CN106831669A - 14-脱氧-穿心莲内酯-19-羧酸衍生物、制备方法及其医药用途 - Google Patents
14-脱氧-穿心莲内酯-19-羧酸衍生物、制备方法及其医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及14‑脱氧‑穿心莲内酯‑19‑羧酸衍生物(I)和(II)、其制备方法及医药用途。药理实验证明,本发明的化合物具有较好的抗纤维化活性,可以用于治疗与纤维化相关的疾病。
Description
技术领域
本发明涉及药物化学领域,具体涉及14-脱氧-穿心莲内酯-19-羧酸衍生物、它们的制备方法、以及在治疗纤维化方面的用途。
背景技术
纤维化(fibrosis)是组织器官细胞发生损伤后,促纤维化因子与抗纤维化因子失衡,从而引起细胞外基质(ECM)的合成增多而降解减少,ECM过度积淀引发的疾病。其病理主要表现为组织器官内纤维结缔组织增多,实质细胞大量减少。它可以影响各种器官和组织,如心血管器官,肝,脾,肺,肾,骨髓,胰腺,和皮肤。随着疾病的进行,会出现结构损伤和器官功能障碍,随后器官硬化,此时患者常常会面临死亡,严重威胁人类健康和生命。据估计,西方发达国家中,纤维化疾病引起的死亡率多达45%,而在发展中国家数据可能会更高。[Ward,P.A,et al.J.Respir.Crit.Care Med.1998,157,S 123.Wang,P,etal.Chin.Pharmaco.Bull.2007,23,1124.Huang,Y.H,et al.J.Th.Mil.Med.Un.2011,33,1353.Zoubek,A,et al.Ped.Hematol.Oncol.1986,3,135.Nakamura,Y,et al.J.Rad.1997,70,956.Dussaul,J.C,et al.Cell Death Diff.2007,14,1343.Liu,Y.H,etal.Chin.J.Nephrol.2010,26,932.]
穿心莲内酯(Andrographolide)为爵床科植物穿心莲Andrographis paniculata(Burm.f.)Nees中提取得到的二萜内酯类化合物,是穿心莲的主要有效成分之一。现代药理学研究表明穿心莲内酯具有抗菌、抗病毒、抗肿瘤、免疫调节、降糖、抗纤维化以及抗HIV等作用。[S.Nanduri,et al.WO2001085709;J.X.Chen,et al.Biol.Pharm.Bull.2009,8:1385-1391;H.Y.Chung,et al.Planta.2005,71:1106-1111;S.Rajagopal,etal.J.Exp.Ther.Oncol.2003,3:147-158;T.G.Kim,et al.In Vivo.2005,19(3):551-557;R.Ajaya.Kumar,et al.J.Ethnopharmacol.2004,92:291-295;C.G.Jiang,etal.Anticancer Res.2007,27:2439-2447;Y.C.Lee,et al.Eur.J.Pharmaol.2010,63:23-32;Y.Ding,et al.J.Exp.Cell Res.2008,314(3):590-602;Nalamolu KoteswaraRao.Journal of Pharmacology&Therapeutics,Vol.5,No.1,2006,pp.47-50.Lee,M.J,etal.J.Journal of ethnopharmacology,2010,132(2):497-505.]
穿心莲内酯
文献报道穿心莲内酯具有抗纤维化作用,Zhu Tao等发现一定剂量穿心莲内酯灌胃可通过抑制NF-κB通路来减轻博来霉素致肺纤维化大鼠肺泡炎和肺纤维化程度。康亚辉等在穿心莲内酯对C57BL/6小鼠放射性肺损伤的保护效应的实验中观察到,穿心莲内酯对放射性肺损伤有一定的防治作用,可以延缓肺部纤维化,且无明显毒性。朱慧兰等通过观察不同剂量的穿心莲内酯灌胃对博来霉素导致的肺纤维化大鼠的肺纤维化程度,支气管肺泡灌洗液中TGF-β和TNF-α浓度及肺部I、III型胶原m-RNA表达的影响,得出结论:对于博来霉素导致的肺纤维化,一定剂量穿心莲内酯灌胃可减轻大鼠肺泡炎和肺纤维化程度。[Zhu T,et al.J.International journal of molecular sciences,2013,14(12):23581-23596.康亚辉等.[J].中华放射医学与防护杂志,2014,34(7):507-511.朱惠兰等.[J].细胞与分子免疫学杂志,2011,27(7):725-729.]
在纤维化的发病过程中,炎症总是伴随始终,且纤维化的前期症状主要是炎症。NF-κB作为各种炎症反应的共同通路,在纤维化的形成中具有重要作用。穿心莲内酯可以抑制NF-κB通路,HIDALGO等研究发现穿心莲内酯可以抑制NF-κB与基因的结合活性。WEN-WANCHAO等通过研究发现14-脱氧穿心莲内酯较穿心莲内酯的抗炎活性有明显提高。此外,穿心莲内酯还能够抑制促纤维化的关键细胞因子转化生长因子TGF-β、碱性成纤维生长因子(basic fibroblast growth factor,bFGF)诱导的细胞增殖,因此,以天然产物穿心莲内酯作为先导化合物进行结构修饰,使其有更好的抗纤维化的作用有很高的研究价值。
发明内容
本发明公开了I、II通式的化合物。药理结果显示,本发明的化合物具有较好的抗纤维化活性。因此,本发明的式I、II及化合物可以用于治疗与纤维化相关的疾病。
其中,R1代表氢、乙酰基、丙酰基或苯甲酰基;
R2代表氢、甲基、乙基、丙基、苄基或2-吡啶基甲基。
本发明最佳的实施例中所述的14-脱氧穿心莲内酯-19-羧酸衍生物为:
I1:3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸甲酯
I2:3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸苄酯
I3:3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸-(2-吡啶基)甲酯
I4:14-脱氧-穿心莲内酯-19-羧酸甲酯
I5:14-脱氧-穿心莲内酯-19-羧酸苄酯
I6:14-脱氧-穿心莲内酯-19-羧酸-(2-吡啶基)甲酯
II1:3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯
II2:3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯
II3:3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯
II4:14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯
II5:14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯
II6:14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯
通式I化合物制备方法,方法如下:
三乙酰穿心莲内酯(1)(制备参照Tetrahedron.1965.21.2617-2632)与NaBH4室温反应7小时得化合物2,2经7%的盐酸甲醇溶液处理得化合物3,3被TEMPO/NCS氧化得化合物4,4被酰化得化合物5,4或5经亚氯酸钠进一步氧化得化合物6,,6与卤代烃成酯得目标产物I。
通式II化合物制备方法,方法如下:
化合物7(制备参照CN201210488589.5)与4-二甲氨基吡啶在二氯甲烷中回流10小时后经盐酸后处理得化合8,8被TEMPO/NCS氧化得化合物9,9酰化得化合物10,9或10被亚氯酸钠进一步氧化得化合物11,,11与卤代烃成酯得目标产物II。
本申请采用下述缩略词:
DMAP:4-二甲氨基吡啶
DCM:二氯甲烷
EA:乙酸乙酯
PE:石油醚
TEMPO:2,2,6,6-四甲基哌啶氮氧化物
NCS:氯代丁二酰亚胺
通过药理实验,详细说明14-脱氧-穿心莲内酯-19-羧酸衍生物对纤维化细胞株的增殖抑制作用:
1.材料和方法
1.1材料与仪器
1.2试验方法
(1)细胞种板:将对数生长期细胞用胰蛋白酶消化,配制成浓度为1-10×104个/ml的细胞悬液,按3000-5000细胞每孔接种于96孔板,每孔加100μl,置于CO2(5%)培养箱中37℃下培养24h以贴壁。
(2)加药处理:24h后分别更换为100μl细胞样品各自对应的含有一定浓度药物的培养基,对照组更换为含溶剂的培养基,处理72h。每个样本浓度设三个重复。
(3)MTT反应:所有孔中加入20μl浓度为5mg/ml的、新鲜配制的MTT溶液,培养箱中孵育2-4小时,使MTT还原为甲臜(此时倒置显微镜下可看到孔板内的细胞周围出现丝状紫色结晶体)。
(4)DMSO溶解甲臜:小心的吸除上清液,每孔加DMSO(二甲基亚砜)150μl,用摇床摇匀。
(5)测吸光度值:使用酶标仪测定490nm光吸收值,以溶剂处理细胞为对照组,按公式计算药物对细胞的抑制率。
抑制率=1-(实验组-空孔)/(对照组-空孔)
2.药理活性数据
A:14-脱氧-穿心莲内酯 B:14-脱氧-11,14-二脱氢穿心莲内酯
通过以上化合物的活性筛选发现,对NIH-3T3细胞株大部分均有较好的抑制作用,其中效果最好的两个化合物为I2及II5,有进一步开发的潜力。
具体实施方式
实施例1
3,19-O-二乙酰基-14-脱氧-穿心莲内酯(2)的制备:
将三乙酰穿心莲内酯(1)(0.4g,0.84mmol)溶于6mlMeOH中,冰浴下,将NaBH4(0.13g,3.36mmol)缓慢加入反应液,加完后撤除冰浴室温反应2h,反应结束后加入EA(60ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=4∶1)。最终得干燥白色固体3,19-O-二乙酰基-14-脱氧-穿心莲内酯(0.32g,0.76mmol,产率91%)。1H NMR(300MHz,CDCl3)δ:7.10(s,1H),4.91(s,1H),4.78(d,J=1.7Hz,2H),4.63(s,1H),4.61-4.55(m,1H),4.37(d,J=11.7Hz,1H),4.10(d,J=11.8Hz,1H),2.53-2.36(m,2H),2.28-2.07(m,1H),2.04(s,6H),1.95-1.80(m,3H),1.74(dd,J=13.8,6.5Hz,2H),1.70-1.60(m,3H),1.50(dd,J=12.8,3.9Hz,1H),1.36-1.26(m,3H),1.02(s,3H),0.72(s,3H).
实施例2
14-脱氧-穿心莲内酯(3)的制备:
将3,19-O-二乙酰基-14-脱氧-穿心莲内酯(0.13g,0.31mmol)溶于6ml 7%盐酸甲醇溶液中,室温反应16h,反应结束后加入EA(60ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=2∶1)。最终得干燥白色固体14-脱氧-穿心莲内酯(0.09g,0.27mmol,产率87%)。1H NMR(300MHz,DMSO-d6)δ7.47(s,1H),5.05(d,J=4.9Hz,1H),4.82(s,3H),4.59(s,1H),4.12(dd,J=7.5,2.6Hz,1H),3.83(dd,J=10.9,2.7Hz,1H),3.29-3.14(m,2H),2.35-2.22(m,2H),2,03-1.87(m,2H),1.70(d,J=13.2Hz,4H),1.65-1.50(m,4H),1.32(dd,J=12.7,3.9Hz,3H),1.15(d,J=10.3Hz,3H),1.07(s,3H),0.60(s,3H).
实施例3
14-脱氧-19-醛基-穿心莲内酯(4)的制备:
将14-脱氧-穿心莲内酯(0.33g,0.99mmol)溶于20ml二氯甲烷中,依次加入20mlpH约为9的碳酸钾-碳酸氢钠缓冲溶液、TEMPO(0.028g,0.18mmol)、TBABr(0.058g,0.18mmol)、NCS(0.48g,3.6mmol),室温剧烈搅拌10小时,反应结束后加入DCM(60ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=2∶1)。最终得淡黄色固体14-脱氧-19-醛基-穿心莲内酯(0.2g,0.60mmol,产率61%)。1H NMR(300MHz,CDCl3)δ9.77(s,1H),7.12(d,J=1.4Hz,1H),4.95(s,1H),4.78(s,2H),4.66(s,1H),3.19(d,J=24.9Hz,2H),2.53-2.37(m,2H),2.19-1.97(m,2H),1.89(dd,J=14.8,2.4Hz,3H),1.78(dd,J=17.5,9.3Hz,2H),1.70-1.56(m,3H),1.37(d,J=13.1Hz,1H),1.29(s,3H),1.26-1.15(m,1H),0.63(s,3H).13C NMR(75MHz,CDCl3)δ207.30,173.78,145.60,143.60,134.03,107.54,76.56,69.63,55.14,54.30,52.32,39.17,37.54,36.44,28.12,24.04,23.61,21.58,18.88,13.23.
实施例4
3-O-乙酰基-14-脱氧-19-醛基-穿心莲内酯(5)的制备:
将14-脱氧-19-醛基-穿心莲内酯(0.92g,2.77mmol)溶于60ml二氯甲烷中,依次加入5.2ml乙酸酐、DMAP(0.068g,0.55mmol),室温反应5小时,反应结束后加入DCM(120ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=3∶1)。最终得白色固体3-O-乙酰基-14-脱氧-19-醛基-穿心莲内酯(0.8g,2.14mmol,产率77%)。1H NMR(300MHz,CDCl3)δ9.97(s,1H),7.05(s,1H),4.85(s,1H),4.72(d,J=1.7Hz,2H),4.69-4.60(m,1H),4.57(s,1H),2.36(dd,J=9.8,3.3Hz,2H),2.06(dd,J=17.1,8.7Hz,1H),1.99(s,3H),1.95-1.79(m,3H),1.78-1.62(m,2H),1.62-1.48(m,2H),1.40(d,J=13.4Hz,1H),1.35-1.20(m,3H),1.02(s,3H),0.56(s,3H).13C NMR(75 MHz,CDCl3)δ203.80,173.74,169.98,145.52,143.64,134.00,107.55,77.88,69.61,56.15,53.98,51.65,38.73,37.22,35.69,23.99,23.67,21.59,20.57,20.41,14.76.
实施例5
14-脱氧-穿心莲内酯-19-羧酸(6a)的制备:
将14-脱氧-19-醛基-穿心莲内酯(0.3g,0.90mmol)溶于20ml叔丁醇中,依次加入8ml水、1.1ml异戊烯、NaClO2(0.29g,3.21mmol)、NaH2PO4(0.5g,3.21mmol),室温反应24小时,反应结束后加入EA(120ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=2∶1)。最终得淡黄色固体14-脱氧-穿心莲内酯-19-羧酸(0.17g,0.49mmol,产率54%)。1H NMR(300MHz,CDCl3)δ7.11(s,1H),4.90(s,1H),4.77(s,2H),4.61(s,1H),3.17(dd,J=11.9,4.2Hz,1H),2.54-2.27(m,2H),2.09-1.92(m,3H),1.92-1.67(m,4H),1.67-1.51(m,2H),1.43(d,J=6.5Hz,3H),1.22(dd,J=19.8,6.4Hz,3H),0.61(s,3H).13C NMR(75MHz,CDCl3)δ181.46,174.01,146.14,143.75,134.09,106.81,77.38,69.72,55.14,54.95,48.78,39.50,37.85,37.11,28.03,25.25,24.09,23.51,21.55,12.26.
实施例6
3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸(6b)的制备:
参照实施例5的制备方法,由3-O-乙酰基-14-脱氧-19-醛基-穿心莲内酯制得,产率87%。1H NMR(300MHz,CDCl3)δ7.11(s,1H),4.91(s,1H),4.78(s,2H),4.64(s,1H),4.58(dd,J=12.1,4.3Hz,1H),2.57-2.28(m,3H),2.14(d,J=8.8Hz,1H),2.07(s,3H),1.95(dd,J=21.1,13.0Hz,3H),1.75(t,J=13.5Hz,2H),1.61(d,J=7.5Hz,3H),1.47-1.31(m,2H),1.27(s,3H),0.68(s,3H).13C NMR(75MHz,CDCl3)δ179.09,173.81,170.45,145.76,143.58,134.10,107.25,78.41,69.63,55.18,55.02,47.76,39.24,37.56,36.50,24.88,24.02,23.52,21.45,20.77,11.99.
实施例7
3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸甲酯(I1)的制备:
将3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸(0.036g,0.092mmol)溶于2ml DMF中,依次加入碳酸钾(0.026g,0.19mmol)、碘甲烷(0.02g,0.14mmol),室温反应0.5小时,反应结束后加入EA(60ml)稀释,分别用水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=3∶1)。最终得淡黄色固体3-O-乙酰基-14-脱氧-穿心莲内酯穿心莲内酯-19-羧酸甲酯(0.032g,0.079mmol,产率86%)。1H NMR(300MHz,CDCl3)δ7.11(s,1H),4.91(s,1H),4.79(s,2H),4.63(s,1H),4.57(dd,J=12.2,4.5Hz,1H),3.65(s,3H),2.44(dd,J=11.0,7.4Hz,3H),2.12(d,J=7.9Hz,1H),2.07(s,3H),2.02-1.84(m,3H),1.84-1.68(m,2H),1.67-1.54(m,2H),1.54-1.43(m,1H),1.43-1.29(m,2H),1.24(s,3H),0.61(s,3H).13C NMR(75MHz,CDCl3)δ173.79,173.54,170.53,145.91,143.51,134.12,107.13,78.73,69.63,55.13,54.96,50.63,47.87,39.06,37.59,36.53,29.18,25.02,23.98,23.48,21.39,20.84,11.95.
实施例8
3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸苄酯(I2)的制备:
参照实施例7的制备方法,由14-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸制得,产率91%。1H NMR(300MHz,CDCl3)δ7.37(d,J=2.4Hz,5H),7.11(s,1H),5.13(q,J=12.6Hz,2H),4.90(s,1H),4.79(d,J=1.5Hz,2H),4.69-4.51(m,2H),2.42(dd,J=18.3,7.4Hz,3H),2.21-2.08(m,1H),2.06(s,3H),2.04-1.85(m,3H),1.85-1.70(m,2H),1.69-1.55(m,3H),1.55-1.34(m,2H),1.29(s,3H),0.58(s,3H).13C NMR(75MHz,CDCl3)δ172.86,170.48,145.83,143.49,135.34,134.15,127.96,127.71,127.58,107.19,78.77,69.64,65.55,55.07,48.01,39.07,37.58,36.48,25.00,24.13,23.98,23.80,21.38,20.82,12.07.
实施例9
3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸-(2-吡啶基)甲酯(I3)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-脱氧-穿心莲内酯-19-羧酸制得,产率82%。1H NMR(300MHz,CDCl3)δ8.60(s,1H),7.70(d,J=7.5Hz,1H),7.43(d,J=7.9Hz,1H),7.26(d,J=9.1Hz,1H),7.11(s,1H),5.24(q,J=13.8Hz,2H),4.91(s,1H),4.80(s,2H),4.62(s,2H),2.44(s,3H),2.17(s,1H),2.07(s,3H),2.03-1.86(m,3H),1.86-1.67(m,3H),1.57(d,J=23.5Hz,3H),1.41(d,J=12.8Hz,1H),1.33(s,3H),0.58(s,3H).13C NMR(75MHz,CDCl3)δ172.60,170.39,155.27,148.69,145.75,143.50,136.33,134.12,122.38,121.42,107.22,78.80,69.62,66.06,55.08,48.08,39.09,37.56,36.46,29.19,24.99,24.13,23.98,23.77,21.39,20.80,12.05.
实施例10
14-脱氧-穿心莲内酯-19-羧酸-甲酯(I4)的制备:
参照实施例7的制备方法,由14-脱氧-19-羧基穿心莲内酯制得,产率84%。1H NMR(300MHz,CDCl3)δ7.12(d,J=1.5Hz,1H),4.92(s,1H),4.79(d,J=1.8Hz,2H),4.63(s,1H),3.66(s,3H),3.20-2.90(m,1H),2.61-2.29(m,2H),2.26-1.95(m,3H),1.92-1.85(m,3H),1.82-1.65(m,2H),1.65-1.50(m,2H),1.41(s,3H),1.32-1.11(m,3H),0.54(s,3H).13C NMR(75MHz,CDCl3)δ177.49,173.81,146.28,143.52,134.14,106.70,77.69,69.62,55.09,54.94,50.75,49.03,39.33,37.89,37.21,28.14,25.55,24.09,23.23,21.52,11.99.
实施例11
14-脱氧-穿心莲内酯-19-羧酸-苄酯(I5)的制备:
参照实施例7的制备方法,由14-脱氧-穿心莲内酯-19-羧酸制得,产率74%。1HNMR(300MHz,CDCl3)δ7.36(d,J=4.4Hz,5H),7.11(s,1H),5.21(d,J=12.4Hz,1H),5.01(d,J=12.4Hz,1H),4.90(s,1H),4.79(d,J=1.6Hz,2H),4.61(s,1H),3.32-3.02(m,2H),2.43(t,J=13.5Hz,2H),2.23-1.96(m,3H),1.87(dd,J=15.4,11.5Hz,3H),1.74(dd,J=12.7,3.8Hz,2H),1.61(d,J=9.7Hz,3H),1.44(s,3H),1.29-1.18(m,4H),0.51(s,3H).13C NMR(75MHz,CDCl3)δ176.61,173.80,146.20,143.48,134.84,134.17,128.10,127.82,127.76,106.74,77.76,69.62,65.78,55.27,54.93,49.21,39.38,37.89,37.23,28.15,25.62,24.10,23.43,21.53,12.12.
实施例12
14-脱氧-穿心莲内酯-19-羧酸-(2-吡啶基)甲酯(I6)的制备:
参照实施例7的制备方法,由14-脱氧-穿心莲内酯-19-羧酸制得,产率84%。1HNMR(300MHz,CDCl3)δ8.58(d,J=4.3Hz,1H),7.71(td,J=7.7,1.6Hz,1H),7.31(d,J=7.8Hz,1H),7.23(d,J=7.0Hz,1H),7.10(s,1H),5.23(q,J=13.5Hz,2H),4.89(s,1H),4.77(d,J=1.7Hz,2H),4.60(s,1H),3.17(dd,J=12.1,4.2Hz,1H),2.56-2.33(m,2H),2.23-1.98(m,3H),1.90(dd,J=15.5,11.9Hz,3H),1.82-1.64(m,2H),1.60(d,J=7.8Hz,2H),1.47(s,3H),1.36-1.10(m,3H),0.53(s,3H).13C NMR(75MHz,CDCl3)δ175.97,154.74,148.93,146.16,143.46,136.36,134.19,122.49,121.29,106.82,77.71,69.62,65.84,55.24,54.96,49.48,39.34,37.84,37.17,28.19,25.51,24.10,23.78,21.52,12.13.
实施例13
14-脱氧-11,14-二脱氢穿心莲内酯(8)的制备:
将14-O-乙酰基-3,9-异丙氧基穿心莲内酯(7)(0.7g,1.62mmol)溶于20ml二氯甲烷,加入4-二甲基氨基吡啶(0.30g,2.43mmol),回流24h,反应结束后加入DCM(100ml)稀释,分别用稀盐酸洗(60ml),水洗(3x60ml),饱和食盐水洗(3x60ml),无水硫酸钠干燥有机层。将干燥有机层浓缩,柱层析纯化(PE∶EA=2∶1)。最终得干燥白色固体14-脱氧-11,14-二脱氢穿心莲内酯(0.46g,1.38mmol,产率85%)。1H NMR(300MHz,DMSO-d6)δ:7.65(s,1H),6.75(dd,J=15.8,10.1Hz,1H),6.13(d,J=15.8Hz,1H),5.05(d,J=4.9Hz,1H),4.89(s,2H),4.73(s,1H),4.43(s,1H),4.14(dd,J=7.4,2.7Hz,1H),3.85(dd,J=10.9,2.7Hz,1H),3.33-3.13(m,2H),2.36(d,J=10.3Hz,2H),2.03-1.92(m,1H),1.74-1.70(m,1H),1.63-1.54(m,2H),1.47-1.40(m,1H),1.38-1.29(m,1H),1.24-1.13(m,2H),1.09(s,3H),0.76(s,3H)
实施例15
14-脱氧-11,14-二脱氢-19-醛基-穿心莲内酯(9)的制备:
参照实施例3的制备方法,由14-脱氧-11,14-二脱氢穿心莲内酯制得,产率91%。1H NMR(300MHz,DMSO-d6)δ:9.97(s,1H),7.69(s,1H),6.73(dd,J=15.9,10.0Hz,1H),6.15(d,J=15.9Hz,1H),5.17(d,J=4.5Hz,1H),4.9(s,2H),4.75(s,1H),4.43(s,1H),3.32(s,1H),2.36(d,J=13.1Hz,1H),2.03-1.90(m,3H),1.79-1.74(m,2H),1.47-1.41(m,2H),1.28-1.23(m,1H),1.21-1.13(m,1H),1.09(s,3H),0.65(s,3H)
实施例16
3-O-乙酰基-14-脱氧-11,14-二脱氢-19-醛基-穿心莲内酯(10)的制备:
参照实施例4的制备方法,由14-脱氧-11,14-二脱氢-19-醛基-穿心莲内酯制得,产率76%。1H NMR(300MHz,CDCl3)δ:10.08(s,1H),7.19(s,1H),6.90(dd,J=15.8,10.1Hz,1H),6.15(d,J=15.8Hz,1H),4.83(s,3H),4.78-4.67(m,1H),4.56(s,1H),2.49-2.39(m,2H),2.06(s,3H),1.96-1.88(m,1H),1.69-1.64(m,3H),1.49-1.37(m,2H),1.35-1.33(m,1H),1.11(s,3H),0.88-0.85(m,1H),0.80(s,3H)
实施例17
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸(11a)的制备:
参照实施例5的制备方法,由14-脱氧-11,14-二脱氢-19-醛基-穿心莲内酯制得,产率64%。1H NMR(300MHz,CDCl3)δ:7.20(s,1H),6.89(dd,J=15.7,10.2Hz,1H),6.13(d,J=15.7Hz,1H),4.82(s,3H),4.55(s,1H),3.19(dd,J=12.1,4.3Hz,1H),2.47(d,J=13.1Hz,1H),2.33(d,J=10.1Hz,1H),2.09-1.95(m,3H),1.92-1.78(m,2H),1.6(d,J=13.7Hz,1H),1.47(s,3H),1.32-1.13(m,3H),0.80(s,3H).13C NMR(75MHz,CDCl3)δ181.09,172.09,147.52,142.90,135.19,128.63,120.71,108.50,77.62,69.32,60.52,54.52,48.75,38.94,38.54,36.32,27.83,24.24,23.52,13.07.
实施例18
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸(11b)的制备:
参照实施例5的制备方法,由3-O-乙酰基-14-脱氧-11,14-二脱氢-19-醛基穿心莲内酯制得,产率78%。1H NMR(300MHz,CDCl3)δ:7.17(s,1H),6.90(dd,J=15.8,10.0Hz,1H),6.12(d,J=15.8Hz,1H),4.81(s,3H),4.61-4.56(m,1H),4.55(s,1H),2.49-2.45(m,1H),2.33(t,J=9.3Hz,1H),2.06(s,3H),2.04-1.95(m,2H),1.77-1.65(m,2H),1.63-1.58(m,2H),1.39(d,J=11.6Hz,1H),1.29(s,3H),0.86(s,3H).13C NMR(75MHz,CDCl3)δ179.49,171.81,170.55,147.08,142.88,135.02,128.63,120.90,109.04,78.56,69.18,60.89,54.34,47.80,38.69,37.89,35.95,23.89,23.59,20.83,12.77.
实施例19
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯(II1)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率:64%。1H NMR(300MHz,CDCl3)δ:7.16(s,1H),6.88(dd,J=15.9,10.1Hz,1H),6.12(d,J=15.8Hz,1H),4.80(s,2H),4.79(s,1H),4.61-4.55(m,1H),4.54(s,1H),3.66(s,3H),2.49-2.41(m,1H),2.40-2.22(m,2H),2.05(s,1H),2.03-1.91(m,2H),1.74-1.66(m,1H),1.64-1.46(m,2H),1.44-1.27(m,2H),1.24(s,3H),0.77(s,3H).13C NMR(75MHz,CDCl3)δ173.49,171.71,170.51,147.28,142.74,135.13,128.66,120.85,108.85,78.90,69.10,60.93,54.32,50.69,47.95,38.50,37.93,36.00,24.02,23.97,23.56,20.81,12.72.
实施例20
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯(II2)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率:62%。1H NMR(300MHz,CDCl3)δ:7.39-7.30(m,5H),7.16(s,1H),6.88(dd,J=15.9,10.1Hz,1H),6.11(d,J=15.8Hz,1H),5.13(q,J=12.5Hz,2H),4.80(s,2H),4.78(s,1H),4.59(dd,J =12.1,4.5Hz,1H),4.53(s,1H),2.47-2.40(m,1H),2.39-2.26(m,2H),2.02(s,3H),1.98-1.95(m,2H),1.74-1.66(m,1H),1.68-1.41(m,3H),1.39-1.33(m,1H),1.29(s,3H),0.73(s,3H).13C NMR(75MHz,CDCl3)δ172.82,171.76,170.45,147.21,142.83,135.13,128.61,127.97,127.67,120.84,108.90,78.94,69.13,65.65,60.87,54.41,48.08,38.51,37.88,35.98,24.04,24.00,23.87,20.78,12.84.
实施例21
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯(II3)的制备:
参照实施例7的制备方法,由3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率:73%。1H NMR(300MHz,CDCl3)δ:8.61(d,J=4.4Hz,1H),7.72(td,J=7.7,1.7Hz,1H),7.44(d,J=7.9Hz,1H),7.25(d,J=6.9Hz,1H),7.18(s,1H),6.90(dd,J=15.8,10.2Hz,1H),6.14(d,J=15.8Hz,1H),5.26(dd,J=26.9,11.0Hz,2H),4.83(s,2H),4.80(s,1H),4.64(dd,J=12.2,4.5Hz,1H),4.55(s,1H),2.55-2.26(m,3H),2.07(s,3H),2.02(d,J=11.7Hz,2H),1.83-1.68(m,1H),1.67-1.51(m,3H),1.41(dd,J=15.2,4.5Hz,1H),1.35(s,3H),0.74(s,3H).13C NMR(75MHz,CDCl3)δ172.60,171.71,170.38,155.20,148.79,147.13,142.73,136.28,135.11,128.65,122.42,121.57,120.85,108.95,78.95,69.10,66.25,60.87,54.44,48.12,38.53,37.88,35.97,29.19,24.00,23.84,20.80,12.81.
实施例22
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯(II4)的制备:
参照实施例7的制备方法,由14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率74%。1H NMR(300MHz,CDCl3)δ:7.17(s,1H),6.90(dd,J=15.8,10.0Hz,1H),6.12(d,J=15.8Hz,1H),4.81(s,2H),4.80-4.75(m,1H),4.54(s,1H),3.67(s,3H),3.12(dd,J=12.0,4.3Hz,1H),2.50-2.41(m,1H),2.31(d,J=10.1Hz,1H),2.04-1.95(m,3H),1.85-1.72(m,2H),1.60-1.56(m,1H),1.42(s,3H),1.29-1.13(m,3H),0.70(s,3H).13C NMR(75MHz,CDCl3)δ177.29,171.72,147.63,142.55,135.29,128.73,120.74,108.41,77.96,69.10,60.63,54.60,50.82,49.16,38.79,38.69,36.39,28.00,24.53,23.30,12.80.
实施例23
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯(II5)的制备:
参照实施例7的制备方法,由14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率65%。1H NMR(300MHz,CDCl3)δ:7.48-7.28(m,5H),7.16(s,1H),6.88(dd,J=15.9,10.3Hz,1H),6.11(d,J=15.8Hz,1H),5.20(d,J=12.3Hz,1H),5.03(d,J=12.3Hz,1H),4.81(s,2H),4.77(s,1H),4.52(s,1H),3.13(dd,J=11.8,4.3Hz,1H),2.49-2.36(m,1H),2.30(d,J=10.2Hz,1H),2.05-1.97(m,3H),1.82-1.70(m,2H),1.60-1.55(m,1H),1.45(s,3H),1.29-1.14(m,3H),0.65(s,3H).13C NMR(75MHz,CDCl3)δ176.40,171.72,147.52,142.53,135.34,128.12,127.89,127.85,120.72,108.47,78.03,69.10,65.91,60.62,54.76,49.31,38.81,38.71,36.37,28.00,24.57,23.51,12.93.
实施例24
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯(II6)的制备:
参照实施例7的制备方法,由14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸制得,产率:56%。1H NMR(300MHz,CDCl3)δ:8.60(d,J=4.5Hz,1H),7.72(td,J=7.7,1.7Hz,1H),7.34(d,J=7.8Hz,1H),7.28-7.23(m,1H),7.17(s,1H),6.90(dd,J=15.8,10.1Hz,1H),6.13(d,J=15.8Hz,1H),5.37-5.18(m,2H),4.82(d,J=1.4Hz,2H),4.80(s,1H),4.54(s,1H),2.53-2.41(m,1H),2.33(d,J=10.3Hz,1H),2.15-1.95(m,4H),1.80(ddd,J=15.4,9.9,4.3Hz,2H),1.72-1.56(m,2H),1.51(s,3H),1.38-1.29(m,2H),0.70(s,3H).13C NMR(75MHz,CDCl3)δ175.80,154.66,148.99,147.52,142.55,136.34,135.36,128.72,122.54,121.45,120.72,108.55,77.97,69.11,65.93,60.65,54.69,49.59,38.77,38.65,36.30,28.05,24.46,23.89,12.93。
Claims (2)
1.14-脱氧穿心莲内酯-19-羧酸衍生物,其特征在于所述的化合物为:
3-O-乙酰基-14-脱氧穿心莲内酯-19-羧酸甲酯;
3-O-乙酰基-14-脱氧穿心莲内酯-19-羧酸苄酯;
3-O-乙酰基-14-脱氧穿心莲内酯-19-羧酸-(2-吡啶基)甲酯;
14-脱氧穿心莲内酯-19-羧酸甲酯;
14-脱氧穿心莲内酯-19-羧酸苄酯;
14-脱氧穿心莲内酯-19-羧酸-(2-吡啶基)甲酯;
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯;
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯;
3-O-乙酰基-14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯;
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸甲酯;
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸苄酯;
14-脱氧-11,14-二脱氢穿心莲内酯-19-羧酸-(2-吡啶基)甲酯。
2.根据权利要求1所述的14-脱氧穿心莲内酯-19-羧酸衍生物在制备抗纤维化药物中的应用。
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CN109734707B (zh) * | 2018-03-02 | 2021-12-24 | 郑州大学 | 穿心莲内酯十氢萘结构修饰衍生物系列ii及其制备方法和用途 |
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