CN112500308A - 金色酰胺醇酯及其氟化衍生物及制备方法和应用 - Google Patents
金色酰胺醇酯及其氟化衍生物及制备方法和应用 Download PDFInfo
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- CN112500308A CN112500308A CN202011174804.5A CN202011174804A CN112500308A CN 112500308 A CN112500308 A CN 112500308A CN 202011174804 A CN202011174804 A CN 202011174804A CN 112500308 A CN112500308 A CN 112500308A
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Abstract
本发明属于医药技术领域，公开了金色酰胺醇酯及其氟化衍生物及制备方法和应用。通式如下所示的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐：
其中，R1表示OH、CH2OH或OCOCH3；R2、R3和R4分別独立表示H、烷基或F。该金色酰胺醇酯及其氟化衍生物或药学上可接受的盐对预防或治疗流感病毒，特别是甲型流感病毒引起的感染具有很好的效果。对金色酰胺醇酯进行氟化改造使金色酰胺醇酯的生物活性更强。该金色酰胺醇酯及其氟化衍生物作用靶标既针对病毒，也针对宿主细胞，故不易产生耐药。
Description
技术领域
本发明属于医药技术领域，特别涉及金色酰胺醇酯及其氟化衍生物及制备方法和应用。
背景技术
季节性流感是由流感病毒引起的急性呼吸道疾病，具有高度传染性。全球每年流感发病率在成人中约为5％-10％，在儿童中约为20％-30％，每年流感造成约300万至500万例严重疾病和约25万至50万例死亡。流感严重威胁人类的生命健康，并造成巨大经济损失。人流感病毒分为甲、乙、丙、丁四型，其中甲型流感对人类威胁最大，H1N1是最主要的季节性甲型流感病毒。预防及控制流感传播的最有效方法是接种疫苗，但是由于流感病毒的抗原变异能力强，疫苗的生产仅针对已流行流感亚型毒株，对于抗原漂移和变异产生的新型流感病毒感染不产生保护作用。因此，流感疫苗预防流感具有一定的滞后性，保护率也有限。目前用于流感治疗的化学药物主要有两类：金刚烷胺类和神经氨酸酶抑制剂，通常需在疾病早期(症状出现后48小时内)给药，且由于作用靶点单一，已出现耐药，极大影响了疗效。因此，临床亟需研发新的抗流感药物。
因此，希望提供一种新的化合物，其对流感具有更好的预防或治疗效果。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出金色酰胺醇酯及其氟化衍生物及制备方法和应用，其氟化衍生物(即为氟化金色酰胺醇酯衍生物或金色酰胺醇酯氟化衍生物)，其对预防或治疗甲型流感病毒引起的感染具有很好的效果。
本发明的第一方面提供金色酰胺醇酯、金色酰胺醇酯氟化衍生物。
具体的，通式如下所示的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐：
其中，R1表示OH、CH2OH或OCOCH3；
R2、R3和R4分別独立表示H、烷基或F。
优选的，所述烷基为碳数为1-5的烷基；进一步优选的，所述烷基为碳数为1-5的烷基；更优选的，所述烷基为CH3。
优选的，R2、R3和R4中至少有一个为F。
优选的，所述药学上可接受的盐包括无机酸盐和有机酸盐。
优选的，所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐。
优选的，所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐。
进一步优选的，所述烷基磺酸盐包括但不仅限于甲基磺酸盐和/或乙基磺酸盐。
进一步优选的，所述芳基磺酸盐包括但不仅限于苯磺酸盐和/或对甲苯磺酸盐。
优选的，金色酰胺醇酯、金色酰胺醇酯氟化衍生物的结构式如下任意一种：
本发明的另一方面提供上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐的制备方法。
具体的，上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐的制备方法，包括以下步骤：
将结构式(III)所示的化合物与酸酐类物质进行酯化，形成酯，然后去掉酯中的Boc保护基，再加入结构式(IV)所示的物质和偶联剂进行反应，即可；
其中，R2、R3和R4分別独立表示H、烷基或F；Boc表示叔丁氧羰基(制得的金色酰胺醇酯、金色酰胺醇酯氟化衍生物中的R1由酸酐类物质进行酯化的过程引入)；
或
将氨基酸、结构式(IV)所示的物质和偶联剂进行反应，得到的产物再与氨基醇类物质和偶联剂进行反应，即可。
优选的，结构式(III)所示的化合物是通过以下步骤制得：将含有Boc保护基的氨基酸、氨基醇类物质以及偶联剂进行反应制得。
进一步优选的，所述含有Boc保护基的氨基酸的结构式如(I)所示：
进一步优选的，所述氨基醇类物质的结构式如(II)所示：
优选的，所述酯化的过程是加入酸酐类物质进行酯化，例如加入乙酸酐进行酯化。
优选的，所述去掉酯中的Boc保护基的过程是加入酸来去掉酯中的Boc保护基，例如加入CF3COOH来去掉酯中的Boc保护基。
优选的，所述偶联剂选自三乙胺、EDCI(即1-乙基-3(3-二甲基丙胺)碳二亚胺1-乙基-3(3-二甲基丙胺)碳二亚胺)、HOBT(即1-羟基苯并三氮唑)中的至少一种。
优选的，所述氨基酸选自苯丙氨酸、酪氨酸、色氨酸、丙氨酸、甘氨酸或亮氨酸中的至少一种。
优选的，上述制备方法涉及的反应的过程中使用一些溶剂；进一步优选的，所述溶剂选自DCM(二氯甲烷)、THF(四氢呋喃)、或吡啶中的至少一种。
本发明的另一方面提供含上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐的药物。
具体的，一种药物，所述药物含上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐，以及辅料。
优选的，所述药物还包含辅料；进一步优选的，所述辅料包含载体、稀释剂、吸收剂、湿润剂、粘合剂、崩解剂、崩解抑制剂或润滑剂中的至少一种。
优选的，药学上常用的辅料有稀释剂和吸收剂，例如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；药学上常用的辅料有湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；药学上常用的辅料有崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；药学上常用的辅料有崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；药学上常用的辅料有润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。关于药学上可接受的载体或辅料不再一一例举，本领域普通技术人员可根据所掌握的公知常识进行具体选择。
优选的，所述药物的剂型为任意剂型；进一步优选的，所述药物的剂型为片剂、胶囊剂(硬胶囊、软胶囊)、颗粒剂、滴丸剂、注射剂、凝胶剂中的一种。
本发明的另一方面提供上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐的应用。
具体的，上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐在制备预防或治疗抗流感病毒的药物中的应用。
优选的，所述流感病毒为甲型流感病毒。
优选的，上述金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐在制备抑制甲型流感病毒复制和/或甲型流感病毒诱导的转录因子NF-κB的活化的药物中的应用。
相对于现有技术，本发明的有益效果如下：
(1)本发明所述的金色酰胺醇酯、其氟化衍生物或药学上可接受的盐对预防或治疗流感病毒，特别是甲型流感病毒引起的感染具有很好的效果。
(2)对金色酰胺醇酯进行氟化改造使金色酰胺醇酯的生物活性更强。
(3)所提供的金色酰胺醇酯及其氟化衍生物的化学合成方法更加简便易行。
(4)金色酰胺醇酯及其氟化衍生物作用靶标既针对病毒，也针对宿主细胞，故不易产生耐药。
(5)金色酰胺醇酯及其氟化衍生物结构明确，化学性质稳定。
附图说明
图1为金色酰胺醇酯及其氟化衍生物对流感病毒A/PR8/3/4(H1N1)活化的NF-κB转录因子的抑制活性。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案，现列举以下实施例进行说明。需要指出的是，以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例中所用的原料、试剂或装置如无特殊说明，均可从常规商业途径得到，或者可以通过现有已知方法得到。
所有有机试剂均购自中国上海的九鼎化学。化合物表征过程中运行XWINNMR软件包的Bruker Ascend 600NMR光谱仪(1H NMR为600MHz，13C NMR为150MHz)用于NMR实验。在正离子或负离子模式下在质谱仪上采集高分辨率MS质谱图配备电喷雾离子源(ESI)的Agilent 6230精确质量飞行时间质谱仪。用硅胶60(200-300目，由Bio-Gene TechnologyLtd.Hong Kong公司提供)进行柱色谱法(CC)分离产物。以下室温指温度为5-40℃，过夜的时长为6-12小时。
实施例1：N-(N-苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1a)的制备
合成路线如下：
向Boc-L-氨基酸1(0.36g，1.36mmol)与L-苯丙氨醇2(0.21g，1.39mmol)的DCM(10mL)溶液中依次加入EDCI(0.29g，1.51mmol)、HOBT(0.20g，1.48mmol)和三乙胺(0.277mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到化合物3(0.41g，产率75％)，然后将化合物3溶于吡啶(10mL)，加入乙酸酐(144.4μL，1.52mmol)酯化，室温过夜，分离纯化后得到化合物4(0.43g，产率96％)，化合物4溶于DCM(9mL)中，加CF3COOH(1mL)除去Boc保护基并纯化得化合物5(0.27g，产率80％)，再将化合物5(0.17g，0.5mmol)溶于DCM(4mL)中，加入PhCOCl(60μL，0.5mmol)和三乙胺(144μL，1.0mmol)，室温搅拌过夜，萃取干燥后用石油醚和正己烷进行硅胶层析柱分离，得N-(N-苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1a)0.19g，产率87％，白色粉末。
化合物1a的核磁和质谱表征结果为：
(c＝0.620,MeOH(甲醇))；1H-NMR(600MHz,CDCl3)δ:7.72(2H,d,J＝7.77Hz),7.53(1H,t,J＝7.46Hz),7.44(2H,t,J＝7.81Hz),7.33-7.31(2H,m),7.29-7.28(2H,m),7.27-7.25(1H,m),7.21-7.19(2H,m),7.18-7.16(1H,m),7.07(2H,d,J＝8.1Hz),6.81(1H,J＝8.4Hz),6.02(1H,J＝8.4Hz),4.82-4.78(1H,m),4.40-4.35(1H,m),3.94(1H,dd,J＝11.3,4.9Hz),3.82(1H,dd,J＝11.3,4.2Hz),3.23(1H,dd,J＝13.7,5.91Hz,H-3b),3.07(1H,dd,J＝13.7,8.5Hz),2.82-2.74(2H,m),2.05(3H,s)；13C-NMR(150MHz,CDCl3)δ:170.8,170.3,167.1,136.7,136.6,133.6,132.0,129.3,129.1,128.8,128.7,128.6,127.2,127.1,126.8,64.6,55.0,49.4,38.4,37.4,20.8.TOF-ESI-MS:467.1810[M+Na]+(计算结果为C27H28N2O4:444.2049)。
实施例2：N-(N-苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2a)的制备
合成路线如下：
将化合物1a(100mg，0.22mmol)溶于无水THF(4mL)中，加入LiAlH4(9.2mg)回流2h，冷至室温，加入冰水淬灭反应，萃取干燥，浓缩分离得到酯水解产物N-(N-苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2a)74mg，产率82％，白色粉末。
化合物2a的核磁和质谱表征结果为：
(c＝0.44,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.49(1H,d,J＝8.4Hz),7.89(1H,d,J＝8.4Hz),7.78(2H,d,J＝7.77Hz),7.53(1H,t,J＝7.46Hz),7.45(2H,t,J＝7.81Hz),7.31-7.29(2H,m),7.24-7.22(2H,m),7.21-7.19(2H,m),7.18-7.16(1H,m),7.15-7.10(1H,m),4.86-4.83(1H,m),4.69-4.66(1H,m),3.91-3.87(1H,m),3.34-3.31(1H,m),3.29-3.25(1H,m),3.03(1H,dd,J＝11.3,4.9Hz),2.95(1H,dd,J＝11.3,4.2Hz),2.87(1H,dd,J＝13.7,5.91Hz),2.67(1H,dd,J＝13.7,8.5Hz).13C-NMR(150MHz,DMSO-d6)δ:171.4,166.6,139.4,138.8,134.5,131.8,129.65,129.63,128.7,128.53,128.49,127.8,126.7,126.4,62.7,55.3,52.9,37.7,36.9.TOF-ESI-MS:425.1732[M+Na]+(计算结果为C25H26N2O3:402.1943)。
实施例3:N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2b)的制备
合成路线如下：
将L-对氟苯丙胺酸7(0.55g，3.0mmol)溶于DCM(8mL)中，在冰浴下加入PhCOCl(0.48mL，4.0mmol)和三乙胺(0.86mL，6.0mmol)，室温继续搅拌5h，加入冰水淬灭反应，萃取干燥，浓缩分离得到产物8(0.73g，85％)，将产物8(0.29g，1.0mmol)溶于DCM(3mL)中，依次加入L-苯丙胺醇(0.15g，1.0mmol)，EDCI(0.23g，1.2mmol)，HOBT(0.16g，1.2mmol)和三乙胺(0.29mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2b)0.33g，产率78％，白色粉末。
化合物2b的核磁和质谱表征结果为：
(c＝0.30,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.70(2H,d,J＝7.77Hz),7.52(1H,t,J＝7.46Hz),7.41(2H,t,J＝7.81Hz),7.37-7.25(2H,m),7.22-7.19(2H,m),7.14-7.10(1H,m),7.05-7.02(2H,m),7.00(1H,d,J＝8.4Hz),6.92-6.89(2H,m),6.59(1H,d,J＝8.4Hz),4.82-4.79(1H,m),4.19-4.14(1H,m),3.67(1H,dd,J＝11.3,4.9Hz),3.50(1H,dd,J＝11.3,4.2Hz),3.07(1H,dd,J＝13.8,7.26Hz),3.02(1H,dd,J＝13.8,6.39Hz),2.77-2.71(2H,m).13C-NMR(150MHz,CDCl3)δ:171.1,167.6,162.8(d,J＝255Hz),137.5,133.4,132.1,132.0(d,J＝3.3Hz),130.9(d,J＝7.8Hz),129.2,128.7,128.6,127.1,126.8,115.5(d,J＝22.8Hz),63.8,55.3,53.0,37.7,36.9.TOF-ESI-MS:419.1917[M-H]-(计算结果为C25H25FN2O3:420.1849).
实施例4:N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1b)的制备
合成路线如下：
将化合物2b(0.21g，0.5mmol)溶于吡啶(3mL)中，加入乙酸酐(57μL，0.6mmol)，室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(1b)0.20g,产率88％，白色粉末。
化合物1b的核磁和质谱表征结果为：
(c＝1.14,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.52(1H,d,J＝8.4Hz),8.17(1H,d,J＝8.4Hz),7.72(2H,d,J＝7.77Hz),7.44(2H,t,J＝7.81Hz),7.35-7.33(2H,m),7.28-7.2-7.25(2H,m),7.25-7.24(1H,m),7.22-7.15(2H,m),7.07(2H,t,J＝8.9Hz),4.67-4.65(1H,m),4.20-4.15(1H,m),4.01(1H,dd,J＝11.3,4.9Hz),3.86(1H,dd,J＝11.3,4.2Hz),3.01(1H,dd,J＝13.7,5.91Hz),2.94(1H,dd,J＝13.7,8.5Hz),2.82-2.75(2H,m),1.98(3H,s).13C-NMR(150MHz,DMSO-d6)δ:171.5,170.8,166.5,162.2(d,J＝241.2Hz),138.4,134.9(d,J＝2.8Hz),134.4,131.8,131.4(d,J＝7.8Hz),129.6,128.70,128.67,127.9,126.7,115.3(d,J＝20.8Hz),65.1,55.3,49.6,36.99,36.85,21.1.TOF-ESI-MS:485.1705[M+Na]+(计算结果为C27H27FN2O4:462.1955)。
实施例5:N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1c)的制备
合成路线如下：
将化合物5(0.34g，1.0mmol)溶于DCM(3mL)中，在冰浴下加入L-对氟苯甲酰氯(127μL，1.1mmol)和三乙胺(0.86mL，6.0mmol)，室温继续搅拌5h，加入冰水淬灭反应，萃取干燥，浓缩分离得到N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1c)0.40g，产率87％，白色粉末。
化合物1c的核磁和质谱表征结果为：
(c＝0.66,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.57(1H,d,J＝8.4Hz),8.16(1H,d,J＝8.4Hz),7.87(2H,dd.J＝8.9,5.5Hz),7.32-7.29(2H,m),7.28-7.27(2H,m),7.26-7.25(2H,m),7.24-7.23(2H,m),7.23-7.21(2H,m),7.18-7.15(2H,m),4.69-4.65(1H,m),4.21-4.17(1H,m),4.02(1H,dd,J＝11.0,4.9Hz),3.86(1H,dd,J＝11.0,6.7Hz),3.02(1H,dd,J＝13.8,7.26Hz),2.97(1H,dd,J＝13.8,6.39Hz),2.83-2.76(2H,m),1.99(3H,s).13C-NMR(150MHz,DMSO-d6)δ:171.6,170.8,165.5,165.2(d,J＝248.6Hz),138.8,138.4,130.9,130.6(d,J＝8.2Hz),129.6,128.7,128.5,126.7(d,J＝2.2Hz),115.6(d,J＝21.6Hz),65.1,55.4,49.6,37.7,37.0,21.1.TOF-ESI-MS:485.1718[M+Na]+(计算结果为C27H27FN2O4:462.1955)。
实施例6:N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2c)的制备
合成路线如下：
将化合物1c(92mg，0.2mmol)溶于无水THF(4mL)中，加入LiAlH4(9.0mg)回流2h，冷至室温，加入冰水淬灭反应，萃取干燥，浓缩分离得到酯水解产物N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2c)68mg，产率81％，白色粉末。
化合物2c的核磁和质谱表征结果为：
(c＝1.62,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.56(1H,d,J＝8.4Hz),7.90(1H,d,J＝8.4Hz),7.87-7.86(2H,m),7.32-7.31(2H,m),7.31-7.27(2H,m),7.26-7.23(2H,m),7.22-7.21(2H,m),7.20-7.18(2H,m),7.17-7.12(2H,m),4.83(1H,t,J＝5.5Hz),4.69-4.65(1H,m),3.93-3.88(1H,m),3.35-3.31(1H,m),3.29-3.26(1H,m),3.05(1H,dd,J＝13.8,4.0Hz),2.96(1H,dd,J＝13.8,8.6Hz),2.88(1H,dd,J＝13.8,6.0Hz),2.68(1H,dd,J＝13.8,8.0Hz).13C-NMR(150MHz,DMSO-d6)δ:171.4,165.5,165.2(d,J＝249.3Hz),139.4,138.8,131.0(d,J＝2.6Hz),130.6(d,J＝7.8Hz),129.64,129.62,126.65,126.49,115.6(d,J＝21.2Hz),62.7,55.3,52.9,37.7,36.9.TOF-ESI-MS:443.1654[M+Na]+(计算结果为C25H25FN2O3:420.1849)。
实施例7:N-(N-苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1d)的制备
合成路线如下：
向Boc-L-氨基酸1(0.36g，1.36mmol)与L-对氟苯丙氨醇9(0.23g，1.38mmol)的DCM(10mL)溶液中依次加入EDCI(0.29g，1.51mmol)、HOBT(0.20g，1.48mmol)和三乙胺(0.277mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到化合物10(0.46g，产率81％)，将化合物10溶于吡啶(10mL)，加入乙酸酐(144.4μL，1.52mmol)酯化，室温过夜，分离纯化后得到化合物11(0.44g，86％)，将化合物11溶于DCM(9mL)中，加CF3COOH(1mL)除去Boc保护基并纯化得化合物12(0.27g，产率79％)，化合物12(0.18g，0.5mmol)溶于DCM(4mL)中，加入PhCOCl(60μL，0.5mmol)和三乙胺(144μL，1.0mmol)，室温搅拌过夜，萃取干燥后用石油醚和正己烷进行硅胶层析柱分离，得N-(N-苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1d)0.19g，产率84％，白色粉末。
化合物1d的核磁和质谱表征结果为：
(c＝0.75,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.70(2H,d,J＝7.77Hz),7.53(1H,t,J＝7.46Hz),7.44(2H,t,J＝7.81Hz),7.32-7.25(4H,m),7.06-7.04(2H,m),6.82(2H,t,J＝8.6Hz),6.78(1H,d,J＝8.4Hz),6.16(1H,d,J＝8.4Hz),4.81-4.77(1H,m),4.34-4.19(1H,m),3.93(1H,dd,J＝11.3,4.9Hz),3.82(1H,dd,J＝11.3,4.3Hz),3.21(1H,dd,J＝13.7,6.1Hz),3.08(1H,dd,J＝13.7,8.5Hz),2.71(2H,d,J＝7.2Hz),2.02(3H,s).13C-NMR(150MHz,CDCl3)δ:170.8,170.3,167.2,162.5(d,J＝245.2Hz),136.6,133.5,132.46(d,J＝3.2Hz),132.0,130.59(d,J＝7.8Hz),129.3,128.76,128.69,127.2,127.0,115.5(d,J＝20.8Hz),64.6,54.9,49.4,38.3,36.6,20.8.TOF-ESI-MS:485.1718[M+Na]+(计算结果为C27H27FN2O4:462.1955)。
实施例8:N-(N-苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2d)的制备
合成路线如下：
将化合物1d(92mg，0.20mmol)溶于无水THF(4mL)中，加入LiAlH4(9.0mg)回流2h，冷至室温，加入冰水淬灭反应，萃取干燥，浓缩分离得到酯水解产物N-(N-苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2d)67mg，产率80％，白色粉末。
化合物2d的核磁和质谱表征结果为：
(c＝0.89,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.56(1H,d,J＝8.4Hz),7.90(1H,d,J＝8.4Hz),7.80-7.79(2H,m),7.53(1H,t,J＝7.46Hz),7.47-7.44(2H,m),7.31(2H,d,J＝7.3Hz),7.26-7.24(2H,m),7.23-7.22(2H,m),7.17-7.15(1H,m),6.98-6.95(2H,m),4.83(1H,t,J＝5.5Hz),4.69-4.65(1H,m),3.90-3.85(1H,m),3.34-3.32(1H,m),3.30-3.26(1H,m),3.03(1H,dd,J＝11.3,4.9Hz),2.97(1H,dd,J＝11.3,4.2Hz),2.88(1H,dd,J＝13.7,5.91Hz),2.65(1H,dd,J＝13.7,8.5Hz).13C-NMR(150MHz,DMSO-d6)δ:171.4,166.5,162.0(d,J＝241.2Hz),138.8,135.5(d,J＝3.2Hz),134.5,131.8,131.4(d,J＝7.6Hz),129.6,128.65,128.49,127.9 126.7,115.2(d,J＝20.6Hz),62.7,55.3,52.9,37.6,36.0.TOF-ESI-MS:443.1620(M-H)(计算结果为C25H25FN2O3:420.1849)。
实施例9:N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2e)的制备
合成路线如下：
将化合物7(0.68g，2.0mmol)溶于DCM(5mL)中，在冰浴下加入L-对氟苯甲酰氯(254μL，2.2mmol)和三乙胺(0.86mL，6.0mmol)，室温继续搅拌5h，加入冰水淬灭反应，萃取干燥，浓缩分离得到产物13(0.49g，80％)，将化合物13(0.31g，1.0mmol)溶于DCM(3mL)中，依次加入L-苯丙胺醇(0.15g，1.0mmol)，EDCI(0.23g，1.2mmol)，HOBT(0.16g，1.2mmol)和三乙胺(0.29mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇(化合物编号为2e)0.31g，产率70％，白色粉末。
化合物2e的核磁和质谱表征结果为：
(c＝0.67,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.54(1H,d,J＝8.4Hz),7.90(1H,d,J＝8.4Hz),7.87-7.85(2H,m),7.34-7.31(2H,m),7.30-7.28(2H,m),7.25-7.24(1H,m),7.22-7.20(2H,m),7.19-7.17(2H,m),7.14-7.12(1H,m),7.07-7.05(2H,m),4.83(1H,t,J＝5.5Hz),4.67-4.63(1H,m),3.92-3.87(1H,m),3.34-3.31(1H,m),3.29-3.26(1H,m),3.03(1H,dd,J＝13.7,5.91Hz),2.94(1H,dd,J＝13.7,8.5Hz),2.87(1H,dd,J＝13.7,5.6Hz),2.68(1H,dd,J＝13.7,8.0Hz).13C-NMR(150MHz,DMSO-d6)δ:171.3,166.3,165.2(d,J＝252.9Hz),162.2(d,J＝252.9Hz),139.4,131.4(d,J＝8.9Hz),130.9(d,J＝2.2Hz),130.5(d,J＝8.9Hz),129.6,129.5,128.7,128.5,126.7,115.6(d,J＝22.8Hz),115.2(d,J＝22.8Hz),62.6,55.4,53.0,38.4,36.8.TOF-ESI-MS:461.1528[M+Na]+(计算结果为C25H24F2N2O4:438.1755)。
实施例10:N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1e)的制备
合成路线如下：
将化合物2e(0.22g，0.5mmol)溶于吡啶(3mL)中，加入乙酸酐(57μL，0.6mmol)，室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-苯基丙氨醇乙酸酯(化合物编号为1e)0.19g，产率79％，白色粉末。
化合物1e的核磁和质谱表征结果为：
(c＝1.77,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.58(1H,d,J＝8.4Hz),8.18(1H,d,J＝8.4Hz),7.89-7.86(2H,m),7.35-7.32(2H,m),7.30-7.28(2H,m),7.27-7.26(1H,m),7.23-7.22(4H,m),7.19-7.15(1H,m),7.09-7.06(2H,m),4.66-4.62(2H,m),4.42-4.35(1H,m),4.18-4.15(1H,m),4.01(1H,dd,J＝11.3,4.9Hz),3.86(1H,dd,J＝11.3,4.2Hz),2.98-2.87(2H,m),2.80-2.77(2H,m),1.99(3H,s).13C-NMR(150MHz,DMSO-d6)δ:171.5,170.8,165.6,165.2(d,J＝252.9Hz),162.2(d,J＝252.9Hz),138.4,131.4(d,J＝8.9Hz),130.89(d,J＝2.2Hz),130.6(d,J＝8.9Hz),129.6,129.5,128.7,126.7,115.6(d,J＝22.8Hz),115.2(d,J＝22.8Hz),64.6,55.4,49.6,38.4,36.8,21.1.TOF-ESI-MS:503.1611[M+Na]+(计算结果为C27H26F2N2O4:480.1861)。
实施例11:N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2f)的制备
合成路线如下：
将化合物8(0.29g，1.0mmol)溶于DCM(3mL)中，依次加入L-对氟苯丙胺醇(0.17g，1.0mmol)，EDCI(0.23g，1.2mmol)、HOBT(0.16g，1.2mmol)和三乙胺(0.29mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2f)0.32g，产率73％，白色粉末。
化合物2f的核磁和质谱表征结果为：
(c＝0.72,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.72(2H,d,J＝7.77Hz),7.57(1H,t,J＝7.46Hz),7.48(2H,t,J＝7.81Hz),7.25-7.23(2H,m),7.11-7.08(2H,m),7.01(2H,t,J＝15.7Hz),6.86(2H,t,J＝15.8Hz),6.73(1H,d,J＝8.4Hz),6.17(1H,d,J＝8.4Hz),4.79-4.75(1H,m),4.13-4.11(1H,m),4.05(1H,dd,J＝11.5,4.1Hz),3.21(1H,dd,J＝13.8,6.1Hz),3.13(1H,dd,J＝13.9,8.2Hz),2.83(1H,dd,J＝13.8,7.1Hz),2.74(1H,dd,J＝14.0,7.5Hz).13C-NMR(150MHz,CDCl3)δ:170.7,167.3,161.2(d,J＝252.9Hz),160.8(d,J＝252.9Hz),133.3,132.95(d,J＝4.0Hz),132.25(d,J＝3.2Hz),132.15,130.9(d,J＝8.9Hz),130.6(d,J＝8.9Hz),128.8,127.0,115.7(d,J＝22.8Hz),115.4(d,J＝22.8Hz),63.6,55.1,52.8,37.4,36.1TOF-ESI-MS:461.1518[M+Na]+(计算结果为C25H24F2N2O4:438.1755)。
实施例12:N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1f)的制备
合成路线如下：
将化合物2f(0.22g，0.5mmol)溶于吡啶(3mL)中，加入乙酸酐(57μL，0.6mmol)，室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得N-(N-苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1f)0.20g，产率84％，白色粉末。
化合物1f的核磁和质谱表征结果为：
(c＝0.54,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.72(2H,d,J＝7.77Hz),7.53(1H,t,J＝7.46Hz),7.44(2H,t,J＝7.81Hz),7.14-7.10(4H,m),7.00-6.96(4H,m),6.83(1H,d,J＝8.4Hz),6.44(1H,d,J＝8.4Hz),4.81(1H,dd,J＝14.2,7.3Hz),4.34-4.31(1H,m),4.04(1H,dd,J＝11.5,4.1Hz),3.97(1H,dd,J＝11.5,5.2Hz),3.11(2H,d,J＝13.8,4.7Hz),2.78(1H,dd,J＝13.9,6.9Hz),2.68(1H,dd,J＝13.9,7.6Hz),1.98(3H,s).13C-NMR(150MHz,CDCl3)δ:171.0,170.3,167.2,162.8(d,J＝252.9Hz,),161.1(d,J＝252.9Hz),133.5,132.6(d,J＝3.0Hz),132.1(d,J＝2.6Hz),130.9(d,J＝8.9Hz),130.7(d,J＝8.9Hz),128.7,127.0,115.61(d,J＝22.8Hz),115.47(d,J＝22.8Hz),64.3,54.8,50.0,37.4,36.5,20.7.TOF-ESI-MS:503.1628[M+Na]+(计算结果为C27H26F2N2O4:480.1861)。
实施例13:N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1g)的制备
合成路线如下：
将化合物12(0.36g，1.0mmol)溶于DCM(3mL)中，在冰浴下加入对氟苯甲酰氯(127μL,1.1mmol)和三乙胺(0.86mL，6.0mmol)，室温继续搅拌5h，加入冰水淬灭反应，萃取干燥，浓缩分离得N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1g)0.41g，产率85％，白色粉末。
化合物1g的核磁和质谱表征结果为：
(c＝0.98,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.75-7.73(2H,m),7.33-7.30(2H,m),7.27-7.26(3H,m),7.14(2H,t,J＝8.6Hz),7.07-7.04(2H,m),6.87(2H,t,J＝8.9Hz),6.77(1H,d,J＝7.5Hz),6.04(1H,d,J＝8.4Hz),4.79-4.75(1H,m),4.36-4.31(1H,m),3.95(1H,dd,J＝11.3,4.9Hz),3.83(1H,dd,J＝11.3,4.2Hz),3.23(1H,dd,J＝13.7,5.9Hz),3.08(1H,dd,J＝13.7,8.5Hz),2.74(2H,d,J＝7.2Hz),2.05(3H,s).13C-NMR(150MHz,CDCl3)δ:170.8,170.3,166.1,165.8(d,J＝252.9Hz),162.5(d,J＝252.9Hz),136.5,132.4(d,J＝3.3Hz),130.6(d,J＝8.9Hz),129.8(d,J＝3.3Hz),129.4(d,J＝8.9Hz),129.3,128.8,127.2,115.8(d,J＝22.8Hz),115.5(d,J＝22.8Hz),64.5,55.0,49.5,38.4,36.6,20.8.TOF-ESI-MS:503.1636[M+Na]+(计算结果为C27H26F2N2O4:480.1861)。
实施例14:N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2g)的制备
合成路线如下：
将化合物1g(96mg，0.20mmol)溶于无水THF(4mL)中，加入LiAlH4(9.0mg)回流2h，冷至室温，加入冰水淬灭反应，萃取干燥，浓缩分离得到酯水解产物N-(N-对氟苯甲酰基-L-苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2g)64mg，产率73％，白色粉末。
化合物2g的核磁和质谱表征结果为：
(c＝0.72,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.56(1H,d,J＝8.4Hz),7.90(1H,d,J＝8.4Hz),7.88-7.85(2H,m),7.32-7.31(2H,m),7.30-7.28(3H,m),7.26-7.22(4H,m),7.17-7.15(1H,m),6.98-6.95(2H,m),4.83(1H,t,J＝5.5Hz),4.68-4.64(1H,m),3.90-3.86(1H,m),3.34-3.31(1H,m),3.29-3.25(1H,m),3.02(1H,dd,J＝13.8,4.6Hz),2.94(1H,dd,J＝13.7,4.9Hz),2.87(1H,dd,J＝13.7,5.3Hz),2.65(1H,dd,J＝13.7,8.5Hz).13C-NMR(150MHz,DMSO-d6)δ:171.4,165.5,165.2(d,J＝252.9Hz),162.0(d,J＝252.9Hz),138.8,135.5,131.4(d,J＝8.9Hz),130.9,130.6(d,J＝8.9Hz),129.6,128.5,126.7,115.7(d,J＝22.8Hz),115.2(d,J＝22.8Hz),62.7,55.3,52.9,37.6,36.0.TOF-ESI-MS:461.1525[M+Na]+(计算结果为C25H24F2N2O4:438.1755)。
实施例15:N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2h)的制备
合成路线如下：
将化合物13(0.31g，1.0mmol)溶于DCM(5mL)中，依次加入L-对氟苯丙胺醇(0.17g，1.0mmol)，EDCI(0.23g，1.2mmol)，HOBT(0.16g，1.2mmol)和三乙胺(0.29mL，2.0mmol)，将反应混合物在室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得到N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇(化合物编号为2h)0.36g，产率80％，白色粉末。
化合物2h的核磁和质谱表征结果为：
(c＝0.21,MeOH)；1H-NMR(600MHz,DMSO-d6)δ:8.55(1H,d,J＝8.4Hz),7.91(1H,d,J＝8.4Hz),7.88-7.86(2H,m),7.35-7.32(2H,m),7.31-7.28(2H,m),7.24-7.22(2H,m),7.07(2H,m),6.97(2H,m),4.84-4.82(1H,m),4.66-4.61(1H,m),3.90-3.86(1H,m),3.31-3.25(1H,m),3.01(1H,dd,J＝13.8,4.7Hz),2.92(1H,dd,J＝13.7,8.5Hz),2.88(1H,dd,J＝13.8,4.7Hz),2.65(1H,dd,J＝13.8,4.7Hz).13C-NMR(150MHz,DMSO-d6)δ:171.2,165.5,165.2(d,J＝252.9Hz),162.1(d,J＝252.9Hz),162.0(d,J＝252.9Hz),135.5(d,J＝2.8Hz),134.9(d,J＝2.8Hz),131.44(d,J＝8.9Hz),131.40(d,J＝8.9Hz),130.9(d,J＝2.8Hz),130.5(d,J＝8.9Hz),115.7(d,J＝22.8Hz),115.3(d,J＝22.8Hz),115.2(d,J＝22.8Hz),62.7,55.3,52.9,36.8,36.0.TOF-ESI-MS:479.1419[M+Na]+(计算结果为C25H23F3N2O4:456.1661)。
实施例16:N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1h)的制备
合成路线如下：
将化合物2h(0.23g，0.5mmol)溶于吡啶(3mL)中，加入乙酸酐(57μL，0.6mmol)，室温搅拌过夜，反应后用乙酸乙酯萃取，干燥，柱层析分离得N-(N-对氟苯甲酰基-L-对氟苯基丙氨酰基)-L-对氟苯基丙氨醇乙酸酯(化合物编号为1h)0.21g，产率86％，白色粉末。
化合物1h的核磁和质谱表征结果为：
(c＝0.32,MeOH)；1H-NMR(600MHz,CDCl3)δ:7.75-7.73(2H,m),7.23-7.21(2H,m),7.17-7.14(2H,m),7.08-7.06(2H,m),7.01-6.97(2H,m),6.71(1H,d,J＝7.8Hz),6.10(1H,d,J＝8.4Hz),4.75-4.72(1H,m),4.38-4.32(1H,m),4.00(1H,dd,J＝13.8,5.0Hz),3.92(1H,dd,J＝13.8,4.2Hz),3.18(1H,dd,J＝13.8,4.7Hz),3.10(1H,dd,J＝13.7,8.5Hz),2.76(2H,d,J＝7.2Hz),2.07(3H,s).13C-NMR(150MHz,CDCl3)δ:170.8,170.1,166.0,165.9(d,J＝252.9Hz),162.8(d,J＝252.9Hz),162.5(d,J＝252.9Hz),132.3(d,J＝2.8Hz),),132.2(d,J＝2.8Hz),130.8(d,J＝8.9Hz),130.6(d,J＝8.9Hz),129.6(d,J＝2.8Hz),129.4(d,J＝8.9Hz),115.9(d,J＝22.8Hz),115.7(d,J＝22.8Hz),115.5(d,J＝22.8Hz),64.6,55.0,49.6,37.5,36.6,20.7TOF-ESI-MS:521.1525[M+Na]+(计算结果为C27H25F3N2O4:498.1766)。
产品效果测试
1.金色酰胺醇酯及其氟化衍生物的抗病毒活性测试
1.1.材料：细胞和病毒
MDCK细胞购自ATCC(美国典型培养物保藏中心)，流感病毒A/PR/8/34(H1N1)来源于ATCC，于9日龄鸡胚中扩增保存；
1.2.金色酰胺醇酯及其氟化衍生物对流感病毒A/PR/8/34(H1N1)的抑制作用
1)96孔板单层MDCK细胞用PBS(磷酸缓冲盐溶液)洗1次；
2)加入100个TCID50病毒液，100μL/孔，37℃孵育2小时；
3)弃去病毒孵育液，药物干预组加入用含终浓度1.5μg/mL的TPCK胰酶的病毒培养液倍比梯度稀释的芥酸(1000μg/mL、500μg/mL、250μg/mL、125μg/mL、62.5μg/mL、31.25μg/mL、15.625μg/mL)。37℃培养48小时后观察结果；
4)观察标准如下表1。
表1：病毒引起的细胞病变(CPE)6级标准
5)CPE法的IC50公式
CPE的药效抑制率＝1-平均每孔病变范围(％)
CPE距离比＝(>50％抑制率-50％)/(>50％抑制率-<50％抑制率)
CPE法的IC50＝小于50％抑制率的药物浓度X2距离比
结果如表2所示。
表2：金色酰胺醇酯及其氟化衍生物抑制流感病毒A/PR/8/34(H1N1)引起的细胞病变的结果
备注：SI为selective index，选择性指数，细胞毒性CC50与IC50的比值，细胞毒性越小，CC50数值就越大，SI值也就越大，抗病毒的选择性就越高。
从表2可以看出金色酰胺醇酯及其氟化衍生物均能有效抑制流感病毒A/PR/8/34(H1N1)引起的细胞病变。
2.金色酰胺醇酯及其氟化衍生物对流感病毒A/PR8/3/4(H1N1)活化的NF-κB转录因子的抑制活性的效果测试
2.1.材料：细胞
稳转了NF-κB-Luciferase的HEK293细胞由关注过后呼吸健康研究院李楚芳研究员馈赠，保存于本实验室。
2.2.金色酰胺醇酯及其氟化衍生物对流感病毒A/PR8/3/4(H1N1)活化的NF-κB转录因子的抑制活性
1)将具有稳定转染的NF-κB荧光素酶报告基因质粒的HEK293细胞以5x 106/孔的浓度接种到96孔板中。
2)长满单层的HEK293细胞弃去原培养基，加入PBS洗涤两次；
3)用20ng/mL TNF-α(肿瘤坏死因子α)刺激细胞24小时，同时在药物干预组加入不同浓度(浓度分别为100μmol/L、50μmol/L、25μmol/L、12.5μmol/L)的金色酰胺醇酯及其氟化衍生物。
4)去除上清液后，按照说明书使用Luciferase Assay System(荧光酶素检测系统)，Promega检测试剂，全波长荧光酶标仪测定萤光素酶活性，从而得出NF-κB的活性，检测的结果如图1所示。
图1为金色酰胺醇酯及其氟化衍生物对流感病毒A/PR8/3/4(H1N1)活化的NF-κB转录因子的抑制活性。图1中的纵坐标“Luciferase Activity”表示荧光酶素的活性，图1中的100、50、25、12.5对应的是不同金色酰胺醇酯及其氟化衍生物(对应的化合物编号为1a、2a、1b、2b、1c、2c、1d、2d、1e、2e、1f、2f、1g、2g、1h、2h)的不同浓度。从图1可以看出，金色酰胺醇酯及其氟化衍生物能抑制TNF-α刺激的NF-κB活化，并表现出一定的浓度依赖关系。“-”以及“+”分别表示未加入和加入TNF-α。
Claims (10)
1.通式如下所示的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐：
其中，R1表示OH、CH2OH或OCOCH3；
R2、R3和R4分別独立表示H、烷基或F。
2.根据权利要求1所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐，其特征在于，所述烷基为碳数为1-5的烷基；优选的，所述烷基为CH3；所述R2、R3和R4中至少有一个为F。
3.根据权利要求1所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐，其特征在于，所述药学上可接受的盐包括无机酸盐和有机酸盐；所述无机酸盐包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐；所述有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐。
4.根据权利要求1所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐，其特征在于，所述金色酰胺醇酯、金色酰胺醇酯氟化衍生物的结构式如下任意一种：
结构式为：
编号为1a；
结构式为：
编号为2a；
结构式为：
编号为1b；
结构式为：
编号为2b；
结构式为：
编号为1c；
结构式为：
编号为2c；
结构式为：
编号为1d；
结构式为：
编号为2d；
结构式为：
编号为1e；
结构式为：
编号为2e；
结构式为：
编号为1f；
结构式为：
编号为2f；
结构式为：
编号为1g；
结构式为：
编号为2g；
结构式为：
编号为1h；
结构式为：
编号为2h。
5.权利要求1-4中任一项所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐的制备方法，其特征在于，包括以下步骤：
将结构式(III)所示的化合物与酸酐类物质进行酯化，形成酯，然后去掉酯中的Boc保护基，再加入结构式(IV)所示的物质和偶联剂进行反应，即可；
其中，R2、R3和R4分別独立表示H、烷基或F；Boc表示叔丁氧羰基；
或
将氨基酸、结构式(IV)所示的物质和偶联剂进行反应，得到的产物再与氨基醇类物质和偶联剂进行反应，即可。
6.一种药物，其特征在于，所述药物含权利要求1-4中任一项所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐，以及辅料。
7.根据权利要求6所述的药物，其特征在于，所述药物的剂型为任意剂型；优选的，所述药物的剂型为片剂、胶囊剂、颗粒剂、滴丸剂、注射剂或凝胶剂中的一种。
8.权利要求1-4中任一项所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐在制备预防或治疗抗流感病毒的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述流感病毒为甲型流感病毒。
10.权利要求1-4中任一项所述的金色酰胺醇酯、金色酰胺醇酯氟化衍生物或金色酰胺醇酯及其氟化衍生物药学上可接受的盐在制备抑制甲型流感病毒复制和/或甲型流感病毒诱导的转录因子NF-κB的活化的药物中的应用。
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| KR20160045980A (ko) * | 2014-10-17 | 2016-04-28 | 한국해양과학기술원 | 아렌시아미드 아세테이트를 유효성분으로 함유하는 퇴행성 신경질환 예방 및 치료용 조성물 |
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| US11377418B2 (en) | 2022-07-05 |
| CN112500308B (zh) | 2023-10-03 |
| AU2020103878A4 (en) | 2021-02-11 |
| US20220127220A1 (en) | 2022-04-28 |
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