CN116535399B - 3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物、制法、药物组合物和应用 - Google Patents
3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物、制法、药物组合物和应用 Download PDFInfo
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- CN116535399B CN116535399B CN202210086106.2A CN202210086106A CN116535399B CN 116535399 B CN116535399 B CN 116535399B CN 202210086106 A CN202210086106 A CN 202210086106A CN 116535399 B CN116535399 B CN 116535399B
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- isoxazol
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Abstract
本发明公开了一类3‑羟基‑5‑(异噁唑‑5‑基)吡啶甲酰甘氨酸类化合物、制备方法、药物组合物和应用。该类化合物结构如式(I),该类化合物衍生物包含其药学上可接受的盐。该类化合物及其药物组合物对HIF抑制因子具有高效的抑制作用,活性最优可达到纳摩尔浓度水平,可制备为治疗脂肪代谢性疾病的药物,所制备药物在分子水平、细胞水平和动物水平均可以发挥药效,应用广泛,并且该类化合物合成方法简便,易操作。
Description
技术领域
本发明涉及一类3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物、制备方法、药物组合物和应用,尤其涉及一类可制备为治疗脂肪代谢性疾病药物的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物、制备方法、药物组合物和应用。
背景技术
非酒精性脂肪肝炎(nonalcoholic steatohepatitis,NASH),又称代谢相关脂肪性肝病(Metabolic-dysfunction-associated fatty liver disease,MAFLD),全球患病率高达10%,严重危害人类健康并对社会造成巨大经济负担。NASH是非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的炎症亚型,与疾病进展、肝硬化的发展和是否需要肝移植有关。NASH与肥胖、血脂异常、II型糖尿病和代谢综合征密切相关。目前,FDA尚未批准用于治疗NASH的药物。据估计,20%的NASH患者将发展为肝硬化,而NASH患者的死亡率也明显高于普通人群或非炎症亚型NAFLD患者。
由于NASH的发病机制及其复杂,至今仍未明确。虽然包括减肥在内的生活方式的改变已经显示出对于改善NASH的明显益处,但长期维持还是需要药物的治疗干预。然而,目前还没有药物被批准用于NASH的治疗。尽管面临这些挑战,NASH药物的开发前景还是相对广阔和多样化的,在代谢、炎症和纤维化领域有超过20个靶标的相关药物正在处于研发当中,处于临床III期研究的包括FXR激动剂、PPAR-α/δ激动剂、ASK1抑制剂、THR-β激动剂等。据推测到2025年全球NASH药物的市场规模可达400亿美元,临床需要远远未被满足。
缺氧诱导因子抑制因子FIH(factor inhibiting HIF)是一类具有JmjC结构域的天冬酰胺羟化酶,它被熟知为“细胞氧感知器”。在亚铁离子,氧气及2OG存在的条件下,其可羟基化HIF-α碳端转录激活结构域(CTAD)特定的天冬酰胺残基,导致HIF-α与转录增强子p300/CBP的结合能力大幅度下降,从而对HIF的转录活性起到负调控作用。研究表明,FIH基因敲除或沉默能够造成细胞内代谢的明显变化,FIH的降低伴随着氧化代谢的增加,这意味着FIH的抑制能够为代谢性疾病的治疗提供新手段。FIH的缺失能明显降低机体体重,改善肥胖。这是由于FIH的缺失导致氧消耗及卡路里的消耗提升约20%,代谢率也明显提升。与此同时,FIH的缺乏也使得脂肪细胞显著减少。对于高脂饮食诱导的脂肪肝小鼠,FIH的缺失有明显改善及保护作用。FIH缺失的小鼠能够表现出明显的较低甘油三酯及胆固醇水平,同时对于肝肥大也有明显改善。因此,FIH的缺失能改善脂肪代谢性疾病。
对于NASH而言,已有的治疗方案都是保守治疗,只能延缓疾病进程,其发病机制复杂,病程周期长,临床上共有二十余个靶点药物在研,目前尚未有药物获得FDA批准。
发明内容
发明目的:针对临床脂肪代谢性疾病治疗药物的短缺,本发明旨在提供一类全新机制并且可以有效治疗高血脂、NASH等脂肪代谢性疾病的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物、制备方法、药物组合物和应用。
技术方案:作为本发明涉及的第一方面,本发明的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物具有式(I)的结构,所述化合物包含其药学上可接受的盐:
其中:
A代表芳环或脂肪环;
R1代表氢、卤素或甲基;
R2代表一个或多个氢、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基或苯基;
R3代表氢、C1-C6烷基、C1-C6环烷基或芳环。
优选,上述结构中:
A代表苯环、萘环、5-6元芳杂环、环己烷或环丙烷。
本发明发现FIH小分子抑制剂能够通过加速机制脂肪代谢,改善高脂血症、肥胖、NASH等脂肪代谢性疾病。此前暂无FIH小分子抑制剂报道,本发明的化合物为fist inclass的FIH小分子抑制剂,有望成为全新机制的脂肪代谢性疾病治疗药物,为脂肪代谢性疾病尤其是NASH药物的研发开辟新领域。
优选,上述结构中:
R2代表一个或多个氢、甲基、叔丁基、甲氧基、三氟甲基、氟、氯、溴、氰基或苯基。
优选,上述结构中:
R3代表氢、甲基、叔丁基、环丙基、环己基或苯基。
更具体地,上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物选自以下任一化合物:
上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物的药学上可接受的盐为所述化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸;所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱或者有机胺。
作为本发明涉及的第二方面,上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物的制备方法为:
化合物(III)经环合、水解反应得到化合物(I);
其中,A、R1、R2、R3的定义如前所述;R代表氢、C1-C4脂肪烃基或苄基;
将相应的酸或碱与以上方法制备的化合物(I)成盐,即得所述化合物的药学上可接受的盐。
作为本发明涉及的第三方面,上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物的药物组合物包含所述化合物以及药学上可接受的载体。
上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面,上述3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物或者其药物组合物作为HIF抑制因子抑制剂药物,用于治疗脂肪代谢性疾病,具体治疗肥胖、高脂血症、高胆固醇血症、酒精性脂肪肝以及非酒精性脂肪肝(NASH)等。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类化合物及其药物组合物可有效抑制HIF抑制因子,IC50值最优达到纳摩尔浓度水平;
(2)该类化合物及其药物组合物应用广泛,可制备为治疗脂肪代谢性疾病的药物;所述药物在分子水平、细胞水平和动物水平均可以发挥药效,显著降低甘油三酯水平,使脂肪代谢水平恢复正常;
(3)化合物制备方法简便、易操作。
附图说明
图1A为本发明化合物对小鼠的降血脂作用结果;
图1B为化合物对小鼠的降胆固醇作用结果;
图2为化合物对小鼠的减肥作用结果;
图3A为化合物对小鼠血清甘油三酯的改善作用结果;
图3B为化合物对小鼠肝脏甘油三酯的改善作用结果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1:化合物I-1的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物176mg,总收率75.8%。m.p.239.4-241.3℃.1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.51(t,J=6.0Hz,1H),8.75(d,J=1.8Hz,1H),8.02–7.87(m,4H),7.58(dd,J=4.7,2.6Hz,3H),4.01(d,J=6.1Hz,2H).;EI-MS m/z:340[M]+。
实施例2:化合物I-2的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间甲基苯基甲酰氯肟(138mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物102mg,总收率44.1%。m.p.250.8-253.1℃.1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.68(s,1H),7.87(d,J=4.8Hz,2H),7.78–7.69(m,2H),7.41(dd,J=32.6,7.7Hz,2H),3.80(d,J=4.9Hz,2H).;EI-MS m/z:354[M]+。
实施例3:化合物I-3的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及4-联苯基甲酰氯肟(189mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物136mg,总收率50.0%。m.p.153.4-155.7℃.δ12.57(s,1H),9.45(t,J=6.1Hz,1H),8.74(s,1H),8.01(d,J=8.0Hz,2H),7.97(s,1H),7.93(s,1H),7.88(d,J=8.0Hz,2H),7.77(d,J=7.7Hz,2H),7.52(t,J=7.6Hz,2H),7.43(d,J=7.3Hz,1H),4.01(d,J=5.9Hz,2H).;EI-MSm/z:416[M]+。
实施例4:化合物I-4的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间甲氧基苯基甲酰氯肟(152mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物159mg,总收率65.7%。254.1-255.5℃.1H NMR(400MHz,DMSO-d6)δ9.21–9.08(m,1H),8.67(d,J=18.0Hz,1H),7.87(t,J=15.4Hz,2H),7.55–7.41(m,3H),7.12(s,1H),3.84(d,J=8.3Hz,5H).;EI-MS m/z:370[M]+。
实施例5:化合物I-5的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间氯苯基甲酰氯肟(154mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物112mg,总收率45.8%。m.p.210.7-212.6℃.1H NMR(400MHz,DMSO-d6)δ9.41(t,J=6.0Hz,1H),8.70(s,1H),8.03–7.86(m,4H),7.62(d,J=6.8Hz,2H),3.97(d,J=5.8Hz,2H).1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.70(s,1H),7.97(s,2H),7.92–7.87(m,2H),7.62(d,J=6.8Hz,2H),3.91(d,J=5.5Hz,2H).;EI-MS m/z:374[M]+。
实施例6:化合物I-6的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间溴苯基甲酰氯肟(190mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物133mg,总收率48.8%。m.p.213.0-215.3℃.1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.48(t,J=6.1Hz,1H),8.71(d,J=1.8Hz,1H),8.10(d,J=2.0Hz,1H),7.99(s,1H),7.94(d,J=7.8Hz,1H),7.90(d,J=1.8Hz,1H),7.77(dd,J=8.0,2.0Hz,1H),7.55(t,J=7.9Hz,1H),4.01(d,J=6.1Hz,2H).;EI-MS m/z:417[M]+。
实施例7:化合物I-7的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及环己基甲酰氯肟(132mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物176mg,总收率77.8%。m.p.247.2-249.4℃.1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),9.44(t,J=6.1Hz,1H),8.65(d,J=1.8Hz,1H),7.84(d,J=1.9Hz,1H),7.33(s,1H),4.00(d,J=6.1Hz,2H),2.80(tt,J=11.3,3.7Hz,1H),1.95(dt,J=13.5,3.2Hz,2H),1.78(dt,J=12.4,3.3Hz,2H),1.54–1.19(m,6H).;EI-MS m/z:346[M]+。
实施例8:化合物I-8的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及环丙基甲酰氯肟(98mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物132mg,总收率66.4%。m.p.232.7-235.3℃.1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.42(t,J=6.1Hz,1H),8.61(d,J=1.9Hz,1H),7.80(d,J=1.8Hz,1H),7.11(s,1H),3.99(d,J=6.0Hz,2H),2.10(tt,J=8.6,4.9Hz,1H),1.15–1.03(m,2H),0.84(dt,J=6.8,4.4Hz,2H).;EI-MS m/z:304[M]+。
实施例9:化合物I-9的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间氰基苯基甲酰氯肟(148mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物154mg,总收率64.6%。m.p.205.4-208.1℃.1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.51(t,J=6.1Hz,1H),8.72(d,J=1.8Hz,1H),8.38(d,J=1.8Hz,1H),8.27(dt,J=8.0,1.5Hz,1H),8.05(d,J=7.2Hz,2H),7.91(d,J=1.8Hz,1H),7.81(t,J=7.8Hz,1H),4.01(d,J=6.1Hz,2H).;EI-MS m/z:365[M]+。
实施例10:化合物I-10的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间三氟甲基苯基甲酰氯肟(183mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物141mg,总收率52.9%。m.p.245.2-247.3℃.1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.50(t,J=6.1Hz,1H),8.74(d,J=1.8Hz,1H),8.28–8.21(m,2H),8.10(s,1H),7.98–7.92(m,2H),7.84(t,J=7.8Hz,1H),4.02(d,J=6.1Hz,2H).;EI-MS m/z:408[M]+。
实施例11:化合物I-11的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及1-萘基甲酰氯肟(168mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物109mg,总收率44.8%。m.p.180.5-183.4℃.1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),9.51(t,J=6.1Hz,1H),8.81(d,J=1.8Hz,1H),8.51–8.43(m,1H),8.15(d,J=8.2Hz,1H),8.11–8.07(m,1H),8.02(d,J=1.8Hz,1H),7.92–7.86(m,2H),7.74–7.62(m,3H),4.03(d,J=6.1Hz,2H),2.51(d,J=5.7Hz,4H).;EI-MS m/z:390[M]+。
实施例12:化合物I-12的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及2-萘基甲酰氯肟(168mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物125mg,总收率49.0%。m.p.259.3-261.4℃.1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.71(s,1H),8.49(s,1H),8.10–8.00(m,5H),7.89(s,1H),7.63(dt,J=6.8,3.4Hz,2H),3.86(d,J=5.2Hz,2H).;EI-MS m/z:390[M]+。
实施例13:化合物I-13的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及邻甲基苯基甲酰氯肟(138mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物131mg,总收率56.6%。m.p.212.2-214.9℃.1H NMR(400MHz,DMSO-d6)δ9.45–9.36(m,1H),8.75(d,J=1.8Hz,1H),7.96(d,J=1.8Hz,1H),7.75(s,1H),7.63(d,J=7.5Hz,1H),7.47–7.35(m,3H),3.95(d,J=5.9Hz,2H),2.52(s,3H).;EI-MS m/z:354[M]+。
实施例14:化合物I-14的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及对甲基苯基甲酰氯肟(138mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物157mg,总收率67.8%。m.p.260.8-262.7℃.1H NMR(400MHz,DMSO-d6)δ9.48–9.35(m,1H),8.72(s,1H),7.96–7.86(m,2H),7.82(d,J=7.8Hz,2H),7.39(d,J=7.8Hz,2H),3.95(d,J=5.8Hz,2H),2.39(s,3H).;EI-MS m/z:354[M]+。
实施例15:化合物I-15的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间二甲基苯基甲酰氯肟(150mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物140mg,总收率58.2%。m.p.277.6-279.8℃.1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),9.50(t,J=6.1Hz,1H),8.73(d,J=1.9Hz,1H),7.92(d,J=2.0Hz,2H),7.55(s,2H),7.19(s,1H),4.01(d,J=6.1Hz,2H),2.37(s,6H).;EI-MS m/z:368[M]+。
实施例16:化合物I-16的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间氟苯基甲酰氯肟(142mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物166mg,总收率70.9%。m.p.236.7-238.9℃.1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.47(t,J=6.1Hz,1H),8.71(d,J=1.8Hz,1H),7.97(s,1H),7.91(d,J=1.8Hz,1H),7.80–7.72(m,2H),7.64(td,J=8.0,5.9Hz,1H),7.42(td,J=8.6,2.7Hz,1H),4.00(d,J=6.0Hz,2H)..;EI-MS m/z:358[M]+。
实施例17:化合物I-17的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及邻氯苯基甲酰氯肟(155mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物116mg,总收率47.4%。m.p.255.9-258.0℃.1H NMR(400MHz,DMSO-d6)δ9.44(t,J=6.0Hz,1H),8.77(d,J=1.9Hz,1H),8.01(d,J=1.8Hz,1H),7.81(s,1H),7.77(dd,J=7.6,1.9Hz,1H),7.71(d,J=7.8Hz,1H),7.62–7.53(m,2H),3.97(d,J=5.9Hz,2H).;EI-MS m/z:374[M]+。
实施例18:化合物I-18的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及对氯苯基甲酰氯肟(155mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物169mg,总收率69.1%。m.p.247.6-249.5℃.1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.68(s,1H),7.94(t,J=7.6Hz,3H),7.87(s,1H),7.66(d,J=8.1Hz,2H),3.74(s,2H).;EI-MS m/z:374[M]+。
实施例19:化合物I-19的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间二氯苯基甲酰氯肟(183mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物143mg,总收率53.6%。m.p.222.8-224.9℃.1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.64(s,1H),8.01(s,1H),7.93(d,J=2.0Hz,2H),7.82(d,J=2.2Hz,2H),3.89(d,J=5.4Hz,2H).;EI-MS m/z:408[M]+。
实施例20:化合物I-20的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及邻溴苯基甲酰氯肟(191mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物124mg,总收率45.4%。m.p.277.7-279.5℃.1H NMR(400MHz,DMSO-d6)δ9.27–9.12(m,1H),8.72(s,1H),7.94(s,1H),7.86(d,J=7.9Hz,1H),7.77–7.65(m,2H),7.54(dt,J=27.3,7.6Hz,2H),3.79(d,J=5.1Hz,2H).;EI-MS m/z:418[M]+。
实施例21:化合物I-21的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及对溴苯基甲酰氯肟(191mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物149mg,总收率55.9%。m.p.215.0-216.3℃.1H NMR(400MHz,DMSO-d6)δ9.38–9.23(m,1H),8.69(s,1H),7.89(t,J=12.5Hz,4H),7.80(d,J=7.9Hz,2H),3.92–3.84(m,2H).;EI-MS m/z:408[M]+。
实施例22:化合物I-22的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及邻三氟甲基苯基甲酰氯肟(183mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物171mg,总收率64.1%。m.p.278.9-281.1℃.1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.57–9.45(m,1H),8.84–8.73(m,1H),8.06–7.98(m,2H),7.84(dd,J=18.0,7.4Hz,2H),7.76(d,J=7.9Hz,1H),7.64(d,J=3.0Hz,1H),4.02(d,J=5.6Hz,2H).;EI-MS m/z:408[M]+。
实施例23:化合物I-23的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及对三氟甲基苯基甲酰氯肟(183mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物120mg,总收率45.0%。m.p.288.8-291.2℃.1H NMR(400MHz,DMSO-d6)δ9.25–9.00(m,1H),8.61(s,1H),8.13(d,J=7.3Hz,2H),7.94(d,J=8.6Hz,3H),7.80(s,1H),3.72–3.64(m,2H).;EI-MS m/z:408[M]+。
实施例24:化合物I-24的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及邻氟苯基甲酰氯肟(142mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物126mg,总收率53.8%。m.p.241.5-243.1℃.1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.80–8.72(m,1H),8.01–7.91(m,2H),7.78(s,1H),7.63(d,J=2.8Hz,1H),7.48–7.38(m,2H),3.94(d,J=5.5Hz,2H).;EI-MS m/z:358[M]+。
实施例25:化合物I-25的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及对氟苯基甲酰氯肟(142mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物191mg,总收率81.6%。m.p.215.1-216.9℃.1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.72(d,J=1.8Hz,1H),8.06(d,J=2.2Hz,1H),8.05(d,J=3.3Hz,2H),8.03(d,J=2.2Hz,1H),7.43(q,J=2.2,1.5Hz,2H),3.96(d,J=5.8Hz,2H).;EI-MS m/z:358[M]+。
实施例26:化合物I-26的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间二氟苯基甲酰氯肟(157mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物188mg,总收率76.5%。m.p.224.6-226.2℃.1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),9.43(s,1H),8.67(s,1H),7.98(s,1H),7.86(s,1H),7.63(d,J=6.8Hz,2H),7.50(d,J=9.4Hz,1H),3.98(d,J=5.8Hz,2H).;EI-MS m/z:376[M]+。
实施例27:化合物I-27的制备
N-((5-(三甲基硅基)乙炔基)-3-羟基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及间叔丁基苯基甲酰氯肟(173mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物188mg,总收率76.5%。m.p.221.1-223.2℃.1H NMR(500MHz,Chloroform-d)δ8.70(d,J=1.4Hz,1H),8.36(t,J=10.3Hz,1H),7.72–7.65(m,2H),7.58(t,J=1.5Hz,1H),7.53(t,J=7.5Hz,1H),7.38(dt,J=7.5,1.5Hz,1H),7.27(s,1H),4.07(d,J=10.1Hz,2H),1.37(s,7H).;EI-MS m/z:396[M]+。
实施例28:化合物I-28的制备
N-((5-(苯乙炔基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(214mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物152mg,总收率70.1%。m.p.278.4-280.3℃.1H NMR(500MHz,Chloroform-d)δ8.35(t,J=10.3Hz,1H),7.75–7.67(m,3H),7.52–7.44(m,2H),7.43–7.36(m,1H),7.26(s,1H),4.07(d,J=10.3Hz,2H),2.79(s,2H).;EI-MS m/z:354[M]+。
实施例29:化合物I-29的制备
N-((5-丙炔基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(171mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物100mg,总收率62.3%。m.p.256.4-258.6℃.1H NMR(500MHz,Chloroform-d)δ8.63(d,J=1.4Hz,1H),8.37(t,J=10.2Hz,1H),7.70(d,J=1.6Hz,1H),7.62–7.56(m,2H),7.49–7.43(m,2H),7.43–7.36(m,1H),4.07(d,J=10.3Hz,2H),2.48(s,2H).;EI-MS m/z:354[M]+。
实施例30:化合物I-30的制备
N-((5-(3,3-二甲基-1-丁炔)基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(200mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物107mg,总收率56.7%。m.p.288.2-289.9℃.1H NMR(500MHz,Chloroform-d)δ8.68(d,J=1.6Hz,1H),8.36(t,J=10.3Hz,1H),7.75(d,J=1.6Hz,1H),7.72–7.66(m,2H),7.50–7.43(m,2H),7.46–7.36(m,1H),4.07(d,J=10.1Hz,2H),1.40(s,7H).;EI-MS m/z:396[M]+。
实施例31:化合物I-31的制备
N-((5-(环丙基)乙炔基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(189mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物76mg,总收率31.2%。m.p.267.7-269.3℃.1H NMR(500MHz,Chloroform-d)δ8.67(d,J=1.6Hz,1H),8.36(t,J=10.3Hz,1H),7.74–7.66(m,3H),7.50–7.43(m,2H),7.46–7.36(m,1H),4.07(d,J=10.1Hz,2H),3.51(p,J=7.0Hz,1H),1.74–1.62(m,2H),0.81–0.69(m,2H).;EI-MS m/z:380[M]+。
实施例32:化合物I-32的制备
N-((5-(环己基)乙炔基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(218mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物95mg,总收率36.5%。m.p.270.3-272.5℃.1H NMR(500MHz,Chloroform-d)δ8.67(d,J=1.5Hz,1H),8.38(t,J=10.2Hz,1H),7.74(d,J=1.5Hz,1H),7.64–7.58(m,2H),7.49–7.42(m,2H),7.42–7.36(m,1H),4.07(d,J=10.1Hz,2H),3.53(p,J=6.8Hz,1H),1.81–1.70(m,2H),1.70–1.58(m,4H),1.61–1.36(m,4H).;EI-MS m/z:422[M]+。
实施例33:化合物I-33的制备
N-((5-(苯基)乙炔基)-3-羟基-6-甲基吡啶甲酰)甘氨酸甲酯(214mg,0.69mmol)溶于10mL甲醇中,加入0.2mL三乙胺,20mg碘化亚铜,1mL TBAF以及苯基甲酰氯肟(127mg,0.82mmol),常规加热至50℃4h,反应完全。反应结束后,抽滤除去碘化亚铜,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,冰浴条件下加入3mmol稀盐酸至白色固体析出,抽滤并干燥后得白色产物97mg,总收率35.8%。m.p.289.6-292.3℃.1H NMR(500MHz,Chloroform-d)δ8.69(d,J=1.5Hz,1H),8.38(t,J=10.2Hz,1H),7.77(d,J=1.5Hz,1H),7.66–7.60(m,2H),7.49–7.37(m,8H),7.37–7.31(m,1H),4.07(d,J=10.1Hz,2H).;EI-MS m/z:416[M]+。
实施例34:化合物对FIH抑制活性——采用荧光偏振的方法测试(FP实验)
测试化合物与荧光基团标记的HIF-1α肽段(FITC-HIF-1α788-822)竞争性结合PHD2蛋白的能力,测试中使用384孔黑板(型号为Corining#3575),测试终体积选择60μL,所测试的化合物和FITC-HIF-1α788-822分别溶解于DMSO和纯水中备用。将化合物用assaybuffer倍比稀释12个浓度梯度后每孔加入20μL稀释好的300nM FIH蛋白。每个化合物浓度设定两个附孔,每次试验设置空白对照(20μL FITC-HIF-1α788-822+40μL assay buffer)和阴性对照(20μL FITC-HIF-1α788-822+20μL FIH+20μL assay buffer)。室温孵育1小时,用Synergy读板器扫板,激发波长设置为485nm,发射波长设置为535nm。计算公式:%抑制率=100×[1-(实测值-空白)/(阴性值-空白)],得出具体浓度所对应的抑制率。将所得数据导入Graphpad prism 8.0分析拟合得IC50值。代表性化合物FP测试结果见表1。
表1.本发明中部分化合物的FIH抑制活性及其相关生物学活性
由表1可见,本发明的化合物具有较强的FIH抑制活性,16个化合物的IC50小于500nM,其中活性最优化合物活性达到100nM水平。
此外,专利US20070299086A1公开了一系列脯氨酸羟化酶抑制剂,其中活性较好的化合物结构:
本发明的化合物的特征在于吡啶母核特别是5位含有异噁唑直接与吡啶环相连。在对比US20070299086A1中化合物对于FIH的抑制活性,可发现其他基团基本相同的情况下,仅有本发明中的异噁唑化合物才具有较好的FIH抑制活性。活性对比结果如下:
表2.本发明中吡啶5位连有异噁唑的化合物与其他结构的化合物FIH抑制活性对比情况
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由表2化合物的数据对比可以看出,在其他基团相同的情况下,吡啶5位连接的芳环不同可造成化合物对FIH抑制活性明显不同,仅有当吡啶5位连接为异噁唑环时,才能表现出较好的FIH抑制活性。意味着,吡啶5位连接异噁唑是保证FIH抑制活性的必要条件。
实施例35:细胞降脂水平检测
细胞水平的降脂能力是通过检测高脂细胞甘油三酯水平来验证化合物在细胞水平是否具有改善高脂的能力(J.Med.Chem.2021,64(5),2815-2828)。本实验采用人肝癌细胞HepG2细胞,通过油酸诱导细胞高脂模型后,孵育给药24h后,超声裂解细胞,根据甘油三酯试剂盒说明书检测甘油三酯含量。
对表1部分化合物进行了动物水平的降脂试验(剂量:25mg/kg;模型:小鼠C57BL/6J雄性7-8周),方法参照(J.Med.Chem.2021,64(2),1037-1053)。由图1可见,本发明的化合物在动物水平可以明显降低血清甘油三酯及胆固醇。
对表1部分化合物进行了动物水平的脂肪肝改善试验(剂量:10mg/kg、模型:小鼠C57BL/6J雄性7-8周),方法参照(J.Med.Chem.2021,64(2),1037-1053)。由图2及图3可见,本发明的化合物在动物水平可以明显改善肥胖,降低血清及肝脏甘油三酯,改善脂肪肝。
Claims (9)
1.一种3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物,其特征在于,具有式(I)的结构,所述化合物包含其药学上可接受的盐:
其中:
A代表苯环、萘环、环己烷或环丙烷;
R1代表氢、卤素或甲基;
R2代表一个或多个氢、C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、氰基或苯基;
R3代表氢、C1-C6烷基、C3-C6环烷基或苯基。
2.根据权利要求1所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物,其特征在于,所述结构中:
R2代表一个或多个氢、甲基、叔丁基、甲氧基、三氟甲基、氟、氯、溴、氰基或苯基。
3.根据权利要求1所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物,其特征在于,所述结构中:
R3代表氢、甲基、叔丁基、环丙基、环己基或苯基。
4.根据权利要求1所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物,其特征在于,选自以下任一化合物:
5.根据权利要求1~4任一所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物,其特征在于,所述药学上可接受的盐为所述化合物与酸形成的盐,所述酸为盐酸、氢溴酸、碳酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
6.一种权利要求1~5任一所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物的制备方法,其特征在于,所述制备方法为:
化合物(III)经环合、水解反应得到化合物(I);
其中,A、R1、R2、R3的定义如权利要求1~4任一所述;R代表氢、C1-C4脂肪烃基或苄基;
将相应的酸与以上方法制备的化合物(I)成盐,即得所述化合物的药学上可接受的盐。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~5任一所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物以及药学上可接受的载体。
8.一种权利要求1~5任一所述的3-羟基-5-(异噁唑-5-基)吡啶甲酰甘氨酸类化合物或者权利要求7所述的药物组合物在制备HIF抑制因子抑制剂药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述药物用于治疗脂肪代谢性疾病。
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WO1993019062A1 (en) * | 1992-03-24 | 1993-09-30 | Warner-Lambert Company | Tetrahydropyridine isoxazoline derivatives |
WO2000045799A2 (de) * | 1999-02-04 | 2000-08-10 | Bayer Aktiengesellschaft | Verwendung von substituierten isoxazolcarbonsäuren und derivaten und neue stoffe |
WO2002058690A2 (en) * | 2001-01-26 | 2002-08-01 | Chugai Seiyaku Kabushiki Kaisha | Methods for the treatment of diseases using malonyl-coa decarbox ylase inhibitors |
WO2004018463A2 (en) * | 2002-08-23 | 2004-03-04 | Rigel Pharmaceuticals, Inc. | Pyridyl substituted heterocycles useful for treating or preventing hcv infection |
WO2011009484A1 (en) * | 2009-07-22 | 2011-01-27 | Novartis Ag | Arylpyrazoles and arylisoxazoles and their use as pkd modulators |
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WO1993019062A1 (en) * | 1992-03-24 | 1993-09-30 | Warner-Lambert Company | Tetrahydropyridine isoxazoline derivatives |
WO2000045799A2 (de) * | 1999-02-04 | 2000-08-10 | Bayer Aktiengesellschaft | Verwendung von substituierten isoxazolcarbonsäuren und derivaten und neue stoffe |
WO2002058690A2 (en) * | 2001-01-26 | 2002-08-01 | Chugai Seiyaku Kabushiki Kaisha | Methods for the treatment of diseases using malonyl-coa decarbox ylase inhibitors |
WO2004018463A2 (en) * | 2002-08-23 | 2004-03-04 | Rigel Pharmaceuticals, Inc. | Pyridyl substituted heterocycles useful for treating or preventing hcv infection |
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