H)。
2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酸乙酯(IV-3)的制备
按照化合物IV-1的制备方法，将3-甲基苄溴换成4-叔丁基苄溴，其余条件相同。化合物IV-3:白色固体，产率74.5％，1H NMR(600MHz,DMSO-d6)δ7.33(d,J＝8.3Hz,1H),7.26(d,J＝8.3Hz,1H),6.92(d,J＝8.4Hz,1H),6.51(d,J＝8.5Hz,1H),6.11(t,J＝6.0Hz,1H),4.18(d,J＝6.0Hz,1H),4.03(q,J＝7.1Hz,1H),3.41(s,1H),1.26(s,5H),1.15(t,J＝7.1Hz,2H)。
实施例2：化合物V-1～3的制备
2-(4-((3-甲基苄基)氨基)苯基)乙酸(V-1)的制备
将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸乙酯(Ⅳ-1，21.19mmol)加入反应烧瓶中，加入无水乙醇20mL搅拌溶解。待完全溶解后，逐滴加入1.0mol/LNaOH的乙醇溶液(25mL)，滴加完毕后，反应温度保持20～40℃，反应12～24h。TLC监控反应(石油醚:乙酸乙酯＝1:1，v/v)。反应结束后，减压蒸除溶剂，加入水(10mL)，冰水浴下缓慢滴加1.0mol/LHCl调节pH至1～2。加入100mL水，用乙酸乙酯(60mL×3)萃取，合并有机相，用饱和NaCl(60mL)洗涤，无水MgSO4干燥，抽滤，减压蒸除溶剂，石油醚/乙酸乙酯为洗脱剂，柱层析得到化合物V-1。黄色固体，产率83.6％，1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),7.20–7.12(m,3H),7.02(d,J＝7.4Hz,1H),6.91(d,J＝8.5Hz,2H),6.50(d,J＝8.5Hz,2H),6.10(s,1H),4.19(s,2H),2.28(s,3H)。
2-(4-((3-氯苄基)氨基)苯基)乙酸(V-2)的制备
按照化合物V-1的制备方法，将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸乙酯(Ⅳ-1)换成化合物2-(4-((3-氯苄基)氨基)苯基)乙酸乙酯(IV-2)，其余条件相同。化合物V-2：黄色固体，产率85.9％，1H NMR(600MHz,DMSO-d6)δ12.07(s,1H),7.39(s,1H),7.36–7.29(m,2H),7.26(d,J＝7.5Hz,1H),6.92(d,J＝8.4Hz,2H),6.50(d,J＝8.5Hz,2H),6.23(s,1H),4.26(d,J＝4.7Hz,2H)。
2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酸(V-3)的制备
按照化合物V-1的制备方法，将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸乙酯(Ⅳ-1)换成化合物2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酸乙酯(IV-3)，其余条件相同。化合物V-3：白色固体，产率82.2％，1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),7.33(d,J＝8.3Hz,2H),7.26(d,J＝8.2Hz,2H),6.91(d,J＝8.4Hz,2H),6.51(d,J＝8.5Hz,1H),6.09(s,1H),4.19(s,1H),3.32(s,2H),1.26(s,9H)。
实施例3：化合物VII-1～9的制备
N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)的制备
将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸(V-1，3.36mmol)加入反应烧瓶中，依次加入无水THF(20mL)、HATU(4.37mmol)、DIPEA(6.72mmol)，常温下活化30min后，加入化合物苯并[d][1,3]二恶茂-5-甲胺(5.04mmol)，升温至45～50℃，反应8～24h。TLC监控(石油醚:乙酸乙酯＝1:1，v/v)反应完全后，减压蒸除溶剂，加入80mL水，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和NaCl(50mL)洗涤，无水MgSO4干燥，抽滤，减压蒸除溶剂，石油醚/乙酸乙酯为洗脱剂，柱层析得到化合物VII-1。棕色固体，产率81.2％，1H NMR(600MHz,DMSO-d6)δ8.26(t,J＝5.8Hz,1H),7.20–7.16(m,2H),7.13(d,J＝7.6Hz,1H),7.02(d,J＝7.4Hz,1H),6.93(d,J＝8.4Hz,2H),6.80(d,J＝7.9Hz,1H),6.76(d,J＝1.3Hz,1H),6.70–6.65(m,1H),6.49(d,J＝8.5Hz,2H),6.06(t,J＝6.0Hz,1H),5.96(s,2H),4.19(d,J＝6.0Hz,2H),4.13(d,J＝5.9Hz,2H),3.24(s,2H),2.27(s,3H)。
N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)的制备
按照化合物VII-1的制备方法，将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸(V-1)换成化合物2-(4-((3-氯苄基)氨基)苯基)乙酸(V-2)，其余条件相同。化合物VII-2：黄色固体，产率84.4％，1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.8Hz,1H),7.39(s,1H),7.36–7.29(m,2H),7.26(dd,J＝7.5,1.6Hz,1H),6.94(d,J＝8.4Hz,2H),6.80(d,J＝7.9Hz,1H),6.76(d,J＝1.4Hz,1H),6.67(dd,J＝7.9,1.4Hz,1H),6.49(d,J＝8.5Hz,2H),6.19(t,J＝6.2Hz,1H),5.96(s,2H),4.26(d,J＝6.2Hz,2H),4.13(d,J＝5.9Hz,2H),3.24(s,2H)。
N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酰胺(VII-3)的制备
按照化合物VII-1的制备方法，将化合物2-(4-((3-甲基苄基)氨基)苯基)乙酸(V-1)换成化合物2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酸(V-3)，其余条件相同。化合物VII-3：白色固体，产率74.4％，1H NMR(600MHz,DMSO-d6)δ8.26(t,J＝5.8Hz,1H),7.32(d,J＝8.3Hz,2H),7.26(d,J＝8.2Hz,2H),6.93(d,J＝8.4Hz,2H),6.80(d,J＝7.9Hz,1H),6.76(d,J＝1.1Hz,1H),6.68(d,J＝7.9Hz,1H),6.50(d,J＝8.5Hz,2H),6.04(t,J＝6.0Hz,1H),5.96(s,2H),4.18(d,J＝6.0Hz,2H),4.13(d,J＝5.9Hz,2H),3.24(s,2H),1.26(s,9H)。
2-(4-((3-甲基苄基)氨基)苯基)-N-(萘-2-基甲基)乙酰胺(VII-4)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物萘-2-甲胺，其余条件相同。化合物VII-4：白色固体，产率74.4％，1H NMR(600MHz,DMSO-d6)δ8.44(t,J＝5.9Hz,1H),7.88–7.85(m,1H),7.83(d,J＝8.4Hz,1H),7.80–7.76(m,1H),7.63(s,1H),7.51–7.44(m,2H),7.36(dd,J＝8.4,1.5Hz,1H),7.21–7.16(m,2H),7.14(d,J＝7.6Hz,1H),7.02(d,J＝7.4Hz,1H),6.99(d,J＝8.4Hz,2H),6.52(d,J＝8.5Hz,2H),6.09(t,J＝6.0Hz,1H),4.40(d,J＝5.9Hz,2H),4.21(d,J＝6.0Hz,2H),3.31(s,2H),2.27(s,3H)。
N-([1,1'-联苯]-4-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-5)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物[1,1'-联苯基]-4-甲胺，其余条件相同。化合物VII-5：白色固体，产率85.8％，1H NMR(600MHz,DMSO-d6)δ8.37(t,J＝5.9Hz,1H),7.63(d,J＝7.2Hz,2H),7.58(d,J＝8.2Hz,2H),7.45(t,J＝7.7Hz,2H),7.35(t,J＝7.4Hz,1H),7.29(d,J＝8.1Hz,2H),7.20–7.14(m,2H),7.13(d,J＝7.6Hz,1H),7.01(d,J＝7.4Hz,1H),6.96(d,J＝8.4Hz,2H),6.51(d,J＝8.4Hz,2H),6.07(t,J＝6.0Hz,1H),4.27(d,J＝5.9Hz,2H),4.20(d,J＝5.8Hz,2H),3.28(s,2H),2.27(s,3H)。
N-(4-甲基苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-6)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物对甲苯甲胺，其余条件相同。化合物VII-6：白色固体，产率73.5％，1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.8Hz,1H),7.20–7.16(m,2H),7.13(d,J＝7.6Hz,1H),7.08(s,4H),7.02(d,J＝7.4Hz,1H),6.94(d,J＝8.4Hz,2H),6.49(d,J＝8.5Hz,2H),6.06(t,J＝6.0Hz,1H),4.18(dd,J＝9.6,6.0Hz,4H),3.24(s,2H),2.27(s,3H),2.26(s,3H)。
N-(4-氯苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-7)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物(4-氯苯基)甲胺，其余条件相同。化合物VII-7：黄色固体，产率81.5％，1H NMR(600MHz,DMSO-d6)δ8.36(t,J＝5.9Hz,1H),7.32(dd,J＝6.3,4.5Hz,2H),7.23–7.15(m,4H),7.13(d,J＝7.6Hz,1H),7.02(d,J＝7.4Hz,1H),6.94(d,J＝8.4Hz,2H),6.50(d,J＝8.5Hz,2H),6.08(t,J＝6.0Hz,1H),4.20(dd,J＝8.9,6.1Hz,4H),3.26(s,2H),2.27(s,3H)。
N-(4-异丙基苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-8)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物(4-异丙基苯基)甲胺，其余条件相同。化合物VII-8：白色固体，产率82.6％，1H NMR(600MHz,DMSO-d6)δ8.27(t,J＝5.8Hz,1H),7.20–7.16(m,3H),7.15–7.10(m,4H),7.02(d,J＝7.4Hz,1H),6.94(d,J＝8.4Hz,2H),6.49(d,J＝8.5Hz,2H),6.07(t,J＝6.0Hz,1H),4.19(dd,J＝8.6,6.1Hz,4H),3.24(s,2H),2.8–2.81(m,1H),2.27(s,3H),1.17(d,J＝6.9Hz,6H)。
4-((2-(4-((3-甲基苄基)氨基)苯基)乙酰氨基)甲基)苯甲酸乙酯(VII-9)的制备
按照化合物VII-1的制备方法，将化合物苯并[d][1,3]二恶茂-5-甲胺换成化合物4-(氨基甲基)苯甲酸乙酯，其余条件相同。化合物VII-9：黄色固体，产率71.3％，1H NMR(600MHz,DMSO-d6)δ8.43(t,J＝5.9Hz,1H),7.88(d,J＝8.2Hz,2H),7.32(d,J＝8.2Hz,2H),7.20–7.15(m,2H),7.13(d,J＝7.6Hz,1H),7.02(d,J＝7.4Hz,1H),6.95(d,J＝8.4Hz,2H),6.51(d,J＝8.5Hz,2H),6.08(t,J＝6.0Hz,1H),4.32–4.28(m,4H),4.20(d,J＝6.0Hz,2H),3.28(s,2H),2.27(s,3H),1.31(t,J＝7.1Hz,3H)。
实施例4：化合物1-14的制备
1.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-N-(3-氯苄基)环戊烷甲酰胺(化合物1)的制备
氮气保护下，将N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(Ⅶ-2,1.22mmol)溶于无水四氢呋喃(20mL)中，依次加入4-二甲氨基吡啶(0.12mmol)、三乙胺(2.44mmol)、环戊基甲酰氯(VIII-1，1.83mmol)，低温下反应6h，减压蒸除四氢呋喃，加入蒸馏水(30mL)，用乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠(20mL)洗涤，无水硫酸镁干燥，抽滤，减压蒸除溶剂，石油醚/乙酸乙酯为洗脱剂，柱层析得到化合物1。产率78.6％，黄色胶状物；1H NMR(600MHz,DMSO-d6)δ8.50(t,J＝5.7Hz,1H),7.35–7.25(m,4H),7.21(s,1H),7.13(d,J＝7.3Hz,1H),7.08(d,J＝8.2Hz,2H),6.80(d,J＝7.9Hz,1H),6.75(d,J＝1.3Hz,1H),6.73–6.65(m,1H),5.96(s,2H),4.82(s,2H),4.16(d,J＝5.8Hz,2H),3.46(s,2H),2.58–2.51(m,1H),1.68(m,2H),1.65–1.54(m,4H),1.42–1.31(m,2H)；13CNMR(151MHz,DMSO-d6)δ176.19,170.14,147.70,146.51,140.99,136.47,133.70,133.40,130.66,128.36,128.05,127.50,126.90,120.84,108.36,101.27,52.23,42.46,42.18,41.73,31.12,26.27.HR-MS(m/z)(ESI):calcd for C29H30ClN2O4[M+H]+:505.1894；found:505.1895。
2.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-N-(4-(叔丁基)苄基)环戊烷甲酰胺(化合物2)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((4-(叔丁基)苄基)氨基)苯基)乙酰胺(VII-3)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物2：产率79.7％，白色固体，1H NMR(600MHz,DMSO-d6)δ8.50(t,J＝5.6Hz,1H),7.31–7.28(m,4H),7.08(d,J＝7.8Hz,4H),6.80(d,J＝7.9Hz,1H),6.76(d,J＝1.2Hz,1H),6.68(dd,J＝7.9,1.5Hz,1H),5.96(s,2H),4.78(s,2H),4.16(d,J＝5.8Hz,2H),3.45(s,2H),2.61–2.50(m,1H),1.71–1.65(m,2H),1.64–1.51(m,4H),1.37–1.34(m,2H),1.25(s,9H)；13C NMR(151MHz,DMSO-d6)δ175.91,170.18,149.73,147.70,146.51,141.40,136.25,135.32,133.71,130.51,128.38,127.82,125.50,120.83,108.36,101.27,52.52,42.46,42.18,41.75,34.63,31.62,31.16,26.29.HR-MS(m/z)(ESI):calcd for C33H39N2O4[M+H]+:527.2910；found:527.2903。
3.N-(3-甲基苄基)-N-(4-(2-((萘-2-基甲基)氨基)-2-氧代乙基)苯基)环戊烷甲酰胺(化合物3)的制备：
按照化合物1的制备方法，用2-(4-((3-甲基苄基)氨基)苯基)-N-(萘-2-基甲基)乙酰胺(VII-4)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物3：产率86.12％，白色固体，1H NMR(400MHz,DMSO-d6)δ8.76(t,J＝5.7Hz,1H),7.92–7.80(m,3H),7.71(s,1H),7.54–7.47(m,2H),7.43–7.37(m,1H),7.33(d,J＝8.1Hz,2H),7.19(t,J＝7.5Hz,1H),7.12(d,J＝8.1Hz,2H),7.05(d,J＝7.5Hz,1H),6.97(d,J＝10.2Hz,2H),4.82(s,2H),4.46(d,J＝5.8Hz,2H),3.54(s,2H),2.61–2.55(m,1H),2.26(s,3H),1.79–1.55(m,6H),1.42–1.33(m,2H)；13C NMR(126MHz,DMSO-d6)δ175.93,170.38,141.23,138.24,137.81,137.45,136.32,133.30,132.51,130.51,128.80,128.67,128.47,128.31,128.10,127.97,127.87,126.65,126.27,126.12,125.66,125.22,52.64,42.76,42.28,41.73,31.15,26.29,21.47.HR-MS(m/z)(ESI):calcdfor C33H35N2O2[M+H]+:491.2699；found:491.2707。
4.N-(4-(2-(([1,1'-联苯]-4-基甲基)氨基)-2-氧代乙基)苯基)-N-(3-甲基苄基)环戊烷甲酰胺(化合物4)的制备：
按照化合物1的制备方法，用N-([1,1'-联苯]-4-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-5)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物4：产率77.04％，白色固体，1H NMR(400MHz,DMSO-d6)δ8.68(t,J＝5.7Hz,1H),7.65(d,J＝7.4Hz,2H),7.60(d,J＝8.1Hz,2H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),7.31(d,J＝7.8Hz,4H),7.18(t,J＝7.5Hz,1H),7.10(d,J＝8.0Hz,2H),7.04(d,J＝7.5Hz,1H),7.00–6.94(m,2H),4.82(s,2H),4.33(d,J＝5.8Hz,2H),3.52(s,2H),2.59–2.55(m,1H),2.26(s,3H),1.75–1.52(m,6H),1.47–1.26(m,2H)；13C NMR(126MHz,DMSO-d6)δ175.92,170.30,141.20,140.39,139.23,139.10,138.24,137.81,136.30,130.50,129.37,128.81,128.66,128.47,128.25,128.09,127.81,127.03,125.23,52.62,42.33,42.23,41.72,38.71,31.14,26.29,21.47.HR-MS(m/z)(ESI):calcd for C35H37N2O2[M+H]+:517.2855；found:517.2866。
5.N-(3-甲基苄基)-N-(4-(2-((4-甲基苄基)氨基)-2-氧代乙基)苯基)环戊烷甲酰胺(化合物5)的制备：
按照化合物1的制备方法，用N-(4-甲基苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-6)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物5：产率68.25％，白色胶状物，1H NMR(400MHz,DMSO-d6)δ8.58(t,J＝5.6Hz,1H),7.29(d,J＝8.0Hz,2H),7.19(t,J＝7.5Hz,1H),7.12–7.03(m,7H),7.02–6.93(m,2H),4.82(s,2H),4.23(d,J＝5.8Hz,2H),3.48(s,2H),2.58(m,1H),2.27(d,J＝3.9Hz,6H),1.80–1.54(m,6H),1.39(s,2H)；13C NMR(126MHz,DMSO-d6)δ175.91,170.18,141.17,138.23,137.81,136.78,136.34,136.24,130.47,129.22,128.81,128.67,128.44,128.10,127.58,125.24,52.61,42.33,42.23,41.73,31.15,26.29,21.48,21.10.HR-MS(m/z)(ESI):calcd for C30H35N2O2[M+H]+:455.2699；found:455.2703。
6.N-(4-(2-((4-氯苄基)氨基)-2-氧代乙基)苯基)-N-(3-甲基苄基)环戊烷甲酰胺(化合物6)的制备：
按照化合物1的制备方法，用N-(4-氯苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-7)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物6：产率76.8％，黄色胶状物，1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝5.7Hz,1H),7.35(d,J＝8.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.16–7.24(m,3H),7.04–7.12(m,3H),7.01–6.93(m,2H),4.82(s,2H),4.27(d,J＝5.9Hz,2H),3.49(s,2H),2.63–2.54(m,1H),2.27(s,3H),1.81–1.54(m,6H),1.39–1.28(m,2H)；13C NMR(126MHz,DMSO-d6)δ175.91,170.37,141.20 138.96,138.22,137.81,136.19,131.75,130.48,129.43,128.80,128.67 128.61,128.47,128.1,125.23,52.60,42.18,41.91,41.73,31.14,26.29,21.48.HR-MS(m/z)(ESI):calcd for C29H32ClN2O2[M+H]+:475.2152；found:475.2162。
7.N-(4-(2-((4-异丙基苄基)氨基)-2-氧代乙基)苯基)-N-(3-甲基苄基)环戊烷甲酰胺(化合物7)的制备：
按照化合物1的制备方法，用N-(4-异丙基苄基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-8)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物7：产率79.13％，白色胶状物，1H NMR(600MHz,DMSO-d6)δ8.51(t,J＝5.6Hz,1H),7.26(d,J＝8.1Hz,2H),7.19–7.00(m,8H),6.98–6.90(m,2H),4.79(s,2H),4.21(d,J＝5.8Hz,2H),3.45(s,2H),2.86–2.81(m,1H),2.61–2.50(m,1H),2.24(s,3H),1.79–1.48(m,6H),1.51–1.29(m,2H),1.17(d,J＝6.9Hz,6H)；13C NMR(151MHz,DMSO-d6)δ175.92,170.16,147.43,141.20,138.27,137.81,137.17,136.35,130.46,128.83,128.66,128.45,128.10,127.73,126.58,125.26,52.65,42.44,42.22,41.76,33.58,31.14,26.30,24.38,21.48.HR-MS(m/z)(ESI):calcd for C32H39N2O2[M+H]+:483.3012；found:483.3018。
8.4-((2-(4-(N-(3-甲基苄基)环戊烷甲酰胺基)苯基)乙酰胺基)甲基)苯甲酸乙酯(化合物8)的制备：
按照化合物1的制备方法，用4-((2-(4-((3-甲基苄基)氨基)苯基)乙酰氨基)甲基)苯甲酸乙酯(VII-9)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，其余条件相同。化合物8：产率71.61％，黄色胶状物，1H NMR(600MHz,DMSO-d6)δ8.67(t,J＝5.8Hz,1H),7.86(d,J＝8.1Hz,2H),7.31–7.28(m,4H),7.16(t,J＝7.5Hz,1H),7.07(d,J＝8.0Hz,2H),7.03(d,J＝7.5Hz,1H),6.98–6.91(m,2H),4.79(s,2H),4.34(d,J＝5.9Hz,2H),4.30(q,J＝7.1Hz,2H),3.49(s,2H),2.58–2.52(m,1H),2.24(s,3H),1.72–1.68(m,2H),1.65–1.53(m,4H),1.41–1.33(m,2H),1.31(t,J＝7.1Hz,3H)；13CNMR(151MHz,DMSO-d6)δ175.91,170.50,166.02,145.55,141.25,138.25,137.82,136.20,130.46,129.56,128.88,128.85,128.66,128.52,128.11,127.62,125.29,61.10,52.64,42.34,42.27,41.78,31.13,26.29,21.46,14.63.HR-MS(m/z)(ESI):calcd for C32H37N2O4[M+H]+:513.2753；found:513.2751。
9.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-N-(3-甲基苄基)环己甲酰胺(化合物9)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，环己基甲酰氯(VIII-2)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物9：产率69.84％，白色胶状物，1H NMR(600MHz,DMSO-d6)δ8.49(t,J＝5.7Hz,1H),7.26(d,J＝8.1Hz,2H),7.16(t,J＝7.5Hz,1H),7.06(d,J＝8.2Hz,2H),7.02(d,J＝7.5Hz,1H),6.98–6.89(m,2H),6.80(d,J＝7.9Hz,1H),6.76(d,J＝1.3Hz,1H),6.68(dd,J＝7.9,1.5Hz,1H),5.96(s,2H),4.76(s,2H),4.16(d,J＝5.8Hz,2H),3.46(s,2H),2.24(s,3H),2.17(t,J＝10.8Hz,1H),1.63(t,J＝14.7Hz,4H),1.51(d,J＝12.4Hz,1H),1.48–1.35(m,2H),1.11(q,J＝12.8Hz,1H),0.87(m,2H)；13C NMR(151MHz,DMSO-d6)δ175.42,170.17,147.70,146.51,141.17,138.25,137.81,136.32,133.71,130.53,128.70,128.10,125.15,120.85,108.37,101.27,52.44,42.47,42.19,41.08,29.58,25.77,25.50,21.47.HR-MS(m/z)(ESI):calcd for C31H35N2O4[M+H]+:499.2597；found:499.2598。
10.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-N-(3-甲基苄基)苯甲酰胺(化合物10)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，苯甲酰氯(VIII-3)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物10：产率:80.56％，白色固体，熔点51.3-54.6℃，1H NMR(400MHz,DMSO-d6)δ8.46(t,J＝5.7Hz,1H),7.35–7.20(m,6H),7.13–7.02(m,5H),7.01(d,J＝8.1Hz,2H),6.82(d,J＝7.9Hz,1H),6.76(s,1H),6.68(d,J＝7.9Hz,1H),6.00(s,2H),5.07(s,2H),4.15(d,J＝5.8Hz,2H),3.36(s,2H),2.29(s,3H)；13C NMR(126MHz,DMSO-d6)δ170.17,170.09,147.67,146.49,141.79,137.94,136.68,134.99,133.66,129.99,129.94,128.76,128.68,128.26,128.20,127.74,125.09,120.84,108.43,108.31,101.27,53.25,42.40,42.02,21.50.HR-MS(m/z)(ESI):calcd for C31H29N2O4[M+H]+:493.2127；found:493.2132。
11.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-2-甲基-N-(3-甲基苄基)苯甲酰胺(化合物11)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，2-甲基苯甲酰氯(VIII-4)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物11：产率79.87％，白色固体，熔点50.8-52.5℃，1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.19(d,J＝7.0Hz,1H),7.15–6.91(m,10H),6.79(d,J＝7.9Hz,1H),6.73(s,1H),6.64(d,J＝7.6Hz,1H),5.97(s,2H),5.05(s,2H),4.11(d,J＝5.3Hz,2H),3.29(s,2H),2.30(s,3H),2.27(s,3H)；13C NMR(151MHz,DMSO-d6)δ170.39,169.97,147.63,146.45,140.74,137.92,137.10,135.23,134.57,133.59,130.38,129.70,128.85,128.74,128.23,127.68,125.40,125.16,120.80,108.37,108.28,101.22,52.32,42.39,41.93,21.45,19.53.HR-MS(m/z)(ESI):calcd for C32H31N2O4[M+H]+:507.2284；found:507.2291。
12.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-4-甲基-N-(3-甲基苄基)苯甲酰胺(化合物12)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，4-甲基苯甲酰氯(VIII-5)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物12：产率73.84％；白色固体，熔点51.2-53.3℃，1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.19(d,J＝7.0Hz,1H),7.15–6.90(m,11H),6.79(d,J＝7.9Hz,1H),6.73(s,1H),6.64(d,J＝7.6Hz,1H),5.97(s,2H),5.05(s,2H),4.11(d,J＝5.3Hz,2H),3.29(s,2H),2.30(s,3H),2.28(s,3H)；13C NMR(151MHz,DMSO-d6)δ170.07,147.63,146.45,142.01,139.70,138.01,137.85,134.83,133.69,133.63,129.93,128.92,128.76,128.68,128.63,128.12,127.58,125.04,120.79,108.37,108.27,101.22,53.34,42.39,41.99,40.38,21.46,21.26.HR-MS(m/z)(ESI):calcd for C32H31N2O4[M+H]+:507.2284；found:507.2297。
13.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-4-乙基-N-(3-甲基苄基)苯甲酰胺(化合物13)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，4-乙基苯甲酰氯(VIII-5)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物13：产率79.22％，白色胶状物，1H NMR(600MHz,DMSO-d6)δ8.41(t,J＝5.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.18(t,J＝7.5Hz,1H),7.11–7.02(m,5H),6.98(d,J＝8.2Hz,1H),6.79(d,J＝7.9Hz,1H),6.74(s,1H),6.65(d,J＝7.9Hz,1H),5.96(s,2H),5.03(s,2H),4.12(d,J＝5.8Hz,2H),3.34(s,1H),2.57–2.47(m,4H),2.26(s,2H),1.10(t,J＝7.6Hz,2H)；13C NMR(151MHz,DMSO-d6)δ170.06,147.63,146.44,145.83,142.02,138.02,137.85,134.84,133.92,133.62,129.93,129.00,128.68,128.62,128.12,127.56,125.03,120.78,108.37,108.27,101.22,53.38,42.39,42.00,28.25,21.46,15.46.HR-MS(m/z)(ESI):calcd for C33H33N2O4[M+H]+:521.2440；found:521.2457。
14.N-(4-(2-((苯并[d][1,3]二恶茂-5-基甲基)氨基)-2-氧代乙基)苯基)-4-氯-N-(3-甲基苄基)苯甲酰胺(化合物14)的制备：
按照化合物1的制备方法，用N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-甲基苄基)氨基)苯基)乙酰胺(VII-1)替换N-(苯并[d][1,3]二恶茂-5-基甲基)-2-(4-((3-氯苄基)氨基)苯基)乙酰胺(VII-2)，4-氯苯甲酰氯(VIII-6)替换环戊基甲酰氯(VIII-1)，其余条件相同。化合物14：产率82.8％，白色胶状物，1H NMR(400MHz,DMSO-d6)δ8.48(t,J＝5.7Hz,1H),7.37–7.30(m,4H),7.21(t,J＝7.5Hz,1H),7.15–6.99(m,7H),6.82(d,J＝7.9Hz,1H),6.76(s,1H),6.68(d,J＝7.9Hz,1H),6.00(s,2H),5.07(s,2H),4.15(d,J＝5.7Hz,2H),3.37(s,2H),2.29(s,3H)；13CNMR(126MHz,DMSO-d6)δ170.07,169.11,147.67,146.49,141.49,137.95,137.74,135.51,135.27,134.63,133.66,130.70,130.07,128.74,128.38,128.25,127.79,125.14,120.82,108.42,108.30,101.27,53.27,42.41,42.01,21.48.HR-MS(m/z)(ESI):calcd for C31H28ClN2O4[M+H]+:527.1738；found:527.1746。
实施例5：FXR拮抗活性测试
本发明根据双荧光素酶报告基因检测法测试所有合成的化合物对FXR的拮抗作用。将HEK293T细胞以20,000/孔的密度种于96孔白板中，37℃、5％ CO2过夜生长至50％～60％密度时，将培养基换成无血清的DMEM培养基。将质粒pCDNA-FXR、PGL3-FXRE-luc、PRL-TK与Lipo转染试剂混匀放置15min，然后将混合物加入到96孔板中(10μL/孔)进行转染。转染6h后换成含10％胎牛血清的DMEM培养基，同时加入不同浓度的化合物以及5μM的GW4064处理24h。24h后去除培养基，加入稀释后的lysis buffer裂解细胞20min，13000转离心5min，吸取上清用双荧光素酶报告基因检测试剂盒(UElandy)在酶标仪上测定FXR拮抗活性，拮抗率的计算公式为：Inhibition rate(％)＝(Max-X)/(Max-Min)×100％。结果值以荧火虫荧光值/海肾荧光值表示，Max代表加入5μM GW4064化合物的阳性对照结果值，X代表加入待测化合物的结果值，Min代表加入DMSO的阴性对照结果值。结果见表1。
实施例6：细胞毒性检测
本发明利用MTT法测试所有合成化合物对HepG2细胞和L02细胞的细胞毒性。HepG2、L02细胞均匀接种于96孔板中,孵育18h待细胞贴壁后，移除原有培养基，分别给予浓度为3.125、6.25、12.5、25、50、100μM的药物于细胞培养箱中培养24h。然后每孔加入20μLMTT溶液反应,避光孵育4h。结束孵育后吸出孔内培养液,每孔加入150μL DMSO,低速震荡,使结晶充分溶解。在490nm处测量各孔吸光度值。细胞活力的计算公式为：细胞活力(％)＝(OD待测-OD空白)/(OD对照-OD空白)×100。结果见表1。
表1：化合物的FXR拮抗活性以及细胞毒性结果
数据以至少三个独立重复试验结果的平均值来表示。TUDCA(牛磺熊去氧胆酸)，GS(没药甾酮)为阳性对照化合物。
表1结果表明，本发明所合成的14个氨基苯乙酰胺类衍生物的FXR拮抗活性都明显强于阳性对照药TUDCA和GS。另外，对比已报道的化合物V023-9340的IC50值为4.31μM，本发明所合成的衍生物6、7、8、9、12、13和14表现出更强的FXR拮抗活性。其中，化合物8表现出最强的FXR拮抗活性(IC50＝0.891μM)，其活性与TUDCA、GS和V023-9340相比，提高了63倍、69倍和4.8倍，属于强效的FXR拮抗剂。另外，本发明所合成的化合物对HepG2细胞以及L02细胞基本无细胞毒性(IC50>100μM)。总之，以上数据表明，本发明合成的化合物具有高效低毒的特点。
实施例7：HepG2细胞中甘油三酯(TG)含量测定，参照图1。
本发明对优选化合物8进一步测定其对HepG2细胞中TG含量影响。
取对数生长期的HepG2细胞种至于6孔板中，待细胞汇合至80％～90％时，弃去旧培养基，用含1％牛血清白蛋白的DMEM培养基进行饥饿处理16h，加入0.6mmol游离脂肪酸(油酸：棕榈酸＝2：1)诱导12h造模细胞脂肪变性模型。然后用不同浓度的化合物培养24h(每个化合物做三个复孔)。化合物处理完毕后每孔加入1mL PBS冲洗两遍，再加入0.25％胰蛋白酶，1000转离心5min，弃去上清。向细胞沉淀加入裂解液1％ Triton X-100裂解细胞30min,充分震荡裂解后，取2.5μL上清液与250μL混合好的甘油三酯检测工作液,在37℃孵育10min,于酶标仪(510nm)检测吸光度值。甘油三酯含量计算公式为：样品浓度(mmol/gprotein)＝(OD样品-OD空白)/(OD标准-OD空白)×标准品浓度(mmol/L)/蛋白浓度(g protein/L)。
从图1可以看出，与模型组相比，不同浓度组的化合物8都能显著降低HepG2细胞内TG含量，且效果优于阳性对照TUDCA组和V023-9340组。数据以平均值±SEM表示，与NASH组相比，*P≤0.05，**P≤0.01，***P≤0.001和****P≤0.0001。
实施例8：油红O染色实验，参照图2。
本发明进一步采用游离脂肪酸(FFA)诱导HepG-2细胞构建细胞脂肪变性模型，考察化合物8改善细胞脂肪变性的作用。
取HepG2细胞种至于6孔板中，待细胞汇合至80％～90％时，弃去旧培养基，用含1％牛血清白蛋白的DMEM培养基进行饥饿处理16h，加入0.6mmol游离脂肪酸(油酸：棕榈酸＝2：1)诱导12h造模细胞脂肪变性模型。造模成功后用不同浓度的化合物培养24h。然后移除孔板内的培养液，PBS洗2次，加油红O固定液固定25min，用蒸馏水清洗2次，60％异丙醇浸洗3min，油红O染色液浸染30min。染色结束后，用60％异丙醇漂洗30s，洗净后每孔加1mL蒸馏水保持湿润，于倒置显微镜下观察。
从图2可以看出，与模型组相比，经过不同浓度的化合物8(10μM，30μM)干预后，红色脂滴得到显著改善，尤其是30μM化合物8，其改善脂肪变性效果优于30μM V023-9340和50μM TUDCA。以上数据表明，化合物8在体外能显著改善FFA诱导的HepG2细胞脂肪变性。
实施例9：抗NASH小鼠药效学实验，参照图3到图8。
本发明选择高脂饮食和化学诱导的方式，高脂饮食伴随每周腹腔注射CCl4会加重小鼠肝损伤从而加速纤维化的发展，有效缩短模型周期，建立伴随有轻中度纤维化的NASH小鼠模型，以此考察化合物8的体内抗NASH活性。
将雄性6周龄C57BL/6J小鼠分为正常组、模型组(NASH组)、阳性化合物V023-9340组(30mg/kg)和TUDCA组(50mg/kg)、化合物8低(5mg/kg)、中(10mg/kg)、高(20mg/kg)剂量组，每组10只。正常组给予标准饲料喂养，其他组均给予高脂饲料连续饲养17周，最后4周，V023-9340组、TUDCA 组和受试化合物8高、中、低剂量组，分别灌服相应剂量药物。正常组和模型组灌服等量0.5％ CMC-Na溶液，并对模型组以及给药组每周腹腔注射两次3.5％ CCl4溶液。整个实验周期，观察小鼠的精神状况，每周记录小鼠的体重1次。实验终点，将小鼠不禁水禁食12h，乙醚麻醉小鼠后腹主动脉采血，分离脏器，生理盐水洗净后分别称重并记录。使用生化检测仪测定小鼠血清中甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、谷丙转氨酶(ALT)、谷草转氨酶(AST)生化指标。
从图3到图8可以看出，连续给药4周，与NASH组相比，不同浓度的化合物8都可以降低NASH小鼠的血清TG、TC、LDL水平，升高HDL水平。化合物8的中(10mg/kg)、高(20mg/kg)剂量组在降低NASH小鼠的血清TG、TC、LDL水平，升高HDL水平方面，效果也优于V023-9340组和TUDCA组。另外，相比较于NSAH组，化合物8的中(10mg/kg)、高(20mg/kg)剂量组都能显著降低谷丙转氨酶(ALT)和谷草转氨酶(AST)水平，其效果也优于V023-9340组和TUDCA组。数据以平均值±SEM表示，与NASH组相比，*P≤0.05，**P≤0.01，***P≤0.001，****P≤0.0001。总之，以上结果表明化合物8可以很好调控NASH小鼠体内的血脂水平，改善血脂紊乱，其改善血脂异常的效果优于V023-9340和TUDCA。
Claims (8)
1.如下结构式所示的氨基苯乙酰胺类衍生物1-14，具体结构式为：
2.如权利要求1所述的氨基苯乙酰胺类衍生物的制备方法，其特征在于，制备路线如下：
制备方法为：
步骤a、在有机溶剂下，将4-氨基苯乙酸乙酯Ⅱ与苄溴衍生物Ⅲ在碱性条件中反应得化合物Ⅳ；
步骤b、化合物Ⅳ在溶剂及碱性条件下水解，然后酸化反应制备得化合物Ⅴ；步骤c、化合物Ⅴ与氨基衍生物Ⅵ在适当溶剂及缩合剂下发生酰胺化反应得化合物Ⅶ；
步骤d、化合物Ⅶ在碱性条件下与酰氯衍生物Ⅷ反应，得到式Ⅰ所示衍生物。
3.如权利要求2所述的氨基苯乙酰胺类衍生物的制备方法，其特征在于：
步骤a中所述4-氨基苯乙酸乙酯Ⅱ与苄溴衍生物Ⅲ的摩尔比为1:1.1，反应温度为45-60℃；
所述有机溶剂选自无水四氢呋喃，N,N-二甲基甲酰胺、二氯甲烷和三氯甲烷中的一种；
所述碱为碳酸钾、碳酸钠和三乙胺中的一种。
4.如权利要求2所述的氨基苯乙酰胺类衍生物的制备方法，其特征在于：
步骤b中所述的溶剂为无水乙醇、甲醇和四氢呋喃中的一种；
所述的碱为氢氧化钠或氢氧化钾；
所述的水解反应温度为20-40℃，反应时间是12-24h；
所述的酸化反应，选用1mol/L盐酸溶液，调节pH＝1-2，在0-5℃下反应。
5.如权利要求2所述的氨基苯乙酰胺类衍生物的制备方法，其特征在于：
步骤c中所述化合物Ⅴ与氨基衍生物Ⅵ的摩尔比为1:1.5，反应温度为45-50℃，反应时间是8-24h；
所述的适当溶剂选自无水四氢呋喃，N,N-二甲基甲酰胺、二氯甲烷和三氯甲烷中的一种；
所述的酰胺化反应的缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺。
6.如权利要求2所述的氨基苯乙酰胺类衍生物的制备方法，其特征在于：
步骤d中化合物Ⅶ与酰氯衍生物Ⅷ的摩尔比为1:1.5，反应温度为10-30℃，反应时间为8-16h；
所述的碱为三乙胺。
7.权利要求1所述的氨基苯乙酰胺类衍生物或其药学上可接受的盐、或其药物组合物作为法尼醇X受体拮抗剂，在制备治疗法尼醇X受体相关疾病的药物中的应用。
8.权利要求1所述的氨基苯乙酰胺类衍生物或其药学上可接受的盐、或其药物组合物在制备治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎药物中的应用。
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