CN116437921A - 鞘氨醇-1-磷酸酯受体激动剂的用途 - Google Patents
鞘氨醇-1-磷酸酯受体激动剂的用途 Download PDFInfo
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- CN116437921A CN116437921A CN202180065509.2A CN202180065509A CN116437921A CN 116437921 A CN116437921 A CN 116437921A CN 202180065509 A CN202180065509 A CN 202180065509A CN 116437921 A CN116437921 A CN 116437921A
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- atopic dermatitis
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Abstract
本发明涉及化学式1的化合物或其药学上可接受的盐用于预防或治疗特应性皮炎的用途。
Description
技术领域
本发明涉及式1的化合物或其药学上可接受的盐用于预防或治疗特应性皮炎的用途：
[式1]
其中X、R1、R2、R3、R4、R5和R6与本文所定义相同。
背景技术
鞘氨醇-1-磷酸酯(S1P)通过细胞内神经酰胺途径产生，其中神经酰胺为起始物质。神经酰胺通过两种途径产生，其中第一种途径为从头生物合成途径。神经酰胺还由细胞中的细胞膜成分鞘磷脂降解产生。各个组织中的S1P水平由两种生物合成鞘氨醇激酶(SphK)和两种生物可降解S1P磷酸酶(S1P溶解酶和溶血磷脂磷酸酶)控制。已知通过鞘氨醇激酶导致鞘氨醇磷酸化产生的S1P介导各种细胞应答，如细胞增殖、细胞骨架组织和迁移、粘附和紧密连接组装以及形态发生。S1P以与血浆蛋白(包括白蛋白)组合的形式以高水平(100-1000nM)存在于血浆中，而它以低水平存在于组织中。
S1P与G蛋白偶联受体S1P受体结合，以显示出各种生物功能。作为S1P受体亚型，迄今已知S1P1至S1P5，分别命名为内皮分化基因(EDG)受体1、5、3、6和8。已知S1P受体参与多种生物功能，如白细胞再循环、神经细胞增殖、形态变化、迁移、内皮功能、血管调节和心血管发育。
近年来，许多研究已经发现通过这些受体的S1P信号传导过程在与多发性硬化相关的一系列反应(包括炎症反应和修复过程)中起重要作用，实际上已批准非选择性S1P1激动剂作为多发性硬化的治疗剂。S1P受体在许多与诱发多发性硬化相关的细胞中广泛表达。尤其，S1P1受体在免疫系统中起主要作用。S1P1受体主要表达于淋巴细胞如T细胞和B细胞的表面上并响应于S1P，从而参与淋巴细胞再循环。在正常条件下，体液中的S1P浓度高于淋巴组织，因此S1P浓度差异导致淋巴细胞离开淋巴组织，从而在输出淋巴循环后进行循环。然而，如果淋巴细胞中的S1P1受体被S1P1激动剂下调，就不会发生淋巴细胞从淋巴组织流出，从而减少造成中枢神经系统(CNS)的炎症和组织损伤的自身侵袭性淋巴细胞的浸润。因此，获得对多发性硬化的治疗效果。已经批准非选择性S1P1激动剂芬戈莫德作为治疗多发性硬化的口服药物。奇怪的是，当它结合在欲激活的S1P1受体处时，所述受体被降解或从淋巴细胞表面内在化，因此它发挥功能性S1P1拮抗作用。
关于此类S1P受体，国际公开第WO 2014/129796号(公开日期：2014年8月28日)公开了有效的S1P受体激动剂化合物。
同时，特应性皮炎是一种慢性复发性皮肤湿疹疾病，虽然目前尚未明确病因，但已经报告由于外部抗原的作用导致免疫相关因子过度反应。用于特应性皮炎的药物主要为免疫抑制剂、局部类固醇、抗组胺剂等。然而，存在与使用此类药物对应的副作用或在改善特应性皮炎方面的限制。因此，持续需要能更有效地预防或治疗特应性皮炎的新药。
发明内容
技术问题
本发明的一个目标是提供下式1的化合物或其药学上可接受的盐在预防或治疗特应性皮炎方面的用途：
[式1]
其中X、R1、R2、R3、R4、R5和R6与本文所定义相同。
技术解决方案
本发明提供了一种用于预防或治疗特应性皮炎的药物，所述药物包含治疗有效量的下式1的化合物或其药学上可接受的盐：
[式1]
其中
X为碳或氮；
R1为氢或烷基；
R2为氢、烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、烷基、卤素、卤代烷基或烷氧基烷基
R5为氢、烷基或卤素；
R6为
R7为氢或烷基；并且
m和n各自独立地为0、1、2或3。
此外，本发明提供了一种用于预防或治疗特应性皮炎的药物组合物，所述药物组合物包含治疗有效量的式1的化合物或其药学上可接受的盐以及药学上可接受的载体。
此外，本发明提供了一种预防或治疗特应性皮炎的方法，所述方法包括向有需要的受试者施用治疗有效量的式1的化合物或其药学上可接受的盐。
此外，本发明提供了式1的化合物或其药学上可接受的盐用于预防或治疗特应性皮炎的用途。
下文详细描述了本发明。
根据本发明的一个方面，提供了一种用于预防或治疗特应性皮炎的药物，所述药物包含治疗有效量的式1的化合物或其药学上可接受的盐。
根据本发明的另一个方面，提供了一种用于预防或治疗特应性皮炎的药物组合物，所述药物组合物包含治疗有效量的式1的化合物或其药学上可接受的盐以及药学上可接受的载体。
国际公开第WO 2014/129796 A1号详述了制备式1的化合物的方法，所述文献通过引用并入本文。
在根据本发明的一个实施方式中，在式1中
X为CH或N；
R1为氢或C1-C5烷基；
R2为氢、C1-C5烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、C1-C5烷基、卤素、卤代C1-C5烷基或C1-C5烷氧基-C1-C5烷基；
R5为氢、C1-C5烷基或卤素；
R6为
R7为氢或C1-C5烷基；并且
m和n各自独立地为0、1、2或3。
在根据本发明的另一个实施方式中，式1的化合物为下式2的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸：
[式2]
在根据本发明的另一个实施方式中，药学上可接受的盐包括例如由含有药学上可接受的阴离子的无毒酸加成盐形成的酸加成盐，诸如无机酸，如盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸；有机酸，如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸；或磺酸，如甲磺酸、苯磺酸、对甲苯磺酸或萘磺酸，但不限于此。
在根据本发明的另一个实施方式中，个别受试者的“治疗有效量”是指足以实现上述药理学效果，即如上所述的治疗效果的量。化合物的量可以取决于受试者的状况和严重程度、施用模式和欲治疗的受试者的年龄而变化，但可以由本领域的普通技术人员根据他们的知识来确定。
在根据本发明的另一个实施方式中，根据施用频率和强度，式1的化合物的治疗有效剂量通常例如在每天约0.1至500mg的范围内。成人的典型每日肌肉内或静脉内施用剂量在每天约0.1至300mg的范围内，可以以分次单位剂量的形式施用。一些患者需要更高的每日剂量。
在本发明中，除了本发明的活性成分以外，“药物组合物”还可以包括其它组分，如载体、稀释剂、赋形剂等。因此，所述药物组合物在有必要时可以包括药学上可接受的载体、稀释剂、赋形剂或其组合。所述药物组合物有助于向体内施用化合物。施用化合物的各种方法包括但不限于口服、注射、气雾剂、肠胃外和局部施用。
在本文中，“载体”意指有助于向细胞或组织中加入化合物的化合物。例如，二甲亚砜(DMSO)是有助于向活细胞或组织施用许多有机化合物的常规载体。
在本文中，“稀释剂”意指不仅能稳定生物活性形式而且能稀释在溶解化合物的溶剂中的化合物。在本领域中，将含溶解盐的缓冲液用作稀释剂。一种常规使用的缓冲液是模拟体液中的盐形式的磷酸盐缓冲生理盐水。由于缓冲溶液可以将溶液的pH控制在低浓度，因此缓冲液稀释剂几乎不改变化合物的生物活性。
在本文中，“药学上可接受的”意指不损害化合物的生物活性和物理性质的性质。
根据本发明的化合物可以配制为各种药学施用剂型。在制备本发明的药物组合物时，将活性成分，具体来说是式1的化合物或其药学上可接受的盐，与考虑要制备的剂型而选择的药学上可接受的载体混合。例如，本发明的药物组合物可以视需要配制为注射液、口服制剂等。
本发明的化合物可以使用已知的药物载体和赋形剂通过常规方法配制，并插入单位容器或多单位容器中。所述制剂可以是油或水性溶剂中的溶液、悬浮液或乳液，并包括常规分散剂、悬浮剂或稳定剂。此外，化合物可以为例如在使用前溶解在灭菌无热原水中的干粉形式。本发明的化合物可以通过使用常规栓剂基质如可可脂或其它甘油酯配制成栓剂。供口服施用的固体形式包括胶囊、片剂、丸剂、粉剂和颗粒剂。优选胶囊和片剂。片剂和丸剂优选是肠溶包衣的。固体形式是通过将本发明的化合物与至少一种选自惰性稀释剂如蔗糖、乳糖或淀粉、润滑剂如硬脂酸镁、崩解剂、粘合剂等的载体混合来制造。此外，它可以配制为透皮剂型，例如洗液、软膏、凝胶、乳霜、贴剂或喷雾剂。
在本文中，术语“预防”是指降低或消除感染疾病的可能性。
在本文中，术语“治疗”用于指在表现出疾病症状的受试者中阻止、延迟或改善疾病进展。
有益效果
根据本发明的药物或药物组合物可以有效地预防或治疗特应性皮炎。
附图说明
图1为示出了诱发特应性皮炎的动物模型的过程的示意图。
图2为在特应性皮炎的动物模型中施用测试物质后测量耳厚度的减少的结果。
图3为在特应性皮炎的动物模型中施用测试物质后测量耳重量的减少的结果。
图4为在特应性皮炎的动物模型中施用测试物质后测量IgE血液水平的减少的结果。
图5为在特应性皮炎的动物模型中施用测试物质后测量表皮厚度的减少的结果。
图6为在特应性皮炎的动物模型中施用测试物质后测量肥大细胞积聚的减少的结果。
图7为在特应性皮炎的动物模型中与作为比较化合物的依曲莫德(etrasimod)相比较的结果。
具体实施方式
下文利用以下实施例更详细地说明本发明。然而，必须理解本发明的保护范围不局限于所述实施例。
制备例：1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基
甲基]-哌啶-4-甲酸的合成
根据国际公开第WO 2014/129796 A1号的实施例153所公开的方法制备1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸(下文称为“测试化合物”)。
实施例1：特应性皮炎的动物模型的诱发
通过使用
唑酮在小鼠(Balb/c)中诱发特应性皮炎的动物模型。在将/>
唑酮致敏第一天设为第0天的情况下，从第7天开始每天一次口服或透皮施用它。当/>
唑酮施用日期与药物施用日期重叠时，在施用/>
唑酮后约6小时施用药物。
对于所有小鼠，在首次施用
唑酮前一天除去腹部毛发。然后，通过使用4:1丙酮/玉米油比制备1％或0.2％/>
唑酮，并且用如表1和图1所示的相同剂量和方案对剃毛的小鼠腹部和双耳进行致敏和诱发。
[表1]
实施例2：用于口服施用的物质的制备
通过使用0.5％甲基纤维素，针对如下表2所示的各个施用剂量制备测试物质(测试化合物和作为阳性对照物的地塞米松)。在测试化合物的情况下，考虑到HCl盐形式来制备它。将测试物质溶解在0.5％甲基纤维素中，然后进行超声处理。如果它没有完全溶解，就以悬浮液状态施用它。
实施例3：用于透皮(局部)施用的物质的制备
通过将测试物质以0.1％(w/v)的浓度溶解在溶液(PEG400:100％乙醇＝1:1)中来制备它们。将5mL PEG400加入10mg测试物质中并进行超声处理。当它们溶解到一定程度后，向其中加入5mL 100％乙醇并进行超声处理以使它们完全溶解。此外，每天制备新鲜的媒剂和测试物质并使用。
[表2]
实施例4：测量结果
在施用测试物质后第14天和第21天测量了耳厚度的减少，结果示于表3和图2中。在施用测试物质后第21天，在尸检后测量耳重量的减少，结果示于表3和图3中。在施用测试物质后第21天测量IgE血液水平的减少，结果示于表3和图4中。此外，在施用测试物质后第21天测量了耳组织表皮厚度和肥大细胞积聚的减少，结果示于表3、图5和图6中。
[表3]
如从表3和图2至图6可见，可知在
唑酮诱发的特应性皮炎动物模型中，与地塞米松(阳性对照物)相比，测试化合物以剂量依赖性方式显示出优越的效果。从这样的结果可以确认，本发明的化合物可以用作预防或治疗特应性皮炎的药物。
实施例5：比较实验
为了与另一种S1P受体激动剂依曲莫德(2-[(3R)-7-[[4-环戊基-3-(三氟甲基)苯基]甲氧基]-1,2,3,4-四氢环戊并[b]吲哚-3-基]乙酸)进行比较，以与实施例4相同的方式测量耳厚度、耳重量、IgE血液水平、上皮厚度和肥大细胞积聚的减少，结果示于表4和图7中。
[表4]
如从表4和图7可见，可知与比较化合物依曲莫德相比，测试化合物即使在较低剂量下也表现出了相等或优越的效果。从这样的结果可以预期，通过施用相同剂量就获得了更好的功效或施用较低剂量就达到了特定的功效水平，可以将由于全身暴露导致的副作用降至最低。此外，就由对能通过S1P受体激动剂诱发心动徐缓的GIRK(G蛋白偶联内整流钾通道)的低亲和力导致的副作用而言，可以预期优越性。
Claims (10)
1.一种用于预防或治疗特应性皮炎的药物，所述药物包含治疗有效量的下式1的化合物或其药学上可接受的盐：
[式1]
其中
X为碳或氮；
R1为氢或烷基；
R2为氢、烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、烷基、卤素、卤代烷基或烷氧基烷基；
R5为氢、烷基或卤素；
R6为
R7为氢或烷基；并且
m和n各自独立地为0、1、2或3。
2.根据权利要求1所述的用于预防或治疗特应性皮炎的药物，其中
X为CH或N；
R1为氢或C1-C5烷基；
R2为氢、C1-C5烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、C1-C5烷基、卤素、卤代C1-C5烷基或C1-C5烷氧基-C1-C5烷基；
R5为氢、C1-C5烷基或卤素；
R6为
R7为氢或C1-C5烷基；并且
m和n各自独立地为0、1、2或3。
3.根据权利要求1所述的用于预防或治疗特应性皮炎的药物，其中所述式1的化合物为下式2的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸：
[式2]
4.根据权利要求1所述的用于预防或治疗特应性皮炎的药物，其中所述药学上可接受的盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。
5.一种用于预防或治疗特应性皮炎的药物组合物，所述药物组合物包含治疗有效量的下式1的化合物或其药学上可接受的盐以及药学上可接受的载体：
[式1]
其中
X为碳或氮；
R1为氢或烷基；
R2为氢、烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、烷基、卤素、卤代烷基或烷氧基烷基；
R5为氢、烷基或卤素；
R6为
R7为氢或烷基；并且
m和n各自独立地为0、1、2或3。
6.根据权利要求5所述的用于预防或治疗特应性皮炎的药物组合物，其中
X为CH或N；
R1为氢或C1-C5烷基；
R2为氢、C1-C5烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、C1-C5烷基、卤素、卤代C1-C5烷基或C1-C5烷氧基-C1-C5烷基；
R5为氢、C1-C5烷基或卤素；
R6为
R7为氢或C1-C5烷基；并且
m和n各自独立地为0、1、2或3。
7.根据权利要求5所述的用于预防或治疗特应性皮炎的药物组合物，其中所述式1的化合物为下式2的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸：
[式2]
8.根据权利要求5所述的用于预防或治疗特应性皮炎的药物组合物，其中所述药学上可接受的盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。
9.一种预防或治疗特应性皮炎的方法，所述方法包括向有需要的受试者施用治疗有效量的下式1的化合物或其药学上可接受的盐：
[式1]
其中
X为碳或氮；
R1为氢或烷基；
R2为氢、烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、烷基、卤素、卤代烷基或烷氧基烷基；
R5为氢、烷基或卤素；
R6为
R7为氢或烷基；并且
m和n各自独立地为0、1、2或3。
10.一种下式1的化合物或其药学上可接受的盐在制造用于预防或治疗特应性皮炎的药物中的用途：
[式1]
其中
X为碳或氮；
R1为氢或烷基；
R2为氢、烷基、卤素、CN、CF3或COCF3；
R3和R4各自独立地为氢、烷基、卤素、卤代烷基或烷氧基烷基；
R5为氢、烷基或卤素；
R6为
R7为氢或烷基；并且
m和n各自独立地为0、1、2或3。
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