CN116891463A - 作为at2r激动剂的杂环化合物 - Google Patents
作为at2r激动剂的杂环化合物 Download PDFInfo
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- CN116891463A CN116891463A CN202310362646.3A CN202310362646A CN116891463A CN 116891463 A CN116891463 A CN 116891463A CN 202310362646 A CN202310362646 A CN 202310362646A CN 116891463 A CN116891463 A CN 116891463A
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Abstract
本发明提供了式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;所述杂环化合物对与AT2受体相关疾病有治疗作用,
Description
优先权信息
本发明请求2022年4月6日向中国国家知识产权局提交的专利申请2022103596406和2022年10月19日向中国国家知识产权局提交的专利申请2022112813695的优先权和权益,并且通过参照将其全文并入此处。
技术领域
本发明属于医药领域,具体地,本发明涉及到一种作为AT2R激动剂的杂环化合物及用途。
背景技术
特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是指肺泡上皮细胞受到损伤后异常修复,致使肺成纤维细胞增殖向肌成纤维细胞转化,细胞外基质分泌过多,胶原沉积,肺泡结构改变,最终形成纤维化。其发病机制尚未完全明确,目前研究认为与氧化应激、炎症反应和体液对肾素—血管紧张素—醛固酮系统(RAAS)的调节密切相关(Raghu G,et al.Am J Respir Crit CareMed,(2011)183:788-824;Du yi,Tianjin Pharmacy,2015.(02):60-63.)。目前认为RAAS系统在肺纤维化进程中扮演重要角色,血管紧张素转化酶(Angiotensin converting enzyme,ACE)可以将血管紧张素Ⅰ(AngiotensinⅠ,AngⅠ)水解为血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ),AngⅡ在各种炎症的发生、发展过程中发挥着重要的作用。
在人体中,已经鉴定出两类主要的AngⅡ受体,分别被命名为AngⅡ1型受体(AT1受体)和AngⅡ2型受体(AT2受体)。AngⅡ在许多器官中显示出调节血压、体液以及电解质的体内平衡这些生理作用,包括肾脏、肾上腺、心脏、血管、脑、胃肠道以及生殖器官。AngⅡ的效应是由AT1R和AT2R两种G蛋白偶联受体(GPCR)表达的平衡来调控。AT1R在整个生命周期均有表达,主要负责调节血压,其阻断剂在临床上被广泛用作降血压药物,AT1R控制多数AngⅡ生理作用。AT2R主要在胚胎组织中表达,与血压调控、神经生长、疼痛控制和心肌再生相关,靶向AT2R的药物可以改善心血管功能、缓解神经性疼痛等(Zhang,et al.Cell.2015May7;161(4):833-44.Zhang,et al.J Biol Chem.2015Dec4;290(49):29127-39.)。但是,在病理情况下,AT2R的表达明显升高,如脉管损伤、伤口愈合以及心力衰竭(de Gasparo et al,Phaemacol.Rev.(2000)52,415-472)。
在成人个体的数项研究似乎证实下列事实:在AngⅡ刺激后响应的调节中,AT2受体激活具有与AT1受体调节相反的效果。
已经证明AT2受体参与细胞凋亡以及细胞增殖的抑制(de Gasparo et al,Phaemacol.Rev.(2000)52,415-472)。最近,已经表明AT2受体激动剂可能用于治疗和/或预防消化道疾病,如消化不良和过敏性肠综合征,以及多器官衰竭(参见国际专利申请WO99/43339)。
仍然存在有效的和/或选择性AT2受体激动剂需求,预期可用于上述疾病。
发明内容
本发明的目的是提供一种作为AT2受体激动剂的杂环化合物及其用途,所述杂环化合物具有如本发明第一方面所示结构,所述杂环化合物可用于制备治疗和/或预防与AT2相关的疾病或病症的药物、药物组合物或制剂;或者治疗和/或预防与AT2相关的疾病或病症。
本发明的第一方面,提供了式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,L为未取代的或被一个或多个取代基取代的C1-C6烷基,每个取代基独立地选自卤素、C1-C6烷基、C1-C6卤代烷基、氧代(=O);
X1独立地选自S、O;
X2和X3各自独立地选自N或CRa;
Ra、R1和R3各自独立地为氢或选自下列取代基:卤素、羟基、氰基、氨基、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、-O-C3-C7环烷基;
所述Ra、R1和R3各自独立地被0、1、2、3、或4个选自下列的取代基取代:卤素、羟基、氨基、氰基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同;
m为0、1、2或3;
R2独立地选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基、C3-C7环烷基-C1-C6烷基;
Z选自O或NR4;
R4选自氢或C1-C3烷基;
环A为5-6元杂芳基;
n选自1、2、3、4或5;当取代基R5为多个时,所述取代基相同或不同;
R5选自H、卤素、-CN、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基;
所述R5中C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基独立地被0、1、2、3或4个选自下列的取代基取代:卤素、羟基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同。
在本发明一优选实施方案中,L为C1-C6烷基;
所述L任选地被下列取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基、氧代(=O)。
在本发明一优选实施方案中,L为C1-C3烷基。
在本发明一优选实施方案中,L为-CH2-。
在本发明一优选实施方案中,具有结构/> Ra为氢、卤素、羟基、氰基、氨基、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基;
Ra被0、1、2、3、或4个选自下列的取代基取代:卤素、羟基、氨基、氰基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同。
在本发明一优选实施方案中,具有结构/>
在本发明一优选实施方案中,R1选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7环烷基-C1-C6烷基。
在本发明一优选实施方案中,R1选自C1-C6烷基。
在本发明一优选实施方案中,R1为异丁基。
在本发明一优选实施方案中,R2选自C1-C6烷基、C1-C6卤代烷基。
在本发明一优选实施方案中,R2选自甲基、乙基、丙基、异丙基、丁基、异丁基。
在本发明一优选实施方案中,R2为丁基。
在本发明一优选实施方案中,R3选自氢、卤素、羟基、氰基、氨基、C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基;
较佳地,R3选自氢、卤素、氰基、甲基、卤代甲基、甲氧基、环丙基。
在本发明一优选实施方案中,Z选自O或NR4。
在本发明一优选实施方案中,Z选自NR4;R4选自氢或C1-C3烷基。
在本发明一优选实施方案中,R4选自氢。
在本发明一优选实施方案中,环A为5-6元杂芳基含1、2、3个杂原子;
n为1、2、3、4或5。
在本发明一优选实施方案中,所述杂原子选自N、O、S。
在本发明一优选实施方案中,所述杂原子为N。
在本发明一优选实施方案中,环A选自:吡咯、吡唑、咪唑、三氮唑、吡啶、嘧啶、哒嗪、吡嗪、三嗪。
在本发明一优选实施方案中,具有结构/>
R5选自H、卤素、-CN、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基;当R5为多个时,所述取代基相同或不同。
在本发明一优选实施方案中,R5选自H、卤素、甲基、环丙基、卤代甲基。
在本发明一优选实施方案中,具有结构/>
在本发明一优选实施方案中,具有结构/>
L为C1-C3烷基;
具有结构/>
R1选自C1-C6烷基;
Z选自O或NR4;
R4选自氢或C1-C3烷基;
R2选自C1-C6烷基。
在本发明一优选实施方案中,所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物包括:
。
本发明第二方面,提供了一种药物组合物,包括如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和药用佐剂、稀释剂或载体。
本发明第三方面,如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或第二方面所述药物组合物的用途,所述用途包括:
作为AT2受体激动剂;
和/或,预防和/或治疗AngⅡ的内源性产生不足的疾病;
和/或,预防和/或治疗期望或需要AngⅡ作用增加的疾病;
和/或,制备作为AT2受体激动剂,和/或预防和/或治疗AT2受体在其中表达并且期望或必需对其进行刺激的疾病的药物、药物组合物或制剂。
提供了如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或第二方面所述药物组合物预期可用于治疗胃肠道、心血管系统、呼吸道、肾脏、眼睛、女性生殖系统或中枢神经系统(CNS)的疾病。
应该提及的胃肠道疾病包括食管炎、巴雷特式食道、胃溃疡、十二指肠溃疡、消化不良(包括非溃疡消化不良)、胃食道反流、过敏性肠综合征、炎性肠炎、胰腺炎、肝病(如肝炎)、胆囊病、多器官衰竭、脓毒病。应该提及的其他胃肠道疾病包括口干燥症、胃炎、胃潴瘤、胃酸过多症、胆道疾病、腹部疾病、节段性回肠炎、溃疡结肠炎、腹泻、便秘、急绞痛、吞咽困难、恶心、呕吐以及舍格伦综合征。
应该提及的呼吸道疾病包括炎性疾病,如哮喘、阻塞性肺病(如慢性阻塞性肺部疾病)、肺炎、肺部高血压、成人呼吸窘迫综合征以及特发性肺纤维化。
应该提及的肾脏疾病包括肾衰、肾炎以及肾高血压。
应该提及的眼睛疾病包括糖尿病性视网膜病变、早产儿视网膜病变以及视网膜微血管化。
应该提及的女性生殖系统疾病包括排卵机制障碍。
应该提及的心血管疾病包括高血压、心肌肥大、心力衰竭、动脉粥样硬化、动脉血栓、静脉血栓、内皮功能障碍、内皮损害、气球扩张术后狭窄、血管生成、糖尿病并发症、微脉管功能障碍、心绞痛、心律不齐、间歇性跛行、先兆子痫、心肌梗塞、再梗死、缺血性损害、勃起功能障碍以及新内膜增生。
应该提及的CNS疾病包括认知功能障碍、摄食功能障碍、口渴、中风、脑出血、脑栓塞和脑梗塞。
如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或第二方面所述药物组合物也可用于生长代谢和增殖的调节,例如用于治疗肥大病、前列腺增生、自体免疫疾病、牛皮癣、肥胖、神经再生、溃疡愈合、脂肪组织肥大的抑制、干细胞分化和增殖、癌症(如胃肠道癌、肺癌等)、细胞凋亡、肿瘤(一般性地)、增生糖尿病、神经损害和器官排斥。
本发明的第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或第二方面所述药物组合物,适用于上述疾病地治疗和/或预防性治疗。
本发明另一方面提供了一种治疗疾病的方法,所属疾病为其中AngⅡ的内源性产生不足的疾病,和/或其中期望或必需增加AngⅡ作用的疾病,和/或其中AT2受体表达并且产生刺激是期望或必需的疾病,该方法包括对正患或易患所述疾病的人使用治疗有效量的本发明的第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或第二方面所述药物组合物。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
术语和定义
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH2O等同于OCH2。如本文所用,或/>表示基团的连接位点。如本文所用,“R1”、“R1”和“R1”的含义相同,可相互替换。对于R2等其它其他符号,类似定义的含义相同。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~6的整数”应当理解为记载了1、2、3、4、5和6的每一个整数。
在本申请中,“AT2受体”和“AT2R”具有相同的定义。
在本申请中,在单独或作为其他取代基一部分时,术语“卤素”是指氟、氯、溴、碘。
如本文所用,在单独或作为其他取代基一部分时,术语"氨基"表示-NH2。
如本文所用,在单独或作为其他取代基一部分时,术语"羟基"表示-OH。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基,叔丁基,戊基,异戊基,新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。
在单独或作为其他取代基一部分时,术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C1-C3烷基”),例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时,术语“C1-C6烷氧基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和烃基和氧原子组成,或者表示为C1-C6烷基-O-C1-C6烷基的定义如本说明书中所述,氧原子可以连接在C1-C6烷基的直链或直链的任何一个碳原子上。包括但不限于:甲氧基(CH3-O-)、乙氧基(C2H5-O-)、丙氧基(C3H7-O-)、丁氧基(C4H9-O-)。
在单独或作为其他取代基一部分时,术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如,“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15,3至9,3至6或3至5个碳原子的环状烷基,它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基,环丁基,环戊基,环己基和金刚烷基,或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中,环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C3-C7环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~7个碳原子,包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在单独或作为其他取代基一部分时,“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw,其中v=1至3,w=1至(2v+1))。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
在单独或作为其他取代基一部分时,术语“卤代”可与术语“卤素取代”互换使用。“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基。
在单独或作为其他取代基一部分时,术语“芳基”是指具有6到20个碳原子的单环或多环碳环,其中至少一个环是芳香环。当其中一个环是非芳香环时,该基团可通过芳香环连接,也可通过非芳香环连接。芳基的实例包括但不限于:苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基。
在单独或作为其他取代基一部分时,术语“杂芳环”是指单环或多环碳环,其中至少一个环原子为独立地选自氧、硫和氮的杂原子,其余的环原子为C,其中至少一个环是芳香环。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的,只要其是可能的即可)。当其中一个环是非芳香环时,该基团可通过芳香环连接,也可通过非芳香环连接。杂芳基的实例包括但不限于:咪唑基、吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、N-甲基吡咯基和四氢喹啉。术语“杂芳环”可以和术语“杂芳香环”、“杂芳基”或“杂芳环基”交换使用。
术语“5或6元杂芳基”应理解为具有5或6个环原子——且包含1-5个独立选自N、O和S的杂原子的芳族环基团,优选1-3个——独立选自N、O和S的杂原子的芳族环基团。杂芳基的实例包括但不限于:噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中,术语“盐”或“药学上可接受的盐”,包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在,例如作为纯旋光异构体,或作为异构体混合物,如作为外消旋和非对映异构体混合物,这取决于不对称碳原子的数量。当描述具有光学活性的化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号,其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时,应当理解为,手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂,当溶剂为水时,则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物,当本发明化合物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(2H),氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
有益效果
本发明人经过广泛而深入地研究,意外地开发了一种作为AT2R激动剂的杂环化合物,所述杂环化合物具有本发明中所示结构。本发明所述杂环化合物,可以预防或治疗与ΑΤ2相关的疾病或病症,表现出优良的药代动力学性质,具备较高的安全性和成药性质。
具体实施方式
以下结合具体实施例,进一步说明本发明。需理解,以下的描述仅为本发明的最优选实施方式,而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上,下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件,本领域技术人员可以对本发明的技术方案作出非本质的改动,这样的改动应当被视为包括于本发明的保护范围之中的。
本申请具有如下定义:
符号或单位:
IC50:半数抑制浓度,指达到最大抑制效果一半时的浓度
M:mol/L,例如正丁基锂(14.56mL,29.1mmol,2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液
N:当量浓度,例如2N盐酸表示2mol/L盐酸溶液
RT:保留时间
中间体A1:中间体A1的制备
(2-(N-(叔丁基)氨磺酰基)-5-异丁基苯基)硼酸
中间体A1的合成路线如下所示:
第一步:N-(叔丁基)-4-异丁基苯磺酰胺的合成
将双(三叔丁基磷)钯(69.9mg,136μmol)和异丁基氯化镁(2.00M,5.13mL)溶解在四氢呋喃(100mL)中,加入氯化锌(1.68g,12.3mmol)和4-溴-N-叔丁基-苯磺酰胺(2.00g,6.84mmol),加完后置换氮气,缓慢升至80℃反应12小时。冷却到室温,将反应液倒入水(200mL)中,再加入乙酸乙酯(200mL)萃取三次,然后用饱和食盐水(50mL)洗涤,有机相加入无水硫酸钠干燥,过滤,浓缩得到产物N-(叔丁基)-4-异丁基苯磺酰胺(900mg,3.34mmol)。
LC-MS,M/Z(ESI):268.1[M-H]+
第二步:(2-(N-(叔丁基)氨磺酰基)-5-异丁基苯基)硼酸的合成
将N-(叔丁基)-4-异丁基苯磺酰胺(900mg,3.34mmol)溶解在四氢呋喃(20mL)中,用干冰乙醇浴将反应液降温至-60℃,在氮气保护下缓慢滴加正丁基锂(2.5M,900mg,845μmol),加完后-60℃反应0.5小时,然后加入三异丙基硼酸酯(3.14g,16.7mmol),-60℃反应1小时。然后将反应液倒入水(20mL)中进行淬灭,然后加入乙酸乙酯(20mL)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到(2-(N-(叔丁基)氨磺酰基)-5-异丁基苯基)硼酸(540mg,1.72mmol)。
LC-MS,M/Z(ESI):312.1[M-H]+
实施例1:目标化合物I-1的制备
((2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯基)磺酰基)氨基甲酸丁酯
目标化合物I-1的合成路线如下所示:
第一步:1-((5-氯噻吩-2-基)甲基)-1H-咪唑的合成
将1H-咪唑(3.34g,49.03mmol),2-氯-5-(氯甲基)噻吩(7.80g,46.7mmol,5.61mL)和碳酸钾(19.4g,140mmol)溶解在乙腈(50mL)中,加热至50℃,反应2小时。然后将反应液倒入水(100mL)中进行淬灭,然后加入乙酸乙酯(100mL)萃取三次,收集有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,浓缩得到1-((5-氯噻吩-2-基)甲基)-1H-咪唑(8.07g,40.6mmol)。
LC-MS,M/Z(ESI):199.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.21(d,1H),7.00(s,2H),6.92(s,1H),5.36(s,2H)
第二步:2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺的合成
将(2-(N-(叔丁基)氨磺酰基)-5-异丁基苯基)硼酸(540mg,1.72mmol)和1-((5-氯噻吩-2-基)甲基)-1H-咪唑(684mg,3.44mmol)溶解在甲苯(10mL),乙醇(5mL),水(2mL)中,加入氢氧化钠(206mg,5.16mmol)和四(三苯基膦)钯(99.3mg,86.0μmol),置换氮气三次,在氮气保护下,加热至100℃,搅拌反应6小时。然后将反应液倒入水(20mL)中进行淬灭,然后加入乙酸乙酯(20mL)萃取三次,收集有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,浓缩。粗品用高效液相色谱分离(column:Waters Xbridge 150*25mm*5μm;溶剂:A=水+0.05%体积氨水(30%),B=乙腈;梯度:52%-82%,9min),得到2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺(74.5mg,0.18mmol)。
LC-MS,M/Z(ESI):432.1[M+H]+
第三步:2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯磺酰胺的合成
将2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺(74.5mg,180μmol)加入二氯甲烷(5mL)和三氟乙酸(5mL)中加热至40℃反应6小时。反应液用饱和碳酸氢钠溶液调至pH=5,然后浓缩得到2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯磺酰胺(100mg,粗品)。
LC-MS,M/Z(ESI):376.0[M+H]+
第四步:((2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯基)磺酰基)氨基甲酸丁酯的合成
2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯磺酰胺(100mg,粗品)和N,N-二异丙基乙胺(69.7mg,540μmol)溶解在二氯甲烷(10mL)中,加入氯甲酸正丁酯(36.7mg,270μmol),室温搅拌,反应2小时。反应液浓缩,粗品用高效液相色谱分离制备(柱子:Phenomenex luna C18 150*25mm*5μm;溶剂:A=水+0.05%体积甲酸(99.0%),B=乙腈;梯度:22%-52%,8分钟),得到((2-(5-((1H-咪唑-1-基)甲基)噻吩-2-基)-4-异丁基苯基)磺酰基)氨基甲酸丁酯(8.18mg,16.3μmol)。
LC-MS,M/Z(ESI):474.1[M-H]+
1H NMR(400MHz,CDCl3)δ8.12(d,1H),7.57-7.72(m,1H),7.13-7.23(m,3H),6.86-7.03(m,3H),5.09-5.32(m,2H),3.83-3.94(m,2H),2.52(d,2H),1.33-1.42(m,2H),1.24-1.30(m,1H),1.08-1.18(m,2H),0.87-0.99(m,6H),0.76-0.84(m,3H).
实施例2:目标化合物I-2的制备
(2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯基)磺酰氨基甲酸丁酯
目标化合物I-2的合成路线如下所示:
/>
第一步:(5-溴呋喃-2-基)甲醇的合成
将5-溴呋喃-2-甲醛(10.0g,57.1mmol)溶解在乙醇(60mL)中,氮气保护下在0℃下加入硼氢化钠(3.29g,86.9mmol),将反应液在20℃反应2小时。将反应液用1M盐酸淬灭,然后倒入水(50mL)中,用乙酸乙酯(100mL)萃取三次,收集有机相,无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=50:1-1:1)得到(5-溴呋喃-2-基)甲醇(4.50g,产率45.6%)。
LC-MS,M/Z(ESI):177.1[M+H]+
第二步:2-溴-5-(溴甲基)呋喃的合成
将(5-溴呋喃-2-基)甲醇(1.00g,5.65mmol)溶解在二氯甲烷(10mL)中,然后在0℃加入三溴化磷(4.59g,16.9mmol),将反应液在25℃反应2小时。后将反应液倒入水(30mL)中,用二氯甲烷(60mL)萃取,收集有机相,无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=50:1-0:1)得到2-溴-5-(溴甲基)呋喃(1.30g,产率93.4%)。
LC-MS,M/Z(ESI):239.1[M+H]+
第三步:1-((5-溴呋喃-2-基)甲基)-1H-咪唑的合成
将2-溴-5-(溴甲基)呋喃(1.20g,5.00mmol)和咪唑(681mg,10.0mmol)溶于丙酮(10mL)中,加入碳酸钾(2.07g,15.0mmol)在40℃反应1小时。将反应液倒入水(50mL)中,用二氯甲烷(100mL)萃取,收集有机相,无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=50:1-2:1)得到1-((5-溴呋喃-2-基)甲基)-1H-咪唑(1.10g,产率88.1%)。
LC-MS,M/Z(ESI):227.1[M+H]+
第四步:2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺的合成
将(2-(N-(叔丁基)氨磺酰基)-5-异丁基苯基)硼酸(450mg,1.44mmol)溶解在四氢呋喃(5mL)和水(5mL),加入1-((5-溴呋喃-2-基)甲基)-1H-咪唑(326mg,1.44mmol),再加入磷酸钾(1.52g,7.18mmol),XPhos Pd G4(123mg,143μmol),然后在氮气保护下60℃搅拌反应4小时。将反应液浓缩得到粗品,用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=50:1-1:1)得到2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺(100mg,产率16.7%)。
LC-MS,M/Z(ESI):416.1[M+H]+
第五步:2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯磺酰胺的合成
将2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-N-(叔丁基)-4-异丁基苯磺酰胺(50.0mg,120μmol)溶于三氟乙酸(1mL)和二氯甲烷(1mL)中,20℃反应8小时。将反应液倒入水(10mL)中,用饱和碳酸氢钠调pH=9,然后用二氯甲烷(30mL)萃取三次,收集有机相,无水硫酸钠干燥,过滤,浓缩。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=10:1-1:1)得到2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯磺酰胺(40.0mg,产率92.4%)。
LC-MS,M/Z(ESI):360.1[M+H]+
第六步:(2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯基)磺酰氨基甲酸丁酯的合成
将2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯磺酰胺(35.0mg,97.3μmol)和N,N-二异丙基乙胺(14.6mg,107μmol)溶解在二氯甲烷(3mL)中,加入氯甲酸丁酯(14.6mg,292μmol),0℃搅拌反应1小时。将反应液浓缩,通过高效液相色谱法分离纯化(柱子:UniSil 3-100C18 UItra(150*25mm*3μm);溶剂:A=水+0.05体积甲酸(99%),B=乙腈;梯度:30%-50%,7分钟),得到(2-(5-((1H-咪唑-1-基)甲基)呋喃-2-基)-4-异丁基苯基)磺酰氨基甲酸丁酯(10.2mg,产率20.5%)。
LC-MS,M/Z(ESI):460.2[M+H]+
1H NMR(DMSO-d6)δ:8.24(s,1H),7.91(d,1H),7.76(s,1H),7.63(s,1H),7.42(s,1H),7.24(s,1H),7.08(d,1H),6.91(s,1H),6.44(d,1H),5.28(s,2H),3.60(t,2H),2.47-2.50(m,2H),1.86-1.88(m,1H),1.24-1.34(m,2H),1.17-1.21(m,2H),0.88(d,6H),0.80(t,3H)
生物测试
可使用下述测试方法。
测试例1:化合物与AT2R结合试验
根据Angiotensin AT2 Receptor Ligand Binding Assay试剂盒(#C1TT1AT2,Cisbio)的实验操作说明书进行。首先将10mM化合物母液按照5×稀释倍数做梯度稀释(包含10个浓度,每个浓度两次重复),将160nL不同浓度的化合物加入384孔板中。在每个孔中加入40μL 1×TLB,室温震荡15分钟。预先准备一支加入5mL 1×TLB的15mL离心管备用。将冻存的标记细胞在37℃水浴中融解(1-2分钟),迅速将融解好的细胞转移至上述15mL离心管中,混匀后室温1000g离心5分钟。去上清,加入2.7mL 1×TLB重悬细胞。取新的384孔板,将10μL混匀的细胞按照试验设计加入相应的孔内。每孔中加入5μL 4×化合物溶液,5μL 4×Tag-lite红色荧光标记配体。室温孵育1小时后,用EnVision的HTRF模式读取数据。分别读取每孔中665nM和615nM激发光强度,计算出比值(Ratio=A665nM/B615nM),使用GraphPad Prism8软件计算出IC50数值,X:化合物浓度的对数值;Y:A665nM/B615nM的比值。
表1:化合物对AT2R结合活性测试的IC50值见下表。
化合物编号 | AT2R IC50(nM) | AT1R IC50(nM) |
I-1 | 18.42 | >10000 |
结论:在受试化合物与AT2R的结合试验中,受试化合物可以很好的将Tag-lite红色荧光标记配体替换掉,与AT2R有较强的结合作用。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (15)
1.式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:
其中,L为未取代的或被一个或多个取代基取代的C1-C6烷基,每个取代基独立地选自卤素、C1-C6烷基、C1-C6卤代烷基、氧代(=O);
X1独立地选自S、O;
X2和X3各自独立地选自N或CRa;
Ra、R1和R3各自独立地为氢或选自下列取代基:卤素、羟基、氰基、氨基、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、-O-C3-C7环烷基;
所述Ra、R1和R3各自独立地被0、1、2、3、或4个选自下列的取代基取代:卤素、羟基、氨基、氰基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同;
m为0、1、2或3;
R2独立地选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基、C3-C7环烷基-C1-C6烷基;
Z选自O或NR4;
R4选自氢或C1-C3烷基;
环A为5-6元杂芳基;
n选自1、2、3、4或5;当取代基R5为多个时,所述取代基相同或不同;
R5选自H、卤素、-CN、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基;
所述R5中C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基独立地被0、1、2、3或4个选自下列的取代基取代:卤素、羟基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同。
2.如权利要求1所述的式I化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,L为C1-C6烷基;
所述L任选地被下列取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基、氧代(=O);
较佳地,L为C1-C3烷基;
更佳地,L为-CH2-。
3.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,具有结构/> Ra为氢、卤素、羟基、氰基、氨基、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基;
Ra被0、1、2、3、或4个选自下列的取代基取代:卤素、羟基、氨基、氰基、C1-C6烷基、C3-C7环烷基;当取代基为多个时,所述取代基相同或不同;
较佳地,具有结构/>
4.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R1选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7环烷基-C1-C6烷基;
较佳地,R1选自C1-C6烷基;
更佳地,R1为异丁基。
5.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R2选自C1-C6烷基、C1-C6卤代烷基;
较佳地,R2选自甲基、乙基、丙基、异丙基、丁基、异丁基;
更佳地,R2为丁基。
6.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R3选自氢、卤素、羟基、氰基、氨基、C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C1-C6烷氧基;
较佳地,R3选自氢、卤素、氰基、甲基、卤代甲基、甲氧基、环丙基。
7.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,Z选自O或NR4;
较佳地,Z选自NR4;
R4选自氢或C1-C3烷基;
较佳地,R4选自氢。
8.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述环A为5-6元杂芳基含1、2、3个杂原子;
n为1、2、3、4或5;
较佳地,所述杂原子选自N、O、S;更佳地,所述杂原子为N;
较佳地,环A选自:吡咯、吡唑、咪唑、三氮唑、吡啶、嘧啶、哒嗪、吡嗪、三嗪;
更佳地,具有结构/>
R5选自H、卤素、-CN、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、-O-C3-C7环烷基;当R5为多个时,所述取代基相同或不同;
较佳地,R5选自H、卤素、甲基、环丙基、卤代甲基;
更佳地,具有结构/>
9.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,具有结构/>
L为C1-C3烷基;
具有结构/>
R1选自C1-C6烷基;
Z选自O或NR4;
R4选自氢或C1-C3烷基;
R2选自C1-C6烷基。
10.如权利要求1所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物包括:
。
11.一种药物组合物,其特征在于,所述药物组合物包括:如权利要求1-10中任一项所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药;和药学上可接受的载体。
12.一种如权利要求1-10中任一项所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途,或权利要求11所述的药物组合物的用途,所述用途包括:
作为AT2受体激动剂;
和/或,预防和/或治疗AngⅡ的内源性产生不足的疾病;
和/或,预防和/或治疗期望或需要AngⅡ作用增加的疾病;
和/或,制备作为AT2受体激动剂,和/或预防和/或治疗AT2受体在其中表达并且期望或必需对其进行刺激的疾病的药物、药物组合物或制剂。
13.如权利要求12所述的用途,其特征在于,所述疾病为胃肠道、心血管系统、呼吸道、肾脏、眼睛、女性生殖系统或中枢神经系统的疾病。
14.如权利要求13所述的用途,所述疾病为食管炎、巴雷特式食道、胃溃疡、十二指肠溃疡、消化不良、胃食道反流、过敏性肠综合征、炎性肠炎、胰腺炎、肝病、胆囊病、多器官衰竭、脓毒病、口干燥症、胃炎、胃潴瘤、胃酸过多症、胆道疾病、腹部疾病、节段性回肠炎、溃疡结肠炎、腹泻、便秘、急绞痛、吞咽困难、恶心、呕吐、舍格伦综合征、炎性疾病、哮喘、阻塞性肺病、肺炎、肺部高血压、成人呼吸窘迫综合征、特发性肺纤维化、肾衰、肾炎、肾高血压、糖尿病性视网膜病变、早产儿视网膜病变、视网膜微血管化、排卵机制障碍、高血压、心肌肥大、心力衰竭、动脉粥样硬化、动脉血栓、静脉血栓、内皮功能障碍、内皮损害、气球扩张术后狭窄、血管生成、糖尿病并发症、微脉管功能障碍、心绞痛、心律不齐、间歇性跛行、先兆子痫、心肌梗塞、再梗死、缺血性损害、勃起功能障碍、新内膜增生、认知功能障碍、摄食功能障碍、口渴、中风、脑出血、脑栓塞、脑梗塞、肥大病、前列腺增生、自体免疫疾病、牛皮癣、肥胖、神经再生、溃疡、脂肪组织肥大的抑制、干细胞分化和增殖、癌症、细胞凋亡、肿瘤、增生糖尿病、神经损害或器官排斥。
15.如权利要求14所述的用途,所述疾病为哮喘、阻塞性肺病、肺炎、肺部高血压、成人呼吸窘迫综合征、特发性肺纤维化;
较佳地,所述疾病为特发性肺纤维化。
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