CN114008022B - 叔胺衍生物及其在治疗病毒感染中的用途 - Google Patents
叔胺衍生物及其在治疗病毒感染中的用途 Download PDFInfo
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- CN114008022B CN114008022B CN202080046204.2A CN202080046204A CN114008022B CN 114008022 B CN114008022 B CN 114008022B CN 202080046204 A CN202080046204 A CN 202080046204A CN 114008022 B CN114008022 B CN 114008022B
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- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
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Abstract
本发明涉及一类新的式(I)的叔胺衍生物及其在治疗病毒感染、特别是病毒性呼吸道感染中的用途。本发明还涉及包含式(I)的化合物的药物组合物。
Description
技术领域
本发明涉及医学领域,特别是叔胺衍生物及其在治疗病毒感染、特别是病毒性呼吸道感染中的用途。
背景技术
病毒是一种仅在其它生物体的活细胞内复制的小型感染因子。它们可以感染所有类型的生命形式,从动植物到微生物,包括细菌和古细菌。它们当中,已知有400多种病毒造成人类疾病,其中许多导致严重的病变和最终的死亡。特别是,HIV在2012年被列为全球第六大主要死亡原因,每年造成150万人死亡(WHO,情况说明书(Fact sheet)N°310,2014)。季节性流感病毒是流感的罪魁祸首,流感每年影响约20%的世界人口,并导致250,000至500,000人死亡(WHO,情况说明书N°211,2014)。乙型和丙型肝炎每年共同造成约140万人死亡,而人类乳头瘤病毒是全球第二最常见女性癌症——宫颈癌的罪魁祸首,2012年导致270,000人死亡(WHO,情况说明书,2016)。
另一种特别严重的病毒是人呼吸道合胞病毒(HRSV),它引起呼吸道感染,特别是在婴儿期和儿童期。到1岁时,60-70%的儿童已感染过HRSV。与HRSV相关的并发症是例如细支气管炎、肺炎、反复呼吸道感染和耳炎。
由于病毒利用宿主细胞内重要的代谢途径进行复制,因此不使用药物很难被清除,而药物通常引起对宿主细胞的毒性效应。对病毒性疾病最有效的医学方法是接种疫苗以提供对感染的免疫力,以及选择性干扰病毒复制的抗病毒药物。疫苗针对稳定病毒的预防性使用非常有效。然而,疫苗在治疗已经感染的患者方面用途有限。它们也很难成功用来对抗快速突变性病毒进行部署,而抗病毒药物在这些情况下可能特别有用。
抗病毒药物是一类专门用于治疗病毒感染的药物。抗病毒药物不消灭它们的目标病原体,而是抑制它们的发展。抗病毒药物可针对病毒生命周期的任何阶段:附着于宿主细胞,将病毒基因和可能的酶释放到宿主细胞中,使用宿主细胞机制复制病毒成分,将病毒成分组装成完整的病毒粒子,以及释放病毒粒子以感染新的宿主细胞。最常见的抗病毒药物是阻断病毒复制的核苷类似物。大多数抗病毒药物用于特定的病毒感染,而广谱抗病毒药物则对多种多样的病毒有效。
一种可商购的预防HRSV的抗病毒药物是帕利珠单抗,它是一种单克隆抗体。帕利珠单抗在RSV季节来临之前通过每月注射施用,这种预防通常连续几个月,一般五个月。然而,帕利珠单抗的成本限制了它在世界许多地方的使用。目前,肾上腺素、支气管扩张剂、类固醇、抗生素、利巴韦林现行用于治疗RSV。然而,它们限于支持性措施,并没有为对象带来真正的好处。
因此,如今强烈需要开发新的抗病毒药物,特别是HRSV抗病毒药物。此外,耐药性的出现对抗病毒药物的应用造成了严重限制,并且产生了对于开发对抗耐药形态的新型抗病毒药物的迫切需要。
发明内容
如实施例所示,本发明人已经证明了本发明的式(I)的化合物的治疗意义。更特别地,这样的化合物表现出抗呼吸道合胞病毒(RSV)的功效。
因此,本发明提供了一种下式(I)的化合物,及其立体异构体和药用盐:
其中:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,或
-R3和R4一起形成包含至少一个氮的杂环烷基或杂芳基;
其中:
-n是0或1,
-R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;以及
其中:
-m和p独立地是0、1或2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
在式(I)的一个优选实施方式中,R1a和R1b是相同的。在式(I)的一个更优选的实施方式中,R1a和R1b是氢或卤素,优选氢。
在式(I)的一个进一步的优选实施方式中,R2或R2’选自氢、氧、任选被至少一个羟基取代的(C1-C3)烷基。
在式(I)的一个进一步的优选实施方式中,R3或R3’选自氢、卤素、(C1-C3)烷氧基。
在式(I)的一个特定实施方式中,B是
其中:
-R2选自氢、氧、(C1-C3)烷基,优选甲基,所述(C1-C3)烷基任选被至少一个羟基取代,
-R3是氢或(C1-C3)烷氧基,优选甲氧基,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,优选氢。
在式(I)的一个进一步的特定实施方式中,B是
其中:
-R2选自氢、氧、(C1-C3)烷基,优选甲基,所述(C1-C3)烷基任选被至少一个羟基取代,并且
R6是氢或(C1-C3)烷基。
在式(I)的一个进一步的特定实施方式中,B是
其中:
-n是0或1,优选1,
-R2’是氢,
-R3’是氢或卤素,优选氟,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基。
在式(I)的一个进一步的特定实施方式中,B是
其中:
-m和p独立地是0、1或2,并且m+p=2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
在一个优选实施方式中,式(I)的化合物选自具有如本文定义的特定式的化合物。
本发明的另一个目的是如上定义的式(I)化合物供作药物使用。本发明的一个进一步的目的是一种药物组合物,其包含如上定义的式(I)的化合物和可接受的药用赋形剂。在另一个进一步的特定实施方式中,本发明涉及一种本发明的化合物或药物组合物供用于治疗病毒感染。优选病毒感染是病毒性呼吸道感染。更优选地,病毒性呼吸道感染由人呼吸道合胞病毒引起。
附图说明
图1-20:被RSV感染的细胞(A)或未被感染的细胞(B)在被本发明的化合物处理后的存活率%(化合物#1,图1A和1B;化合物#2,图2A和2B;化合物#3,图3A和3B;化合物#4,图4A和4B;化合物#5,图5A和5B;化合物#6,图6A和6B;化合物#7,图7A和7B;化合物#8,图8A和8B;化合物#9,图9A和9B;化合物#10,图10A和10B;化合物#11,图11A和11B;化合物#12,图12A和12B;化合物#13,图13A和13B;化合物#14,图14A和14B;化合物#15,图15A和15B;化合物#16,图16A和16B;化合物#17,图17A和17B;化合物#18,图18A和18B,化合物#19,图19A和19B,化合物#20,图20A和20B)。
具体实施方式
定义
根据本发明,以下术语具有以下含义:
本文中提及的带有前缀如C1-C3的术语也可以与较低的碳原子数如C1-C2一起使用。例如,如果使用术语C1-C3,是指相应的烃链可包含1至3个碳原子,尤其是1、2或3个碳原子。例如,如果使用术语C1-C3,是指相应的烃链可包含1至3个碳原子,尤其是1、2或3个碳原子。
术语“烷基”是指饱和的直链或支链脂族基团。术语“(C1-C3)烷基”更具体地是指甲基、乙基、丙基或异丙基。在一个优选实施方式中,“烷基”是甲基。
术语“烷氧基”对应于通过-O-(醚)键与分子键合的如上定义的烷基基团。(C1-C3)烷氧基包括甲氧基、乙氧基、丙氧基和异丙氧基。在一个优选实施方式中,“烷氧基”是甲氧基。
术语“环烷基”对应于包含3和20个碳原子之间的饱和或不饱和的单环、双环或三环烷基基团。它还包括稠合、桥连或螺连接的环烷基基团。术语“环烷基”包括例如环丙基、环丁基、环戊基和环己基。
术语“杂环烷基”对应于如上定义的饱和或不饱和环烷基,其还包含至少一个杂原子,如氮、氧或硫原子,优选至少一个氮原子。它还包括稠合、桥连或螺连接的杂环烷基基团。代表性的杂环烷基基团包括但不限于3-二氧戊环、苯并[1,3]二氧戊环基、氮杂环丁烷基、氧杂环丁烷基、吡唑啉基、吡喃基、硫代吗啉基、吡唑烷基、哌啶基、哌嗪基、1,4-二烷基、咪唑啉基、吡咯啉基、吡咯烷基、哌啶基、咪唑烷基、吗啉基、1,4-二噻烷基、吡咯烷基、唑啉基、唑烷基、异唑啉基、异唑烷基、噻唑啉基、噻唑烷基、异噻唑啉基、异噻唑啉基、二氢吡喃基、四氢吡喃基、四氢呋喃基、和四氢噻吩基。在一个优选实施方式中,杂环烷基基团是吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、哌啶基或哌嗪基。
术语“芳基”对应于具有6至12个碳原子的单环或双环芳族烃。例如,术语“芳基”包括苯基、联苯基或萘基。在一个优选实施方式中,芳基是苯基。
如本文所用的术语“杂芳基”对应于包含5和14个原子之间且包含至少一个杂原子如氮、氧或硫原子的芳族单环或多环基团。这样的单环和多环杂芳基的实例可以是:吡啶基、噻唑基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、苯并呋喃基、硫杂萘基(thianaphthalenyl)、吲哚基、二氢吲哚基、喹啉基、异喹啉基、苯并咪唑基、四氢喹啉基、四氢异喹啉基、三嗪基、噻蒽基、异苯并呋喃基、色烯基、呫吨基、吩噻基、异噻唑基、异唑基、吡嗪基、哒嗪基、吲嗪基、异吲哚基、吲唑基、嘌呤基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、菲咯啉基、吩嗪基、吩噻嗪基、呋咱基、吩嗪基、异色满基、色满基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、二氢吲哚基、异二氢吲哚基、唑烷基、苯并三唑基、苯并异唑基、羟吲哚基、苯并唑啉基、苯并噻吩基、苯并噻唑基、靛红基、二氢吡啶基、嘧啶基、均三嗪基、唑基、或硫代呋喃基。在一个优选实施方式中,杂芳基基团是吡咯基、吡唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、三嗪基、吲唑基,更优选吲唑基。
术语“卤素”对应于氟、氯、溴或碘原子,优选氟。
表述“被至少.....取代”是指该基团被清单中的一种或几种基团取代。
表述“任选取代的”是指,在没有任何其它确切描述的情况下,任选被羟基、卤素、任选被至少一个卤素取代且优选任选被至少一个氟取代的(C1-C6)烷基、或任选被至少一个卤素取代且优选任选被至少一个氟取代的(C1-C6)烷氧基所取代。
“立体异构体”是具有相同的分子式和键合原子序列、但它们的原子在空间的3D维度取向上不同的异构化合物。立体异构体包括对映异构体、非对映异构体、顺反和E-Z异构体、构象异构体和端基异构体。在本发明的一个优选实施方式中,立体异构体包括非对映异构体和对映异构体。
“药用盐”包括无机和有机酸盐。合适的无机酸的代表性实例包括盐酸、氢溴酸、氢碘酸、磷酸等。合适的有机酸的代表性实例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、柠檬酸、富马酸、马来酸、甲磺酸等。药用无机酸或有机酸加成盐的其它实例包括下列文献中列举的药用盐:J.Pharm.Sci.1977,66,2,以及P.Heinrich Stahl和CamilleG.Wermuth编著的《药用盐手册:性质、选择和用途》(Handbook of Pharmaceutical Salts:Properties,Selection and Use),2002。在一个优选实施方式中,所述盐选自马来酸盐、盐酸盐、氢溴酸盐和甲磺酸盐。“药用盐”还包括无机和有机碱盐。合适的无机碱的代表性实例包括钠盐或钾盐、碱土金属盐如钙盐或镁盐、或铵盐。合适的与有机碱的盐的代表性实例包括例如与甲胺、二甲胺、三甲胺、哌啶、吗啉或三-(2-羟乙基)胺的盐。在一个优选实施方式中,盐选自钠盐和钾盐。
如本文所用的术语“治疗”是指旨在改善患者健康状态的任何行为,例如治疗、防止、预防和延缓疾病,特别是病毒感染。在某些实施方式中,这样的术语是指疾病或与之相关的症状的改善或消除。在其它实施方式中,该术语是指对患有疾病的对象施用一种或多种治疗剂致使这样的疾病的扩散或恶化最小化。
如本文所用的术语“对象”、“个体”或“患者”是可互换的并且是指动物,优选是指哺乳动物,更加优选是指人类,包括成人、儿童、初生儿和处于出生前阶段的人类。然而,术语“对象”也可以指非人类动物,特别是哺乳动物,如狗、猫、马、牛、猪、羊和非人类灵长类动物等。
术语“量”和“剂量”在本文可互换使用,并且可以指分子的绝对定量。
如本文所用的术语“活性要素”、“活性成分”和“活性药物成分”是等同的,并且是指药物组合物中具有治疗效应的组分。
如本文所用的术语“治疗效应”是指由活性成分或本发明的药物组合物诱导的效应,其能够预防或延迟疾病或病症的出现或发展,或能够治愈或减轻疾病或病症的效应。
如本文所用的术语“有效量”是指预防、去除或减少疾病、特别是感染性疾病的有害效应的活性成分或药物组合物量。显然,本领域技术人员可以根据要治疗的对象、疾病的性质等来调整要施用的量。特别地,施用的剂量和方案可随待治疗疾病的性质、阶段和严重程度、以及待治疗对象的体重、年龄和整体健康状况、以及医生的判断而变。
如本文所用的术语“可接受的药用赋形剂”是指除活性成分以外存在于药物组合物中的任何成分。其添加可以旨在赋予最终产品特定的稠度或其它物理或味觉性质。可接受的药用赋形剂必须没有与活性成分的任何相互作用,特别是化学相互作用。
化合物
本文公开了下式(I0)的化合物,及其立体异构体和药用盐:
其中:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,或
-R3和R4一起形成包含至少一个氮的杂环烷基或杂芳基;
其中:
-n是0或1,
-R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;以及
其中:
-m和p独立地是0、1或2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
在一个特定的方面,化合物具有式(I0),其中:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基;并且
其中R2、R3、R4、R2’、R3’、R4’、R4”、n、m和p如本文、包括特定和优选实施方式中所定义。
在一个优选的方面,B’和B”是:
其中:
-R2是氢,
-R3是氢或卤素如氟,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,优选氢。
在式(I0)的一个更优选的方面,B’和B”是相同的。
在式(I0)的一个进一步更优选的方面,
其中:
-R2是氢,
-R3是氢或卤素如氟,优选氟,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,优选氢;并且
其中R2、R3、R4、R2’、R3’、R4’、R4”、n、m和p如本文、包括特定和优选实施方式中所定义。
在一个进一步的特定方面,化合物具有式(I0),其中:
其中:
-n是0或1,
-R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;并且
其中R2、R3、R4、R2’、R3’、R4’、R4”、n、m和p如本文、包括特定和优选实施方式中所定义。
在一个优选的方面,B’和B”是:
其中:
-n是0或1,优选1,
-R2’是氢,
-R3’是氢或卤素,优选氟,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基。
在式(I0)的一个更优选的方面,B’和B”是相同的。
在式(I0)的一个进一步更优选的方面,
其中:
-n是0或1,优选1,
-R2’是氢
-R3’是氢或卤素,优选氟,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;并且
其中R2、R3、R4、R2’、R3’、R4’、R4”、n、m和p如本文、包括特定和优选实施方式中所定义。
根据本发明,化合物具有下式(I),及其立体异构体和药用盐:
其中:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,或
-R3和R4一起形成包含至少一个氮的杂环烷基或杂芳基;
其中:
-n是0或1,
-R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;以及
其中:
-m和p独立地是0、1或2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
根据本发明,R1a和R1b独立地选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代。(C1-C3)烷基或(C1-C3)烷氧基任选被至少一个卤素取代通常被指定为-CF3、-CHF2、-CH2F、-OCF3、-OCHF2或-OCH2F基团。(C1-C3)烷基任选被至少一个羟基取代通常被指定为-CH2OH、-CH2CH2OH、-CH2CHOHCH3或-CH2CH2CH2OH。特别地,R1a和R1b是相同的或等价的,意味着R1a和R1b表示相同的化学基团。在本发明的一个优选实施方式中,R1a和R1b是相同的。它们选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代。在一个优选实施方式中,R1a和R1b相同或不同地是氢、卤素如氟、或(C1-C3)烷氧基如甲氧基。在一个更优选的实施方式中,R1a和R1b相同或不同地是氢、或卤素如氟。在一个更优选的实施方式中,R1a和R1b相同地是氢、或氟,优选氢。在一个特定的方面,R1a和R1b在间位或对位位置。在一个特定的方面,R1a和R1b均在对位位置。
根据本发明,R2或R2’选自氢、氧、任选被至少一个羟基取代的(C1-C3)烷基。在一个特定的实施方式中,R2或R2’选自氢、任选被至少一个羟基取代的甲基、和氧。在一个特定的方面,当R2或R2’是氧时,所述键是双键,而当R2或R2’是氢或任选被至少一个羟基取代的甲基时所述键是单键。在一个优选实施方式中,R2是氢、甲基、氧、被羟基取代的甲基(-CH2OH)。在一个进一步优选的实施方式中,R2’是氢。
根据本发明,R3或R3’选自氢、卤素和(C1-C3)烷氧基。在一个特定的实施方式中,R3或R3’选自氢、氟和甲氧基,优选氢。在一个优选实施方式中,R3是氢或甲氧基。在一个进一步优选的实施方式中,R3’是氢或氟。在一个方面,R3在对位位置。在另一个方面,R3在间位位置。
根据本发明,R4、R4’和R4”分别是-CONHR5、-CONHR5’和-CONHR5”基团,其中R5、R5’和R5”是氢或(C1-C3)烷基,优选氢或甲基,更优选氢。
根据本发明的一个特定实施方式,特别是根据式(I)的化合物,B表示:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基。
优选地,B表示:
其中:
-R2选自氢、氧和(C1-C3)烷基,优选甲基,所述(C1-C3)烷基任选被至少一个羟基取代,
-R3是氢、(C1-C3)烷氧基,优选甲氧基,或卤素,优选氟,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基如甲基,优选氢。
本发明的一个优选的化合物是下述的式(I)的化合物,其中:
其中:
-R2选自氢、氧、任选被羟基取代的甲基,
-R3是甲氧基或氢,并且
-R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,优选甲基。
根据一个进一步的特定实施方式,B表示:
其中:
-R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R3和R4一起形成包含至少一个氮的杂环烷基或杂芳基。
优选地,B表示:
其中:
-R2选自氢、氧、(C1-C3)烷基,优选甲基,所述(C1-C3)烷基任选被至少一个羟基取代,并且
-R6是氢或(C1-C3)烷基。
本发明的一个优选的化合物是下述的式(I)的化合物,其中:
其中:
-R2是氢,并且
-R6是氢。
根据本发明的一个进一步的特定实施方式,B表示:
其中:
-n是0或1,
-R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
-R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基。
优选地,B表示:
其中:
-n是0或1,优选1,
-R2’选自氢、氧和(C1-C3)烷基,优选甲基,所述(C1-C3)烷基任选被至少一个羟基取代,R2’更优选是氢,
-R3’是氢,(C1-C3)烷氧基如甲氧基,或卤素,优选氟,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基,优选甲基。
本发明的一个优选的化合物是下述的式(I)的化合物,其中:
其中:
-n是0或1,优选1,
-R2’是氢,
-R3’是氢或卤素,优选氟,并且
-R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基。
根据本发明的一个进一步的特定实施方式,B表示:
其中:
-m和p独立地是0、1或2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基,优选甲基。
优选地,B表示:
其中:
-m和p独立地是0、1或2,并且m+p=2,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基,优选甲基。
更优选地,B表示:
其中:
-m和p是1,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
本发明的一个优选的化合物是下述的式(I)的化合物,其中:
其中:
-m和p是1,并且
-R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
在本发明的一个优选实施方式中,式(I)的化合物选自:
本发明的式(I)的化合物可以根据技术人员已知的任何化学路线制备,例如实施例中所介绍的一般合成路线。因此要理解,有机化学领域的技术人员使用适当的起始材料、常规化学反应、标准和文献程序以及合成式(I)的化合物的实验条件,可以容易地合成式(I)的化合物。
治疗应用
如实施例所示,本发明人已经证明了本发明的新化合物的治疗利益。事实上,本发明人表明,本发明的化合物具有抗病毒活性,尤其是对呼吸道合胞病毒具有抗病毒活性。另外,大多数化合物呈现出对受感染细胞选择性的抗病毒活性。因此,本发明的化合物可用作药物,尤其是作为抗病毒剂。
因此,本发明涉及一种如本文定义的化合物,其供用作药物或医药。本发明还涉及一种包含本发明的化合物的药物组合物或兽医组合物。优选地,所述药物组合物还包含可接受的药用或兽医用载体或赋形剂。本发明涉及本发明的化合物作为药物或医药的用途。本发明还涉及一种治疗对象的疾病的方法,其中向所述有需要的对象施用治疗有效量的本发明的新化合物。本发明还涉及本发明的新化合物在制造药物中的用途。本发明还涉及包含本发明的化合物的药物组合物供用作药物。
本发明涉及本发明的化合物供用于治疗病毒感染。本发明还涉及本发明的化合物在制造治疗病毒感染的药物中的用途。本发明还涉及包含本发明的化合物的药物组合物供用于治疗病毒感染。最后,本发明涉及一种治疗有需要的对象的病毒感染的方法,其中向所述有需要的对象施用治疗有效量的本发明的化合物。
本发明涉及本发明的化合物作为抗病毒剂的用途。本发明还涉及本发明的化合物作为研究工具、尤其是在研究病毒感染中的用途。本发明还涉及一种在细胞、组织或对象中阻断病毒感染的方法。
病毒因子可以是DNA病毒或RNA病毒。
病毒因子可以选自甲病毒(Alphaviridae)、黄病毒(Flaviviridae)、嗜肝DNA病毒(Hepadnaviridae)、疱疹病毒(Herpesviridae)、正粘病毒(Orthomyxoviridae)、乳多空病毒(Papovaviridae)、副粘病毒(Paramyxoviridae)、小RNA病毒(Picornaviridae)、多瘤病毒(Polyomaviridae)、呼肠孤病毒(Reoviridae)、逆转录病毒(Retroviridae)、弹状病毒(Rhabdoviridae)和烟草花叶病毒(Tobamoviruses)。
在一个实施方式中,甲病毒选自巴马森林(Barmah Forest)病毒、米德尔堡(Middelburg)病毒、恩杜姆(Ndumu)病毒、贝巴鲁(Bebaru)病毒、基孔肯雅(Chikungunya)病毒、马雅罗(Mayaro)病毒、阿尼昂-尼昂(O’nyong’nyong)病毒、罗斯河(Ross River)病毒、塞姆利基森林(Semliki Forest)病毒、辛德比斯(Sindbis)病毒、乌纳(Una)病毒、东方马脑炎(Eastern equine encephalitis)病毒、托纳特(Tonate)病毒、委内瑞拉马脑炎(Venezuelan equine encephalitis)病毒、卡巴苏(Cabassou)病毒、大沼泽地(Everglades)病毒、Mosso das Pedras病毒、穆坎布(Mucambo)病毒、Parmana病毒、Pixuna病毒、内格罗河(Rio Negro)病毒、Trocara病毒、Aura病毒、Babanki病毒、Kyzylagach病毒、Ockelbo病毒、沃达罗河(Whataroa)病毒、睡眠病病毒、Samon胰腺病病毒、南方象海豹病毒和西方马脑炎病毒;优选选自巴马森林病毒、基孔肯雅病毒、马雅罗病毒、阿尼昂-尼昂病毒、罗斯河病毒、塞姆利基森林病毒、辛德比斯病毒、乌纳病毒、东方马脑炎病毒、托纳特病毒、委内瑞拉马脑炎病毒和西方马脑炎病毒。
在一个实施方式中,黄病毒选自登革热(dengue)病毒、丙型肝炎病毒、日本脑炎病毒、西尼罗河(West Nile)病毒、黄热病病毒、寨卡(Zika)病毒、蜱传脑炎病毒、科萨努尔森林病(Kyasanur forest disease)病毒、墨累山谷脑炎(Murray Valley encephalitis)病毒和圣路易脑炎(Saint Louis encephalitis)病毒。
在一个实施方式中,嗜肝DNA病毒选自乙型肝炎病毒。
在一个实施方式中,疱疹病毒选自单纯疱疹病毒1(HSV-1),单纯疱疹病毒2(HSV-2),水痘带状疱疹病毒(VZV),Epstein–Barr病毒(EBV),巨细胞病毒(CMV),玫瑰疹病毒(HHV-6A和6B)、HHV-7和卡波西氏肉瘤相关疱疹病毒(KSHV)。
在一个实施方式中,正粘病毒选自甲型流感病毒、乙型流感病毒、丙型流感病毒、Isavirus病毒、Thogotovirus病毒和Quaranjavirus病毒,优选选自甲型流感病毒和乙型流感病毒。在一个实施方式中,甲型流感病毒选自H1N1、H1N2、H2N2、H3N1、H3N2、H3N8、H5N1、H5N2、H5N3、H5N8、H5N9、H7N1、H7N2、H7N3、H7N4、H7N7、H7N9、H9N2和H10N7中的亚型。
在一个实施方式中,乳多空病毒选自乳头瘤病毒(HPC)和多瘤病毒,特别是猿猴病毒40、默克尔细胞多瘤病毒、Trichodysplasia spinulosa多瘤病毒、BK多瘤病毒、JC多瘤病毒和人多瘤病毒7。
在一个实施方式中,小RNA病毒选自口蹄疫病毒(Aphthovirus)、Aquamavirus、禽肝炎病毒(Avihepatovirus)、心病毒(Cardiovirus)、Cosavirus、Dicipivirus、肠病毒(Enterovirus)、马鼻病毒(Erbovirus)、肝病毒(Hepatovirus)、嵴病毒(Kobuvirus)、Megrivirus、副肠孤病毒(Parechovirus)、Piscevirus、鼻病毒(Rhinovirus)、Salivirus、萨佩罗病毒(Sapelovirus)、塞内卡病毒(Senecavirus)、Techovirus、震颤病毒(Tremovirus)。在一个特定的实施方式中,小RNA病毒是鼻病毒,例如鼻病毒A、鼻病毒B或鼻病毒C。
在一个实施方式中,逆转录病毒选自:甲型逆转录病毒;尤其是禽白血病病毒和劳斯肉瘤病毒;乙型逆转录病毒,尤其是小鼠乳腺肿瘤病毒;丙型逆转录病毒,尤其是鼠白血病病毒和猫白血病病毒;丁型逆转录病毒,尤其是牛白血病病毒和嗜人T淋巴细胞病毒;戊型逆转录病,尤其是大眼狮鲈皮肤肉瘤病毒;慢病毒,尤其是人类免疫缺陷病毒1和猿、猫免疫缺陷病毒;泡沫病毒,尤其是猿泡沫病毒。
在一个实施方式中,弹状病毒选自:水疱性病毒、尤其是水疱性口炎病毒,狂犬病毒属病毒,狂犬病毒,暂时热病毒,诺拉弹状病毒,细胞质弹状病毒,和胞核弹状病毒。
在一个实施方式中,本发明的病毒因子选自:疱疹病毒,如水痘带状病毒(VZV)、Epstein-Barr(EB)病毒、1型单纯疱疹病毒(HSV-1)、卡波西氏肉瘤疱疹病毒(KSHV)、鼠γ-HV68病毒(γ-MHV68)或人巨细胞病毒(HCMV);嗜肝DNA病毒如乙型肝炎病毒(HBV);乳多空病毒如人乳头瘤病毒16型(HPV16);细小病毒如人细小病毒B19;多瘤病毒如猿猴病毒40;逆转录病毒如人类免疫缺陷病毒1(HIV-1)、或猿猴免疫缺陷病毒1型(SIV1);正粘病毒,如甲型流感病毒;黄病毒,如登革病毒或丙型肝炎病毒;小RNA病毒,如脊髓灰质炎病毒、柯萨奇病毒B3(CVB3)、或柯萨奇病毒B4(CVB4);呼肠孤病毒,如轮状病毒;甲病毒,如辛德比斯病毒;烟草花叶病毒科病毒,如烟草花叶病毒;弹状病毒,如水疱性口炎病毒。更优选地,本发明的病毒因子是流感病毒。更优选地,本发明的病毒因子是甲型或乙型流感病毒,更加优选甲型流感病毒。
在一个优选的实施方式中,病毒是副粘病毒。副粘病毒可以选自腮腺炎病毒(Rubulavirus)、麻疹病毒(Morbillivirus)、肺病毒(Pneumovirus)、偏肺病毒(Metapneumovirus)、禽腮腺炎病毒(Avulavirus)、费尔拉病毒(Ferlavirus)、亨尼巴病毒(Henipavirus)和呼吸病毒(Respirovirus)。在一个特定的实施方式中,副粘病毒是腮腺炎病毒、麻疹病毒、人类副流感病毒(HPIV)尤其是HPIV-1、HPIV-2、HPIV-3或HPIV-4、呼吸道合胞病毒(RSV)特别是人呼吸道合胞病毒(HRSV)、犬瘟热病毒、海豹瘟热病毒、鲸麻疹病毒、新城疫病毒、牛瘟病毒、亨德拉(Hendra)病毒和尼帕(Nipah)病毒。在一个优选实施方式中,病毒因子是呼吸道合胞病毒(RSV),特别是人呼吸道合胞病毒(HRSV)。在一个优选的方面,病毒是呼吸道合胞病毒(RSV),特别是人呼吸道合胞病毒(HRSV),并且对象患有支气管炎、细支气管炎或肺炎。
在一个实施方式中,本发明的化合物可以与另一种抗病毒药物组合使用,所述另一种抗病毒药物例如且非穷举地,是选自神经氨酸苷酶抑制剂、M2抑制剂、RNA聚合酶抑制剂、干扰素(免疫系统调节剂干扰素α-2a和聚乙二醇化干扰素α-2a(Pegasys)和干扰素α-2b(ViraferonPeg ou Introna))、抗病毒疫苗、抗原多肽或针对病毒抗原多肽的中和抗体。更特别地,在RSV感染的情况下,本发明的化合物可以与帕利维珠单抗组合。另外,或替代地,本发明的化合物也可与肾上腺素、支气管扩张剂、类固醇、抗生素和/或抗病毒药物特别是核苷类似物如利巴韦林组合。
本发明的化合物或本发明的药物组合物可通过任何常规施用途径施用。特别地,本发明的化合物或药物组合物可以通过局部、肠内、口服、肠外、鼻内、静脉内、动脉内、肌内、瘤内、皮下或眼内施用等进行施用。
特别地,本发明的化合物或本发明的药物组合物可以被配制成用于局部、肠内、口服、肠外、鼻内、静脉内、动脉内、肌内、瘤内、皮下或眼内施用等。
优选地,本发明的化合物或本发明的药物组合物通过肠内或肠外施用途径进行施用。当肠外施用时,本发明的化合物或本发明的药物组合物优选通过静脉内施用途径进行施用。当肠内施用时,本发明的化合物或本发明的药物组合物优选通过口服施用途径进行施用。
包含所述分子的药物组合物按照本领域技术人员已知的标准制药实践进行配制(Lippincott Williams&Wilkins,2000,以及《制药技术全书》(Encyclopedia ofPharmaceutical Technology),J.Swarbrick和J.C.Boylan编著,1988-1999,MarcelDekker,New York)。
对于口服施用,所述组合物可以配制成常规口服剂型如片剂、胶囊、粉剂、颗粒剂和液体制剂如糖浆、酏剂和浓缩滴剂。可以使用无毒的固体载体或稀释剂,包括,例如,药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石粉、纤维素、葡萄糖、蔗糖、镁、碳酸盐等。对于压制片剂,粘结剂也是必要的,它是赋予粉状材料粘聚性质的试剂。例如,淀粉、明胶、糖如乳糖或葡萄糖、以及天然或合成的树胶可以用作粘结剂。崩解剂在片剂中也是必需的,以促进片剂的破碎。崩解剂包括淀粉、粘土、纤维素、藻酸、树胶和交联聚合物。此外,在片剂中还包括润滑剂和助流剂,以防止在制造过程中片剂材料粘附于表面并改善粉末材料在制造期间的流动特性。胶体二氧化硅最常用作助流剂,化合物如滑石粉或硬脂酸最常用作润滑剂。
对于经皮施用,可以将所述组合物配制成软膏、乳膏或凝胶形式,并且可以使用适当的渗透剂或洗涤剂如二甲亚砜、二甲基乙酰胺和二甲基甲酰胺来促进渗透。
对于经粘膜施用,可以使用鼻喷雾剂、直肠或阴道栓剂。所述活性化合物可以通过本领域中已知的方法纳入到任何已知的栓剂基质中。这样的基质的实例包括可可脂、聚乙二醇(Carbowaxes)、聚乙烯山梨糖醇酐单硬脂酸酯、以及这些与用以改变熔点或溶解速率的其它相容材料的混合物。
本发明的药物组合物可以配制成在施用后几乎立即释放活性药物或在施用后的任何预定时间或时间段释放活性药物。
优选地,在诊断出疾病后不超过一个月、优选不超过一周开始用本发明的化合物或本发明的药物组合物进行治疗。在一个最优选的实施方式中,在诊断之日起开始治疗。
本发明的化合物或本发明的药物组合物可作为单剂或以多剂施用。
优选地,所述治疗定期施用,优选周期在每天至每个月之间,更优选在每天至每两周之间,更优选在每天至每周之间,更加优选每天施用所述治疗。在一个特定的实施方式中,所述治疗一天施用几次,优选一天2或3次,更加优选一天3次。
用本发明的化合物或本发明的药物组合物治疗的持续时间优选在1天至20周之间,更优选在1天至10周之间,更加优选在1天至4周之间,更加优选在1天至2周之间。在一个特定的实施方式中,治疗的持续时间为约1周。或者,只要疾病持续,治疗就可持续。
本发明的化合物或本发明的药物组合物的施用量必须通过本领域普通技术人员公知的标准程序来确定。患者的生理数据(例如年龄、体型和体重)和施用途径必须加以考虑,以确定适当的剂量,以便给患者施用的是治疗有效量。
在一个优选实施方式中,每次施用本发明的化合物或本发明的药物组合物的总化合物剂量在0.00001g至1g之间,优选在0.01mg至10mg之间。
药物组合物的形式、本发明的化合物或本发明的药物组合物的施用途径和施用剂量可以由本领域技术人员根据疾病的类型和严重性以及患者、特别是其年龄、体重、性别和一般身体状况进行调节。
药盒以及药盒的用途
本发明还涉及本发明的化合物与至少另一种活性成分、优选为抗病毒剂的组合使用,用于治疗病毒感染,优选病毒性呼吸道感染。
本发明还涉及一种产品,其包含本发明的化合物和另一种活性成分,作为用于同时、分开或顺序使用的组合制剂,特别是用于治疗病毒性疾病或病毒感染。优选地,另一种活性成分是抗病毒剂。
本发明的其它方面和优点将在以下实施例中进行描述,这些实施例应被视为说明性的而非限制性的。
实施例
实施例A–化学
一般合成路线:
1.苄型和芳族取代
-路线A:
通过1)使用K2CO3(碳酸钾)和CH3CN(乙腈)进行苄型或芳族取代,随后2)使用a)LiOH(氢氧化锂)和b)NH3(氨)和HATU(氮杂苯并三唑四甲基脲鎓六氟磷酸盐)形成酰胺,来制备B为的式(I)的化合物。
-路线B:
通过1)使用K2CO3(碳酸钾)、CH3CN(乙腈)和威尔金森催化剂(RhCl(PPh3)3)进行钌催化的合成,随后2)使用NaBH4(硼氢化钠)、AcOH(乙酸)和MeOH(甲醇)或NaBH(OAc)3(三乙酰氧基硼氢化钠)、和DCE(二氯乙烷)进行苄型或芳族取代,制备B为的式(I)的化合物。
2.脂族和杂环烷基酰胺
通过1)使用K2CO3(碳酸钾)和CH3CN(乙腈)进行取代,2)使用TFA(三氟乙酸)和DCM(二氯甲烷)或TMSNCO(三甲基异氰酸酯)进行脱保护反应,和3)使用a)LiOH(氢氧化锂)、和b)NH3(氨)和HATU(氮杂苯并三唑四甲基脲鎓六氟磷酸盐)形成酰胺,来制备B为的式(I)的化合物。
实施例B–生物学
抗病毒效应
材料&方法
细胞病变效应(CPE)测定实验程序:
RSV滴度:6.9x106 pfu/ml
MOI=用于感染的Pfu/细胞数
1)将HEp-2细胞以5000个细胞/孔接种在384孔板中的25μl测定培养基中,在37℃下5%CO2中温育24小时。除第一行只含培养基(低对照)外,每个孔都接种细胞。
2)使用Echo550液体处理器分配化合物。所有化合物均以10mM原液浓度使用。所有测定中均包括阳性对照利巴韦林作为对照化合物。
3)预计细胞每过24小时翻倍。
4)第二天以RSV MOI 0.5感染细胞,添加5μl在测定培养基中稀释的病毒。
5)用5μl测定培养基处理未感染的细胞(高对照)。
6)将板以400rpm离心10秒,以让病毒沉到细胞上。
7)将细胞在37℃下5%CO2中温育3天。
9)将板在室温下温育30分钟。
10)在Envision读板器上测量发光。
结果
图1-20中显示了对感染和未感染细胞的结果。结果表明,经式(I)的化合物处理的被HRSV感染和未感染的细胞呈现高的存活率%,从而证明了本发明的化合物对HRSV的有效抗病毒效应。
Claims (12)
1.由下式(I)表示的化合物,及其立体异构体和药用盐:
其中:
R1a和R1b独立地选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代;并且
B选自:
其中:
R2选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
R3选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
R4是-CONHR5基团,其中R5是氢或(C1-C3)烷基,
其中:
R2选自氢、氧、(C1-C3)烷基,所述(C1-C3)烷基任选被至少一个羟基取代,并且
R6是氢或(C1-C3)烷基,
其中:
n是0或1,
R2’选自氢、氧、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,
R3’选自氢、卤素、羟基、氰基、(C1-C3)烷基和(C1-C3)烷氧基,所述(C1-C3)烷基和(C1-C3)烷氧基任选被至少一个卤素或羟基取代,并且
R4’是氢或-CONHR5’基团,其中R5’是氢或(C1-C3)烷基;
或B选自:
其中:
m和p独立地是0、1或2,并且
R4”是-CONHR5”基团,其中R5”是氢或(C1-C3)烷基。
2.根据权利要求1所述的化合物,其中R1a和R1b相同。
3.根据权利要求1或2所述的化合物,其中R1a和R1b是氢或卤素。
4.根据权利要求1所述的化合物,其中R2或R2’选自氢、氧和任选被至少一个羟基取代的(C1-C3)烷基。
5.根据权利要求1所述的化合物,其中R3或R3’选自氢、卤素和(C1-C3)烷氧基。
11.一种药物组合物,其包含如权利要求1至10中的任一项所定义的化合物和可接受的药用赋形剂。
12.根据权利要求11所述的药物组合物在制备用于治疗由人呼吸道合胞病毒引起的病毒性呼吸道感染的药物中的用途。
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