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CN102875474A - 用于抗变异流感病毒的新型环烷胺类化合物 - Google Patents

用于抗变异流感病毒的新型环烷胺类化合物 Download PDF

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CN102875474A
CN102875474A CN2012104086888A CN201210408688A CN102875474A CN 102875474 A CN102875474 A CN 102875474A CN 2012104086888 A CN2012104086888 A CN 2012104086888A CN 201210408688 A CN201210408688 A CN 201210408688A CN 102875474 A CN102875474 A CN 102875474A
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胡文辉
赵昕
曾少高
崔巍
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Guangzhou Institute of Biomedicine and Health of CAS
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Priority to PCT/CN2013/085596 priority patent/WO2014063597A1/zh
Priority to CN201310499915.7A priority patent/CN103772288B/zh
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Abstract

本发明公开了一种具有式Ⅰ结构的用于抗变异流感病毒的环烷胺类化合物，其中，n独立选自0，1；R1选自氢原子、烷基、环烷基、杂环烷基、芳基、咪唑基、杂芳基、芳烷基、杂芳烷基、芳并杂环基；R2、R3独立选自氢原子、烷基、环烷基、杂环烷基、脒基、胍基、胍脒基、咪唑基、2-噻吩、3-噻吩、呋喃、酰基、芳基、杂芳基、芳烷基、杂芳烷基、芳并杂环基、芳硫基、芳硫基烷基。该化合物通过阻断M2离子通道进而抑制病毒的复制，从而抑制细胞病变的发生和细胞死亡。

Description

用于抗变异流感病毒的新型环烷胺类化合物
技术领域
本发明属于药物化学领域，特别是涉及一种用于抗变异流感病毒的新型环烷胺类化合物。
背景技术
流行性感冒(以下简称流感)是一种严重危害人类健康的急性呼吸道传染病，由流感病毒引发，具有高患病率、流行广泛、传播迅速的特点。历史上曾发生过多次世界范围的流感大流行，其中以1918年的西班牙流感流行最为严重，有2000多万人被流感夺去了生命。2009年，由墨西哥爆发的“猪流感”目前正严重威胁全球人类的生命，给人类生命及社会经济带来极大的损失。
目前预防和治疗流感的主要手段是M2离子通道蛋白抑制剂、神经氨酸酶抑制剂和流感疫苗(John Beigel,Mike Bray.Antiviral Research.2008,78,91–102)，研究中的抗流感病毒手段有反义寡核苷酸、核酶和脱氧核酶抑制流感病毒复制或RNA表达等(Christopher F.Basler.Infectious Disorders-DrugTargets.2007,7,282-293)。目前临床上只有两类抗流感病毒药物可供选择(Erik De Clercq.Nat Rev Drug Dis cov.2006,5(12):1015-25)：M2离子通道蛋白抑制剂，包括金刚烷胺(Amantadine)和金刚乙胺(rimantadine)；和神经氨酸苷酶抑制剂，包括奥司他韦(oseltamivir)和扎那米韦(zanamivir)。
M2抑制剂类药物以流感病毒基质蛋白M2为作用靶点，通过阻断质子通道来抑制流感病毒的复制(Lawrence H.Pinto,and Robert A.Lamb.J Biol Chem.2006,281(14):8997-9000)，抑制病毒的脱壳和核酸释放，从而起到抑制病毒复制和繁殖的作用，进而达到抗流感病毒的目的。目前市面上仅有的两个药物都是金刚烷胺衍生物，其中，金刚烷胺在1966年被FDA批准在美国上市（束梅英,等.中国医药情报,2000,6,6:39-40），用于治疗A型流感病毒性感染。金刚乙胺由Roche公司研发，1987年被批准上市，金刚乙胺口服制剂的药效比金刚烷胺强4～6倍。这两个药物的主要优点是价格低廉、口服生物利用度高，可以明显减轻A型流感的症状，且金刚乙胺在儿童中的耐受性较好。
但是，该类药物存在以下明显缺点（Schnell JR,Chou JJ.Nature.2008，451(7178):591-5）：（1）对B型流感病毒无效；（2）存在明显副作用,引起明显的胃肠道不良反应；产生中枢神经毒副作用，主要表现为失眠、注意力分散和神经质；（3）治疗过程中易产生耐药株。尽管从这两个单一骨架的药物上市至今已过去了几十年，但并没有任何新型结构的药物出现，研究中的药物绝大部分抑制剂仍以金刚烷作为骨架，因此急需寻找新型结构的抑制剂。本发明首次鉴定出一个新型的抑制剂，研发出新型的抗变异流感病毒的苗头化合物，为解决部分上述的缺点提供了可能。
发明内容
基于此，本发明的目的是提供一种用于抗变异流感病毒的环烷胺类化合物。
具体的技术方案如下：
具有式Ⅰ结构的用于抗变异流感病毒的环烷胺类化合物：
Figure BDA00002294466700021
其中，n独立选自0，1；
R1选自氢原子、烷基、环烷基、杂环烷基、芳基、咪唑基、杂芳基、芳烷基、杂芳烷基、芳并杂环基；
R2、R3独立选自氢原子、烷基、环烷基、杂环烷基、脒基、胍基、胍脒基、咪唑基、2-噻吩、3-噻吩、呋喃、酰基、芳基、杂芳基、芳烷基、杂芳烷基、芳并杂环基、芳硫基、芳硫基烷基。
在其中一些实施例中，该化合物具有如下通式结构：
其中，X、Y分别独立选自C、N、S、O；X、Y可同时为N，不可同时为S、O；R4、R5、R6独立选自甲基、三氟甲基、乙基、丙基、异丙基、环丙基、叔丁基、芳基、杂环芳基、芳烷基、金刚烷基；Y为S、O时，R6不存在。
在其中一些实施例中，所述环烷胺类化合物为：(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-环丙基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-1H-4-吡唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2乙基-5-甲基--1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-呋喃基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-呋喃基)甲基)二环[3.1.1]庚烷-3-胺。
本发明的另一目的是提供上述环烷胺类化合物在制备预防和治疗抗变异流感病毒药物中的应用。
具体的技术方案如下：
上述用于抗变异流感病毒的环烷胺类化合物或其药学上可接受的盐在制备预防和治疗抗变异流感病毒药物中的应用。
本发明的另一目的是提供一种用于预防和治疗抗变异流感病毒的药物组合物。
具体的技术方案如下：
一种用于预防和治疗抗变异流感病毒的药物组合物，包括上述用于抗变异流感病毒的环烷胺类化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
本发明所述的通式I结构的环烷胺类化合物，或其药学上可接受的盐，可以按如下步骤合成：
Figure BDA00002294466700041
1）制备中使用的原料、试剂来自供应商alfa、sigma、aldrich等试剂公司。
2）氨基取代化合物的合成：
蒎胺9（(1R,2R,3R,5S)-(-)-蒎胺）与不同的醛类化合物在NaBH(OAc)3的作用下进行还原氨化反应，最后成盐得到化合物盐酸盐。
生物学研究：
借助于实施例12的方法可以测定通式I化合物对M2离子通道蛋白及流感病毒的抑制活性。测试的基本原理是（Sidwell RW.Antiviral Research,2000;48:1–16）：流感病毒感染MDCK细胞可以引起病变，并导致细胞的死亡。化合物通过阻断M2离子通道进而抑制病毒的复制，从而抑制细胞病变的发生和细胞死亡。通过CCK-8试剂测定细胞的活力可以反映化合物阻断M2离子通道的活性及其抗流感病毒活性。
通式Ｉ的化合物可以作为药物组合物中的活性成分，制成药学上可接受的载体材料或稀释剂混合，作为单元剂给药。适当的单元剂包括：口服剂型、注射剂型、直肠剂型等，每日的剂量依赖于疾病的严重性、用药方式和化合物本身。
具体实施方式
本发明所述的式I化合物，术语中“烷基”是指C1-C8烷基，包括直链或支链烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基等；“环烷基”是指C3-C8环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基；“杂环烷基”是指含有一个或者多个选自N、O、S等杂原子作为环原子的饱和环烃基，如四氢吡咯基、四氢呋喃基、哌嗪基、吗啡啉基等；“胺基”包括甲胺基、乙胺基、丙胺基、二甲胺基、二乙胺基等；“酰胺基”包括甲酰胺基、乙酰胺基、丙酰胺基、丁酰胺基等；“芳基”是指碳环芳烃，如苯基、萘基、蒽基或菲基等；“杂芳基”是指含有一个或者多个选自N、O、S等杂原子作为环原子的芳基，如吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基等；“芳并杂环基”是指碳环芳烃（主要指苯环芳烃）并上含有一个或者多个选自N、O、S等杂原子作为环原子的饱和或不饱和杂环基，如吲哚基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、苯并咪唑、苯并吡咯啉等；“杂芳并杂环基”主要指嘧啶和咪唑或吡嗪的并环，如嘌呤、蝶啶等。
所述药学上可接受的盐。合适的酸的例子有盐酸、氢溴酸、硫酸、硝酸、过氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯酸磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、苯磺酸或萘磺酸等。从适当的碱得到的盐包括碱金属如钠或钾、碱土金属如镁或钙、铵等得到的盐。
下面通过制备例和实施例对本发明作进一步说明。这些实施例仅用于说明本发明，但不以任何方式限制本发明，在本发明的构思前提下对本发明的简单改进都属于本发明要求保护的范围。除非另有说明，本发明中的百分数是重量分数。
实施例1：化合物1-10的通用合成步骤：
在CH3OH(20mL)中溶解(1R,2R,3R,5S)-(-)-蒎胺(1g,6.5mmol)之后，加入醛或酮(1.5equiv.,9.8mmol)，反应液在室温下搅拌1h，随后加入NaBH(OAc)3(5.5g,26mmol)，滴加1滴醋酸后，搅拌反应10h。然后加入饱和碳酸氢钠溶液淬灭反应，用二氯甲烷(3x20ml)萃取，有机相合并之后用饱和食盐水洗涤两次，无水硫酸钠干燥。通过柱色谱分离得到的油状物用HCl/CH3OH(20mL)处理后，蒸干得到的固体用乙醚(3x20mL)洗涤得到目标化合物。
实施例2：(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺(化合物1)
Figure BDA00002294466700061
1HNMR(400MHz,DMSO-d6)δ0.92(s,3H),1.17(d,3H,J=7.2Hz),1.19(s,3H),1.45(d,2H,J=9.6Hz),1.78(s,1H),1.95(s,2H),2.02–2.07(m,1H),2.19–2.27(m,2H),2.34(s,1H),2.38(s,3H),3.53(s,1H),4.28(s,2H),9.08(s,1H),9.54(s,1H),10.10(s,1H),14.90(br,2H);13CNMR(125MHz,DMSO-d6)δ9.13,20.75,23.26,27.23,30.55,31.72,37.13,38.38,40.00,40.28,46.97,55.96,119.91,129.79,133.16;HRMS:calculated for C15H25N3(M+H+):248.38,found:248.2121。
实施例3：(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-环丙基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺(化合物2)
Figure BDA00002294466700062
1HNMR(400MHz,DMSO-d6)δ0.92(s,3H),1.01(d,2H,J=8.8Hz),1.12(s,3H,J=7.2),1.17–1.20(m,6H),1.75–1.81(m,2H),1.90–1.97(m,2H),2.00–2.07(m,3H),3.53(s,1H),4.36(s,2H),8.27(br,1H),9.03(d,1H,J=8),9.57(br,1H),10.13(br,1H),14.66(br,1H);ESI-MS:calculated for C17H27N3(M+H+):274.42,found:274.3。
实施例4：(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-1H-4-吡唑基)甲基)二环[3.1.1]庚烷-3-胺(化合物3)
Figure BDA00002294466700063
1HNMR(400MHz,DMSO-d6)δ0.90(s,3H),1.12(d,3H,J=7.2Hz),1.20(s,3H),1.48(d,1H,J=9.6Hz),1.76–1.79(m,1H),1.95–2.01(m,2H),2.15–2.18(m,1H),2.22–2.33(m,1H),2.35–2.38(m,4H),3.37(s,1H),4.00(s,2H),8.00(s,1H);13CNMR(125MHz,DMSO-d6)δ9.82,20.68,23.20,27.26,30.86,31.75,38.11,38.41,40.33,47.00,54.90,108.78,136.43,142.39,145.37;ES I-MS:calculated for C15H25N3(M+H+):248.38,found:248.2。
实施例5：(1R,2R,3R,5S)-2,6,6-三甲基-N-((2乙基-5-甲基--1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺(化合物4)
Figure BDA00002294466700071
1HNMR(400MHz,DMSO-d6)δ0.92(s,3H),1.17(d,3H,J=7.2Hz),1.19(s,3H),1.34(t,3H),1.45(d,1H,J=9.6Hz),1.80–1.96(m,1H),2.01–2.07(m,2H),2.20–2.40(m,3H),2.34(s,3H),2.88–2.94(m,2H),8.26(br,1H),9.47(br,1H),9.99(br,1H),14.64(br,1H);13CNMR(125MHz,DMSO-d6)δ9.05,11.04,18.84,20.74,23.24,27.39,30.60,31.75,37.28,38.14,40.37,41.31,46.85,55.91,118.97,128.92,147.27;ESI-MS:calculated for C17H29N3(M+H+):276.43,found:276.2。
实施例6：(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-噻吩基)甲基)二环[3.1.1]庚烷-3-胺(化合物5)
Figure BDA00002294466700072
1HNMR(400MHz,DMSO-d6)δ0.83(s,3H),1.08(d,3H,J=7.2Hz),1.19(s,3H),1.44(d,1H,J=9.6Hz),1.76-1.79(m,1H),1.94-2.03(m,2H),2.16-2.33(m,3H),3.19-3.23(m,1H),4.13-4.21(m,2H),7.45–7.46(m,1H),7.60–7.62(m,1H),7.83–7.84(m,1H);13CNMR(125MHz,DMSO-d6)δ20.61,23.18,27.25,30.60,31.78,38.41,40.00,40.29,42.66,47.00,54.68,126.87,127.07,128.97,132.54;ESI-MS:calculatedfor C15H23NS(M+H+):250.41,found:250.1。
实施例7：(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺(化合物6)
Figure BDA00002294466700081
1HNMR(400MHz,DMSO-d6)δ0.84(s,3H),1.08(d,3H,J=7.2Hz),1.09(s,3H),1.39(d,1H,J=9.6Hz),1.77–1.79(m,1H),1.95–2.02(m,2H),2.13–2.17(m,1H),2.25–2.32(m,2H),3.28–3.29(m,1H),4.37–4.40(m,2H),7.10–7.12(m,1H),7.43–7.44(m,1H),7.63–7.65(m,1H);ESI-MS:calculated for C15H23NS(M+H+):250.41,found:250.1。
实施例8：(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺(化合物7)
1HNMR(400MHz,DMSO-d6)δ0.85(s,3H),1.07(d,3H,J=7.2Hz),1.19(s,3H),1.38(d,1H,J=9.6Hz),1.77–1.79(m,1H),1.94–1.99(m,2H),2.12–2.15(m,1H),2.24–2.34(m,2H),2.45(s,3H),3.28(s,1H),4.29–4.30(m,2H),6.77–6.79(m,1H),7.18–7.19(m,1H);13CNMR(125MHz,DMSO-d6)δ14.93,20.51,23.17,27.22,30.59,31.85,38.36,40.29,42.32,46.96,54.37,125.52,130.29,130.92,130.92,141.60;ESI-MS:calculated for C16H25NS(M+H+):264.44,found:265.1。
实施例9：(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺(化合物8)
Figure BDA00002294466700091
1HNMR(400MHz,DMSO-d6)δ0.90(s,3H),1.11(d,3H,J=7.2Hz),1.20(s,3H),1.39(d,1H,J=9.6Hz),1.78–1.80(m,1H),1.96–2.00(m,2H),2.12–2.16(m,1H),2.20–2.40(m,2H),2.35(s,3H),3.44(s,1H),4.29–4.32(m,2H),6.94–6.96(m,1H),7.56–7.57(m,1H);13CNMR(125MHz,DMSO-d6)δ13.62,20.47,22.97,27.14,30.64,31.65,38.25,40.32,40.62,47.01,55.21,126.35,126.52,129.88,138.91;ESI-MS:calculated for C16H25NS(M+H+):264.44,found:265.1。
实施例10：(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-呋喃基)甲基)二环[3.1.1]庚烷-3-胺(化合物9)
Figure BDA00002294466700092
1HNMR(400MHz,DMSO-d6)δ0.87(s,3H),1.08(d,3H,J=7.2Hz),1.19(s,3H),1.40(d,1H,J=9.6Hz),1.77–1.79(m,1H),1.92–1.96(m,2H),2.11–2.15(m,1H),2.24–2.34(m,2H),3.26(s,1H),4.23(m,2H),6.53–6.54(m,1H),6.72–6.73(m,1H),7.78–7.79(m,1H);13CNMR(125MHz,DMSO-d6)δ20.40,22.93,27.09,30.43,31.68,38.17,40.45,46.98,42.66,55.06,110.84,112.07,143.76,145.74。
实施例11：(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-呋喃基)甲基)二环[3.1.1]庚烷-3-胺(化合物10)
Figure BDA00002294466700093
13CNMR(125MHz,DMSO-d6)δ20.58,23.18,27.23,30.57,31.80,38.37,40.00,40.27,46.98,54.39,111.55,116.27,143.28,143.81。
实施例12:流感病毒抑制实验
实验材料：
流感病毒：A/WSN/33(H1N1,金刚烷胺耐药株)，细胞：MDCK传代细胞。标准化合物：金刚烷胺，Sigma Aldrich。细胞培养：10%FBS，DMEM，在37°C，5%CO2下培养。其他试剂：TPCK胰酶（Sigma Aldrich），Hanks缓冲液，7.5%BSA（Invitogen），CCK-8（Donjindo，Japan）。
试验方法：
1.取状态良好的MDCK细胞按每孔2×104接种96孔板，37°C，5%CO2孵育24小时，准备两块96孔板，一块板A/WS/33(H1N1,金刚烷胺耐药株)，一块板A/Hong Kong/8/68(H3N2,金刚烷胺敏感株)。
2.化合物的准备：化合物以100mmol/L溶于DMSO保存。化合物用DMEM稀释，从2mmol/L的浓度开始5倍比稀释至1.28×10-4mmol/L，各取50μl/孔化合物加入96孔板细胞中，每个浓度6个复孔。
3.在细胞长满单层的96孔板中，吸去培养上清用50μl/孔Hanks缓冲液洗细胞2次。加入含待测化合物的培养基，孵育1h。
4.病毒感染：保存病毒按100倍TCID50稀释于DMEM培养基（含1μg/mlTPCK，0.6%BSA）。每块板用一种病毒，6个复孔中三个加病毒，三个不加病毒，加感染培养基（DMEM含1μg/ml TPCK，0.6%BSA），作为化合物毒性实验孔。每孔加50μl/孔。
5.72h后加入CCK-8试剂5μl/孔（详细操作见说明书），3h后测OD450。
6.数据分析：数据用GraphPad Prism软件分析，计算化合物抑制病毒的IC50值。结果见下表。
表1：化合物对变异流感病毒的抑制作用
Figure BDA00002294466700101
Figure BDA00002294466700111
Figure BDA00002294466700121
7、抗变异流感病毒的化合物构效分析：
上表中化合物共同特征为环烷胺骨架连接胍类或芳香类药效团，如连接苯环和胍类，化合物对变异流感病毒无明显活性。将药效团换为实施例2-5所示的咪唑类基团，对变异流感病毒可产生抑制活性。将药效团更换为实施例6、7中的噻吩基，可大幅度提高活性，在噻吩环上加入取代基，如甲基等（实施例8、9）可进一步提高活性。将噻吩环换成呋喃（实施例10、11），活性有所减弱。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (5)

1.具有式Ⅰ结构的用于抗变异流感病毒的环烷胺类化合物：
Figure FDA00002294466600011
其中，n独立选自0，1；
R1选自氢原子、烷基、环烷基、杂环烷基、芳基、咪唑基、杂芳基、芳烷基、杂芳烷基、芳并杂环基；
R2、R3独立选自氢原子、烷基、环烷基、杂环烷基、脒基、胍基、胍脒基、咪唑基、2-噻吩、3-噻吩、呋喃、酰基、芳基、杂芳基、芳烷基、杂芳烷基、芳并杂环基、芳硫基、芳硫基烷基。
2.根据权利要求1所述的用于抗变异流感病毒的环烷胺类化合物，其特征在于，该化合物具有如下通式结构：
Figure FDA00002294466600012
其中，X、Y分别独立选自C、N、S、O；X、Y可同时为N，不可同时为S、O；R4、R5、R6独立选自甲基、三氟甲基、乙基、丙基、异丙基、环丙基、叔丁基、芳基、杂环芳基、芳烷基、金刚烷基；Y为S、O时，R6不存在。
3.根据权利要求1所述的用于抗变异流感病毒的环烷胺类化合物，其特征在于，所述环烷胺类化合物为：(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-环丙基-1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-1H-4-吡唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2乙基-5-甲基--1H-4-咪唑基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((5-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-甲基-2-噻吩基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((2-呋喃基)甲基)二环[3.1.1]庚烷-3-胺、(1R,2R,3R,5S)-2,6,6-三甲基-N-((3-呋喃基)甲基)二环[3.1.1]庚烷-3-胺。
4.权利要求1-3任一项所述的用于抗变异流感病毒的环烷胺类化合物或其药学上可接受的盐在制备预防和治疗抗变异流感病毒药物中的应用。
5.一种用于预防和治疗抗变异流感病毒的药物组合物，其特征在于，包括权利要求1-3任一项所述的用于抗变异流感病毒的环烷胺类化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
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US20160310448A1 (en) * 2015-04-21 2016-10-27 Commissariat A L'energie Atomique Et Aux Energies Alternatives Adamantane or Pinene Derivatives for Use in the Treatment of Chlamydiales Infections
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