CN114853670B - 含有酰胺基团的喹啉类化合物及其制备与应用 - Google Patents
含有酰胺基团的喹啉类化合物及其制备与应用 Download PDFInfo
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- CN114853670B CN114853670B CN202210561962.9A CN202210561962A CN114853670B CN 114853670 B CN114853670 B CN 114853670B CN 202210561962 A CN202210561962 A CN 202210561962A CN 114853670 B CN114853670 B CN 114853670B
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- methoxyphenoxy
- benzamide
- ethyl
- amino
- compound
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Abstract
本发明的含有酰胺基团的喹啉类化合物及其制备与应用,属于医药技术领域。具体为结构通式如下(I)所述的含有酰胺基团的喹啉类化合物、其前体药物和药物活性代谢物和药学上可接受的盐,其中R如权利要求书和说明书中所述,相应的含有酰胺基团的喹啉类化合物以及该类化合物药学上适用的酸和药学上可接受的盐可以与现有药物合并或单独使用作为流感病毒抑制剂,用于治疗流感,尤其是对各种A型流感具有较好的疗效。
Description
技术领域
本发明属于医药技术领域,具体涉及一种含有酰胺基团的喹啉类化合物及其制备与应用,具体作为抗流感病毒药物应用。
背景技术
流感病毒属于正黏病毒科(orthomyxoviridae family)流感病毒属,是一种单链的RNA病毒。流感病毒可引起人、禽、猪、马、蝙蝠等多种动物感染和发病。根据流感病毒表面基质蛋白(matrix protein,MP)和核蛋白(nucleoprotein,NP)抗原性的不同,可以将其分为A、B、C和D四型。甲型流感病毒抗原性易发生变异,多次引起世界性大流行。例如1918~1919年的大流行中,全世界至少有2000万~4000万人死于流感。甲型流感病毒于1933年分离成功。甲型流感病毒高变异性的特点使得人们应对流行性感冒的难度加大。
流感病毒RNA聚合酶是病毒RNA复制、转录和翻译所必须的。RNA聚合酶由聚合酶酸性蛋白(polymerase acid protein A,PA)、聚合酶碱性蛋白1(polymerase basic protein1,PB1)和聚合酶碱性蛋白2(polymerase basic protein 2,PB2)三个蛋白亚基组成。PA蛋白亚基发挥激酶或解旋酶的作用;PB1蛋白亚基负责识别和切割宿主mRNA5’端帽子结构引物;PB2蛋白亚基负责催化新合成RNA链的延伸反应。PA,PB1和PB2三者相互结合发挥功能,在流感病毒的转录复制过程中发挥着重要作用(PORTELA A,Digard P.The influenzavirus nucleoprotein:a multifunctional RNA-binding protein pivotal to virusreplication.Journal of General Virology,2002,83(4):723-734)。研究表明,RNA聚合酶具有高度保守性,选择性作用于RNA聚合酶的抗病毒药物不容易对人体产生毒副反应。因此,作用于RNA聚合酶上的流感病毒抑制剂具有重要的研究意义。
计算机辅助药物设计是目前研究和开发药物的重要手段。以流感病毒RNA聚合酶(PDB ID:3CM8)(HE X,ZHOU J,BARTLAM M,et al.Crystal structure of the polymerasePAC–PB1Ncomplex from an avian influenza H5N1 virus.Nature,2008,454(7208),1123–1126.)为靶点,利用Schrodinger的Gild板块对实验室的化合物数据库进行虚拟筛选。化合物4-[(喹啉-4-基)氨基]苯甲酸与3CM8的对接得分为-5.574kcal/mol,其结构中的苯环可以与TRP706形成π-π堆积相互作用,苯甲酸中的氧原子与LYS643形成盐桥相互作用(图1)。通过细胞保护实验验证,4-[(喹啉-4-基)氨基]苯甲酸具有温和的抗流感病毒能力(EC50=22.94μM)。之后,运用生物电子等排原理和局部修饰策略,设计了一系列含有酰胺基团的喹啉类化合物。经Schrodinger的Gild板块分子对接虚拟筛选发现,含有2-甲氧基苯氧基基团的[(喹啉-4-基)氨基]苯甲酰胺类化合物均与3CM8具很好的结合作用。由N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与3CM8的分子对接结果可以看出,两个苯环分别与PHE658和TRP706形成π-π堆积相互作用,与喹啉环4位连接的氨基(-NH)与ILE621形成氢键相互作用苯甲酰基中的氧原子和甲氧基中的氧原子均与LYS643形成氢键相互作用。N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺和3CM8的关键相互作用相较于4-[(喹啉-4-基)氨基]苯甲酸和3CM8的关键相互作用明显增多,其对接得分也明显提高(-7.370kcal/mol)。4-[(喹啉-4-基)氨基]苯甲酸与RNA聚合酶(PDB ID:3CM8)的2D分子对接图如图1A所示,4-[(喹啉-4-基)氨基]苯甲酸与RNA聚合酶(PDB ID:3CM8)的3D分子对接图如图1B所示;N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNA聚合酶(PDB ID:3CM8)的2D分子对接图如图2A所示,N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNA聚合酶(PDB ID:3CM8)的3D分子对接图如图2B所示。
因此,设计合成了11个含有酰胺基团的喹啉类化合物,并对其进行生物活性研究。新型的RNA聚合酶抑制剂是开发新型流感病毒抑制剂研究的重要方向。
发明内容
本发明所解决的技术问题是,提供一种含有酰胺基团的喹啉类化合物及其制备与应用,具体为结构式如式I所示的含有酰胺基团的喹啉类化合物、其前体药物和药物活性代谢物以及该化合物的立体异构体及其药学上可接受的盐,并提供了其在制备治疗与流感相关的疾病的药物中的应用。
结构式如式I所示的含有酰胺基团的喹啉类化合物、其前体药物和药物活性代谢物以及该化合物的立体异构体及其药学上可接受的盐:
其中,R独立地选自氢,C1-C8烷基,C1-C8烷氧基,卤素,硝基;
进一步,R可以独立地选自氢,甲基,三氟甲基,三氟甲氧基,氯,溴,硝基。
更进一步地,所述含有酰胺基团的喹啉类化合物为如下化合物中的任一个:
N-[2-(2-甲氧基苯氧基)乙基]-4-[(喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-氯喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-溴喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-硝基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺。
本发明还提供一种药物组合物,包含式I所示含有2-甲氧基苯氧基基团的[(喹啉-4-基)氨基]苯甲酰胺类化合物和药学上可接受的载体或稀释剂。
该药物组合物用于制备治疗流感病毒疾病的药物。例如采用盐水的水溶液作为载体,pH值为7.4,则该药物组合物以溶液形式通过局部推注而被引入到患者的血流中。
本发明的化合物可以单独给予或依据常规的制药习惯与药学上可接受的载体或稀释剂等辅剂联合,以药物组合物的形式给予。给药途径包括经口服给予或经非胃肠道包括静脉内、肌肉内、腹膜内、皮下、直肠和局部途径给予。
对于口服给药途径,除片剂或胶囊的形式,还可以采用水溶液或混悬液的形式给予。通过口服给药时,活性药物成分与可口服,无毒,药学上可接受的惰性载体组合形成药物组合物,对片剂或胶囊形式的口服给药来说,载体包括乳糖,淀粉,蔗糖,葡萄糖,甲基纤维素,硬脂酸镁,磷酸二钙,硫酸钙,甘露醇,山梨醇;对液体形式的口服给药来说,载体包括乙醇,甘油,水及其组合。此外,还可以在药物组合物中加入药学上可接受的的粘合剂,润滑剂,崩解剂和着色剂。粘合剂包括淀粉,明胶,天然糖,如葡萄糖或乳糖,玉米甜味剂,天然和合成的树胶如阿拉伯胶,西黄蓍胶或海藻酸钠,羧甲基纤维素,聚乙二醇,蜡。润滑剂包括油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,醋酸钠,氯化钠。当水性混悬液口服使用时,将活性成分与乳化剂和混悬剂组合。也可加入甜味剂或矫味剂。对肌内,腹膜内,皮下和静脉内使用来说,通常制备成活性成分的无菌溶液,溶液的pH值应该作适当的调节和缓冲。对静脉内使用来说,应当控制溶质的总浓度以使制剂维持等渗。
本发明的含有酰胺基团的喹啉类化合物还可与已知的可用于治疗或预防流感的药剂组合使用。优选的组合包括本发明化合物和M2离子通道蛋白抑制剂、本发明化合物和神经氨酸酶抑制剂、本发明化合物和干扰素诱导剂、本发明化合物和反义寡核苷酸、以及本发明化合物和肌苷单磷酸脱氢酶抑制剂。
有关本发明的术语“给予”及其变体(例如:“给予”化合物)的意思是:将含有酰胺基团的喹啉类化合物或该化合物的前药引入需要治疗的动物系统中。当含有酰胺基团的喹啉类化合物或其前药与一种或多种其他活性剂组合提供时,“给予”及其变体都可以被理解为包括同时和相继引入含有酰胺基团的喹啉类化合物或其前药以及其他药剂。通常,所述前药是含有酰胺基团的喹啉类化合物的官能衍生物,其在体内易于转变为所需的化合物。在本发明中,术语“给予”将包含用具体公开的含有酰胺基团的喹啉类化合物或可能未被具体公开的化合物,但是其能在给予患者后于体内转化为特定的化合物。
当本发明的化合物被给予人类受试中,日剂量将通常由处方医师确定,剂量一般根据患者个体的年龄、体重和反应以及患者症状的严重程度而变化。在一个示例性应用中,将适宜量的化合物给予接受治疗的哺乳动物。当用于所指示的作用时,本发明的口服剂量将为约0.01mg每kg体重每天(mg/kg/天)到约100mg/kg/天,优选0.01mg/kg/天到10mg/kg/天,最优选0.1mg/kg/天到5.0mg/kg/天。对口服给药来说,组合物优选以片剂的形式被提供,其中片剂包含0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100和500mg的活性成分,优选1mg到100mg活性成分。对于静脉注射,在恒速输注期间,最优选的剂量为0.1mg/kg/min到10mg/kg/min。本发明的化合物或包含该化合物的药物组合物可以以每日一次的剂量给予,或者是可以将每日总剂量分为每日两次、三次或四次的剂量给予。对于经皮给药系统的形式进行的给药来说,剂量给药在整个给药方案中当然将是连续的而不是间断的。
使用本发明化合物的剂量方案将根据多种因素进行选择,包括患者的类型,种属,年龄,体重,性别和医学状况;受治状况的严重程度;给药途径;患者的肾和肝功能;以及所用的特定化合物或其盐。普通技术医师,兽医或临床医师可容易地确定和开具需要预防、抗击或阻止状况发展的有效药量。
在本发明的方法中,在此详细描述的化合物能形成活性成分,并根据给药形式即口服片剂,胶囊,酏剂,糖浆剂等而与适当选择的适宜的药学稀释剂,赋形剂或载体(在此统称为“载体”物质)混合,并符合常规的药学习惯。
本发明化合物的药学上可接受的盐类指保留了式I化合物的生物效力和性质,并与合适的非毒性有机酸或无机酸或有机碱或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、磷酸盐、硫酸盐、高氯酸盐、硫氰酸盐、硫酸氢盐、过硫酸盐、硼酸盐、甲酸盐、乙酸盐、丙酸盐、戊酸盐、新戊酸盐、己酸盐、庚酸盐、辛酸盐、异辛酸盐、十一烷酸盐、月桂酸盐、棕榈酸盐、硬脂酸盐、油酸盐、环丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、己二酸盐、壬二酸盐、丙烯酸盐、草莓盐、巴豆酸盐、惕格酸盐、衣康酸盐、山梨酸盐、肉桂酸盐、乙醇酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、亚酒石酸盐、扁桃酸盐、二苯乙醇酸盐、托品酸盐、抗坏血酸盐、葡萄糖酸盐、葡庚糖酸盐、葡萄糖二酸盐、甘露糖酸盐、乳糖酸盐、苯甲酸盐、酞酸盐、对酞酸盐、糠酸盐、烟酸盐、异烟酸盐、水杨酸盐、乙酰水杨酸盐、酪酸盐、没食子酸盐、咖啡酸盐、阿魏酸盐、苦味酸盐、樟脑酸盐、樟脑磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐、对甲苯磺酸盐、对氨基苯磺酸盐、氨基磺酸盐、牛磺酸盐、2-羟基乙磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、色氨酸盐、酪氨酸盐、天冬氨酸盐、天冬酰胺盐、谷氨酸盐、赖氨酸盐、谷氨酰胺盐、甲硫氨酸盐、丝氨酸盐、苏氨酸盐、半胱氨酸盐、脯氨酸盐、组氨酸盐、精氨酸盐、依地酸盐、丙酮酸盐、α-酮戊二酸盐、藻酸盐、环戊烷丙酸盐、3-苯基丙酸盐、3-环己基丙酸、2-萘甲酸盐、2-萘磺酸盐、双羟萘酸盐、月桂基硫酸盐、甘油磷酸盐、月桂基硫酸盐、果胶脂酸盐等。碱加成盐包括铵盐,碱金属盐,例如钠和钾盐,碱土金属盐,例如钙和镁盐,有机碱的盐,例如二环己胺盐,N-甲基-D-葡糖胺盐等,而且,碱性含氮基团可以用这样的试剂季铵化,例如低级烷基卤化物,如甲基、乙基、丙基和丁基的氯、溴和碘化物;硫酸二烷基酯,如硫酸二甲酯、二乙酯、二丁酯和二戊酯;长链卤化物,如癸基、月桂基、肉豆蔻基和硬脂酰基的氯、溴和碘化物;芳烷基卤化物,如苄基和苯乙基的溴化物等。
本发明还提供通式I所示含有酰胺基团的喹啉类化合物的制备方法,包括以下步骤:
其中,R独立地选自氢,C1-C8烷基,C1-C8烷氧基,卤素,硝基。
进一步,R可以独立地选自氢,甲基,三氟甲基,三氟甲氧基,氯,溴,硝基。
本发明的有益效果:
本发明提供的化合物用于抑制流感病毒,是一类作用于NP蛋白和RNA聚合酶的新型流感病毒抑制剂。与现已上市的作用于其他靶点的抗流感病毒药物相比,作用在NP蛋白和RNA聚合酶的流感病毒抑制剂具有稳定性。这类流感病毒抑制剂化合物对流感具有广泛的治疗作用。本发明所述化合物制备方法简单,收率稳定,制备的化合物能较好地治疗流感相关的疾病。
附图说明
图1为背景技术中4-[(喹啉-4-基)氨基]苯甲酸与RNA聚合酶(PDB ID:3CM8)的分子对接图;其中,图1A为4-[(喹啉-4-基)氨基]苯甲酸与RNA聚合酶(PDB ID:3CM8)的2D分子对接图,图1B为4-[(喹啉-4-基)氨基]苯甲酸与RNA聚合酶(PDB ID:3CM8)的3D分子对接图;
图2为背景技术中N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNA聚合酶(PDB ID:3CM8)的分子对接图,其中,图2A为N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNA聚合酶(PDB ID:3CM8)的2D分子对接图(A),图2B为N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNA聚合酶(PDB ID:3CM8)的3D分子对接图(B)。
具体实施方式
以下述实施例详细叙述本发明技术方案。但是,应当明白,本发明不限于具体叙述的下述实例。
实施例1:N-[2-(2-甲氧基苯氧基)乙基]-4-[(喹啉-4-基)氨基]苯甲酰胺(化合物ZD01)的制备
步骤A:2-[(苯基氨基)亚甲基]丙二酸二乙酯的制备
于100mL的茄形瓶中加入苯胺0.93g(0.01mol)、乙氧基亚甲基丙二酸二乙酯2.16g(0.01mol),分别于30℃、50℃、70℃、75℃反应1h、1.5h、1.5h、2h。反应停止后,将茄形瓶中的液体冷却至有固体析出,抽滤,得到2-[(苯基氨基)亚甲基]丙二酸二乙酯白色固体2.26g,收率为85.80%;m.p.:50.2–52.1℃。(文献(AYYANGAR N R,LAHOTI R J,DANIEL T.Aconvenient synthesis of ethylα-arbethoxy-β-(arylamino)acrylates and relatedcompounds.Organic Preparations and Procedures International,1982,14(5):327-331.)值:50℃)。
步骤B:4-羟基喹啉-3-羧酸乙酯的制备
于250mL的三颈瓶中加入2-[(苯基氨基)亚甲基]丙二酸二乙酯5.27g(0.02mol)、二苯醚20mL,回流反应40min,静置析出固体。用20mL石油醚搅拌,抽滤,得到4-羟基喹啉-3-羧酸乙酯白色固体3.95g,收率为91.02%;m.p.:270.1–272.3℃。(文献(LAGER E,ANDERSSON P,NILSSON J,et al.4-quinolone derivatives:high-affinity ligands atthe benzodiazepine site of brain GABA A receptors.synthesis,pharmacology,andpharmacophore modeling.J.Med.Chem,2006,49:2526-2533.)值:270–272℃)。
步骤C:4-羟基喹啉-3-羧酸的制备
于250mL的茄形瓶中加入4-羟基喹啉-3-羧酸乙酯6.52g(0.03mol),氢氧化钠12.00g(0.3mol),5滴无水乙醇以及100mL蒸馏水,回流直至反应完全。静置冷却,用3mol/L的盐酸调pH值至2-3,析出大量白色固体,抽滤,得到4-羟基喹啉-3-羧酸白色固体5.06g,收率为89.24%;m.p.:269.5–270.7℃。(文献(SCHOFIELD K,SIMPSON J C E.Thepreparation of quinoline derivatives from aromatic amines and ethylethoxymethylenemalonate.Journal of the Chemical Society(Resumed),1946:1033-1035.)值:269–270℃)。
步骤D:4-羟基喹啉的制备
于250mL的三颈瓶中加入4-羟基喹啉-3-羧酸5.68g(0.03mol)和30mL二苯醚,设定加热温度为260℃。25min之后,停止反应,向反应瓶中加入30mL石油醚,搅拌10min,抽滤,得到4-羟基喹啉棕黄色固体4.13g,收率为94.76%;m.p.:214.3–215.5℃。(文献(RIEGEL B,LAPPIN G R,ADELSON B H,et al.The synthesis of some 4-quinolinols and 4-chloroquinolines by the ethoxymethylenemalonic ester method.Journal of theAmerican Chemical Society,1946,68(7):1264-1266.)值:214℃)。
步骤E:4-氯喹啉的制备
于100mL的茄形瓶中加入4-羟基喹啉1.45g(0.01mol),三氯氧磷4.60g(0.03mol),加热至105℃反应3h,之后抽真空条件下蒸除剩余的三氯氧磷,得到黑色油状物。向反应瓶中加入饱和碳酸氢钠溶液,边加入边搅拌,抽滤,用蒸馏水洗涤一次滤饼,得黑色固体。经柱层析分离[V(乙酸乙酯):V(石油醚)=1:10]得到4-氯喹啉白色固体3.15g,收率为64.28%;m.p.:34.5–35.8℃。(文献(HAUSER C R,REYNOLDS G A.Relative ease of cyclization of 2-,3-,and 4-aminopyridine derivatives.synthesis of naphthyridines.The Journal ofOrganic Chemistry,1950,15(6):1224-1232.)值:34–35℃)。
步骤F:4-[(喹啉-4-基)氨基]苯甲酸的制备
于100mL茄形瓶中依次加入4-氯喹啉4.64g(0.02mol),10mL无水乙醇,3.62g 4-氨基苯甲酸(0.024mol),再滴加15滴浓盐酸,回流反应2h。反应结束向茄形瓶中再加入饱和碳酸氢钠溶液,直至析出固体,此时反应液为碱性,抽滤,蒸馏水洗涤三次滤饼,得到4-[(喹啉-4-基)氨基]苯甲酸白色固体,收率76.81%;m.p.:228.1–229.4℃;HRMS(ESI):265.09561([M+H]+);1H NMR(400MHz,DMSO-d6)δ14.96(s,1H),11.18(s,1H),8.89(d,J=8.5Hz,1H),8.60(d,J=6.9Hz,1H),8.16–8.04(m,4H),7.86–7.82(m,1H),7.66(d,J=8.4Hz,2H),7.06(d,J=6.9Hz,1H)。
步骤G:N-[2-(2-甲氧基苯氧基)乙基]-4-[(喹啉-4-基)氨基]苯甲酰胺(化合物ZD01)的制备
向100mL茄形瓶中,依次加入4-[(喹啉-4-基)氨基]苯甲酸0.53g(0.002mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,EDCI)0.41g(0.0025mol),1-羟基苯并三唑(1-Hydroxybenzotriazole,HOBt)0.34g(0.0025mol),三乙胺0.40g(0.004mol)以及20mL N,N-二甲基甲酰胺,室温搅拌1h后,加入含有0.0015mol甲胺的甲胺甲醇溶液与15mL N,N-二甲基甲酰胺的混合溶液,室温搅拌12h,停止反应。将反应液缓慢滴入150mL饱和碳酸氢钠溶液中,搅拌下有大量固体析出,抽滤,滤饼以蒸馏水洗涤三次,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为33.52%;m.p.:319.5–320.2℃;HRMS(ESI):414.17886([M+H]+),436.16083([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.62–8.59(m,1H),8.55(d,J=5.2Hz,1H),8.36(d,J=8.3Hz,1H),7.93–7.89(m,3H),7.75–7.70(m,1H),7.58–7.54(m,1H),7.42(d,J=8.7Hz,2H),7.16(d,J=5.2Hz,1H),7.03(dd,J1=7.3Hz,J2=2.2Hz,1H),6.97(dd,J1=7.6Hz,J2=2.1Hz,1H),6.93–6.86(m,2H),4.10(t,J=6.1Hz,2H),3.75(s,3H),3.65–3.60(m,2H);13C NMR(101MHz,DMSO-d6)δ166.46,151.20,149.71,149.52,148.43,146.87,144.44,129.86,129.74,129.10,128.66,125.42,122.73,121.76,121.27,120.83,120.26,114.41,112.94,103.99,67.40,56.00,39.44。
实施例2:N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-氯喹啉-4-基)氨基]苯甲酰胺(化合物ZD02)的制备
参考实施例1的制备方法,以4-氯苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-氯喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为33.85%;m.p.:247.7–248.4℃;HRMS(ESI):448.13965([M+H]+),470.12170([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),6.64–8.61(m,1H),8.56(d,J=5.3Hz,1H),8.52–8.51(m,1H),7.94–7.91(m,3H),7.74(dd,J1=9.0Hz,J2=2.3Hz,1H),7.43(d,J=8.4Hz,2H),7.18(d,J=5.3Hz,1H),7.04(dd,J1=7.4Hz,J2=2.2Hz,1H),6.98(dd,J1=7.6Hz,J2=2.1Hz,1H),6.94–6.86(m,2H),4.11(t,J=6.1Hz,2H),3.75(s,3H),3.65–3.61(m,2H);13C NMR(101MHz,DMSO-d6)δ166.42,151.69,149.73,148.45,148.01,146.41,143.96,131.88,130.32,130.08,129.14,129.07,121.91,121.77,121.50,121.27,120.52,114.45,112.97,104.28,67.42,56.01,39.47。
实施例3:N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺(化合物ZD03)的制备
参考实施例1的制备方法,以4-溴苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺黄色固体,收率为35.88%;m.p.:240.5–241.3℃;HRMS(ESI):492.08942([M+H]+),514.07074([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.66(s,1H),8.64–8.61(m,1H),8.57(d,J=5.3Hz,1H),8.92(d,J=8.7Hz,2H),7.85(s,2H),7.43(d,J=8.5Hz,2H),7.18(d,J=5.3Hz,1H),7.04(dd,J1=7.4Hz,J2=2.2Hz,1H),6.98(dd,J1=7.6Hz,J2=2.1Hz,1H),6.94–6.86(m,2H),4.11(t,J=6.1Hz,2H),3.75(s,3H),3.65–3.61(m,2H);13C NMR(101MHz,DMSO-d6)δ166.42,151.70,149.72,148.43,148.10,146.36,143.94,132.93,131.90,129.14,129.10,125.11,122.02,121.77,121.26,120.56,118.55,114.42,112.94,104.25,67.40,56.00,39.46。
实施例4:N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-三氟甲基喹啉-4-基)氨基]苯甲酰胺(化合物ZD04)的制备
参考实施例1的制备方法,以4-三氟甲基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为53.59%;m.p.:225.3–227.3℃;HRMS(ESI):482.16592([M+H]+),504.14728([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.89(s,1H),8.67–8.64(m,2H),8.08(d,J=8.8Hz,1H),7.96(dd,J1=8.9Hz,J2=2.3Hz,3H),7.46(d,J=8.6Hz,2H),7.20(d,J=5.4Hz,1H),7.04(dd,J1=7.3Hz,J2=2.2Hz,1H),6.98(dd,J1=7.5Hz,J2=2.1Hz,1H),6.94–6.86(m,2H),4.12(t,J=6.0Hz,2H),3.76(s,3H),3.67–3.63(m,2H);13C NMR(101MHz,DMSO-d6)δ166.41,153.47,150.72,149.69,148.42,143.82,131.13,129.49,126.33,125.54,123.62,121.75,119.80,114.37,112.90,104.23,67.37,55.97,39.47。
实施例5:N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-甲基喹啉-4-基)氨基]苯甲酰胺(化合物ZD05)的制备
参考实施例1的制备方法,以3-甲基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为53.81%;m.p.:209.6–210.6℃;HRMS(ESI):428.19495([M+H]+),450.17685([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.59(d,J=5.5Hz,1H),8.50(d,J=5.2Hz,1H),8.25(d,J=8.6Hz,1H),7.90(d,J=8.7Hz,2H),7.70(s,1H),7.41(d,J=8.6Hz,3H),7.10(d,J=5.2Hz,1H),7.03(dd,J1=7.4Hz,J2=2.2Hz,1H),6.97(dd,J1=7.6Hz,J2=2.1Hz,1H),6.93–6.85(m,2H),4.10(t,J=6.1Hz,2H),3.75(s,3H),3.65–3.60(m,2H),2.50(s,3H);13C NMR(101MHz,DMSO-d6)δ166.47,151.16,149.80,149.70,148.43,146.66,144.54,139.55,129.09,128.77,128.48,127.42,122.54,121.75,121.26,120.07,118.79,114.39,112.92,103.53,67.39,55.99,39.44,21.62。
实施例6:N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(化合物ZD06)的制备
参考实施例1的制备方法,以3-三氟甲基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为43.03%;m.p.:1997.6–199.4℃;HRMS(ESI):482.16843([M+H]+),504.14996([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.67–8.62(m,3H),8.23(s,1H),7.95(d,J=8.2Hz,2H),7.84(d,J=8.8Hz,1H),7.46(d,J=8.2Hz,2H),7.26–7.24(m,1H),7.03(s,1H),6.97(d,J=7.6Hz,1H),6.93–6.86(m,2H),4.12(t,J=6.1Hz,2H),3.76(s,3H),3.65–3.64(m,2H);13CNMR(101MHz,DMSO-d6)δ166.37,152.86,149.68,148.41,147.28,129.15,124.99,121.73,121.23,120.89,120.46,114.37,112.90,105.01,67.37,55.96;IR:(KBr,cm-1)υ3309.99,1626.49,1583.30,1528.38,1505.80,1432.59,1376.22,1323.49,1253.86,1160.85,1120.34,1075.22,919.71,897.68,865.56,823.68,736.99,682.62,593.58,495.55,479.98。
实施例7:N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺(化合物ZD07)的制备
参考实施例1的制备方法,以3-三氟甲氧基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为36.52%;m.p.:229.5–230.7℃;HRMS(ESI):498.16077([M+H]+),520.14301([M+Na]+);1HNMR(400MHz,DMSO-d6)δ9.36(s,1H),8.64–8.61(m,1H),8.58(d,J=5.3Hz,1H),8.53(d,J=9.3Hz,1H),7.94–7.91(m,2H),7.79(d,J=1.3Hz,1H),7.57(dd,J1=9.0Hz,J2=2.6Hz,1H),7.45–7.41(m,2H),7.16(d,J=5.3Hz,1H),7.03(dd,J1=7.4Hz,J2=2.2Hz,1H),6.97(dd,J1=7.6Hz,J2=2.1Hz,1H),6.94–6.86(m,2H),4.11(t,J=6.1Hz,2H),3.75(s,3H),3.65–3.61(m,2H);13C NMR(101MHz,DMSO-d6)δ165.35,151.74,148.23,148.21,147.37,146.41,143.00,128.09,124.72,120.70,120.20,119.78,118.48,117.72,113.34,111.87,111.84,102.95,66.33,54.93,38.40。
实施例8:N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-硝基喹啉-4-基)氨基]苯甲酰胺(化合物ZD08)的制备
参考实施例1的制备方法,以3-硝基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-硝基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为35.61%;m.p.:217.0–218.5℃;HRMS(ESI):459.16367([M+H]+),481.14566([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.70(d,J=5.3Hz,1H),8.68–8.63(m,3H),8.30(dd,J1=9.3Hz,J2=2.5Hz,1H),7.94(d,J=8.6Hz,2H),7.46(d,J=8.4Hz,2H),7.28(d,J=5.4Hz,1H),7.03(dd,J1=7.4Hz,J2=2.2Hz,1H),6.97(dd,J1=7.6Hz,J2=2.1Hz,1H),6.93–6.86(m,2H),4.11(t,J=6.1Hz,2H),3.75(s,3H),3.66–3.61(m,2H);13C NMR(101MHz,DMSO-d6)δ166.37,153.74,149.72,148.58,148.43,148.24,147.46,143.52,129.64,129.19,125.34,125.17,124.26,121.77,121.26,121.09,118.31,114.43,112.95,105.57,67.40,56.00,39.48。
实施例9:N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺(化合物ZD09)的制备
参考实施例1的制备方法,以2-甲基苯胺替换苯胺为原料,得到N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为42.35%;m.p.:150.2–151.7℃;HRMS(ESI):428.19495([M+H]+),450.17685([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.60–8.58(m,2H),8.19(d,J=8.5Hz,1H),7.91–7.88(m,2H),7.59(d,J=6.9Hz,1H),7.46–7.39(m,3H),7.18(d,J=5.1Hz,1H),7.03(dd,J1=7.4Hz,J2=2.2Hz,1H),6.97(dd,J1=7.6Hz,J2=2.1Hz,1H),6.93–6.86(m,2H),4.10(t,J=6.0Hz,2H),3.75(s,3H),3.65–3.60(m,2H),2.69(s,3H)。
实施例10:N-[2-(2-甲氧基苯氧基)乙基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZD10)的制备
参照实施例1的制备方法,得到N-[2-(2-甲氧基苯氧基)乙基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为38.05%;m.p.:173–175℃;HRMS(ESI):482.2([M+H]+);1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.92(s,1H),8.67(s,1H),8.38(d,J=8.8Hz,1H),8.23(s,1H),7.87(s,1H),7.81(d,J=7.8Hz,1H),7.67(s,1H),7.59–7.55(m,1H),7.24–7.20(m,2H),6.91–6.77(m,4H),3.93(t,J=6.0Hz,2H),3.66(s,3H),3.59–3.55(m,2H);IR:(KBr,cm-1):υ3330,2919,1635,1582,1508,1329,1257,1125,816,748,680。
实施例11:N-[2-(2-甲氧基苯氧基)乙基]-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(化合物ZD11)的制备
参照实施例1的制备方法,用2-(2-甲氧基苯氧基)乙胺替换乙胺,得到N-[2-(2-甲氧基苯氧基)乙基]-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体,收率为29.88%;m.p.:159.1–160.1℃;HRMS(ESI):482.16779([M+H]+),504.14956([M+Na]+);1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.77–8.74(m,1H),8.65(d,J=8.8Hz,1H),8.60(d,J=5.3Hz,1H),8.21(s,1H),7.91(s,1H),7.83(d,J=8.8Hz,1H),7.70–7.68(m,1H),7.55–7.53(m,2H),7.06(d,J=4.8Hz,1H),7.01(d,J=7.2Hz,1H),6.96–6.94(m,1H),6.91–6.84(m,2H),4.11(t,J=6.0Hz,2H),3.72(s,3H),3.66–3.62(m,2H);13C NMR(101MHz,DMSO-d6)δ166.59,152.83,149.66,148.37,148.22,140.77,136.12,129.99,126.94,125.73,124.83,123.28,121.90,121.75,121.23,120.37,120.33,114.32,112.86,103.61,67.24,55.92;IR:(KBr,cm-1)υ3219.02,2923.25,2852.06,1638.79,1572.06,1536.82,1506.29,1466.48,1378.89,1325.42,1254.33,1156.59,1111.21,1019.33,893.37,857.22,820.26,737.22,469.58。
实施例12:流感病毒核糖核蛋白复合物活化活性测试实验(RNP活化活性测试实验)
流感病毒核糖核蛋白复合物活化活性测试实验使用293T细胞为测试细胞系。以Nucleozin为活性对照药。该核糖核蛋白复合物包含流感病毒NP和RNA聚合酶(包括PA、PB1和PB2亚基)片段。
首先培养293T细胞:在一个培养皿中(直径6cm),加入混有1/10T75的培养液,并检查一下对于转染是否有足够的质粒。
将1×105个293T细胞接种在96孔微量滴定板上过夜。将125ng pcDNA3a-PB1,pcDNA3a-PB2,pcDNA3a-PA,pcDNA3a-NP,pPOL-NS-Luci质粒和pEGFP共转染到293T细胞中,用Lipofectamine 2000(Invitrogen)重构RNP复合物。转染6小时后,加入含有被测试化合物的生长培养基。24小时后,通过Steady-Glo荧光素酶底物(Promega)测定荧光素酶活性。使用VICTOR 3Multilabel板读数器(Perkin Elmer)读取GFP表达和发出的荧光。
RNP活化活性测试实验的结果(%),是将含有被测试化合物的荧光素酶信号(相对发光值)除以阴性对照品(DMSO)的荧光素酶信号(相对发光值)来计算的。RNP活化活性值低,说明被测试化合物与RNP发生了相互作用,具有一定的流感病毒抑制活性。对每一种被测试化合物,本实验均用其最高的非细胞毒性浓度进行测试。
本发明方法制得的部分含有酰胺基团的喹啉类样品RNP活化活性测试实验结果列表如下(n=3):
从受试目标化合物的流感病毒核糖核蛋白复合物活化活性测试实验的初步筛选结果可以看出,本发明提供的含有2-甲氧基苯氧基基团的[(喹啉-4-基)氨基]苯甲酰胺类化合物与RNP均明显存在相互作用,对流感病毒具有抑制活性,其中实施例6制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺与RNP相互作用最强。
实施例13:考察化合物对流感病毒感染细胞的存活率的影响。
将MDCK细胞接种在96孔板中,每孔3000个细胞,培养24h。加入100TCID50(50%tissue culture infective dose,引起半数培养细胞病变的病毒量的100倍)的不同亚型流感病毒,吸附细胞3h后,吸出病毒,将化合物稀释成多个浓度,加到96孔板中,每个浓度做4个复孔。同时设病毒对照组、细胞对照组和空白培养基对照组,培养36h。加入CCK-8试剂,采用MTT法,测试并计算感染了流感病毒、且添加了目标化合物(或对照化合物)的细胞的吸光度与未感染病毒的细胞的吸光度的比值,测试结果表示目标化合物存在下细胞的存活率,通过观察化合物是否能够提高感染病毒后细胞的存活率,来评估化合物对流感病毒感染的细胞的保护作用。
本发明方法制得的部分含有2-甲氧基苯氧基基团的[(喹啉-4-基)氨基]苯甲酰胺类样品对流感病毒感染细胞的存活率活性测试实验结果列表如下(n=3):
从受试目标化合物对MDCK细胞保护的测试实验的筛选结果表明,本发明化合物能明显保护MDCK细胞,有效地抑制流感病毒的活性,其中实施例3制备的N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺和实施例6制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺对MDCK细胞保护活性最强。
实施例14:受试化合物对流感病毒的抑制率测定
采用标准蚀斑法对部分目标化合物的抗流感病毒活性进行测试,以A/WSN/33(H1N1)流感病毒为测试病毒株,受试化合物以DMSO溶解,用培养液稀释配制为100μM的浓度,以二甲基亚砜为空白对照。
将MDCK细胞按一定浓度接种于96孔细胞培养板,在5%CO2、37℃的环境中培养细胞24h,除去培养液,将A/WSN/33(H1N1)流感病毒接种于MDCK细胞,37℃下吸附2h,倾去病毒液。加入100μmol·L-1的受试化合物,每个化合物做3个复孔,设置病毒对照组(感染病毒,不加化合物)37℃下继续培养24h,用MDCK细胞的标准蚀斑测定法测定细胞的病毒株数量,计算病毒存活率。病毒存活率=(实验组病毒株数/病毒对照组病毒株数)×100%。
按照上述方法测定本发明的化合物对流感病毒的抑制活性,结果示于下表。
从受试目标化合物对A/WSN/33(H1N1)流感病毒抑制活性测试实验的筛选结果表明,本发明化合物能明显减少流感病毒的存活量,有效地抑制流感病毒的活性,其中实施例3制备的N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺、实施例6制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例7制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺和实施例9制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺具有较强的流感病毒抑制活性。
实施例15:受试化合物对多种流感病毒株的IC50测定
采用标准蚀斑法对部分目标化合物的抗流感病毒活性进行测试,多种测试病毒株分别为A/WSN/33(H1N1)、A/PR/8(H1N1)、A/HK/68(H3N2)和B型流感病毒株,受试化合物以DMSO溶解,用培养液稀释配制为100Μm的浓度,以二甲基亚砜为空白对照。
将MDCK细胞按一定浓度接种于96孔细胞培养板,在5%CO2、37℃的环境中培养细胞24h,除去培养液,将流感病毒株A/WSN/33(H1N1)/A/PR/8(H1N1)/A/HK/68(H3N2)或B型流感病毒株接种于MDCK细胞,37℃下吸附2h,倾去病毒液。加入不同浓度(100、50、25、12.5、6.25、3.125μmol·L-1)的受试化合物,每个化合物做3个复孔,设置病毒对照组(感染病毒,不加化合物)37℃下继续培养24h,用MDCK细胞的标准蚀斑测定法测定细胞的病毒株数量,计算病毒存活率。根据不同浓度下的病毒存活率计算每个化合物对不同病毒株的IC50。
对实施例3制备的N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺、实施例6制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例7制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺和实施例9制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺进行进一步的流感病毒抑制实验,测得其对病毒株A/WSN/33(H1N1)的IC50分别为1.51±0.33、3.17±0.89、4.84±2.13和2.79±1.11μM;对病毒株A/PR/8(H1N1)的IC50分别为3.18±0.96、2.19±0.77、1.68±1.03和1.45±0.13μM;对病毒株A/HK/68(H3N2)的IC50分别为1.77±0.63、2.79±0.42、3.10±0.81和3.55±0.27μM;对B型病毒株的IC50分别为4.22±1.13、3.21±1.09、2.68±0.96和3.19±1.01μM。结果示于下表。因此,实施例3制备的N-[2-(2-甲氧基苯氧基)乙基]-4-{[(6-溴喹啉)-4-基]氨基}苯甲酰胺、实施例6制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例7制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺和实施例9制备的N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺均是广谱抗流感病毒抑制剂。
在下述制剂中,“活性组分”是指式I所示化合物,或其盐或溶剂化物。
实施例16:明胶胶囊
实施例17:片剂
实施例18:片剂
将活性组分、淀粉和纤维素通过45目U.S.筛并充分混合,将所得粉末与聚乙烯吡咯烷酮混合,然后通过14目U.S.筛,将这样得到的颗粒在50-60℃干燥,并通过18目U.S.筛。将羧甲基纤维素钠、硬脂酸镁和滑石,先通过60目U.S.筛,然后加入至上述颗粒中,混合后,在压片机上压制成片剂。
实施例19:悬浮剂
将药物通过45目U.S.筛,并与羧甲基纤维素钠及糖浆混合,以形成均匀糊状物,将苯甲酸溶液、矫味剂和着色剂用一些水稀释,并边搅拌边加入,然后加入足够量水,以达到所需的体积。
实施例20:气溶胶
将活性成分与乙醇混合,并将所得混合物加入至抛射剂22中,冷却至30℃,并转移至容器中。然后将所需量加入至不锈钢容器中,并用剩余喷射剂稀释,然后安装阀门装置。
实施例21:栓剂
将活性组分通过60目U.S.筛,并将其悬浮于预先熔化的饱和脂肪酸甘油酯类化合物中,然后将混合物倾入至标准的2g腔栓剂模中并冷却。
实施例22:可注射制剂
将以上溶液静脉内注射给药至患者,速度约1mL/min。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (9)
1.一种结构式如式(I)所述的含有酰胺基团的喹啉类化合物或其药学上可接受的盐:
其中,R独立地选自氢,C1-C4烷基,C1-C4烷氧基,卤素,硝基。
2.一种结构式如式(I)所述的含有酰胺基团的喹啉类化合物或其药学上可接受的盐,其特征在于,
R独立地选自氢,甲基,三氟甲基,三氟甲氧基,氯,溴或硝基。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于,所述的化合物为以下化合物中的任一个:
N-[2-(2-甲氧基苯氧基)乙基]-4-[(喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-氯喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-溴喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(6-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-三氟甲氧基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(7-硝基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-4-[(8-甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺;
N-[2-(2-甲氧基苯氧基)乙基]-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺。
4.权利要求1所述的含有酰胺基团的喹啉类化合物的制备方法,其特征在于,包括以下步骤:
其中,R如权利要求1所述。
5.一种药物组合物,其特征在于,包括作为活性成分的权利要求1-3任一项所述的化合物或其在药学上可接受的盐中任何一个的化合物和药物可接受的载体或稀释剂。
6.权利要求1-3任何一项所述的化合物或其药学上可接受的盐在制备流感病毒治疗药物中的应用。
7.权利要求5所述的药物组合物在制备流感病毒治疗药物中的应用。
8.根据权利要求6所述的应用,其特征在于,以有效量的该结构式的化合物作用于流感病毒的核蛋白或RNA聚合酶,抑制流感病毒的复制。
9.根据权利要求7所述的应用,其特征在于,以有效量的药物组合物作用于流感病毒的核蛋白或RNA聚合酶,抑制流感病毒的复制。
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