CN103804377A - 柯楠因碱类化合物及其制备方法 - Google Patents
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Abstract
本发明属医药学领域,涉及柯楠因碱类化合物及其制备方法。所述的柯楠因碱类化合物具有式(1)和(2)结构,本发明中,以色胺为起始原料,经过Pictet-Spengler反应,丁基铝锂氢还原,Knoevenagel/hetero-Diels±Alder串联反应,以及氢化加氢反应等多步反应,获得具有通式(1)和(2)的柯楠因碱类似物。本发明所述的柯楠因碱类似物为具有直接扩血管活性的新化合物,具有合成方法简便,易于控制,合成产物量大和纯度高等优点;制得的产物自身稳定性好,具有广泛修饰范围,可用于制备扩张外周血管类抗高血压的候选药物,并可作为一种潜在药理学工具。
Description
技术领域
本发明属医药学领域,涉及柯楠因碱类化合物及其制备方法。本发明以色胺为起始原料,经过多步反应,合成得到柯楠因碱类似物及其衍生物;所述制备方法具有操作性强,反应条件简单,易于控制,产品纯度高等优点;制得的产物自身稳定性好,可用于制备扩张外周血管类抗高血压候选药物,并可作为一种潜在的药理学工具。
背景技术
钩藤(Ucaria)是传统的降血压中药,经研究其主要降压成分为其所含有的生物碱。近年来,对钩藤中生物碱的研究表明,该类生物碱具有高效低毒的特点,而柯楠因碱(corynantheine)是钩藤中存在的生物碱之一,迄今,尚未见关于柯楠因碱及其类似化合物的单体药物活性的报道研究。
目前,对于钩藤中生物碱的研究主要通过对钩藤植物进行天然产物提取的方法,由于提取的钩藤总碱成分复杂,各有效单体的含量不明是当前方法的局限性所在。
发明内容
本发明的目的是提供柯楠因碱类化合物及其制备方法。
更具体的,本发明提供了具有通式(1)和(2)结构的柯楠因碱类化合物及其制备方法以及作为扩张血管药物的应用。
本发明所述的柯楠因碱类化合物,具有式(1)和(2)的结构,
其中,R1为羟基,乙酰氧基,丙酰氧基,苄氧基;
R2为羟基,乙酰氧基,丙酰氧基,苄氧基,苯甲酰氧基,苯环上有甲基、卤素、甲氧基取代的苯甲酰氧基,1-4个碳取代的硅氧基。
本发明所述的柯楠因碱类化合物通过下述反应式(1),(2)和(3)合成反应:反应式(1):
试剂:(a)(OC2H5)2CHCH2COOC2H5,TFA,DCM;(b)Cbz-Cl,DCM;(c)(Boc)2O,DCM;(d)DIHALH,THF;(e)1,2-dihydroxy-furan,EDDA,Meldrum's acid,toluene;(f)K2CO3,H2,MeOH.;
反应式(2):
试剂:(a)(CH3O)2O,DMAP,TEA,DCM;(b)C2H5COCl,DCM;(c)TBDMSCl,imidazole,DMF;(d)TEA,parachlorobenzoyl chloride,DCM;(e)TEA,parachlorobenzoyl fluoride,DCM;
反应式(3):
试剂::(i)(CH3O)2O,DMAP,TEA,DCM;(ii)C2H5COCl,DCM;(iii)TBDMSCl,imidazole,DMF;(iv)TEA,parachlorobenzoyl chloride,DCM;(v)TEA,parachlorobenzoyl fluoride,DCM;
上述反应式(1)中,以色胺为原料,通过Pictet-Spengler反应,胺的苄氧羰基酰化,胺的叔丁氧羰基酰化,氢化铝锂还原合成柯南因碱类似物3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(5);以中间体1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉(4)为起始原料,经过丁基铝锂氢还原,Knoevenagel/hetero-Diels±Alder串联反应,以及氢化加氢反应获得柯南因碱类似物15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(8);
上述反应式(2)中,以3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(5)为原料合成柯楠因碱类似物9-11;
上述反应式(3)中,以15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(8)为原料合成柯楠因碱类似物12-16;
更具体的,本发明的柯楠因碱类化合物的制备方法,其特征在于,包括以下步骤:
1)将15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪溶于无水二氯甲烷中,依次加入三乙胺,4-二甲氨基吡啶,乙酸酐,室温搅拌1-2小时后,水洗反应液,二氯甲烷萃取,合并有机相,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-甲羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪;
2)将15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪溶于无水二氯甲烷中,加入丙酰氯,室温搅拌1-2小时后,水洗反应液,二氯甲烷萃取,合并有机相,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-乙羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪;
3)将15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪溶于无水N,N-二甲基甲酰胺中,依次加入咪唑,叔丁基二甲基硅烷氯,室温搅拌2-3小时后,加入二氯甲烷萃取,水洗反应液,合并有机相,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-叔丁基二甲基硅烷氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪;
4)将15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪溶于无水二氯甲烷中,依次加入三乙胺,对氯苯甲酰氯,室温搅拌2-3小时后,水洗反应液,合并有机相,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-对氯苯羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪;
5)将15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪溶于无水二氯甲烷中,依次加入三乙胺,对氟苯甲酰氯,室温搅拌2-3小时后,水洗反应液,合并有机相,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-对氟苯羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪。
其中,所述步骤4)中的15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪8按如下步骤制备:
1)将色胺溶于二氯甲烷中,依次加入3,3-二乙氧基丙酸乙酯,三氟乙酸,室温搅拌30小时后饱和碳酸氢钠中和反应液,二氯甲烷萃取有机相,蒸干溶剂,柱层析得到1-乙氧羰甲基-1,2,3,4-四氢咔啉;
2)1-乙氧羰甲基-1,2,3,4-四氢咔啉溶解在二氯甲烷中,依次加入三乙胺,4-二甲氨基吡啶,氯甲酰苄酯,室温搅拌2小时后曾干溶剂,柱层析得到1-乙氧羰甲基-N2-苄氧羰基-1,2,3,4-四氢咔啉;
3)将1-乙氧羰甲基-N2-苄氧羰基-1,2,3,4-四氢咔啉溶解在二氯甲烷中,依次加入二碳酸叔丁酯,4-二甲氨基吡啶,室温搅拌2小时后蒸干溶剂,柱层析得到1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉;
4)将1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉溶解在无水四氢呋喃中,氮气保护下在-78℃,加入二异丁基氢化铝,保持低温继续搅拌3小时后以盐酸溶液淬灭反应,萃取有机相,蒸干,柱层析得到1-羰甲基-N2-苄氧羰基-N12-叔丁氧羰基-1,2,3,4-四氢咔啉;
5)将1-羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉溶于甲苯中,加入乙二胺二乙酸,2,3-二氢呋喃,丙二酸亚异丙酯,六十度下超声反应12小时,蒸干溶剂,柱层析后得到1-(四氢呋喃并(2,3-b)吡喃-4’-羰基-1’-甲基)-N2-苄氧羰基-N12-叔丁基氧羰基-1,2,3,4-四氢咔啉;
6)将1-(四氢呋喃并(2,3-b)吡喃-4’-羰基-1’-甲基)-N2-苄氧羰基-N12-叔丁基氧羰基-1,2,3,4-四氢咔啉溶于甲醇中,加入钯碳,碳酸钾,在氢氛中剧烈震荡反应9小时,蒸干溶剂,柱层析得到15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪。
本发明与已有技术相比具有如下有点及效果:
所合成的柯楠因碱类似物是新的具有直接舒张血管活性的化合物,其药理活性强于天然产物钩藤碱,并且具有合成路线简单,易于控制,原料要求局限小,产率高,便于大量生产等特点,产物自身稳定性好,具有广泛的修饰范围,可用于制备研究扩张外周血管类抗高血压药物,并可作为一种潜在的药理学工具。
附图说明
图1是本发明的化合物舒张由1μM苯肾上腺素诱导产生的完整离体血管环收缩的作用,其中所有数据以均数±标准差表示,N=4-6。
具体实施方式
1:化学合成与制备
本发明中所采用的所有溶剂,原料和试剂如不特别指明,均为分析纯或化学纯;溶剂的无水处理按照常规方法进行。
产物分离,鉴定的仪器和方法:薄层层析硅胶GF254,柱层析粗孔硅胶(200-300目),均为青岛海洋化工厂生产;TLC通过154nm紫外检测;核磁共振使用Varian VXR-500核磁共振仪测定,氢谱,碳谱以TMS为内标。
1.1合成1-乙氧羰甲基-1,2,3,4-四氢咔啉(式2)
在500ml圆底烧瓶中,依次加入200ml溶解有8g(50mmol)色胺的二氯甲烷和30ml3,3-二乙氧基丙酸乙酯后,在搅拌条件下缓慢滴加12ml三氟乙酸,室温搅拌30小时,反应完成后以饱和碳酸氢钠溶液调节pH=7.0,二氯甲烷萃取反应液三次,合并有机相并用无水硫酸钠干燥,蒸干溶剂得到棕色油状物,以二氯甲烷:甲醇=60:1,300目的硅胶柱层析得到产物10.9g,收率84.5%。
(M+H)+:259.159;1H NMR(400Hz,CDCl3)δ:8.64(s,1H,N1-H),7.49(d,J=7.68Hz,1H,H10),7.34(d,J=7.93Hz,1H,H11),7.18-7.08(m,2H,H9,H12),4.48(t,J=6.61Hz,1H,H3),4.23(dd,J1=14.23Hz,J2=7.09Hz,2H,H16),3.27-3.07(m,2H,H5),2.83(d,J=6.45Hz,2H,H5),2.75(t,J=4.94Hz,2H,H14),1.98(s,1H,N4-H),1.30(t,J=9.07Hz,3H,H17);13CNMR(CDCl3)δ:135.386,134.876,127.008,121.634,119.187,118.036,110.893,108.865,61.052,48.672,41.865,40.721,22.479,14.116.
数据表明合成产物正确。
1.2合成1-乙氧羰甲基-N2-苄氧羰基-1,2,3,4-四氢咔啉(式3)
在500ml圆底烧瓶中,加入200ml溶解有4g(15mmol)化合物2的二氯甲烷溶液,依次加入6.38ml三乙胺,0.352g4-二甲氨基吡啶后,在搅拌条件下缓慢滴加4.30ml氯甲酰苄酯,室温搅拌2小时后,水洗猝灭反应,萃取合并有机相并以无水硫酸钠干燥,蒸干溶剂得到深黄色油状物,以石油醚:乙酸乙酯=15:1,300目的硅胶逐层析得到产物4.8g,收率81.6%。
(M+H)+:392.1;1H NMR(400Hz,CDCl3)δ:8.28(s,1H,N1-H),7.60(d,J=7.44Hz,2H,H10,H11),7.55(d,J=3.13Hz,4H,H21,H22,H24,H25),7.25(t,J=8.22Hz,1H,H23),7.15(t,J=7.04Hz,1H,H12),7.08(s,1H,H9),5.94-5.88(m,1H,H3),5.14(s,2H,H19),1.28(s,3H,H17),4.31-4.07(m,2H,H16),3.53(dd,J1=12.91Hz,J2=6.54Hz,2H,H5),3.42(dd,J1=9.39Hz,J2=7.04Hz,1H,H14),3.29(dd,J1=9.39Hz,J2=1.18Hz,1H,H14),2.98(t,J=6.65Hz,2H,H6);13CNMR(CDCl3)δ:169.447,156.312,136.720,136.545,136.065,128.533,128.487,128.327,128.144,128.068,124.234,122.656,122.305,122.229,113.317,110.291,66.693,63.903,41.156,40.584,31.588,14.688,14.398.
数据表明合成产物正确。
1.3合成1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉(式4)
在500ml圆底烧瓶中,加入200ml溶解有1g(2.5mmol)化合物3的二氯甲烷溶液,在搅拌的条件下依次加入2.82g二碳酸二叔丁酯,0.195g4-二甲氨基吡啶,室温搅拌2小时,反应完成后蒸干溶剂得到黄色油状物,以石油醚:乙酸乙酯=15:1,300目硅胶柱层析分离化合物,得到产物1.1g,收率89.4%。
(M+H)+:493.1;1H NMR(400Hz,CDCl3)δ:7.43-7.29(m,9H,H9,H10,H11,H12,H21,H22,H23,H24,H25),6.32(dd,J1=38.84Hz,J2=9.34Hz,1H,H3),5.16(d,J=14.96Hz,2H,H19),4.07(m,2H,H16),3.32(t,J=8.51Hz,1H,H5),3.06(d,J=14.28Hz,1H,H5),2.95-2.82(m,2H,H14),2.79-2.69(m,2H,H6),1.60(s,9H,H27,H28,H29),1.18(t,J=6.94Hz,3H,H17);13CNMR(CDCl3)δ:170.118,155.374,149,687,136.560,136.202,133.824,128.533,128.434,128.350,128.159,127.961,127.748,122.907,122.777,118.051,115.787,115.299,77.313,67.715,60.595,49.770,39.029,36.719,28.143,21.175,14.040.
数据表明合成产物正确。
1.4合成3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(式5)
在250ml圆底烧瓶中加入1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉(1g,2.0mmol),用无水二氯甲烷溶解,在室温搅拌的条件下加入硼氢化钠(84mg,2.2mmol),继续搅拌1小时。反应用1M盐酸溶液猝灭,水洗反应液,二氯甲烷萃取混合液三次,合并有机相,无水硫酸钠干燥旋干后得到淡黄色油状物。以石油醚:乙酸乙酯=4:1,300目硅胶柱层析得到产物0.8g,产率88.9%。
(M+H)+:451;1H NMR(400Hz,cdcl3)δ:7.40-7.22(m,9H,H9,H10,H11,H12,H19,H20,H21,H22,H23),5.24(dd,2H,H17,J1=21.72Hz,J2=12.13Hz),4.42(dd,1H,J1=13.5Hz,J2=5.87Hz),3.65(t,2H,J=10.95Hz),3.46(s,1H,H5),3.18-3.12(m,1H,H5),2.87-2.79(m,1H,H6),2.73-2.68(m,1H,H6),2.37-2.31(m,1H,-OH),2.05-1.89(m,2H,H14),1.73(s,9H,H26,H27,H28);13CNMR(cdcl3)δ:156.586,149.871,136.240,136.011,134.998,128.541,128.259,128.175,127.855,124.279,122.831,122.694,117.746,115.703,76.992,67.707,58.887,49.587,36.795,35.537,28.127,28.036,21.190.
1.5合成1-羰甲基-N2-苄氧羰基-N12-叔丁氧羰基-1,2,3,4-四氢咔啉(式6)
在250ml三颈瓶中加入50ml溶解了1g(2.0mmol)化合物4的干燥四氢呋喃,用氮气排除三颈瓶内的空气。-78℃搅拌条件下缓慢滴加二异丁基氢化铝5.65ml,保持低温搅拌反应3小时,完成后1M的盐酸溶液调节pH=7.0后迅速将体系升至室温,蒸干反应液有机相,二氯甲烷萃取残留液体三次,合并有机相以无水硫酸钠干燥,抽滤得到淡黄色油状物。以石油醚:乙酸乙酯=15:1,300目硅胶柱层析得到产物0.63g,产率70.3%。
(M+MeOH+Na)+:503;1H NMR(400Hz,CDCl3)δ:9.95(s,1H,H15),7.56(m,2H,H10,H11),7.29(m,5H,H19,H20,H21,H22,H23),6.58(d,J=9.78Hz,1H,H12),6.43(d,J=9.39Hz,1H,H9),5.57-5.51(m,1H,H3),5.21(m,2H,H17),3.29-3.22(m,2H,H5),3.03-2.99(m,2H,H14),2.78-2.71(m,2H,H6),1.64(s,9H,H25,H26,H27);13CNMR(CDCl3)δ:201.198,155.603,149.764,136.576,136.301,136.034,129.051,128.968,128.480,128.152,128.015,123.075,122.945,118.196,116.122,115.551,76.718,67.608,49.983,47.818,36.307,29.690,20.565.
数据表明合成产物正确。
1.6合成1-(四氢呋喃并(2,3-b)吡喃-4’-羰基-1’-甲基)-N2-苄氧羰基-N12-叔丁基氧羰基-1,2,3,4-四氢咔啉(式7)
向500ml超声管中加入100ml溶解了750mg(1.67mmol)化合物5,依次加入29.6mg(0.335mmol)乙二胺二乙酸,351.6mg(5.022mmol)2,3-二氢呋喃,244.7mg(1.674mmol)丙二酸亚二异丙酯,密封在60℃下超声12小时,完成后蒸干溶剂得到淡黄色油状物,以石油醚:乙酸乙酯=4:1,300目硅胶柱层析得到产物420mg,产率45.0%
(M+H)+:561.3;1H NMR(400Hz,CDCl3)δ:7.33-7.24(m,9H,H9,H10,H11,H12,H25,H26,H27,H28,H29),6.17-6.14(m,1H,H18),5.21(s,2H,H23),5.05(d,J=4.69Hz,1H,H3),3.94(t,J=8.61Hz,2H,H19),3.27-3.23(m,2H,H5),2.82(t,J=5.87Hz,2H,H6),2.53-2.51(m,1H,H21),2.44-2.41(m,2H,H16),2.08-2.04(m,2H,H20),1.93-1.88(m,1H,H15),1.84-1.77(m,2H,H14),1.73(s,9H,H31,H32,H33);13CNMR(CDCl3)δ:170.545,156.068,150.320,136.537,136.194,135.684,128.853,128.777,128.617,128.556,128.320,128.228,124.462,122.976,118.204,115.863,114.926,106.357,77.473,68.797,67.677,50.372,49.793,39.928,36.833,34.333,28.897,28.288,28.196,21.288.
数据表明合成产物正确。
1.7合成15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式8)
向500ml氢化管中加入100ml溶解有1g(1.78mmol)化合物6的干燥甲醇,依次加入100mg(0.5mmol)碳酸钾,35.6mg(0.36mmol)钯碳,在氢氛下剧烈震荡反应9小时,结束后反应液在有硅藻土的布氏漏斗上抽滤除去钯碳,蒸干溶剂得到淡黄色油状物,以石油醚:乙酸乙酯=2:1,300目硅胶柱层析得到产物480mg,产率61.0%。
(M+H)+:443.0;1H NMR(400Hz,CDCl3)δ:7.44(d,J=7.05Hz,1H,H10),7.30-7.26(m,3H,H9,H11,H12),5.12(s,2H,H22),4.81(d,J=20.74Hz,1H,H28),3.95-3.82(m,2H,H5),3.32(s,3H,H20),2.83-2.80(m,1H,H3),2.75-2.68(m,4H,H6,H18),2.16-2.12(m,2H,H17),2.09-2.04(m,2H,H14),1.94-1.92(m,1H,H15),1.71(s,9H,H24,H25,H26),1.62-1.59(m,1H,H16),1.25-1.18(m,2H,H21);13CNMR(CDCl3)δ:173.602,150.549,135.485,133.580,127.839,122.694,121.642,118.150,115.208,114.057,77.320,59.215,55.952,55.533,54.489,51.607,33.044,32.389,31.924,29.698,28.150,20.451,18.492.
数据表明合成产物正确。
1.8合成3-甲羰氧乙基-4-苄氧羰基-1-叔丁氧羰基-1,2,3,4-四氢咔啉(式9)
在250ml圆底烧瓶中加入3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(100mg,0.22mmol),4-DMAP(5mg,0.04mmol),TEA(46mg,0.46mmol),溶于无水二氯甲烷,加入乙酸酐(26mg,0.25mmol),室温搅拌2小时。水洗反应液,二氯甲烷萃取混合液三次,合并有机相,无水硫酸钠干燥后旋干,得到淡黄色油状物。以石油醚:乙酸乙酯=10:1为流动相,300目硅胶柱层析得到产物86.4mg,产率79.8%。
(M+H)+:493.1;1H NMR(400Hz,cdcl3)δ:7.41-7.21(m,9H,H9,H10,H11,H12,H21,H22,H23,H24,H25),5.19-5.11(m,2H,H19),4.56-4.51(m,1H,H3),4.29-4.11(m,2H,H15),3.26-3.21(m,1H,H5),2.89-2.81(m,1H,H5),2.72-2.65(m,1H,H6),2.39-2.26(m,1H,H6),2.06(s,2H,H14),1.98(s,3H,H17),1.60(s,9H,H28,H29,H30);13CNMR(cdcl3)δ:171.139,155.717,149.809,136.568,136.232,134.731,128.685,128.495,128.426,128.167,128.022,127.778,124.394,122.823,117.982,115.795,115.230,77.343,67.662,61.639,50.037,36.597,32.275,28.173,21.236.
1.9合成3-乙羰氧乙基-4-苄氧羰基-1-叔丁氧羰基-1,2,3,4-四氢咔啉(化合物10)
在250ml圆底烧瓶中加入3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(100mg,0.22mmol),溶于无水二氯甲烷,加入丙酰氯(20mg,0.25mmol),室温搅拌1小时。水洗反应液,二氯甲烷萃取混合液三次,合并有机相,无水硫酸钠干燥后旋干,得到淡黄色油状物。以石油醚:乙酸乙酯=10:1为流动相,300目硅胶柱层析得到产物95.0mg,产率85.3%。
(M+H)+:507.2;1H NMR(400Hz,cdcl3)δ:7.43-7.21(m,9H,H9,H10,H11,H12,H21,H22,H23,H24,H25),5.29-5.11(m,2H,H20),4.56-4.51(m,1H,H3),4.30-4.24(m,2H,H15),3.27-3.22(m,1H,H5),2.89-2.85(m,1H,H5),2.72-2.68(m,2H,H6),2.38-2.22(m,2H,H17),2.05-1.97(m,2H,H14),1.72(s,9H,H29,H30,H31);13CNMR(cdcl3)δ:174.463,155.687,149.771,136.545,135.920,134.754,128.678,128.464,128.403,128.129,127.984,127.748,124.363,124.241,122.793,117.960,115.772,77.297,67.631,61.517,50.105,36.574,32.305,28.150,27.998,27.464,27.380,21.213,8.947.
1.10合成3-苄氧乙基-4-苄氧羰基-1-叔丁氧羰基-1,2,3,4-四氢咔啉(化合物11)
在250ml圆底烧瓶中加入3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(100mg,0.22mmol),溶于无水四氢呋喃,在0℃下缓慢加入加入钠氢(6.3mg,0.26mmol),溴苄(41.4mg,0.24mmol),在0℃下搅拌4小时。水洗反应液,二氯甲烷萃取混合液三次,合并有机相,无水硫酸钠干燥后旋干,得到淡黄色油状物。以石油醚:乙酸乙酯=15:1为流动相,300目硅胶柱层析得到产物89.0mg,产率75.0%。
(M+H)+:541;1H NMR(400Hz,cdcl3)δ:7.52-7.14(m,12H,H10,H11,H17,H18,H19,H20,H21,H26,H27,H28,H29,H30),7.05(d,1H,H12,J=6.65Hz),7.00(s,1H,H9),5.43-5.32(m,2H,H15),5.19-5.05(m,2H,H24),4.59-4.42(m,1H,H3),4.15(t,2H,H23,J=5.48Hz),3.33-3.28(m,1H,H5),3.00-2.94(m,1H,H5),2.81-2.78(m,2H,H6),2.11-2.07(m,2H,H22),1.49(s,9H,H33,H34,H35);13CNMR(cdcl3)δ:155.794,153.301,137.102,136.553,134.860,134.380,128.754,128.701,128.480,128.411,127.984,127.778,127.672,127.390,126.597,126.078,126.017,121.969,119.553,118.303,109.993,108.728,81.970,77.023,67.372,63.697,47.757,37.756,33.189,27.701,20.756.
1.11合成15-甲氧羰甲基-20-甲羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式12)
在250ml的圆底烧瓶中加入100ml溶解了100mg(0.23mmol)15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪的二氯甲烷溶液,在搅拌的条件下依次加入26mg(0.25mmol)乙酸酐,5mg(0.04mmol)4-二甲氨基吡啶,46mg(0.46mmol)三乙胺,室温搅拌1-2小时后加入50ml二氯甲烷后,水洗三次,合并有机相后无水硫酸钠干燥,蒸干溶剂得到棕色油状物。以石油醚:乙酸乙酯=10:1,300目硅胶柱层析得到产物87.6mg,产率78.6%。
(M+H)+:485.4;1H NMR(400Hz,CDCl3)δ:7.94(d,J=7.43Hz,1H,H10),7.42(dd,J1=7.04Hz,J2=6.26Hz,1H,H11),7.29-7.22(m,2H,H9,H12),4.14(t,J=6.65Hz,2H,H22),3.73(s,3H,H20),3.00-2,82(m,4H,H5,H6),2.70-2.66(dd,J1=8.22Hz,J2=4.31Hz,3H,H3,H18),2.63-2.60(m,1H,H15),2.06(s,4H,H17,H24),2.02(d,J=3.92Hz,2H,H14),1.98-1,83(m,3H,H24),1.68(s,9H,H26,H27,H28),1.61(d,J=2.73Hz,1H,H16);13CNMR(CDCl3)δ:173.289,171.254,150.488,136.728,136.560,129.242,123.784,122.549,117.952,116.991,115.177,83.701,62.920,55.830,54.016,53.421,51.500,37.131,35.027,33.479,29.667,28.905,28.127,21.457,21.000.
数据表明合成产物正确。
1.12合成15-甲氧羰甲基-20-乙羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式13)
在250ml的圆底烧瓶中加入100ml溶解了100mg(0.23mmol)15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪的干燥二氯甲烷溶液,在搅拌的条件下缓慢滴加20mg(0.25mmol)丙酰氯,室温搅拌1小时,完成后水洗反应液,二氯甲烷萃取混合液三次,合并有机相,干燥旋干后得到淡棕色油状物。以石油醚:乙酸乙酯=10:1,300目硅胶柱层析得到产物96mg,产率83.8%。
(M+H)+:499.2;1H NMR(400Hz,CDCl3)δ:7.93(d,J=7.82Hz,1H,H10),7.42(d,J=7.04Hz,1H,H11),7.28-7.21(m,2H,H9,H12),4.16(t,J=6.65Hz,2H,H22),3.73(s,3H,H20),2.95-2.86(m,3H,H3,H5),2.79-2.72(m,1H,H6),2.70-3.66(t,J=7.43Hz,3H,H6,H18),2.59-2.56(d,J=14.48Hz,1H,H15),2.34(dd,J1=15.26Hz,J2=7.43Hz,2H,H17),2.05-1,99(m,2H,H24),1.88-1.81(m,2H,H14),1.68(s,9H,H27,H28,H29),1,58(s,1H,H16),1.33-1.28(m,2H,H21),1.15(t,J=7.44Hz,3H,H25);174.608,173.342,150.541,137.277,136.537,129.356,123.647,122.488,117.921,115.124,83.594,62.889,56.295,54.435,51.470,51.233,37.230,35.187,33.662,32.000,31.344,29.667,28.143,27.571,21.953,9.115.
数据表明合成产物正确。
1.13合成15-甲氧羰甲基-20-叔丁基二甲基硅烷氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式14)
在250ml的圆底烧瓶中加入100ml溶解了100mg(0.23mmol)15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪的N,N-二甲基甲酰胺溶液,依次加入1.36mg(0.02mmol)咪唑,38.1mg(0.25mmol)叔丁基二甲基氯硅烷,室温搅拌1-2小时,完成后水洗反应液,二氯甲烷萃取混合液三次,合并有机相,干燥旋干后得到淡棕色油状物。以石油醚:乙酸乙酯=10:1,300目硅胶柱层析得到产物108mg,产率84.4%。
(M+H)+:499.2;1H NMR(400Hz,CDCl3)δ:7.93(d,J=7.82Hz,1H,H10),7.42(d,J=7.04Hz,1H,H11),7.28-7.21(m,2H,H9,H12),4.16(t,J=6.65Hz,2H,H22),3.73(s,3H,H20),2.95-2.86(m,3H,H3,H5),2.79-2.72(m,1H,H6),2.70-3.66(t,J=7.43Hz,3H,H6,H18),2.59-2.56(d,J=14.48Hz,1H,H15),2.34(dd,J1=15.26Hz,J2=7.43Hz,2H,H17),2.05-1,99(m,2H,H24),1.88-1.81(m,2H,H14),1.68(s,9H,H27,H28,H29),1,58(s,1H,H16),1.33-1.28(m,2H,H21),1.15(t,J=7.44Hz,3H,H25);174.608,173.342,150.541,137.277,136.537,129.356,123.647,122.488,117.921,115.124,83.594,62.889,56.295,54.435,51.470,51.233,37.230,35.187,33.662,32.000,31.344,29.667,28.143,27.571,21.953,9.115.
数据表明合成产物正确。
1.14合成15-甲氧羰甲基-20-对氯苯羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式15)
在250ml的圆底烧瓶中加入100ml溶解了100mg(0.23mmol)15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪的干燥二氯甲烷溶液,在搅拌的条件下依次加入25.6mg(0.25mmol)三乙胺,21.0mg(0.17mmol)4-二甲氨基吡啶,44.3mg(0.25mmol)对氯苯甲酰氯,室温搅拌1-2小时,完成后水洗反应液,二氯甲烷萃取混合液三次,合并有机相,干燥旋干后得到淡棕色油状物。以石油醚:乙酸乙酯=10:1,300目硅胶柱层析得到产物115mg,产率86.2%。
(M+H)+:581.4;1H NMR(400Hz,CDCl3)δ:7.96(dd,J1=17.6Hz,J2=8.99Hz,2H,H10,H11),7.43-7.22(m,6H,H9,H12,H25,H26,H27,H28),4.41(t,J=8.9Hz,2H,H22),3.70(s,3H,H20),2.97(dd,J1=11.35Hz,J2=2.74Hz,2H,H5),2.90-2.75(m,3H,H6,H3),2.71(d,J=7.43Hz,2H,H18),2.26(s,1H,H15),2.18-1.99(m,4H,H14,H17),1.94-1.87(m,1H,H16),1.69(s,9H,H30,H31,H32),1.67(s,2H,H21);13CNMR(CDCl3)δ:173.289,165.734,150.526,139.228,136.964,136.560,130.934,129.295,128.769,128.632,123.761,122.556,117.960,117.144,115.169,83.670,63.758,56.196,54.321,53.444,51.477,37.199,35.164,33.654,32.061,29.561,28.006,21.785.
数据表明合成产物正确。
1.15合成15-甲氧羰甲基-20-对氟苯羰氧乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(式16)
在250ml的圆底烧瓶中加入100ml溶解了100mg(0.23mmol)15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪的干燥二氯甲烷溶液,在搅拌的条件下依次加入25.6mg(0.25mmol)三乙胺,21.0mg(0.17mmol)4-二甲氨基吡啶,39.6mg(0.25mmol)对氟苯甲酰氯,室温搅拌1-2小时,完成后水洗反应液,二氯甲烷萃取混合液三次,合并有机相,干燥旋干后得到淡棕色油状物。以石油醚:乙酸乙酯=10:1,300目硅胶柱层析得到产物114mg,产率87.9%。
(M+H)+:565.26;1H NMR(400Hz,CDCl3)δ:8.05(dd,J1=9.00Hz,J2=3.52Hz,2H,H10,H11),7.45-7.00(m,6H,H9,H12,H25,H26,H27,H28),4.40(t,J=6.26,2H,H22),3.69(s,3H,H20),3,06(t,J=6.26Hz,2H,H5),2.90(d,J=7.04Hz,2H,H6),2.76(dd,J1=12.13Hz,J2=3.52Hz,1H,H3),2.69(d,J=7.04Hz,2H,H18),2.21(d,J=3.13Hz,1H,H15),2.11-1.93(m,4H,H14,H17),1.74(s,1H,H16),1.68(s,9H,H30,H31,H32),1.66(d,J=4.3Hz,2H,H21);13CNMR(CDCl3)δ:173.205,166.916,165.620,164.393,150.480,136.576,132.101,132.009,131.918,129.173,126.482,123.890,122.602,117.990,115.535,114.872,106.212,83.800,63.461,55.754,53.429,51.485,50.570,37.115,35.011,33.799,31.970,29.667,28.120,21.267.
数据表明合成产物正确。
表1本发明制得的化合物:
2:药理活性检测:
具有通式(1)和(2)的柯楠因碱类似物,按常规方法进行离体动物实验,药理结果显示,所述的化合物具有直接扩血管的活性,可进一步用于制备抗高血压的候选药物,尤其是扩张外周血管类抗高血压的药物。
2.1血管离体实验生理液的配制:
生理盐溶液(Physiological Salt Solution,PSS)其成分为(mM):氯化钠115.5,氯化钾4.6,磷酸二氢钠1.3,碳酸氢钠22,氯化钙22.5,硫酸镁41.2,葡萄糖11.1at pH7.4.称取葡萄糖1.98g和碳酸氢钠粉末2.268g,倒入1L大烧杯中,加入约800ml去离子水溶解,同时加入100倍的氯化钠,氯化钾,磷酸二氢钠,硫酸镁母液10ml。混合均匀后,加入10ml氯化钙母液,调整pH为7.4,定容至1L。将溶液加入血管环浴槽后,持续用95%O2及5%CO2混合气体饱和并利用恒温水槽保持生理液在37℃
2.2化合物溶液的配置:
精密称取化合物6-16,以无水乙醇为溶剂,配制成为100mM的母液,利用乙醇逐步稀释成为10mM,1mM,100uM,10uM共五个浓度的溶液。实验时,取10ul溶液加入到含有10ml生理盐溶液的浴槽中,使其在浴槽中的终浓度为1×10-4M,1×10-5M,1×10-6M,1×10-7M,1×10-8M。
2.3去甲肾上腺素溶液的配制:
称取去甲肾上腺素加去离子水稀释至浓度为1mM,-20℃冰箱分装保存备用。实验时向浴槽中加入10ul溶液,使其在浴管内的终浓度为10-4M。
2.4乙酰胆碱溶液的配制方法同去甲肾上腺素溶液(实验中所述浓度均为浴管内试剂的终浓度)。
2.5离体SD雄性大鼠离体主动脉环张力实验
实验准备工作参照大鼠离体主动脉环张力实验标准操作,测量化合物对PE诱发收缩的血管张力的影响。血管环在Kerbs’生理液中稳定后,化合物组和溶剂对照组加入10-6M的PE,收缩达到坪值后,化合物组累积加入1×10-8M、1×10-7M、1×10-6M、l×10-5M、l×10-4M的化合物,溶剂对照组累积加入相应等体积的溶剂。观察并记录胸主动脉环张力的变化,以加入10-6M诱发的血管环的最大收缩幅度为100%,计算加入不同浓度化合物后血管收缩的幅度占最大收缩幅度的百分比,即加药后舒张幅度与10-6M PE诱发的血管环最大收缩幅度的百分比。建立浓度效应曲线,观察化合物对于引起血管收缩的舒张作用。每条血管环只测一个化合物。
2.6统计方法:
以加入10-6M PE诱发血管环收缩的最大幅度为100%,计算累加不同浓度化合物后血管最大舒张百分比的变化,即加药后舒张幅度与10-6M PE诱发的血管环收缩最大幅度的百分比,求出各化合物在不同浓度下的对血管最大舒张百分比的变化。实验数据采用血管环张力值变化反映药物作用,单位为g。所有数据以均数±标准差表示,以GraphPad Prism5软件完成。
2.7实验结果:
药理实验结果表明:1)溶剂乙醇的加入不影响主动脉环的张力;2)15个新合成化合物中有14个降低了离体血管环的张力表现出扩张血管的活性;3)其中化合物5和8表现出最好的药理活性(IC50=2.173,1.293μM),8个化合物均表现出了比天然产物钩藤碱(IC50=128.5μM)更强的药理活性。
表2是本发明的化合物的半数抑制浓度IC50(化合物舒张血管的幅度为最大收缩幅度一半时所需的浓度)。
表2
*:No vasodilatory activity。
Claims (7)
1.式(1)的柯楠因碱类似物
其中,R1为羟基,乙酰氧基,丙酰氧基,苄氧基。
3.权利要求1或2所述的柯楠因碱类似物的制备方法,其特征在于,通过下述反应式(1),(2)和(3),
其中,反应式(1)中,以色胺为原料,通过Pictet-Spengler反应,胺的苄氧羰基酰化,胺的叔丁氧羰基酰化,氢化铝锂还原合成柯南因碱类似物3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(5);以中间体1-乙氧羰甲基-N2-苄氧羰基-N12-叔丁氧羰基1,2,3,4-四氢咔啉(4)为起始原料,经过丁基铝锂氢还原,Knoevenagel/hetero-Diels±Alder串联反应,以及氢化加氢反应获得柯南因碱类似物15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(8);
反应式(2)中,以3-羟乙基-4-苄氧羰基-1-叔丁基氧羰基-1,2,3,4-四氢咔啉(5)为原料合成柯楠因碱类似物9-11;
反应式(3)中,以15-甲氧羰甲基-20-羟乙基-N1-叔丁基氧代羰基-吲哚(2,3-c)并八氢喹嗪(8)为原料合成柯楠因碱类似物12-16;
反应式(1):
反应式(2):
反应式(3):
4.按权利要求3所述的制备方法,其特征在于,通过反应式(1),(2)和(3)合成柯楠因碱类化合物及中间体2-16。
5.权利要求1的柯楠因碱类化合物在制备抗高血压的药物中的用途。
6.权利要求4的制备方法制得的柯楠因碱类化合物的中间体2-16在制备抗高血压的药物中的用途。
7.按权利要求5或6的用途,其特征在于,所述药物是扩张外周血管类抗高血压的药物。
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