CN113509467A - 治疗肺动脉高压的化合物及其应用 - Google Patents
治疗肺动脉高压的化合物及其应用 Download PDFInfo
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Abstract
本发明首次发现了质子泵抑制剂及其衍生物在治疗肺动脉高压中的新用途。本发明采用野百合碱诱导大鼠肺动脉高压模型，血小板衍生物生长因子‑BB(Platelet‑derived growth factor,PDGF‑BB)诱导肺动脉平滑肌细胞(Pulmonary Arterial Smooth Muscle Cell,PASMC)的异常增殖，发现右兰索拉唑等质子泵抑制剂及其衍生物能够降低肺动脉压力、减轻肺中小动脉增厚、抑制PASMC的异常增殖，从而实现了治疗肺动脉高压。
Description
技术领域
本发明涉及药物化学领域；具体地说，本发明涉及具备肺动脉高压治疗活性的质子泵抑制剂类化合物及其衍生物及其在治疗肺动脉高压中的应用。
背景技术
肺动脉高压(Pulmonary arterial hypertension，PAH)是指在静息状态下测得右心导管平均肺动脉压(mPAP)≥25mmHg，在运动时为30mmHg的一类最常见的肺血管疾病。以肺动脉压力进行性增高、肺血管重构为病理特点，临床表现为呼吸困难、活动耐量减低、乏力、心绞痛、晕厥等。根据病理表现、血流动力学特征以及临床诊治策略可将其分为五大类：①动脉性肺动脉高压；②左心疾病所致肺动脉高压；③缺氧和/或肺部疾病引起的肺动脉高压；④慢性血栓栓塞性肺动脉高压；⑤多种机制和/或不明机制引起的肺动脉高压。该疾病是比较严重的一种疾病，具有生存率低、预后不良，临床治疗困难等问题，已严重威胁人类的生命健康。基于代表症状严重性的WHO功能分级将CTEPH患者分为I～IV级。I级：日常体力活动没有症状；II级：在静息时是舒适的，但进行一般体力活动出现症状，日常活动轻微受限；III级：在静息时可以无症状，但轻微活动后出现症状，日常活动明显受限；IV级：肺动脉高压使患者不能承受任何体力活动，有右心衰竭的体征，休息时可能有呼吸困难和/或疲乏，任何体力活动都会使症状加重。
目前，临床上治疗PAH的药物主要有三类：前列环素类药物(依前列醇，贝前列环素)，内皮素受体拮抗剂(波生坦，马西替坦)，磷酸二酯酶-5抑制剂(西地那非等)，可通过舒张血管来缓解病情，但效果不佳，死亡率依旧很高。近年来，血管重构被视为是导致PAH的主要原因，因此抗血管重构被认为是较有潜力的治疗方法。其中sGC刺激剂和激动剂由于其作用途径的独特性而备受关注。利奥西呱是德国拜耳开发的首个新一类sGC刺激剂，于2013年被美国食品药物管理局(FDA)批准上市，用于治疗PAH和慢性血栓栓塞性肺动脉高压，是第一个用于多病因的抗肺动脉高压药物。尽管PAH治疗药物的研发取得了实质性进展，但患者的预后仍不理想
除了上述药物，临床实践中还发现一些针对其他适应症开发的药物具有改善PAH的作用。如酪氨酸激酶抑制剂(Tyrosine kinase inhibitors，TKI)伊马替尼(Imatinib)主要用于治疗慢性髓性白血病和恶性胃肠道间质肿瘤。但研究表明伊马替尼能够逆转PAH动物模型的疾病发展[Schermuly,R.T.,E.Dony,et al.(2005)."Reversal of experimentalpulmonary hypertension by PDGF inhibition."J Clin Invest 115(10):2811-2821]。继伊马替尼之后，索拉菲尼(Sorafenib)、尼洛替尼(Nilotinib)等TKI也被研究用于治疗PAH，在临床试验中同样能够改善PAH患者的病情[Klein,M.；Schermuly,etc.,Combinedtyrosine and serine/threonine kinase inhibition by sorafenib preventsprogression of experimental pulmonary hypertension and myocardialremodeling.Circulation 2008,118(20),2081-2090]。与这些TKI不同的是，Bcr-Abl激酶抑制剂达沙替尼(Dasatinib)却被发现在临床应用中有可能增加PAH出现几率。他汀类药物是内源性胆固醇合成抑制剂，作用于3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶。既往研究结果显示多种他汀类药物单独使用[Kao,P.N.(2005)."Simvastatin treatment ofpulmonary hypertension:an observational case series."Chest 127(4):1446-1452]或与他达拉非[Girgis,R.E.,D.Li,et al.(2003)."Attenuation of chronic hypoxicpulmonary hypertension by simvastatin."Am J Physiol Heart Circ Physiol 285(3):H938-945]等PAH特异性药物联合使用时能够改善PAH动物的血流动力学、肺血管和右心肥厚等。罗格列酮是过氧化物酶增殖物激活受体(Peroxisome proliferator activatedreceptor,PPARγ)高选择性的激动剂，临床上作为胰岛素增敏剂治疗2型糖尿病。由于PPARγ在PAH发病过程起重要作用，罗格列酮改善PAH的作用逐渐为大家所识[Crossno,J.T.,Jr.；Garat,C.V.；Reusch,J.E.；Morris,K.G.；Dempsey,E.C.；McMurtry,I.F.；Stenmark,K.R.；Klemm,D.J.,Rosiglitazone attenuates hypoxia-induced pulmonary arterialremodeling.American journal of physiology.Lung cellular and molecularphysiology 2007,292(4),L885-97]。文献也报道过罗格列酮对低氧诱导的肺动脉高压大鼠mPAP和红细胞压积的改善作用[Crossno,J.T.,Jr.；Garat,C.V.；Reusch,J.E.；Morris,K.G.；Dempsey,E.C.；McMurtry,I.F.；Stenmark,K.R.；Klemm,D.J.,Rosiglitazoneattenuates hypoxia-induced pulmonary arterial remodeling.American journal ofphysiology.Lung cellular and molecular physiology 2007,292(4),L885-97]。但是这些药物均尚未批准用于治疗PAH这一适应症。
综上所述，研发作为治疗肺动脉高压的药物具有重要的临床意义和应用前景。
发明内容
本发明的目的在于提供一种具备肺动脉高压治疗活性的化合物；具体地说，本发明的化合物能够治疗、减轻或缓解肺动脉高压、肺动脉高压所致的右心肥厚、肺动脉高压所致的肺中小动脉肥厚以及肺动脉平滑肌细胞的异常增殖。
在第一方面，本发明提供质子泵抑制剂类化合物在制备治疗肺动脉高压及其相关疾病的药物中的用途。
在优选的实施方式中，所述肺动脉高压相关疾病包括但不限于：肺炎、炎性病症、炎性肠病、心血管疾病、肾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病症、泌尿系统病症及神经病症。
在具体的实施方式中，所述质子泵抑制剂类化合物是式I所示化合物或式II所示化合物
式中，
A环是5元或6元芳环或杂芳环；
n是0-3的整数；
R1选自：H、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的5元或6元芳基或杂芳基、卤素、氨基、硝基、羟基；
B环是5元或6元芳环或含1-2个选自N、O或S的杂原子的5元或6元杂芳环；
R2选自：H、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷硫基、吗啉基、NR4R5，其中R4和R5各自独立选自H或取代或未取代的C1-6烷基；
m是0-4的整数；
R3选自：H、取代或未取代的C1-6烷基；
式中，
C环选自6-10元芳环或杂芳环；
R9选自：H、卤素、取代或未取代的C1-6烷基、R11R12NC1-3酰基，其中R11和R12各自独立选自H或取代或未取代的C1-3烷基；
o是0-3的整数；
Y选自：SO2、NR13、O，其中R13选自H或取代或未取代的C1-3烷基；
q是0-2的整数；
D环是5元或6元芳环或含1-2个选自N、O或S的杂原子的5元或6元杂芳环或杂环；
R10选自：卤素、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的6-10元芳基或杂芳基或杂环基、NR14R15，其中R14和R15各自独立选自H、取代或未取代的C1-6烷基或取代或未取代的C1-6酯基；
p是1-4的整数。
在具体的实施方式中，在式I中，
A环是苯环、吡啶环或噻吩环；
n是0、1或2；
R1选自：H、取代或未取代的C1-6烷氧基、取代或未取代的吡咯基，或者两个R1形成含有选自N、O或S的杂原子的4-6元杂环；
B环是苯环或吡啶环；
R2选自：取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷硫基、吗啉基、NR4R5，其中R4和R5各自独立为取代或未取代的C1-4烷基，或者两个R2形成含有选自N、O或S的两个杂原子的4-6元杂环；
m是1、2或3；
R3为H，或者R3与R2形成取代或未取代的6-8碳环。
在具体的实施方式中，所述化合物选自下组：
在具体的实施方式中，所述化合物如下式I-1所示：
式中，
R1选自：H、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷基；
R6、R7和R8独立选自：H、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷基。
在具体的实施方式中，所述化合物选自下组：
在具体的实施方式中，在式II中，
C环选自苯基、吡啶基、咪唑并吡啶基或苯并咪唑基；
R9选自：H、F、取代或未取代的C1-3烷基、R11R12NC1-3酰基，其中R11和R12各自独立选自取代或未取代的C1-3烷基；
Y选自：SO2、NH或O；
q是0或1；
D环选自：吡咯基、嘧啶基、苯基、苯并二氢吡喃基；
R10选自：F、取代或未取代的C1-3烷基、取代或未取代的苯基、取代或未取代的四氢异喹啉基、NR14R15，其中R14和R15各自独立选自H、或取代或未取代的C1-3酯基；
p是1、2或3。
在具体的实施方式中，所述化合物选自下组：
在第二方面，本发明提供式I-2所示化合物，
式中，
B环是苯基或吡唑基；
R2选自：H、取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、吗啉基，或者两个R2形成含有两个O的4-6元杂环；
m是1、2或3。
在具体的实施方式中，所述化合物选自下组：
在第三方面，本发明还提供第一方面所述的化合物，用于治疗肺动脉高压及其相关疾病。
在优选的实施方式中，所述肺动脉高压相关疾病包括但不限于：肺炎、炎性病症、炎性肠病、心血管疾病、肾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病症、泌尿系统病症及神经病症。
在第四方面，本发明提供肺动脉高压及其相关疾病的治疗方法，所述方法包括将治疗有效量的第一方面所述化合物给予需要治疗肺动脉高压及其相关疾病的患者。
在优选的实施方式中，所述肺动脉高压相关疾病包括但不限于：肺炎、炎性病症、炎性肠病、心血管疾病、肾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病症、泌尿系统病症及神经病症。
在第五方面，本发明提供一种包含第一方面所述的化合物用于治疗肺动脉高压及其相关疾病的药物。
在优选的实施方式中，所述肺动脉高压相关疾病包括但不限于：肺炎、炎性病症、炎性肠病、心血管疾病、肾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病症、泌尿系统病症及神经病症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了右兰索拉唑对野百合碱所致的肺动脉高压大鼠RVSP、mPAP和RVHI的影响(图1A为RVSP：肺动脉收缩压；图1B为mPAP：肺动脉平均压；图1C为RVHI：右心肥厚指数)；
图2显示了右兰索拉唑对野百合碱致肺动脉高压大鼠肺小动脉重构的影响(图2A为肺部H&E染色图；图2B为WT％：肺中小动脉管壁厚度占血管外径的百分比；，图2C为为WA％：肺中小动脉管壁面积占血管总面积的百分比)；
图3显示了埃索美拉唑镁、富马酸沃诺拉赞、普马拉唑和兰索拉唑衍生物119对野百合碱所致的肺动脉高压大鼠RVSP、mPAP和RVHI的影响(图3A为RVSP：肺动脉收缩压；图3B为mPAP：肺动脉平均压；图3C为RVHI：右心肥厚指数；
图4显示了右兰索拉唑对PDGF-BB诱导的PASMC增殖的影响。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现属于质子泵抑制剂的一系列化合物，这些化合物能够治疗、减轻或缓解肺动脉高压、肺动脉高压所致的右心肥厚、肺动脉高压所致的肺中小动脉肥厚以及肺动脉平滑肌细胞的异常增殖，从而能够用作治疗肺动脉高压及其所致疾病的药物。在此基础上完成了本发明。
基团定义
在本文中，基团的定义与本领域技术人员常规理解的相同。为清晰起见对其中的一些基团定义如下：
在本文中，“5元或6元芳环”是指含有5或6个碳原子的环状芳族基团，例如苯基。芳环可任选地被1-4个(例如，1、2、3或4个)选自以下的取代基取代：卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
术语“5元或6元杂芳环”是指形成芳环骨架的原子中至少一个原子不是碳，而是氮、氧或硫等。通常，杂环包含不超过4个氮、不超过2个氧和/或不超过2个硫。除非另外指明，杂环可以是饱和的、部分不饱和的或完全不饱和的环。
术语“C1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“C1-6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基或类似基团。类似地，“烷硫基”是指烷氧基中的氧原子被硫原子取代得到的基团。
术语“卤素”指氟、氯、溴、或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，例如三氟甲基、五氟乙基、七氟异丙基、或类似基团。
术语“C1-3酰基”是指R-C(O)-所示基团，其中R为H、C1-2烷基；类似地，术语“C1-6酯基”是指Q-C(O)-O-所示基团，其中Q为H或C1-5烷基。
质子泵抑制剂类化合物及其在预防和治疗肺动脉高压中的用途
本文所述的“质子泵抑制剂”具有本领域技术人员常规理解的含义；即，存在于生物膜上，逆着膜两侧H的电化学势差(△μH+)而主动运输H+的膜蛋白。胃H+-K+ATP酶(质子泵)的功能是泵出H+(质子)，使之进入胃粘膜腔，提高胃内的酸度，作为交换，将K+泵入胃壁细胞。所谓的“质子泵抑制剂”能够与H+-K+ATP酶共价结合，不可逆地使之失活，因而能够用作抑制胃酸分泌的药物。目前临床上常见的质子泵抑制剂类有奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑和艾司奥美拉唑等。
然而，本发明人出乎意料地发现质子泵抑制剂类化合物能够治疗肺动脉高压及其相关疾病。
在具体的实施方式中，本发明的质子泵抑制剂类化合物是式I所示化合物或式II所示化合物：
式中，C环、R9、o、Y、q、D环、R10和p如上文所定义。
在具体的实施方式中，本发明的质子泵抑制剂类化合物是选自下组的化合物：
在优选的实施方式中，本发明提供兰索拉唑或右兰索拉唑作为预防和/或治疗肺动脉高压的药物，所述兰索拉唑和右兰索拉唑的结构式如以下所示：
在以上发现的基础上，本发明还提供了兰索拉唑的各种衍生物作为预防和/或治疗肺动脉高压的药物。例如，本发明提供以下式I-2所示化合物作为预防和/或治疗肺动脉高压的药物，
式中，
B环、R2、m如上文所述。
在具体的实施方式中，式I-2所示化合物是选自下组的化合物：
在优选的实施方式中，式II所示化合物是以下化合物：
在本发明的化合物的基础上，本领域技术人员可以将其制成药学上可接受的盐。例如，可以将本发明的化合物与无机酸或有机酸反应形成常规的可药用盐。所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者将本发明的化合物与无机碱形成钠盐、钾盐、钙盐、铝盐或铵盐；或者与有机碱形成甲胺盐、乙胺盐或乙醇胺盐。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明的药物组合物以及给药方法
本发明的质子泵抑制剂类化合物能够预防和/或治疗肺动脉高压以及相关的疾病。所述的肺动脉高压表现为肺动脉压力升高、肺中小动脉增厚等现象。本领域技术人员知晓，肺动脉高压相关疾病包括但不限于：肺炎、炎性病症、炎性肠病、心血管疾病、肾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病症、泌尿系统病症及神经病症，等等。
有鉴于此，在本发明的质子泵抑制剂类化合物及其药学上可接受的盐的基础上。本发明还提供了包含所述质子泵抑制剂类化合物的药物组合物，所述药物组合物任选包含药学上可接受的赋形剂。
本领域技术人员应该理解，本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐以及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。
“药学上可以接受的赋形剂或载体”是指：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括但并不限于口服。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量。本发明的化合物和药物组合物可通过口或者胃肠道等的给药途径。最优选为口服，一次性服用或分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
在具体的实施方式中，利用野百合碱所致的大鼠肺动脉高压模型作为动物模型，本发明人初步确定了右兰索拉唑的剂量为5-20mg/kg，连续给药21天，口服。
在具体的实施方式中，右兰索拉唑在预防和(或)治疗肺动脉高压药物的用途中具有以下效果：
(1)右兰索拉唑各剂量显著降低野百合碱所致肺动脉高压大鼠的肺动脉压力，抑制肺中小动脉肥厚；
(2)右兰索拉唑各剂量显著抑制血小板衍生物生长因子-BB(Platelet derivedgrowth factor-BB，PDGF-BB)(20ng/mL)诱导的大鼠原代肺动脉平滑肌细胞的异常增殖。
本发明的主要优点：
1.本发明首次证实，质子泵抑制剂类化合物，例如右兰索拉唑具有治疗野百合碱致大鼠肺动脉高压的作用，可以用于制备肺动脉高压的治疗药物；
2.本发明的药物与已知的肺动脉高压治疗药物的结构明显不同，从而能够为肺动脉高压治疗药物的看法奠定了全新的物质基础。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1.苯并咪唑类质子泵抑制剂衍生物的合成
1.化合物119的合成
(1)胡椒基氯
将胡椒醇(0.5g,3.3mmol)和无水DCM放于50mL反应瓶中，氩气保护，在冰浴下滴加二氯亚砜(0.782mg,6.6mmol)，在冰浴下搅拌10分钟后，常温搅拌1.5小时，反应完成，旋干溶剂和剩余的二氯亚砜，石油醚过柱，得到黄色油状液体430mg，产率为76.9％。GC-MS:m/z:170.0。
(2)2-((苯并[1,3]二氧环戊烷-5-甲基)-巯基)-1-氢-苯并咪唑
先将NaOH(174mg,4.4mmol)溶解在乙醇中，60℃搅拌30分钟，加入上步产物(370mg,2.2mmol)和2-巯基苯并咪唑(325mg,2.2mmol)，升温回流，反应逐渐析出固体，4小时后反应完成，抽滤，少量乙醇洗涤，烘干，得到白色固体570mg，产率为92.5％
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.53-7.37(m,2H),7.13-7.11(m,2H),7.02(d,J＝1.6Hz,1H),6.93-6.91(m,1H),6.83(d,J＝8Hz,1H),5.98(s,2H),4.49(s,2H)。LC-MS:m/z:285.10(M+H)+。
(3)2-((苯并[1,3]二氧环戊烷-5-甲基)-亚砜)-1-氢-苯并咪唑
取上步产物(464mg,1.63mmol)溶于DCM中，冰浴下搅拌，滴加氧化剂(338mg,1.96mmol)，冰浴下搅拌30分钟，室温搅拌2小时，反应完成，加碳酸钠中和，搅拌30分钟，抽滤，旋干滤液过柱。得到白色固体410mg，产率为83.7％。
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.53-7.37(m,2H),7.13-7.11(m,2H),7.02(d,J＝1.6Hz,1H),6.93-6.91(m,1H),6.83(d,J＝8Hz,1H),5.98(s,2H),4.49(s,2H)。LC-MS:m/z:301.10(M+H)+。
2.化合物120的合成
2-((苯并[1,3]二氧环戊烷-4-甲基)-亚砜)-1-氢-苯并咪唑
1H NMR(400MHz,DMSO-d6)δ13.50(s,1H),7.65-7.63(m,2H),7.32-7.28(m,2H),6.87(dd,J1＝0.8Hz,J2＝6.8Hz,1H),6.75(t,J＝8Hz,1H),6.64(dd,J1＝1.2Hz,J2＝6.8Hz,1H),5.70(d,J＝4Hz,2H),4.62-4.44(m,2H)。LC-MS:m/z:301.10(M+H)+。
3.化合物121的合成
4-(2-(((1苯并咪唑)-2-亚砜)甲基)苯基)吗啉
1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.38-7.30(m,3H),7.27-7.16(m,3H),7.06(t,J＝7.6Hz,1H),4.86(d,J＝12.4Hz,1H),4.49(d,J＝12.8Hz,1H),3.88-3.66(m,4H),2.85-2.73(m,4H)。
4.化合物122的合成
(1)1-(3-三氟甲基苄基)-吡唑-4-乙酸乙酯
将3-三氟甲基-1-苄基氯(1.04g,5.35mmol)、4-吡唑甲酸乙酯(0.5g,3.57mmol)和碳酸铯(3.49g,10.70mmol)放于100mL反应瓶中加乙腈溶解，室温反应4小时，析出固体，抽滤，滤液旋干。得到白色固体980mg，产率为92.2％。
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.91(s,1H),7.73(d,J＝8.4Hz,2H),7.46(d,J＝8Hz,2H),5.50(s,2H),4.22(q,J＝7.2Hz,2H),1.27(t,J＝6.8Hz,3H)。GC-MS:m/z:298.10。
(2)1-(3-三氟甲基苄基)-吡唑-4-乙醇
将上步产物(488mg,1.6mmol)放于25mL两口瓶中加无水THF溶解，氩气保护，冰浴下滴加锂铝氢(75mg,2.1mmol)，缓慢升至室温，反应5小时，反应完成，加水淬灭反应，DCM萃取，旋干滤液，抽滤，滤液旋干。得到油状液体256mg，产率为61.1％。LC-MS:m/z:257.10(M+H)+。
(3)1-(3-三氟甲基苄基)-吡唑-4-乙基氯
将醇产物(256mg,1mmol)和氯仿放于50mL反应瓶中，氩气保护，在冰浴下滴加二氯亚砜(238mg,2mmol)，在冰浴下搅拌10分钟后，回流搅拌2小时，反应完成，旋干溶剂和剩余的二氯亚砜，得到黄色油状液体272mg，产率为98.5％。直接投于下一步。
(4)2-(((1-(3-(三氟甲基)苯基)-1-吡唑)-4-甲基)巯基)-1-苯并咪唑
先将NaOH(80mg,1.9mmol)溶解在乙醇中，60℃搅拌30分钟，加入上步产物(272mg,0.98mmol)和2-巯基苯并咪唑(148mg,0.98mmol)，升温回流，反应逐渐析出固体，4小时后反应完成，抽滤，少量乙醇洗涤，旋干，过柱，得到白色固体237mg，产率为62.4％。
1H NMR(400MHz,DMSO-d6)δ7.51(s,1H),7.47-7.45(m,4H),7.37(s,1H),7.21-7.18(m,2H),7.12(d,J＝8Hz,2H),5.20(s,2H),4.38(s,2H)。LC-MS:m/z:389.15(M+H)+。
(5)2-(((1-(3-(三氟甲基)苯基)-1-吡唑)-4-甲基)亚砜)-1-苯并咪唑
取上步产物(237mg,0.61mmol)溶于DCM中，冰浴下搅拌，滴加氧化剂(126mg,0.73mmol)，冰浴下搅拌30分钟，室温搅拌4小时，反应完成，加碳酸钠中和，搅拌30分钟，抽滤，旋干滤液过柱。得到白色固体180mg，产率为72.2％。
1H NMR(400MHz,DMSO-d6)δ7.64-7.61(m,5H),7.28-7.18(m,5H),5.34(s,2H),4.60-4.36(m,2H)。LC-MS:m/z:405.15(M+H)+。
实施例2.质子泵抑制剂右兰索拉唑对肺动脉高压动物的治疗作用
1.实验目的
通过皮下注射野百合碱建立肺动脉高压动物模型，同时给予质子泵抑制剂右兰索拉唑进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标RVHI，判断右兰索拉唑的药效。
2.实验动物和实验方法
体重200-230g的雄性SD大鼠(购自上海西普尔-必凯实验动物有限公司)，饲养条件：恒温22±2℃，恒湿55±5％，光照明暗各12h/天，24h自由摄食饮水。实验过程中将SD大鼠随机分为6组：空白对照组、肺动脉高压模型组、赛乐西帕(selexipag)治疗组、右兰索拉唑(安耐吉化学有限公司)低剂量、中剂量和高剂量治疗组，每组6只。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱(成都普瑞法生物科技有限公司)溶液，剂量为60mg/kg。Selexipag(1mg/kg,bid)和右兰索拉唑(5、10、20mg/kg，qd)自造模当日起连续给药21天(给药量为0.5ml/100g体重，灌胃给药)，空白对照组和模型组按体重给予相应体积的溶剂。
给药结束后，启动Powerlab生物信息采集与处理系统，连接预制的右心导管，充盈0.2％肝素钠(北京索莱宝科技有限公司)溶液后压力校零备用。向大鼠腹腔注射20％的乌拉坦(上海源叶生物科技有限公司)溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统(ADInstruments)读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数＝RV/(LV+S)。分离出肺右下部肺叶组织，浸泡于4％的多聚甲醛(Sigma)中固定1周左右后制作厚度为3μm的石蜡切片，然后进行苏木素-伊红(武汉谷歌生物科技有限公司)染色。每组大鼠肺组织石蜡切片HE染色完成后，置于倒置显微镜(Nikon TS100)下观察，每张切片分别取5条肺动脉在200×视野下拍照记录。使用Image-pro plus6.0软件对直径为100～300μm的肺中小动脉进行分析，计算管壁厚度占血管外径的百分比(WT％)和管壁面积占血管总面积的百分比(WA％)。
3.实验结果
(1)由图1A、B可得，空白对照组大鼠的右心室收缩压(RVSP)和右心室平均压(mPAP)分别为21.74±4.95mmHg、8.85±1.90mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均明显上升(p<0.001,p<0.001)。兰索拉唑各剂量治疗组的压力均高于空白对照组大鼠，但明显低于未用药的模型组(与模型组相比RVSP：p<0.05,p<0.01,p<0.01，mPAP：p<0.01,p<0.001,p<0.001)。右兰索拉唑10mg/kg和20mg/kg治疗组的效果接近，均优于5mg/kg剂量的治疗组。实验并设selexipag阳性药对照组(与模型组相比RVSP：p<0.01，mPAP：p<0.001)，提示右兰索拉唑(5mg/kg、10mg/kg、20mg/kg)具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)由图1C可得空白对照组大鼠和模型组大鼠的右心肥厚指数分别为0.196±0.022和0.430±0.044，模型组的右心肥厚指数明显升高(p<0.001)。右兰索拉唑各剂量治疗组的右心肥厚指数均高于空白对照组大鼠，但明显低于未用药的模型组，在剂量为20mg/kg时呈现显著性差异(与模型组相比p<0.01)，同时selexipag治疗组的右心肥厚指数为0.296±0.027，与模型组相比显著性降低(p<0.01)。提示右兰索拉唑具有缓解肺动脉高压所致的右心肥厚作用。
(3)由图2A可得，肺动脉高压模型组大鼠在经野百合碱造模肺中小动脉明显增厚，WT％和WA％(图2B和图2C)相比空白对照组有明显的升高(p<0.001,p<0.001)。对比模型组，右兰索拉唑各剂量给药组大鼠肺组织肺中小动脉肥厚病理变化减轻，WT％和WA％下降(与模型组相比WT％：p<0.05,p<0.05,p<0.01，WA％：p<0.05,p<0.05,p<0.001)。实验并设selexipag阳性药对照组(与模型组相比WT％：p<0.001，WA％：p<0.001)，提示右兰索拉唑(5mg/kg、10mg/kg、20mg/kg)具有减轻野百合碱致肺动脉高压大鼠肺组织中小动脉肥厚的作用。
表1.各实验组血流动力学指标、右心肥厚指标和肺中小动脉肥厚指标的比较
实施例3.质子泵抑制剂埃索美拉唑镁对肺动脉高压动物的治疗作用
1.实验目的
通过皮下注射野百合碱建立肺动脉高压动物模型，同时给予质子泵抑制剂埃索美拉唑镁进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标，判断埃索美拉唑镁的药效。
2.实验动物和实验方法
体重200-230g的雄性SD大鼠，饲养条件为恒温22±2℃，恒湿55±5％，光照明暗各12h/天，24h自由摄食饮水。实验过程中将SD大鼠随机分为4组：空白对照组、肺动脉高压模型组、selexipag阳性药(1mg/kg，bid)治疗组、埃索美拉唑镁(10mg/kg，qd)治疗组，每组6只。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱溶液，剂量为60mg/kg。阳性药和埃索美拉唑镁自造模当日起连续给药21天(给药量为0.5ml/100g体重，灌胃给药)，空白对照组和模型组按体重给予相应体积的溶剂。
给药结束后，启动Powerlab生物信息采集与处理系统，连接预制的右心导管，充盈肝素钠溶液后压力校零备用。向大鼠腹腔注射20％的乌拉坦溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数＝RV/(LV+S)。
3.实验结果
(1)空白对照组大鼠的右心室收缩压(RVSP)和右心室平均压(mPAP)分别为31.44±2.30mmHg、10.88±2.09mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(p<0.001,p<0.001)。埃索美拉唑镁治疗组的压力均高于空白对照组大鼠，但明显低于未用药的模型组(RVSP：p<0.01，mPAP：p<0.05)。实验并设selexipag阳性药对照组(与模型组相比RVSP：p<0.001，mPAP：p<0.001)，提示埃索美拉唑镁具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)空白对照组大鼠和模型组大鼠的右心肥厚指数分别为0.190±0.045和0.382±0.085，模型组的右心肥厚指数明显升高(p<0.001)。埃索美拉唑镁治疗组的右心肥厚指数高于空白对照组大鼠，但明显低于未用药的模型组(p<0.01)，同时selexipag治疗组的右心肥厚指数为0.271±0.068，与模型组相比显著性降低(p<0.01)。提示埃索美拉唑镁具有缓解肺动脉高压所致的右心肥厚作用。
表2.各实验组血流动力学指标、右心肥厚指标和肺中小动脉肥厚指标的比较
| 实验动物分组 | RVSP/mmHg | mPAP/mmHg | RVHI/％ |
| 空白对照组 | 31.44±2.30 | 7.776±1.89 | 0.190±0.045 |
| 模型组 | 65.43±6.47 | 21.66±2.78 | 0.382±0.085 |
| selexipag组 | 42.32±4.78 | 15.76±2.71 | 0.271±0.068 |
| 埃索美拉唑镁10mg/kg | 50.04±7.27 | 17.00±2.44 | 0.273±0.054 |
实施例4.质子泵抑制剂富马酸沃诺拉赞对肺动脉高压动物的治疗作用
1.实验目的
通过皮下注射野百合碱建立肺动脉高压动物模型，同时给予质子泵抑制剂富马酸沃诺拉赞进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标，判断富马酸沃诺拉赞的药效。
2.实验动物和实验方法
体重200-230g的雄性SD大鼠，饲养条件为恒温22±2℃，恒湿55±5％，光照明暗各12h/天，24h自由摄食饮水。实验过程中将SD大鼠随机分为4组：空白对照组、肺动脉高压模型组、selexipag阳性药(1mg/kg，bid)治疗组、富马酸沃诺拉赞(10mg/kg，qd)治疗组，每组6只。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱溶液，剂量为60mg/kg。阳性药和富马酸沃诺拉赞自造模当日起连续给药21天(给药量为0.5ml/100g体重，灌胃给药)，空白对照组和模型组按体重给予相应体积的溶剂。
给药结束后，启动Powerlab生物信息采集与处理系统，连接预制的右心导管，充盈肝素钠溶液后压力校零备用。向大鼠腹腔注射20％的乌拉坦溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数＝RV/(LV+S)。
3.实验结果
(1)空白对照组大鼠的右心室收缩压(RVSP)和右心室平均压(mPAP)分别为31.44±2.30mmHg、7.776±1.89mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(p<0.001,p<0.001)。富马酸沃诺拉赞治疗组的压力均高于空白对照组大鼠，但明显低于未用药的模型组(RVSP：p<0.001，mPAP：p<0.01)。实验并设selexipag阳性药对照组(与模型组相比RVSP：p<0.001，mPAP：p<0.001)，提示富马酸沃诺拉赞具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)空白对照组大鼠和模型组大鼠的右心肥厚指数分别为0.190±0.045和0.382±0.085，模型组的右心肥厚指数明显升高(p<0.001)。富马酸沃诺拉赞治疗组的右心肥厚指数高于空白对照组大鼠，但明显低于未用药的模型组(p<0.001)，同时selexipag治疗组的右心肥厚指数为0.271±0.068，与模型组相比显著性降低(p<0.01)。提示富马酸沃诺拉赞具有缓解肺动脉高压所致的右心肥厚作用。
表3.各实验组血流动力学指标、右心肥厚指标和肺中小动脉肥厚指标的比较
| 实验动物分组 | RVSP/mmHg | mPAP/mmHg | RVHI/％ |
| 空白对照组 | 31.44±2.30 | 7.776±1.89 | 0.190±0.045 |
| 模型组 | 65.43±6.47 | 21.66±2.78 | 0.382±0.085 |
| selexipag组 | 42.32±4.78 | 15.76±2.71 | 0.271±0.068 |
| 富马酸沃诺拉赞10mg/kg | 46.97±8.49 | 16.74±3.08 | 0.260±0.037 |
实施例5.质子泵抑制剂普马拉唑对肺动脉高压动物的治疗作用
1.实验目的
通过皮下注射野百合碱建立肺动脉高压动物模型，同时给予质子泵抑制剂普马拉唑进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标，判断普马拉唑的药效。
2.实验动物和实验方法
体重200-230g的雄性SD大鼠，饲养条件为恒温22±2℃，恒湿55±5％，光照明暗各12h/天，24h自由摄食饮水。实验过程中将SD大鼠随机分为4组：空白对照组、肺动脉高压模型组、selexipag阳性药(1mg/kg，bid)治疗组、普马拉唑(10mg/kg，qd)治疗组，每组6只。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱溶液，剂量为60mg/kg。阳性药和普马拉唑自造模当日起连续给药21天(给药量为0.5ml/100g体重，灌胃给药)，空白对照组和模型组按体重给予相应体积的溶剂。
给药结束后，启动Powerlab生物信息采集与处理系统，连接预制的右心导管，充盈肝素钠溶液后压力校零备用。向大鼠腹腔注射20％的乌拉坦溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数＝RV/(LV+S)。
3.实验结果
(1)空白对照组大鼠的右心室收缩压(RVSP)和右心室平均压(mPAP)分别为31.44±2.30mmHg、7.776±1.89mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(p<0.001,p<0.001)。普马拉唑治疗组的压力均高于空白对照组大鼠，但明显低于未用药的模型组(RVSP：p<0.01，mPAP：p<0.05)。实验并设selexipag阳性药对照组(与模型组相比RVSP：p<0.001，mPAP：p<0.001)，提示普马拉唑具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)空白对照组大鼠和模型组大鼠的右心肥厚指数分别为0.190±0.045和0.382±0.085，模型组的右心肥厚指数明显升高(p<0.001)。普马拉唑治疗组的右心肥厚指数高于空白对照组大鼠，但明显低于未用药的模型组(p<0.001)，同时selexipag治疗组的右心肥厚指数为0.271±0.068，与模型组相比显著性降低(p<0.01)。提示普马拉唑具有缓解肺动脉高压所致的右心肥厚作用。
表4.各实验组血流动力学指标、右心肥厚指标和肺中小动脉肥厚指标的比较
| 实验动物分组 | RVSP/mmHg | mPAP/mmHg | RVHI/％ |
| 空白对照组 | 31.44±2.30 | 7.776±1.89 | 0.190±0.045 |
| 模型组 | 65.43±6.47 | 21.66±2.78 | 0.382±0.085 |
| selexipag组 | 42.32±4.78 | 15.76±2.71 | 0.271±0.068 |
| 普马拉唑10mg/kg | 48.89±6.64 | 16.74±3.08 | 0.262±0.031 |
实施例6.右兰索拉唑衍生物119对肺动脉高压动物的治疗作用
1.实验目的
通过皮下注射野百合碱建立肺动脉高压动物模型，同时给予右兰索拉唑衍生物119进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标，判断右兰索拉唑衍生物119的药效。
2、实验动物和实验方法
体重200-230g的雄性SD大鼠，饲养条件为恒温22±2℃，恒湿55±5％，光照明暗各12h/天，24h自由摄食饮水。实验过程中将SD大鼠随机分为4组：空白对照组、肺动脉高压模型组、selexipag阳性药(1mg/kg，bid)治疗组、119(10mg/kg，qd)治疗组，每组6只。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱溶液，剂量为60mg/kg。阳性药和119自造模当日起连续给药21天(给药量为0.5mL/100g体重，灌胃给药)，空白对照组和模型组按体重给予相应体积的溶剂。
给药结束后，启动Powerlab生物信息采集与处理系统，连接预制的右心导管，充盈肝素钠溶液后压力校零备用。向大鼠腹腔注射20％的乌拉坦溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数＝RV/(LV+S)。分离出肺右下部肺叶组织，浸泡于4％的多聚甲醛中固定1周左右后制作厚度为3μm的石蜡切片，然后进行苏木素-伊红染色。每组大鼠肺组织石蜡切片HE染色完成后，置于倒置显微镜下观察，每个切片分别取5条肺动脉在200×视野下拍照记录。使用Image-pro plus 6.0软件对直径为100～300μm的肺中小动脉进行分析，计算管壁厚度占血管外径的百分比(WT％)和管壁面积占血管总面积的百分比(WA％)。
3.实验结果
(1)空白对照组大鼠的右心室收缩压(RVSP)和右心室平均压(mPAP)分别为31.44±2.30mmHg、10.88±2.09mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(p<0.001,p<0.001)。右兰索拉唑衍生物119治疗组的压力均高于空白对照组大鼠，但RVSP明显低于未用药的模型组(p<0.01)，mPAP也呈现。实验并设selexipag阳性药对照组(与模型组相比RVSP：p<0.001，mPAP：p<0.001)，提示右兰索拉唑衍生物119具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)空白对照组大鼠和模型组大鼠的右心肥厚指数分别为0.190±0.045和0.382±0.085，模型组的右心肥厚指数明显升高(p<0.001)。化合物119的右心肥厚指数高于空白对照组大鼠，但明显低于未用药的模型组(p<0.05)，同时selexipag治疗组的右心肥厚指数为0.271±0.068，与模型组相比显著性降低(p<0.01)。提示右兰索拉唑衍生物119具有缓解肺动脉高压所致的右心肥厚作用。
表5.各实验组血流动力学指标、右心肥厚指标和肺中小动脉肥厚指标的比较
实施例6.质子泵抑制剂对细胞增殖的影响
1.大鼠原代PASMC的培养
4-5周龄SD大鼠，腹腔注射10％水合氯醛麻醉，在75％酒精中浸泡消毒后，于安全柜中开胸后，取出完整心肺至于冷的D-Hanks中清洗2-3次。分离出一段肺动脉，去除血管周围组织和血管外膜。纵向剖开肺动脉去除血管内膜。然后在3.5cm的培养皿中用眼科手术剪将血管剪成1mm3左右的小块并分散。将培养皿翻转(即有细胞的一面朝上)，放入37℃、5％CO2环境的培养箱中干涸30分钟。30分钟后取出培养皿并正置，慢慢加入2mL含20％胎牛血清的DMEM(高糖型)培养基。之后，将培养皿移入细胞培养箱中静置3天不动，每隔3天换液，至细胞生长至融合状态后传代。取3-6代的细胞进行实验。
2.MTT法检测PDGF-BB诱导的PASMC增殖
将长至融合状态的PASMC经消化、重悬后均匀铺于透明的96孔板中，每孔5000个细胞，置于细胞培养箱中过夜。第二日弃去旧培养基，全部更换为不含血清的DMEM培养基，使细胞的生长速率归一化。24h后，分组加入右兰索拉唑刺激。分组设置为：正常组(模型组)、PDGF-BB组、PDGF-BB+右兰索拉唑10μM组、PDGF-BB+右兰索拉唑50μM组和PDGF-BB+右兰索拉唑100μM组。其中正常组(模型组)加入不含化合物的DMEM培养基，其余各组分别加入含不同浓度右兰索拉唑的培养基和终浓度为20ng/mL的PDGF-BB。48h后向各孔中分别加入浓度为5mg/mL的MTT溶液10μL，在37℃环境下静置4h后，吸除原来的培养基并加入150μL二甲亚砜，振荡均匀后，使用多功能酶标仪(BioTek公司)，在490nm吸光值下读数。
3.实验结果
由图4得，只加入PDGF-BB的PASMC的增殖速率是对照组的1.5倍，而在加入100μM、50μM和10μM浓度的右兰索拉唑后，PASMC的增殖速率是对照组1.15倍、1.28倍和1.35倍，说明右兰索拉唑对PDGF-BB诱导的PASMC的增殖具有抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.质子泵抑制剂类化合物在制备治疗肺动脉高压及其相关疾病的药物中的用途。
2.如权利要求1所述的用途，其特征在于，所述质子泵抑制剂类化合物是式I所示化合物或式II所示化合物
式中，
A环是5元或6元芳环或杂芳环；
n是0-3的整数；
R1选自：H、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的5元或6元芳基或杂芳基、卤素、氨基、硝基、羟基；
B环是5元或6元芳环或含1-2个选自N、O或S的杂原子的5元或6元杂芳环；
R2选自：H、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷硫基、吗啉基、NR4R5，其中R4和R5各自独立选自H或取代或未取代的C1-6烷基；
m是0-4的整数；
R3选自：H、取代或未取代的C1-6烷基；
式中，
C环选自6-10元芳环或杂芳环；
R9选自：H、卤素、取代或未取代的C1-6烷基、R11R12NC1-3酰基，其中R11和R12各自独立选自H或取代或未取代的C1-3烷基；
o是0-3的整数；
Y选自：SO2、NR13、O，其中R13选自H或取代或未取代的C1-3烷基；
q是0-2的整数；
D环是5元或6元芳环或含1-2个选自N、O或S的杂原子的5元或6元杂芳环或杂环；
R10选自：卤素、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的6-10元芳基或杂芳基或杂环基、NR14R15，其中R14和R15各自独立选自H、取代或未取代的C1-6烷基或取代或未取代的C1-6酯基；
p是1-4的整数。
3.如权利要求2所述的用途，其特征在于，在式I中，
A环是苯环、吡啶环或噻吩环；
n是0、1或2；
R1选自：H、取代或未取代的C1-6烷氧基、取代或未取代的吡咯基，或者两个R1形成含有选自N、O或S的杂原子的4-6元杂环；
B环是苯环或吡啶环；
R2选自：取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷硫基、吗啉基、NR4R5，其中R4和R5各自独立为取代或未取代的C1-4烷基，或者两个R2形成含有选自N、O或S的两个杂原子的4-6元杂环；
m是1、2或3；
R3为H，或者R3与R2形成取代或未取代的6-8碳环。
4.如权利要求3所述的用途，其特征在于，所述化合物选自下组：
5.如权利要求3所述的用途，其特征在于，所述化合物如下式I-1所示：
式中，
R1选自：H、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷基；
R6、R7和R8独立选自：H、取代或未取代的C1-3烷氧基、取代或未取代的C1-3烷基。
6.如权利要求5所述的用途，其特征在于，所述化合物选自下组：
7.如权利要求2所述的用途，其特征在于，在式II中，
C环选自苯基、吡啶基、咪唑并吡啶基或苯并咪唑基；
R9选自：H、F、取代或未取代的C1-3烷基、R11R12NC1-3酰基，其中R11和R12各自独立选自取代或未取代的C1-3烷基；
Y选自：SO2、NH或O；
q是0或1；
D环选自：吡咯基、嘧啶基、苯基、苯并二氢吡喃基；
R10选自：F、取代或未取代的C1-3烷基、取代或未取代的苯基、取代或未取代的四氢异喹啉基、NR14R15，其中R14和R15各自独立选自H、或取代或未取代的C1-3酯基；
p是1、2或3。
8.如权利要求7所述的用途，其特征在于，所述化合物选自下组：
9.式I-2所示化合物，
式中，
B环是苯基或吡唑基；
R2选自：H、取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、吗啉基，或者两个R2形成含有两个O的4-6元杂环；
m是1、2或3。
10.如权利要求9所述的化合物，其特征在于，所述化合物选自下组：
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| CN85106252A (zh) * | 1984-07-06 | 1986-06-10 | 菲索斯公立有限公司 | 化合物的制取方法及其应用 |
| CN107648610A (zh) * | 2017-11-14 | 2018-02-02 | 上海市第人民医院 | 质子泵抑制剂在制备降低肺部炎症及治疗急性、慢性气道炎症性疾病的药物中的应用 |
| CN109512818A (zh) * | 2018-12-14 | 2019-03-26 | 张锐 | 环格列酮在制备治疗肺动脉高压的药物中的应用 |
| CN110339194A (zh) * | 2019-07-31 | 2019-10-18 | 沈阳药科大学 | 拉唑类化合物在制备预防和治疗纤维化疾病药物中的用途 |
| CN110585205A (zh) * | 2019-09-17 | 2019-12-20 | 中国人民解放军总医院 | Wnk激酶抑制剂在预防和/或治疗肺动脉高压中的用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85106252A (zh) * | 1984-07-06 | 1986-06-10 | 菲索斯公立有限公司 | 化合物的制取方法及其应用 |
| CN107648610A (zh) * | 2017-11-14 | 2018-02-02 | 上海市第人民医院 | 质子泵抑制剂在制备降低肺部炎症及治疗急性、慢性气道炎症性疾病的药物中的应用 |
| CN109512818A (zh) * | 2018-12-14 | 2019-03-26 | 张锐 | 环格列酮在制备治疗肺动脉高压的药物中的应用 |
| CN110339194A (zh) * | 2019-07-31 | 2019-10-18 | 沈阳药科大学 | 拉唑类化合物在制备预防和治疗纤维化疾病药物中的用途 |
| CN110585205A (zh) * | 2019-09-17 | 2019-12-20 | 中国人民解放军总医院 | Wnk激酶抑制剂在预防和/或治疗肺动脉高压中的用途 |
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