CN115611855A - 烟碱酰胺型化合物及其在制备减肥药物中的应用 - Google Patents
烟碱酰胺型化合物及其在制备减肥药物中的应用 Download PDFInfo
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- CN115611855A CN115611855A CN202210513052.3A CN202210513052A CN115611855A CN 115611855 A CN115611855 A CN 115611855A CN 202210513052 A CN202210513052 A CN 202210513052A CN 115611855 A CN115611855 A CN 115611855A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明公开了一类烟碱酰胺型化合物及其在制备减肥药物中的应用，该化合物的结构式为
或
或
或
Description
技术领域
本发明属于化学药物技术领域，具体涉及一类烟碱酰胺型化合物及其在制备减肥药物中的应用。
背景技术
烟碱(Nicotine)，又名尼古丁，是一种存在于茄科植物中的生物碱。烟碱具有旋光性，有(R)-烟碱和(S)-烟碱两种对映异构体。天然产物以(S)-烟碱为主，(R)-烟碱是较少丰富的对映异构体，其含量通常不超过10％。由于共同的理化性质(R)-烟碱的药理作用在性质上与(S)-烟碱的药理作用相似，两者的给药途径的效率基本相同且穿越生物屏障的难易程度也是相同的。(R)-烟碱与(S)-烟碱具有本质相似的药理学作用，只是在作用时间上稍慢于(S)-烟碱，但其毒性远远低于(S)-烟碱。目前，市场上所用的烟碱主要为(S)-烟碱，大多从烟草中提取得到。但由于受到烟草原材料生长、产量、气候等因素的影响，含量较低，成本较高，难以工业化生产，所以合成烟碱越来越受到人们的重视。
近年来，烟碱对中枢神经系统(CNS)疾病的潜在药理作用已引起大量有机合成和药物化学等领域学者的关注，尤其是烟碱可能对帕金森病(PD)、阿尔茨海默病(AD)、精神分裂症和抑郁症的治疗具有有益作用。此外，烟碱在某些疾病的治疗和功能调节方面具有多种药理作用，如增强人类相关的听觉处理、增加认知功能和刺激交感肾上腺素能系统和具有治疗结节病的潜力。烟碱是一种具有较强生长抑制活性和良好药代动力学特性的抗生素化合物。
现有技术对烟碱进行修饰的报道较多，而关于烟碱2位或6位酰胺型化合物进行的减肥药物的研究尚未见报道。
发明内容
本发明的目的是提供一类新的烟碱酰胺型化合物，并为该类化合物提供一种新用途。
针对上述目的，本发明所采用的烟碱酰胺型化合物的结构式为：
其中，R代表芳香酰基和脂肪酰基，具体可以选自乙酰基、氯乙酰基、硬脂酰基、软脂酰基、正庚酰基、正辛酰基、苯丙酰基、烟酰基、戊炔酰基、氰基乙酰基、三氟甲磺酸酰基、苯甲酰基、对氯苯甲酰基、间氯苯甲酰基、邻氯苯甲酰基、对溴苯甲酰基、对氟苯甲酰基、邻二氟苯甲酰基、对甲基苯甲酰基、对乙基苯甲酰基、间二氯苯甲酰基、对甲苯磺酰基等中任意一种。
本发明烟碱酰胺型化合物优选下述化合物1-30中任意一种：
本发明烟碱酰胺型化合物的合成路线和具体合成方法如下：
1、合成烟碱酰胺型化合物1-17
以干燥的二氯甲烷为溶剂，将化合物A或B与羧酸类化合物ROH、二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)按摩尔比为1:1.1～3.5:1.1～2.5:0.1～0.6，室温搅拌反应12～24h。反应完毕后，减压浓缩除去溶剂，浓缩物经硅胶柱层析，得到化合物1-17。
2、合成烟碱酰胺型化合物18-30
以干燥的二氯甲烷为溶剂，将化合物A或B与酰氯RCl、三乙胺按摩尔比为1:1.1～2.5:1.1～3.5，室温搅拌反应4～6h。反应完毕后，萃取，过滤，减压蒸除溶剂，浓缩物经硅胶柱层析，得到化合物18-30。
本发明烟碱酰胺型化合物在制备减肥药物中的用途，其按常规药用制剂，与药学上可接受的载体按照各种制剂的常规制备工艺制成，可以是片剂、颗粒剂、胶囊剂。
本发明的有益效果如下：
本发明以烟碱为母体，将其2位或6位引入氨基后连接不同的羧基制备烟碱酰胺型化合物。经药理活性检测，此类化合物对脂肪酶显示出很好的抑制活性，可以用于制备减肥药物。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。
实施例1
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、软脂酸(144mg，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝32:1)，得到白色固体化合物1(83.9mg，产率为71％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝15:1)。化合物1的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.34–11.18(m,1H),8.37(d,J＝5.0Hz,1H),7.43(d,J＝7.4Hz,1H),6.96–6.92(m,1H),4.53–4.44(m,1H),3.44(s,1H),3.29(t,J＝8.3Hz,1H),3.18(d,J＝8.9Hz,1H),2.49(t,J＝7.8Hz,2H),2.33(t,J＝8.0Hz,2H),2.22(s,2H),1.96–1.90(m,5H),1.72–1.61(m,5H),1.25(s,17H),0.89(d,J＝6.2Hz,4H)ppm；13C NMR(101MHz,CDCl3)δ177.98,157.19,147.24,138.30,123.77,118.61,71.18,56.39,49.25,40.08,34.22,33.86,31.95,31.58,29.72,29.55,29.48,29.40,29.33,29.19,25.63,25.59,24.94,22.72,22.67,14.17ppm；HRMS(ESI)m/z:[M+H]+C26H46N3O理论值416.3635,实测值416.3621。
实施例2
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、3-苯丙酸(85mg，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝27:1)，得到白色固体化合物2(76mg，产率为87％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝13:1)。化合物2的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.21(s,1H),8.35(d,J＝4.9Hz,1H),7.44(d,J＝7.5Hz,1H),7.29(d,J＝7.6Hz,2H),7.24–7.19(m,3H),6.97–6.93(m,1H),3.42(dd,J＝9.6,5.2Hz,1H),3.25(dd,J＝10.1,5.0Hz,1H),2.84(s,2H),2.65(t,J＝8.0Hz,2H),2.31–2.26(m,1H),2.17(s,3H),1.92(d,J＝8.7Hz,1H),1.85–1.81(m,2H),1.70(d,J＝5.2Hz,1H)ppm；13C NMR(101MHz,CDCl3)δ177.65,157.44,150.20,147.08,141.04,138.38,128.49,128.34,126.09,124.06,118.88,111.34,70.92,56.32,40.01,33.79,25.58,24.91,22.63ppm；HRMS(ESI)m/z:[M+H]+C19H24N3O理论值310.1914,实测值310.1900。
实施例3
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、硬脂酸(160mg，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝32:1)，得到白色固体化合物3(104mg，产率为83％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝15:1)。化合物3的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.26(s,1H),8.37(d,J＝4.9Hz,1H),7.42(d,J＝7.4Hz,1H),6.93(d,J＝2.3Hz,1H),4.44(s,1H),3.44(d,J＝11.0Hz,1H),3.29(s,1H),3.17(s,1H),2.48(d,J＝7.8Hz,2H),2.32(t,J＝7.5Hz,2H),2.22(s,2H),2.00–1.92(m,5H),1.73–1.66(m,5H),1.25(s,21H),0.88(s,4H)ppm；13C NMR(101MHz,CDCl3)δ178.26,157.12,147.25,138.28,123.70,118.57,71.21,56.39,49.20,40.08,34.68,33.88,31.95,31.57,30.92,29.72,29.66,29.54,29.48,29.39,29.27,25.63,25.60,25.13,24.95,22.72,22.67,14.17ppm；HRMS(ESI)m/z:[M+H]+C28H50N3O理论值444.3948,实测值444.3934。
实施例4
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、正辛酸(0.1mL，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝30:1)，得到白色固体化合物4(60mg，产率为70％)，TLC:Rf＝0.5(CH2Cl2:CH3OH＝12:1)。化合物4的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.21(s,1H),8.37(d,J＝4.9Hz,1H),7.44(d,J＝7.5Hz,1H),6.94(dd,J＝7.5,5.0Hz,1H),4.63–4.55(m,1H),3.43(s,1H),3.30(t,J＝8.3Hz,1H),3.18(t,J＝8.0Hz,1H),2.50(t,J＝7.7Hz,2H),2.33(s,3H),2.22(s,2H),1.94–1.92(m,3H),1.69(t,J＝4.1Hz,3H),1.31(s,4H),0.88(s,4H)ppm；13C NMR(101MHz,CDCl3)δ178.37,157.33,147.17,138.31,123.95,118.68,71.09,56.38,49.30,40.05,33.81,31.67,29.10,28.94,25.58,24.90,22.61,14.07ppm；HRMS(ESI)m/z:[M+H]+C18H30N3O理论值304.2383,实测值304.2371。
实施例5
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、正庚酸(0.08mL，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝30:1)，得到白色固体化合物5(64mg，产率为78％)，TLC:Rf＝0.5(CH2Cl2:CH3OH＝12:1)。化合物5的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.24(s,1H),8.37(d,J＝4.9Hz,1H),7.43(d,J＝7.4Hz,1H),6.94(d,J＝2.4Hz,1H),3.45(d,J＝4.0Hz,1H),3.29(s,1H),3.15(s,1H),2.33(s,2H),2.22(s,2H),1.93(d,J＝3.1Hz,3H),1.68(t,J＝4.0Hz,4H),1.30(s,5H),0.88(s,4H)ppm；13C NMR(101MHz,CDCl3)δ178.55,157.23,147.20,138.30,123.82,118.64,71.15,56.38,49.24,40.06,33.85,31.54,28.92,25.59,24.92,22.52,14.05ppm；HRMS(ESI)m/z:[M+H]+C17H28N3O理论值290.2227,实测值290.2151。
实施例6
称取化合物A(50mg，0.28mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、4-戊炔酸(56mg，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝26:1)，得到白色固体化合物6(65mg，产率为89％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝12:1)。化合物6的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.27(s,1H),8.34(d,J＝4.9Hz,1H),7.47(d,J＝7.4Hz,1H),6.97(dd,J＝5.2,3.1Hz,1H),3.42(d,J＝4.7Hz,1H),3.33(d,J＝8.5Hz,1H),3.22(t,J＝8.3Hz,1H),2.59–2.56(m,2H),2.52(dd,J＝5.7,3.6Hz,2H),2.35(d,J＝8.9Hz,1H),2.23(s,3H),1.94(s,2H),1.72–1.69(m,2H)ppm；13C NMR(101MHz,CDCl3)δ157.43,150.08,147.03,138.44,124.06,118.99,82.96,70.92,68.78,56.35,49.33,40.06,33.77,24.89,14.47ppm；HRMS(ESI)m/z:[M+H]+C15H20N3O理论值258.1601,实测值258.1590。
实施例7
称取化合物A(70mg，0.395mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(122mg，0.59mmol)、DMAP(24mg，0.198mmol)、2-吡啶甲酸(97mg，0.79mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝28:1)，得到淡黄色固体化合物7(78mg，产率为70％)，TLC:Rf＝0.5(CH2Cl2:CH3OH＝14:1)。化合物7的结构表征数据为：1H NMR(400MHz,CDCl3)δ13.27(s,1H),8.61(d,J＝4.7Hz,1H),8.49(dd,J＝4.7,2.2Hz,1H),8.34(d,J＝7.8Hz,1H),7.87(t,J＝7.7Hz,1H),7.50(d,J＝7.5Hz,1H),7.46–7.42(m,1H),6.99(dd,J＝7.4,5.1Hz,1H),3.48(s,1H),3.28(t,J＝8.5Hz,1H),2.40(t,J＝8.8Hz,1H),2.28(d,J＝1.7Hz,3H),2.11–1.94(m,3H),1.85–1.78(m,1H)ppm；13CNMR(101MHz,CDCl3)δ162.25,156.85,151.23,150.52,148.02,147.40,138.06,137.24,126.10,123.13,118.92,70.63,56.58,40.01,31.95,22.81ppm；HRMS(ESI)m/z:[M+H]+C16H19N4O理论值283.1553,实测值283.1536。
实施例8
称取化合物A(119mg，0.67mmol)溶解在4mL干燥的二氯甲烷中，向溶液中依次加入DCC(207mg，1.01mmol)、DMAP(41mg，0.335mmol)、乙酸(0.1mL，1.34mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝25:1)，得到白色固体化合物8(119mg，产率为81％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝10:1)。化合物8的结构表征数据为：1H NMR(400MHz,CDCl3)δ11.19(s,1H),8.33(d,J＝4.9Hz,1H),7.44(dd,J＝7.5,1.7Hz,1H),6.95(ddd,J＝6.4,5.0,1.3Hz,1H),3.34–3.29(m,1H),3.18(t,J＝8.5Hz,1H),2.33(d,J＝7.3Hz,4H),2.22(d,J＝1.3Hz,3H),2.17–1.96(m,4H)ppm；13C NMR(101MHz,CDCl3)δ150.32,146.99,138.36,123.95,118.72,111.62,71.07,56.41,40.08,31.67,24.99,22.73ppm；HRMS(ESI)m/z:[M+H]+C12H18N3O理论值220.1444,实测值220.1435。
实施例9
称取化合物B(67mg，0.38mmol)溶解在2mL干燥的二氯甲烷中，向溶液中依次加入DCC(117mg，0.57mmol)、DMAP(23mg，0.19mmol)、乙酸(0.05mL，0.76mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝14:1)，得到黄色油状化合物9(43mg，产率为51％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝8:1)。化合物9的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.20(d,J＝2.6Hz,2H),7.78(d,J＝8.7Hz,1H),3.32(t,J＝9.3Hz,1H),3.18(d,J＝21.8Hz,1H),2.42–2.34(m,1H),2.21(s,6H),1.93–1.36(m,4H)ppm；13C NMR(101MHz,CDCl3)δ168.78,146.81,138.05,130.93,128.85,114.13,68.72,56.77,40.04,34.66,24.66,22.34ppm；HRMS(ESI)m/z:[M+H]+C12H18N3O理论值220.1444,实测值220.1432。
实施例10
称取化合物B(119mg，0.67mmol)溶解在4mL的二氯甲烷中，向溶液中依次加入DCC(207mg，1.01mmol)、DMAP(41mg，0.335mmol)、软脂酸(344mg，1.34mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝22:1)，得到白色固体化合物10(162mg，产率为58％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝10:1)。化合物10的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.25(d,J＝8.6Hz,1H),8.13(d,J＝2.2Hz,1H),7.75(d,J＝8.7Hz,1H),3.27(t,J＝8.8Hz,1H),3.07(t,J＝8.3Hz,1H),2.43–2.33(m,4H),2.17(s,3H),1.70(dt,J＝15.4,7.5Hz,4H),1.25(s,24H),0.88(s,4H)ppm；13CNMR(101MHz,CDCl3)δ178.53,172.32,150.91,145.98,138.35,114.34,68.56,56.83,40.19,37.62,34.87,34.49,31.94,29.72,29.68,29.65,29.50,29.39,29.35,29.25,29.22,25.42,25.05,22.72,22.42,14.15ppm；HRMS(ESI)m/z:[M+H]+C26H46N3O理论值416.3635,实测值416.3621。
实施例11
称取化合物B(67mg，0.38mmol)溶解在2mL的二氯甲烷中，向溶液中依次加入DCC(117mg，0.57mmol)、DMAP(23mg，0.19mmol)、3-苯丙酸(113mg，0.76mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝16:1)，得到白色固体化合物11(48mg，产率为41％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝8:1)。化合物11的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.21–8.14(m,2H),7.71(dd,J＝8.6,2.3Hz,1H),7.27(d,J＝7.1Hz,2H),7.21(d,J＝7.1Hz,3H),3.26–3.21(m,1H),3.07–3.01(m,3H),2.69(t,J＝7.8Hz,2H),2.29(q,J＝9.0Hz,1H),2.14(s,3H),1.97–1.69(m,4H)ppm；13C NMR(101MHz,CDCl3)δ170.69,150.64,146.95,140.50,137.69,134.70,128.61,128.32,126.35,114.14,68.56,56.95,40.31,39.33,35.09,31.27,22.49ppm；HRMS(ESI)m/z:[M+H]+理论值C19H24N3O 310.1914,实测值310.1904。
实施例12
称取化合物B(190mg，1.07mmol)溶解在6mL的二氯甲烷中，向溶液中依次加入DCC(331mg，1.60mmol)、DMAP(65mg，0.53mmol)、硬脂酸(608mg，2.14mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝22:1)，得到白色固体化合物12(292mg，产率为61％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝10:1)。化合物12的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.26(d,J＝8.6Hz,1H),8.13(d,J＝2.3Hz,1H),7.76(dd,J＝8.7,2.3Hz,1H),3.27(t,J＝8.7Hz,1H),3.08(t,J＝8.5Hz,1H),2.38(dt,J＝25.6,7.5Hz,4H),2.17(s,3H),1.69(dq,J＝15.0,7.4Hz,5H),1.25(s,27H),0.88(t,J＝6.6Hz,4H)ppm；13C NMR(101MHz,CDCl3)δ172.37,156.96,150.96,145.94,138.38,114.39,68.55,56.81,49.23,40.17,37.60,34.85,33.92,31.94,29.72,29.68,29.54,29.51,29.39,29.27,29.22,25.61,25.42,25.11,24.94,22.71,22.42,14.14ppm；HRMS(ESI)m/z:[M+H]+理论值C28H50N3O 444.3948,实测值444.3932。
实施例13
称取化合物B(51mg，0.28mmol)溶解在2mL的二氯甲烷中，向溶液中依次加入DCC(87mg，0.42mmol)、DMAP(17mg，0.14mmol)、正辛酸(0.1mL，0.56mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝18:1)，得到淡黄色固体化合物13(75mg，产率为85％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝8:1)。化合物13的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.28(d,J＝8.6Hz,1H),8.11(d,J＝2.3Hz,1H),7.76(dd,J＝8.9,2.3Hz,1H),3.26(t,J＝8.6Hz,1H),3.07(t,J＝8.3Hz,1H),2.42(t,J＝7.5Hz,2H),2.33(q,J＝9.5,8.5Hz,3H),2.16(s,3H),1.69(dd,J＝15.1,7.3Hz,5H),1.30–1.28(m,6H),0.90–0.87(m,4H)ppm；13C NMR(101MHz,CDCl3)δ172.58,151.01,145.60,138.58,134.03,114.53,68.50,56.79,40.18,37.51,34.83,33.89,31.70,29.23,29.03,25.42,22.65,14.11ppm；HRMS(ESI)m/z:[M+H]+理论值C18H30N3O 304.2383,实测值304.2371。
实施例14
称取化合物B(96mg，0.54mmol)溶解在3mL的二氯甲烷中，向溶液中依次加入DCC(167mg，0.81mmol)、DMAP(33mg，0.27mmol)、正庚酸(0.15mL，1.08mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝18:1)，得到淡黄色固体化合物14(104mg，产率为67％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝8:1)。化合物14的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.47–8.36(m,1H),8.22–8.17(m,2H),7.74(d,J＝9.0Hz,1H),4.28(dt,J＝18.7,7.3Hz,1H),3.28(t,J＝8.8Hz,1H),3.09(t,J＝8.4Hz,1H),2.38(t,J＝7.5Hz,2H),2.18(s,3H),1.85–1.67(m,6H),1.30(dq,J＝7.2,4.5,3.2Hz,6H),0.90–0.86(m,3H)ppm；13C NMR(101MHz,CDCl3)δ171.80,156.79,147.11,137.79,128.85,113.98,65.59,56.82,49.15,37.82,33.97,31.54,28.89,25.63,24.96,22.50,14.04ppm；HRMS(ESI)m/z:[M+H]+理论值C17H28N3O 290.2227,实测值290.2209。
实施例15
称取化合物B(100mg，0.56mmol)溶解在3mL的二氯甲烷中，向溶液中依次加入DCC(173mg，0.84mmol)、DMAP(34mg，0.28mmol)、氰乙酸(95mg，1.12mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝14:1)，得到淡黄色固体化合物15(92mg，产率为68％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝7:1)。化合物15的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.69–9.10(m,1H),8.25(s,1H),8.10(d,J＝8.6Hz,1H),7.78(d,J＝8.7Hz,1H),3.65(s,1H),3.28(t,J＝8.8Hz,1H),3.14(t,J＝8.3Hz,1H),2.20(d,J＝8.8Hz,3H),1.96–1.84(m,2H),1.26(s,2H),0.92–0.83(m,2H)ppm；13C NMR(101MHz,CDCl3)δ159.85,149.82,147.08,138.17,135.59,114.59,113.94,68.50,56.88,40.25,34.98,29.71,22.51ppm；HRMS(ESI)m/z:[M+H]+理论值C13H17N4O 245.1397,实测值245.1382。
实施例16
称取化合物B(100mg，0.56mmol)溶解在3mL的二氯甲烷中，向溶液中依次加入DCC(173mg，0.84mmol)、DMAP(34mg，0.28mmol)、4-戊炔酸(110.6mg，1.12mmol)，在室温下反应24h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝15:1)，得到棕色油状化合物16(114mg，产率为79％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝8:1)。化合物16的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.27(d,J＝8.6Hz,1H),8.14(t,J＝2.1Hz,1H),7.80–7.77(m,1H),3.30(t,J＝8.8Hz,1H),3.13(t,J＝8.3Hz,1H),2.69–2.65(m,2H),2.61–2.58(m,2H),2.55(d,J＝6.7Hz,1H),2.35(d,J＝9.0Hz,1H),2.18(d,J＝1.7Hz,3H),1.95–1.84(m,2H),1.74–1.58(m,2H)ppm；13C NMR(101MHz,CDCl3)δ169.83,156.75,147.04,138.16,114.30,106.67,82.65,69.48,68.76,56.64,40.02,36.14,34.34,22.23,14.48ppm；HRMS(ESI)m/z:[M+H]+理论值C15H20N3O 258.1601,实测值258.1588。
实施例17
称取化合物B(140mg，0.79mmol)溶解在5mL的二氯甲烷中，向溶液中依次加入DCC(244mg，1.18mmol)、DMAP(48mg，0.395mmol)、2-吡啶甲酸(195mg，1.58mmol)，在室温下反应12h后减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝20:1)，得到黄色固体化合物17(150mg，产率为67％)，TLC:Rf＝0.5(CH2Cl2:CH3OH＝10:1)。化合物17的结构表征数据为：1H NMR(400MHz,CDCl3)δ10.55(s,1H),8.64(d,J＝4.8Hz,1H),8.39(dd,J＝8.5,2.0Hz,1H),8.31–8.27(m,2H),7.91(t,J＝7.7Hz,1H),7.78(d,J＝8.6Hz,1H),7.49(t,J＝6.3Hz,1H),3.26(t,J＝8.7Hz,1H),3.08(t,J＝8.2Hz,1H),2.30(t,J＝8.9Hz,1H),2.19(d,J＝2.1Hz,3H),1.80(td,J＝15.9,13.7,7.5Hz,2H),1.32(dd,J＝18.8,7.7Hz,2H)ppm；13C NMR(101MHz,MeOD)δ162.75,158.46,150.41,148.90,148.46,147.41,137.84,133.79,127.08,122.08,113.69,68.51,56.45,39.09,33.37,24.67ppm；HRMS(ESI)m/z:[M+H]+理论值C16H19N4O 283.1553,实测值283.1539。
实施例18
称取化合物A(100mg，0.56mmol)溶解在3mL的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加4-氯苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL的二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:2)，得到黄色固体化合物18(132.1mg，产率为52％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝1:1)。化合物18的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.37(d,J＝4.6Hz,1H),8.10(d,J＝7.9Hz,1H),7.73(dd,J＝11.7,8.0Hz,4H),7.32(dd,J＝14.0,8.8Hz,5H),3.30(t,J＝8.3Hz,1H),3.21(t,J＝8.6Hz,1H),2.27(d,J＝9.1Hz,1H),2.12(s,3H),1.98–1.50(m,4H)ppm；13C NMR(101MHz,CDCl3)δ172.24,172.08,151.52,148.15,139.01,138.10,137.45,132.93,132.79,130.69,128.95,128.85,124.64,65.38,56.65,40.40,34.21,22.91ppm；HRMS(ESI)m/z:[M+H]+理论值C24H22Cl2N3O2454.1084,实测值454.1070。
实施例19
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加2,6-二氟苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:1.5)，得到淡黄色固体化合物19(147.3mg，产率为57％)，TLC:Rf＝0.5(乙酸乙酯:石油醚＝1.5:1)。化合物19的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.41(dd,J＝4.4,2.2Hz,1H),8.17–8.11(m,1H),7.34–7.21(m,3H),6.80(dt,J＝27.0,8.6Hz,4H),3.49(t,J＝8.2Hz,1H),3.22(t,J＝8.4Hz,1H),2.35(d,J＝9.0Hz,1H),2.16(s,3H),1.94–1.57(m,4H)ppm；13C NMR(101MHz,CDCl3)δ162.89,162.87,160.50,157.97,149.04,147.95,138.62,137.68,132.72,132.62,132.51,125.14,111.82,111.70,111.66,111.61,111.57,111.49,111.45,64.41,56.85,40.20,34.66,23.06ppm；HRMS(ESI)m/z:[M+H]+C24H20F4N3O2理论值458.1486,实测值458.1384。
实施例20
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加间氯苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL的二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:3)，得到黄色固体化合物20(168.5mg，产率为66％)，TLC:Rf＝0.4(乙酸乙酯:石油醚＝1:2)。化合物20的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.41–8.36(m,1H),8.15(dd,J＝7.9,1.7Hz,1H),7.74(d,J＝16.4Hz,2H),7.66(t,J＝8.3Hz,2H),7.43(t,J＝9.1Hz,2H),7.32(ddt,J＝15.8,7.6,4.1Hz,3H),3.35(s,1H),3.28(s,1H),2.35–2.31(m,1H),2.18(s,3H),2.01–1.62(m,4H)ppm；13C NMR(101MHz,CDCl3)δ171.91,151.28,148.24,138.20,136.84,136.22,136.08,134.81,132.61,130.01,129.86,129.56,129.31,129.14,128.00,127.30,127.18,124.77,65.59,56.59,40.43,34.14,22.83ppm；HRMS(ESI)m/z:[M+H]+C24H22Cl2N3O2理论值454.1084,实测值454.1042。
实施例21
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加邻氯苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:1)，得到黄色油化合物21(156mg，产率为61％)，TLC:Rf＝0.4(乙酸乙酯:石油醚＝1.5:1)。化合物21的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.53(dd,J＝4.5,2.0Hz,1H),8.35(dd,J＝7.7,1.8Hz,1H),7.71–7.65(m,2H),7.41(d,J＝3.0Hz,1H),7.21(d,J＝4.4Hz,6H),3.80(t,J＝8.4Hz,1H),3.60–3.55(m,1H),2.51(q,J＝9.0Hz,1H),2.36(d,J＝1.4Hz,3H),2.16–1.88(m,4H)ppm；13C NMR(101MHz,CDCl3)δ169.30,150.64,148.87,138.04,135.61,134.83,132.10,131.83,130.50,130.40,130.33,129.63,126.69,126.57,126.47,125.15,65.73,56.49,39.92,33.90,22.46ppm；HRMS(ESI)m/z:[M+H]+C24H22Cl2N3O2理论值454.1084,实测值454.1032。
实施例22
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，加入4-溴苯甲酰氯(134mg，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:2.5)，得到淡黄色固体化合物22(160.7mg，产率为53％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝1:1)。化合物22的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.37(d,J＝4.7Hz,1H),8.10(d,J＝7.8Hz,1H),7.65(dd,J＝12.2,8.1Hz,4H),7.49(dd,J＝14.6,8.1Hz,4H),7.31(dd,J＝7.8,4.7Hz,1H),3.29(t,J＝8.2Hz,1H),3.21(t,J＝8.5Hz,1H),2.27(d,J＝9.0Hz,1H),2.12(s,3H),1.95–1.55(m,4H)ppm；13C NMR(101MHz,CDCl3)δ172.38,172.23,151.45,148.14,138.12,137.44,133.35,133.21,131.94,131.84,131.51,131.45,130.78,127.65,124.65,65.38,56.65,40.42,34.21,22.92ppm；HRMS(ESI)m/z:[M+H]+C24H22Br2N3O2理论值542.0073,实测值542.0032。
实施例23
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加对氟苯甲酰氯(0.07mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:1.5)，得到淡黄色固体化合物23(141.2mg，产率为60％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝1:1)。化合物23的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.42–8.38(m,1H),8.13–8.10(m,1H),7.83–7.79(m,3H),7.32(dd,J＝7.9,4.7Hz,1H),7.14–6.97(m,5H),3.34(t,J＝8.3Hz,1H),3.24(t,J＝8.5Hz,1H),2.32–2.26(m,1H),2.13(s,3H),1.94–1.59(m,4H)ppm；13C NMR(101MHz,CDCl3)δ172.12,171.98,166.43,163.90,151.79,148.19,138.09,137.32,132.53,132.44,131.98,131.89,124.60,115.95,115.86,115.72,115.64,115.50,115.29,65.40,56.63,40.34,34.16,22.85ppm；HRMS(ESI)m/z:[M+H]+C24H22F2N3O2理论值422.1675,实测值422.1627。
实施例24
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加对甲基苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:3)，得到淡黄色固体化合物24(178.9mg，产率为77％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝1:2)。化合物24的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.36(d,J＝4.6Hz,1H),8.08(d,J＝7.8Hz,1H),7.70(dd,J＝10.7,8.0Hz,4H),7.23(d,J＝7.5Hz,1H),7.12(dd,J＝14.6,7.8Hz,4H),3.38(t,J＝8.3Hz,1H),3.21(t,J＝8.5Hz,1H),2.85(s,1H),2.33(d,J＝6.2Hz,6H),2.15(d,J＝2.0Hz,3H),1.94–1.55(m,4H)ppm；13C NMR(101MHz,CDCl3)δ173.44,173.25,152.34,147.94,143.17,137.75,137.32,132.07,131.94,129.97,129.56,129.51,129.19,129.08,128.97,124.15,65.29,56.71,40.44,34.19,22.92,21.66,21.61ppm；HRMS(ESI)m/z:[M+H]+C26H28N3O2理论值414.2176,实测值414.2134。
实施例25
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加对乙基苯甲酰氯(0.09mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:2.5)，得到淡黄色固体化合物25(192.1mg，产率为78％)，TLC:Rf＝0.4(乙酸乙酯:石油醚＝1:1)。化合物25的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.35(dd,J＝4.7,2.3Hz,1H),8.06(d,J＝7.8Hz,1H),7.71(dd,J＝14.6,7.8Hz,4H),7.26(t,J＝2.3Hz,1H),7.13(dd,J＝16.9,7.8Hz,4H),3.36(t,J＝8.2Hz,1H),3.17(t,J＝8.5Hz,1H),2.62(p,J＝7.7Hz,4H),2.26(t,J＝9.0Hz,1H),2.14(d,J＝1.7Hz,3H),1.93–1.70(m,4H),1.19(q,J＝7.4Hz,6H)ppm；13C NMR(101MHz,CDCl3)δ173.52,173.23,152.37,149.25,149.21,147.88,137.66,137.59,132.32,132.24,129.67,129.58,127.97,127.85,124.09,65.23,56.78,40.50,34.28,28.86,23.01,15.07ppm；HRMS(ESI)m/z:[M+H]+C28H32N3O2理论值442.2489,实测值442.2441。
实施例26
称取化合物A(90mg，0.508mmol)溶解在3mL的二氯甲烷中，加入三乙胺(0.12mL，0.76mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加苯甲酰氯(0.07mL，0.558mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL的二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:1.5)，得到黄色油状物26(108.3mg，产率为55％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝1:1)。化合物26的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.39(d,J＝4.6Hz,1H),8.12–8.08(m,1H),7.79(t,J＝8.8Hz,4H),7.43(d,J＝8.9Hz,2H),7.36–7.28(m,5H),3.41(t,J＝8.3Hz,1H),3.25(t,J＝8.6Hz,1H),2.27(t,J＝9.0Hz,1H),2.17(s,3H),1.96–1.57(m,4H)ppm；13C NMR(101MHz,CDCl3)δ173.45,173.27,152.07,148.10,137.85,137.19,134.91,134.79,132.74,132.42,129.95,129.38,129.34,128.50,128.40,128.28,124.37,65.42,56.68,40.39,34.17,22.87ppm；HRMS(ESI)m/z:[M+H]+理论值C24H24N3O2 386.1863,实测值386.1855。
实施例27
称取化合物A(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加3,5-二氯苯甲酰氯(0.09mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL的二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝1:6)，得到白色固体化合物27(143.1mg，产率为49％)，TLC:Rf＝0.4(乙酸乙酯:石油醚＝1:4)。化合物27的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.39(dd,J＝4.4,2.0Hz,1H),8.17(d,J＝7.8Hz,1H),7.61(d,J＝13.3Hz,4H),7.46(d,J＝11.5Hz,2H),7.36(dd,J＝8.1,4.7Hz,1H),3.31(dt,J＝16.8,8.5Hz,2H),2.38(d,J＝9.8Hz,1H),2.19(s,3H),2.09–1.64(m,4H)ppm；13C NMR(101MHz,CDCl3)δ170.51,150.63,148.42,138.52,136.47,135.55,134.93,132.52,128.28,127.32,125.10,124.86,65.69,56.51,40.44,34.12,22.83ppm；HRMS(ESI)m/z:[M+H]+C24H20Cl4N3O2理论值522.0304,实测值522.0262。
实施例28
称取化合物B(53mg，0.3mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，加入对甲苯磺酰氯(69mg，0.36mmol)，然后将反应混合物在室温下搅拌4h。向其中加入1mol/L的盐酸水溶液除去吡啶，再用5mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝13:1)，得到白色固体化合物28(61mg，产率为42％)，TLC:Rf＝0.3(CH2Cl2:CH3OH＝7:1)。化合物28的结构表征数据为：1HNMR(400MHz,CDCl3)δ8.21(d,J＝5.8Hz,5H),6.51(d,J＝5.9Hz,6H),3.02(s,12H),1.92(dd,J＝12.7,4.1Hz,1H),1.68(d,J＝12.0Hz,1H),1.26(s,2H)ppm；13C NMR(101MHz,CDCl3)δ154.53,148.73,148.67,130.93,128.84,106.58,65.58,49.00,39.14,33.96,29.71,25.65,24.97ppm；HRMS(ESI)m/z:[M+H]+理论值C24H28N3O4S2 486.1516,实测值486.1494。
实施例29
称取化合物B(79mg，0.44mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.1mL，0.675mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加氯乙酰氯(0.04mL，0.49mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为乙酸乙酯:石油醚＝2:1)，得到棕色油状化合物29(143.1mg，产率为44％)，TLC:Rf＝0.3(乙酸乙酯:石油醚＝4:1)。化合物29的结构表征数据为：1H NMR(400MHz,CDCl3)δ9.21(d,J＝44.9Hz,1H),8.24(d,J＝8.4Hz,1H),7.82(dt,J＝7.6,3.5Hz,1H),4.93(ddd,J＝35.9,8.9,5.5Hz,1H),4.22(s,2H),4.07(d,J＝3.5Hz,2H),3.59(dt,J＝14.0,7.2Hz,1H),3.40–3.33(m,1H),3.07(d,J＝1.2Hz,2H),2.95(s,1H),2.08–1.67(m,4H)ppm；13C NMR(101MHz,CDCl3)δ166.76,164.73,150.20,145.89,137.68,134.28,114.10,59.60,46.80,42.83,41.35,36.58,35.48,24.30ppm；HRMS(ESI)m/z:[M+H]+C14H18Cl2N3O2理论值330.0771,实测值330.0753。
实施例30
称取化合物B(100mg，0.56mmol)溶解在3mL干燥的二氯甲烷中，加入三乙胺(0.12mL，0.84mmol)，室温下搅拌5min，然后在冰浴中冷却反应溶液，滴加邻氯苯甲酰氯(0.08mL，0.61mmol)，在室温下反应4h后加入5mL水淬灭反应，再用10mL二氯甲烷萃取3次，合并二氯甲烷相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，得到的浓缩物通过硅胶柱分离(洗脱剂为CH2Cl2:CH3OH＝30:1)，得到黄色油状化合物30(127mg，产率为50％)，TLC:Rf＝0.4(CH2Cl2:CH3OH＝18:1)。化合物30的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.07(d,J＝8.2Hz,1H),7.77(d,J＝7.5Hz,1H),7.52(dd,J＝10.8,8.2Hz,3H),7.40(d,J＝7.7Hz,1H),7.34–7.27(m,2H),7.22–7.19(m,2H),3.61(t,J＝8.9Hz,1H),3.50(t,J＝8.5Hz,1H),2.61(q,J＝9.1Hz,1H),2.27(s,3H),2.26–1.92(m,4H)ppm；13C NMR(101MHz,CDCl3)δ169.15,151.80,149.36,137.98,135.10,132.50,131.50,131.40,130.95,130.73,130.50,130.02,129.54,126.64,126.48,123.39,68.56,56.01,39.01,33.28,21.96ppm；HRMS(ESI)m/z:[M+H]+C24H22Cl2N3O2理论值454.1084,实测值454.1015。
实施例31
本发明烟碱酰胺型化合物在制备减肥药物中的应用
分别将上述化合物1～30作为受试化合物，测试其对脂肪酶的抑制活性，具体试验情况如下：
将三油酸(80mg)、磷脂酰胆碱(10mg)和牛磺胆酸(5mg)悬浮在含有0.1M氯化钠的9mL0.1MN-三(羟甲基)甲基-2-氨基-乙烯磺酸(TES)缓冲液(pH7.0)中，超声处理5分钟。将超声处理的基质悬浮液(100μL)与50μL(10个单位)的胰脂肪酶和100μL各种样品溶液一起在37℃培养30分钟，最终体积为250μL，测定释放的油酸量。将培养混合物添加到含有2％(v/v)MeOH的1:1(v/v)CHCl3和正庚烷混合物的3mL等分试样中，并通过在振动筛中水平摇动试管10min进行提取。将混合物在2000g下离心10分钟，并通过抽吸去除上层水相。然后将铜试剂(1mL)添加到较低的有机相中。将混合物以2000g离心10min，并用0.5mL0.1％(w/v)巴妥卡因在含有0.05％(w/v)3(2)-叔丁基-4-羟基茴香醚的氯仿中处理0.5mL上层有机相(其中含有提取的游离脂肪酸的铜盐)。然后在480nm处测量吸光度。
试验结果见表1。
表1化合物1～30对胰脂肪酶的抑制活性
从表1的胰脂肪酶抑制活性数据可知，本发明的烟碱酰胺型化合物对胰脂肪酶表现出了很好的抑制活性，效果明显优于烟碱，可用于制备减肥药物。
Claims (3)
1.烟碱酰胺型化合物，其特征在于该化合物的结构式为：
其中，R代表芳香酰基和脂肪酰基。
2.根据权利要求1所述的烟碱酰胺型化合物，其特征在于：所述R选自乙酰基、氯乙酰基、硬脂酰基、软脂酰基、正庚酰基、正辛酰基、苯丙酰基、烟酰基、戊炔酰基、氰基乙酰基、三氟甲磺酸酰基、苯甲酰基、对氯苯甲酰基、间氯苯甲酰基、邻氯苯甲酰基、对溴苯甲酰基、对氟苯甲酰基、邻二氟苯甲酰基、对甲基苯甲酰基、对乙基苯甲酰基、间二氯苯甲酰基、对甲苯磺酰基中任意一种。
3.权利要求1或2所述的烟碱酰胺型化合物在制备减肥药物中的应用。
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