CN117886773A - 联苯羧酸类化合物及其制法和药物用途 - Google Patents
联苯羧酸类化合物及其制法和药物用途 Download PDFInfo
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Abstract
本发明属于药物化学领域,公开了一种联苯羧酸类化合物及其制法和药物用途。具体公开了式(I)化合物所示的联苯羧酸类化合物及其生理上可接受的盐,所述化合物的制备方法、药物组合物和在制备URAT1抑制剂中的用途,以及在制备预防和/或治疗高尿酸血症、痛风中的应用。
Description
技术领域
本发明属于药物化学领域,具体涉及通式(I)所示的联苯羧酸类化合物及其生理上可接受的盐,这些化合物在制备尿酸盐转运蛋白1(urate transporter 1,URAT1)抑制剂中的用途,在制备预防或治疗URAT1相关疾病的药物中的应用,还涉及其用于治疗的方法,以及含有所述化合物的药物组合物。
背景技术
痛风是尿酸单钠盐在关节及外周组织中沉积析出所导致的炎性关节疾病。尿酸生成增加或(和)排泄减少所导致的高尿酸血症是痛风的直接诱因。高尿酸血症还与代谢综合症、高血压、糖尿病、心血管疾病等多种疾病密切相关。
降尿酸疗法(urate-lowering therapy,ULT)是治疗高尿酸血症和慢性痛风的主要策略。目前降尿酸疗法主要分为三类:(1)抑制尿酸生成的黄嘌呤氧化酶(xanthineoxidase,XOD)抑制剂;(2)促进尿酸排泄的尿酸盐转运蛋白1(urate transporter 1,URAT1)抑制剂;(3)使尿酸转化为水溶性物质的尿酸酶(uricase)。约90%高尿酸血症患者的发病机制与尿酸排泄减少有关,而URAT1是经临床验证调控尿酸重吸收,促进尿酸排泄的重要靶点,因此URAT1抑制剂是重要的降尿酸疗法。目前,在全球范围内获批上市的URAT1抑制剂有苯溴马隆、丙磺舒、雷西纳德和Dotinurad,我国临床上应用的仅有丙磺舒和苯溴马隆。然而,丙磺舒和苯溴马隆存在耐受性差、毒副反应多等问题。2015年底上市的雷西纳德在临床上需要与XOD抑制剂别嘌呤醇联用治疗高尿酸血症和慢性痛风,其对URAT1的抑制活性偏弱,临床上使用剂量大(200mg/d)。Dotinurad于2020年1月在日本上市,目前临床应用还较为有限。
近年来,随着人们饮食结构的改变和人口老龄化的加速,痛风发病率在持续上升,已经成为一个不可忽视的全民健康问题。目前临床治疗药物较少,而且各自存在不同的缺陷。URAT1是经临床验证的降尿酸疗法有效靶点,因此,研究新型URAT1抑制具有重要的现实意义和市场前景。
发明内容
本发明旨在提供一种如通式(I)所示的联苯羧酸类化合物。
本发明的另一目的在于提供一种制备通式(I)所示的联苯羧酸类化合物的方法。
本发明的又一目的在于提供通式(I)所示的联苯羧酸类化合物在制备URAT1抑制剂中的用途,以及在制备预防或治疗URAT1相关疾病的药物中的应用。
本发明解决的技术问题是提供一种式(I)所示的联苯羧酸类化合物及其生理上可接受的盐,其制备方法、药物组合物和在制备URAT1抑制剂中的用途,以及在制备预防和/或治疗高尿酸血症、痛风中的应用。
为了解决本发明的技术问题,本发明采用的技术方案在于提供通式(I)所示的联苯羧酸类化合物及其生理上可接受的盐:
Ar选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的萘基、取代或未取代的嘧啶基、取代或未取代的噻吩基、取代或未取代的呋喃基;所述的取代基为单取代或多取代基团,其各自独立地选自氢、卤素、C1-C3烷基、C1-C3烷氧基。
本发明的又一技术方案在于提供通式(IA)所示的化合物及其生理上可接受的盐:
R1或R2独立地选自氢、卤素、C1-C3烷基、C1-C3烷氧基。
本发明的又一技术方案在于提供通式(IB)所示的化合物及其生理上可接受的盐:
R3选自氢、卤素、C1-C3烷基、C1-C3烷氧基;
本发明的又一技术方案在于提供所示的化合物及其生理上可接受的盐,其特征在于,所述的化合物选自:
本发明的又一技术方案在于提供通式(I)所示的化合物制备方法,其特征在于,包括以下步骤:
芳基氰基化合物Ar-CN与盐酸羟胺在碳酸钠催化下反应得到中间体I-1,随后I-1与联苯酸酐在氢氧化钠催化下反应生成目标物I;
Ar的定义同权利要求1~4。
为了制成药剂,可将通式(I)化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合,并被制成片剂或包衣的片剂,或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明还涉及一种含有药物有效剂量的如通式(I)所述的化合物和药学上可接受的载体的药物组合物。
药理学研究表明,本发明的通式(I)化合物具有抑制URAT1的活性,可用于治疗与URAT1相关的疾病,如高尿酸血症和痛风。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂,非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂,例如淀粉,明胶,阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂例如有水,乙醇,丙二醇,植物油类如玉米油,花生油,橄榄油等。含有本发明化合物的制剂中还可有其他助剂,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂,色素等。
有益技术效果:
URAT1抑制剂是临床上使用的重要降尿酸药物。本发明涉及的化合物具有显著的URAT1抑制作用。其中,部分化合物与临床同类产品苯溴马隆比较,体外抑制URAT1活性更强。
具体实施方式
以下结合实施例对发明作进一步的说明,但这些实施例并不限制本发明的范围。
合成实验中所使用的试剂和溶剂均通过商业途径购买,未经处理直接使用。无水溶剂为商业购买的超干溶剂,溶剂的混合比例为体积比。所有反应监测均采用GF-254薄层硅胶板,柱层析分离采用200-300目硅胶。1H-NMR由Varian Mercury400-MHz核磁共振仪采集获得。化学位移(δ)以百万分之一(ppm)给出,内标为TMS,偶合常数以赫兹(Hz)为单位。
实施例1:TM-1
(1)中间体IA-1的制备
将4-氰基吡啶(0.521g,5mmol),盐酸羟胺(0.521g,6mmol),碳酸钠(1.06g,10mmol)加入30mL乙醇-水(4:1)的混合溶剂中,反应体系加热至70℃反应6h。TLC监测反应完全,减压除去溶剂后,柱色谱分离(石油醚-乙酸乙酯=3:1)得到中间体IA-1,0.63g,收率:92%。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.61–8.53(m,2H),7.67–7.61(m,2H),6.00(s,2H)。
(2)目标物TM-1的制备
将中间体IA-1(0.411g,3mmol),联苯酸酐(0.673g,3mmol)加入15mL二甲基亚砜中,常温反应3h,加入氢氧化钠(0.240g,6mmol),常温反应3h,TLC监测反应完全,向反应液中加入100mL水,用1N盐酸水溶液缓慢调节pH至4-5,析出固体,过滤,干燥,乙酸乙酯重结晶得目标物TM-1 0.67g,收率:65%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.80–8.75(m,2H),8.20(dd,J=7.8,1.3Hz,1H),7.96(dd,J=7.8,1.3Hz,1H),7.81–7.76(m,2H),7.73(td,J=7.8,1.3Hz,1H),7.64(tt,J=7.8,1.3Hz,2H),7.56(td,J=7.8,1.3Hz,1H),7.41(dd,J=7.8,1.3Hz,1H),7.30(dd,J=7.8,1.3Hz,1H)。
实例2:TM-2
合成方法与TM-1类似,不同之处在于第一步用2-溴-4-氰基吡啶替代4-氰基吡啶,最后一步收率39%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.59(d,J=5.0Hz,1H),8.21(d,J=7.7Hz,1H),7.96(d,J=7.7Hz,1H),7.93(s,1H),7.84(d,J=5.0Hz,1H),7.74(t,J=7.7Hz,1H),7.64(t,J=7.7Hz,2H),7.56(t,J=7.7Hz,1H),7.41(d,J=7.7Hz,1H),7.29(d,J=7.7Hz,1H)。
实例3:TM-3
合成方法与TM-1类似,不同之处在于第一步用2-氯-4-氰基吡啶替代4-氰基吡啶,最后一步收率63%,白色固体。1H NMR(400MHz,DMSO--d6)δ12.57(s,1H),8.69–8.59(m,1H),8.22(dd,J=7.8,1.3Hz,1H),7.96(dd,J=7.8,1.3Hz,1H),7.84–7.79(m,2H),7.74(td,J=7.8,1.3Hz,1H),7.64(tt,J=7.8,1.3Hz,2H),7.56(td,J=7.8,1.3Hz,1H),7.41(dd,J=7.8,1.3Hz,1H),7.30(dd,J=7.8,1.3Hz,1H)。
实例4:TM-4
合成方法与TM-1类似,不同之处在于第一步用3-氯-4-氰基吡啶替代4-氰基吡啶,最后一步收率55%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.85(d,J=0.6Hz,1H),8.70(d,J=5.0Hz,1H),8.20(dd,J=7.6,1.3Hz,1H),7.96(dd,J=7.6,1.3Hz,1H),7.77(dd,J=5.0,0.6Hz,1H),7.74(td,J=7.6,1.3Hz,1H),7.64(tdd,J=7.6,3.8,1.3Hz,3H),7.55(td,J=7.6,1.3Hz,1H),7.40(dd,J=7.6,1.3Hz,1H),7.30(dd,J=7.6,1.3Hz,1H)。
实例5:TM-5
合成方法与TM-1类似,不同之处在于第一步用2-氟-4-氰基吡啶替代4-氰基吡啶,最后一步收率62%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.46(d,J=5.1Hz,1H),8.21(dd,J=7.6,1.4Hz,1H),7.96(dd,J=7.6,1.4Hz,1H),7.78–7.70(m,2H),7.68–7.60(m,2H),7.56(td,J=7.6,1.4Hz,1H),7.51(s,1H),7.41(dd,J=7.6,1.4Hz,1H),7.30(dd,J=7.6,1.4Hz,1H)。
实例6:TM-6
合成方法与TM-1类似,不同之处在于第一步用2-甲基-4-氰基吡啶替代4-氰基吡啶,最后一步收率65%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.63(dd,J=5.2,0.9Hz,1H),8.20(dd,J=7.8,1.4Hz,1H),7.96(dd,J=7.8,1.4Hz,1H),7.73(td,J=7.8,1.4Hz,1H),7.68–7.60(m,3H),7.60–7.52(m,2H),7.40(dd,J=7.8,1.4Hz,1H),7.29(dd,J=7.8,1.4Hz,1H),2.55(s,3H)。
实例7:TM-7
合成方法与TM-1类似,不同之处在于第一步用2-甲氧基-4-氰基吡啶替代4-氰基吡啶,最后一步收率52%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.34(d,J=5.3Hz,1H),8.19(dd,J=7.8,1.4Hz,1H),7.96(dd,J=7.8,1.4Hz,1H),7.73(td,J=7.8,1.4Hz,1H),7.63(td,J=7.8,1.4Hz,2H),7.56(td,J=7.8,1.4Hz,1H),7.42–7.37(m,2H),7.29(dd,J=7.8,1.4Hz,1H),7.12(t,J=1.4Hz,1H),3.90(s,3H)。
实例8:TM-8
合成方法与TM-1类似,不同之处在于第一步用2,6二甲基-4-氰基吡啶替代4-氰基吡啶,最后一步收率63%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.19(dd,J=7.6,1.4Hz,1H),7.96(dd,J=7.6,1.4Hz,1H),7.73(td,J=7.6,1.4Hz,1H),7.63(tdd,J=7.6,2.7,1.4Hz,2H),7.56(td,J=7.6,1.4Hz,1H),7.45(s,2H),7.40(dd,J=7.6,1.4Hz,1H),7.29(dd,J=7.6,1.4Hz,1H),2.49(s,6H)。
实例9:TM-9
合成方法与TM-1类似,不同之处在于第一步用喹啉-4-甲腈替代4-氰基吡啶,最后一步收率53%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),9.06(d,J=4.4Hz,1H),8.42(dd,J=8.6,1.4Hz,1H),8.25(dd,J=7.8,1.4Hz,1H),8.14(dd,J=8.6,1.4Hz,1H),8.00(dd,J=7.8,1.4Hz,1H),7.96(d,J=4.4Hz,1H),7.87(ddd,J=8.6,6.8,1.4Hz,1H),7.76(td,J=7.5,1.4Hz,1H),7.72–7.64(m,4H),7.61(td,J=7.5,1.4Hz,1H),7.43(dd,J=7.5,1.4Hz,1H),7.36(dd,J=7.5,1.4Hz,1H)。
实例10:TM-10
合成方法与TM-1类似,不同之处在于第一步用3-氰基喹啉替代4-氰基吡啶,最后一步收率51%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.27(d,J=2.2Hz,1H),8.90(dd,J=2.2,0.8Hz,1H),8.26(dd,J=7.8,1.5Hz,1H),8.17(dd,J=8.4,1.5Hz,1H),8.11(dd,J=8.4,1.1Hz,1H),8.00(dd,J=7.8,1.5Hz,1H),7.90(ddd,J=8.4,6.9,1.5Hz,1H),7.74(qd,J=7.8,1.5Hz,2H),7.66(td,J=7.8,1.5Hz,2H),7.59(td,J=7.8,1.5Hz,1H),7.43(dd,J=7.8,1.5Hz,1H),7.32(dd,J=7.8,1.5Hz,1H)。
实例11:TM-11
合成方法与TM-1类似,不同之处在于第一步用4-氰基嘧啶替代4-氰基吡啶,最后一步收率66%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),9.38(d,J=1.4Hz,1H),9.07(d,J=5.1Hz,1H),8.21(dd,J=7.8,1.4Hz,1H),7.96(dd,J=7.8,1.4Hz,1H),7.90(dd,J=5.1,1.4Hz,1H),7.74(td,J=7.8,1.4Hz,1H),7.64(tdd,J=7.8,2.5,1.4Hz,2H),7.56(td,J=7.8,1.4Hz,1H),7.40(dd,J=7.8,1.4Hz,1H),7.30(dd,J=7.8,1.4Hz,1H)。
实例12:TM-12
合成方法与TM-1类似,不同之处在于第一步用3-氰基吡啶替代4-氰基吡啶,最后一步收率52%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),9.00(s,1H),8.75(s,1H),8.20(d,J=7.5Hz,2H),7.97(d,J=7.5Hz,1H),7.72(t,J=7.5Hz,1H),7.63(t,J=7.5Hz,2H),7.60–7.52(m,2H),7.40(d,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H)。
实例13:TM-13
合成方法与TM-1类似,不同之处在于第一步用2-氰基吡啶替代4-氰基吡啶,最后一步收率50%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.76–8.70(m,1H),8.20(d,J=7.6Hz,1H),8.03–7.93(m,2H),7.86(dd,J=8.0,0.8Hz,1H),7.72(t,J=7.6Hz,1H),7.63(t,J=7.6Hz,2H),7.60–7.52(m,2H),7.39(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H)。
实例14:TM-14
合成方法与TM-1类似,不同之处在于第一步用对氟苯腈替代4-氰基吡啶,最后一步收率55%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.18(d,J=7.7Hz,1H),7.96(d,J=7.7Hz,1H),7.94–7.86(m,2H),7.76–7.67(m,1H),7.68–7.59(m,2H),7.55(t,J=7.7Hz,1H),7.38(t,J=8.9Hz,3H),7.28(d,J=7.7Hz,1H)。
实例15:TM-15
合成方法与TM-1类似,不同之处在于第一步用对三氟甲基苯腈替代4-氰基吡啶,最后一步收率61%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.20(d,J=7.5Hz,1H),8.06(d,J=8.1Hz,2H),7.97(d,J=7.5Hz,1H),7.90(d,J=8.1Hz,2H),7.72(t,J=7.5Hz,1H),7.63(t,J=7.5Hz,2H),7.55(t,J=7.5Hz,1H),7.40(d,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H)。
实例16:TM-16
合成方法与TM-1类似,不同之处在于第一步用对氯苯腈替代4-氰基吡啶,最后一步收率61%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.18(d,J=7.8Hz,1H),7.96(d,J=7.8Hz,1H),7.86(d,J=8.7Hz,2H),7.72(t,J=7.8Hz,1H),7.66–7.59(m,4H),7.55(t,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),7.28(d,J=7.8Hz,1H)。
实例17:TM-17
合成方法与TM-1类似,不同之处在于第一步用对溴苯腈替代4-氰基吡啶,最后一步收率51%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.18(d,J=7.5Hz,1H),7.95(d,J=7.5Hz,1H),7.79(d,J=8.5Hz,2H),7.74(d,J=8.5Hz,2H),7.70(d,J=7.5Hz,1H),7.62(t,J=7.5Hz,2H),7.55(t,J=7.5Hz,1H),7.39(d,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H)。
实例18:TM-18
合成方法与TM-1类似,不同之处在于第一步用4-甲氧基氰苯替代4-氰基吡啶,最后一步收率51%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.17(dd,J=7.6,1.3Hz,1H),7.97(dd,J=7.6,1.3Hz,1H),7.83–7.75(m,2H),7.70(td,J=7.6,1.3Hz,1H),7.65–7.58(m,2H),7.55(td,J=7.6,1.3Hz,1H),7.38(dd,J=7.6,1.3Hz,1H),7.27(dd,J=7.6,1.3Hz,1H),7.10–7.02(m,2H),3.81(s,3H)。
实例19:TM-19
合成方法与TM-1类似,不同之处在于第一步用对甲苯腈替代4-氰基吡啶,最后一步收率60%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.18(d,J=7.6Hz,1H),7.96(d,J=7.6Hz,1H),7.75(d,J=8.0Hz,2H),7.71(t,J=7.6Hz,1H),7.67–7.59(m,2H),7.55(t,J=7.6Hz,1H),7.38(d,J=7.6Hz,1H),7.33(d,J=8.0Hz,2H),7.28(d,J=7.6Hz,1H),2.36(s,3H)。
实例20:TM-20
合成方法与TM-1类似,不同之处在于第一步用3-溴苯腈替代4-氰基吡啶,最后一步收率60%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.19(d,J=7.6Hz,1H),8.00–7.93(m,2H),7.86(d,J=7.6Hz,1H),7.81–7.75(m,1H),7.72(td,J=7.6,1.2Hz,1H),7.67–7.59(m,2H),7.56(td,J=7.6,1.2Hz,1H),7.49(t,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),7.29(d,J=7.6Hz,1H)。
实例21:TM-21
合成方法与TM-1类似,不同之处在于第一步用2-氰基呋喃替代4-氰基吡啶,最后一步收率58%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.15(d,J=7.5Hz,1H),7.94(d,J=9.2Hz,2H),7.75–7.67(m,1H),7.65–7.58(m,2H),7.58–7.50(m,1H),7.38(d,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),7.06(d,J=3.4Hz,1H),6.77–6.67(m,1H)。
实例22:TM-22
合成方法与TM-1类似,不同之处在于第一步用2-氰基噻吩替代4-氰基吡啶,最后一步收率58%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.16(d,J=7.5Hz,1H),7.96(d,J=7.5Hz,1H),7.84(d,J=4.9Hz,1H),7.71(t,J=7.5Hz,1H),7.67–7.58(m,3H),7.54(t,J=7.5Hz,1H),7.38(d,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),7.23(t,J=4.9Hz,1H)。
实例23:TM-23
合成方法与TM-1类似,不同之处在于第一步用3-氰基噻吩替代4-氰基吡啶,最后一步收率58%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.16(d,J=7.6Hz,1H),8.10(d,J=2.8Hz,1H),7.95(d,J=7.6Hz,1H),7.74(dd,J=5.0,2.8Hz,1H),7.70(t,J=7.6Hz,1H),7.62(t,J=7.6Hz,2H),7.54(t,J=7.6Hz,1H),7.45(d,J=5.0Hz,1H),7.38(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H)。
实例24:TM-24
合成方法与TM-1类似,不同之处在于第一步用喹啉-6-甲腈替代4-氰基吡啶,最后一步收率48%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.00(dd,J=4.2,1.7Hz,1H),8.57(d,J=1.7Hz,1H),8.53(dd,J=8.3,1.7Hz,1H),8.25(dd,J=7.6,1.4Hz,1H),8.20–8.11(m,2H),8.00(dd,J=7.6,1.4Hz,1H),7.73(dd,J=7.6,1.4Hz,1H),7.69–7.62(m,3H),7.59(td,J=7.6,1.4Hz,1H),7.42(dd,J=7.6,1.4Hz,1H),7.32(dd,J=7.6,1.4Hz,1H)。
实例25:TM-25
合成方法与TM-1类似,不同之处在于第一步用4-甲氧基-1-萘甲腈替代4-氰基吡啶,最后一步收率36%,白色固体。1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.60–8.45(m,1H),8.29–8.24(m,1H),8.22(dd,J=7.5,1.4Hz,1H),8.07–7.96(m,2H),7.73(td,J=7.5,1.4Hz,1H),7.69–7.54(m,5H),7.41(dd,J=7.5,1.4Hz,1H),7.34(dd,J=7.5,1.4Hz,1H),7.10(d,J=8.3Hz,1H),4.05(s,3H)。
药理实验:
实验例1:目标化合物对hURAT1的体外的抑制活性
方法:
培养稳定表达hURAT1的HEK-293T细胞株(DMEM培养基+10%胎牛血清+500μg/mLG418+1% P/S),将细胞接种到96孔细胞培养板中,培养12~24小时。化合物用DMSO配成10mM浓度的母液,再用缓冲液稀释成1mM,进一步进行4倍等比稀释。待96孔板中细胞培养贴壁后即可进行14C-尿酸在稳定表达hURAT1细胞中的吸收试验。每孔加入50微升相应化合物和0.1Ci/mL 14C-尿酸溶液,在37℃培养箱中孵育5分钟后,立即加入150微升冰冷的缓冲液以终止吸收。加入50微升/孔的裂解液到所有孔中,置于振荡器上以900rpm的速度振荡5分钟;加入150微升/孔的闪烁液Microsint40,以900rpm的速度振荡5分钟;采用MicroBetaTrilux(PerkinElmer公司生产)仪器测定放射活性,并通过XL-fit软件进行分析数据。
结果:
分别测定了上述化合物在浓度为10μM时对hURAT1的抑制率;测定并计算抑制活性较好的化合物的IC50值,结果如表1所示。
表1.化合物对hURAT1的抑制作用
*:抑制率在10μM下测得;
ND:Not Determined,未测试。
Claims (10)
1.一种由下述通式(I)表示的联苯羧酸类化合物及其生理上可接受的盐,
其中,
Ar选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的萘基、取代或未取代的嘧啶基、取代或未取代的噻吩基、取代或未取代的呋喃基;所述的取代基为单取代或多取代基团,其各自独立地选自氢、卤素、C1-C3烷基、C1-C3烷氧基。
2.根据权利要求1所述的化合物及其生理上可接受的盐,其特征在于,所述的化合物是通式(IA)所示的化合物及其生理上可接受的盐:
其中,
R1、R2独立地选自氢、卤素、C1-C3烷基、C1-C3烷氧基。
3.根据权利要求1所述的化合物及其生理上可接受的盐,其特征在于,所述的化合物是通式(IB)所示的化合物及其生理上可接受的盐:
其中,
R3选自氢、卤素、C1-C3烷基、C1-C3烷氧基。
4.根据权利要求1所述的化合物及其生理上可接受的盐,其特征在于,所述化合物选自:
5.权利要求1~4任一项所述化合物的制备方法,其特征在于,包括以下步骤:
芳基氰基化合物Ar-CN与盐酸羟胺在碳酸钠催化下反应得到中间体I-1,随后I-1与联苯酸酐在氢氧化钠催化下反应生成目标物I;
其中,Ar的定义同权利要求1~4。
6.一种药物组合物,其特征在于,所述的药物组合物含有有效剂量的如权利要求1~4任一项所述的任一化合物及其生理上可接受的盐及药学上可接受的载体。
7.根据权利要求6所述的药物组合物,其特征在于,所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
8.权利要求1~4任一项所述的化合物及其生理上可接受的盐在制备尿酸盐转运蛋白1抑制剂中的用途。
9.权利要求1~4任一项所述的化合物或其生理上可接受的盐在制备预防和/或治疗URAT1相关疾病的药物中的应用。
10.根据权利要求9所述的应用,所述的疾病选自高尿酸血症和痛风。
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