CN109970794B - S-取代-3-吲哚硫磷酸酯类衍生物及制备方法和应用 - Google Patents
S-取代-3-吲哚硫磷酸酯类衍生物及制备方法和应用 Download PDFInfo
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Abstract
S‑取代‑3‑吲哚硫磷酸酯类衍生物及制备方法和应用,涉及吲哚类药物。以吲哚衍生物、硫粉和氢亚磷酸酯为原料,碘化物为催化剂,加入溶剂,在搅拌状态下加入过氧化物类氧化剂,升温加热至回流,即得S‑取代‑3‑吲哚硫磷酸酯类衍生物。S‑取代‑3‑吲哚硫磷酸酯类衍生物及药物组合物可在制备诊断和治疗炎症性药物的应用。将吲哚模块和有机硫磷模块共同构建在同一分子内,这类化合物表现了一定的抗炎活性。所述S‑取代‑3‑吲哚硫磷酸酯类衍生物的结构上具有较高的创造性。同时,S‑取代‑3‑吲哚硫磷酸酯类衍生物的制备方法反应成本低,产率高,反应过程简单易控制,适用于工业化生产。
Description
技术领域
本发明涉及吲哚类药物,尤其是涉S-取代-3-吲哚硫磷酸酯类衍生物及其制备方法和应用。
背景技术
吲哚类药物广泛用于炎症的治疗,同时,吲哚衍生物具有丰富的生物活性,所以近百年来,研究构建新型的吲哚衍生物并研究其新的生物活性成为药学家和合成化学家的重点课题。生命体中的色氨酸也是吲哚的衍生物;吲哚类生物碱具有很好的生理活性([1]Shiri,M.Chem.Rev.2012,112,3508;[2]Walker,S.R.;Carter,E.J.;Huff,B.C.;Morris,J.C.Chem.Rev.2009,109,3080;[3]Chadha,N.;Silakari,O.Eur.J.Med.Chem.2017,134,159),目前,已有很多吲哚类生物碱开发成为药物,代表药物主要有那拉曲坦(Naratriptan)、吲哚美辛(Indomethacin)、阿莫曲坦(Almotriptan)、利扎曲普坦(Rizatriptan)、佐米曲普坦(Zolmitriptan)、夫罗曲坦(Frovatriptan)、阿西美辛(Acemetacin)等。
另一方面,硫磷酸酯是比较常见的一种有机磷化合物,在药物合成、农药以及有机合成等众多领域有着十分广泛的应用,其结构都非常简单,但具有很强的生物活性([4]Azran,S.;Danino,O.;D.;Kenigsberg,S.;Reiser,G.;Dixit,M.;Singh,V.;Major,D.T.;Fischer,B.J.Med.Chem.2015,58,8427;[5]Shivalingam,A.;Tyburn,A.E.S.;El-Sagheer,A.H.;Brown,T.J.Am.Chem.Soc.2017,139,1575.),如比较常见的对硫磷(Parathion)、碘硫磷(Iodofenphos)、內吸磷(Demeton)、马拉硫磷(Malathion)、氧乐果(Omethoate)、稻瘟净(Kitazin)等。
发明内容
本发明的第一目的在于提供具有新结构的一类S-取代-3-吲哚硫磷酸酯类衍生物及其制备方法。
本发明的第二目的在于提供一类S-取代-3-吲哚硫磷酸酯类衍生物及药物组合物在制备诊断和治疗炎症性药物的应用。
所述S-取代-3-吲哚硫磷酸酯类衍生物的通式如下:
其中,R1代表H或烷基或各类芳香基团或胺类或羧酸衍生物或烷氧基或卤素等,优选为H、Cl、F、烷氧基、羧酸酯、酰胺;R2代表H或烷基或各类芳香基团,优选为H或甲基或苯基;R3代表烷基或各类芳香基团,优选C1~C4的直链烷基、C5或C6的环烷基、金刚烷基、取代或未取代的芳香烷基、取代或未取代的苄基、取代或未取代的杂环化合物,最好为甲基、乙基、异丙基。
所述S-取代-3-吲哚硫磷酸酯类衍生物的制备方法的具体步骤如下:
以吲哚衍生物、硫粉和氢亚磷酸酯为原料,碘化物为催化剂,加入溶剂,在搅拌状态下加入过氧化物类氧化剂,升温加热至回流,即得S-取代-3-吲哚硫磷酸酯类衍生物。
所述碘化物可选自碘化钠、碘化钾、四丁基碘化铵等中的一种;所述溶剂可选自乙腈、乙醇、水等中的一种;所述过氧化物类氧化剂可选自过氧化叔丁醇、双氧水等中的一种。
所述S-取代-3-吲哚硫磷酸酯类衍生物的合成路线为:
所述S-取代-3-吲哚硫磷酸酯类衍生物及药物组合物可在制备诊断和治疗炎症性药物的应用。所述炎症可包括胃炎、肺炎等。
本发明将吲哚模块和有机硫磷模块共同构建在同一分子内,这类化合物表现了一定的抗炎活性。所述S-取代-3-吲哚硫磷酸酯类衍生物的结构上具有较高的创造性。同时,S-取代-3-吲哚硫磷酸酯类衍生物的制备方法反应成本低,产率高,反应过程简单易控制,适用于工业化生产。
附图说明
图1为本发明实施例部分化合物的细胞毒性(20μmol/L)
具体实施方式
为了便于理解本发明,现结合具体实施方式对本发明作进一步说明。
为了清楚说明本发明,实施例中所描述的化合物结构和编号列在以下的表格中。
方法一:实施例1:S-取代-3-吲哚硫磷酸二乙酯的制备(化合物7)
在250mL反应瓶中依次加入硫粉(3.84g,0.12mol),氢亚磷酸二乙酯(13.80g,0.10mol),三乙胺(10.10g,0.10mol),二氯甲烷(100mL),室温搅拌10h,TLC检测反应已结束,停止反应。反应液加入盐酸水溶液洗涤,有机相减压浓缩得浅黄色液体硫代磷酸二乙酯17.0g,收率100%,31PNMR:58ppm。
在150mL反应瓶中,先依次加入吲哚(1.17g,10mmol),硫代磷酸二乙酯(2.55g,15mmol),碘化钠(0.15g,1mmol),加入乙醇20mL,再在搅拌状态下加入过氧化叔丁醇(70%浓度,2.6g,20mmol),60℃保温反应8h。TLC检测反应已结束,停止反应。反应液冷却至室温,在搅拌下加入80mL乙酸乙酯,并用碳酸氢钠调pH为7~8;液体过滤后分液,有机相用15g无水硫酸钠干燥0.5h,过滤,滤液减压浓缩得到的固体用硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=3∶1,v/v),得产物S-取代-3-吲哚硫磷酸二乙酯2.80g,收率98%。1H NMR(500MHz,CDCl3)δ(ppm)9.83(s,1H),7.61(d,J=7.7Hz,1H),7.16(d,J=7.5Hz,1H),7.09~7.01(m,3H),4.16~4.07(m,4H),1.21(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)136.3(s),131.6(d,J=6.1Hz),129.2(d,J=1.8Hz),122.5(s),120.5(s),118.7(s),112.2(s),93.3(d,J=7.3Hz),64.4(d,J=6.6Hz),16.2(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.8.HRMS Calcd forC12H16NNaO3PS+[M+Na]+308.0481,found 308.0478.
方法二:实施例2:S-取代-3-吲哚硫磷酸二乙酯的制备(化合物7)
在250mL双颈瓶中依次加入硫代磷酸二乙酯(1.70g,0.01mol),加入乙腈10mL,在搅拌状态下加入过氧化叔丁醇(70%浓度,1.3g,0.01mol),60℃保温反应8h,减压浓缩,然后用硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=10∶1,v/v),得产物过硫磷酰化合物3.21克,产率95%。31PNMR:21ppm。
在150mL反应瓶中,先依次加入吲哚(1.17g,10mmol),过硫磷酰化合物(1.69g,5mol),碘化钠(0.15g,1mmol),加入乙腈20mL,再在搅拌状态下加入过氧化叔丁醇(70%浓度,2.6g,20mmol),60℃保温反应8h。TLC检测反应已结束,停止反应。反应液冷却至室温,在搅拌下加入80mL乙酸乙酯,并用碳酸氢钠调pH为7~8;液体过滤后分液,有机相用15g无水硫酸钠干燥0.5h,过滤,滤液减压浓缩得到的固体用硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=3∶1,v/v),得产物S-取代-3-吲哚硫磷酸二乙酯2.6g,收率90%。
方法三:实施例3:S-取代-3-吲哚硫磷酸二乙酯的制备(化合物7)
在150mL反应瓶中,先依次加入氢亚磷酸二乙酯(2.07g,15mmol),硫粉(0.48g,15mmol),三乙胺(1.52g,15mmol),碘化钠(0.15g,1mmol),吲哚(1.17g,10mmol),加入乙腈20mL,60℃保温反应20min,然后加入三氟乙酸,调至pH<3,加入过氧化叔丁醇(70%浓度,3.9g,30mmol),80℃保温反应5h。TLC检测反应已结束,停止反应。反应液冷却至室温,在搅拌下加入80mL乙酸乙酯,并用碳酸氢钠调pH为7~8;液体过滤后分液,有机相用15g无水硫酸钠干燥0.5h,过滤,滤液减压浓缩得到的固体用硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=3∶1,v/v),得产物S-取代-3-吲哚硫磷酸二乙酯2.82g,收率80%。
实施例4:S-取代-3-(1-甲基)吲哚硫磷酸二乙酯的制备(化合物1)
利用方法一,以1-甲基吲哚为原料,收率92%。1H NMR(500MHz,CDCl3)δ(ppm)7.65(d,J=7.9Hz,1H),7.25~7.12(m,4H),4.12~4.06(m,4H),3.72(s,3H),1.18(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)137.1(s),134.8(d,J=5.43Hz),130.0(d,J=2.5Hz),122.6(s),120.60(s),119.4(s),109.9(s),93.6(d,J=7.7Hz),64.0(d,J=6.3Hz),33.4(s),16.2(d,J=7.2Hz).31P NMR(202MHz,CDCl3)δ(ppm)23.8.HRMS Calcd forC13H18NNaO3PS+[M+Na]+322.0637,found 322.0643.
实施例5:S-取代-3-(7-甲基)吲哚硫磷酸二乙酯的制备(化合物2)
利用方法一,以7-甲基吲哚为原料,用双氧水(30%浓度,2.0g,20mmol)取代TBHP,收率90%。1H NMR(500MHz,CDCl3)δ(ppm)9.72(s,1H),7.53(d,J=7.9Hz,1H),7.19(dd,J=4.2,3.2Hz,1H),7.08(dd,J=7.5,8.7Hz,1H),6.9(d,J=7.8Hz,1H),4.28~4.18(m,4H),2.20(s,3H),1.34(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)135.8(s),131.6(d,J=6.0Hz),128.9(d,J=1.8Hz),123.0(s),121.8(s),120.7(s),116.3(s),93.6(d,J=7.3Hz),64.3(d,J=6.6Hz),16.26(s),16.24(d,J=6.8Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.9.HRMS Calcd for C13H18NNaO3PS+[M+Na]+322.0637,found 322.0637.
实施例6:S-取代-3-(2-甲基)吲哚硫磷酸二乙酯的制备(化合物3)
利用方法三,以2-甲基吲哚为原料,收率86%。1H NMR(500MHz,CDCl3)δ(ppm)9.57(s,1H),7.60(d,J=7.8Hz,1H),7.17~7.05(m,3H),4.26~4.13(m,4H),2.22(d,J=3.0Hz,3H),1.34(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)142.3(d,J=6.3Hz),135.5(s),130.3(s),121.7(s),120.2(s),118.1(s),111.3(s),90.4(d,J=6.9Hz),64.2(d,J=7.1Hz),16.2(d,J=7.1Hz),12,1(d,J=1.7Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.7.HRMSCalcd for C13H18NNaO3PS+[M+Na]+322.0637,found 322.0637.
实施例7:S-取代-3-(5-甲氧羰基)吲哚硫磷酸二乙酯的制备(化合物4)
利用方法二,以5-甲氧羰基吲哚为原料,收率65%。1H NMR(500MHz,CDCl3)δ(ppm)10.49(s,1H),8.39(s,1H),7.68(d,J=8.6Hz,1H),7.12~7.07(m,2H),4.32~4.18(m,4H),3.92(s,3H),1.35(t,J=7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)168.1(s),139.0(s),133.1(d,J=6.3Hz),128.6(d,J=1.6Hz),123.6(s),122.4,(s),121.6(s),112.0(s),94.8(d,J=7.3Hz),64.7(d,J=7.1Hz),51.9(s),16.1(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.4.HRMS Calcd for C14H18NNaO5PS+[M+Na]+366.0536,found 366.0528.
实施例8:S-取代-3-(5-甲氧基)吲哚硫磷酸二乙酯的制备(化合物5)
利用方法一,以5-甲氧基吲哚为原料,用碘化钾取代碘化钠,收率81%。1H NMR(500MHz,CDCl3)δ(ppm)9.63(s,1H),7.26~7.10(m,3H),6.80-6.78(m,1H),4.26~4.14(m,4H),3.86(s,3H),1.30(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)155.0(s),131.9(d,J=5.9Hz),131.3(s),129.9(d,J=1.7Hz),113.05(s),112.97(s),100.4(s),93.1(d,J=6.9Hz),64.3(d,J=6.6Hz),55.9(s),16.2(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.8.HRMS Calcd for C13H18NNaO4PS+[M+Na]+338.0586,found 338.0585.
实施例9:S-取代-3-(5-氯)吲哚硫磷酸二乙酯的制备(化合物6)
利用方法一,以5-氯吲哚为原料,用碘化钾取代碘化钠,收率89%。1H NMR(500MHz,CDCl3)δ(ppm)10.15(s,1H),7.59(s,1H),7.04~6.94(m,3H),4.33~4.20(m,4H),1.39(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)134.7(s),132.9(d,J=5.8Hz),130.2(d,J=1.6Hz),126.4(s),122.7(s),118.0(s),113.3(s),92.63(d,J=6.9Hz),64.7(d,J=7.0Hz),16.2(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.8.HRMS Calcd forC12H15ClNNaO3PS+[M+Na]+342.0091,found342.0089.
实施例10:S-取代-3-(4-苯氧基)吲哚硫磷酸二乙酯的制备(化合物8)
利用方法三,以4-苯氧基吲哚为原料,用浓硫酸取代三氟乙酸,收率80%。1H NMR(500MHz,CDCl3)δ(ppm)9.94(s,1H),7.63(d,J=7.6Hz,2H),7.40(dd,J=7.9,7.5Hz,2H),7.32(dd,J=8.1,7.3Hz,1H),7.12(s,1H),7.01(dd,J=8.4,8.0Hz,1H),6.93(d,J=8.3Hz,1H),6.59(d,J=7.8Hz,1H),5.22(s,2H),4.19~4.04(m,4H),1.20(t,J=7.1Hz,6H).13CNMR(125MHz,CDCl3)δ(ppm)153.0(s),138.3(s),137.6(s),131.2(d,J=5.8Hz),128.5(s),127.7(s),127.3(s),123.1(s),118.6(d,J=2.5Hz),106.0(s),102.2(s),92.6(s),70.2(s),64.1(d,J=8.4Hz),16.1(d,J=7.2Hz).31P NMR(202MHz,CDCl3)δ(ppm)25.3.HRMSCalcd for C19H22NNaO4PS+[M+Na]+414.0899,found 414.0892.
实施例11:S-取代-3-(5-溴)吲哚硫磷酸二乙酯的制备(化合物9)
利用方法一,以5-溴吲哚为原料,用乙醇作溶剂,收率85%。1H NMR(500MHz,CDCl3)δ(ppm)10.23(s,1H),7.74(s,1H),7.09~7.07(m,1H),7.01(dd,J=4.2,3.4Hz,1H),6.9(d,J=8.7Hz,1H),4.33~4.19(m,4H),1.39(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)135.0(s),132.8(d,J=6.0Hz),130.7(d,J=1.7Hz),125.2(s),121.0(s),113..98(s),113.69(s),92.4(d,J=7.1Hz),64.7(d,J=7.1Hz),16.2(d,J=7.2Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.7.HRMS Calcd for C12H15BrNNaO3PS+[M+Na]+385.9586,found 385.9577.
实施例12:S-取代-3-(5-碘)吲哚硫磷酸二乙酯的制备(化合物10)
利用方法一,以5-碘吲哚为原料,用乙醇作溶剂,收率90%。1H NMR(500MHz,CDCl3)δ(ppm)10.25(s,1H),7.93(s,1H),7.24(d,J=8.6Hz,1H),6.96(dd,J=4.0,3.2Hz,1H),6.78(d,J=8.6Hz,1H),4.33~4.20(m,4H),1.40(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)135.4(s),132.4(d,J=6.2Hz),131.4(d,J=1.6Hz),130.6(s),127.3(s),114.2(s),92.0(d,J=7.2Hz),84.3(s),64.7(d,J=7.1Hz),16.3(d,J=7.2Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.7.HRMS Calcd for C12H15INNaO3PS+[M+Na]+433.9447,found 433.9440.
实施例13:S-取代-3-吲哚硫磷酸二甲酯的制备(化合物11)
利用方法一,以吲哚和氢亚磷酸二甲酯为原料,收率92%。1H NMR(500MHz,CDCl3)δ(ppm)9.55(s,1H),7.62(d,J=7.6Hz,1H),7.18(d,J=7.7Hz,1H),7.12~7.07(m,3H),3.76(d,J=12.5Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)136.3(s),131.5(d,J=6.0Hz),129.1(d,J=1.7Hz,),122.7(s),120.8(s),118.6(s),112.2(s),93.2(d,J=7.4Hz),54.6(d,J=6.6Hz).31P NMR(202MHz,CDCl3)δ(ppm)27.7.HRMS Calcd for C10H12NNaO3PS+[M+Na]+280.0168,found 280.0162.
实施例14:S-取代-3-(2-苯基)吲哚硫磷酸二乙酯的制备(化合物12)
利用方法一,以2-苯基吲哚为原料,收率95%。1H NMR(500MHz,CDCl3)δ(ppm)10.14(s,1H),7.74(d,J=7.5Hz,1H),7.28(d,J=7.8Hz,1H),7.17~7.09(m,3H),4.83~4.76(m,2H),1.34(d,J=6.3Hz,6H),1.26(d,J=6.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)136.3(s),131.5(d,J=6.0Hz),129.2(d,J=2.0Hz,),122.3(s),120.3(s),119.1(s),112.2(s),93.8(d,J=7.3Hz),73.5(d,J=7.3Hz),24.0(d,J=4.4Hz),23.7(d,J=5.4Hz).31P NMR(202MHz,CDCl3)δ(ppm)22.9.HRMS Calcd for C14H20NNaO3PS+[M+Na]+336.0794,found336.0794.
实施例14:S-取代-3-(1-甲基-5-羧基)吲哚硫磷酸二乙酯的制备(化合物15)
利用方法一,以1-甲基-5-羧基吲哚为原料,收率65%。1H NMR(500MHz,CDCl3)δ(ppm)8.56(s,1H),8.03(d,J=8.7Hz,1H),7.37(d,J=3.6Hz,1H),7.33(d,J=8.7Hz,1H),4.26~4.13(m,4H),3.82(s,3H),1.27(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)172.4(s),139.9(s),136.4(d,J=5.6Hz),129.5(d,J=1.9Hz),124.5(s),123.2(s),122.3(s),109.8(s),96.0(d,J=7.6Hz),,64.4(d,J=6.5Hz),33.6(s),16.2(d,J=6.9Hz).31PNMR(202MHz,CDCl3)δ(ppm)23.3.HRMS Calcd for C14H18NNaO5PS+[M+Na]+366.0536,found366.0530.
实施例15:S-取代-3-(1-苯基)吲哚硫磷酸二乙酯的制备(化合物16)
利用方法一,以1-苯基吲哚为原料,收率91%。1H NMR(500MHz,CDCl3)δ(ppm)7.82~7.79(m,1H),7.55-7.46(m,6H),7.38(dd,J=7.6,7.2Hz,1H),7.28~7.23(m,2H),4.27~4.14(m,4H),1.27(t,J=7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)138.8(s),136.3(s),133.6(d,J=6.1Hz),130.4(d,J=2.0Hz),129.8(s),127.3(s),124.5(s),123.4(s),121.4(s),119.7(s),111.0(s),97.1(d,J=7.5Hz),64.1(d,J=6.3Hz),16.1(d,J=6.9Hz).31PNMR(202MHz,CDCl3)δ(ppm)23.4.HRMS Calcd for C18H20NNaO3PS+[M+Na]+384.0794,found384.0789.
实施例16:S-取代-3-(5-氟)吲哚硫磷酸二乙酯的制备(化合物18)
利用方法三,以5-氟吲哚为原料,收率80%。1H NMR(500MHz,CDCl3)δ(ppm)10.06(s,1H),7.21~7.18(m,1H),7.01~6.93(m,2H),6.72~6.68(m,1H),4.22~4.10(m,4H),1.28(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)158.6(d,J=235.6Hz),133.3(d,J=5.7Hz),132.8(s),129.7(d,J=10.1Hz),113.0(d,J=9.7Hz),110.9(d,J=26.4Hz),103.5(d,J=24.5Hz),92.9(s),64.6(d,J=6.9Hz),16.2(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.8.HRMS Calcd for C12H15FNNaO3PS+[M+Na]+326.0386,found 326.0381.
实施例17:S-取代-3-(5-甲酰基)吲哚硫磷酸二乙酯的制备(化合物19)
利用方法一,以5-甲酰基吲哚为原料,收率60%。1H NMR(500MHz,CDCl3)δ(ppm)10.56(s,1H),10.01(S,1H),8.18(s,1H),7.49(d,J=8.4Hz,1H),7.16(dd,J=4.3,2.9Hz,1H),7.09(d,J=8.5Hz,1H),4.36~4.23(m,4H),1.39(t,J=7.0Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)192.4(s),139.9(s),133.5(d,J=6.3Hz),130.0(s),128.9(d,J=1.7Hz),123.08(s),122.99(s),112.7(s),95.5(d,J=7.2Hz),64.7(d,J=7.1Hz),16.1(d,J=7.0Hz).31P NMR(202MHz,CDCl3)δ(ppm)24.4.HRMS Calcd for C13H16NNaO4PS+[M+Na]+336.0430,found 336.0430.
实施例18:S-取代-3-(1-(3’-溴)丙基)吲哚硫磷酸二乙酯的制备(化合物22)
利用方法一,以1-(3’-溴)丙基吲哚为原料,收率70%。1H NMR(500MHz,CDCl3)δ(ppm)7.66(d,J=7.8Hz,1H),7.31~7.29(m,2H),7.20~7.12(m,2H),4.07(t,J=8.0Hz,2H),4.14~4.05(m,4H),3,21(t,J=6.0Hz,2H),2.28~2.23(m,2H)1.18(t,J=7.0Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)136.2(s),133.9(d,J=5.7Hz),130.1(d,J=2.0Hz),122.8(s),120.8(s),119.7(s),109.9(s),94.5(d,J=7.4Hz),64.0(d,J=6.3Hz),44.4(s),32.5(s),30.2(s),16.2(d,J=7.1Hz).31P NMR(202MHz,CDCl3)δ(ppm)23.6.HRMS Calcd forC15H21BrNNaO3PS+[M+Na]+428.0055,found 428.0047.
实施例19:S-取代-3-(2-p-甲氧基苯基)咪唑并[1,2-a]吡啶硫磷酸二乙酯的制备(化合物26)
方法五:在150mL反应瓶中,先依次加入2-p-甲氧基苯基咪唑并[1,2-a]吡啶(2.24g,10mmol),硫代磷酸二乙酯(2.55g,15mmol),碘化钾(0.17g,1mmol),加入乙腈20mL,再在搅拌状态下加入过氧化叔丁醇(70%浓度,2.6g,20mmol),60℃保温反应2h。TLC检测反应已结束,停止反应。反应液冷却至室温,在搅拌下加入80mL乙酸乙酯,并用碳酸氢钠调pH为7~8;液体过滤后分液,有机相用15g无水硫酸钠干燥0.5h,过滤,滤液减压浓缩得到的固体用硅胶柱层析分离(洗脱剂为石油醚∶乙酸乙酯=3∶1,v/v),得产物S-取代-3-(2-p-甲氧基苯基)咪唑并[1,2-a]吡啶硫磷酸二乙酯3.32g,收率85%。1H NMR(500MHz,CDCl3)δ(ppm)8.49(d,J=6.8Hz,1H),8.14(d,J=8.8Hz,2H),7.62(d,J=8.9Hz,1H),7.29(dd,J=9.3,8.5Hz,1H),6.99(d,J=8.8Hz,2H),6.91(dd,J=7.5,6.8Hz,1H),3.98~3.84(m,4H),3.83(s,3H),1.03(t,J=7.0Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)160.0(s),151.1(d,J=5.6Hz),147.2(s),130.0(s),126.5(s),126.0(d,J=1.8Hz),125.3(s),117.3(s),113.8(s),112.6(s),99.0(d,J=7.8Hz),64.7(d,J=7.2Hz),55.4(s),15.9(d,J=7.0Hz).31PNMR(202MHz,CDCl3)δ(ppm)19.2.HRMS Calcd for C18H21N2NaO4PS+[M+Na]+415.0852,found415.0846.
实施例20:S-取代-3-(4-甲基-2-苯基)咪唑并[1,2-a]吡啶硫磷酸二乙酯的制备(化合物28)
利用方法五,以4-甲基-2-苯基咪唑并[1,2-a]吡啶为原料,收率83%。1H NMR(500MHz,CDCl3)δ(ppm)8.39(d,J=6.8Hz,1H),8.14(d,J=7.7Hz,2H),7.46(dd,J=8.6,7.7Hz,2H),7.37(dd,J=8.4,7.4Hz,1H),7.10(d,J=6.8Hz,1H),6.85(dd,J=7.4,6.8Hz,1H),3.94~3.78(m,4H),2.65(s,3H),1.01(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)150.9(d,J=5.6Hz),147.6(s),133.6(d,J=1.9Hz),128.9(s),128.5(s),128.4(s),127.6(s),125.4(s),123.2(s),112.8(s),100.3(d,J=8.0Hz),64.7(d,J=6.9Hz),16.8(s),15.9(d,J=6.8Hz).31P NMR(202MHz,CDCl3)δ(ppm)19.2.HRMS Calcd forC18H21N2NaO3PS+[M+Na]+399.0903,found 399.0909.
实施例21:S-取代-3-(2-p-氯苯基)咪唑并[1,2-a]吡啶硫磷酸二乙酯的制备(化合物31)
利用方法五,以2-p-氯苯基咪唑并[1,2-a]吡啶为原料,收率83%。1H NMR(500MHz,CDCl3)δ(ppm)8.52(d,J=6.9Hz,1H),8.15(d,J=8.4Hz,2H),7.65(d,J=9.0Hz,1H),7.44(dd,J=8.6,8.4Hz,2H),7.33(dd,J=8.1.7.8Hz,1H),6.96(dd,J=7.4,6.8Hz,1H),4.02~3.85(m,4H),1.06(t,J=7.1Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)149.9(d,J=5.6Hz),147.2(d,J=2.2Hz),134.6(s),131.9(s),129.9(s),128.6(s),126.9(s),125.4(s),117.6(s),112.9(s),100.1(d,J=7.9Hz),64.9(d,J=7.4Hz),15.9(d,J=6.8Hz).31PNMR(202MHz,CDCl3)δ(ppm)19.0.HRMS Calcd for C17H18ClN2NaO3PS+[M+Na]+419.0356,found 419.0354.
实施例22:S-取代-3-(2-苯基)咪唑并[1,2-a]吡啶硫磷酸二异丙酯的制备(化合物32)
利用方法五,以2-苯基咪唑并[1,2-a]吡啶和亚磷酸二异丙酯为原料,收率90%。1HNMR(500MHz,CDCl3)δ(ppm)8.56(d,J=6.9Hz,1H),8.20(d,J=7.84Hz,2H),7.64(d,J=9.0Hz,1H),7.45(dd,J=8.1,7.7Hz,2H),7.37(dd,J=8.2,7.4Hz,1H),7.31(dd,J=9.1,7.5Hz,1H),6.93(dd,J=7.5,6.8Hz,1H),4.63~4.56(m,2H),1.13~1.04(m,12H).13C NMR(125MHz,CDCl3)δ(ppm)151.0(d,J=5.8Hz),147.2(d,J=1.8Hz),133.5(d,J=2.4Hz),128.9(s),128.6(s),128.4(s),126.6(s),125.8(s),117.5(s),112.6(s),100.7(d,J=8.0Hz),74.5(d,J=8.1Hz),23.7(d,J=4.2Hz),23.4(d,J=5.5Hz).31P NMR(202MHz,CDCl3)δ(ppm)17.4.HRMS Calcd for C19H23N2NaO3PS+[M+Na]+413.1059,found 413.1058.
实施例23:S-取代-3-(4,6-二甲基-2-苯基)咪唑并[1,2-a]吡啶硫磷酸二乙酯的制备(化合物33)
利用方法五,以4,6-二甲基-2-苯基咪唑并[1,2-a]吡啶为原料,收率80%。1H NMR(500MHz,CDCl3)δ(ppm)8.01(d,J=7.7Hz,2H),7.46(dd,J=8.2,7.6Hz,2H),7.38(dd,J=8.5,7.5Hz,1H),7.34(s,1H),6.47(s,1H),3.93~3.51(m,4H),3.13(s,3H),2.37(s,3H),1.01~0.87(m,6H).13C NMR(125MHz,CDCl3)δ(ppm)153.7(d,J=5.7Hz),149.3(d,J=2.2Hz),138.04(s),137.97(s),133.8(s),129.6(s),128.4(s),128.2(s),117.8(s),114.8(s),99.8(d,J=9.2Hz),64.4(d,J=68.6Hz),21.9(s),21.0(s),15.8(d,J=6.3Hz).31PNMR(202MHz,CDCl3)δ(ppm)19.1.HRMS Calcd for C19H23N2NaO3PS+[M+Na]+413.1059,found413.1059.
实施例24:体外生物活性评价——抗炎活性评价
炎症是一种非常常见且重要的基本病理过程,它与许多疾病相关,如癌症、动脉粥样硬化、糖尿病和阿尔茨海默病。促炎细胞因子如肿瘤坏死因子(TNF-),白细胞介素1(IL-1)和白细胞介素-6(IL-6)在炎症过程中起着重要作用。利用实时荧光定量PCR法,评估合成化合物在脂多糖(LPS)刺激的巨噬细胞Raw 264.7炎症模型中的抗炎特性。
实验方法:巨噬细胞Raw 264.7用含20%血清的RPMI-1640,37℃,5%CO2培养。将Raw 264.7接种于6孔板中,每孔6×105个细胞,培养12h后换无血清培养基饥饿细胞,6h后先加入一定浓度的化合物预处理2h。而后加入LPS(工作浓度100ng/mL),诱导3h后移去培养基,用PBS洗2-3次。用TRIZOL(Yesen,Shanghai,China)提取总RNA;再利用逆转录试剂盒(HifairTM first Strand cDNA Synthesis Kit,Yesen,Shanghai,China)将提取出的RNA进行逆转录得到cDNA;最后用Green(Yesen,Shanghai,China)将获得的cDNA进行实时定量荧光PCR检测IL-6,IL-1β,TNF-α相对于各自GAPDH的mRNA表达水平。
实验结果:发现S-取代-3-吲哚硫磷酸酯类衍生物具有一定的抗炎活性(如表1所示);其中4、5、16、26、33抗炎效果较好,对LPS诱导的TNF-、IL-1、IL-6三个因子中的1个或2个因子的半数抑制率浓度(IC50)在0.5~10μmol/L的范围内。
表1、部分活性化合物的抗炎作用(50μmol/L)
*表示IC50在0.5~10μmol/L范围内。
实施例25:体外生物活性评价——细胞毒性评价
实验方法:MTT法。巨噬细胞Raw 264.7用含20%血清的RPMI-1640,37℃,5%CO2培养。
将Raw 264.7接种于96孔板中,每孔5×103个细胞,培养过夜后用含0.5%血清的培养基加测试化合物,使其终浓度为20μmol/L。培养24h后加入MTT(终浓度为0.5mg/mL),37℃,5%CO2培养3-4h后,移去培养基,每孔加入100μL DMSO,560nm波长下测吸光值。
实验结果:利用MTT法测定化合物的细胞毒性(如图1所示),发现化合物7、20、33有一定的细胞毒性,而1、4、5、16、18、19、22等的细胞毒性低。
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