CN110452168A - N-苯基-n-喹啉羧酸类化合物及其制法和药物用途 - Google Patents
N-苯基-n-喹啉羧酸类化合物及其制法和药物用途 Download PDFInfo
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- CN110452168A CN110452168A CN201810424880.3A CN201810424880A CN110452168A CN 110452168 A CN110452168 A CN 110452168A CN 201810424880 A CN201810424880 A CN 201810424880A CN 110452168 A CN110452168 A CN 110452168A
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- Prior art keywords
- compound
- phenyl
- substituted
- halogen
- hydroxy
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Abstract
本发明公开了式I化合物所示N‑苯基‑N‑喹啉羧酸类化合物及其生理上可接受的盐，含有所述化合物的药物制剂，以及所述化合物的在制备预防或治疗高尿酸血症和痛风中的应用。
Description
技术领域
本发明涉及治疗高尿酸血症和痛风相关的药物领域。具体而言，本发明涉及对高尿酸血症和痛风有治疗作用的新型N-苯基-N-喹啉羧酸类化合物、制备方法、含有它们的药物组合物以及在医药上的用途。
背景技术
据估计，目前全球痛风患者有2000多万。痛风是一种慢性代谢性疾病，以高尿酸血症和尿酸单钠盐(MSU)沉积在关节等部位而引起的疼痛为主要特征。研究发现高尿酸血症是痛风发病最重要的生化基础。目前用于治疗痛风的药物包括用于缓解疼痛的抗炎药物(如秋水仙碱等)、抑制尿酸生成药物(以别嘌呤醇和非布索坦为代表的黄嘌呤氧化酶抑制剂)、促尿酸排泄药物(以丙磺舒、苯溴马隆为代表的尿酸盐阴离子转运蛋白(urate-aniontransporter，URAT1)抑制剂)和尿酸酶(以pegloticase为代表)。这些药物存在不同程度的毒副作用，如苯溴马隆有引起爆发性肝炎的危险，别嘌呤醇有肝脏及骨髓毒性和变态反应等不良反应，丙磺舒与非甾体抗炎药、青霉素等药物的相互作用也限制了其临床应用。
在2015年底，由Ardea公司研发的Lesinurad(RDEA-594)，作为一种新型URAT1抑制剂被批准上市，是一种通过抑制URAT1重吸收尿酸盐促进排泄的口服药物，与黄嘌呤氧化酶抑制剂合用能够有效降低血尿酸浓度。
本发明公开了一类新型N-苯基-N-喹啉羧酸类化合物，这些化合物可用于制备治疗高尿酸血症和痛风的药物。
发明内容
本发明的目的在于提供一种式I所示的N-苯基-N-喹啉羧酸类化合物。
本发明的另一目的在于提供式I所示的N-苯基-N-喹啉羧酸类化合物及其类似物的制备方法。
本发明的又一目的在于提供式I所示的化合物在制备预防或治疗高尿酸血症或痛风药物中的用途。
为了完成本发明的目的，本发明采用如下技术方案：
本发明是涉及具有通式I的新型化合物及生理上可接受的盐：
其中，R1选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、C1-C4烷基；优选的R1为氢、卤素、甲氧基、苯基或C1-C2烷基；
R2选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、取代或未取代的萘基、C1-C4烷基、一或多取代的C1-C4烷基；优选的R2选自氢、卤素、取代或未取代的苯基、萘基、三氟甲基；
所述取代基选自一个或多个羟基、甲氧基或卤素；优选的取代基为甲氧基或氟；
L选自C1-C4烷基或苯基；优选的L选自C1-C4烷基或苯基。
最优选的化合物选自下列群组：
本发明还公开了制备本发明化合物的方法，所述化合物由下述方法一或方法二合成：
方法一：式II化合物与式III化合物通过亲核取代反应生成式IV重要中间体，后者与化合物V通过金属偶联反应生成化合物VI，再经过水解反应得到式Ia化合物：
其中，R1选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、C1-C4烷基；
R2选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、取代或未取代的萘基、C1-C4烷基、一或多取代的C1-C4烷基；
所述取代基选自一个或多个羟基、甲氧基或卤素。
L选自C1-C4烷基或苯基；
R3选自氰基或乙氧甲酰基；
X选自氯或溴；
方法二：以间氟苯胺和4-溴丁腈为原料生成4-((3-氟苯基)氨基)丁腈，后者与6-溴-4-碘喹啉反应得到4-((3-氟苯基)(6-溴喹啉-4-代)氨基)丁腈，再与各种芳基硼酸类化合物经金属偶联反应得到化合物VII，最后经过水解反应得到式Ib化合物：
其中，R2选自取代或未取代的苯基、萘基；
所述取代基选自一个或多个羟基、甲氧基或卤素。
本发明再一方面还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的通式1化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-500mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的第四方面是提供了所述通式I的N-苯基-N-喹啉羧酸类化合物及其生理上可接受的盐在制备预防或治疗高尿酸血症或痛风药物中的应用。该类化合物具有URAT1的抑制作用，可作为有效成分用于制备高尿酸血症和痛风的治疗药物。
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。
实施例1
Reagents and conditions:a)碳酸钾,碘化钾,80℃；b)醋酸钯,碳酸铯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,110℃,N2；c)氢氧化钠,乙醇,50℃
A.化合物IV-1的合成
将化合物II-1(1.1g,10mmol)，化合物III-1(1.5g,10mmol)溶于20mL DMF中，加入碳酸钾(2.8g,20mmol)，碘化钾(332mg,0.2mmol)，85℃反应10h。TLC监测反应完全后，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，蒸除溶剂后柱层析分离(石油醚-乙酸乙酯10:1-6:1)，得到化合物IV-1，浅黄色油状物1.44g，收率：80％。HR-ESI-MS:m/z＝179.0974[M+H]+,calculated for C10H12FN2:179.0979.
B.化合物VI-1的合成
向化合物IV-1(128mg,0.7mmol)，化合物V-1(200mg,0.9mmol)，碳酸铯(328mg,1mmol)，醋酸钯(8mg,0.03mmol)，xant-phos(17mg,0.03mmol)中，加入8mL无水1,4-二氧六环，氮气保护下110℃反应12h。反应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8:1-1:1)，得到化合物VI-1，白色油状物164mg，收率50％。HR-ESI-MS:m/z＝374.1264[M+H]+,calculated for C20H16F4N3:374.1275.
C.化合物Ia-1的合成
将化合物VI-1(30mg,0.08mmol)溶于2mL无水乙醇中，加入6mL 1M NaOH溶液，50℃下加热回流8h。TLC监测反应完全后，蒸除溶剂，加入少量DCM萃取萃取，分离出水相，用1NHCl中和到pH至1～2左右，再用乙酸乙酯萃取，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，得到化合物Ia-1，黄色固体24mg，收率:77％。1H NMR(400MHz,DMSO-d6):δ12.08(s,1H),8.98(d,J＝4.8Hz,1H),8.17(d,J＝8.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.83(s,1H),7.54(d,J＝5.2Hz,1H),7.18(dd,J＝15.2,7.6Hz,1H),6.83-6.67(m,2H),6.55(d,J＝8.4Hz,1H),3.99-3.84(m,2H),2.29(t,J＝6.8Hz,2H),1.91-1.74(m,2H)；HR-ESI-MS:m/z＝393.1209[M+H]+,calculated for C20H17F4N2O2:393.1221.
实施例2～19
按照实施例1的合成方法制备实施例2～19。
实施例2：合成方法与实施例1类似，不同之处在于第一步用间氯苯胺替代间氟苯胺，收率70％。
实施例3：合成方法与实施例1类似，不同之处在于第二步用6-氟-4-氯喹啉替代4-氯-6-(三氟甲基)喹啉，收率52％。
实施例4：合成方法与实施例1类似，不同之处在于第二步用4-氯-7-(三氟甲基)喹啉替代4-氯-6-(三氟甲基)喹啉，收率40％。
实施例5：合成方法与实施例1类似，不同之处在于第一步用5-溴戊腈替代4-溴丁腈，收率72％。
实施例6：合成方法与实施例1类似，不同之处在于第一步用间溴苯胺替代间氟苯胺，收率60％。
实施例7：合成方法与实施例1类似，不同之处在于第一步用对氯苯胺替代间氟苯胺，收率70％。
实施例8：合成方法与实施例1类似，不同之处在于第一步用对氟苯胺替代间氟苯胺，收率75％。
实施例9：合成方法与实施例1类似，不同之处在于第二步用4-氯-6-溴喹啉替代4-氯-6-(三氟甲基)喹啉，收率50％。
实施例10：合成方法与实施例1类似，不同之处在于第二步用4,7-二氯喹啉替代4-氯-6-(三氟甲基)喹啉，收率30％。
实施例11：合成方法与实施例1类似，不同之处在于第一步用邻氟苯胺替代间氟苯胺，收率63％。
实施例12：合成方法与实施例1类似，不同之处在于第二步用4-氯喹啉替代4-氯-6-(三氟甲基)喹啉，收率55％。
实施例13：合成方法与实施例1类似，不同之处在于第一步用3-甲基苯胺替代间氟苯胺，收率77％。
实施例14：合成方法与实施例1类似，不同之处在于第一步用3-叔丁基苯胺替代间氟苯胺，收率76％。
实施例15：合成方法与实施例1类似，不同之处在于第一步用6-溴己腈替代4-溴丁腈，收率62％。
实施例16：合成方法与实施例1类似，不同之处在于第一步用3-甲氧基苯胺替代间氟苯胺，收率79％。
实施例17：合成方法与实施例1类似，不同之处在于第一步用苯胺替代间氟苯胺，收率66％。
实施例18：合成方法与实施例1类似，不同之处在于第一步用3-氯甲基苯甲酸乙酯替代4-溴丁腈，收率60％。
实施例19：合成方法与实施例1类似，不同之处在于第一步用3-氨基联苯替代间氟苯胺，收率75％。
参照实施例1操作步骤，最终制备了下表所列化合物。
实施例2：
黄色固体，产率70％
1H NMR(400MHz,CH3OH-d4):δ8.79(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.75(d,J＝2.0Hz,1H),7.72(dd,J＝9.2,2.0Hz,1H),7.48(d,J＝5.2Hz,1H),7.22-7.16(m,1H),6.68-6.60(m,3H),3.97(t,J＝8Hz,2H),2.22(t,J＝7.2Hz,2H),2.01-1.94(m,2H)；.HR-ESI-MS:m/z＝409.0922[M+H]+,calculated for C20H17N2O2ClF3:409.0925.
实施例3：
黄色固体，产率65％
1H NMR(400MHz,Acetone-d6):δ9.04(d,J＝4.8Hz,1H),8.24(d,J＝9.2Hz,1H),8.06(s,1H),7.90(dd,J＝8.8,2.0Hz,1H),7.62(d,J＝4.8Hz,1H),7.27-7.21(m,1H),6.80-6.76(m,1H),6.73-6.68(m,2H),4.10(t,J＝7.6Hz,2H),2.48(t,J＝7.2Hz,2H),2.06-2.03(m,2H)；HR-ESI-MS:m/z＝343.1248[M+H]+,calculated for C19H17N2O2F2:343.1253.
实施例4：
黄色固体，产率70％
1H NMR(400MHz,CDCl3):δ8.97(s,1H),8.39(s,1H),7.74(d,J＝8.8Hz,1H),7.47(d,J＝8.8Hz,1H),7.41(s,1H),7.17-7.11(m,1H),6.67-6.54(m,3H),3.97(s,2H),2.45(s,2H),2.06(s,2H)；HR-ESI-MS:m/z＝393.1216[M+H]+,calculated for C20H17F4N2O2:393.1221.
实施例5：
黄色固体，产率64％
1H NMR(400MHz,Acetone-d6):δ9.03(s,1H),8.25(d,J＝8.4Hz,1H),8.04(s,1H),7.90(d,J＝8.4Hz,1H),7.56(d,J＝5.2Hz,1H),7.28-7.22(m,1H),6.72-6.68(m,3H),4.07(t,J＝8.0Hz,2H),2.37-2.33(m,2H),1.88-1.84(m,2H),1.76-1.69(m,2H)；HR-ESI-MS:m/z＝407.1367[M+H]+,calculated for C21H19F4N2O2:407.1377.
实施例6：
黄色固体，产率50％
1H NMR(400MHz,CH3OH-d4):δ8.87(d,J＝5.2Hz,1H),8.10(d,J＝8.8Hz,1H),7.88(s,1H),7.81(dd,J＝8.8,1.6Hz,1H),7.54(d,J＝5.2Hz,1H),7.28-7.22(m,1H),6.80-6.73(m,3H),4.05(t,J＝8.0Hz,2H),2.40(t,J＝6.8Hz,2H),2.05-1.97(m,2H)；HR-ESI-MS:m/z＝453.0413[M+H]+,calculated for C20H17F3N2O2Br:453.0420.
实施例7：
黄色固体，产率60％
1H NMR(400MHz,Acetone-d6):δ9.00(d,J＝5.2Hz,1H),8.23(d,J＝8.8Hz,1H),8.00(s,1H),7.87(dd,J＝8.8,2.0Hz,1H),7.59(d,J＝5.2Hz,1H),7.31-7.27(m,2H),7.06-7.02(m,2H),4.10(t,J＝8.0Hz,2H),2.48(t,J＝8.0Hz,2H),2.11-2.03(m,2H)；HR-ESI-MS:m/z＝409.0922[M+H]+,calculated for C20H17ClF3N2O2:409.0925.
实施例8：
黄色固体，产率62％
1H NMR(400MHz,CH3OH-d4):δ8.85(d,J＝4.8Hz,1H),8.09(d,J＝8.8Hz,1H),7.86(s,1H),7.82(d,J＝8.8Hz,1H),7.53(d,J＝5.2Hz,1H),7.32-7.29(m,2H),7.04-7.02(m,2H),4.06(m,2H),2.43(s,2H),2.05-2.00(m,2H)；HR-ESI-MS:m/z＝393.1215[M+H]+,calculated for C20H17F4N2O2:393.1221.
实施例9：
黄色固体，产率82％
1H NMR(500MHz,DMSO-d6):δ8.93(d,J＝4.0Hz,1H),7.97(d,J＝9.0Hz,1H),7.81(d,J＝8.5Hz,1H),7.68(s,1H),7.51(s,1H),7.20-7.15(m,1H),6.68-6.64(m,2H),6.47(d,J＝8.0Hz,1H),3.87(s,2H),2.12(s,2H),1.78(s,2H)；HR-ESI-MS:m/z＝403.0457[M+H]+,calculated for C19H17BrFN2O2:403.0452.
实施例10：
黄色固体，产率77％
1H NMR(400MHz,Acetone-d6):δ8.79(d,J＝4.8Hz,1H),7.95(d,J＝2.0Hz,1H),7.47(d,J＝8.8Hz,1H),7.33(d,J＝4.4Hz,1H),7.15(dd,J＝9.2,2.0Hz,1H),7.03-6.97(m,1H),6.45-6.41(m,3H),3.70(s,2H),2.14-2.07(m,2H),1.79(s,2H)；HR-ESI-MS:m/z＝359.0967[M+H]+,calculated for C19H17ClFN2O2:359.0957.
实施例11：
黄色固体，产率50％
1H NMR(400MHz,Acetone-d6):δ8.92(s,1H),8.19(s,1H),7.89(s,1H),7.80(dd,J＝8.8,2.0Hz,1H),7.52(d,J＝5.2Hz,1H),7.30-7.18(m,4H),4.04(t,J＝8.0Hz,2H),2.52(t,J＝7.2Hz,2H),2.07-2.04(m,2H)；HR-ESI-MS:m/z＝393.1216[M+H]+,calculated forC20H17F4N2O2:393.1221.
实施例12：
黄色固体，产率73％
1H NMR(400MHz,Acetone-d6):δ8.93(d,J＝4.4Hz,1H),8.15(d,J＝6.4Hz,1H),7.72-7.67(m,2H),7.50(d,J＝5.2Hz,1H),7.43-7.39(m,1H),7.21-7.11(m,1H),6.70-6.60(m,3H),4.06-4.01(m,2H),2.43(t,J＝7.2Hz,2H),2.04-2.00(m,2H)；HR-ESI-MS:m/z＝325.1344[M+H]+,calculated for C19H18FN2O2:325.1347.
实施例13：
黄色固体，产率60％
1H NMR(400MHz,CH3OH-d4):δ8.74(d,J＝5.2Hz,1H),7.98(d,J＝8.4Hz,1H),7.81(s,1H),7.68(d,J＝8.8Hz,1H),7.44(d,J＝5.6Hz,1H),7.17-7.13(m,1H),6.93-6.89(m,2H),6.82(d,J＝8.0Hz,1H),4.00(t,J＝8.4Hz,2H),2.26-2.21(m,5H),2.02-1.99(m,2H)；HR-ESI-MS:m/z＝389.1470[M+H]+,calculated for C21H20F3N2O2:389.1471.
实施例14：
黄色固体，产率55％
1H NMR(400MHz,Acetone-d6):δ8.95(s,1H),8.38(s,1H),7.82(dd,J＝8.8,1.6Hz,1H),7.66(s,1H),7.57(d,J＝5.6Hz,1H),7.36-7.30(m,3H),7.09-7.06(m,1H),4.20(t,J＝8.0Hz,2H),2.50(t,J＝6.8Hz,2H),2.03-2.01(m,2H),1.19(s,9H)；HR-ESI-MS:m/z＝431.1935[M+H]+,calculated for C24H26F3N2O2:431.1941.
实施例15：
黄色固体，产率70％
1H NMR(400MHz,Acetone-d6):δ9.04(d,J＝4.4Hz,1H),8.25(d,J＝8.8Hz,1H),8.05(s,1H),7.90(d,J＝8.8Hz,1H),7.56(d,J＝4.8Hz,1H),7.28-7.22(m,1H),6.73-6.68(m,3H),4.04(t,J＝8.4Hz,2H),2.28(t,J＝7.2Hz,2H),1.87-1.79(m,2H),1.67-1.59(m,2H),1.52-1.45(m,2H)；HR-ESI-MS:m/z＝421.1527[M+H]+,calculated for C22H21F4N2O2:421.1534.
实施例16：
黄色固体，产率64％
1H NMR(400MHz,Acetone-d6):δ8.93(d,J＝5.2Hz,1H),8.31(d,J＝7.6Hz,1H),7.90(s,1H),7.84(dd,J＝8.8,2.0Hz,1H),7.55(d,J＝5.6Hz,1H),7.22(t,J＝8.4Hz,1H),6.77(t,J＝2.0Hz,1H),6.73-6.70(m,1H),6.68-6.65(m,1H),4.13(t,J＝8.0Hz,2H),3.70(s,3H),2.47(t,J＝7.2Hz,2H),2.03-2.01(m,2H)；HR-ESI-MS:m/z＝405.1415[M+H]+,calculated for C21H20F3N2O3:405.1421.
实施例17：
黄色固体，产率60％
1H NMR(400MHz,CH3OH-d4):δ8.77(d,J＝5.2Hz,1H),7.99(d,J＝8.8Hz,1H),7.81(s,1H),7.70(d,J＝8.8Hz,1H),7.48(d,J＝5.2Hz,1H),7.28(t,J＝8.0Hz,2H),7.10-7.03(m,3H),4.03(t,J＝8.0Hz,2H),2.26(s,2H),2.02-1.99(m,2H)；HR-ESI-MS:m/z＝375.1312[M+H]+,calculated for C20H18F3N2O2:375.1315.
实施例18：
黄色固体，产率82％
1H NMR(400MHz,CH3OH-d4):δ8.83(d,J＝5.2Hz,1H),8.14-8.09(m,2H),8.04(s,1H),7.90-7.84(m,2H),7.64(d,J＝7.6Hz,1H),7.47(d,J＝5.2Hz,1H),7.41(t,J＝7.6Hz,1H),7.29-7.24(m,1H),6.84-6.76(m,3H),5.34(s,2H)；HR-ESI-MS:m/z＝441.1202[M+H]+,calculated for C24H17F4N2O2:441.1221.
实施例19：
黄色固体，产率52％
1H NMR(400MHz,CDCl3):δ9.00(d,J＝5.6Hz,1H),8.18(d,J＝8.8Hz,1H),7.83(s,1H),7.70(dd,J＝8.8,1.6Hz,1H),7.61(d,J＝5.6Hz,1H),7.44-7.32(m,7H),7.24(s,1H),7.04-7.01(m,1H),4.12(d,J＝7.6Hz,2H),2.52(d,J＝6.4Hz,2H),2.17-2.13(m,2H)；HR-ESI-MS:m/z＝451.1624[M+H]+,calculated for C26H22F3N2O2:451.1628.
实施例20：
Reagents and conditions:a)碳酸钾,碘化钾,80℃；b)醋酸钯,碳酸铯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,110℃,N2；c)四三苯基膦钯,碳酸钾,95℃,N2.d)氢氧化钠,乙醇,50℃
A.4-((3-氟苯基)氨基)丁腈的合成
将间氟苯胺(1.1g,10mmol)，4-溴丁腈(1.5g,10mmol)溶于20mL DMF中，加入碳酸钾(2.8g,20mmol)，碘化钾(332mg,0.2mmol)，85℃反应10h。TLC监测反应完全后，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，蒸除溶剂后柱层析分离(石油醚-乙酸乙酯10:1-6:1)，得到4-((3-氟苯基)氨基)丁腈，浅黄色油状物1.44g，收率：80％。HR-ESI-MS:m/z＝179.0974[M+H]+,calculated for C10H12FN2:179.0979.
B.4-((3-氟苯基)(6-溴喹啉-4-代)氨基)丁腈的合成
向4-((3-氟苯基)氨基)丁腈(142mg,0.8mmol)，6-溴-4-碘喹啉(319mg,0.96mmol)，碳酸铯(364mg,1.1mmol)，醋酸钯(9mg,0.04mmol)，xant-phos(23mg,0.04mmol)中，加入8mL无水1,4-二氧六环，氮气保护下110℃反应12h。反应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1:1)，得到4-((3-氟苯基)(6-溴喹啉-4-代)氨基)丁腈，白色油状物160mg，收率52％。HR-ESI-MS:m/z＝384.0505[M+H]+,calculated for C19H16N3BrF:384.0506.
C.化合物VII-1的合成
将4-((3-氟苯基)(6-溴喹啉-4-代)氨基)丁腈(115mg,0.3mmol)溶于14mL甲苯:水:乙醇为4:2:1的混合溶剂中，加入4-氟苯硼酸(63mg,0.45mmol)，碳酸钾(187mg,1.35mmol)，四三苯基膦钯(34mg,0.03mmol)，氮气保护下，95℃加热反应10h。TLC监测反应完全后，蒸除溶剂，加入乙酸乙酯和水萃取，有机相用无水硫酸钠干燥，蒸除溶剂后柱层析分离(石油醚-乙酸乙酯3:1-1:1-1:2)，得到化合物VII-1，白色油状物89mg，收率75％。HR-ESI-MS:m/z＝400.1547[M+H]+,calculated for C25H20F2N3:400.1548.
D.化合物Ib-1的合成
将化合物VII-1(100mg,0.25mmol)溶于2mL无水乙醇中，加入6mL 1M NaOH溶液，50℃下加热回流8h。TLC监测反应完全后，蒸除溶剂，加入少量DCM萃取萃取，分离出水相，用1NHCl中和到pH至1～2左右，再用乙酸乙酯萃取，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，得到化合物Ib-1，黄色固体64mg，收率:61％。1H NMR(400MHz,Acetone-d6):δ8.89(d,J＝4.8Hz,1H),8.16(d,J＝8.4Hz,1H),7.99-7.95(m,1H),7.87-7.86(m,1H),7.51-7.48(m,3H),7.24-7.21(m,1H),7.18-7.13(m,2H),6.76-6.65(m,3H),4.08(t,J＝8.0Hz,2H),2.45(t,J＝7.2Hz,2H),2.09-2.03(m,2H)；HR-ESI-MS:m/z＝419.1563[M+H]+,calculated for C25H21F2N2O2:419.1566.
实施例21～23
参照实施例20的合成方法制备实施例21～23。
实施例21：合成方法与实施例20类似，不同之处在于第三步用苯硼酸替代4-氟苯硼酸，收率77％。
实施例22：合成方法与实施例20类似，不同之处在于第三步用2-萘硼酸替代4-氟苯硼酸，收率67％。
实施例23：合成方法与实施例20类似，不同之处在于第三步用4-甲氧基苯硼酸替代4-氟苯硼酸，收率79％。
参照实施例20操作步骤，最终制备了下表所列化合物。
实施例21：
黄色固体，产率59％
1H NMR(400MHz,Acetone-d6):δ9.02(d,J＝5.2Hz,1H),8.31(d,J＝8.8Hz,1H),8.12(dd,J＝8.8,2.0Hz,1H),8.01(d,J＝2.0Hz,1H),7.64(d,J＝4.8Hz,1H),7.59-7.56(m,2H),7.53-7.49(m,2H),7.46-7.42(m,1H),7.37-7.32(m,1H),6.90-6.77(m,3H),4.22(t,J＝7.6Hz,2H),2.58(t,J＝6.8Hz,2H),2.15-2.13(m,2H)；HR-ESI-MS:m/z＝401.1655[M+H]+,calculated for C25H22FN2O2:401.1660.
实施例22：
黄色固体，产率75％
1H NMR(500MHz,CH3OH-d4):δ8.85(d,J＝5.5Hz,1H),8.13(d,J＝8.5Hz,1H),7.90-7.82(m,3H),7.74(d,J＝1.5Hz,1H),7.58(d,J＝5.5Hz,1H),7.53(d,J＝8.5Hz,1H),7.48-7.45(m,2H),7.34-7.31(m,1H),7.25-7.19(m,2H),6.76-6.69(m,3H),4.06(t,J＝7.5Hz,2H),2.38(t,J＝7.0Hz,2H),2.03-1.98(m,2H)；HR-ESI-MS:m/z＝451.1810[M+H]+,calculated for C29H24FN2O2:451.1816.
实施例23：
黄色固体，产率73％
1H NMR(400MHz,Acetone-d6):δ8.88(d,J＝4.8Hz,1H),8.09(d,J＝8.4Hz,1H),7.96(dd,J＝8.8,2.0Hz,1H),7.86(d,J＝2.0Hz,1H),7.47-7.43(m,3H),7.20-7.14(m,1H),6.95(d,J＝8.8Hz,2H),6.67-6.54(m,3H),4.05(t,J＝8.0Hz,2H),3.79(s,3H),2.44(t,J＝6.8Hz,2H),2.03-2.01(m,2H)；HR-ESI-MS:m/z＝431.1760[M+H]+,calculated forC26H24FN2O3:431.1765.
药理实验
URAT1抑制活性测试
实验试剂的配制
细胞培养及接种
(1)培养稳定表达hURAT1的HEK-293T细胞株，培养基组成为：DMEM培养基+10％胎牛血清+500μg·mL-1G418+1％P/S。
(2)待细胞长到80％满的时候，弃掉培养基，加PBS清洗细胞一次，之后加入胰酶-EDTA进行消化，待细胞脱壁时加入培养基，吹打使细胞脱落，离心收集细胞，加入培养基吹打成细胞悬液。
(3)调整细胞密度为3×105/mL，然后按100微升/孔的量接种到96孔的壁白底透的细胞培养板中，培养12～24小时。
化合物配制
(1)化合物用DMSO配成10mM浓度的母液，再用缓冲液稀释成1mM的浓度加入96孔。
(2)在96孔板上，以1mM的起始浓度进行4倍等比稀释，10个梯度，另分别设置质控化合物，此为10x化合物板。
(3)之后在一块新的96孔板上加入45微升/孔的含0.1μCi/mL14C-尿酸的缓冲液和5微升/孔的10×已稀释好的化合物，将此配置成1×的化合物板待用。
14C‐尿酸在稳定表达hURAT1细胞中的吸收
(1)待96孔板中细胞培养贴壁后即可进行吸收试验。
(2)用200微升/孔预热的缓冲液洗细胞1次。
(3)吸干各孔，之后立即加入50微升/孔含有相对应的化合物和0.1Ci/mL14C-尿酸溶液。
(4)将加完化合物的板子在37℃培养箱中孵育5分钟。
(5)立即在每个孔中加入150微升冰冷的缓冲液液以终止吸收。用缓冲液清洗每孔三次。清洗过程中，尽量避免细胞脱落。
(6)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。
(7)加入150微升/孔的闪烁液Microsint40到所有孔中，以900rpm的速度振荡5分钟。
(8)最后，微孔板送至MicroBeta Trilux(PerkinElmer公司生产)仪器上测定放射活性。
(9)分析数据。
对所合成的目标化合物进行了体外细胞水平的URAT1抑制活性测试。细胞水平的生物学评价采用苯溴马隆(Benzbromarone)作为阳性对照，通过评价14C-尿酸在稳定表达hURAT1细胞中的吸收，来测定化合物在10μmol·L-1浓度下对URAT1的单浓度抑制率及部分化合物的IC50值。结果如表所示。
*抑制率在10μmol·L-1浓度下测得
上述实验结果表明，本发明的化合物为强的URAT1抑制剂，可以用来制备治疗高尿酸血症和痛风的药物。
Claims (6)
1.一种由下述通式I表示的N-苯基-N-喹啉羧酸类化合物及其生理上可接受的盐：
其中，
R1选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、C1-C4烷基；
R2选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、取代或未取代的萘基、C1-C4烷基、一或多取代的C1-C4烷基；
所述取代基选自一个或多个羟基、甲氧基或卤素；
L选自C1-C4烷基或苯基。
2.根据权利要求1所述的N-苯基-N-喹啉羧酸类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：
3.权利要求1～2任一项所述N-苯基-N-喹啉羧酸类化合物及其生理上可接受的盐的制备方法，其特征在于，所述化合物由下述方法一或方法二合成，
方法一：式II化合物与式III化合物通过亲核取代反应生成式IV重要中间体，后者与化合物V通过金属偶联反应生成化合物VI，再经过水解反应得到式Ia化合物：
其中，R1选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、C1-C4烷基；
R2选自氢、卤素、羟基、甲氧基、取代或未取代的苯基、取代或未取代的萘基、C1-C4烷基、一或多取代的C1-C4烷基；
所述取代基选自一个或多个羟基、甲氧基或卤素；
L选自C1-C4烷基或苯基；
R3选自氰基或乙氧甲酰基；
X选自氯或溴；
方法二：以间氟苯胺和4-溴丁腈为原料生成4-((3-氟苯基)氨基)丁腈，后者与6-溴-4-碘喹啉反应得到4-((3-氟苯基)(6-溴喹啉-4-代)氨基)丁腈，再与各种芳基硼酸类化合物经金属偶联反应得到化合物VII，最后经过水解反应得到式Ib化合物：
其中，R2选自取代或未取代的苯基、萘基；
所述取代基选自一个或多个羟基、甲氧基或卤素。
4.一种药物组合物，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1～2任一项所述的N-苯基-N-喹啉羧酸类化合物及其生理上可接受的盐和药学上可接受载体。
5.根据权利要求4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。
6.权利要求1～2任一项的N-苯基-N-喹啉羧酸类化合物及其生理上可接受的盐在制备预防或治疗高尿酸血症或痛风药物中的应用。
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| WO2011054433A1 (en) * | 2009-11-07 | 2011-05-12 | Merck Patent Gmbh | Heteroarylaminoquinolines as tgf-beta receptor kinase inhibitors |
| WO2014183555A1 (zh) * | 2013-05-13 | 2014-11-20 | 上海恒瑞医药有限公司 | 环烷基甲酸类衍生物、其制备方法及其在医药上的应用 |
| CN106831569A (zh) * | 2015-12-07 | 2017-06-13 | 成都海创药业有限公司 | 喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 |
| CN107108478A (zh) * | 2014-12-29 | 2017-08-29 | 日本化学药品株式会社 | Urat1抑制剂 |
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| WO2011054433A1 (en) * | 2009-11-07 | 2011-05-12 | Merck Patent Gmbh | Heteroarylaminoquinolines as tgf-beta receptor kinase inhibitors |
| WO2014183555A1 (zh) * | 2013-05-13 | 2014-11-20 | 上海恒瑞医药有限公司 | 环烷基甲酸类衍生物、其制备方法及其在医药上的应用 |
| CN107108478A (zh) * | 2014-12-29 | 2017-08-29 | 日本化学药品株式会社 | Urat1抑制剂 |
| CN106831569A (zh) * | 2015-12-07 | 2017-06-13 | 成都海创药业有限公司 | 喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 |
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