CN115413239A - 用于治疗造影引起的急性肾脏损伤的试剂 - Google Patents
用于治疗造影引起的急性肾脏损伤的试剂 Download PDFInfo
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- CN115413239A CN115413239A CN202180027048.XA CN202180027048A CN115413239A CN 115413239 A CN115413239 A CN 115413239A CN 202180027048 A CN202180027048 A CN 202180027048A CN 115413239 A CN115413239 A CN 115413239A
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- pyridin
- pyrazol
- phenyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供一种用于通过降低造影剂引起的肾毒性来保护肾脏或用于治疗造影剂引起的急性肾脏损伤的药物组合物，其包含化学式1的化合物，所述化合物是吡唑衍生物或其药学上可接受的盐。
Description
技术领域
本申请要求在韩国知识产权局于2020年4月8日提交的韩国专利申请No.10-2020-0042899和于2021年3月22日提交的韩国专利申请No.10-2021-0036838的权益，这两项专利申请的公开内容通过引用全部并入本说明书中。
本发明涉及一种用于通过降低造影剂引起的肾毒性来保护肾脏，或用于预防和治疗造影剂引起的急性肾脏损伤的吡唑衍生物；制备所述吡唑衍生物的方法；和所述吡唑衍生物的药物组合物。
背景技术
造影剂(CM)是一种被引入到胃、肠道、血管、脑脊髓腔、关节腔等中的药物，以通过人为地增加各个组织中X射线吸收的差异来增加图像的对比度，以便在诸如磁共振成像(MRI)或计算机断层扫描(CT)成像的放射学检查中可以清楚地看到组织或血管。通过使用造影剂，通过能够很好地将生物结构或病变与其周围环境区分开来提高诊断价值。
造影剂一般分为阴性造影剂和阳性造影剂，其中，阴性造影剂比周围组织透射更多的X射线来显示出图像。阳性造影剂包括含碘造影剂、硫酸钡等，阴性造影剂包括空气、气体、二氧化碳等。
有些人对造影剂敏感，可能会引起过敏反应，导致皮疹、瘙痒、发烧、恶心、呕吐、关节痛、出血倾向等。
作为造影剂的副作用，可能极少发生休克或过敏反应，可能出现诸如荨麻疹、潮红、皮疹和瘙痒的超敏反应，严重的可能发生急性肾脏损伤。
特别是，虽然尚不清楚造影剂引起的急性肾脏损伤的确切机理，但是它发生在碘基造影剂给药之后，并且已知是医院获得性急性肾脏损伤的主要原因。
由于造影剂引起的急性肾脏损伤定义为在使用48小时内，血液中的肌酐水平比现有水平增加25％以上或0.5mg/dL以上，并且在这种情况下，患者不应有引起肾脏损伤的其他原因，如血压下降、其他肾毒性等。
通常，血液中肌酐水平在造影剂给药之后的第3天至第5天达到峰值，然后在7天至10天内恢复到之前的水平。造影剂引起的急性肾脏损伤约占医院获得性急性肾脏损伤的12％，并且与缺血性急性肾脏损伤(42％)和尿路梗阻引起的急性肾脏损伤(18％)一起作为住院患者的急性肾脏损伤的三大原因之一。据报道，在肾功能正常的患者中，造影剂引起的急性肾脏损伤的发生率低(0％至5％)，但是在肾功能减退的患者中发病率增加到12％至27％。特别是，据报道，在高风险患者如伴有脱水、糖尿病肾病、肾脏损伤、血容不足或充血性心力衰竭的患者以及老年患者中，发病率增加到50％，并据报道，15％的患者需要透析。
尽管存在这些风险，特别是在高风险和患有严重合并症的老年患者中，在50岁以上的患者中，使用放射造影剂进行计算机断层扫描和血管介入迅速增加到20％以上。因此，在使用造影剂接受检查的受试患者中，在易受造影剂引起的肾脏损伤影响的老年患者组以及患有糖尿病、高血压和心力衰竭的患者组越来越多的情况下，非常迫切开发预防和治疗方法以减少造影剂引起的肾毒性。
虽然尚未明确阐明造影剂引起的肾脏疾病的病理生理学，但是假设主要机理是由肾血流量减少引起的缺血性损伤和由造影剂引起的肾小管细胞直接损伤。
在缺血性损伤的情况下，已知由于在造影剂给药之后调节肾血流量的激素发生变化，血管收缩激素腺苷和内皮素增加，而血管扩张激素一氧化氮(NO)和前列腺素减少，由于血流量减少和低氧，特别是在肾髓质的区域引起损伤。从特征上看，已知缺血性损伤和肾小管细胞损伤最终会增加肾组织中氧自由基的合成，造成广泛的氧化应激，而这反过来会因为由细胞因子增加引起的炎症和细胞凋亡的增加而造成肾脏细胞损伤。
在造影剂引起的肾脏疾病的情况中，与其他急性肾脏损伤一样，由于阻断已发生的肾脏损伤的进展的方法尚不清楚并且诱导时间明确，因此，主要是通过积极预防来努力阻断其发生，并且正在进行多项研究以减少造影剂引起的肾脏损伤。
已知，预防造影剂引起的肾毒性的常规治疗方法是在给予足够的液体供应的同时尝试防止电解质紊乱，但没有明确的治疗或预防方法来防止肾脏损伤的进展，并且在一些情况下，透析是必要的，因此，需要更多的研究来开发一种预防方法以防止其在早期发生。
近来，在实验室水平，有报道称内肽酶抑制剂或一些芳香-阳离子肽可以预防由造影剂引起的急性肾脏损伤。
然而，大多数研究是实验室或小规模患者的观察性研究，迄今为止，通过使用这些药物是否可以有效预防造影剂引起的肾脏损伤的结论还不清楚，也没有具体的造影剂引起的肾脏损伤的治疗方法。
因此，本发明人通过确定尽管有各种研究，但仍然有必要开发一种用于由造影剂引起的急性肾脏损伤的预防和治疗剂，从而完成本发明。
另一方面，现有技术文献均未公开本发明的吡唑类化合物在预防和治疗造影剂引起的急性肾脏损伤方面的有效性。
[现有技术文献]
(专利文献1)韩国专利No.10-1280160
(专利文献2)韩国专利No.10-1886894
(专利文献3)美国专利特许公开No.US 2019-0388492
(非专利文献1)Persson PB,Hansell P,Liss P.Pathophysiology of contrastmedium-induced nephropathy.Kidney Int 2005；68:14-22。
(非专利文献2)Heyman SN,Reichman J,Brezis M.Pathophysiology ofradiocontrast nephropathy:a role for medullary hypoxia.Invest Radiol1999；34:685-691。
发明内容
技术问题
本发明的一个目的是提供一种包含化学式1的化合物或其药学上可接受的盐的药物组合物。
本发明的另一目的是提供一种通过降低造影剂引起的肾毒性以保护肾脏的药物组合物，其包含化学式1的化合物或其药学上可接受的盐。
本发明的另一目的是提供一种用于治疗和预防造影剂引起的急性肾脏损伤的药物组合物，其包含化学式1的化合物或其药学上可接受的盐。
本发明的另一目的是使用化学式1的化合物或其药学上可接受的盐提供造影剂引起的肾脏损伤减少效果、血肌酐水平改善效果和肾小管损伤改善效果。
本发明的另一目的是提供一种通过向个体给药化学式1的化合物或其药学上可接受的盐，来减少造影剂引起的肾毒性从而保护肾脏的方法或预防或治疗造影剂引起的急性肾脏损伤的方法。
本发明的又一目的是提供化学式1的化合物或其药学上可接受的盐用于预防或治疗造影剂引起的急性肾脏损伤的用途。
技术方案
为了实现上述目的，本发明提供一种通过降低造影剂引起的肾毒性来保护肾脏的组合物或用于预防和改善或治疗造影剂引起的急性肾脏损伤的药物组合物，其包含由下面化学式1表示的吡唑类化合物或其药学上可接受的盐作为活性成分。
<化学式1>
其中，R是具有1至10个碳原子的直链或支链烷基。
有益效果
根据本发明的吡唑类化合物及其药学上可接受的盐可以有效地减轻通过造影剂给药引起的急性肾脏损伤的症状，由此，可以有效地用于通过减少造影剂引起的肾毒性来保护肾脏，或者用于预防或治疗造影剂引起的急性肾脏损伤。
附图说明
图1示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中的作用的结果。
图2示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对改善血尿素氮(BUN)水平的作用的结果。
图3示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对改善血肌酐水平的作用的结果。
图4示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对降低肾脏损伤标志物NGAL、KIM-1和尿微量蛋白(白蛋白)的作用的结果。
图5示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对改善肾小管损伤的作用的结果。
图6示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对改善肾组织的炎症的作用的结果。
图7示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对减少肾组织内的炎症细胞的浸润的作用的结果。
图8示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对减少作为肾组织内氧化应激的指标的活性氧的作用的结果。
图9示出了分析本发明的化合物在具有造影剂引起的急性肾脏损伤的动物模型中对降低作为肾组织内氧化应激的标志物的硝基酪氨酸的作用的结果。
具体实施方式
下文中，将参照实施方案更详细地描述本发明。
然而，本发明不受已通过实例的方式表示的实施方案的限制，本发明仅由所附权利要求书的范围界定。此外，即使是实施本发明所必需的组成，也将省略对本领域技术人员可以容易实施的组成的具体描述。
本说明书和权利要求书中使用的术语和词语不应理解为限于常规的或字典的含义，而是应当基于发明人能够适当地定义术语的概念，以最佳方式描述其发明的原则，理解为与本发明的技术构思一致的含义和概念。
本发明中使用的术语仅用于描述特定实施方案的目的，并不旨在限制本发明。除非上下文另有明确指示，否则单数表达包括复数表达。在本发明中，诸如“包含”和“具有”的术语旨在表明存在本说明书中描述的特征、数目、步骤、操作、组件、部分或它们的组合，并且应当理解的是，这些术语并不预先排除存在或添加一个或多个其他特征、数目、步骤、操作、组件、部分或它们的组合的可能性。
随着使用造影剂的诊断方法的数量增加，造影剂的使用增加，同时，造影剂引起的副作用也是成为一个问题。除了造影剂引起的诸如过敏的过敏性反应之外，严重地，可能会发生急性肾脏损伤。此外，已知越来越多的老年患者患有如糖尿病和高血压的主要基础疾病，这些患者越来越多地使用放射性造影剂也是医院获得性急性肾脏损伤的主要原因之一。
然而，作为造影剂引起的急性肾脏损伤的治疗方法，只报道了充分的液体补充和防止电解质紊乱的治疗方法，还没有具体报道用于预防造影剂引起的急性肾脏损伤的方法或确定的治疗。
由此，本发明提供一种能够预防或治疗造影剂引起的急性肾脏损伤的药物组合物，其包含选自由化学式1表示的吡唑类化合物中的一种或多种化合物或其药学上可接受的盐。
本发明中使用的吡唑类化合物由下面化学式1表示：
<化学式1>
其中，R是具有1至10个碳原子的直链或支链烷基。
本发明的药物组合物中包含的吡唑类化合物的药学上可接受的盐是指保留母体化合物的生物有效性和性能，并且当以单次剂量给药时对生物学或其他方面没有危害的盐。此外，是指制药工业中常用的盐。
具体地，药学上可接受的碱加成盐可以由无机碱和有机碱制备。来自无机碱的盐可以包括，但不限于，钠、钾、锂、铵、钙和镁的盐。来自有机碱的盐包括，但不限于，伯胺、仲胺和叔胺的盐；取代的胺，包括自然发生的取代的胺；和异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴胺、胆碱、甜菜碱、乙二胺、氨基葡萄糖、N-烷基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶和/或环胺包括N-乙基哌啶。
还应理解的是，其它羧酸衍生物，具体地，羧酸酰胺，包括甲酰胺、低级烷基羧酰胺、二(低级烷基)羧酰胺等，也可用于本发明的实践。
此外，药学上可接受的酸加成盐可以由无机酸和有机酸制备。来自无机酸的盐包括盐酸、氢溴酸、硫酸、硝酸、磷酸、高氯酸、碘酸、酒石酸等。来自有机酸的盐可以包括，但不限于，乙酸、三氟乙酸、丙酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸、丙酮酸、草酸、苹果酸、丙二酸、乳酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸和/或水杨酸等。
所述药学上可接受的盐可以是盐酸盐。
本发明的药物组合物中包含的由化学式1表示的吡唑类化合物或其药学上可接受的盐具体例示如下：
3-苯基-4-甲基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-乙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-异丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正丁基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-叔丁基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正戊基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正己基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐。
具体地，本发明的药物组合物中包含的吡唑类化合物可以是3-苯基-4-正丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐。
本发明的化学式1的化合物可以抑制肾组织中活性氧的产生。
在本发明中，氧化应激是指由于活性氧(ROS)的产生与生物分子、细胞和组织的抗氧化防御机制之间的平衡被打破而产生的相对过量的活性氧所引起的组织损伤。在这种情况下，“活性氧”可以指活性氧、活化氧和激活氧，它们指的是同一种物质。
本发明的“造影剂”是本领域技术人员已知的。造影剂使得身体的特定部分与密度相似的周边部分能够区分开。优选地，本发明上下文中的造影剂是不透明的或阳性造影剂，即具有比周围组织更大的衰减密度的造影剂，从而增强X射线的吸收。
阳性造影剂在本领域中是公知的并且是非碘基造影剂、碘基造影剂，即碘化造影剂。非碘基造影剂和碘基造影剂的实例是本领域技术人员已知的。
单体造影剂分为离子型和非离子型，具体的离子型单体造影剂包括碘甘酸盐(ioglycate)(Rayvist)、碘达胺(Uromiro)、醋碘苯酸盐(Diaginol，Urokon)、泛影酸盐(Angiografin；Hypaque；Renografin；Urografin；Urovison)和甲泛影酸(Isopaque；Triosil)。
具体的非离子型单体造影剂包括甲泛葡胺(Amipaque)、碘海醇(Omnipaque)、碘帕醇(Iopamiro)、碘喷托(Imagopecque)、碘普罗胺(Ultravist)和碘佛醇(Optiray)。
二聚碘基造影剂优选包含两个三碘苯环。它们可以分为离子型静脉胆道造影剂、单酸离子型造影剂和非离子型造影剂。二聚碘造影剂优选为碘克沙酸(Hexabrix)、碘曲仑(Isovist)和碘克沙醇(Visipaque；Optiprep)。
非碘造影剂通常包含钡，主要是不溶性硫酸钡的形式。它们优选用于胃肠道检查。
造影剂可以通过任何认为适当的方法给药。本领域技术人员知道，给药所选择的方法可以取决于施用造影剂的检查的目的和/或造影剂。具体地，钡基造影剂通过吞咽或灌肠的形式给药。碘基造影剂优选通过注射到静脉、椎管或动脉中给药。可以使用用于碘基造影剂给药的导管。
碘基造影剂的给药用于计算机断层扫描，并且最优选用于血管造影。在本发明中进一步考虑适用于超声检查或磁共振成像(MRI)的造影剂的给药。
本发明的“急性肾脏损伤”或“AKI”或“急性肾功能衰竭(ARF)”在本领域中是公知的。如本发明中所使用的，所述术语是指肾功能的快速丧失。肾功能的快速丧失是由肾脏的损伤引起的。AKI的诊断和分类标准基于血清肌酐水平和尿排泄中的变化。所述术语在KDIGO指南(KDIGO,Kidney International Supplements(2012)2,69-88)中被定义，该指南通过引用全部并入本说明书中。
造影剂引起的急性肾脏损伤定义为在使用造影剂后48小时内，血液中肌酐水平比现有水平增加25％以上或0.5mg/dL以上，而不是由于其他原因如低血压、使用其他肾毒性药物、尿路梗阻和栓塞引的肾功能下降。
通常，即使当给药给肾功能正常的人时，造影剂在一些情况下也会表现出诸如肾功能下降的副作用，但是特别是在给药给肾功能下降的人时，会更容易表现出肾功能恶化和加重肾功能下降。
虽然造影剂引起的急性肾脏损伤的确切机理尚未完全阐明，但是已知的是，造影剂增加渗透压，降低肾血流量，并且引起肾动脉收缩。此外，已知肾小管坏死或肾脏灌注减少是造影剂引起的急性肾脏损伤的原因。已知在这种状态下，促进了活性氧的产生并引起缺血性肾小管损伤，这可能是肾小管毒性的直接原因。此外，已知炎症是原因之一。
因此，为了预防或治疗造影剂引起的急性肾脏损伤，尽管已经报道通过充足的液体补充和用抗氧化剂如碳酸氢盐、N-乙酰半胱氨酸或抗坏血酸治疗来减少活性氧的肾脏保护作用，但是目前还没有确定的治疗方法，并且预防是唯一的治疗方法。
本发明的药物组合物，特别是所有的3-苯基-4-乙基-1-(吡啶-2-基)-1H-吡唑-5-醇、3-苯基-4-正丙基-1-(吡啶-2基)-1H-吡唑-5-醇和3-苯基-4-正丁基-1-(吡啶-2-基)-1H-吡唑-5-醇均表现出对活性氧的形成的抑制作用。
如本发明的实施例中的动物实验所证实的，作为造影剂引起的急性肾脏损伤的指标的血清肌酐浓度显著降低，并且肾小管损伤程度也降低。此外，作为肾脏损伤的标志物的中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、肾脏损伤分子-1(KIM-1)和尿微量蛋白减少，并且肾脏组织内炎症细胞的浸润以及作为氧化应激指标的活性氧和硝基酪氨酸减少。
因此，在造影剂引起的急性肾脏损伤模型中，证实了通过抑制肾组织中的活性氧的产生来抑制炎症反应，从而预防或减轻急性肾脏损伤的作用。
除了化学式1的化合物或其盐，本发明的药物组合物还可以包含碳酸氢盐和/或用于去除活性氧的抗氧化剂。
在不损害本发明效果的范围内，本发明的药物组合物可以包含药学上可接受的载体。
所述“药学上可接受的载体”包括任意和所有种类的溶剂、分散介质、涂料、表面活性剂、抗氧化剂、防腐剂(抗菌剂或抗真菌剂)、等渗剂、稀释剂、吸收延迟剂、盐类、防腐剂、稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料等，以及它们的组合，如本领域技术人员已知的。
稀释剂可以选自，但不限于，微晶纤维素、乳糖一水合物、乳糖酐、乳糖、淀粉、甘露醇、羧甲基纤维素、山梨醇和它们的组合。
崩解剂可以选自，但不限于，低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羟基乙酸淀粉钠、F-melt和它们的组合。
粘合剂可以选自，但不限于，羟丙基纤维素、羟丙基甲基纤维素、羟丙甲基纤维素、聚乙烯乙酸、聚维酮、聚乙烯吡咯烷酮、共聚维酮、聚乙二醇、十二烷基硫酸钠、轻质无水硅酸、合成硅酸铝、硅酸盐衍生物如硅酸钙或偏硅酸镁铝酸盐、磷酸盐如磷酸氢钙、碳酸盐如碳酸钙、预糊化淀粉、树胶如阿拉伯胶、明胶、纤维素衍生物如乙基纤维素和它们的混合物。
润滑剂可以选自，但不限于，硬脂酸镁、二氧化硅、滑石、轻质无水硅酸、硬脂富马酸钠和它们的组合。
作为pH调节剂，可以使用酸化剂如乙酸、己二酸、抗坏血酸、抗坏血酸钠、乙醚酸钠、苹果酸、琥珀酸、酒石酸、富马酸和柠檬酸，以及碱化剂如氨水、碳酸钠、氧化镁、碳酸镁、柠檬酸钠和磷酸三钙。
作为抗氧化剂，可以使用二丁基羟基甲苯、丁基化羟基苯甲醚、生育酚乙酸酯、生育酚、没食子酸丙酯、亚硫酸氢钠、焦亚硫酸钠等。
此外，可以通过选择性地使用选自着色剂和调味剂的各种添加剂作为药学上可接受的添加剂来配制本发明的试剂。
在本发明中，添加剂的范围不限于使用添加剂，并且可以通过选择性地使用添加剂来配制成包含正常范围内的剂量。
根据本发明的药物组合物可以通过常规方法以口服制剂的形式配制和使用，例如粉末、颗粒、片剂、胶囊、混悬剂、乳剂、糖浆和气雾剂、外用制剂、栓剂或无菌注射液。
在本发明的一个方面，其是一种用于预防、改善或治疗造影剂引起的急性肾脏损伤的药物组合物，基于药物组合物的总重量，包含0.00001重量％至100重量％、0.0001重量％至95重量％或0.001重量％至90重量％的范围内的活性成分。
在根据本发明的用于造影剂引起的急性肾脏损伤的预防或治疗药剂中，由化学式1表示的吡唑类化合物或其药学上可接受的盐的剂量可以根据患者的年龄和体重、症状、给药途径等适当地改变。
本发明的由化学式1表示的吡唑类化合物或其药学上可接受的盐的剂量可以为0.00001mg/kg/天至2000mg/kg/天、0.0001mg/kg/天至1000mg/kg/天、0.001mg/kg/天至800mg/kg/天、0.001mg/kg/天至500mg/kg/天、0.001mg/kg/天至100mg/kg/天、0.001mg/kg/天至80mg/kg/天或0.01mg/kg/天至70mg/kg/天。
本发明的由化学式1表示的吡唑类化合物或其药学上可接受的盐的含量可以为每单位剂型0.00001重量％至100重量％、0.0001重量％至95重量％、0.0001重量％至90重量％、0.001重量％至70重量％或0.001重量％至50重量％。
本发明的由化学式1表示的吡唑类化合物或其药学上可接受的盐的给药浓度可以为0.0001μM至500μM、0.001μM至300μM、0.001μM至150μM、0.001μM至130μM、0.001μM至100μM、0.001μM至80μM或0.01μM至70μM。
本发明的药物组合物可以通过常规途径与造影剂一起给药或与造影剂分开给药，并且可以具体地配制用于肌肉内、鞘内、消化内、心血管内、肾内或静脉内的给药。配制方法采用本领域技术人员已知的常规方法。
用于肌肉内或鞘内给药的常规组合物可以由，但不限于，例如，活性成分和包含葡萄糖、氯化钠或葡萄糖和氯化钠两者的无菌等渗水溶剂组成。其它实例包括，但不限于，乳酸林格氏注射液、乳酸林格氏注射液+葡萄糖注射液、Normosol-M和葡萄糖、Isolyte E、酰化林格注射液等。任选地，本发明制剂可以包含，但不限于，助溶剂，如聚乙二醇；螯合剂，如乙二胺四乙酸；和抗氧化剂，如焦亚硫酸钠。任选地，但不限于，所述溶液可以被冻干，然后在即将给药之前用合适的溶剂重构。
提供优选的实施例以帮助理解本发明。提供以下实施例不是为了限制本发明，而是为了便于理解本发明。
<合成例>
<合成例1>3-苯基-4-乙基-1-(吡啶-2-基)-1H-吡唑-5-醇的合成
在圆底烧瓶中，在没有溶剂的情况下将2-乙基-3-氧-3-苯基丙酸乙酯(10.7g，49mmol)和2-肼基吡啶(5.6g，51.4mmol)在氮气条件下加热回流1天。将得到的固体用己烷和乙酸乙酯纯化，然后真空干燥，得到产率为70％的标题化合物。
1H NMR(300MHz，DMSO-d6)δ8.25-8.24(1H，d)，8.00-7.97(1H，d)，7.84-7.82(1H，t)，7.73-7.71(2H，m)，7.46-7.37(3H，m)7.12-7.11(1H，t)，2.62-2.57(2H，m)，1.23-1.17(3H，m)；ESI(m/z)266.1[M+H]+
<合成例2>3-苯基-4-丁基-1-(吡啶-2-基)-1H-吡唑-5-醇的合成
在圆底烧瓶中，在没有溶剂的情况下将2-丁基-3-氧-3-苯基丙酸乙酯(12.1g，49mmol)和2-肼基吡啶(5.6g，51.4mmol)在氮气条件下加热回流1天。将得到的固体用己烷和乙酸乙酯纯化，然后真空干燥，得到产率为75％的标题化合物。
1H NMR(300MHz，DMSO-d6)δ8.25-8.24(1H，d)，8.03-8.02(1H，d)，7.85-7.83(1H，t)，7.70-7.69(2H，m)，7.44-7.35(3H，m)7.12-7.11(1H，t)，2.56-2.53(2H，t)，1.58-1.52(2H，m)，1.38-1.24(2H，m)，0.89-0.86(3H，t)；ESI(m/z)294.0[M+H]+
<合成例3>3-苯基-4-丙基-1-(吡啶-2-基)-1H-吡唑-5-醇的合成
将2-丙基-3-氧-3-苯基丙酸乙酯(2.52g，10.7mmol)和10mL的乙醇置于圆底烧瓶中，然后将2-肼基吡啶(1.29g，1.18mmol)稀释在3mL的乙醇中的溶液在0℃下缓慢逐滴加入其中。在100℃下加热回流3天。通过减压蒸馏除去溶剂，并将得到的固体用己烷和乙酸乙酯洗涤，然后真空干燥，得到产率为82％的标题化合物。
1H NMR(300MHz，CDCl3)δ12.50(1H，s)，8.27-8.25(1H，m)，8.01(1H，d，J＝8.5Hz)，7.81(1H，m)，7.69(2H，m)，7.48-7.34(3H，m)，7.12-7.10(1H，m)，2.54(2H，d，J＝7.5Hz)，1.64(2H，m)，0.93(3H，t，J＝7.3Hz)；EIMS(70eV)m/z(rel intensity)279(M+，37)，250(100)
<合成例4>3-苯基-4-丙基-1-(吡啶-2-基)-1H-吡唑-5-醇盐酸盐(化合物1)的合成
将上述合成例3中制备的3-苯基-4-丙基-1-(吡啶-2-基)-1H-吡唑-5-醇(280mg，1.0mmol)在圆底烧瓶中溶解在4mL的乙醚中，然后将溶解在2M HCl中的0.55mL的乙醚在0℃下缓慢逐滴加入到其中。将由反应溶液产生的固体减压过滤，除去溶剂，用己烷和乙酸乙酯洗涤，然后真空干燥，得到标题化合物(270mg，0.85mmol)。
1H NMR(300MHz，CDCl3)δ8.44(1H，d，J＝4.2Hz)，8.0-8.03(2H，m)，7.66-7.64(2H，m)，7.48-7.42(3H，m)，7.34-7.30(1H，m)，2.49(2H，brs)，2.43(2H，t，J＝7.5Hz)，1.48(2H，m)，0.48(3H，t，J＝7.3Hz)
<实施例>造影剂引起的小鼠急性肾脏损伤动物模型的疗效评价
作为实验动物，从LionBio购买6周龄的雄性C57BL/6小鼠。所有小鼠都在标准条件下维持。繁殖约2周后，在8周龄时，在造影剂给药之前口服化合物1(3-苯基-4-正丙基-1-(吡啶-2-基)-1H-吡唑-5-醇盐酸盐)，剂量为60mg/kg/天，持续5天。
为了诱导急性肾脏损伤，在禁食16小时后，在造影剂给药15分钟之前，将抗炎止痛药吲哚美辛(10mg/kg)和NO阻滞剂N-硝基-L-精氨酸(L-NAME，10mg/kg)腹腔内给药，并且15分钟之后腹腔内给药造影剂(Iohexol，4000mg碘/kg)。进食进水24小时后，将动物试验物质分为三组：赋形剂给药组(对照，Control)和造影剂给药组(碘海醇)，以及造影剂和化合物1同时给药组(碘海醇+化合物1)。
试验结束后，将动物麻醉，从每个个体中摘除肾脏组织，并抽血检查。将组织固定在10％的中性福尔马林缓冲溶液中。将固定组织切片至一定厚度，并通过常规的组织处理工艺石蜡包埋，以制备4μm至5μm的组织切片，然后进行作为常规染色法的苏木精&伊红染色(H&E染色)，以在组织病理学上观察肾皮质和肾髓质区域中的肾脏损伤程度，并进行F4/80染色、Tunel染色、DHE染色和硝基酪氨酸染色，以观察炎症和氧化应激在肾脏损伤组织中的影响。
取血并在3000rpm、4℃下离心分离10分钟，取上层血清，使用自动血液生化分析仪(AU480，Beckman Coulter，USA)测定血尿素氮(BUN)和肌酐水平，以确认肾脏损伤的指标。肾脏损伤程度的组织学评价如下计算，无肾小管损伤为0分，轻度损伤为1分，小管内空泡病变小于25％至60％为2分，小管内空泡病变为60％以上为3分，从而得出显微镜视野下肾小管损伤的平均值。
图1显示的照片示出了在使用造影剂引起的小鼠急性肾脏损伤的动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组减少肾脏组织中肾小管损伤的效果。如图1所示，作为采集肾脏组织并确认肾皮质和肾髓质区域中的肾脏损伤程度的结果，可以发现，与正常对照组相比，在用造影剂处理的组中，由于肾小管细胞损伤而出现空泡变化，并且由于刷状缘消失而出现严重的肾小管组织损伤，而用化合物1处理的组中的肾髓质和肾皮质的损伤显著减少。
图2和图3示出了示出在使用造影剂引起的小鼠急性肾脏损伤动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组在血液试验中减少肾脏损伤的效果的图。如图2和图3所示，可以发现，与正常对照组相比，用造影剂处理的组中BUN和肌酐(血清Cr)的浓度显著升高，而用化合物1处理的组中BUN和肌酐的浓度下降，特别是肌酐浓度下降，这减少肾脏损伤。
图4示出了示出在使用造影剂引起的小鼠急性肾脏损伤动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组减少尿液中的肾脏损伤标志物NGAL、KIM-1和尿微量蛋白(白蛋白)的效果的图。如图4所示，可以发现，与正常对照组相比，用造影剂处理的组中NGAL、KIM-1和尿微量蛋白(白蛋白)的浓度显著增加，而用化合物1处理的组中NGAL、KIM-1和尿微两蛋白(白蛋白)的浓度下降，这减少肾脏损伤。
图5示出了示出在使用造影剂引起的小鼠急性肾脏损伤的动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组在肾活检中减少肾小管损伤的效果的图。图5示出了收集肾脏组织并比较肾小管损伤减少程度的结果，可以发现，与正常对照组相比，用造影剂处理的组中的肾小管损伤评分显著增加，而用化合物1处理的组中的肾小管损伤评分显著降低。
图6示出了示出在使用造影剂引起的小鼠急性肾脏损伤的动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组减少肾脏组织中的炎症的效果的图。图6示出了在肾脏组织中作为炎症指标的单核细胞趋化蛋白-1(MCP-1)基因的表达水平的分析，可以发现，与正常对照组相比，用造影剂处理的组中MCP-1的表达增加，而用化合物1处理的组中炎症(MCP-1)显著减少
图7示出了在使用造影剂引起的小鼠急性肾脏损伤动物模型的评估中，在用化合物1以每天一次、每次60mg/kg、持续5天给药的组中肾脏组织中炎症细胞(巨噬细胞、F4/80阳性细胞)的浸润程度的分析，可以发现，与正常对照组相比，用造影剂处理的组中的炎症细胞的浸润显著增加，并且与用造影剂处理的组相比，用化合物1处理的组中的炎症细胞的浸润显著减少。
图8示出了在使用造影剂引起的小鼠急性肾脏损伤动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组中对作为肾脏组织中氧化应激的指标的活性氧(DHE染色)的程度的分析，可以发现，与正常对照组相比，用造影剂处理的组中活性氧显著增加，并且与用造影剂处理的组相比，用化合物1处理的组中活性氧显著减少。
图9示出了在使用造影剂引起的小鼠急性肾脏损伤动物模型的评估中，用化合物1以每天一次、每次60mg/kg、持续5天给药的组中对肾脏组织中作为氧化应激的指标的硝基酪氨酸的程度的分析，可以发现，与正常对照组相比，用造影剂处理的组中的硝基酪氨酸显著增加，并且与用造影剂处理的组相比，用化合物1处理的组中硝基酪氨酸显著降低。
因此，可以证实，本申请的化合物在造影剂引起的急性肾脏损伤模型中具有显著的肾脏保护作用。
Claims (11)
1.一种用于通过降低造影剂引起的肾毒性来保护肾脏或用于预防或治疗造影剂引起的急性肾脏损伤的药物组合物，包含下面化学式1的化合物或其药学上可接受的盐：
化学式1
其中，R是具有1至10个碳原子的直链或支链烷基。
2.根据权利要求1所述的药物组合物，其中，在化学式1中，R是具有1至6个碳原子的直链或支链烷基。
3.根据权利要求2所述的药物组合物，其中，所述化学式1的化合物为：
3-苯基-4-甲基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-乙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-异丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正丁基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-叔丁基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；
3-苯基-4-正戊基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐；或
3-苯基-4-正己基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐。
4.根据权利要求3所述的药物组合物，其中，所述化学式1的化合物是3-苯基-4-正丙基-1-(吡啶-2-基)-1H-吡唑-5-醇或其盐酸盐。
5.根据权利要求1至4中任一项所述的药物组合物，其中，所述造影剂选自离子型单体造影剂或非离子型单体造影剂。
6.根据权利要求5所述的药物组合物，其中，所述离子型单体造影剂选自碘甘酸盐、碘达胺、醋碘苯酸盐、泛影酸盐和甲泛影酸。
7.根据权利要求5所述的药物组合物，其中，所述非离子型单体造影剂选自甲泛葡胺、碘海醇、碘帕醇、碘喷托、碘普罗胺和碘佛醇。
8.根据权利要求7所述的药物组合物，其中，所述非离子型单体造影剂是碘海醇。
9.根据权利要求1至4中任一项所述的药物组合物，其中，所述急性肾脏损伤是由肾小管坏死或肾脏灌注减少引起的。
10.根据权利要求1至4中任一项所述的药物组合物，其中，所述急性肾脏损伤是由氧化应激或炎症引起的。
11.根据权利要求1至4中任一项所述的药物组合物，其中，所述药物组合物还包含药学上可接受的载体或赋形剂。
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| KR10-2021-0036838 | 2021-03-22 | ||
| PCT/KR2021/003536 WO2021206316A1 (ko) | 2020-04-08 | 2021-03-23 | 조영제 유발 급성 신부전 치료제 |
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| CN115990166B (zh) * | 2023-02-20 | 2023-09-15 | 牡丹江医学院 | 一种预防ct造影剂肾病的药物组合物及其用途 |
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| EP4134079A1 (en) | 2023-02-15 |
| CL2022002641A1 (es) | 2023-06-16 |
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