CN114599367A - 用于预防或治疗慢性阻塞性肺病(copd)的组合物 - Google Patents
用于预防或治疗慢性阻塞性肺病(copd)的组合物 Download PDFInfo
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- CN114599367A CN114599367A CN202080073146.2A CN202080073146A CN114599367A CN 114599367 A CN114599367 A CN 114599367A CN 202080073146 A CN202080073146 A CN 202080073146A CN 114599367 A CN114599367 A CN 114599367A
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Abstract
本发明涉及一种用于预防或治疗慢性阻塞性肺病的药物组合物,其包含由由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分,本发明涉及通过使用所述化合物或所述组合物预防或治疗慢性阻塞性肺病的方法,以及涉及所述化合物或所述组合物在制备用于治疗慢性阻塞性肺病的药物中的用途。
Description
技术领域
本发明涉及一种用于预防或治疗慢性阻塞性肺病的药物组合物,其包含由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分,本发明涉及使用所述化合物或所述组合物预防或治疗慢性阻塞性肺病的方法,以及涉及所述化合物或所述组合物在制备用于治疗慢性阻塞性肺病的药物中的用途。
发明背景
慢性阻塞性肺病(COPD)是由于气道和肺实质炎症引起的细支气管和肺实质的病理改变所致的疾病,具有阻塞性细支气管炎和肺气肿(肺实质破坏)的特征。慢性阻塞性肺病的类型包括慢性阻塞性支气管炎、慢性细支气管炎、肺气肿等。
吸烟被认为是导致COPD的最重要原因。烟雾在肺组织中作为强毒性物质,促进氧化物、促炎因子和趋化因子的产生,从而促进诸如中性粒细胞等炎症细胞的过度迁移。已经迁移到肺组织中的炎症细胞会分泌许多炎症介质,进一步加剧肺组织中的炎症。作为促进这种炎症反应的介质,TNF-α等主要是已知的并且被用作由烟草烟雾引起的炎症反应的重要标志物。
在最近的一项研究中,报道了上皮细胞向间充质细胞转化(epithelial-to-mesenchymal transition,EMT)可能是慢性阻塞性疾病的致病机制之一(Courtney JM等人,Cells Tissues Organs.2017;203(2):99-104),也已经报道了在COPD患者的气道中发现了FN-EDA(含额外结构域A的纤连蛋白),它是细胞外基质(ECM)中的主要蛋白质之一(Annoni R等人,Eur Respir J.2012;40(6):1362-73)。
目前,已经开发了用于治疗慢性阻塞性肺病的物质主要用于改善肺组织炎症,主要使用类固醇、抗炎药等。但这些物质会引起如免疫抑制、耐药性等多种副作用,不适合需要长期治疗的慢性阻塞性肺病患者。因此,迫切需要开发一种能够有效治疗COPD的药物。
[相关技术参考]
(专利文件1)韩国专利公开号10-2014-0128886
发明详述
技术问题
本发明提供一种用于预防或治疗慢性阻塞性肺病的药物组合物,其包含由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分。
本发明提供一种预防或治疗慢性阻塞性肺病的方法,其包括将所述药物组合物给药至个体。
本发明提供所述组合物在制备预防或治疗慢性阻塞性肺病的药物中的用途。
本发明提供一种预防或治疗慢性阻塞性肺病的方法,其包括将治疗有效量的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐给药至个体。
本发明提供由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐用于预防或治疗慢性阻塞性肺病的用途。
本发明提供由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐在制备用于治疗慢性阻塞性肺病的药物中的用途。
技术方案
在上述背景下,本发明人进行了开发慢性阻塞性肺病的治疗剂的研究工作,结果确认了本发明的化合物在具有诱导的COPD的小鼠肺组织中对免疫细胞的浸润、炎症细胞的浸润和炎性细胞因子的表达表现出抑制作用,并且对TGF-β1诱导的EMT和作为主要ECM蛋白的FN-EDA的表达表现出抑制作用,从而完成本发明。
这会在下面详细描述。同时,本发明中公开的每个描述和实施方案也可以分别适用于其它描述和实施方案。换言之,本发明所公开的各要素的所有组合均落在本发明的范围内。此外,不能视作本发明的范围限于以下描述的具体描述。
本发明提供了一种用于预防或治疗慢性阻塞性肺病的药物组合物,其包含由以下化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分:
[化学式I]
其中
Xa和Xb各自独立地为CH或N,
L1和L2各自独立地为氢、卤素、-CF3或者-C1-3直链或支链烷基,
Q是C(=O)、S(=O)2、S(=O)或C(=NH),
Y选自以下基团:
M是C、N、O、S或S(=O)2(此时,如果M是C,则l和m是1;如果M是N,则l是1且m是0;如果M是O、S或S(=O)2,则l和m是0),
Ra1和Ra2各自独立地为氢;羟基;-C1-4直链或支链烷基,其是未取代的或被至少一个卤素取代;-C1-4直链或支链醇;二苯甲基(benzhydryl);-C1-4直链或支链烷基,其被具有1至3个选自N、O或S的杂原子作为环成员的饱和或不饱和的五至七元杂环化合物取代(此时,杂环化合物可以是未取代的,或者至少一个氢可任选地被OH、OCH3、CH3、CH2CH3或卤素取代);具有1至3个选自N、O或S的杂原子作为环成员的饱和或不饱和的五至七元杂环化合物(此时,杂环化合物可以是未取代的,或者至少一个氢可任选地被OH、OCH3、CH3、CH2CH3或卤素取代);苯基,其是未取代的或者其中至少一个氢被卤素、C1-4烷氧基、C1-2烷基或羟基取代;苄基,其是未取代或者其中至少一个氢被卤素、C1-4烷氧基、C1-2烷基或羟基取代;-S(=O)2CH3;卤素;-C1-6直链或支链烷氧基;-C2-6烷氧基烷基;-C(=O)Rx,其中Rx是C1-3直链或支链烷基或C3-10环烷基;其中Rc和Rd独立地是氢或者C1-3直链或支链烷基;
n是0、1或2的整数,
Rb是氢;羟基;-C1-6直链或支链烷基,其是未取代的或者其中至少一个氢被卤素取代;-C(=O)CH3;-C1-4直链或支链羟基烷基;-C1-6直链或支链烷氧基;-C2-6直链或支链烷氧基烷基;-CF3;卤素;或
Re和Rf各自独立地为氢或者-C1-3直链或支链烷基,并且
Z选自以下基团:
Pa和Pb各自独立地为氢;羟基;-C1-4直链或支链烷基,其是未取代的或者其中至少一个氢被卤素取代;卤素;-CF3;-OCF3;-CN;-C1-6直链或支链烷氧基;-C2-6直链或支链烷基烷氧基;-CH2F;或-C1-3醇,
x、y和z各自独立地为0或1的整数,并且
Rg1、Rg2和Rg3各自独立地选自氢;羟基;-C1-3烷基;-CF3;-C1-6直链或支链烷氧基;-C2-6直链或支链烷基烷氧基;-C(=O)CH3;-C1-4直链或支链羟基烷基;-N(CH3)2;卤素;苯基;-S((=O)2)CH3;或以下基团:
在本发明中,由上述化学式I表示的化合物可以是由以下化学式Ia表示的化合物:
[化学式Ia]
其中
Y选自以下基团:
其中M、l、m、n、Ra1、Ra2和Rb各自与上述化学式I中定义的相同,
Pa和Pb各自独立地为氢;羟基;-C1-4直链或支链烷基,其是未取代的或者其中至少一个氢被卤素取代;卤素;-CF3;-OCF3;-CN;-C1-6直链或支链烷氧基;-C2-6直链或支链烷基烷氧基;-CH2F;或-C1-3醇。
根据本发明的一个实施方案,
Y选自以下基团:
其中n和Rb各自与上述化学式I中定义的相同,
Pa和Pb各自独立地为氢;卤素;-CF3;或-C1-6直链或支链烷氧基。
在本发明中,“卤素”是F、Cl、Br或I。
根据本发明的一个具体实施方案,由上述化学式I表示的化合物可以是下表所述的化合物。
根据本发明的一个具体实施方案,由上述化学式I表示的化合物可以是下表所述的化合物。
在本发明中,由上述化学式I表示的化合物可以通过韩国未审查专利公开第2014-0128886号中公开的方法制备,但不限于此。
在本发明中,术语“药学上可接受的”可以指的是生理学可接受的并且当给药至个体时通常不会引起过敏反应如胃肠道紊乱、头晕等或其它类似反应的药物。
本发明的药学上可接受的盐可以通过本领域技术人员已知的常规方法制备。
本发明的药学上可接受的盐可以包括例如由钙、钾、钠、镁等制备的无机离子盐;由盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸、硫酸、氢碘酸等制备的无机酸盐;由乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸等制备的有机酸盐;由甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸等制备的磺酸盐;由甘氨酸、精氨酸、赖氨酸等制备的氨基酸盐;由三甲胺、三乙胺、氨、吡啶、甲基吡啶等制备的胺盐;等等,但不限于此。在本发明中,优选的盐可以包括盐酸、三氟乙酸、柠檬酸、溴酸、马来酸、磷酸、硫酸和酒石酸的盐。
在本发明中,术语“慢性阻塞性肺病(COPD)”可以是指伴随有气道不可逆阻塞且由气道和肺实质炎症引起的细支气管和肺实质的病理改变所致的疾病,包括慢性阻塞性支气管炎、慢性细支气管炎、肺气肿(肺实质破坏)等。
在本发明中,术语“预防”可以指通过给药本发明的化学式I的化合物、其旋光异构体或其药学上可接受的盐而抑制或延缓疾病发生的所有行为。
在本发明中,术语“治疗”可以指通过给药本发明的化学式I的化合物、其旋光异构体或其药学上可接受的盐,从而使可能发生疾病或患有疾病的个体的症状得到改善或好转的所有行为。
本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐可用于预防或治疗慢性阻塞性肺病。
包含由本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分的药物组合物可用于预防或治疗慢性阻塞性肺病。
在这方面,根据本发明的一个具体实施方案,证实本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐抑制免疫细胞的浸润(图2),通过减少总细胞、巨噬细胞和中性粒细胞的数量来抑制炎症细胞的浸润(图3),并降低炎症细胞因子(特别是IL-6、IFN-γ、MCP-1和TNF-α)的表达(图4)。
此外,证实了上述化合物显著增加上皮标记蛋白E-Cad的表达,显著降低抑制TGF-β1诱导的EMT的间充质标记蛋白N-Cad的表达(图5),以及降低作为主要ECM蛋白的FN-EDA的表达(图6)。
本发明的药物组合物可显示预防或治疗慢性阻塞性肺病的效果,其效果水平可被认为与传统已知的用于治疗COPD的组合物相似、基本相同或更好。
除了由上述化学式I表示的化合物、其旋光异构体或其药学上可接受的盐外,本发明的药物组合物还可以进一步包含至少一种类型的药学上可接受的载体。所述药学上可接受的载体可以是本领域常规使用的载体,具体包括但不限于乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油。除上述成分外,本发明的药物组合物还可以包含润滑剂、保湿剂、甜味剂、调味剂、乳化剂、助悬剂、防腐剂、分散剂、稳定剂等。此外,本发明的药物组合物可通过使用药学上可接受的载体和赋形剂配制成诸如片剂、粉末、颗粒剂、丸剂、胶囊剂、混悬剂、乳剂、供内服使用的液体(liquid for internal use)、油剂(oiling agent)、糖浆剂等口服剂型,以及外用制剂、栓剂和注射用无菌溶液剂形式,因此可以单位剂量形式制备或通过加入多剂量容器中而制备。此类制剂可以根据本领域用于配制的常规方法或Remington's PharmaceuticalScience(第19版,1995)中公开的方法制备,并且可以根据每种疾病或成分配制成不同制剂。
作为使用本发明的药物组合物的用于口服给药的制剂的非限制性实例,可以是片剂、糖锭剂(troches)、锭剂(lozenges)、水溶性混悬剂、油混悬剂、制备的粉末(preparedpowders)、颗粒剂、乳剂、硬胶囊剂、软胶囊剂、糖浆剂、酏剂等。为了将本发明的药物组合物配制成用于口服给药的制剂,可以使用以下:粘合剂,如乳糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、支链淀粉、纤维素、明胶等;赋形剂,如磷酸二钙等;崩解剂,如玉米淀粉、甘薯淀粉等;润滑剂,如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠、聚乙二醇蜡等;其中也可以使用甜味剂、调味剂、糖浆等。此外,在胶囊剂的情况下,除了上述材料之外,还可以使用诸如脂肪油等液体载体。
作为使用本发明的药物组合物的肠胃外制剂的非限制性实例,可以是注射溶液剂、栓剂、用于呼吸吸入的粉末、用于喷雾的气雾剂、软膏剂、用于涂抹的粉末(powders forapplication)、油剂(oils)、乳膏剂等。为了将本发明的药物组合物配制成用于肠胃外给药的制剂,可以使用以下:无菌水溶液、非水溶剂、混悬剂、乳剂、冻干制剂、外用制剂(external preparations)等。作为所述非水溶剂和混悬剂,可以使用以下但不限于:丙二醇、聚乙二醇、植物油如橄榄油、可注射酯如油酸乙酯等。
本发明的药物组合物可根据预期的方法进行口服给药或肠胃外给药,优选口服给药,但不限于此。
本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐的日剂量具体可以为约0.1至10,000mg/kg、约1至8,000mg/kg、约5至6,000mg/kg,或约10至4,000mg/kg,更具体地约50至2,000mg/kg,但不限于此,也可以通过将化合物的日剂量分开来一天一次或一天数次施用。
本发明的药物组合物的药学有效剂量和有效剂量可根据所述药物组合物的配制方法、给药方式、给药时间和/或给药途径等而变化,也可以根据各种因素(包括通过给药所述药物组合物所要实现的反应类型和程度,给药个体的类型,个体的年龄、体重、一般健康状况、疾病症状或严重程度、性别、饮食和排泄,同一时间或不同时间所要用于相应个体的其它药物组合物的成分等,以及制药领域熟知其它类似因素)而多样化,本领域技术人员可以很容易地确定和开处用于指定治疗的有效剂量。
本发明的药物组合物可以一天给药一次,或者通过将组合物的日剂量分开而分成一天数次给药。本发明的药物组合物可以作为单独的治疗剂或与其它治疗剂组合给药,并且可以与常规治疗剂相继或同时给药。考虑到所有上述因素,本发明的药物组合物可以以最小量达到最大效果而没有副作用的量给药,这种量可由本发明所属领域技术人员容易地确定。
本发明的药物组合物即使单独使用也可以表现出优异的效果,但为了提高疗效,还可以进一步与诸如激素疗法、药物治疗等各种方法组合使用。
本发明提供了一种预防或治疗慢性阻塞性肺病的方法,其包括将所述药物组合物给药至个体。
本发明提供了一种预防或治疗慢性阻塞性肺病的方法,其包括将治疗有效量的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐给药至个体。
所述术语“慢性阻塞性肺病”、“预防”和“治疗”的含义可以与上述相同。
在本发明中,术语“给药”可以指通过适当的方法将预定物质给药至个体。
在本发明中,术语“个体”可以指可能或已经发生慢性阻塞性肺病的所有动物,如大鼠、小鼠、家畜等,包括人,特别是指哺乳动物,包括人,但不限于此。
根据本发明的用于预防或治疗慢性阻塞性肺病(COPD)的方法可以指给药治疗有效量的所述药物组合物。
在本发明中,术语“治疗有效量”可以指足以以适用于医学治疗的合理风险/收益比治疗疾病并且不会引起副作用的量,并且可以由本领域技术人员根据包括患者的性别、年龄、体重和健康状况、疾病类型、严重程度、药物活性、对药物的敏感性、给药方法、给药时间、给药途径、排泄率、治疗时间、药物组合或并用等因素以及药物领域众所熟知的其它因素加以确定。优选的是,特定的治疗有效量是根据各种因素不同地施用于每个特定患者的量,所述因素包括所要由此实现的反应的类型和程度,包括存在在某些情况下使用的其它制剂的特定组合物,患者的年龄、体重、一般健康状况、性别和饮食,给药时间,给药途径,组合物的分泌率,治疗期和与特定组合物一起或同时使用的药物,以及在制药领域熟知的其它类似因素。
通过给药由上述化学式I表示的化合物、其旋光异构体或其药学上可接受的盐,根据本发明的预防或治疗慢性阻塞性肺病的方法不仅可以包括在其症状表现之前处理疾病本身,而且还可以包括抑制或避免这些症状。在管理疾病中,某种活性成分的预防或治疗剂量可以根据疾病或病症的特征和严重程度以及该活性成分的给药途径而变化。其剂量和频率可以根据个体患者的年龄、体重和反应而变化。自然考虑到这些因素,本领域技术人员可以容易地选择合适的剂量和用法。此外,根据本发明的预防或治疗慢性阻塞性肺病的方法可以进一步包括与上述由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐化合物一起给药治疗有效量的有助于预防或治疗该疾病的其它活性剂,所述其它活性剂可与由上述化学式I表示的化合物、其旋光异构体或其药学上可接受的盐一起表现出协同作用或加和作用。
本发明提供了由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐用于预防或治疗慢性阻塞性肺病的用途。
本发明提供了由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐在制备用于预防或治疗慢性阻塞性肺病的药物中的用途。
本发明提供了本发明的药物组合物在制备用于预防或治疗慢性阻塞性肺病的药物中的用途。
所述术语“慢性阻塞性肺病”、“预防”和“治疗”的含义可以与上述相同。
为了制备药物,可以将本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐与药学上可接受的辅剂、稀释剂、载体等混合,并且可以与其它活性剂一起制成复合制剂,从而提供协同作用。
如果不相互矛盾,本发明的药物组合物、治疗方法和用途中提及的事项同样适用。
有益效果
本发明的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐对免疫细胞的浸润和炎症细胞的浸润表现出优异的抑制作用,并在具有诱导的COPD的小鼠中表现出抗炎作用,以及对TGF-β1诱导的EMT和作为主要ECM蛋白的FN-EDA的表达表现出抑制作用,因此可用于预防或治疗慢性阻塞性肺病。
附图简述
图1是显示用于确定肺组织中细胞浸润程度的参考图像的视图。
图2是显示通过观察在分别给药对比组合物和实施方案组合物的组中的细胞浸润程度而测量的分值的示意图。
图3是显示在分别给药对比组合物和实施方案组合物的组中的总细胞、巨噬细胞和嗜中性粒细胞数量的示意图。
图4是显示在分别给药对比组合物和实施方案组合物的组中的炎症细胞因子(IL-6、IFN-γ、MCP-1和TNF-α)的表达水平的示意图。
图5是显示在分别用对比组合物和实施例组合物处理的组中的上皮标记蛋白(E-Cad)和间充质标记蛋白(N-Cad)的表达水平的示意图。
图6是显示在分别用对比组合物和实施方案组合物处理的组中的主要ECM蛋白(FN-EDA)的表达水平的示意图。
最佳实施方式
在下文中,通过示例性实施方案更详细地描述本发明。提供这些示例性实施方案仅用于示例说明本发明的目的,因此本领域技术人员会清楚本发明的范围不限于此。
制备例1:N-(4-(羟基氨基甲酰基)苄基)-N-(3-(三氟甲基)苯基)吗啉-4-甲酰胺
[化合物374]的合成
[步骤1]4-((3-(三氟甲基)苯基氨基)甲基)苯甲酸甲酯)的合成
将3-(三氟甲基)苯胺(0.30g,1.84mmol)和碳酸钾(0.76g,5.53mmol)溶解在二甲基甲酰胺(DMF,5mL)中,然后加入4-(溴甲基)苯甲酸甲酯(0.42g,1.84mmol)。使所得溶液在室温下反应一天并用乙酸乙酯稀释。将反应物用水和饱和氯化钠水溶液洗涤,然后用无水硫酸镁干燥并过滤,之后减压浓缩。将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=20%),由此获得标题化合物(0.37g,65%)。
1H NMR(400MHz,DMSO-d6)δ7.93(d,2H,J=8.3Hz),7.49(d,2H,J=8.3Hz),7.24(t,1H,J=7.9Hz),6.88-6.78(m,4H),4.42(d,2H,J=6.1Hz),3.83(s,3H),MS(ESI)m/z 310(M++H).
[步骤2]4-((((4-硝基苯氧基)羰基)(3-(三氟甲基)苯基)氨基)甲基)苯甲酸甲酯的合成
将4-((3-(三氟甲基)苯基氨基)甲基)苯甲酸甲酯(0.26g,0.82mmol)和4-硝基苯基氯甲酸酯(0.33g,1.65mmol)溶解在乙腈(10mL)中,然后加入碳酸钾(0.34g,2.47mmol)。将所得溶液在室温下反应一天并用乙酸乙酯稀释。将反应物用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥并过滤,之后减压浓缩。将剩余物经柱层析(二氧化硅;乙酸乙酯/己烷=20%)纯化,由此获得无色油状物形式的标题化合物(0.35g,89%)。
1H NMR(400MHz,CDCl3)δ8.20(d,2H,J=10.2Hz),8.01(d,2H,J=7.8Hz),7.56-7.46(m,3H),7.35(d,3H,J=8.0Hz),7.26(d,2H,J=8.1Hz),5.01(bs,2H),3.90(s,3H).
[步骤3]4-((N-(3-(三氟甲基)苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将4-((((4-硝基苯氧基)羰基)(3-(三氟甲基)苯基)氨基)甲基)苯甲酸甲酯(0.29g,0.60mmol)溶解在二甲基甲酰胺(10ml)中,然后加入碳酸钾(0.25g,1.81mmol)和吗啉(0.05mL,0.60mmol)。将所得溶液在60℃反应两天,然后用饱和氯化铵溶液稀释。用乙酸乙酯萃取,之后将所得萃取物干燥并用无水硫酸钠过滤,然后减压浓缩。将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=50%),由此获得标题化合物(0.15g,60%)。
1H NMR(400MHz,DMSO-d6)δ7.97(d,2H,J=8.2Hz),7.43-7.32(m,5H),7.20(d,1H,J=8.0Hz),4.94(s,2H),3.90(s,3H),3.50(t,4H,J=4.8Hz),3.25(t,4H,J=4.8Hz);MS(ESI)m/z 423(M++H).
[步骤4]N-(4-(羟基)氨基甲酰基)苄基-N-(3-(三氟甲基)苯基)吗啉-4-甲酰胺的合成
将4-((N-(3-(三氟甲基)苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯(15g,0.36mmol)溶解在甲醇(55mL)中,然后加入羟胺水溶液(55wt%,1mL)和氢氧化钾(0.10g,1.81mmol)并搅拌过夜。反应完成后,对所得溶液进行减压蒸馏以从中除去甲醇,然后用乙酸乙酯和水进行萃取,从而进行后处理。将所得萃取物用无水硫酸钠干燥并过滤,然后减压浓缩。将剩余物在乙醚中搅拌,之后制备固体产物,过滤并干燥,从而获得呈白色固体形式的标题化合物(0.082g,54%)。
1H NMR(400MHz,MeOD-d3)δ11.14(brs,1H),8.99(brs,1H),7.85(d,2H,J=8.0Hz),7.66-7.27(m,6H),4.94(s,2H),3.41(s,2H),3.15(s,2H).MS(ESI)m/z 424(M++H).
制备例2.N-(2,4-二氟苯基)-N-(4-(羟基氨基甲酰基)苄基)吗啉-4-甲酰胺[化合
物413]的合成
[步骤1]4-((2,4-二氟苯基氨基)甲基)苯甲酸甲酯的合成
将2,4-二氟苯胺(3.0g,23.2mmol)和4-甲酰基苯甲酸甲酯(3.81g,23.2mmol)溶解在甲醇(500mL)中并在室温下搅拌2小时,然后加入乙酸(1.33mL,23.2mmol)和氰基硼氢化钠(1.46g,23.2mmol)并搅拌一天。用空气稍微除去甲醇,然后沉淀出固体,过滤并干燥,从而获得呈白色固体形式的标题化合物(2.9g,45%)。
[步骤2]4-(((2,4-二氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯的合成
将4-((2,4-二氟苯基氨基)甲基)苯甲酸甲酯(2g,7.21mmol)和4-硝基苯基氯甲酸酯(1.45g,7.21mmol)溶解在二氯甲烷(50mL)中并在室温下搅拌三天,然后加入水以从中萃取有机层。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将剩余物干燥,从而获得呈黄色油状物形式的标题化合物(2.5g,78%)。
[步骤3]4-((N-(2,4-二氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将4-(((2,4-二氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯(0.50g,1.13mmol)和吗啉(0.098mL,1.13mmol)溶解在二甲基甲酰胺(10mL)中,并在60℃加热和搅拌两天。减压除去二甲基甲酰胺后,向反应混合物中倒入水,用乙酸乙酯进行萃取。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将剩余物通过柱层析(二氧化硅;乙酸乙酯/己烷=30%)纯化并浓缩,从而获得无色油状物形式的标题化合物(0.44g,98%)。
[步骤4]N-(2,4-二氟苯基)-N-(4-(羟基氨基甲酰基)苄基)吗啉-4-甲酰胺的合成
将4-((2,4-二氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯(0.10g,0.256mmol)溶解在甲醇(20mL)中,然后加入盐酸羟胺(0.089g,1.28mmol)和将氢氧化钾(0.144g,2.56mmol)加入并搅拌,由此滴加羟胺(50wt%水溶液;0.329mL,5.12mmol)并在室温下搅拌3小时。反应完成后,减压除去甲醇,然后将水倒入反应混合物中,并用乙酸乙酯进行萃取。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。然后,将所得浓缩物溶解在二氯甲烷中,之后加入己烷并沉淀固体,过滤,干燥,获得淡黄色固体形式的标题化合物(0.076g,76%)。
1H NMR(400MHz,MeOD-d3)δ7.65(d,2H,J=8.3Hz),7.41(d,2H,J=8.2Hz),7.27-7.25(m,1H),7.04-6.96(m,2H),4.80(s,2H),3.46-3.43(m,4H),3.22-3.19(m,4H);MS(ESI)m/z 392.1(M++H).
制备例3.N-(3-氯-4-氟苯基)-N-(4-(羟基氨基甲酰基)苄基)吗啉-4-甲酰胺[化
合物458]的合成
[步骤1]4-((3-氯-4-氟苯基氨基)甲基)苯甲酸甲酯的合成
将3-氯-4-氟苯胺(2.0g,13.7mmol)和4-甲酰基苯甲酸甲酯(2.26g,13.7mmol)溶解在甲醇(500mL)中并在室温下搅拌3小时,然后加入乙酸(0.786mL,13.7mmol)和氰基硼氢化钠(0.86g,13.7mmol)并搅拌一天。用空气稍微除去甲醇,然后沉淀出固体,过滤并干燥,从而获得灰色固体形式的标题化合物(2.9g,72%)。
[步骤2]4-(((3-氯-4-氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯的合成
将4-((3-氯-4-氟苯基氨基)甲基)苯甲酸甲酯(2.5g,8.51mmol)和4-硝基苯基氯甲酸酯(2.06g,10.2mmol)溶解在二氯甲烷(50mL)中并在室温下搅拌三天,然后加入水以萃取有机层。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将剩余物干燥,从而获得紫色油状物形式的标题化合物(2.5g,64%)。
[步骤3]4-((N-(3-氯-4-氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将4-(((-3-氯-4-氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯(0.20g,0.436mmol)和吗啉(0.038mL,0.436mmol)溶解在二甲基甲酰胺(10mL)中并在60℃加热并搅拌12小时。减压除去二甲基甲酰胺,然后向反应混合物中倒入水,用乙酸乙酯萃取。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将剩余物通过柱层析(二氧化硅;乙酸乙酯/己烷=20%)纯化并浓缩,从而获得无色油状物形式的标题化合物(0.022g,12%)。
[步骤4]N-(3-氯-4-氟苯基)-N-(4-(羟基氨基甲酰基)苄基)吗啉-4-甲酰胺的合成
将4-((N-(3-氯-4-氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯(0.050g,0.123mmol)溶解在甲醇(5mL)中,然后加入盐酸羟胺(0.043g,0.614mmol)和氢氧化钾(0.069g,1.23mmol)并搅拌,然后滴加羟胺(50wt%水溶液;0.158mL,2.46mmol)并在室温下搅拌3小时。反应完全后,减压除去甲醇,加入饱和碳酸氢钠水溶液,形成固体,过滤并干燥,由此获得白色固体形式的标题化合物(0.017g,34%)。
1H NMR(400MHz,DMSO-d6)δ7.63(d,2H,J=8.2Hz),7.44-7.42(m,1H),7.33-7.29(m,3H),7.15-7.11(m,1H),4.84(s,2H),3.41-3.40(m,4H),3.14-3.12(m,4H);MS(ESI)m/z408.1(M++H).
制备例4.N-(4-(羟基氨基甲酰基)苄基)-N-(3-甲氧基苯基)吗啉-4-甲酰胺[化合
物484]的合成
[步骤1]4-(((3-甲氧基苯基)氨基)甲基)苯甲酸甲酯的合成
将间茴香胺(3.23g,26.2mmol)和4-(溴甲基)苯甲酸甲酯(5.00g,21.8mmol)溶解在乙腈(50mL)中,然后加入N,N-二异丙基乙胺(5.80mL,32.7mmol)并在室温下搅拌16小时。当反应完成时,用乙酸乙酯和饱和碳酸氢钠水溶液进行萃取,然后将有机层用无水硫酸镁干燥并过滤。将剩余滤液减压浓缩,之后将剩余物经柱层析(二氧化硅;乙酸乙酯/己烷=5%)纯化并浓缩,由此获得黄色液体形式的标题化合物(5.14g,87%)。
[步骤2]4-(((3-甲氧基苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯的合成
将4-(((3-甲氧基苯基)氨基)甲基)苯甲酸甲酯(5.14g,18.9mmol)和4-硝基苯基氯甲酸酯(4.20g,20.8mmol)溶解在乙腈(100mL)中,然后加入碳酸钾(3.93g,28.4mmol)并在室温下搅拌3小时。当反应完成时,用乙酸乙酯和饱和碳酸氢钠水溶液进行萃取,之后将有机层用无水硫酸镁干燥并过滤。将剩余滤液减压浓缩,之后将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=20%)并浓缩,由此获得黄色液体形式的标题化合物(5.88g,71%)。
[步骤3]4-((N-(3-甲氧基苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将4-(((3-甲氧基苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯(5.88g,13.5mmol)溶解在二甲基甲酰胺(50mL)中,然后加入吗啉(2.35g,27.0mmol)和碳酸钾(5.60g,40.5mmol)并在60℃搅拌16小时。当反应完成时,用乙酸乙酯和饱和氯化铵水溶液进行萃取,然后将有机层用无水硫酸镁干燥并过滤。将剩余滤液减压浓缩,之后将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=30%)并浓缩,由此获得黄色固体形式的标题化合物(3.69g,71%)。
[步骤4]N-(4-(羟基氨基甲酰基)苄基)-N-(3-(甲氧基苯基)吗啉-4-甲酰胺的合成
将4-((N-(3-(甲氧基苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯(0.180g,0.468mmol)溶于甲醇(10mL)中,然后在室温加入羟胺(50.0wt%水溶液;1.43mL,23.4mmol),之后加入氢氧化钾(0.263g,4.68mmol)并在相同温度下搅拌30分钟。然后,在减压下从反应混合物中除去溶剂。将饱和氯化铵水溶液倒入所得浓缩物中,用乙酸乙酯萃取,将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将剩余物在室温下用二氯甲烷(2mL)和己烷(10mL)结晶,由此获得白色固体形式的标题化合物(0.140g,78%)。
1H NMR(400MHz,DMSO-d6)δ7.63(d,2H,J=8.1Hz),7.32(m,2H),7.19(t,1H,J=8.4Hz),6.69-6.67(m,2H),6.62(m,1H),4.84(s,2H),3.69(s,3H),3.39-3.36(m,4H),3.15-3.12(m,4H).MS(ESI)m/z 386(M++H).
制备例5.(N-(3-氟苯基)-N-(4-羟基氨基甲酰基)苄基)吗啉-4-甲酰胺[化合物
530]的合成
[步骤1]4-((3-氟苯基氨基)甲基)苯甲酸甲酯的合成
将4-甲酰基苯甲酸甲酯(1.47g,8.99mmol)溶解在甲醇(50mL)中,然后加入3-氟苯胺(1.0g,8.99mmol)。使所得溶液在室温下反应3小时,然后加入氰基硼氢化钠(NaCNBH3,0.56g,8.99mmol)和乙酸(1.03mL,17.99mmol)。将反应物在室温下反应一天后,减压除去反应溶剂,然后倒入饱和碳酸氢钠水溶液,用乙酸乙酯萃取。将有机层用无水硫酸镁脱水,减压浓缩。将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=20%),由此获得标题化合物(1.84g,79%)。
[步骤2]4-(((3-氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯的合成
将4-((3-氟苯基氨基)甲基)苯甲酸甲酯(2.7g,10.4mmol)和4-硝基苯基氯甲酸酯(4.20g,20.8mmol)溶解在乙腈(100mL)中,然后加入碳酸钾(4.32g,31.2mmol)。将所得溶液在室温下反应一天并用乙酸乙酯稀释。将反应物用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥并过滤,之后减压浓缩。将剩余物经柱层析(二氧化硅;乙酸乙酯/己烷=20%)纯化,由此获得无色油状物形式的标题化合物(2.65g,60%)。
[步骤3]4-((N-(3-氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将4-(((3-氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯(0.32g,0.75mmol)溶解在二甲基甲酰胺(5ml)中,然后加入碳酸钾(0.31g,2.24mmol)和吗啉(0.13mL,1.49mmol)。将所得溶液在60℃反应一天,然后用饱和氯化铵溶液稀释。用乙酸乙酯进行萃取,然后将所得萃取物用无水硫酸钠干燥并过滤,之后减压浓缩。将剩余物经柱层析纯化(二氧化硅;乙酸乙酯/己烷=30%),由此获得标题化合物(0.13g,45%)。
[步骤4]N-(3-氟苯基)-N-(4-羟基氨基甲酰基)苄基)吗啉-4-甲酰胺的合成
将4-((N-(3-氟苯基)吗啉-4-甲酰胺基)甲基)苯甲酸甲酯(0.108g,0.290mmol)溶于甲醇(10mL)中,然后在室温下加入羟胺(50.0wt%水溶液;1.19mL,19.4mmol),然后加入氢氧化钾(0.156g,2.78mmol)并在相同温度下搅拌16小时。然后,在减压下从反应混合物中除去溶剂,然后将饱和碳酸氢钠水溶液倒入所得浓缩物中,并用乙酸乙酯进行萃取。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,然后减压浓缩。过滤沉淀的固体并干燥,从而获得呈白色固体形式的标题化合物(0.062g,57%)。
1H NMR(400MHz,DMSO-d6)δ11.14(brs,1H),8.99(brs,1H),7.65(d,2H,J=7.0Hz),7.38-7.30(m,3H),7.05-6.85(m,3H),4.89(s,1H),3.44-3.42(m,4H),3.18-3.15(m,4H),2.08(s,3H).MS(ESI)m/z 374(M++H).
制备例6.N-(3-氟苯基)-N-(4-N-羟基氨基甲酰基)苄基)-1,4-氧氮杂环庚烷
(oxazepane)-4-甲酰胺[化合物652]的合成
[步骤1]4-((N-(3-氟苯基)-1,4-氧氮杂环庚烷-4-甲酰胺基)甲基)苯甲酸甲酯的合成
将制备例5步骤2获得的4-(((3-氟苯基)((4-硝基苯氧基)羰基)氨基)甲基)苯甲酸甲酯(0.290g,0.683mmol)、1,4-氧氮杂环庚烷(0.188g,1.367mmol)和碳酸钾(0.283g,2.050mmol)溶解在DMF(10mL)中,然后将反应溶液在60℃搅拌一天,然后将饱和NaHCO3水溶液倒入反应混合物中,之后用乙酸乙酯萃取。将有机层用饱和氯化钠水溶液洗涤,然后用无水硫酸镁脱水,之后减压浓缩。将所得浓缩物通过柱层析(二氧化硅,15g柱;乙酸乙酯/己烷=20至50%)纯化并浓缩,得到无色液体形式的标题化合物(0.116g,43.9%)。
[步骤2]N-(3-氟苯基)-N-(4-羟基氨基甲酰基)苄基)-1,4-氧氮杂环庚烷-4-甲酰胺的合成
将4-((N-(3-(氟苯基)-1,4-氧氮杂环庚烷-4-甲酰胺基)甲基)苯甲酸甲酯(0.116g,0.3mmol)溶解在甲醇(10mL)中,然后加入羟胺水溶液(加入50wt%,1mL)和氢氧化钾(0.168g,3.01mmol)并搅拌过夜。反应完成后,将所得溶液进行减压蒸馏以从中除去甲醇,然后用乙酸乙酯和水进行萃取,由此完成工作。将所得萃取物用无水硫酸钠干燥并过滤,减压浓缩,然后将剩余物在乙醚中搅拌,得到固体产物,过滤并干燥,由此获得白色固体形式的标题化合物(0.032g,27.5%)。
<实施例1>在具有诱导的COPD的动物模型中的治疗作用分析
<实施例1-1>具有诱导的COPD的动物模型的准备(吸烟+Poly I:C COPD模型)
将C57BL/6小鼠(雌性,7周龄)置于密封的烟雾箱中并暴露于香烟烟雾中一段时间以诱导COPD疾病。具体而言,将小鼠放入烟雾盒中,然后点燃香烟,将其过滤嘴连接到负压的管子上,这样就可以连续产生香烟烟雾。然后,将烟雾盒封闭,使小鼠在吸气的同时被迫吸入香烟烟雾。使小鼠共吸烟四周。小鼠在第一周的第一天、第二天和第三天分别暴露在一支、两支和四支香烟中一次,并在第四天和第五天分别再次暴露在四支香烟中两次和三次。之后,在剩下的三周内,小鼠每天3次暴露于四支香烟。在吸烟诱导期间的第3周和第4周期间,将Poly I:C(聚肌苷酸:聚胞苷酸)每周2次给药于麻醉小鼠的鼻腔,从而诱导吸烟+PolyI:C COPD(慢性阻塞性肺病)模型。
为了确认本发明的化合物的给药效果,将具有诱导的COPD的小鼠分成每组6只小鼠,如下表1所示根据给药物质[载体(Veh),化合物374(SM+1)或化合物458(SM+2)]、给药途径[口服给药(P.O.)]和给药间隔[每日一次(Q.D.)]对每组分类。
【表1】
组 | 给药剂量(mg/kg) | 给药途径 | 给药间隔 | 动物数量 |
Veh | - | P.O. | Q.D. | 6 |
SM+1 | 30 | P.O. | Q.D. | 6 |
SM+2 | 30 | P.O. | Q.D. | 6 |
(Veh:在DW中的0.5%MC)
<实施例1-2>评估免疫细胞浸润
为了确认本发明的化合物对预防或治疗慢性阻塞性肺病的作用,评估了免疫细胞浸润的程度。在从各组小鼠取出肺后,对肺组织切片进行H&E染色,并进行病理分析。根据图1的参考图像,细胞浸润程度被确定为0至3的分数,所述评分是通过观察每组的载玻片测量的[图1:0-无,1-轻度,2-中度和3-重度]。
结果,如图2所示,与吸烟+Poly I:C(SM+无药物)组相比,给药本发明化合物的组(SM+1和SM+2)表现出细胞浸润评分降低。由此可知,本发明的化合物表现出抑制免疫细胞浸润的作用,因此可用于慢性阻塞性肺病的预防或治疗。
<实施例1-3>支气管肺泡灌洗液(BAL液)分析
为了确认本发明的化合物对预防或治疗慢性阻塞性肺病的作用,对支气管肺泡灌洗液(BAL液)进行了分析。从各组小鼠中分离出2mL BAL液并离心。之后,将所得液体悬浮在磷酸盐缓冲溶液(PBS)中,然后计数总细胞数,并通过细胞离心涂片器将2×105个细胞附着在载玻片上。用diff-quick染色试剂盒染色后,根据染色细胞的性质将所得细胞分为巨噬细胞、中性粒细胞等,共计数300个细胞,然后关于总细胞数计算各细胞的比率以进行组间比较。
结果,如图3所示,将给药本发明化合物的组(SM+1和SM+2)与吸烟+Poly I:C(SM+无药物)的组进行比较,从而得出总细胞数、巨噬细胞数和中性粒细胞减少。由此可知,本发明的化合物表现出抑制炎症细胞浸润的作用,因此可用于预防或治疗慢性阻塞性肺病。(*P<0.05,**P<0.01,和***P<0.001)
<实施例1-4>肺组织中炎症细胞因子表达的分析
为了确认本发明的化合物对预防或治疗慢性阻塞性肺病的作用,分析了肺组织中炎症细胞因子的表达。从每组小鼠中取出肺,然后从肺组织中分离RNA。对于每种RNA,使用逆转录酶进行cDNA合成,然后通过实时PCR分析炎症细胞因子标志物如IL-6、IFN-γ、MCP-1和TNF-α的表达,从而比较各组之间诱导的炎症的程度。在这种情况下,实验中使用的引物序列如下表2所示。(*P<0.05,**P<0.01,***P<0.001)
【表2】
结果,如图4所示,将给药本发明化合物的组(SM+1和SM+2)与吸烟+Poly I:C(SM+无药物)的组进行比较,从而得出IL-6、IFN-γ、MCP-1和TNF-α的表达降低。因此,可以理解,本发明的化合物表现出抗炎作用,因此可用于预防或治疗慢性阻塞性肺病。
<实施例2>对TGF-β1-诱导的EMT的抑制作用
为了确认本发明的化合物对预防或治疗慢性阻塞性肺病的作用,分析了上皮标记蛋白(E-Cad)和间充质标记蛋白(N-Cad)的表达。将A549细胞在含有10%胎牛血清(FBS)和1%青霉素-链霉素(P/S)的RPMI-1640培养基中培养。将1.5×105个细胞铺在6孔板中并温育过夜。将所述细胞用5 ng/mL重组人转化生长因子β1(TGF-β1)培养,以诱导上皮细胞向间充质细胞转化(EMT)。将TGF-β1用RPMI-1640(1%FBS,1%P/S)稀释并与细胞一起温育48小时。将500μL培养基加样于离心过滤器(Ultra-0.5 mL)上并以14,000×g离心10分钟。将富集的培养基与15μL 4X样品缓冲液在100℃下沸腾5分钟,然后使用Western印迹进行分析。通过使用含有蛋白酶抑制剂混合物和磷酸酶抑制剂混合物的RIPA缓冲液裂解细胞。将裂解物在冰上温育3分钟并在13,000×g、4℃下离心20分钟。通过使用BCA蛋白质测定试剂盒对上清液进行定量并通过Western印迹分析。将制备的样品加载于NuPAGE Novex 4-12%Bis-Tris凝胶上,并在120V下分解。使用iBlot机器将蛋白质转移到硝酸纤维素膜上。根据制造商的说明使用EzBlock Chemi封闭所述膜。使用诸如E-钙粘蛋白(E-Cad)、N-钙粘蛋白(N-cad)、纤连蛋白-EDA(FN-EDA)等抗体。在与辣根过氧化物酶(HRP)缀合的二抗反应后,使用AmershamTM ECL selectTM Western印迹检测试剂显示免疫反应蛋白,并通过ChemiDocTM MP成像系统检测。用ImageJ软件量化条带的强度并标准化为β-肌动蛋白。
结果,如图5所示,与Vhcl(TGF-β1)处理相比,用本发明的化合物(374、458、413、484、530和652)处理的组表现出上皮标记蛋白E-Cad的表达显著增加,而间充质标记蛋白N-Cad的表达显著降低。
由此可知,本发明的化合物表现出抑制TGF-β1诱导的EMT的作用,因此可用于预防或治疗慢性阻塞性肺病。(*P<0.05,**P<0.01,且***P<0.001)
<实施例3>对降低FN-EDA蛋白质的作用
为了确认本发明的化合物对预防或治疗慢性阻塞性肺病的作用,分析了关键的细胞外基质(ECM)蛋白FN-EDA的表达。通过与上述实施例2中所述相同的方法进行分析。
结果,如图6所示,与Vhcl(TGF-β1)处理组相比,用本发明的化合物(374、458、413、484、530和652)处理的组表现出关键ECM蛋白FN-EDA的表达显著降低。
因此,可以理解,本发明的化合物表现出降低关键ECM蛋白FN-EDA的作用,因此可用于预防或治疗慢性阻塞性肺病。(*P<0.05,**P<0.01且***P<0.001)
<实施例4>统计学分析
使用Graph Pad Prism 5.0软件(post hoc:Dunnett)进行非配对T检验,所有数据均表示为平均值±SEM。P<0.05被认为具有统计学意义。
尽管上面已经详细描述了本发明的具体部分,但是对于本领域技术人员显而易见的是,这些详细描述仅用于示例说明示例性实施方案,而不是解释为限制本发明的范围。因此,应当理解,本发明的实质范围由所附权利要求及其等同物限定。
<110> 株式会社 钟根堂
<120> 用于预防或治疗慢性阻塞性肺病(COPD)的组合物
<130> P20018-CKD
<150> KR 10-2019-0132501
<151> 2019-10-23
<160> 8
<170> KoPatentIn 3.0
<210> 1
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 引物(F)_mIL-6
<400> 1
ctgcaagaga cttccatcca g 21
<210> 2
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物(R)_mIL-6
<400> 2
agtggtatag acaggtctgt tgg 23
<210> 3
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 引物(F)_mIFN-γ
<400> 3
atgaacgcta cacactgcat c 21
<210> 4
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 引物(R)_mIFN-γ
<400> 4
ccatcctttt gccagttcct c 21
<210> 5
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物(F)_mMCP-1
<400> 5
ttaaaaacct ggatcggaac caa 23
<210> 6
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物(R)_mMCP-1
<400> 6
gcattagctt cagatttacg ggt 23
<210> 7
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 引物(F)_mTNF-α
<400> 7
ctgaacttcg gggtgatcgg 20
<210> 8
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物(R)_mTNF-α
<400> 8
ggcttgtcac tcgaattttg aga 23
Claims (9)
1.用于预防或治疗慢性阻塞性肺病的药物组合物,其包含由以下化学式I表示的化合物、其旋光异构体或其药学上可接受的盐作为有效成分:
[化学式I]
其中
Xa和Xb各自独立地为CH或N,
L1和L2各自独立地为氢、卤素、-CF3或-C1-3直链或支链烷基,
Q是C(=O)、S(=O)2、S(=O)或C(=NH),并且
Y选自以下基团:
M是C、N、O、S或S(=O)2(此时,当M是C时,l和m是1;当M是N时,l是1且m是0;且当M是O、S或S(=O)2时,l和m是0),
Ra1和Ra2各自独立地为氢;羟基;-C1-4直链或支链烷基,其未被取代或被至少一个卤素取代;-C1-4直链或支链醇;二苯甲基;-C1-4直链或支链烷基,其被具有1至3个选自N、O或S的杂原子作为环成员的饱和或不饱和的五元至七元杂环化合物取代(此时,所述杂环化合物可以是未取代的或者至少一个氢可以任选地被OH、OCH3、CH3、CH2CH3或卤素取代);具有1至3个选自N、O或S的杂原子作为环成员的饱和或不饱和的五元至七元杂环化合物(此时,所述杂环化合物可以是未取代的或者至少一个氢可以任选地被OH、OCH3、CH3、CH2CH3或卤素取代);苯基,其是未取代的或者其中至少一个氢被卤素、C1-4烷氧基、C1-2烷基或羟基取代;苄基,其是未取代或者其中至少一个氢被卤素、C1-4烷氧基、C1-2烷基或羟基取代;-S(=O)2CH3;卤素;-C1-6直链或支链烷氧基;-C2-6烷氧基烷基;-C(=O)Rx,其中Rx是C1-3直链或支链烷基或者C3-10环烷基;其中Rc和Rd独立地为氢或C1-3直链或支链烷基;
N是0、1或2的整数,
Rb是氢;羟基;-C1-6直链或支链烷基,其是未取代的或者其中至少一个氢被卤素取代;-C(=O)CH3;-C1-4直链或支链羟基烷基;-C1-6直链或支链烷氧基;-C2-6直链或支链烷氧基烷基;-CF3;卤素;或
Re和Rf各自独立地为氢或者-C1-3直链或支链烷基,并且
Z选自以下基团:
Pa和Pb各自独立地为氢;羟基;-C1-4直链或支链烷基,其是未取代的或者其中至少一个氢被卤素取代;卤素;-CF3;-OCF3;-CN;-C1-6直链或支链烷氧基;-C2-6直链或支链烷基烷氧基;-CH2F;或-C1-3醇,
x、y和z各自独立地是0或1的整数,并且
Rg1、Rg2和Rg3各自独立地选自氢;羟基;-C1-3烷基;-CF3;-C1-6直链或支链烷氧基;-C2-6直链或支链烷基烷氧基;-C(=O)CH3;-C1-4直链或支链羟基烷基;-N(CH3)2;卤素;苯基;-S((=O)2)CH3;或以下基团:
6.根据权利要求1的药物组合物,其中所述药物组合物是口服给药的。
7.预防或治疗慢性阻塞性肺病的方法,所述方法包括将治疗有效量的根据权利要求1的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐给药至个体。
8.根据权利要求1的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐用于预防或治疗慢性阻塞性肺病的用途。
9.根据权利要求1的由化学式I表示的化合物、其旋光异构体或其药学上可接受的盐在制备用于治疗慢性阻塞性肺病的药物中的用途。
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AU (1) | AU2020370210A1 (zh) |
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NL2013012B1 (en) * | 2014-06-17 | 2016-07-05 | Sulfateq Bv | Compounds for the treatment of chronic obstructive airway diseases. |
CN110730660A (zh) * | 2017-04-26 | 2020-01-24 | 伊利诺伊大学评议会 | Nrf和HIF活化剂/HDAC抑制剂和使用其的治疗方法 |
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SIMON G. ROYCE ET AL.: "Histone deacetylases and their inhibitors: new implications for asthma and chronic respiratory conditions", 《CURR OPIN ALLERGY CLIN IMMUNOL》, vol. 14, no. 1, pages 44 - 48 * |
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US20230248735A1 (en) | 2023-08-10 |
EP4048280A1 (en) | 2022-08-31 |
WO2021079300A1 (en) | 2021-04-29 |
KR20210048431A (ko) | 2021-05-03 |
EP4048280A4 (en) | 2023-11-15 |
JP2022553549A (ja) | 2022-12-23 |
MX2022004809A (es) | 2022-05-16 |
AU2020370210A1 (en) | 2022-04-21 |
CA3150236A1 (en) | 2021-04-29 |
BR112022007623A2 (pt) | 2022-07-12 |
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