CN111662239A - 1,2,4-三唑类化合物及其制法和药物用途 - Google Patents
1,2,4-三唑类化合物及其制法和药物用途 Download PDFInfo
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- CN111662239A CN111662239A CN201910167460.6A CN201910167460A CN111662239A CN 111662239 A CN111662239 A CN 111662239A CN 201910167460 A CN201910167460 A CN 201910167460A CN 111662239 A CN111662239 A CN 111662239A
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Abstract
本发明公开了式(I)化合物所示新的1,2,4‑三唑类化合物，及其生理上可接受的盐，溶剂化物以及结晶形式，所述化合物的制备方法，含有所述化合物的药物制剂，以及所述化合物在预防和治疗与高尿酸血症相关疾病如痛风等临床中的应用。
Description
技术领域
本发明涉及通式I的新的1,2,4-三唑类化合物，以及它们生理上可接受的盐。这些化合物在与高尿酸血症以及痛风的治疗过程中的用途，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
高尿酸血症是一种因尿酸代谢障碍，导致血液中尿酸水平升高的疾病，极易引发痛风等其它代谢性疾病。统计显示，高尿酸血症及其引发的痛风已成为世界上仅次于糖尿病的第二大代谢性疾病。近年来，随着我国人们生活水平的提高，高尿酸血症和痛风的发病率也呈逐年上升趋势，给社会和家庭带来沉重负担。
人体内尿酸产生过多和尿酸排泄过少都有可能造成血尿酸水平增高，产生高尿酸血症。高水平血尿酸与很多疾病密切相关。首先是痛风，当体内尿酸水平超过其溶解限度时，尿酸盐出现结晶化，沉积在关节或软组织，引起炎症反应，继而诱发痛风。研究表明，超过21％的高尿酸血症患者最终发展为痛风。此外，高水平血尿酸还能够引起很多并发症。流行病学研究表明，高尿酸血症与很多疾病密切相关，如高血压、2型糖尿病、非酒精性脂肪肝病、肥胖症、慢性肾病、心血管疾病、中风等。
降低体内尿酸水平的主要途径包括抑制尿酸生成和促进尿酸排泄，因此，临床上使用的降尿酸药物主要分为两类，即抑制尿酸生成的黄嘌呤氧化酶(Xanthine oxidase,XO)抑制剂(别嘌呤醇、非布索坦、托匹司他等)及促进尿酸排泄的药物。而作为尿酸生成代谢途径中的关键酶，黄嘌呤氧化酶抑制剂在其中占据重要地位。
本发明旨在提供一种新的1,2,4-三唑类化合物，其具有高的黄嘌呤氧化酶抑制活性，可用于治疗高尿酸血症以及高尿酸血症引起的痛风等疾病。
发明内容
本发明的目的在于提供一种式I所示的新型1,2,4-三唑类化合物。
本发明的另一目的在于提供一种制备式I所示的1,2,4-三唑类化合物及其类似物的方法。
本发明的又一目的在于提供式I所示的化合物在抑制黄嘌呤氧化酶中的用途，以及治疗与高尿酸血症有关的痛风等疾病中的用途。
为了完成本发明的目的，本发明采用如下技术方案：
其中，Ar选自取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的嘧啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吲哚基、取代或未取代的喹啉基、取代或未取代的萘基；X选自氧或硫原子；n为1,2,3,4或5；R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；
上述取代基选自卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基、C1-C3烷磺酰基。
本发明的又一目的在于提供通式(IAa)所示的化合物及其生理上可接受的盐：
其中，n为1、2、3、4或5；X选自氧或硫原子；R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基。
本发明的又一目的在于提供通式(IB)所示的化合物及其生理上可接受的盐：
其中，n为1,2,3,4或5；R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基、C1-C3烷磺酰基。
本发明的又一目的在于提供通式(IAa1)所示的化合物及其生理上可接受的盐：
其中，R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基。
本发明的取代基C1-C6烷基优选C1-C4烷基，更优选C1-C3烷基，最优选甲基、乙基；C1-C3烷氧基优选甲氧基、乙氧基；C1-C3烷磺酰基优选甲磺酰基、乙磺酰基；卤代C1-C3烷基中卤代所用的卤素优选：氟、氯、溴。
本发明的又一目的在于提供所述的化合物及其生理上可接受的盐，其特征在于，所述的化合物选自：
本发明的又一目的在于提供式I所示的化合物的合成方法，包括以下步骤：
式II化合物与卤代物反应生成的式III化合物，式III化合物肼解得到式IV化合物，式IV化合物与氰基化合物反应生成式I化合物：
其中，n、X、R1及Ar的定义同权利要求1。
本发明提供上述的1,2,4-三唑类化合物，存在(I-1)、(I-2)、(I-3)三种异构体，统称为1,2,4-三唑，用通式(I)来表示。
异构体(I-1)
异构体(I-2)
异构体(I-3)
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化合物具有抑制黄嘌呤氧化酶的活性，可有效降低体内的血尿酸水平，从而达到治疗的目的。
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。
附图说明
图1.化合物YDA-4-43的体内降尿酸作用
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。
化合物的结构是通过核磁共振(NMR)或质谱(MS)或高分辨质谱(HRMS)来确定的。NMR位移(δ)以百万分之一(ppm)的单位给出。m.p.是以℃给出的熔点，温度未加校正。柱层析一般使用200～300目硅胶为载体。NMR测定是用INOVA-300，测定溶剂为CDCl3、DMSO-D6，内标为TMS，化学位移是以ppm作为单位给出。MS的测定用Agilent LC/MSD TOF液质联用仪。
实施例1：TAZ-3-1
a)100mL圆底烧瓶中分别加入4-羟基-3,5-二氯苯甲酸乙酯(2.35g,10mmol)，N-(3-氯丙基)吗啉(1.96g,12mmol)，碳酸钾(2.76g,20mmol)，DMF(15mL)，80℃下反应12h，反应完成后蒸出大部分DMF，残余物加水溶解，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥备用。
b)100mL圆底烧瓶中依次加入上述产物,水合肼(80％N2H4,5mL)，乙醇(20mL)，90℃下回流反应6h，溶液颜色由深变浅，反应后TLC检测，原料反应完全，蒸出乙醇和过量的水合肼，出现黄色固体，用混合溶剂(石油醚:乙酸乙酯＝1:1)洗,干燥备用。
c)在微波反应封管中依次加入3-氰基吡啶(156mg,1mmol)，4-异丁氧基-3-硝基苯甲酰肼(253mg,1mmol)，碳酸钾(276mg,2mmol)，正丁醇(3mL)，125℃下反应12h，反应后，蒸出溶剂，加水稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，柱层析分离(二氯甲烷:甲醇＝50:1)，得白色固体220mg，收率50.7％。1H NMR(400MHz,DMSO-d6)δ14.85(s,1H),9.25(d,J＝1.7Hz,1H),8.70(dd,J＝4.8,1.5Hz,1H),8.41(dt,J＝8.0,1.9Hz,1H),8.12(s,2H),7.58(dd,J＝7.9,4.8Hz,1H),4.12(t,J＝6.3Hz,2H),3.64–3.53(m,4H),2.58–2.46(m,2H),2.39(s,4H),2.06–1.77(m,2H).
实施例2：TAZ-3-2
制备方法与实施例1类似，不同之处在于，用2,5-二甲基-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.87(s,1H),8.09(s,2H),7.66(s,2H),4.10(t,J＝6.3Hz,2H),3.65–3.53(m,4H),2.61–2.49(m,2H),2.38(s,4H),1.96(dd,J＝13.6,6.6Hz,2H).
实施例3：TAZ-3-3
制备方法与实施例1类似，不同之处在于，用2-氯-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.96(s,1H),8.57(d,J＝5.1Hz,1H),8.13(s,2H),8.11–7.96(m,2H),4.12(t,J＝6.2Hz,2H),3.58(d,J＝4.3Hz,2H),2.52(dd,J＝12.9,4.3Hz,2H),2.40(s,4H),2.18–1.76(m,2H).
实施例4：TAZ-3-4
制备方法与实施例1类似，不同之处在于，第一步用3-氯-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.97(s,1H),8.81(s,1H),8.66(d,J＝5.0Hz,1H),8.11(s,2H),8.00(d,J＝5.0Hz,1H),4.12(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.57–2.45(m,2H),2.38(s,4H),2.03–1.86(m,2H).
实施例5：TAZ-3-5
制备方法与实施例1类似，不同之处在于，用2-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ15.01(s,1H),8.74(d,J＝4.5Hz,1H),8.19(d,J＝7.8Hz,1H),8.14–7.99(m,3H),7.64–7.50(m,1H),4.11(t,J＝6.2Hz,2H),3.58(d,J＝4.3Hz,4H),2.52(d,J＝11.9Hz,2H),2.38(s,4H),2.06–1.74(m,2H).
实施例6：TAZ-3-6
制备方法与实施例1类似，不同之处在于，用N-(2-氯乙基)吗啉替代实施例1中的N-(3-氯丙基)吗啉，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.99(s,1H),8.75(d,J＝5.1Hz,2H),8.12(s,2H),8.09–7.98(m,2H),4.21(t,J＝5.6Hz,2H),3.59–3.46(m,4H),2.78(t,J＝5.6Hz,2H),2.56–2.34(m,4H).
实施例7：TAZ-3-7
制备方法与实施例1类似，不同之处在于，用4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.64(s,1H),8.71(d,J＝5.9Hz,2H),8.05–7.96(m,4H),7.12(d,J＝8.8Hz,2H),4.09(t,J＝6.4Hz,2H),3.58(t,J＝4.5Hz,4H),2.47–2.31(m,4H),1.91(p,J＝6.6Hz,2H).
实施例8：TAZ-3-8
制备方法与实施例1类似，不同之处在于，用3-甲氧基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1HNMR(400MHz,DMSO-d6)δ14.64(s,1H),8.72(dd,J＝4.5,1.5Hz,2H),8.01(dd,J＝4.5,1.6Hz,2H),7.70–7.62(m,2H),7.15(d,J＝8.9Hz,1H),4.09(t,J＝6.4Hz,2H),3.88(s,2H),3.63–3.52(m,4H),2.43(dd,J＝19.6,12.5Hz,2H),1.92(dq,J＝13.5,6.6Hz,2H).
实施例9：TAZ-3-9
制备方法与实施例1类似，用3-氟-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.74(s,1H),8.73(d,J＝5.9Hz,2H),8.00(dd,J＝4.5,1.6Hz,2H),7.88(dt,J＝7.3,2.5Hz,2H),7.38(t,J＝8.8Hz,1H),4.19(t,J＝6.4Hz,2H),3.63–3.52(m,4H),2.48–2.34(m,6H),2.02–1.73(m,2H).
实施例10：TAZ-3-10
制备方法与实施例1类似，不同之处在于，用3-氯-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.73(s,1H),8.71(d,J＝5.4Hz,2H),8.10(d,J＝2.1Hz,1H),8.04–7.95(m,3H),7.34(d,J＝8.7Hz,1H),4.19(t,J＝6.3Hz,2H),3.61–3.51(m,4H),2.45(d,J＝7.0Hz,2H),2.37(s,4H),1.93(p,J＝6.6Hz,2H).
实施例11：TAZ-3-11
制备方法与实施例1类似，不同之处在于，用3-溴-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.75(s,1H),8.73(dd,J＝4.5,1.5Hz,2H),8.29(d,J＝2.1Hz,1H),8.07(dd,J＝8.6,2.1Hz,1H),8.00(dd,J＝4.4,1.6Hz,2H),7.32(d,J＝8.7Hz,1H),4.20(t,J＝6.2Hz,2H),3.64–3.53(m,4H),2.54–2.44(m,2H),2.39(s,4H),2.01–1.83(m,2H).
实施例12：TAZ-3-12
制备方法与实施例1类似，不同之处在于，用4-羟基-3,5-二溴苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1HNMR(400MHz,DMSO-d6)δ14.89(s,1H),8.75(d,J＝5.4Hz,2H),8.31(s,2H),8.01(d,J＝6.0Hz,2H),4.09(t,J＝6.3Hz,2H),3.60(d,J＝4.5Hz,2H),2.61–2.47(m,6H),2.42(s,4H),2.08–1.86(m,2H).
实施例13：TAZ-3-13
制备方法与实施例1类似，不同之处在于，用3-甲基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.56(s,1H),8.69(dd,J＝4.5,1.5Hz,2H),7.98(dd,J＝4.5,1.6Hz,2H),7.91–7.84(m,2H),7.10(d,J＝9.2Hz,1H),4.09(t,J＝6.2Hz,2H),3.61–3.52(m,4H),2.46(t,J＝7.1Hz,2H),2.37(s,4H),2.23(s,3H),1.98–1.79(m,2H).
实施例14：TAZ-3-14
制备方法与实施例1类似，不同之处在于，用3-三氟甲基-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1HNMR(400MHz,DMSO-d6)δ14.82(s,1H),8.72(d,J＝5.6Hz,2H),8.30(d,J＝6.1Hz,2H),7.99(d,J＝5.9Hz,2H),7.46(d,J＝9.3Hz,1H),4.24(t,J＝6.0Hz,2H),3.63–
3.50(m,4H),2.44(t,J＝7.0Hz,2H),2.35(s,4H),1.96–1.85(m,2H).
实施例15：TAZ-3-15
制备方法与实施例1类似，不同之处在于，用3-碘-4-羟基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.70(s,1H),8.71(d,J＝5.8Hz,2H),8.47(d,J＝1.9Hz,1H),8.06(dd,J＝8.6,1.9Hz,1H),7.98(d,J＝5.9Hz,2H),7.17(d,J＝8.7Hz,1H),4.16(t,J＝6.0Hz,2H),3.65–3.49(m,4H),2.53(s,2H),2.39(s,4H),1.93(dd,J＝13.7,7.1Hz,2H).
实施例16：TAZ-3-20
制备方法与实施例1类似，不同之处在于，用2-氰基妇男替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ8.07(s,2H),7.92(dd,J＝1.9,0.6Hz,1H),7.12(d,J＝4.1Hz,1H),6.72(dd,J＝3.6,1.9Hz,1H),4.17–4.05(m,2H),3.64–3.53(m,4H),2.53(d,J＝7.9Hz,2H),2.38(d,J＝4.5Hz,4H),1.96(t,J＝7.2Hz,2H).
实施例17：TAZ-3-21
制备方法与实施例1类似，不同之处在于，用5-氰基吲哚替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.45(s,1H),11.38(s,1H),8.32(s,1H),8.14–8.08(m,1H),7.97(s,1H),7.84(dd,J＝8.5,1.6Hz,1H),7.55(d,J＝8.5Hz,1H),7.46(t,J＝2.7Hz,1H),6.58(s,1H),4.15–4.03(m,2H),3.58(dd,J＝9.5,5.3Hz,4H),2.56–2.47(m,2H),2.39(s,4H),2.01–1.89(m,2H).
实施例18：TAZ-3-22
制备方法与实施例1类似，不同之处在于，用4-溴苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.74(s,1H),8.10(s,2H),8.02(d,J＝8.5Hz,2H),7.76(d,J＝8.4Hz,2H),4.12(t,J＝6.2Hz,2H),3.65–3.54(m,4H),2.56–2.44(m,2H),2.39(s,4H),2.07–1.82(m,2H).
实施例19：TAZ-3-23
制备方法与实施例1类似，不同之处在于，用2-氟苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.60(s,1H),8.66(s,1H),8.16–8.06(m,3H),7.98(s,1H),7.65–7.54(m,1H),7.49–7.36(m,2H),4.12(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.58–2.44(m,2H),2.39(s,4H),2.04–1.89(m,2H).
实施例20：TAZ-3-24
制备方法与实施例1类似，不同之处在于，用3-氟苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.77(s,1H),8.12(s,2H),7.96–7.91(m,1H),7.85(ddd,J＝10.0,2.5,1.5Hz,1H),7.61(td,J＝8.1,6.1Hz,1H),7.36(td,J＝8.3,2.2Hz,1H),4.13(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.58–2.48(m,2H),2.39(s,4H),2.02–1.89(m,2H).
实施例21：TAZ-3-25
制备方法与实施例1类似，不同之处在于，用4-氯苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.73(s,1H),8.11–8.07(m,4H),7.65–7.60(m,2H),4.12(t,J＝6.3Hz,2H),3.63–3.54(m,4H),2.57–2.48(m,2H),2.39(s,4H),2.00–1.91(m,2H).
实施例22：TAZ-3-26
制备方法与实施例1类似，不同之处在于，用4-甲基苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.59(s,1H),8.09(s,2H),7.97(d,J＝8.1Hz,2H),7.37(d,J＝8.2Hz,2H),4.11(t,J＝6.3Hz,2H),3.63–3.54(m,4H),2.57–2.46(m,2H),2.39(s,7H),1.96(p,J＝6.5Hz,2H).
实施例23：TAZ-3-27
制备方法与实施例1类似，不同之处在于，用4-甲磺酰基苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.88(s,1H),8.33–8.24(m,2H),8.13–8.01(m,4H),4.08(t,J＝6.3Hz,2H),3.60–3.50(m,4H),3.26(s,3H),2.55–2.45(m,2H),2.35(s,4H),1.99–1.87(m,2H).
实施例24：TAZ-3-28
制备方法与实施例1类似，不同之处在于，用4-氟苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.67(s,1H),8.16–8.02(m,4H),7.39(t,J＝8.8Hz,2H),4.11(t,J＝6.3Hz,2H),3.63–3.53(m,4H),2.56–2.47(m,2H),2.39(s,4H),1.96(p,J＝6.6Hz,2H).
实施例25：TAZ-3-29
制备方法与实施例1类似，不同之处在于，用4-氰基喹啉替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.99(s,1H),9.17(d,J＝8.3Hz,1H),9.05(d,J＝4.5Hz,1H),8.19(s,2H),8.15–8.08(m,2H),7.85(ddd,J＝8.4,6.9,1.4Hz,1H),7.76(ddd,J＝8.3,6.8,1.3Hz,1H),4.13(t,J＝6.3Hz,2H),3.61–3.52(m,4H),2.58–2.46(m,2H),2.39(s,4H),2.04–1.90(m,2H).
实施例26：TAZ-3-30
制备方法与实施例1类似，不同之处在于，用2-氰基噻吩替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.61(s,1H),8.02(s,2H),7.71(d,J＝4.3Hz,2H),7.23–7.15(m,1H),4.07(t,J＝6.3Hz,2H),3.58–3.50(m,4H),2.54–2.44(m,2H),2.35(s,4H),1.99–1.82(m,2H).
实施例27：TAZ-3-31
制备方法与实施例1类似，不同之处在于，用3-氰基噻吩替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.54(s,1H),8.18(dd,J＝2.9,1.1Hz,1H),8.11–7.98(m,2H),7.74(dd,J＝5.0,2.9Hz,1H),7.66(dd,J＝5.0,1.2Hz,1H),4.09(t,J＝6.3Hz,2H),3.61–3.51(m,4H),2.55–2.46(m,2H),2.37(s,4H),2.01–1.87(m,2H).
实施例28：TAZ-3-32
制备方法与实施例1类似，不同之处在于，用1-氰基萘替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.78(s,1H),8.68(s,1H),8.23–8.06(m,5H),8.06–7.94(m,1H),7.68–7.57(m,2H),4.13(t,J＝6.3Hz,2H),3.64–3.53(m,4H),2.58–2.47(m,2H),2.39(s,4H),2.04–1.84(m,2H).
实施例29：TAZ-3-33
制备方法与实施例1类似，不同之处在于，用苯腈替代实施例1中的3-氰基吡啶。1HNMR(400MHz,DMSO-d6)δ14.67(s,1H),8.11–8.03(m,3H),7.96(s,1H),7.59–7.45(m,3H),4.10(t,J＝6.3Hz,2H),3.61–3.50(m,4H),2.55–2.46(m,2H),2.37(s,4H),2.01–1.85(m,2H).
实施例30：TAZ-3-34
制备方法与实施例1类似，不同之处在于，用4-巯基苯甲酸甲酯替代实施例1中的4-羟基-3,5-二氯苯甲酸乙酯，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ8.74–8.68(m,2H),7.99(ddd,J＝7.4,5.4,2.0Hz,4H),7.48(dd,J＝6.5,4.4Hz,2H),3.64–3.48(m,4H),3.08(t,J＝7.4Hz,1H),2.56–2.45(m,4H),2.39(t,J＝7.1Hz,1H),2.36–2.22(m,3H),1.76(t,J＝7.4Hz,1H).
实施例31：TAZ-3-35
制备方法与实施例1类似，不同之处在于，用2-氟-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.99(s,1H),8.40(d,J＝5.2Hz,1H),8.13(d,J＝3.1Hz,2H),7.95(dt,J＝5.2,1.5Hz,1H),7.69(s,1H),4.11(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.56–2.47(m,2H),2.38(s,4H),2.02–1.85(m,2H).
实施例32：TAZ-3-36
制备方法与实施例1类似，不同之处在于，用2-溴-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.99(s,1H),8.51(d,J＝5.0Hz,1H),8.13(d,J＝0.4Hz,1H),8.08(s,2H),7.99(dd,J＝5.1,1.3Hz,1H),4.08(t,J＝6.3Hz,2H),3.63–3.48(m,4H),2.58–2.45(m,2H),2.36(s,4H),2.05–1.75(m,2H).
实施例33：TAZ-3-37
制备方法与实施例1类似，不同之处在于，用2-氰基噻唑替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ15.16(s,1H),8.09–8.04(m,2H),7.98(d,J＝3.2Hz,1H),4.11(t,J＝6.3Hz,2H),3.60–3.51(m,4H),2.56–2.46(m,2H),2.38(s,4H),2.03–1.86(m,2H).
实施例34：TAZ-3-38
制备方法与实施例1类似，不同之处在于，用2-甲基-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ8.61(d,J＝5.2Hz,1H),8.12(s,2H),7.89(s,1H),7.83–7.77(m,1H),4.12(t,J＝6.3Hz,2H),3.66–3.54(m,4H),2.58(s,3H),2.56–2.50(m,2H),2.40(s,4H),1.97(p,J＝6.5Hz,2H).
实施例35：TAZ-3-39
制备方法与实施例1类似，不同之处在于，用2-甲氧基-4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ8.33(dd,J＝5.3,0.7Hz,1H),8.11(s,2H),7.61(dd,J＝5.3,1.4Hz,1H),7.40(dd,J＝1.3,0.7Hz,1H),4.12(t,J＝6.3Hz,2H),3.93(s,3H),3.62–3.54(m,4H),2.56–2.48(m,6H),2.03–1.89(m,2H).
实施例36：TAZ-3-40
制备方法与实施例1类似，不同之处在于，用2-氰基嘧啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ15.21(s,1H),9.01(d,J＝4.9Hz,2H),8.09(s,2H),7.64(t,J＝4.9Hz,1H),4.10(t,J＝6.3Hz,2H),3.62–3.52(m,4H),2.56–2.46(m,2H),2.38(s,4H),2.03–1.87(m,2H).
实施例37：YDA-4-43
制备方法与实施例1类似，不同之处在于，用4-氰基吡啶替代实施例1中的3-氰基吡啶。1H NMR(400MHz,DMSO-d6)δ14.97(s,1H),8.76(d,J＝5.9Hz,2H),8.14(s,2H),8.01(dd,J＝4.6,1.5Hz,2H),4.13(t,J＝6.3Hz,2H),3.67–3.48(m,4H),2.58–2.49(m,2H),2.40(s,4H),1.98(p,J＝6.6Hz,2H).
实施例38：YDA-4-31
制备方法与实施例1类似，不同之处在于，用4-三氟甲基苯腈替代实施例1中的3-氰基吡啶。1H NMR(400MHz,CD3OD)δ8.25(d,J＝7.6Hz,2H),8.10(s,2H),7.82(d,J＝7.6Hz,2H),4.16(t,J＝5.6Hz,2H),3.72(m,4H),2.79–2.63(m,2H),2.55(s,4H),2.12–2.07(m,2H).
药理实验
实验例1：本发明的化合物对黄嘌呤氧化酶的抑制作用方法：
采用非布索坦与托匹司他作为阳性对照，利用比色法测定各化合物在10μmol·L-1浓度下对黄嘌呤氧化酶的单浓度抑制率，对于单浓度抑制率较高的化合物，进一步测定其对黄嘌呤氧化酶的半数有效抑制浓度(IC50)。
具体方法为：将测试样品溶解于DMSO中，配置成10mM储备液。在37℃、pH7.4下，采用96孔板测定各化合物对XOD-催化黄嘌呤(XAN)水解作用的影响。反应体系中含10μmol·L-1的化合物(终浓度)，3U/L XOD(对照组不加，以0.01％DMSO代替)，及缓冲液(3.5mMKH2PO4,15.2mM K2HPO4,0.25mM EDTA,及50μM XAN,pH 7.4)。采用酶标仪检测293nm波长下产物尿酸的光度，来测定XOD-催化的黄嘌呤(XAN)水解作用，依据OD值计算抑制率。根据多个浓度的OD值计算IC50值。
结果：
分别测定了上述化合物在终浓度为10-5μmol·L-1时对黄嘌呤氧化酶的抑制率；测定并计算几种本发明化合物的IC50值。结果如表1所示。
表1.化合物对黄嘌呤氧化酶的抑制作用
ND：未测定。
实验例2：本发明化合物YDA-4-43的体内降尿酸作用方法：
将雄性ICR小鼠皮下注射氧嗪酸钾(300mg/kg体重)每日一次连续注射2周。选择血尿酸水平高且稳定的动物作为高尿酸血症(HUA)模型小鼠。将HUA小鼠按血尿酸水平随机分5组(n＝8)，分别为模型对照、非布索坦、不同剂量YDA-4-43组，分别灌胃给予水、阳性药非布索坦0.5mg/kg和化合物YDA-4-43 0.1，0.5，2.5mg/kg，连续给药2天。同时，设同批ICR小鼠作为正常对照组(n-＝8)，灌胃给予同体积水。监测动物血尿酸水平。
结果：
连续给药2天后，各组动物血尿酸水平如图1所示(***，p<0.001vs正常对照组；#，##，###，p<0.05,0.01，0.001vs模型对照组)，口服化合物YDA-4-43在0.1，0.5，2.5mg/kg均可显著降低HUA小鼠的血尿酸水平。化合物YDA-4-43降低HUA小鼠血尿酸水平的作用与阳性对照药非布索坦类似。
Claims (11)
1.一种由下述通式(I)表示的1,2,4-三唑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、取代或未取代的嘧啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吲哚基、取代或未取代的喹啉基、取代或未取代的萘基；
X选自氧或硫原子；
n为1,2,3,4或5；
R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；
上述取代基选自卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基、C1-C3烷磺酰基。
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，
n为1、2、3、4或5；
X选自氧或硫原子；
R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；
R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基。
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，
n为1,2,3,4或5；
R1为苯环上的单取代或多取代基团，选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基；
R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基、C1-C3烷磺酰基。
4.根据权利要求2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(IAa)所示的化合物及其生理上可接受的盐：
其中，R2选自氢、卤素、C1-C6烷基、C1-C3烷氧基、羟基、三氟甲基、卤代C1-C3烷基。
5.根据权利要求1-4任一项所述的化合物及其生理上可接受的盐，其特征在于，所述的化合物选自：
6.权利要求1～5任一项所述化合物的制备方法，其特征在于，包括以下步骤：
式II化合物与卤代物反应生成的式III化合物，式III化合物肼解得到式IV化合物，式IV化合物与氰基化合物反应生成式I化合物：
其中，n、X、R1及Ar的定义同权利要求1。
7.一种药物组合物，含有有效剂量的如权利要求1～5任一项所述的化合物及其生理上可接受的盐和在药学上可接受的载体。
8.根据权利要求7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。
9.如权利要求1～5任一项所述的化合物作为黄嘌呤氧化酶抑制剂的用途。
10.如权利要求1～5任一项所述的化合物及其生理上可接受的盐用于制备预防和/或治疗黄嘌呤氧化酶相关疾病的药物中的应用。
11.根据权利要求10所述的应用，所述的黄嘌呤氧化酶相关疾病选自高尿酸血症、痛风。
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