CN116003386B - 一种氘代n-苄基吡啶酮吡唑甲酰胺类化合物、药物组合物和用途 - Google Patents
一种氘代n-苄基吡啶酮吡唑甲酰胺类化合物、药物组合物和用途 Download PDFInfo
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- CN116003386B CN116003386B CN202211451455.6A CN202211451455A CN116003386B CN 116003386 B CN116003386 B CN 116003386B CN 202211451455 A CN202211451455 A CN 202211451455A CN 116003386 B CN116003386 B CN 116003386B
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Abstract
本发明公开了式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，药物组合物和用途。本发明提供的式I所示化合物对血浆肌肽释放酶具有很好的抑制活性，对血管性水肿具有良好的治疗作用。
Description
技术领域
本发明属于创新药物化学领域，涉及一种氘代N-苄基吡啶酮吡唑酰胺类化合物、药物组合物及应用。
背景技术
血浆激肽释放酶(KLKB1)一种可以从激肽原释放激肽的胰蛋白酶样丝氨酸蛋白酶。血浆前激肽释放酶由单一基因编码并在肝脏中合成，其与高分子量激肽原结合形成的异二聚体复合物在血浆中循环，其被活化而产生具有活性的血浆激肽释放酶。KLKB1在血浆接触激活系统、激肽释放素-激肽系统(KKS)、补体通路和肾素-血管紧张素系统(RAS)中发挥多种生物学功能。此外，它还参与纤溶和炎症过程。当KLKB1的主要抑制剂—丝氨酸蛋白酶抑制蛋白C1酯酶抑制剂缺失时，发生遗传性血管性水肿(HAE)，其导致脸、手、咽喉、胃肠道和生殖器的间歇性肿胀。急性发病期间所形成的水泡含有高水平的血浆激肽释放酶，其裂解高分子量激肽原释放缓激肽，导致血管通透性增加、血管舒张、免疫细胞激活。蛋白类KLKB1抑制剂通过阻止缓激肽的释放而有效治疗HAE。血浆激肽释放酶-激肽系统在患有晚期糖尿病黄斑水肿的患者中异常高表达。KLKB1增加了糖尿病大鼠的视网膜血管功能障碍。此外，KLKB1抑制剂ASP-440能够减轻糖尿病大鼠的视网膜血管通透性和视网膜血液流动异常。另外，KLKB1在血栓形成、炎症和血压调节的发病机制中发挥着核心作用。在生理条件下，KLKB1是一种心脏保护酶。然而，KLKB1的血浆浓度增加或波动促进了心血管疾病的发展进程。目前，KLKB1被认为是糖尿病黄斑水肿、遗传性水肿、糖尿病视网膜病变和糖尿病的其他并发症如脑出血、肾病、心肌病和神经病以及心血管疾病治疗的潜在有效靶点。目前，报道的多种KLKB1抑制剂存在选择性较低、口服生物利用较差等问题。蛋白类血浆激肽释放酶抑制剂存在过敏性反应的风险。因此，新型KLKB1抑制剂的开发与研究具有重要意义。KVD-900是一种KLKB1小分子抑制剂，目前处于临床III期研究阶段，用于治疗缓激肽介导的血管性水肿。
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期会延长。自2000年以来，氘代策略便被广泛应用于药物的研究中。
发明内容
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，其结构如下：
其中，R1、R2、R3、R4、R5、R6或R7独立地选自氢或氘，
同时，R1、R2、R3、R4、R5、R6或R7至少有一个为氘。
其中，R1、R2、R3、R4、R5、R6或R7独立地选自氢或氘，
同时，R1、R2、R3、R4、R5、R6或R7至少有一个为氘。
在一些实施方案中，所述的R1为氘。
在一些实施方案中，所述化合物由以下任一结构式表示：
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备血浆激肽释放酶抑制剂中的用途。
本发明提供了一种I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备药物中的用途，所述药物用于治疗或预防其中涉及血浆激肽释放酶活性的疾病。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病选自受损视敏度，糖尿病视网膜病，糖尿病黄斑水肿，遗传性血管性水肿，糖尿病，胰腺炎，脑出血，肾病，心肌病，神经病，炎性肠病，关节炎，感染性休克，低血压，癌症，成人呼吸窘迫综合征，弥漫性血管内凝血，心肺旁路手术和外科手术后出血。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为糖尿病黄斑水肿。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为遗传性血管性水肿。
本发明提供了一种药物组合物，其含有如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，及药学上可接受的载体或辅料。
在所述的药物组合物中，所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物用量为治疗有效量。
本发明提供了一种药物组合物在制备血浆激肽释放酶抑制剂中的用途。
本发明提供了一种药物组合物在制备药物中的用途，所述药物用于治疗或预防其中涉及血浆激肽释放酶活性的疾病。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病选自受损视敏度，糖尿病视网膜病，糖尿病黄斑水肿，遗传性血管性水肿，糖尿病，胰腺炎，脑出血，肾病，心肌病，神经病，炎性肠病，关节炎，感染性休克，低血压，癌症，成人呼吸窘迫综合征，弥漫性血管内凝血，心肺旁路手术和外科手术后出血。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为糖尿病黄斑水肿。
在一些实施方案中，所述的涉及血浆激肽释放酶活性的疾病为遗传性血管性水肿。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“异构体”是指具有相同化学式而有不同的原子排列的化合物。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此，本发明包括本发明的化合物的代谢产物，包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如，大于约0.5mg/kg)非肠道给予动物，例如大鼠、小鼠、豚鼠、猴、或人，允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离，因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构，例如，通过MS，LC/MS或NMR分析。通常，代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现，否则它们可用于本发明化合物的治疗剂量给药的检定测定法。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。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。
本发明的积极进步效果在于：
(1)本发明化合物对血浆激肽释放酶具有很好的抑制活性。
(2)本发明化合物的口服生物利用度较高，半衰期较长，可以降低单次给药的剂量。
(3)本发明化合物对糖尿病视网膜病变和糖尿病黄斑水肿具有良好的治疗作用。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：化合物I-1的合成
步骤一：化合物b的合成
将原料a(3.1g，20mmol)溶于DCM中，0℃下，向上述溶液中加入Boc酸酐(5.2g，24mmol)，然后加入三乙胺(4.2mL，30mmol)和催化量的DMAP。转移至室温，室温下搅拌反应3h。待反应完成后，加入水淬灭反应，DCM萃取(10mL×3)，合并有机相，10％稀盐酸洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物b(4.4g，85％)。MS(ESI,m/z):257(M++1).
步骤二：化合物c的合成
将化合物b(4g，15.7mmol)溶于无水THF(30mL)中，0℃下向上述溶液中加入NaH(750mg，19mmol)。转移至室温搅拌30min，然后转移至0℃下，将氘代碘甲烷(2.7g，18.8mmol)的THF(5mL)溶液缓慢滴加至上述反应液中，滴加完成后，反应液加热回流，反应过夜。待反应完成后，冷却至室温，加入饱和氯化铵淬灭反应，减压除掉溶剂，乙酸乙酯萃取(10mL×3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物c(3.1g，73％)。MS(ESI,m/z):274(M++1).
步骤三：化合物d的合成
将化合物c(2.73g,10mmol)溶于乙酸乙酯(30mL)中，向上述溶液中滴加乙酸乙酯/HCl溶液(4M，7.5mL，30mmol)，室温下搅拌反应3h。待反应完成后，抽滤，收集滤饼，真空干燥制得化合物d。MS(ESI,m/z):174(M++1).
步骤四：化合物e的合成
将原料d(2.09g，10mmol)溶于DMF(20mL)中，向上述溶液中加入碳酸钾(4.14g，30mmol)和原料e(2.33g，10mmol)，反应升温至80℃，反应过夜。待反应完成后，冷却至室温，加水淬灭反应，乙酸乙酯萃取(10mL×3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物e(2.5g，67％)。MS(ESI,m/z):371(M++1).
步骤五：化合物1的合成
将原料e(2.5g，6.7mmol)溶于甲醇(10mL)中，向上述溶液中加入氢氧化钠水溶液(1M,13mL,13.5mmol)，室温下搅拌反应3h。反应完成后，10％HCl调pH至2-3，抽滤，收集滤饼，真空干燥制得化合物1。
步骤六：化合物I-1的合成
将化合物1(35.6mg，0.1mmol)溶于DMF(2mL)中，向溶液中加入化合物2(17mg，0.11mmol)、EDCI(33mg，0.17mmol)、HOBT(18mg，0.13mmol)和TEA(42μL，0.3mmol)，室温下搅拌反应5h。加入水淬灭反应，乙酸乙酯萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤浓缩制得化合物I(40mg，80％)。合成方法如实施例1，只需更换相应的原料即可。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),8.11(d,J＝7.3Hz,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H),3.36(s,3H).MS(ESI,m/z):496(M++1).
实施例2：化合物I-2的合成
步骤一：化合物4的合成
向化合物3(166mg,0.47mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入氢氧化钾(105.5mg,1.88mmol)和碘单质(239mg,0.94mmol)，室温反应3小时，TLC监测反应完全，加入亚硫酸钠饱和溶液淬灭反应，水相用乙酸乙酯(10mL×2)萃取，水(20mL*2)洗，饱和食盐(20mL)水洗无水硫酸钠干燥，浓缩柱层析分离纯化制得化合物4(104mg，46％)。MS(ESI,m/z):480(M++1).
步骤二：化合物5的合成
向化合物4(172mg,0.36mmol)的氘代醋酸溶液(8mL)中加入醋酸钠(97.9mg,0.72mmol)，2小时滴完，室温反应24小时，TLC检测反应完全，减压浓缩，柱层析分离纯化制得化合物5(102mg,80％)。MS(ESI,m/z):355(M++1).
步骤三：化合物I-2的合成
将化合物5(35.4mg，0.1mmol)溶于DMF(2mL)中，向溶液中加入化合物2(17mg，0.11mmol)、EDCI(33mg，0.17mmol)、HOBT(18mg，0.13mmol)和TEA(42μL，0.3mmol)，室温下搅拌反应5h。加入水淬灭反应，乙酸乙酯萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤浓缩制得化合物I(40mg，80％)。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),8.11(d,J＝7.3Hz,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H),3.88(s,3H),3.36(s,3H).MS(ESI,m/z):493(M++1).
实施例3：化合物I-3的合成
合成方法如实施例2，只需将原料化合物3更换成化合物1，将原料2更换为即可。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H).MS(ESI,m/z):495(M++1).
实施例4：化合物I-4的合成
合成方法如实施例2，只需将原料化合物3更换成化合物1即可。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H),3.36(s,3H).MS(ESI,m/z):496(M++1).
实施例5：化合物I-5的合成
合成方法如实施例2，只需将原料2更换为即可。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H),3.88(s,3H).MS(ESI,m/z):496(M++1).
实施例6：化合物I-6的合成
合成方法如实施例1，只需将原料化合物2更换为即可。1H NMR(500MHz,DMSO-d6)δ8.27(d,J＝5.5Hz,1H),8.11(s,1H),7.56(t,J＝6.1Hz,1H),7.23(s,3H),7.23(t,J＝7.6Hz,1H),7.17–7.11(m,1H),6.25–6.15(m,2H),5.54(s,2H),5.19(s,2H),4.53–4.47(m,5H),3.88(s,3H).MS(ESI,m/z):495(M++1).
实施例7：血浆激肽释放酶抑制活性和选择性测试
血浆激肽释放酶体外抑制活性测试参照WO2016/083820公开的实验方法。人血浆激肽释放酶在25℃与荧光底物H-DPro-Phe-Arg-AFC和各种浓度的待测化合物温育。残留的酶活性(初始反应速率)通过测量410nm的光学吸光度的变化确定，并且由此确定待测化合物对血浆激肽释放酶的抑制活性(IC50)。
KLK1酶抑制活性测试参照WO2016/083820公开的实验方法。人KLK1在25℃与荧光底物H-DVal-Leu-Arg-AFC和各种浓度的待测化合物温育。残留的酶活性(初始反应速率)通过测量410nm的光学吸光度的变化确定，并且由此确定待测化合物对KLK1酶的抑制活性(IC50)。
FXIa的酶抑制活性测试参照WO2016/083820公开的实验方法。将人FXIa在25℃与荧光底物Z-Gly-Pro-Arg-AFC和40μM的待测化合物一起温育。残留酶活性(初始反应速率)通过测量在410nm的光吸收的变化来确定，并且由此确定待测化合物40μM对FXIa酶活性的抑制率。
表1待测化合物对血浆激肽释放酶的抑制活性和选择性
| 化合物名称 | 血浆激肽释放酶(IC50 nM) | KLK1(IC50 nM) | FXIa |
| I-1 | 1.3 | ＞10000 | 0％ |
| I-2 | 2.2 | ＞10000 | 0％ |
| I-3 | 1.8 | ＞10000 | 0％ |
| I-4 | 1.5 | ＞10000 | 0％ |
| I-5 | 1.7 | ＞10000 | 0％ |
| I-6 | 2.1 | ＞10000 | 0％ |
| KVD-900 | 6.2 | ＞10000 | 0％ |
如表1所示，化合物I-1～I-6对血浆激肽释放酶表现出显著的抑制活性，且抑制活性优于KVD-900。并且化合物I-1～I-6对KLK1和FXIa的抑制活性较低，这说明化合物I对血浆激肽释放酶具有较高的选择性。
实施例8：待测化合物药代动力学性质检测
选用雄性SD大鼠，口服(10mg/kg)或静脉注射(2mg/kg)给药，于给药后5min，15min，30min，1h，2h，4h，8h，10h，24h，从眼底静脉丛连续取血置于含有肝素的EP管中，离心、取上层血浆进行LC-MS/MS分析，根据测试所得的血药浓度-时间数据，采用WinNonlin软件计算药代动力学参数，计算口服生物利用度。
研究结果表明，KVD-900在大鼠中的口服生物利用度为37％，而化合物I-1口服生物利用度提高至64％；尼拉帕尼的半衰期为3.0h，而化合物I-1的半衰期延长至6.8h，这说明可以降低化合物I-1的单次给药的剂量。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.化合物或其药学上可接受的盐，其结构如下：
。
2.一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的如权利要求1所述化合物或其药学上可接受的盐，及药学上可接受的载体或辅料。
3.一种如权利要求1所述化合物或其药学上可接受的盐、或如权利要求2所述的药物组合物在制备血浆激肽释放酶抑制剂中的用途。
4.一种如权利要求1所述化合物或其药学上可接受的盐、或如权利要求2所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防其中涉及血浆激肽释放酶活性的疾病。
5.根据权利要求4所述的用途，其特征在于，所述的涉及血浆激肽释放酶活性的疾病选自受损视敏度，糖尿病视网膜病，糖尿病黄斑水肿，遗传性血管性水肿，糖尿病，胰腺炎，脑出血，肾病，心肌病，神经病，炎性肠病，关节炎，感染性休克，低血压，癌症，成人呼吸窘迫综合征，弥漫性血管内凝血，心肺旁路手术和外科手术后出血。
6.根据权利要求4所述的用途，其特征在于，所述的涉及血浆激肽释放酶活性的疾病为与糖尿病视网膜病和糖尿病黄斑水肿相关的视网膜血管通透性。
7.根据权利要求4所述的用途，其特征在于，所述的涉及血浆激肽释放酶活性的疾病为糖尿病黄斑水肿。
8.根据权利要求4所述的用途，其特征在于，所述的涉及血浆激肽释放酶活性的疾病为遗传性血管性水肿。
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