CN116987079A - 一种苦豆碱衍生物及其制备方法、药物组合物和用途 - Google Patents

一种苦豆碱衍生物及其制备方法、药物组合物和用途 Download PDF

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CN116987079A
CN116987079A CN202210439039.8A CN202210439039A CN116987079A CN 116987079 A CN116987079 A CN 116987079A CN 202210439039 A CN202210439039 A CN 202210439039A CN 116987079 A CN116987079 A CN 116987079A
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aloperine
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alo
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潘显道
刘凤喜
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Ordos Golden Camel Pharmaceutical Co ltd
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Abstract

本发明属于化学药物技术领域，涉及一种苦豆碱衍生物及其制备方法、药物组合物和用途。所述的苦豆碱衍生物为式(Ⅰ)所示结构的化合物或其可药用盐、溶剂合物、前药，其中：X选自S或O原子；R选自苯基、取代苯基、萘基、吡啶基、酰基、C1‑6烷基、C1‑6取代烷基、C3‑6环烷基。本发明的苦豆碱衍生物及其药物组合物能够更好的用于病毒性疾病的预防或治疗。

Description

一种苦豆碱衍生物及其制备方法、药物组合物和用途
技术领域
本发明属于化学药物技术领域，涉及一种苦豆碱衍生物及其制备方法、药物组合物和用途。
背景技术
中药苦豆子是豆科槐属植物苦豆子(Sophora alopecuroides L.)的干燥全草、根及种子，又名苦豆草、苦豆根、苦甘草、西豆根等。该药性寒，味苦，有毒，具有清热解毒、抗菌消炎作用。
苦豆子中主要含有喹诺里西丁类生物碱，其中苦豆碱(aloperine，ALO，结构如式(IⅠ))是其代表性生物碱之一。药理研究发现，苦豆碱具有抗病毒、抗肿瘤、抗炎、抗菌等作用。
中国专利申请CN101209252A公开了苦豆碱在制备治疗慢性乙型肝炎药物中的用途；中国专利申请CN106892920A公开了苦豆碱12-N-苄基、芳酰基衍生物在制备治疗慢性乙型肝炎、慢性丙型肝炎和流感药物中的用途；中国专利申请CN106822129A公开了苦豆碱12-N-苯磺酰基衍生物在制备治疗肿瘤药物中的用途。但人们仍期待发现新结构类型、抗病毒活性较高、成药性好的苦豆碱衍生物。
发明内容
本发明的首要目的是提供一种苦豆碱衍生物，以能够更好的用于病毒性疾病的预防或治疗。
为实现此目的，在基础的实施方案中，本发明提供一种苦豆碱衍生物，所述的苦豆碱衍生物为如下式(Ⅰ)所示结构的化合物或其可药用盐、溶剂合物、前药，
其中：
X选自S或O原子；
R选自苯基、取代苯基、萘基、吡啶基、酰基、C1-6烷基、C1-6取代烷基、C3-6环烷基。
在一种优选的实施方案中，本发明提供一种苦豆碱衍生物，其中：
所述的取代苯基的苯环上的每个取代基各自独立地选自卤素、硝基、氨基、酰基、氰基、甲巯基、卤代甲基、卤代甲氧基、C1-3烷基、C1-3烷氧基或C1-3烷氨基，苯基取代为单取代或多取代；
所述的酰基选自芳酰基或烷酰基；
所述的C1-6取代烷基的每个取代基各自独立地选自烯基、卤素、甲巯基或苯基，取代为单取代。
在一种优选的实施方案中，本发明提供一种苦豆碱衍生物，其中所述的可药用盐为无机盐或有机盐，选自盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、甲酸盐、乙酸盐、苯甲酸盐、丁二酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。
在一种优选的实施方案中，本发明提供一种苦豆碱衍生物，其中所述的苦豆碱衍生物选自下列各式结构的化合物之一：
本发明的第二个目的是提供一种如上所述的苦豆碱衍生物的制备方法，以能够更好的制备如上所述的苦豆碱衍生物，制得苦豆碱衍生物能够更好的用于病毒性疾病的预防或治疗。
为实现此目的，在基础的实施方案中，本发明提供一种如上所述的苦豆碱衍生物的制备方法，所述的制备方法的制备反应式如下(苦豆碱12-位胺基和异硫氰酸酯或异氰酸酯在乙腈中室温反应得到本发明通式(I)所示的化合物)：
本发明的第三个目的是提供如上所述的苦豆碱衍生物的药物组合物，以能够更好的用于病毒性疾病的预防或治疗。
为实现此目的，在基础的实施方案中，本发明提供如上所述的苦豆碱衍生物的药物组合物，所述的药物组合物含有预防或治疗有效量的如上所述的苦豆碱衍生物，以及适宜量的可药用辅料。
在一种优选的实施方案中，本发明提供如上所述的苦豆碱衍生物的药物组合物，其中所述的药物组合物为片剂、胶囊剂、丸剂、注射剂或滴眼剂。
在一种优选的实施方案中，本发明提供如上所述的苦豆碱衍生物的药物组合物，其中所述的药物组合物为控释给药剂型、缓释给药剂型或各种微粒给药系统。
本发明的第四个目的是提供如上所述的苦豆碱衍生物或如上所述的药物组合物用于制备预防或治疗病毒性疾病的药物的用途，以能够更好的用于病毒性疾病的预防或治疗。
为实现此目的，在基础的实施方案中，本发明提供如上所述的苦豆碱衍生物或如上所述的药物组合物用于制备预防或治疗病毒性疾病的药物的用途。
在一种优选的实施方案中，本发明提供如上所述的苦豆碱衍生物或如上所述的药物组合物用于制备预防或治疗病毒性疾病的药物的用途，其中引起所述的病毒性疾病的病毒选自流感病毒、艾滋病毒、手足口病病毒EV71与CAV16、柯萨奇病毒A16、新冠病毒SARS-CoV-2中的一种或几种。
本发明的化合物可以例如胶囊剂、片剂、粉剂、粒剂、糖浆或类似剂型形式口服给药，或通过注射、软膏、栓剂或类似剂型非肠胃给药。这些药物制剂可通过使用本领域熟知的辅助剂，如粘合剂、赋形剂、稳定剂、崩解剂、矫味剂、润滑剂等等以普通方法生成。虽然剂量随症状和病人的年龄、疾病或失调的性质及严重性和给药的途径和方式而变，但对成年病人口服给药的情况来说，本发明的化合物正常口服给药为每天总剂量1至1000mg，优选为5至500mg，以为单剂量，或者为分剂量形式(例如每日二次或三次)；对于静脉注射的情况，每天可以分一至三次给用0.1至100mg，优选为0.5至50mg的剂量。
本发明的有益效果在于，本发明的苦豆碱衍生物及其药物组合物能够更好的用于病毒性疾病的预防或治疗。
本发明的苦豆碱衍生物在苦豆碱的12-位氮原子上引入了不同的取代基团，通过初步的活性筛选显示，此类衍生物比苦豆碱的抗病毒活性提高，选择性指数增大，提示此类衍生物具有较好的抗病毒应用前景。
具体实施方式
以下结合实施例对本发明的具体实施方式作出进一步的说明。实施例1-33的化合物的通用合成方法如下：
在反应瓶中加入1mmol苦豆碱、1.1mmol异硫氰酸酯或异氰酸酯(购自北京伊诺凯科技有限公司)和3ml乙腈，反应混合物室温搅拌2小时，TLC分析反应完成后浓缩除去乙腈，产物用硅胶柱层析(洗脱剂二氯甲烷-甲醇)得到目标化合物，可进一步用2M 1,4-二氧六环氯化氢溶液成盐后过滤得到目标化合物盐酸盐。
实施例1：12-N-(苯胺基硫代甲酰基)苦豆碱(ALO-1)
ALO-1：白色固体，mp 125-127℃，收率75％。1H NMR(400MHz,DMSO-D6)δ8.97(s,1H),7.44–7.24(m,4H),7.12(s,1H),5.61(s,1H),3.70(s,1H),3.10(s,1H),2.82–2.57(m,4H),2.45–2.15(m,2H),2.07–1.19(m,12H),1.16–0.96(m,1H).13C NMR(101MHz,CDCl3)δ181.40,139.94,135.83,129.58,128.74,127.97,127.34,125.64,125.46,77.26,64.28,59.12,54.11,46.66,44.80,34.96,28.16,26.15,24.96,23.94,23.49,19.10.HRMS(ESI)m/z计算值C22H30ON3[M+H]+352.2383,实测值352.2394.
实施例2：12-N-(4-氟苯胺基硫代甲酰基)苦豆碱(ALO-3)
ALO-3：白色固体，mp 170-172℃，收率85％。1H NMR(400MHz,CDCl3)δ7.36–7.22(m,2H),7.13–6.77(m,3H),5.64(d,J＝5.4Hz,1H),4.96(s,1H),4.06–3.78(m,1H),3.14(dd,J＝11.8,3.4Hz,1H),2.89–2.70(m,2H),2.67–2.42(m,3H),2.29(t,J＝11.2Hz,1H),2.16–1.57(m,10H),1.53–1.38(m,1H),1.11(dd,J＝17.2,13.5Hz,2H).13C NMR(126MHz,CDCl3)δ181.29,161.55(d,J＝245.7Hz),135.80(d,J＝3.8Hz),135.69,128.08,128.00(d,J＝3.8Hz),127.98,115.4(d,J＝22.7Hz),115.4(d,J＝22.7Hz),77.26,58.99,54.04,46.52,44.65,34.87,31.98,28.09,26.08,24.87,23.82,23.39,18.99.HRMS(ESI)m/z计算值C22H29N3FS[M+H]+386.2061,实测值386.2064.
实施例3：12-N-(4-腈苯胺基基硫代甲酰基)苦豆碱(ALO-5)
ALO-5：白色固体，mp 90-92℃，收率80％。1H NMR(400MHz,DMSO-D6)δ7.67(d,J＝8.5Hz,2H),7.53(d,J＝8.5Hz,2H),5.58(d,J＝4.9Hz,1H),3.32–3.23(m,4H),3.04(d,J＝10.8Hz,1H),2.78–2.61(m,2H),2.56(d,J＝10.8Hz,1H),2.49–2.43(m,4H),2.22(t,J＝11.5Hz,1H),2.07–1.70(m,4H),1.63–1.48(m,2H),1.42–1.32(m,1H),1.24–1.15(m,1H),1.10–0.94(m,2H).13C NMR(101MHz,CDCl3)δ180.18,144.09,135.41,133.65,132.67,128.40,126.50,123.77,118.94,107.50,77.25,64.66,58.99,54.12,46.63,45.06,34.87,28.05,26.02,24.90,23.83,23.53,19.01.HRMS(ESI)m/z计算值C23H29N4S[M+H]+393.2107,实测值393.2098.
实施例4：12-N-(4-甲氧苯胺基硫代甲酰基)苦豆碱(ALO-7)
ALO-7：白色固体，mp 166-168℃，收率88％。1H NMR(400MHz,CDCl3)δ7.25–7.19(m,2H),6.96(s,1H),6.90–6.85(m,2H),5.63(d,J＝5.5Hz,1H),4.96(s,1H),3.90(s,1H),3.80(s,3H),3.12(d,J＝3.5Hz,1H),2.88–2.47(m,5H),2.28(t,J＝11.2Hz,1H),2.21–1.56(m,10H),1.53–1.39(m,1H),1.11(dd,J＝17.5,13.6Hz,2H).13C NMR(126MHz,CDCl3)δ181.66,157.69,135.91,132.78,127.98,127.84,126.99,114.79,113.92,77.29,59.06,55.43,54.07,46.56,44.67,34.91,32.03,28.15,26.11,24.90,23.89,23.41,19.05.HRMS(ESI)m/z计算值C23H32ON3S[M+H]+398.2261,实测值398.2254.
实施例5：12-N-(4-硝苯胺基硫代甲酰基)苦豆碱(ALO-8)
ALO-8：白色固体，mp 170-172℃，收率52％。1H NMR(500MHz,CDCl3)δ8.19(d,J＝8.6Hz,2H),7.58(d,J＝8.6Hz,2H),5.68(d,J＝5.0Hz,1H),5.07(s,1H),4.01(s,1H),3.17(dd,J＝11.9,2.8Hz,1H),2.93–2.42(m,5H),2.33(t,J＝11.7Hz,1H),2.21–1.58(m,11H),1.55–1.41(m,1H),1.13(t,J＝15Hz,2H).13C NMR(101MHz,CDCl3)δ179.99,146.03,143.57,135.29,128.43,126.37,124.39,122.83,77.23,64.71,58.96,54.11,46.61,45.23,34.83,27.98,25.97,24.86,23.80,23.55,18.98.HRMS(ESI)m/z计算值C22H29O2N4S[M+H]+413.2006,实测值413.2018.
实施例6：12-N-(4-三氟甲基苯胺基硫代甲酰基)苦豆碱(ALO-9)
ALO-9：白色固体，mp 174-176℃，收率71％。1H NMR(500MHz,CDCl3)δ7.57(d,J＝8.3Hz,2H),7.50(d,J＝8.3Hz,2H),7.08(s,1H),5.66(d,J＝5.9Hz,1H),3.97(s,1H),3.16(dd,J＝11.8,3.3Hz,1H),2.93–2.41(m,5H),2.31(t,J＝11.7Hz,1H),2.20–1.63(m,11H),1.55–1.35(m,1H),1.12(dd,J＝20.2,14.1Hz,2H).13C NMR(101MHz,CDCl3)δ180.60,143.04,135.51,128.22,126.67(q,J＝33.3Hz),126.4(q,J＝4.0Hz),124.22,124.10(q,J＝272.7Hz),77.23,64.48,59.01,54.09,46.61,44.90,34.87,28.05,26.04,24.89,23.84,23.50,19.01.HRMS(ESI)m/z计算值C23H29N3F3S[M+H]+436.2029,实测值436.2037.
实施例7：12-N-(4-氯苯胺基硫代甲酰基)苦豆碱(ALO-11)
ALO-11：白色固体，mp 166-168℃，收率65％。1H NMR(500MHz,CDCl3)δ7.38–7.21(m,4H),6.96(s,1H),5.65(d,J＝4.7Hz,1H),3.94(s,1H),3.15(dd,J＝11.7,2.7Hz,1H),2.85–2.47(m,5H),2.30(t,J＝11.7Hz,1H),2.19–1.62(m,10H),1.55–1.37(m,1H),1.37–1.22(m,1H),1.11(dd,J＝21.2,13.9Hz,2H).13C NMR(101MHz,CDCl3)δ180.06,146.08,143.58,135.36,128.42,126.40,125.30,124.41,122.85,77.26,64.73,58.99,54.15,46.64,45.28,34.84,28.01,25.97,24.86,23.83,23.59,19.01.HRMS(ESI)m/z计算值C22H29N3ClS[M+H]+402.1765,实测值402.1777.
实施例8：12-N-(3,4,5-三甲氧苯胺基硫代甲酰基)苦豆碱(ALO-12)
ALO-12：白色固体，mp 158-160℃，收率68％。1H NMR(400MHz,CDCl3)δ6.95(s,1H),6.58(s,2H),5.61(d,J＝5.5Hz,1H),4.00–3.69(m,11H),3.13(dd,J＝11.8,3.5Hz,1H),2.84–2.37(m,5H),2.27(t,J＝11.2Hz,1H),2.16–1.57(m,10H),1.47–1.39(m,1H),1.08(t,J＝14.6Hz,2H).13C NMR(101MHz,CDCl3)δ180.95,153.02,135.78,135.66,127.96,103.40,103.27,77.29,60.93,59.10,56.19,54.09,46.66,44.68,34.93,32.06,28.13,26.11,24.90,23.94,23.49,19.09.HRMS(ESI)m/z计算值C25H36O3N3S[M+H]+458.2472,实测值458.2484.
实施例9：12-N-(4-溴苯胺基硫代甲酰基)苦豆碱(ALO-13)
ALO-13：白色固体，mp 178-180℃，收率63％。1H NMR(400MHz,CDCl3)δ7.45–7.39(m,2H),7.23–7.16(m,2H),6.97(s,1H),5.62(d,J＝5.6Hz,1H),3.99–3.82(m,1H),3.12(dd,J＝11.8,3.5Hz,1H),2.84–2.42(m,5H),2.27(t,J＝11.4Hz,1H),2.21–1.58(m,11H),1.50–1.34(m,1H),1.09(t,J＝15.0Hz,2H).13C NMR(101MHz,CDCl3)δ180.90,138.99,135.66,132.78,131.65,128.09,127.21,127.16,118.70,77.27,64.34,59.05,54.10,46.60,44.76,34.91,28.11,26.10,24.92,23.88,23.47,19.05.HRMS(ESI)m/z计算值C22H29N3BrS[M+H]+446.1260,实测值446.1273.
实施例10：12-N-(4-乙基苯胺基硫代甲酰基)苦豆碱(ALO-15)
ALO-15：白色固体，mp 138-140℃，收率90％。1H NMR(400MHz,CDCl3)δ7.23–7.19(m,2H),7.17–7.12(m,2H),6.97(s,1H),5.61(d,J＝5.6Hz,1H),3.88(td,J＝12.4,3.5Hz,1H),3.12(dd,J＝11.8,3.5Hz,1H),2.82–2.69(m,2H),2.65–2.58(m,4H),2.51(d,J＝11.9Hz,1H),2.26(t,J＝11.4Hz,1H),2.18–1.95(m,4H),1.94–1.75(m,4H),1.68(dd,J＝18.8,6.3Hz,3H),1.52–1.34(m,1H),1.28–1.15(m,3H),1.09(dd,J＝17.5,13.5Hz,2H).13CNMR(101MHz,CDCl3)δ181.42,141.77,137.47,135.90,128.97,128.12,127.87,125.74,125.65,77.28,64.18,59.12,54.10,46.63,44.71,34.95,28.39,28.17,26.14,24.94,23.95,23.48,19.10,15.43.HRMS(ESI)m/z计算值C24H34N3S[M+H]+396.2468,实测值396.2482.
实施例11：12-N-(3,4-二甲氧苯胺基硫代甲酰基)苦豆碱(ALO-16)
ALO-16：白色固体，mp 72-74℃，收率88％。1H NMR(400MHz,CDCl3)δ7.02(s,1H),6.96(d,J＝1.9Hz,1H),6.85–6.73(m,2H),5.63(d,J＝5.6Hz,1H),3.87(d,J＝2.9Hz,6H),3.15(dd,J＝11.8,3.4Hz,1H),2.87–2.40(m,5H),2.36–2.24(m,1H),2.20–1.54(m,10H),1.53–1.38(m,1H),1.32–1.20(m,2H),1.11(t,J＝16.0Hz,2H).13C NMR(126MHz,CDCl3)δ181.41,148.68,147.20,132.96,127.85,118.40,111.17,110.80,110.66,59.04,55.99,55.96,54.06,46.58,34.89,31.94,29.72,28.13,27.22,26.08,24.86,23.88,23.40,19.04.MS(ESI)m/z计算值C24H35N3O2S[M+H]+428.2,实测值428.2
实施例12：12-N-(4-三氟甲氧苯胺基硫代甲酰基)苦豆碱(ALO-17)
ALO-17：白色固体，mp 76-78℃，收率78％。1H NMR(500MHz,CDCl3)δ7.40(d,J＝8.5Hz,2H),7.18(d,J＝8.5Hz,2H),7.00(s,1H),5.65(d,J＝4.4Hz,1H),3.95(s,1H),3.15(d,J＝11.5Hz,1H),2.89–2.46(m,5H),2.31(t,J＝11.5Hz,1H),2.22–1.97(m,3H),1.97–1.60(m,7H),1.51–1.38(m,1H),1.34–1.21(m,1H),1.12(dd,J＝20.5,12.4Hz,2H).13C NMR(126MHz,CDCl3)δ180.91,146.37,138.39,135.69,128.12,127.11,126.72,121.18,119.43,77.25,64.29,59.01,54.08,46.56,44.63,34.87,31.92,28.09,26.06,24.88,23.84,23.41,19.01.HRMS(ESI)m/z计算值C23H29ON3F3S[M+H]+452.1978,实测值452.1967.
实施例13：12-N-(4-甲巯苯胺基硫代甲酰基)苦豆碱(ALO-18)
ALO-18：白色固体，mp 152-154℃，收率46％。1H NMR(500MHz,CDCl3)δ7.29–7.21(m,4H),6.97(s,1H),5.64(d,J＝6.0Hz,1H),3.92(s,1H),3.15(dd,J＝11.9,3.4Hz,1H),2.90–2.44(m,8H),2.29(t,J＝11.5Hz,1H),2.23–1.59(m,11H),1.53–1.37(m,1H),1.11(dd,J＝22.0,13.6Hz,2H).13C NMR(101MHz,CDCl3)δ181.15,137.22,135.77,135.39,127.93,127.12,127.04,126.16,126.06,77.23,64.23,59.05,54.07,46.59,44.72,34.90,28.11,26.07,24.89,23.89,23.44,19.04,16.27.HRMS(ESI)m/z计算值C23H32N3S2[M+H]+414.2032,实测值414.2044.
实施例14：12-N-(3,4-亚甲二氧苯胺基硫代甲酰基)苦豆碱(ALO-11)
ALO-11：白色固体，mp 166-168℃，收率65％。1H NMR(400MHz,CDCl3)δ6.94–6.88(m,2H),6.87–6.72(m,1H),6.67(dd,J＝8.2,2.0Hz,1H),5.97(s,2H),5.63(d,J＝5.8Hz,1H),3.90(s,1H),3.14(dd,J＝11.8,3.5Hz,1H),2.96–2.35(m,6H),2.28(t,J＝11.4Hz,1H),2.22–2.04(m,2H),2.03–1.95(m,2H),1.92–1.79(m,3H),1.76–1.62(m,3H),1.51–1.40(m,1H),1.11(dd,J＝17.4,13.4Hz,2H).13C NMR(126MHz,CDCl3)δ181.61,147.58,145.81,133.90,127.88,119.56,108.70,107.78,101.47,77.29,64.05,59.06,54.06,46.56,44.63,34.92,32.02,28.13,26.11,24.89,23.89,23.42,19.05.HRMS(ESI)m/z计算值C23H30O2N3S[M+H]+412.2053,实测值412.2041.
实施例15：12-N-(4-乙酰苯胺基甲酰基)苦豆碱(ALO-14)
ALO-14：白色固体，mp 96-98℃，收率42％.1H NMR(400MHz,CDCl3)δ8.14(d,J＝9.2Hz,2H),7.58(d,J＝8.9Hz,2H),6.72(s,1H),5.65(d,J＝3.6Hz,1H),4.51(d,J＝4.4Hz,1H),3.69(d,J＝4.2Hz,2H),3.11(d,J＝10.8Hz,1H),2.97–2.11(m,8H),2.07–1.53(m,10H),1.50–1.37(m,1H),1.32–1.02(m,2H).13C NMR(126MHz,CDCl3)δ151.77,150.68,145.75,142.18,136.11,128.10,126.04,125.09,123.94,118.24,77.24,70.66,59.19,57.11,54.27,46.48,44.72,34.77,28.22,25.80,24.60,24.11,23.98,19.13.HRMS(ESI)m/z计算值C24H32ON3S[M+H]+410.2261,实测值410.2254.
实施例16：12-N-(2-萘胺基甲酰基)苦豆碱(ALO-33)
ALO-33：白色固体，mp 92-94℃，收率％。1H NMR(500MHz,CDCl3)δ7.91–7.74(m,3H),7.57–7.38(m,4H),7.22–7.14(m,1H),5.62(d,J＝30.2Hz,1H),3.22(d,J＝11.4Hz,1H),2.87–2.64(m,4H),2.36–1.99(m,5H),1.94–1.66(m,6H),1.53–1.37(m,1H),1.30–1.08(m,4H),0.91–0.84(m,1H).
实施例17：12-N-(3-吡啶胺基甲酰基)苦豆碱(ALO-32)
ALO-32：白色固体，mp 96-98℃，收率％。1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.40(dd,J＝4.7,1.3Hz,1H),8.00–7.91(m,1H),7.30–7.27(m,1H),5.67(d,J＝5.2Hz,1H),3.99(s,1H),3.17(dd,J＝11.8,3.2Hz,1H),2.89–2.46(m,5H),2.40–2.26(m,1H),2.18–1.66(m,10H),1.49–1.42(m,1H),1.29–1.23(m,2H),1.13(s,1H),0.88(t,J＝6.8Hz,1H).
实施例18：12-N-(叔丁胺基甲酰基)苦豆碱盐酸盐(ALO-2)
ALO-2：白色固体，mp 274-276℃，收率71％。HRMS(ESI)m/z计算值C20H34N3S[M+H]+348.2468,实测值348.2458.
实施例19：12-N-(正丁胺基甲酰基)苦豆碱盐酸盐(ALO-27)
ALO-27：白色固体，mp 62-64℃，收率61％。HRMS(ESI)m/z计算值C20H34N3S[M+H]+384.2468,实测值384.2464.
实施例20：12-N-(苄胺基甲酰基)苦豆碱(ALO-4)
ALO-4：白色固体，mp 72-74℃，收率83％。1H NMR(400MHz,CDCl3)δ7.38–7.25(m,5H),5.60(d,J＝5.1Hz,2H),4.96(dd,J＝14.5,4.8Hz,1H),4.83(dd,J＝14.5,4.8Hz,1H),3.92–3.73(m,1H),3.16–3.01(m,1H),2.82–2.33(m,5H),2.25(t,J＝11.4Hz,1H),2.14–1.93(m,3H),1.91–1.55(m,7H),1.52–1.36(m,1H),1.33–1.22(m,1H),1.08(t,J＝14.8Hz,2H).13C NMR(101MHz,CDCl3)δ181.11,138.46,135.97,128.78,127.82,127.75,127.55,77.38,63.60,59.07,54.05,50.13,46.47,34.88,32.17,28.17,26.11,24.84,23.92,23.39,19.06.HRMS(ESI)m/z计算值C23H32N3S[M+H]+382.2312,实测值382.2315.
实施例21：12-N-(苯甲酰胺基甲酰基)苦豆碱(ALO-6)
ALO-6：白色固体，mp 92-94℃，收率65％。1H NMR(400MHz,DMSO-D6)δ10.61(s,1H),7.95(d,J＝8.0Hz,2H),7.61(t,J＝6.7Hz,1H),7.50(t,J＝7.7Hz,2H),5.69(s,1H),4.34–3.56(m,2H),3.08–2.66(m,1H),2.38–1.52(m,12H),1.53–0.97(m,7H).13C NMR(126MHz,CDCl3)δ181.06,171.20,138.36,135.94,128.81,127.88,127.61,126.84,77.27,60.43,58.46,54.05,46.45,34.83,29.72,28.14,26.10,24.85,23.91,19.03,18.47.HRMS(ESI)m/z计算值C23H30N3OS[M+H]+396.2104,实测值396.2104.
实施例22：12-N-(烯丙胺基甲酰基)苦豆碱(ALO-10)
ALO-10：白色固体，mp 74-76℃，收率82％。1H NMR(500MHz,CDCl3)δ5.96(dq,J＝10.8,5.6Hz,1H),5.61(d,J＝4.4Hz,1H),5.39(s,1H),5.19(dd,J＝19.6,13.8Hz,2H),4.45–4.27(m,2H),3.83(s,1H),3.10(d,J＝9.9Hz,1H),2.89–2.39(m,5H),2.25(t,J＝10.9Hz,1H),2.15–1.54(m,11H),1.44(q,J＝12.7Hz,1H),1.11(t,J＝15.0Hz,2H).13C NMR(101MHz,CDCl3)δ181.11,136.06,134.55,127.69,116.71,77.26,63.56,59.08,54.05,48.49,46.47,44.02,34.89,32.17,28.15,24.83,23.91,23.32,19.04.HRMS(ESI)m/z计算值C19H30N3S[M+H]+332.2155,实测值332.2162.
实施例23：12-N-(4-甲苯胺基甲酰基)苦豆碱(ALO-19)
ALO-19：白色固体，mp 88-90℃，收率36％。1H NMR(500MHz,CDCl3)δ7.28(d,J＝8.2Hz,2H),7.07(d,J＝8.2Hz,2H),6.26(s,1H),5.61(d,J＝4.2Hz,1H),4.49(d,J＝4.2Hz,1H),3.72(dd,J＝12.9,6.0Hz,1H),3.55(dd,J＝12.9,6.0Hz,1H),3.07(dd,J＝11.5,3.0Hz,1H),2.82–2.68(m,2H),2.57(d,J＝11.1Hz,2H),2.32–2.14(m,5H),1.99–1.65(m,9H),1.52–1.35(m,1H),1.10(dd,J＝19.3,14.5Hz,2H).13C NMR(101MHz,CDCl3)δ155.33,136.78,132.14,129.32,129.02,127.52,126.86,124.59,119.77,77.27,70.87,59.45,54.27,46.62,44.51,34.96,33.16,28.36,26.01,24.76,24.25,20.75,19.34.HRMS(ESI)m/z计算值C23H32ON3[M+H]+366.2540,实测值366.2547.
实施例24：12-N-(4-三氟甲苯胺基甲酰基)苦豆碱(ALO-20)
ALO-20：白色固体，mp 74-76℃，收率60％。1H NMR(500MHz,CDCl3)δ7.42(d,J＝8.5Hz,2H),7.13(d,J＝8.5Hz,2H),6.41(s,1H)5.64(d,J＝4.8Hz,1H),4.49(d,J＝4.6Hz,1H),3.81–3.39(m,2H),3.09(dd,J＝11.7,3.4Hz,1H),2.89–2.49(m,4H),2.40–2.10(m,3H),2.05–1.77(m,6H),1.74–1.63(m,2H),1.53–1.35(m,1H),1.13(dd,J＝16.5,15.8Hz,2H).13C NMR(101MHz,CDCl3)δ154.89,144.20,138.09,127.78,121.65,121.35(q,J＝38.4Hz),121.82(q,J＝255.5Hz),120.54,77.22,59.46,59.38,54.23,46.57,40.34,34.92,33.10,28.26,25.98,24.19,24.15,19.26.HRMS(ESI)m/z计算值C23H29ON3F3[M+H]+420.2257,实测值420.2295.
实施例25：12-N-(4-甲氧苯胺基甲酰基)苦豆碱(ALO-21)
ALO-21：白色固体，mp 74-76℃，收率82％。1H NMR(500MHz,CDCl3)δ7.25(dd,J＝40.5,8.6Hz,2H),6.85(dd,J＝18.5,8.7Hz,2H),6.18(s,1H),5.62(d,J＝5.1Hz,1H),4.48(d,J＝3.8Hz,1H),3.78(s,3H),3.75–3.45(m,2H),3.08(dd,J＝11.5,3.2Hz,1H),2.83–2.53(m,4H),2.37–2.07(m,3H),1.96–1.64(m,8H),1.52–1.35(m,1H),1.11(dd,J＝19.2,14.9Hz,2H).HRMS(ESI)m/z计算值C23H32O2N3[M+H]+382.2489,实测值382.2496.
实施例26：12-N-(4-腈苯胺基甲酰基)苦豆碱(ALO-22)
ALO-22：白色固体，mp 108-110℃，收率62％。1H NMR(400MHz,CDCl3)δ7.60–7.49(m,5H),5.65(d,J＝4.9Hz,1H),4.52(d,J＝4.3Hz,1H),3.76–3.59(m,2H),3.11(dd,J＝11.7,2.9Hz,1H),2.91–2.67(m,1H),2.66–2.51(m,1H),2.41–2.24(m,1H),2.66–2.51(m,1H),2.05–1.63(m,11H),1.56–1.02(m,3H).13C NMR(101MHz,CDCl3)δ154.28,143.93,135.65,133.07,127.95,126.63,119.41,119.04,118.94,104.88,77.28,59.30,54.25,46.54,40.60,34.85,32.92,28.21,25.89,24.69,24.20,24.07,19.21.HRMS(ESI)m/z计算值C23H29ON4[M+H]+377.2336,实测值377.2345.
实施例27：12-N-(4-氟苯胺基甲酰基)苦豆碱(ALO-23)
ALO-23：白色固体，mp 154-156℃，收率61％。1H NMR(400MHz,CDCl3)δ7.38–7.30(m,2H),7.04–6.74(m,2H),6.44(s,1H),5.62(d,J＝5.5Hz,1H),4.49(d,J＝5.5Hz,1H),3.72(dd,J＝13.6,6.6Hz,1H),3.56(td,J＝13.1,5.4Hz,1H),3.07(dd,J＝11.6,3.6Hz,1H),2.83–2.66(m,2H),2.57(t,J＝10.8Hz,2H),2.38–2.06(m,3H),2.04–1.57(m,8H),1.53–1.29(m,1H),1.11(t,J＝15.4Hz,2H).13C NMR(101MHz,CDCl3)δ159.84,156.36(d,J＝218.2Hz),135.94,135.37(d,J＝2.0Hz),127.70,121.69(d,J＝7.07Hz),115.38(d,J＝22.2Hz),77.30,59.44,54.21,46.62,40.15,34.99,33.16,28.28,26.10,24.82,24.26,24.20,19.32.HRMS(ESI)m/z计算值C22H29ON3F[M+H]+370.2289,实测值370.2307.
实施例28：12-N-(4-氯苯胺基甲酰基)苦豆碱(ALO-24)
ALO-24：白色固体，mp 86-88℃，收率72％。1H NMR(500MHz,CDCl3)δ7.35(d,J＝8.7Hz,2H),7.23(d,J＝8.7Hz,2H),6.31(s,1H),5.63(d,J＝4.5Hz,1H),4.48(d,J＝4.3Hz,1H),3.80–3.46(m,2H),3.09(dd,J＝11.6,3.2Hz,1H),2.86–2.54(m,4H),2.35–2.25(m,2H),2.15(dd,J＝19.8,10.9Hz,1H),2.00–1.79(m,5H),1.76–1.62(m,3H),1.52–1.34(m,1H),1.11(t,J＝15.0Hz,2H).13C NMR(101MHz,CDCl3)δ154.91,137.99,128.95,128.78,127.74,127.55,120.79,77.25,59.40,54.26,46.59,40.38,34.93,33.08,28.29,25.98,25.92,24.76,24.18,19.28.HRMS(ESI)m/z计算值C22H29ON3Cl[M+H]+386.1994,实测值386.2003.
实施例29：12-N-(4-硝基苯胺基甲酰基)苦豆碱(ALO-25)
ALO-25：白色固体，mp 202-204℃，收率83％。1H NMR(500MHz,CDCl3)δ7.19(dd,J＝26.3,8.1Hz,2H),7.02(s,1H),6.86(t,J＝9.0Hz,2H),5.63(s,1H),3.99–3.84(m,1H),3.47(s,1H),3.14(d,J＝11.5Hz,1H),2.87–2.45(m,5H),2.36–1.96(m,5H),1.95–1.80(m,3H),1.75–1.58(m,3H),1.53–1.34(m,1H),1.11(dd,J＝23.2,13.2Hz,2H).HRMS(ESI)m/z计算值C22H29O3N4[M+H]+397.2234,实测值397.2240.
实施例30：12-N-(4-甲巯苯胺基甲酰基)苦豆碱(ALO-26)
ALO-26：白色固体，mp 78-80℃，收率65％。1H NMR(400MHz,CDCl3)δ7.46(t,J＝1.9Hz,1H),7.17(t,J＝7.8Hz,1H),7.11(ddd,J＝8.1,1.8,1.0Hz,1H),6.90(ddd,J＝8.1,1.8,1.0Hz,1H),6.33(s,1H),5.63(s,1H),4.51(s,1H),3.87–3.50(m,2H),3.09(d,J＝8.5Hz,1H),2.66–2.78(m,4H),2.48(s,3H),2.37–2.09(m,3H),2.03–1.78(m,5H),1.75–1.59(m,3H),1.53–1.33(m,1H),1.21–1.01(m,2H).13C NMR(126MHz,CDCl3)δ154.89,139.93,139.18,135.92,129.05,127.77,120.75,117.12,116.07,77.26,59.37,54.22,46.56,40.18,34.94,33.20,28.28,26.11,24.82,24.22,24.14,19.27,15.80.HRMS(ESI)m/z计算值C23H32ON3S[M+H]+398.2261,实测值398.2252.
实施例31：12-N-(3-氯-4-氟苯胺基甲酰基)苦豆碱(ALO-28)
ALO-28：白色固体，mp 178-180℃，收率67％。1H NMR(400MHz,CDCl3)δ7.59(dd,J＝6.5,2.6Hz,1H),7.24–7.15(m,1H),7.03(t,J＝8.8Hz,1H),6.36(s,1H),5.68–5.59(m,1H),4.48(d,J＝5.4Hz,1H),3.81–3.46(m,2H),3.10(dd,J＝11.7,3.4Hz,1H),2.92–2.50(m,4H),2.48–2.08(m,3H),2.06–1.78(m,5H),1.74–1.62(m,3H),1.54–1.38(m,1H),1.25–0.97(m,2H).13C NMR(101MHz,CDCl3)δ155.08,153.79(d,J＝227.3Hz),136.12(d,J＝3.0Hz),135.80,127.80,121.91,120.75,120.57,119.41(d,J＝6.1Hz),77.28,59.38,54.23,46.57,40.24,34.93,33.09,28.25,26.03,24.76,24.21,24.14,19.26.HRMS(ESI)m/z计算值r C22H28ON3ClF[M+H]+404.1899,实测值404.1919.
实施例32：12-N-(4-异丙基苯胺基甲酰基)苦豆碱(ALO-29)
ALO-29：白色固体，mp 176-178℃，收率62％。1H NMR(400MHz,CDCl3)δ7.37–7.26(m,2H),7.18–6.99(m,2H),6.26(s,1H),5.60(d,J＝5.0Hz,1H),4.48(d,J＝5.1Hz,1H),3.82–3.42(m,2H),3.05(dd,J＝11.7,3.7Hz,1H),2.94–2.43(m,5H),2.38–2.03(m,3H),2.00–1.37(m,11H),1.29–1.11(m,6H).13C NMR(101MHz,CDCl3)δ155.26,143.34,137.02,136.12,127.61,126.71,119.83,77.27,59.50,59.46,54.25,46.65,40.11,35.02,33.51,33.24,28.34,26.15,24.86,24.28,24.13,19.37.HRMS(ESI)m/z计算值C25H36ON3[M+H]+394.2853,实测值394.2864.
实施例33：12-N-(3-硝基-4-甲基苯胺基甲酰基)苦豆碱(ALO-30)
ALO-30：白色固体，mp 100-102℃，收率82％。1H NMR(400MHz,CDCl3)δ7.99(d,J＝2.3Hz,1H),7.69(dd,J＝8.4,2.3Hz,1H),7.23(d,J＝8.4Hz,1H),6.45(s,1H),5.69–5.59(m,1H),4.57–4.42(m,1H),3.80–3.51(m,2H),3.10(dd,J＝11.7,3.6Hz,1H),2.87–2.50(m,7H),2.37–2.09(m,3H),2.04–1.65(m,8H),1.51–1.40(m,1H),1.11(t,J＝14.5Hz,2H).13CNMR(101MHz,CDCl3)δ154.69,148.95,138.44,132.95,127.91,127.26,124.27,122.13,115.25,77.24,59.47,59.34,54.24,46.55,34.90,33.02,28.24,25.86,24.72,24.18,24.10,19.90,19.23.HRMS(ESI)m/z计算值C23H31O3N4[M+H]+411.2391,实测值411.2392.
实施例34：体外抗流感病毒A/PR/8/34(H1N1)实验
(一)测试材料和方法
1.病毒株：流感病毒A/PR/8/34(H1N1)，在鸡胚尿囊腔内培养传代(2018.3)，-80℃保存。
2.样品处理：样品临用前用DMSO配成母液,再用培养液作3倍稀释，各8个稀释度。
3.阳性对照药：利巴韦林(RBV)，湖北天药药业股份有限公司(批号31712252)；磷酸奥司他韦，上海罗氏制药有限公司分装(批号SH0071)。
4.测试方法：MDCK细胞接种96孔培养板，置5％CO2，37℃培养。24小时后感染流感病毒10-5，吸附2小时，弃病毒液，加入含有不同稀释度样品及阳性对照药的维持液，同时设细胞对照孔和病毒对照孔，5％CO2，37℃培养。待病毒对照组病变程度(CPE)达4+时观察各组细胞病变程度(CPE)，用Reed-Muench法分别计算样品对细胞的半数有毒浓度(TC50)和对病毒的半数抑制浓度(IC50)。
(二)测试结果
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注：
TC50：药物半数有毒浓度；IC50：药物对病毒半数抑制浓度。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若对本发明的这些修改和变型属于本发明权利要求及其同等技术的范围之内，则本发明也意图包含这些改动和变型在内。上述实施例或实施方式只是对本发明的举例说明，本发明也可以以其它的特定方式或其它的特定形式实施，而不偏离本发明的要旨或本质特征。因此，描述的实施方式从任何方面来看均应视为说明性而非限定性的。本发明的范围应由附加的权利要求说明，任何与权利要求的意图和范围等效的变化也应包含在本发明的范围内。

Claims (10)

1.一种苦豆碱衍生物，其特征在于：所述的苦豆碱衍生物为如下式(Ⅰ)所示结构的化合物或其可药用盐、溶剂合物、前药，
其中：
X选自S或O原子；
R选自苯基、取代苯基、萘基、吡啶基、酰基、C1-6烷基、C1-6取代烷基、C3-6环烷基。
2.根据权利要求1所述的苦豆碱衍生物，其特征在于：
所述的取代苯基的苯环上的每个取代基各自独立地选自卤素、硝基、氨基、酰基、氰基、甲巯基、卤代甲基、卤代甲氧基、C1-3烷基、C1-3烷氧基或C1-3烷氨基，苯基取代为单取代或多取代；
所述的酰基选自芳酰基或烷酰基；
所述的C1-6取代烷基的每个取代基各自独立地选自烯基、卤素、甲巯基或苯基，取代为单取代。
3.根据权利要求1所述的苦豆碱衍生物，其特征在于：所述的可药用盐为无机盐或有机盐，选自盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、甲酸盐、乙酸盐、苯甲酸盐、丁二酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。
4.根据权利要求1所述的苦豆碱衍生物，其特征在于，所述的苦豆碱衍生物选自下列各式结构的化合物之一：
5.一种根据权利要求1-4之一所述的苦豆碱衍生物的制备方法，其特征在于，所述的制备方法的制备反应式如下：
6.药物组合物，其特征在于：所述的药物组合物含有预防或治疗有效量的根据权利要求1-4之一所述的苦豆碱衍生物，以及适宜量的可药用辅料。
7.根据权利要求6所述的药物组合物，其特征在于：所述的药物组合物为片剂、胶囊剂、丸剂、注射剂或滴眼剂。
8.根据权利要求6所述的药物组合物，其特征在于：所述的药物组合物为控释给药剂型、缓释给药剂型或各种微粒给药系统。
9.根据权利要求1-4之一所述的苦豆碱衍生物或根据权利要求6-8之一所述的药物组合物用于制备预防或治疗病毒性疾病的药物的用途。
10.根据权利要求9所述的用途，其特征在于：引起所述的病毒性疾病的病毒选自流感病毒、艾滋病毒、手足口病病毒EV71与CAV16、柯萨奇病毒A16、新冠病毒SARS-CoV-2中的一种或几种。
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