CN111763180A - 苯并氮杂环类化合物及其制法和药物用途 - Google Patents
苯并氮杂环类化合物及其制法和药物用途 Download PDFInfo
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- CN111763180A CN111763180A CN201910263449.XA CN201910263449A CN111763180A CN 111763180 A CN111763180 A CN 111763180A CN 201910263449 A CN201910263449 A CN 201910263449A CN 111763180 A CN111763180 A CN 111763180A
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Abstract
本发明公开了式I化合物所示新的苯并氮杂环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，以及所述化合物在治疗与人尿酸盐转运蛋白1(hURAT1)相关疾病如高尿酸血症、痛风等临床中的应用。
Description
技术领域
本发明涉及通式I的新型苯并氮杂环类化合物，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
尿酸是人类体内嘌呤类化合物的最终代谢产物，同时也与多种疾病的发病机制相关。高尿酸血症是一种因嘌呤代谢障碍，使尿酸积累而引起的疾病,其临床治疗主要有抑制尿酸生成和促进尿酸排泄两种途径。约90％的高尿酸血症与体内肾小管对尿酸的清除减少有关，随着尿酸盐转运蛋白1(urate transporter 1,URAT1)抑制剂雷西纳德(Lesinurad)在2015年底的上市，使得URAT1成为开发新型抗高尿酸血症药物的重要靶点。
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。
由于高尿酸血症的主要诱因是体内尿酸增多，因此有效地降低体内尿酸水平，是治疗高尿酸血症的关键。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)及促进尿酸排泄的人尿酸盐转运蛋白1(hURAT1)抑制剂(丙磺舒、苯溴马隆、雷西纳德等)，通过抑制肾小管中尿酸的重吸收，增加尿酸的排出，从而降低血尿酸水平。在2015年底上市的hURAT1抑制剂Lesinurad(雷西纳德)，证明了URAT1可以成为开发新型抗高尿酸血症药物的重要靶点。目前已上市的URAT1抑制剂的种类有限且存在活性偏低、需要联合用药或毒副作用较大等问题，因此亟需研制新的高效低毒的URAT1抑制剂。
本发明旨在提供一种新的苯并氮杂环类化合物，其具有较高的URAT1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和其他相关疾病。
发明内容
本发明的目的在于提供一种式I所示的新型苯并氮杂环类化合物。
本发明的另一目的在于提供一种制备式I所示的苯并氮杂环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所示的化合物在制备hURAT1抑制剂中的应用，以及在制备预防或治疗高尿酸血症或痛风的药物中的应用。
为了完成本发明的目的，本发明采用如下技术方案：
其中，R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；X选自氧或碳原子；n为0或1；A为共价键或羰基；R2选自氢或C1-C3烷基；Y选自氧、碳或氮原子；R3选自COR4或SO2R4，R4选自C1-C3烷基、三氟甲基或吡啶基；或R3选自CR5R6COOH或CR5R6CH2COOH，R5及R6独立地选自氢、C1-C3烷基。
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：
其中，m为0或1；W选自氧或硫原子；R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；R2选自氢、C1-C3烷基；R5及R6独立地选自氢、C1-C3烷基。
本发明的又一技术方案在于提供通式(IAa)所示的化合物及其生理上可接受的盐：
其中，R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；R5及R6独立地选自氢、C1-C3烷基。
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：
其中，R5及R6独立地选自氢、C1-C3烷基。
本发明的又一技术方案在于提供通式(IC)所示的化合物及其生理上可接受的盐：
其中，X选自氧或碳原子；n为0或1；R4选自C1-C3烷基、三氟甲基或吡啶基。
本发明的又一技术方案在于提供通式(ICa)所示的化合物及其生理上可接受的盐：
其中，R4选自C1-C3烷基、三氟甲基或吡啶基。
本发明的又一技术方案在于提供通式(ID)所示的化合物及其生理上可接受的盐：
其中，X选自氧或碳原子；n为0或1；R4选自C1-C3烷基、三氟甲基或吡啶基。
本发明的又一技术方案在于提供通式(IDa)所示的化合物及其生理上可接受的盐：
其中，R4选自C1-C3烷基、三氟甲基或吡啶基。
本发明的又一技术方案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：
本发明的又一技术方案在于提供式I所示的化合物的合成方法，包括以下步骤：
1)化合物A和B通过亲核反应生成中间体C，中间体C和化合物D通过C-N偶联反应生成中间体E，中间体E水解得到式IA目标化合物。
其中，m、W、R1、R2、R5及R6的定义同通式IA的定义。
2)巯基苯甲酸和溴乙酸乙酯发生亲核反应生成中间体F,中间体F和苯并吗啉发生酰化生成中间体G，中间体G水解得到目标物IB。
其中，R5及R6的定义同通式IB的定义。
3)化合物H和硝基苯甲酸发生酰化反应生成中间体J，中间体J还原生成中间体K，中间体K磺酰化生成目标物IC
其中n、X、R4的定义同通式IC的定义。
4)化合物H和硝基苯甲酸发生酰化反应生成中间体J，中间体J还原生成中间体K，中间体K酰化生成目标物ID
其中n、X、R4的定义同通式ID的定义。
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。
本发明的又一技术方案提供了本发明化合物在制备hURAT1抑制剂中的应用，以及在制备预防或治疗高尿酸血症或痛风的药物中的应用。
附图说明
图1：1A和1B为化合物TM-1和TM-2抗急性高尿酸血症药效学评价
图2：化合物TM-1和TM-2抗慢性高尿酸血症药效学评价
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：TM-1
1)中间体1-1的制备
将2-溴苯硫酚(188mg,1mmol)溶于10mL DMF中，加入2-溴-2-甲基丙酸乙酯(238.3mg,1.2mmol)，碳酸钾(138.2mg,1mmol)，85℃下反应10h。TLC监测完全反应后，蒸除大部分DMF，加入乙酸乙酯和水萃取，有机相用无水硫酸钠干燥，蒸除溶剂，得到黄色油状物297mg，柱层析分离(石油醚-乙酸乙酯200:1)，得到浅黄色油状物296mg，收率98％。HR-MS(ESI)m/z:Cald for C12H16BrO2S[M+H]+303.0049,found 303.0039
2)中间体1-2的制备
将苯并吗啉(324mg,2.4mmol)，中间体1-1(604mg,2mmol),溶于10mL无水甲苯中，加入碳酸铯(1.9g,6mmol)，Pd2(dba)3(73mg,0.08mmol)，X-Phos(76mg,0.2mmol)，氮气保护下，110℃下加热回流12h。TLC监测反应完全后，用加硅藻土的漏斗过滤掉反应残渣，滤液浓缩后，柱层析分离(石油醚-乙酸乙酯100:1)，最终得到浅色油状物543mg，收率76％。1H NMR(400MHz,CDCl3):δ7.49(d,J＝8.0Hz,1H,ArH),7.30(d,J＝4.0Hz,2H,ArH),7.19-7.10(m,1H,ArH),6.89-6.83(m,1H,ArH),6.74-6.64(m,2H,ArH),6.53-6.45(m,1H,ArH),4.49-4.17(m,2H,OCH2 CH2NH),4.01(q,J＝6.8Hz,2H,OCH2 CH3),3.80-3.48(m,2H,OCH2 CH2 NH),1.48(s,6H,C(CH3)2 ),1.18(t,J＝6.8Hz,3H,OCH2 CH3 )；HR-MS(ESI)m/z:Cald for C20H24NO3S[M+H]+358.1471,found 358.1461。
3)目标物TM-1的制备
将中间体1-2(60mg,0.2mmol)溶于3mL无水乙醇中，加入1M NaOH溶液6mL，室温反应48h，TLC监测完全反应后，蒸除乙醇，加入少量DCM萃取，分离出水相，用1N HCl调节pH至1～2左右，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸除溶剂，得到浅色固体23mg，收率41％。mp:151-153℃；1H NMR(400MHz,CDCl3):δ7.57(d,J＝7.6Hz,1H,ArH),7.37-7.27(m,2H,ArH),7.20-7.12(m,1H,ArH),6.85(dd,J＝7.6,2.8Hz,1H,ArH),6.75-6.63(m,2H,ArH),6.50-6.47(m,1H,ArH),4.43-4.15(m,2H,OCH2 CH2NH),3.81-3.53(m,2H,OCH2 CH2 NH),1.48(s,6H,C(CH3)2 )；HR-MS(ESI)m/z:Cald for C18H20NO3S[M+H]+330.1158,found 330.1155。
实施例2：TM-2
制备方法与实施例1类似,不同之处在于第一步用乙基1-溴环丁烷甲酸酯替代2-溴-2-甲基丙酸乙酯，最后一步收率50％。1H NMR(400MHz,DMSO-d6):δ7.37(dd,J＝8.0,2.4Hz,1H,ArH),7.20-7.12(m,3H,ArH),6.73(dd,J＝7.2,2.4Hz,1H,ArH),6.60-6.52(m,2H,ArH),6.06(dd,J＝7.2,2.4Hz,1H,ArH),4.26(s,2H,OCH2CH2N),3.48(s,2H,OCH2CH2N),2.74-2.62(m,2H,cyclobutane-H),2.01-1.94(m,3H,cyclobutane-H),1.84-1.76(m,1H,cyclobutane-H)；HR-ESI-MS:m/z＝342.1151[M+H]+,calculated for C19H20NO3S:342.1158.
实施例3：TM-3
制备方法与实施例1类似,不同之处在于第一步用2-溴戊酸乙酯替代2-溴-2-甲基丙酸乙酯，最后一步收率80％。1H NMR(400MHz,Acetone-d6):δ7.65(d,J＝5.6Hz,1H,ArH),7.31-7.29(m,3H,ArH),6.79-6.77(m,1H,ArH),6.63(s,2H,ArH),6.26(s,1H,ArH),4.33(s,2H,OCH2CH2NH),3.93-3.89(m,1H,SCH),3.62(s,2H,OCH2CH2NH)；1.90-1.86(m,1H,CH2CH2CH3),1.73(s,1H,CH2CH2CH3),1.46-1.43(m,2H,CH2CH2CH3),0.89(s,3H,CH2CH2CH3)；HR-ESI-MS:m/z＝344.1307[M+H]+,calculated for C19H22NO3S:344.1315.
实施例4：TM-4
制备方法与实施例1类似，不同之处在于第一步用2-溴异戊酸乙酯替代2-溴-2-甲基丙酸乙酯，最后一步收率60％。1H NMR(400MHz,Acetone-d6):δ7.64(d,J＝6.8Hz,1H,ArH),7.28(s,3H,ArH),6.79-6.77(m,1H,ArH),6.62(s,2H,ArH),6.27(s,1H,ArH),4.35(s,2H,OCH2 CH2N),3.70(d,J＝8.4Hz,1H,SCH),3.64(s,2H,OCH2 CH2 N)；2.14-2.09(m,1H,CH(CH3)2),1.10-1.06(m,6H,CH(CH3)2 )；HR-ESI-MS:m/z＝344.1305[M+H]+,calculated forC19H22NO3S:344.1315.
实施例5：TM-5
制备方法与实施例1类似，不同之处在于3-溴丙酸乙酯替代2-溴-2-甲基丙酸乙酯，最后一步收率66％。1H NMR(600MHz,Acetone-d6):δ7.48(d,J＝7.8Hz,1H,ArH),7.34-7.32(m,1H,ArH),7.28-7.26(m,2H,ArH),6.77-6.75(m,1H,ArH),6.62-6.58(m,2H,ArH),6.18-6.16(m,1H,ArH),4.32(d,J＝4.2Hz,2H,OCH2 CH2N),3.58(t,J＝4.2Hz,2H,OCH2 CH2 N),3.19(t,J＝7.2Hz,2H,SCH2 )；2.65(t,J＝7.2Hz,,2H,CH2 COOH)；HR-ESI-MS:m/z＝316.0990[M+H]+,calculated for C17H18NO3S:316.1002.
实施例6：TM-6
制备方法与实施例1类似，不同之处在于第一步用3-溴苯硫酚替代2-溴苯硫酚，最后一步收率56％。1H NMR(400MHz,Acetone-d6):δ7.39-7.28(m,3H,ArH),7.22(d,J＝7.6Hz,1H,ArH),6.92-6.90(m,1H,ArH),6.83(dd,J＝8.0,2.0Hz,1H,ArH),6.75-6.72(m,2H,ArH),4.27(t,J＝4.0Hz,2H,OCH2 CH2N),3.73(t,J＝4.4Hz,2H,OCH2 CH2 N),1.48(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝330.1146[M+H]+,calculated for C18H20NO3S:330.1158.
实施例7：TM-7
制备方法与实施例1类似，不同之处在于第一步用4-溴苯硫酚替代2-溴苯硫酚，最后一步收率55％。1H NMR(400MHz,Acetone-d6):δ7.45(d,J＝8.4Hz,2H,ArH),7.19(d,J＝8.4Hz,2H,ArH),6.98-6.92(m,1H,ArH),6.81(dd,J＝8.0,1.6Hz,1H,ArH),6.77-6.71(m,2H,ArH),4.24(t,J＝4.4Hz,2H,OCH2 CH2N),3.73(t,J＝4.4Hz,2H,OCH2 CH2 N),1.43(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝330.1143[M+H]+,calculated for C18H20NO3S:330.1158.
实施例8：TM-8
制备方法与实施例1类似，不同之处在于第二步用6-溴-3,4-二氢-2H-1，4-苯并恶嗪替代苯并吗啉，最后一步收率75％。1H NMR(400MHz,Acetone-d6):δ7.67(d,J＝8.0Hz,1H,ArH),7.48-7.45(m,1H,ArH),7.38(d,J＝8.0Hz,1H,ArH),7.34-7.30(m,1H,ArH),6.72(s,2H,ArH),6.31(s,1H,ArH),4.38-4.32(m,2H,OCH2 CH2N),3.69(t,J＝4.4Hz,2H,OCH2 CH2 N),1.50(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝408.0261[M+H]+,calculated for C18H19NO3SBr:408.0264.
实施例9：TM-9
制备方法与实施例1类似，不同之处在于第一步用2-溴苯酚替代2-溴苯硫酚，最后一步收率74％。1H NMR(400MHz,Acetone-d6):δ7.25-7.23(m,1H,ArH),7.16-7.11(m 1H,ArH),7.02-6.98(m,2H,ArH),6.74(dd,J＝7.6,1.6Hz,1H,ArH),6.64-6.56(m,2H,ArH),6.40(dd,J＝8.0,2.0Hz,1H,ArH),4.25(t,J＝4.8Hz,2H,OCH2 CH2N),3.64(t,J＝4.0Hz,2H,OCH2 CH2 N),1.45(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝314.1375[M+H]+,calculated forC18H20NO4:314.1387.
实施例10：TM-10
制备方法与实施例1类似，不同之处在于第二步用6-氯-3,4-二氢-2H-1，4-苯并恶嗪替代苯并吗啉，最后一步收率50％。1H NMR(400MHz,Acetone-d6):δ7.68(d,J＝7.6Hz,1H,ArH),7.49-7.45(m,1H,ArH),7.39(d,J＝8.0Hz,1H,ArH),7.34-7.30(m,1H,ArH),6.77(dd,J＝8.4,1.2Hz,1H,ArH),6.61-6.58(m,1H,ArH),6.17-6.16(m,1H,ArH),4.37-4.32(m,2H,OCH2 CH2N),3.69(t,J＝4.4Hz,2H,OCH2 CH2 N),1.48(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝364.0762[M+H]+,calculated for C18H19NO3ClS:364.0769.
实施例11：TM-11
制备方法与实施例1类似，不同之处在于第二步用6-甲基-3,4-二氢-2H-1，4-苯并恶嗪替代苯并吗啉，最后一步收率70％。1H NMR(400MHz,Acetone-d6):δ7.60(dd,J＝8.0,1.6Hz,1H,ArH),7.39-7.35(m,1H,ArH),7.29(dd,J＝8.0,1.2Hz,1H,ArH),7.23-7.19(m,1H,ArH),6.63(d,J＝8.4Hz,1H,ArH),6.42-6.40(m,1H,ArH),6.09(d,J＝1.6Hz,1H,ArH),4.28-4.20(m,2H,OCH2 CH2N),3.61(s,2H,OCH2 CH2 N),2.01(s,3H,CH3),1.45(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝344.1307[M+H]+,calculated for C19H22NO3S:344.1315.
实施例12：TM-12
制备方法与实施例1类似，不同之处在于第二步用2-甲基-3,4-二氢-2H-1，4-苯并恶嗪替代苯并吗啉，最后一步收率50％。1H NMR(400MHz,Acetone-d6):δ7.63(d,J＝5.6Hz,1H,ArH),7.40-7.20(m,3H,ArH),6.78-6.18(m,4H,ArH),4.48-4.17(m,1H,OCHCH2N),3.55-3.32(m,2H,OCHCH2 N),1.47(s,6H,C(CH3)2 ),1.37(d,J＝5.6Hz,3H,CHCH3 )；HR-ESI-MS:m/z＝344.1308[M+H]+,calculated for C19H22NO3S:344.1315.
实施例13：TM-13
制备方法与实施例1类似，不同之处在于第二步用6,8-二甲基-3,4-二氢-2H-1，4-苯并恶嗪替代苯并吗啉，最后一步收率48％。1H NMR(400MHz,Acetone-d6):δ7.62(d,J＝8.0Hz,1H,ArH),7.40-7.37(m,1H,ArH),7.30-7.28(m,1H,ArH),7.24-7.20(m,1H,ArH),6.34(s,1H,ArH),5.98(s,1H,ArH),4.33-4.27(m,2H,OCH2 CH2N),3.62(s,2H,OCH2 CH2 N),2.12(s,3H,CH3),2.00(s,3H,CH3),1.48(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝358.1463[M+H]+,calculated for C20H24NO3S:358.1471.
实施例14：TM-14
1).中间体14-1的制备
将2-溴苯硫酚(188mg,1mmol)溶于10mL DMF中，加入中间体14-1(238.3mg,1.2mmol)，碳酸钾(138.2mg,1mmol)，85℃下反应10h。TLC监测完全反应后，蒸除大部分DMF，加入乙酸乙酯和水萃取，有机相用无水硫酸钠干燥，蒸除溶剂，得到黄色油状物297mg，柱层析分离(石油醚-乙酸乙酯200:1)，得到浅黄色油状物296mg，收率98％。HR-MS(ESI)m/z:Cald for C12H16BrO2S[M+H]+303.0049,found 303.0039。
2).中间体14-2的制备
将6-溴-3,4-二氢-2H-1,4-苯并恶嗪(511mg,2.4mmol)，中间体14-1(604mg,2mmol),溶于10mL无水甲苯中，加入碳酸铯(1.9g,6mmol)，Pd2(dba)3(73mg,0.08mmol)，X-Phos(76mg,0.2mmol)，氮气保护下，110℃下加热回流12h。TLC监测反应完全后，用加硅藻土的漏斗过滤掉反应残渣，滤液浓缩后，柱层析分离(石油醚-乙酸乙酯150:1)，最终得到浅色油状物522mg，收率60％。HR-MS(ESI)m/z:Cald for C20H23BrNO3S[M+H]+436.0504,found436.0494。
3).中间体14-3的制备
将中间体14-2(200mg,0.46mmol)和对甲氧基苯硼酸(140mg,0.92mmol)溶于10mL二氧六环:水为4:1的混合溶剂中，加入反-二氯双(三-O-甲苯膦)钯(18mg,0.023mmol)和碳酸钾(158mg,1.15mmol)，氮气保护下，95℃下加热回流12h。TLC监测反应完全后，用加硅藻土的漏斗过滤掉反应残渣，滤液浓缩后，柱层析分离(石油醚-乙酸乙酯120:1)，最终得到浅色油状物149mg，收率70％。HR-MS(ESI)m/z:Cald for C27H30NO4S[M+H]+464.1817,found464.1812。
4).目标物TM-14的制备
将中间体14-3(93mg,0.2mmol)溶于3mL无水乙醇中，加入1M NaOH溶液6mL，室温反应48h，TLC监测完全反应后，蒸除乙醇，加入少量DCM萃取，分离出水相，用1N HCl调节pH至1～2左右，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸除溶剂，得到浅色油状物48mg，收率55％。1H NMR(400MHz,Acetone-d6):δ7.66(d,J＝7.6Hz,1H,ArH),7.42-7.36(m,2H,ArH),7.31-7.21(m,3H,ArH),6.88-6.82(m,4H,ArH),6.54(s,1H,ArH),4.39-4.27(m,2H,OCH2 CH2N),3.75(s,3H,OCH3),3.72-3.69(m,2H,OCH2 CH2 N),1.49(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝436.1562[M+H]+,calculated for C25H26NO4S:436.1577.
实施例15：TM-15
制备方法与实施例14类似，不同之处在于第三步用苯并-1,4-二氧六环-6-硼酸替代对甲氧基苯硼酸，最后一步收率58％。1H NMR(400MHz,Acetone-d6):δ7.67(dd,J＝8.0,1.2Hz,1H,ArH),7.43-7.39(m,2H,ArH),7.27-7.23(m,1H,ArH),6.87-6.82(m,4H,ArH),6.77-6.75(m,1H,ArH),6.51(d,J＝2.0Hz,1H,ArH),4.39-4.30(m,2H,OCH2 CH2N),4.22(s,4H,OCH2CH2 O),3.72(d,J＝3.2Hz,2H,OCH2 CH2 N),1.50(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝464.1507[M+H]+,calculated for C26H26NO5S:464.1526.
实施例16：TM-16
制备方法与实施例14类似，不同之处在于第三步用苯硼酸替代对甲氧基苯硼酸，最后一步收率68％。1H NMR(400MHz,Acetone-d6):δ7.64(d,J＝8.0Hz,1H,ArH),7.41-7.35(m,4H,ArH),7.30-7.15(m,4H,ArH),6.92-6.83(m,2H,ArH),6.57(s,1H,ArH),4.37-4.29(m,2H,OCH2 CH2N),3.70(d,J＝3.6Hz,2H,OCH2 CH2 N),1.47(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝406.1458[M+H]+,calculated for C24H24NO3S:406.1471.
实施例17：TM-17
制备方法与实施例14类似，不同之处在于第三步用对氟苯硼酸替代对甲氧基苯硼酸最后一步收率65％。1H NMR(400MHz,Acetone-d6):δ7.64(d,J＝8.0Hz,1H,ArH),7.41-7.35(m,4H,ArH),7.24-7.21(m,1H,ArH),7.07-7.02(m,2H,ArH),6.88-6.82(m,2H,ArH),6.52(s,1H,ArH),4.37-4.29(m,2H,OCH2 CH2N),3.69(d,J＝3.6Hz,2H,OCH2 CH2 N),1.47(s,6H,C(CH3)2 )；HR-ESI-MS:m/z＝424.1361[M+H]+,calculated for C24H23NO3FS:424.1377.
实施例18：TM-18
1).中间体1的制备
将2-巯基苯甲酸(1540mg,10mmol)加入30mL乙腈中，然后再依次加入溴乙酸乙酯(2004mg,12mmol),碳酸钠(1590mg,15mmol)在80℃反应6h。TLC监测完全反应后，将反应液用100mL乙酸乙酯稀释，然后水洗一次，有机层用无水硫酸钠干燥，减压浓缩得产品白色固体2100mg,收率87％。1H NMR(400MHz,DMSO-d6):δ13.12(s,1H),7.90(dd,J＝7.6Hz,1.6Hz,1H),7.54-7.50(m,1H),7.35(d,J＝7.6Hz,1H),7.23(td,J＝7.6Hz,1.6Hz,1H),4.11(q,J＝7.2Hz,2H),3.90(s,2H),1.16(t,J＝7.2Hz,3H).
2).中间体2的制备
将中间体18-1(264mg,1.1mmol)加入二氯甲烷10mL,加入3滴DMF，然后缓慢滴加草酰氯(190mg,1.5mmol),室温下反应1h,减压浓缩除去反应溶剂，再将其溶于二氯甲烷10mL中备用；将苯并吗啉(135mg,1mmol),三乙胺(202mg,2mmol)加入二氯甲烷5mL中，然后缓慢滴加上述制备的酰氯，室温反应2h,TLC检测反应完全。将反应液用二氯甲烷稀释，水洗，减压浓缩拌样，柱层析得到产品180mg,收率50％。HR-MS(ESI)m/z:Cald for C19H19NO4S[M+H]+358.1035,found 358.1039。
3).目标物TM-18的制备
将中间体18-2(180mg,0.5mmol)加入THF-EtOH-H2O(2:1:1)混合溶剂8mL中，然后再加入氢氧化锂一水合物(42mg,1.0mmol),室温反应1-2h,TLC检测反应完全。减压蒸除有机溶剂，加入少量乙醚萃取，分离出水相，用1N HCl调节pH至1～2左右，加入乙酸乙酯萃取，有机相依次用水洗，饱和食盐水洗，无水硫酸钠干燥，蒸除溶剂，得到目标化合物98mg，收率58％。1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.64-7.55(brs,1H),7.50(d,J＝8.1Hz,1H),7.44-7.39(m,1H),7.35(d,J＝6.9Hz,1H),7.27(t,J＝7.2Hz,1H),7.02(t,J＝7.2Hz,1H),6.90(d,J＝7.7Hz,1H),6.74(brs,1H),4.34(s,2H),3.74(brs,4H).
实施例19：TM-19
制备方法与实施例18类似，不同之处在于，第一步用3-巯基苯甲酸替代实施例1中的2-巯基苯甲酸。1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.56–7.23(m,5H),7.06–6.97(m,1H),6.91(dd,J＝8.2,1.5Hz,1H),6.75(t,J＝7.6Hz,1H),4.45–4.13(m,2H),3.85–3.81(m,4H).
实施例20：TM-20
1).中间体1的制备
将间硝基苯甲酸(1002mg,6mmol)加入DCM 10mL中，滴入5滴DMF，然后缓慢加入草酰氯(953mg,7.5mmol)室温下搅拌反应1h，减压除去反应溶剂，然后再将其溶解于DCM 10mL中备用；将吲哚林(595mg,5mmol)加入DCM 5mL中，再加入三乙胺(1010mg,10mmol)，然后在缓慢加入上述酰氯，室温下反应2h,将反应液用DCM稀释，水洗2次，有机相干燥，浓缩拌样，柱层析得产品1250mg，收率93％。1H NMR(400MHz,DMSO-d6)δ8.44–8.31(m,2H),8.07(d,J＝7.3Hz,2H),7.80(t,J＝8.0Hz,1H),7.30(d,J＝7.4Hz,1H),7.22(s,1H),7.15–7.00(m,1H),4.02(t,J＝7.8Hz,2H),3.10(t,J＝7.8Hz,2H).
2).中间体2的制备
将中间体1(536mg,2mmol)加入THF-MeOH(2:1)混合溶剂10mL中，加入10％钯碳60mg,用氢气置换反应体系，室温下反应4h,TLC监测反应完全，硅藻土过滤，甲醇洗2次，减压浓缩得产品490mg，收率95％。1H NMR(400MHz,DMSO-d6)δ8.51(brs,1H),7.25(d,J＝7.3Hz,1H),7.22–7.07(m,2H),7.00(t,J＝7.2Hz,1H),6.75–6.60(m,3H),5.29(s,2H),3.98(t,J＝8.3Hz,2H),3.09–3.00(m,2H).
3).目标物TM-20的制备
将中间体2(120mg,0.5mmol)加入DCM 5mL中，缓慢滴加三氟甲磺酸酐(169mg,0.6mmol)，然后加入吡啶(79mg,1.0mmol)，室温下反应2h,TLC监测反应完全，将反应液用DCM 30mL稀释，水洗2次，有机相减压浓缩，拌样柱层析得产品80mg,收率43％。1H NMR(400MHz,Acetone-d6)δ10.44(brs,1H),8.10(brs,1H),7.62–7.53(m,4H),7.26(d,J＝8.6Hz,1H),7.17(s,1H),7.04(t,J＝7.4Hz,1H),4.06(t,J＝8.3Hz,2H),3.15(t,J＝8.3Hz,2H).
实施例21：TM-21
制备方法与实施例20类似，不同之处在于，第三步用三氟乙酸酐替代实施例20中的三氟甲磺酸酐，最后一步收率61％。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.07(brs,1H),7.88(s,1H),7.81(d,J＝8.1Hz,1H),7.56–7.51(m,1H),7.45(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.18(brs,1H),7.07–7.01(m,1H),4.01(t,J＝8.2Hz,2H),3.09(t,J＝8.2Hz,2H).
实施例22：TM-22
制备方法与实施例20类似，不同之处在于，第一步用2-硝基苯甲酸替代实施例20中的3-硝基苯甲酸，最后一步收率40％。1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝8.2Hz,1H),7.56–7.44(m,2H),7.41–7.31(m,2H),7.29–7.25(m,1H),7.22(d,J＝8.9Hz,1H),7.11–7.03(m,1H),3.82(t,J＝8.4Hz,2H),3.04(t,J＝8.4Hz,2H).
实施例23：TM-23
制备方法与实施例20类似，不同之处在于，第一步用2-硝基苯甲酸替代实施例20中的3-硝基苯甲酸，第三步用三氟乙酸酐替代三氟甲磺酸酐，最后一步收率54％。1H NMR 1HNMR(400MHz,DMSO-d6)δ11.32(s,1H),8.04(d,J＝6.4Hz,1H),7.64(d,J＝6.4Hz,1H),7.56(t,J＝7.4Hz,1H),7.48(d,J＝7.7Hz,1H),7.43(t,J＝7.1Hz,1H),7.27(d,J＝7.3Hz,1H),7.21(brs,1H),7.11–6.76(m,1H),3.97(t,J＝8.2Hz,2H),3.07(t,J＝8.2Hz,2H).
实施例24：TM-24
制备方法与实施例20类似，不同之处在于，第三步用甲磺酸酐替代三氟甲磺酸酐，最后一步收率61％。1H NMR(400MHz,Chloroform-d)δ8.22(brs,1H),7.55(s,1H),7.47–7.37(m,3H),7.36–7.29(m,1H),7.22(d,J＝8.0Hz,1H),7.04(brs,1H),4.05(brs,2H),3.12(t,J＝8.2Hz,2H),2.98(s,3H).
实施例25：TM-25
制备方法与实施例20类似，不同之处在于，第一步用1,2,3,4-四氢喹啉替代吲哚林，最后一步收34％。1H NMR(400MHz,Chloroform-d)δ9.65(s,1H),7.61(s,1H),7.41(ddd,J＝8.2,2.2,0.8Hz,1H),7.18(d,J＝7.5Hz,1H),7.13(t,J＝7.9Hz,1H),7.05(td,J＝7.5,1.0Hz,1H),6.89(t,J＝6.3Hz,2H),6.66(brs,1H),3.95(t,J＝6.6Hz,2H),2.85(t,J＝6.6Hz,2H),2.12–2.04(m,2H).
实施例26：TM-26
制备方法与实施例20类似，不同之处在于，第一步用1,2,3,4-四氢喹啉替代吲哚林，第三步用三氟乙酸酐替代三氟甲磺酸酐，最后一步收率34％。1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),7.79(t,J＝1.7Hz,1H),7.72(dd,J＝7.8,1.6Hz,1H),7.34(t,J＝7.9Hz,1H),7.20(d,J＝7.3Hz,1H),7.09(d,J＝7.7Hz,1H),7.01(td,J＝7.4,1.0Hz,1H),6.97–6.89(m,1H),6.83(d,J＝7.4Hz,1H),3.75(t,J＝6.4Hz,2H),2.81(t,J＝6.6Hz,2H),1.99-1.91(m,2H).
实施例27：TM-27
制备方法与实施例20类似，不同之处在于第一步用1,2,3,4-四氢喹啉替代吲哚林；并且用2-硝基苯甲酸替代3-硝基苯甲酸，最后一步收率57％。1H NMR(400MHz,Acetone-d6)δ10.13(s,1H),7.59–7.47(m,2H),7.26–7.20(m,3H),7.06–6.91(m,3H),3.84(t,J＝6.4Hz,2H),2.89(t,J＝6.4Hz,2H),2.08–2.02(m,2H).
实施例28：TM-28
制备方法与实施例20类似，不同之处在于第一步用1,2,3,4-四氢喹啉替代吲哚林；并且用2-硝基苯甲酸替代3-硝基苯甲酸，第三步用三氟乙酸酐替代三氟甲磺酸酐，最后一步收率61％。1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.51–7.41(m,2H),7.35–7.05(m,4H),6.99(t,J＝7.3Hz,1H),6.96–6.83(m,1H),3.70(brs,2H),2.79(t,J＝6.6Hz,2H),1.97–1.90(m,2H).
实施例29：TM-29
制备方法与实施例20类似，不同之处在于第一步用苯并吗啉替代吲哚林；并且用2-硝基苯甲酸替代3-硝基苯甲酸，第三步用三氟乙酸酐替代三氟甲磺酸酐，最后一步收率41％。1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),8.28–7.32(m,5H),7.00(t,J＝7.2Hz,1H),6.89(d,J＝8.0Hz,1H),6.76(brs,1H),4.33(brs,2H),3.79(brs,2H).
实施例30：TM-30
制备方法与实施例20类似，不同之处在于第一步用苯并吗啉替代吲哚林，第三步用三氟乙酸酐替代三氟甲磺酸酐，最后一步收率69％。1H NMR(400MHz,Chloroform-d)δ9.05(s,1H),7.91(d,J＝7.7Hz,1H),7.74(s,1H),7.33(t,J＝7.8Hz,1H),7.19(d,J＝7.4Hz,1H),7.11–6.84(m,3H),6.69(brs,1H),4.38(brs,2H),4.01(brs,2H).
实施例31：TM-31
制备方法与实施例20类似，不同之处在于第一步用苯并吗啉替代吲哚林，最后一步收率42％。1H NMR(400MHz,Chloroform-d)δ9.16(s,1H),7.56(s,1H),7.48(d,J＝8.0Hz,1H),7.31-7.21(m,3H),7.11–6.99(m,1H),6.93(d,J＝7.9Hz,1H),6.68(s,1H),4.42(brs,2H),4.05(brs,2H).
实施例32：TM-32
制备方法与实施例20类似，不同之处在于第一步用苯并吗啉替代吲哚林，第三步用吡啶-3-磺酰氯替代三氟甲磺酸酐，最后一步收率46％。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.87(d,J＝2.3Hz,1H),8.81(dd,J＝4.8,1.6Hz,1H),8.11(ddd,J＝8.1,2.3,1.6Hz,1H),7.62(ddd,J＝8.1,4.8,0.8Hz,1H),7.37–7.27(m,1H),7.24–7.21(m,2H),7.18(d,J＝7.5Hz,1H),7.14–6.92(m,2H),6.89(dd,J＝8.3,1.5Hz,1H),6.65(t,J＝7.5Hz,1H),4.28(t,J＝4.4Hz,2H),3.75(t,J＝4.4Hz,2H).
药理实验
实验例1：本发明的化合物对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，并用XL-fit软件进行分析数据。
结果：
分别测定了上述化合物在终浓度为10μmol·L-1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
ND：未测定。
实验例2：本发明化合物的体内降尿酸作用
1)抗急性高尿酸血症药效学评价
方法：
雄性ICR小鼠，22-24g，皮下注射氧嗪酸钾联合口服次黄嘌呤，形成急性高尿酸血症小鼠模型。模型动物分为6组(n＝8)：模型对照Mod组、Feb、ZL-10-16、ZL-11-1、SMJ-3-21、SMJ-3-15组，分别灌胃给予水、阳性药非布索坦0.5mg/kg和受试药ZL-10-16 50mg/kg、ZL-11-1 50mg/kg、SMJ-3-21 50mg/kg、SMJ-3-15 50mg/kg，观察给药后血尿酸水平的变化，并计算血尿酸-时间曲线下面积(AUC)。同时，设同批正常小鼠作为正常对照Con组，灌胃给予同体积水。
结果：
如图1A和图1B所示，与阳性对照药非布索坦类似，受试药ZL-10-16(TM-1)、SMJ-3-15(TM-2)均可显著降低急性高尿酸血症小鼠的血尿酸峰值，降低血尿酸-时间曲线下面积AUC水平。
2)抗慢性高尿酸血症药效学评价
方法：
雄性ICR小鼠，22-24g，皮下注射氧嗪酸钾(300mg/kg体重，s.c.)，每日一次。连续注射2周。连续2天内眦取血测定血尿酸水平，选择尿酸水平较高且较稳定的动物作为HUA小鼠模型。将HUA模型按血尿酸水平随机分为6组(n＝8)：模型对照组(Mod)、非布索坦组(Feb)及受试药ZL-10-16、ZL-11-1、SMJ-3-21、SMJ-3-15组。分别灌胃给予水、阳性药非布索坦0.5mg/kg和受试药ZL-10-16、ZL-11-1、SMJ-3-21、SMJ-3-15各50mg/kg，连续给药2天。同时，设同批正常小鼠作为正常对照组(Con)，灌胃给予同体积水。监测动物血尿酸水平。
结果：
连续给药2天各组血尿酸水平，如图2所示，与阳性对照药非布索坦类似，受试药ZL-10-16(TM-1)、SMJ-3-15(TM-2)均可显著降低HUA小鼠的血尿酸水平。
Claims (14)
1.一种由下述通式(I)表示的苯并氮杂环类化合物及其生理上可接受的盐，
其中，
R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；
X选自氧或碳原子；
n为0或1；
A为共价键或羰基；
R2选自氢或C1-C3烷基；
Y选自氧、硫或氮原子；
R3选自COR4或SO2R4，R4选自C1-C3烷基、三氟甲基或吡啶基；或R3选自CR5R6COOH或CR5R6CH2COOH，R5及R6独立地选自氢、C1-C3烷基。
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，
m为0或1；
W选自氧或硫原子；
R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；
R2选自氢、C1-C3烷基；
R5及R6独立地选自氢、C1-C3烷基。
3.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，
R1选自氢、C1-C3烷基、C1-C3烷氧基、卤素、取代或未取代的苯基，取代基选自卤素、C1-C3烷基、C1-C3烷氧基；
R5及R6独立地选自氢、C1-C3烷基。
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，R5及R6独立地选自氢、C1-C3烷基。
5.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(IC)所示的化合物及其生理上可接受的盐：
其中，
X选自氧或碳原子；
n为0或1；
R4选自C1-C3烷基、三氟甲基或吡啶基。
6.根据权利要求5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(ICa)所示的化合物及其生理上可接受的盐：
其中，R4选自C1-C3烷基、三氟甲基或吡啶基。
7.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(ID)所示的化合物及其生理上可接受的盐：
其中，
X选自氧或碳原子；
n为0或1；
R4选自C1-C3烷基、三氟甲基或吡啶基。
8.根据权利要求7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(IDa)所示的化合物及其生理上可接受的盐：
其中，R4选自C1-C3烷基、三氟甲基或吡啶基。
9.根据权利要求1-8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：
10.权利要求1～9任一项所述化合物的制备方法，其特征在于，包括以下步骤：
1)化合物A和B通过亲核反应生成中间体C，中间体C和化合物D通过C-N偶联反应生成中间体E，中间体E水解得到式IA目标化合物；
其中，m、W、R1、R2、R5及R6的定义同权利要求2；
2)巯基苯甲酸和溴乙酸乙酯发生亲核反应生成中间体F,中间体F和苯并吗啉发生酰化生成中间体G，中间体G水解得到目标物IB；
其中，R5及R6的定义同权利要求4；
3)化合物H和硝基苯甲酸发生酰化反应生成中间体J，中间体J还原生成中间体K，中间体K磺酰化生成目标物IC；
其中n、X、R4的定义同权利要求5；
4)化合物H和硝基苯甲酸发生酰化反应生成中间体J，中间体J还原生成中间体K，中间体K酰化生成目标物ID；
其中n、X、R4的定义同权利要求7。
11.一种含有有效剂量的如权利要求1～9任一项所述的任一化合物和在药学上可接受的载体的药物组合物。
12.根据权利要求11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。
13.如权利要求1～9任一项所述的化合物作在制备hURAT1抑制剂中的应用。
14.如权利要求1～9任一项所述的化合物在制备预防或治疗高尿酸血症或痛风的药物中的应用。
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| CN113234060A (zh) * | 2021-04-30 | 2021-08-10 | 山东大学 | 一种稠杂环吡啶巯乙酸类衍生物及其制备方法与应用 |
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| WO2017205536A2 (en) * | 2016-05-24 | 2017-11-30 | Genentech, Inc. | Therapeutic compounds and uses thereof |
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| JPH04321669A (ja) * | 1991-04-19 | 1992-11-11 | Otsuka Pharmaceut Co Ltd | バソプレシン拮抗剤 |
| US20050070573A1 (en) * | 2003-04-11 | 2005-03-31 | Chu-Chung Lin | Aminoquinoline compounds |
| WO2006057460A1 (ja) * | 2004-11-29 | 2006-06-01 | Japan Tobacco Inc. | 窒素含有縮合環化合物及びその用途 |
| WO2017205536A2 (en) * | 2016-05-24 | 2017-11-30 | Genentech, Inc. | Therapeutic compounds and uses thereof |
| CN108084186A (zh) * | 2016-11-16 | 2018-05-29 | 江苏新元素医药科技有限公司 | Urat1抑制剂及其应用 |
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| WO2022026500A1 (en) * | 2020-07-29 | 2022-02-03 | Fmc Crporation | Substituted haloalkyl sulfonanilide herbicides |
| CN112194667A (zh) * | 2020-11-06 | 2021-01-08 | 湖南科技大学 | 取代1,4-苯并噁嗪并二氮*类化合物及其制备方法和用途 |
| CN113234060A (zh) * | 2021-04-30 | 2021-08-10 | 山东大学 | 一种稠杂环吡啶巯乙酸类衍生物及其制备方法与应用 |
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| CN111763180B (zh) | 2023-06-09 |
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