CN109535157B - 一种半蜡梅碱类似物、其合成方法及其用途 - Google Patents

一种半蜡梅碱类似物、其合成方法及其用途 Download PDF

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CN109535157B
CN109535157B CN201811465098.2A CN201811465098A CN109535157B CN 109535157 B CN109535157 B CN 109535157B CN 201811465098 A CN201811465098 A CN 201811465098A CN 109535157 B CN109535157 B CN 109535157B
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郑绍军
朱瑞
魏洋
韩珂
唐冰
蔡星伟
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Abstract

本发明涉及一类半蜡梅碱类似物、其合成方法及其抑制乙酰胆碱酯酶活性的用途。所述的半蜡梅碱类似物的制备方法是以9‑甲基‑1,2,3,4,9,9a‑6氢‑4aH‑吡啶并[2,3‑b]吲哚‑4a‑醇为底物，加入无水吡啶溶解，缓慢滴加反应试剂有机酸或者酸酐，待反应完全，加入淬灭剂淬灭反应，减压浓缩除去甲醇和吡啶，合成工艺简单、产品纯度高，能够抑制乙酰胆碱酯酶活性。

Description

一种半蜡梅碱类似物、其合成方法及其用途
技术领域
本发明属于药物合成领域，具体涉及半蜡梅碱类似物、其合成方法及其应用。
背景技术
阿尔茨海默病(Alzheimer Disease，AD)是一种病因及发病机制尚未完全阐明的神经退行性疾病，其表现为记忆力下降和日常行为能力的丧失、认知障碍和人格改变。是影响老年人群健康的重要疾病,目前尚无有效预防与治疗方法。
张琳琳等从AD的发病机制及治疗药物两方面做了综述：发病机制包括与微环境相关的Aβ－淀粉样肽级联假说、胆碱能损伤学说、免疫异常学说等，与神经元相关的Tau蛋白假说、神经细胞凋亡学说等，与基因相关的载脂蛋白ε4 基因、早老素1和早老素2基因、淀粉样前体蛋白基因等；其药物治疗有西药治疗，包括乙酰胆碱酯酶抑制剂、减少β-淀粉样蛋白(Aβ)的产生、沉积药物、抗氧化剂等；中药治疗，包括补虚类药物、活血化瘀药、化痰平喘药等。
Ellman等研究的是一种快速测定乙酰胆碱酯酶抑制剂的方法。其原理为:乙酰胆碱酯酶水解底物丁酰硫代胆碱(acetylthiocholine)，生成的产物硫代胆碱再与显色剂二硫二硝基苯甲酸(DTNB)[5,5’-dithiobis-(2-nitrobenzoic acid)]反应生成在410nm处有特征吸收的化合物2-硝基-5-巯基苯甲酸(5-thio-2-nitrobenzoic acid)，通过测定410nm处的吸光度的增量可以间接测定乙酰胆碱酯酶的活性。当该技术首次报道出来后，利用可见分光光度计和酶标仪测定乙酰胆碱酯酶抑制剂的活性得到广泛应用。在该技术的基础上，利用TLC生物自显影也可对具有胆碱酶抑制活性的化合物进行筛选。
乙酰胆碱酯酶抑制剂目前仍是治疗AD的一线药物。其中他克林、多奈哌齐、卡巴拉汀和加兰他敏均为美国FDA批准药物。其中多奈哌齐(Donepezil) 用于治疗轻-中度AD，对中枢神经***的乙酰胆碱酯酶具有更高的选择性，抑制酶的活性持续时间长且没有外周作用，能显著提高中枢神经***乙酰胆碱浓度，从而改善认知功能。卡巴拉汀能选择性增强脑皮质和海马等部位的乙酰胆碱活性，并且可以减慢APP的形成。其他药物还有利斯的明(Rivastigmine)、石山碱甲(Huperzine A)、毒扁豆碱(Physotigmine)及其衍生物。
限制乙酰胆碱降解以提高其活性的药物如毒扁豆碱：毒扁豆碱是经典的胆碱酯酶抑制剂，应用后可增加突触间隙乙酰胆碱的浓度，提高中枢胆碱能活性，改善AD患者的症状。石杉碱甲(Huperzine A)是中国科学院上海药物研究所从中草药蛇足石杉中提取出的一种生物碱,是我国首创的目前最有前途的治疗AD的药物。
发明内容
为了克服现有技术的不足，本发明的目的是提供一种半蜡梅碱类似物，该半蜡梅碱类似物对乙酰胆碱酯酶具有良好的抑制活性。
为了实现上述发明目的，本发明采用了以下的技术方案：
具有通式(I)的半蜡梅碱类似物：
Figure BDA0001889577060000021
具有式(I)的半蜡梅碱类似物的合成路线如下：
Figure BDA0001889577060000022
所述的R1为以下基团之任意一种：
Figure BDA0001889577060000031
具体而言，具有式(I)的半蜡梅碱类似物的合成工艺，步骤如下：
底物9-甲基-1,2,3,4,9,9a-6氢-4aH-吡啶并[2,3-b]吲哚-4a-醇，加入无水吡啶溶解，再向其中缓慢滴加反应试剂，TLC跟踪检测，待反应完全，向反应液中滴加甲醇淬灭反应，减压浓缩除去甲醇和吡啶，合并有机相，减压浓缩，粗产物用柱层析分离，得到半蜡梅碱类似物。
所采用的反应试剂为乙酸酐、丙酸酐、丁酸酐、异丁酸酐、戊酸、己酸、庚酸、辛酸、邻氟苯甲酸、间氟苯甲酸、对氟苯甲酸、间甲苯甲酸、对甲苯甲酸或者苯甲酸。
本发明提供的半蜡梅碱类似物具有结构简单、原料易得，反应条件温和，工艺简单的特点，具有抑制乙酰胆碱酯酶活性，样品浓度为1mg/mL时，化合物2和11的IC50值分别为0.01、0.13ng/mL，具有优良的应用前景。
具体实施方式
下面结合实施例，对本发明作详细说明。
实施例1
Figure BDA0001889577060000032
的合成
称取200mg底物9-甲基-1,2,3,4,9,9a-6氢-4aH-吡啶并[2,3-b]吲哚-4a-醇，置于50mL干燥的圆底烧瓶中，加入5mL的无水吡啶搅拌溶解，将体系置于0℃的冰水浴中，向其中缓慢滴加反应试剂0.07mL(0.72mmol)乙酸酐，待滴加完全，移至室温，TLC跟踪检测，待反应完全，向反应液中滴加适量甲醇淬灭反应，减压浓缩除去甲醇和少量吡啶，再用乙酸乙酯萃取3次，合并有机相，依次用饱和CuSO4溶液洗涤3次，饱和NaCl溶液洗涤3次，无水NaSO4干燥。减压浓缩，粗产物用柱层析分离(PE:EA＝6:1)，得到216mg N位乙酰化衍生物1 (96％)。
性状鉴定：无色油状，1H-NMR(400MHz,CDCl3),δ7.34–7.14(m,2H),6.90 –6.47(m,2H),5.24(s,1H),4.45–3.57(m,1H),3.31–3.22(m,1H),2.81(ddd,J＝ 13.2,8.5,4.8Hz,1H),2.64(d,J＝27.4Hz,3H),2.19(d,J＝11.1Hz,3H),2.02–1.71(m,2H),1.70–1.22(m,2H).13C NMR(100MHz,CDCl3)δ172.30(C), 149.52(C),133.33(C),129.52(CH),129.36(CH),122.05(CH),119.11(CH), 108.34(CH),86.45(C),41.96(CH2),37.14(CH3),33.31(CH2),22.14(CH3), 19.02(CH2).MS(ESI(+))calcd for C14H18N2O2[M+H]+:246.3；found:247.0。
实施例2-14与实施例1不同之处在于所采用的化学试剂不同，具体如表1 所示：
表1半蜡梅碱类似物的理化常数
Figure BDA0001889577060000041
实施例2
Figure BDA0001889577060000051
的合成
无色油状，1H-NMR(400MHz,CDCl3),δ7.34–7.04(m,2H),6.86–6.46(m, 2H),5.30(s,1H),4.45–3.63(m,1H),3.29–3.17(m,1H),2.81(ddd,J＝13.1,8.3, 4.8Hz,1H),2.64(d,J＝25.6Hz,3H),2.58–2.34(m,2H),1.96–1.72(m,2H),1.67 –1.24(m,2H),1.17(dt,J＝10.0,7.4Hz,3H).13C NMR(100MHz,CDCl3)δ 175.45(C),149.54(C),133.41(C),129.52(CH),129.33(CH),122.04(CH), 119.06(CH),108.34(CH),85.36(C),40.95(CH2),37.20(CH3),33.29(CH2), 27.06(CH2),19.06,9.60(CH3)。
MS(ESI(+))calcd for C15H20N2O2[M+H]+:260.3；found:261.0。
实施例3
Figure BDA0001889577060000052
淡黄色油状，1H-NMR(400MHz,CDCl3),δ7.26(s,2H),6.84–6.45(m,2H), 5.30(s,1H),4.44–3.62(m,1H),3.22(ddt,J＝13.2,9.2,4.2Hz,1H),3.01(s,1H), 2.80(ddd,J＝13.1,8.3,4.8Hz,1H),2.63(d,J＝32.5Hz,3H),2.55–2.23(m,2H), 1.96–1.74(m,2H),1.73–1.35(m,3H),0.96(dt,J＝10.8,7.4Hz,3H).13C NMR (100MHz,CDCl3)δ174.68(C),149.54(C),133.48(C),129.27(CH×2),122.03(CH), 119.02(CH),108.30(CH),85.35(C),41.10(CH2),37.11(CH3),35.31(CH2), 32.91(CH2),19.40(CH2),18.54(CH2),13.96.(CH3)。
MS(ESI(+))calcd for C16H22N2O2[M+H]+:274.4；found:275.1.
实施例4
Figure BDA0001889577060000061
无色油状，1H-NMR(400MHz,CDCl3),δ7.72–7.12(m,2H),6.83–6.50(m, 2H),5.35(s,1H),4.44–3.71(m,1H),3.30–3.16(m,1H),2.92(dp,J＝9.8,6.7Hz, 1H),2.79(ddd,J＝13.2,8.4,4.8Hz,1H),2.63(d,J＝26.5Hz,3H),1.98–1.83(m, 1H),1.82–1.61(m,2H),1.55–1.37(m,1H),1.22–1.14(m,6H).13C NMR(100 MHz,CDCl3)δ178.69(C),149.55(C),133.44(C),129.59(CH),129.32(CH), 122.00(CH),119.02(CH),108.31(CH),84.92(C),40.74(CH2),37.14(CH3), 33.60(CH2),31.07(CH),19.78(CH3×2),18.52(CH2)。
MS(ESI(+))calcd for C16H22N2O2[M+H]+:274.4；found:275.0。
实施例5
Figure BDA0001889577060000062
无色油状，1H-NMR(400MHz,CDCl3),δ7.82–6.92(m,2H),6.88–6.44(m, 2H),5.31(s,1H),4.49–3.61(m,2H),3.01(ddd,J＝13.1,8.8,5.5Hz,1H),2.63(d, J＝30.5Hz,3H),2.56–2.26(m,3H),1.95–1.72(m,2H),1.70–1.55(m,3H),1.41 –1.33(m,2H),0.92(dt,J＝13.4,7.3Hz,3H).13C NMR(100MHz,CDCl3)δ 175.01(C),149.52(C),133.47(C),129.49(CH),129.27(CH),122.05(CH), 119.06(CH),108.32(CH),85.37(C),41.16(CH2),37.16(CH3),33.68(CH2), 31.96(CH2),27.29(CH2),22.46(CH2),19.11(CH2),13.92(CH3)。
MS(ESI(+))calcd for C17H24N2O2[M+H]+:288.4；found:289.1。
实施例6
Figure BDA0001889577060000071
白色固体，1H-NMR(400MHz,CDCl3),δ7.76–7.07(m,2H),6.86–6.46(m, 2H),5.30(s,1H),4.44–4.05(m,1H),3.76–3.18(m,1H),3.00(s,1H),2.80(ddd,J ＝13.1,8.3,4.8Hz,1H),2.63(d,J＝30.1Hz,3H),2.54–2.21(m,2H),1.96–1.72 (m,2H),1.71–1.59(m,3H),1.36–1.29(m,4H),0.92–0.87(m,3H).13C NMR (100MHz,CDCl3)δ174.93(C),149.53(C),133.46(C),129.51(CH),129.28(CH), 122.04(CH),119.04(CH),108.31(CH),85.37(C),41.13(CH2),37.13(CH3), 33.96(CH2),33.06(CH2),31.75(CH2),25.11(CH2),22.49(CH2),19.11(CH2), 14.01(CH3)。
MS(ESI(+))calcd for C18H26N2O2[M+H]+:302.4；found:303.1.
实施例7
Figure BDA0001889577060000072
淡黄色油状，1H-NMR(400MHz,CDCl3),δ7.71–7.13(m,2H),6.84–6.43(m, 2H),5.31(s,1H),4.43–4.03(m,1H),3.68(dt,J＝11.8,4.4Hz,1H),3.02(dddd,J ＝13.2,8.7,4.5Hz,1H),2.64(d,J＝27.7Hz,3H),2.57–2.24(m,3H),1.96–1.71 (m,2H),1.63(tdd,J＝14.8,11.4,7.3Hz,3H),1.32–1.27(m,6H),0.90–0.86(m, 3H).13C NMR(100MHz,CDCl3)δ178.66(C),175.14(C),149.52(C),133.40(CH), 129.29(CH),122.06(CH),119.08(CH),108.13(CH),85.38(C),41.17(CH2), 37.17(CH3),33.92(CH2),33.09(CH2),31.67(CH2),29.03(CH2),25.18(CH2), 22.57(CH2),19.09(CH2),14.03(CH3)。
MS(ESI(+))calcd for C19H28N2O2[M+H]+:316.4；found:317.1。
实施例8
Figure BDA0001889577060000081
淡黄色油状，1H-NMR(400MHz,CDCl3),δ7.72–7.13(m,2H),6.87–6.24(m, 2H),5.32(s,1H),4.46–4.03(m,1H),3.68(dt,J＝12.3,4.6Hz,1H),3.02(ddd,J＝ 13.1,8.6,4.4Hz,1H),2.64(d,J＝26.8Hz,3H),2.56–2.25(m,3H),1.97–1.73(m, 2H),1.72–1.57(m,3H),1.31–1.26(m,8H),0.88(t,J＝4.7Hz,3H).13C NMR (100MHz,CDCl3)δ178.69(C),175.12(C),149.53(C),133.38(CH),129.31(CH), 122.06(CH),119.08(CH),108.33(CH),85.39(C),41.16(CH2),37.16(CH3), 33.92(CH2),33.08(CH2),31.79(CH2),29.45(CH2),29.03(CH2),25.22(CH2), 22.61(CH2),19.09(CH2),14.08(CH3)。
MS(ESI(+))calcd for C20H30N2O2[M+H]+:330.5；found:331.2。
实施例9
Figure BDA0001889577060000082
白色油状，1H-NMR(400MHz,CDCl3),δ8.16–6.96(m,6H),6.87–6.37(m, 2H),5.88–4.62(m,1H),4.53–4.01(m,1H),3.47–3.20(m,1H),3.06(ddd,J＝ 12.9,7.5,5.3Hz,1H),2.66(s,3H),2.09–1.68(m,2H),1.55–0.84(m,2H).13C NMR(100MHz,CDCl3)δ168.56(C),159.05(C),148.87(C),134.95(C),133.28(CH), 131.49(CH),129.61(C),129.42(CH),129.02(CH),124.85(CH),124.39(CH), 121.97(CH),119.31(CH),108.43(CH),87.02(C),42.37(CH2),37.79(CH3), 33.12(CH2),19.09(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0。
实施例10
Figure BDA0001889577060000091
白色油状，1H-NMR(400MHz,CDCl3),δ7.98–6.99(m,6H),6.88–6.39(m, 2H),5.86–4.72(m,1H),4.44–4.01(m,1H),3.66–3.17(m,1H),3.10(dt,J＝12.9, 6.1Hz,1H),2.64(s,3H),2.12–1.72(m,2H),1.56–0.84(m,2H).13C NMR(100 MHz,CDCl3)δ171.52(C),164.58(C),148.86(C),137.62(C),132.30(C),129.70(CH), 125.85(CH),123.58(CH),122.10(CH),120.40(CH),119.43(CH),117.06(CH), 115.01(CH),108.24(CH),86.74(C),43.19(CH2),38.25(CH3),34.19(CH2), 18.29(CH2).
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0.
实施例11
Figure BDA0001889577060000092
无色油状，1H-NMR(400MHz,CDCl3),δ7.74–7.37(m,2H),7.25–6.95(m, 4H),6.88–6.32(m,2H),5.28(s,1H),4.43–4.00(m,1H),3.64–3.16(m,1H),3.14 –2.79(m,3H),2.60(m,2H),2.09–1.67(m,1H),1.57–1.22(m,1H).13C NMR (100MHz,CDCl3)δ172.16(C),163.35(C),148.92(C),133.43(C),132.32(C), 131.63(CH),130.24(CH),130.15(CH),129.64(CH),129.39(CH),122.15(CH), 119.32(CH),115.65(CH),108.13(CH),86.84(C),43.31(CH2),38.35(CH3), 34.16(CH2),18.24(CH2)。
MS(ESI(+))calcd for C19H19FN2O2[M+H]+:326.4；found:327.0。
实施例12.
Figure BDA0001889577060000101
白色油状，1H-NMR(400MHz,CDCl3),δ7.33–7.08(m,6H),6.86–6.40(m, 2H),5.93–4.83(m,1H),4.44–4.01(m,1H),3.66–3.16(m,1H),3.08(dt,J＝12.7, 6.1Hz,3H),2.81–2.28(m,3H),2.05–1.94(m,1H),1.94–1.69(m,2H),1.55– 1.19(m,1H).13C NMR(100MHz,CDCl3)δ173.20(C),148.98(C),138.31(C), 135.63(C),132.46(C),130.39(CH),129.61(CH),128.34(CH),127.55(CH), 124.79(CH),123.84(CH),122.10(CH),119.19(CH),108.06(CH),86.69(C), 43.13(CH2),38.03(CH3),34.15(CH2),21.41(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1。
实施例13.
Figure BDA0001889577060000102
淡黄色固体，1H-NMR(400MHz,CDCl3),δ7.99–7.51(m,1H),7.38(dd,J＝ 13.3,7.5Hz,2H),7.30–7.10(m,4H),6.84–6.37(m,2H),5.35(s,1H),4.43–3.52 (m,1H),3.28–2.95(m,1H),2.61(s,3H),2.43–2.28(m,3H),2.03–1.70(m,2H), 1.54–0.83(m,2H).13C NMR(100MHz,CDCl3)δ173.37(C),148.98(C),144.10(C), 139.80(C),132.68(C),130.16(CH),129.10(CH),129.07(CH),127.90(CH), 127.15(CH),127.00(CH),122.14(CH),119.16(CH),108.01(CH),86.69(C), 43.27(CH2),38.16(CH3),34.18(CH2),21.39(CH3),18.38(CH2)。
MS(ESI(+))calcd for C20H22N2O2[M+H]+:322.4；found:323.1。
实施例14
Figure BDA0001889577060000111
白色固体，1H-NMR(400MHz,CDCl3),δ7.51–7.03(m,7H),6.88–6.39(m, 2H),5.78–4.56(m,1H),4.44–4.14(m,1H),3.95–3.17(m,1H),3.09(dt,J＝12.7, 6.1Hz,1H),2.89–2.45(m,3H),2.08–1.93(m,1H),1.87–1.70(m,1H),1.45– 1.21(m,1H),0.99–0.82(m,1H).13C NMR(100MHz,CDCl3)δ173.04(C), 148.94(C),135.67(C),132.43(C),130.03(CH),129.69(CH),129.61(CH), 129.38(CH),128.47(CH),127.76(CH),126.97(CH),122.11(CH),119.24(CH), 108.10(CH),86.69(C),43.18(CH2),38.09(CH3),34.17(CH2),18.37(CH2)。
MS(ESI(+))calcd for C19H20N2O2[M+H]+:308.4；found:309.1。
实施例15
所得化合物对乙酰胆碱酯酶的抑制率测定，结果见表2。其中C1-C14分别对应实施例1-14的所得化合物。
表2化合物对乙酰胆碱酯酶的抑制率
Figure BDA0001889577060000112
由表2 可知，化合物2和11具有较高的乙酰胆碱酯酶抑制活性，IC50值分别为0.01、0.13ng/mL。

Claims (2)

1.通式（I）所示的半蜡梅碱类似物：
Figure DEST_PATH_IMAGE001
式（I）
所述的R1为以下基团之任意一种：
Figure 951901DEST_PATH_IMAGE002
。
2.权利要求1所述的具有通式（I）的半蜡梅碱类似物用于制备治疗抑制乙酰胆碱酯酶活性类药物的用途。
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