CN102905708A - 用于治疗葡萄膜炎的a3ar激动剂 - Google Patents
用于治疗葡萄膜炎的a3ar激动剂 Download PDFInfo
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- CN102905708A CN102905708A CN2011800121918A CN201180012191A CN102905708A CN 102905708 A CN102905708 A CN 102905708A CN 2011800121918 A CN2011800121918 A CN 2011800121918A CN 201180012191 A CN201180012191 A CN 201180012191A CN 102905708 A CN102905708 A CN 102905708A
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明涉及A3AR激动剂诸如IB-MECA用于治疗或预防受试者中的葡萄膜炎的用途，以及用于这种治疗的方法和包含有效治疗葡萄膜炎的量的IB-MECA的药物组合物。
Description
技术领域
本发明涉及用于治疗葡萄膜炎的方法和组合物。
背景技术
葡萄膜炎具体地是指为视网膜提供大部分血液供应的眼睛中层(“葡萄膜”)的炎症，但在普遍的用法中可以指涉及眼内部的任何炎症过程，特别地，称为虹膜睫状体炎的葡萄膜炎症。
葡萄膜炎典型地由自体免疫性疾病、感染或接触毒素引起。葡萄膜炎的症状包括眼部发红、视力模糊、对光敏感(畏光)、视觉中漂浮的黑斑和眼部疼痛。
据估计美国大约10％的失明归因于葡萄膜炎。葡萄膜炎需要紧急转诊并由眼科医生充分检查，同时紧急治疗以控制炎症。对于接受及时诊断和治疗的患者预后一般良好，但如果不治疗则可能导致严重的并发症(包括白内障、青光眼、视网膜内积液、视网膜剥离和视力减退、带状角膜病变、视网膜水肿和永久性视力丧失)。葡萄膜炎的类型、及其严重性、持续时间和对治疗的反应性、或任何相关疾病，所有这些因素均要考虑。
滴眼剂，尤其是糖皮质类固醇(例如，醋酸泼尼松龙)和扩瞳剂，或采用泼尼松龙片的口服治疗是用于减轻葡萄膜炎中的炎症和疼痛的药物疗法。此外可以使用局部睫状肌麻痹剂，诸如阿托品或后马托品。对于较深的炎症，使用类固醇或免疫抑制剂的口服用药或眼周注射。还经常使用抗代谢物药物疗法，诸如甲氨蝶呤，用于葡萄膜炎的顽固病例或侵袭性较强的病例。[Nussenblatt RB，Whitcup SM.(2004)Uveitis：Fundamentals and Clinical Practice(葡萄膜炎：原理和临床实践)(第三版)，Mosby/Elsevier；2004；Gery I，Nussenblatt RB，Chan CC，Caspi RR.Autoimmune diseases of the eye.The molecular pathology of autoimmune diseases(眼的自体免疫性疾病。自体免疫性疾病的分子病理学).第二版。New York，NY：Taylor and Francis；2002：978-98]
可接受的实验性自体免疫性葡萄膜炎(EAU)模型是一种器官特异性的、T细胞介导的自体免疫性疾病，其靶向神经视网膜和相关组织，并被认为是人类自体免疫性葡萄膜炎的模型。其通过用视网膜抗原免疫大鼠或小鼠来诱发。EAU的病理学与具有推测的自体免疫特征的人葡萄膜炎疾病非常类似，其中患者显示出对视网膜抗原的免疫应答[Caspi RR，Silver PB，Luger D，Tang J，Cortes LM，Pennesi G，Mattapallil MJ，Chan CC.Mouse models of experimental autoimmune uveitis(实验性自体免疫性葡萄膜炎的小鼠模型).Ophthalmic Res.2008；40：169-74；Smith JR，Hart PH，Williams KA.Basic pathogenic mechanisms operating in experimental models of acute anterior uveitis(急性前葡萄膜炎的实验模型中起作用的基本发病机理).Immunol.Cell Biol.1998；76，497-512；Caspi RR.于Cohen，I.R.和Miller，A.(eds.)，Animal Models for Autoimmune Diseases：AGuidebook(自体免疫性疾病的动物模型：指南)，Academic Press p.57-81.1994].
发明内容
本发明基于下面的发现：N6-(3-碘苄基)-2-甲基氨基-9-[5-(甲基酰氨基)-β-D-呋喃核糖基]-腺嘌呤(本文中缩写为IB-MECA)在下列各项中是有效的：
-其抑制动物模型中实验性自体免疫性葡萄膜炎的发展；
-其抑制实验性自体免疫性葡萄膜炎(EAU)的组织病理学评分；
-其改善抗原特异性T细胞应答。
基于这些发现，已经想到作为示例性A3AR激动剂的A3腺苷受体(A3AR)激动剂，IB-MECA，可以用于治疗或预防葡萄膜炎。
因此，根据其第一个方面，本发明提供了A3AR激动剂用于治疗或预防葡萄膜炎的用途。
根据第二个方面，本发明提供了一种治疗葡萄膜炎的方法，所述方法包括向受试者施用一定量的A3AR激动剂，所述量有效地治疗或预防葡萄膜炎。
还在第三个方面，本发明提供了一种用于治疗葡萄膜炎的药物组合物，所述药物组合物包含作为活性成分的一定量的A3AR激动剂和生理学可接受的载体，所述A3AR激动剂的量有效地治疗所述葡萄膜炎。
附图说明
为了理解本发明并且明白本发明在实践中如何实施，现在将仅通过非限制性实施例，参照附图描述实施方案，在附图中：
图1是显示由代号CF101标识的IB-MECA抑制EAU发生的条形图。
图2是显示由代号CF101标识的IB-MECA降低EAU的组织病理学评分的条形图。
图3是显示由代号CF101标识的IB-MECA改善抗原特异性T细胞应答的条形图。
具体实施方式
如所理解，尽管在下面的详述中参照利用A3AR激动剂治疗葡萄膜炎的方法描述了本发明，但要理解的是其还涵盖A3AR激动剂用于治疗葡萄膜炎的用途以及用于所述治疗的包含A3AR的任何药物组合物。
在本发明的上下文中，术语“葡萄膜炎”表示眼内部部分的炎症，特别是，眼睛中层(葡萄膜)的炎症。更具体地，葡萄膜炎包括前葡萄膜炎，前葡萄膜炎是葡萄膜前部的炎症；前葡萄膜炎包括虹膜的炎症(虹膜炎)以及虹膜和睫状体的炎症(虹膜睫状体炎)；中间葡萄膜炎(周边葡萄膜炎或慢性睫状体炎)，其是玻璃体中的炎症；以及后葡萄膜炎，其是眼晶状体后的葡萄膜部分的炎症；脉络膜的炎症(脉络膜炎)以及脉络膜和视网膜的炎症(脉络膜视网膜炎)；以及影响整个葡萄膜的全葡萄膜炎或弥漫性葡萄膜炎。
术语“治疗”等在本文中用来指获得期望的药理学和生理学效应。所述效应就在任何受试者中改善或减少的眼内部部分中的炎性反应而言可以是治疗性的和/或就在任何受试者中预防或部分预防眼内部部分中炎症的发展而言是预防性 的，所述受试者可能易于发展眼内部中的炎症，例如，由内眼创伤、眼部和全身感染(病毒性、细菌性、寄生虫性葡萄膜炎)以及全身自体免疫性疾病中的一种或多种引起的炎症。所述治疗要被理解为涵盖对哺乳动物，特别是人的疾病的任何治疗。
在本发明的上下文中，术语“A3腺苷受体激动剂”(A3AR激动剂)是指能够与A3腺苷受体(A3AR)特异性结合从而完全或部分激活所述受体的任何分子。A3AR激动剂因此是通过A3AR的结合和激活发挥其主要效应的分子。这意味着在其被施用的剂量下，其基本上仅结合和激活A3AR。在优选的实施方案中，A3AR激动剂与人A3AR的结合亲和力(Ki)的范围为小于100nM，典型地小于50nM，优选小于20nM，更优选小于10nM和理想地小于5nM。特别优选地是对人A3R的Ki小于2nM且期望地小于1nM的A3AR激动剂。
然而，应当理解的是一些A3AR激动剂也可以与其他受体相互作用并激活所述其他受体，然而，具有较低的亲和力(即较高的Ki)。在本发明的上下文中，一个分子如果其与A3AR的亲和力比与任何其他的腺苷受体(即A1、A2a和A2b)的亲和力高至少3倍(即，其对A3AR的Ki低至少3倍)、优选地10倍、期望地20倍和最优选地至少50倍，则该分子将被认为是A3AR激动剂(即通过A3AR的结合和激活发挥其主要效应的分子)。
A3AR激动剂对人A3AR的亲和力以及其对其他人腺苷受体的相对亲和力可以通过许多测定法来确定，诸如结合测定法。结合测定法的实例包括提供包含受体的膜，并测量所述A3AR激动剂置换结合的放射性激动剂的能力；利用展示各种人腺苷受体的细胞，并在功能测定法中测量所述A3AR激动剂激活或失活(视情况而定)下游信号事件的能力(诸如通过cAMP水平的增加或减少测量到的对腺苷酸环化酶的效应)；等等。显然，如果A3AR激动剂的施用水平增加使得其血液水平达到接近A1、A2a和A2b腺苷受体的Ki的血液水平的水平，则伴随所述施用，除了A3AR激活以外，可能出现这些受体的激活。A3AR激动剂因此优选以使得血液水平使基本上仅A3AR被激活的剂量施用。
一些腺苷A3AR激动剂的特性及其制备方法详细地记述在尤其是US 5,688,774；US 5,773,423、US 5,573,772、US 5,443,836、US 6,048,865、WO 95/02604、WO 99/20284、WO 99/06053、WO 97/27173和WO 01/19360中，所有这些文献通过引用结合在本文中。
根据本发明的一个实施方案，A3AR激动剂是通过腺苷A3AR的结合和激活来发挥其主要效应的化合物并且是落在通式(I)的范围内的嘌呤衍生物：
其中，
-R11表示烷基、羟烷基、羧烷基或氰烷基或下列通式(II)的基团：
其中：
-Y表示氧、硫或CH2；
-X11表示H、烷基、ReRfNC(＝O)-或HORg-，其中
-Re和Rf可以相同或不同并且选自由下列各项组成的组：氢、烷基、氨基、卤代烷基、氨基烷基、BOC-氨基烷基和环烷基或连接在一起形成包含2至5个碳原子的杂环；且
-Rg选自由下列各项组成的组：烷基、氨基、卤代烷基、氨基烷基、BOC-氨基烷基和环烷基；
-X12是H、羟基、烷基氨基、烷基酰氨基或羟烷基；
-X13和X14独立地表示氢、羟基、氨基、酰氨基、叠氮基、卤代、烷基、烷氧基、羧基、次氮基、硝基、三氟代、芳基、烷芳基、硫代、硫酯、硫醚、-OCOPh、 -OC(＝S)OPh或X13和X14两者为连接至＞C＝S以形成5元环的氧，或X12和X13形成式(III)的环：
其中R′和R″独立地表示烷基；
-R12选自由下列各项组成的组：氢、卤代、烷基醚、氨基、肼基、烷基氨基、烷氧基、硫代烷氧基、吡啶硫代(pyridylthio)、烯基；炔基、硫代和烷基硫代；且
-R13是式-NR15R16的基团其中
-R15是氢原子或选自烷基、取代烷基、或芳基-NH-C(Z)-的基团，Z为O、S或NRa，Re具有上述含义；其中当R15为氢时则
-R16选自由下列各项组成的组：未取代的或在一个或多个位置中被取代基取代的R-和S-1-苯乙基、苄基、苯乙基或苯胺基团，所述取代基选自由下列各项组成的组：烷基、氨基、卤代、卤代烷基、硝基、羟基、乙酰氨基、烷氧基和磺酸或其盐；苯并二 烷甲基(benzodioxanemethyl)、糠基(fururyl)、L-丙基丙氨酰基-氨基苄基、β-丙氨酰基氨基-、苄基、T-BOC-β-丙氨酰基氨基苄基、苯基氨基、氨基甲酰基、苯氧基或环烷基；或R16是下式的基团：
或当R15是烷基或芳基-NH-C(Z)-时，则，R16选自由下列各项组成的组：杂芳基-NRa-C(Z)-、杂芳基-C(Z)-、烷芳基-NRa-C(Z)-、烷芳基-C(Z)-、芳基-NR-C(Z)-和芳基-C(Z)-；Z表示氧、硫或胺。
示例性的A3AR激动剂(公开在US 5,688,774的第4栏，第67行-第6栏，第16行；第5栏，第40-45行；第6栏，第21-42行；第7栏，第1-11行；第7栏， 第34-36行；和第7栏，第60-61行)：
N6-(3-碘苄基)-9-甲基腺嘌呤；
N6-(3-碘苄基)-9-羟乙基腺嘌呤；
R-N6-(3-碘苄基)-9-(2，3-二羟丙基)腺嘌呤；
S-N6-(3-碘苄基)-9-(2，3-二羟丙基)腺嘌呤；
N6-(3-碘苄基腺嘌呤-9-基)乙酸；
N6-(3-碘苄基)-9-(3-氰丙基)腺嘌呤；
2-氯-N6-(3-碘苄基)-9-甲基腺嘌呤；
2-氨基-N6-(3-碘苄基)-9-甲基腺嘌呤；
2-肼基-N6-(3-碘苄基)-9-甲基腺嘌呤；
N6-(3-碘苄基)-2-甲基氨基-9-甲基腺嘌呤；
2-二甲基氨基-N6-(3-碘苄基)-9-甲基腺嘌呤；
N6-(3-碘苄基)-9-甲基-2-丙基氨基腺嘌呤；
2-己基氨基-N6-(3-碘苄基)-9-甲基腺嘌呤；
N6-(3-碘苄基)-2-甲氧基-9-甲基腺嘌呤；
N6-(3-碘苄基)-9-甲基-2-甲基硫代腺嘌呤；
N6-(3-碘苄基)-9-甲基-2-(4-吡啶基硫代)腺嘌呤；
(1S，2R，3S，4R)-4-(6-氨基-2-苯乙基氨基-9H-嘌呤-9-基)环戊烷-1，2，3-三醇；
(1S，2R，3S，4R)-4-(6-氨基-2-氯-9H-嘌呤-9-基)环戊烷-1，2，3-三醇；
(±)-9-[2α，3α-二羟基-4β-(N-甲基氨基甲酰基)环戊-1β-基)]-N6-(3-碘苄基)-腺嘌呤；
2-氯-9-(2′-氨基-2′，3′-二脱氧-β-D-5′-甲基-阿拉伯呋喃糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
2-氯-9-(2′，3′-二脱氧-2′-氟-β-D-5′-甲基-阿拉伯呋喃糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
9-(2-乙酰基-3-脱氧-β-D-5-甲基-呋喃核糖酰氨基)-2-氯-N6(3-碘苄基)腺嘌呤；
2-氯-9-(3-脱氧-2-甲磺酰基-β-D-5-甲基-呋喃核糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
2-氯-9-(3-脱氧-β-D-5-甲基-呋喃核糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
2-氯-9-(3，5-1，1，3，3-四异丙基二甲硅烷氧基-β-D-5-呋喃核糖基)-N6-(3-碘苯基)腺嘌呤；
2-氯-9-(2′，3′-O-硫代羰基-β-D-5-甲基-呋喃核糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
9-(2-苯氧基硫代羰基-3-脱氧-β-D-5-甲基-呋喃核糖酰氨基)-2-氯-N6-(3-碘苄基)腺嘌呤；
1-(6-苄基氨基-9H-嘌呤-9-基)-1-脱氧-N，4-二甲基-β-D-呋喃核糖苷糖醛酰胺(ribofuranosiduronamide)；
2-氯-9-(2，3-二脱氧-β-D-5-甲基-呋喃核糖酰氨基)-N6苄基腺嘌呤；
2-氯-9-(2′-叠氮基-2′，3′-二脱氧-β-D-5′-甲基-阿拉伯呋喃糖酰氨基)-N6-苄基腺嘌呤；2-氯-9-(β-D-赤式呋喃糖苷)-N6-(3-碘苄基)腺嘌呤；
N6-(苯并二 
烷甲基)腺苷；
1-(6-糠基氨基-9H-嘌呤-9-基)-1-脱氧-N-甲基-β-D-呋喃核糖苷糖醛酰胺；
N6-[3-(L-脯氨酰基氨基)苄基]腺苷-5′-N-甲基糖醛酰胺；
N6-[3-(β-丙氨酰基氨基)苄基]腺苷-5′-N-甲基糖醛酰胺；
N6-[3-(N-T-Boc-β-丙氨酰基氨基)苄基]腺苷-5′-N-甲基糖醛酰胺
6-(N′-苯基肼基)嘌呤-9-β-呋喃核糖苷-5′-N-甲基糖醛酰胺；
6-(O-苯基羟基氨基)嘌呤-9-β-呋喃核糖苷-5′-N-甲基糖醛酰胺；
9-(β-D-2′，3′-二脱氧赤式呋喃糖基)-N6-[(3-β-丙氨酰基氨基)苄基]腺苷；
9-(β-D-赤式呋喃糖苷)-2-甲基氨基-N6-(3-碘苄基)腺嘌呤；
2-氯-N-(3-碘苄基)-9-(2-四氢呋喃基)-9H-嘌呤-6-胺；
2-氯-(2′-脱氧-6′-硫代-L-阿拉伯糖基)腺嘌呤；和
2-氯-(6′-硫代-L-阿拉伯糖基)腺嘌呤。
在US 5,773,423中公开的其他示例性A3AR激动剂为下式的化合物：
其中
X1为RaRbNC(＝O)，其中Ra和Rb可以相同或不同，并且选自由下列各项组成的组：氢、C1-C10烷基、氨基、C1-C10卤代烷基、C1-C10氨基烷基和C3-C10环烷基；
R2选自由下列各项组成的组：氢、卤代、C1-C10烷氧基、氨基、C2-C10烯基和C2-C10炔基；且
R5选自由下列各项组成的组：R-和S-1-苯乙基、未取代的苄基、和在一或多个位置被取代基取代的苄基，所述取代基选自由下列各项组成的组：C1-C10烷基、氨基、卤代、C1-C10卤代烷基、硝基、羟基、乙酰氨基、C1-C10烷氧基和磺基。
更具体的化合物包括上式的那些化合物，其中Ra和Rb可以相同或不同并选自由氢和C1-C10烷基组成的组，特别是当R2为氢或卤代，尤其是氢时的化合物。
另外的具体化合物是其中Ra为氢且R2为氢、特别是当R5为未取代苄基时的那些化合物。
更具体的化合物是这样的化合物，其中Rb为C1-C10烷基或C3-C10环烷基，特别地为C1-C10烷基，更特别地为甲基。
尤其具体的是那些化合物，其中Ra为氢，Rb为C1-C10烷基或C3-C10环烷基，且R5为R-或S-1-苯乙基或在一或多个位置被取代基取代的苄基，所述取代基选自由下列各项组成的组：卤代、氨基、乙酰氨基、C1-C10卤代烷基和磺基， 其中磺基衍生物是盐，诸如三乙基铵盐。
特别优选的化合物的实例是IB-MECA(公开在US 5,773,423中)。另外，其中R2为式Rd-C＝C-的C2-C10亚链烯基，其中Rd是C1-C8烷基的那些化合物也特别地记述在US 5,773,423中。
还具体的是其中R2不是氢的那些化合物，特别是这样的化合物，其中R2为卤代、C1-C10烷基氨基或C1-C10烷基硫代，并且更优选地，此时，额外地，Ra为氢，Rb为C1-C10烷基，和/或R5为取代的苄基。
在US 5,773,423中公开的其他示例性A3AR激动剂是具有下式的修饰的黄嘌呤-7-核苷：
其中
X为O；
R6为RaRbNC(＝O)，其中Ra和Rb可以相同或不同且选自由下列各项组成的组：氢、C1-C10烷基、氨基、C1-C10卤代烷基、C1-C10氨基烷基和C3-C10环烷基；
R7和R8可以相同或不同且选自由下列各项组成的组：C1-C10烷基、R-和S-1-苯乙基、未取代的苄基和在一或多个位置被取代基取代的苄基，所述取代基选自由下列各项组成的组：C1-C10烷基、氨基、卤代、C1-C10卤代烷基、硝基、羟基、乙酰氨基、C1-C10烷氧基和磺基；且
R9选自由下列各项组成的组：卤代、苄基、苯基和C3-C10环烷基。
WO 99/06053在实施例19-33中公开了选自下列的化合物：
N6-(4-联苯基-羰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(2，4-二氯苄基-羰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-甲氧基苯基-羰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-氯苯基-羰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(苯基-羰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(苄基氨基甲酰基氨基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-亚磺酰氨基-苯基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-乙酰基-苯基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-((R)-α-苯乙基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-((S)-α-苯乙基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(5-甲基-异 
唑基-3-基-氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(1，3，4-噻二唑-2-基-氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-正丙氧基-苯基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-二-(4-硝基苯基氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺；和
N6-二-(5-氯-吡啶-2-基-氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺。
更具体公开地化合物包括：
2-氯-N6-(3-碘苄基)-9-[5-(甲基酰氨基)-β-D-呋喃核糖基]-腺嘌呤，也称为2-氯-N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺或缩写为Cl-IB-MECA；
N6-(3-碘苄基)-2-甲基氨基-9-[5-(甲基酰氨基)-β-D-呋喃核糖基]-腺嘌呤，也称为N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺或称为1-脱氧-1-[6-[[(3-碘苯基)甲基]氨基]-9H-嘌呤-9-基]-N-甲基-D-呋喃核糖糖醛酰胺或缩写为IB-MECA；
N6-2-(4-氨基苯基)乙基腺苷(APNEA)；
N6-(4-氨基-3-碘苄基)腺苷-5′-(N-甲基糖醛酰胺)(AB-MECA)。
IB-MECA是根据本发明最优选的化合物。
本发明还涵盖以上限定的化合物的任何生理学可接受的盐。当提到本发明采用的化合物的“生理学可接受的盐”时，其是指制药工业中普遍使用的任何无毒的碱金属盐、碱土金属盐和铵盐，包括钠盐、钾盐、锂盐、钙盐、镁盐、钡盐、 铵盐和精蛋白锌盐，这些盐通过本领域已知的方法制备。该术语还包括无毒的酸加成盐，酸加成盐通常通过将本发明的化合物与合适的有机酸或无机酸反应制备。酸加成盐是保留了游离碱的生物效应和定性性质并且是无毒的或不是以其他方式不合乎需要的那些。实例包括，尤其是，源自矿物酸、盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等的酸。有机酸包括，尤其是，酒石酸、乙酸、丙酸、柠檬酸、苹果酸、丙二酸、乳酸、富马酸、苯甲酸、肉桂酸、扁桃酸、乙醇酸、葡糖酸、丙酮酸、琥珀酸、水杨酸和芳基磺酸，例如，对甲苯磺酸。
在本发明的上下文中术语“有效量”或“对于......有效的量”是指在易于发展或已经发展了葡萄膜炎的受试者中预防或治疗葡萄膜炎的A3AR激动剂的量。“有效量”可以根据本发明通过向多个被测试的受试者施用各种量的A3AR激动剂，然后对生理反应(例如，组合数种治疗有益效果的综合“SS指数”)作为所述量的函数作图而容易地确定。可选地，有效量有时也可以通过在合适的动物模型中进行的实验，然后使用多种换算方法之一推算至人来确定；或通过测量随时间变化的血浆浓度或血浆浓度的曲线下面积(AUC)并计算有效剂量以便得到相当的血浆浓度或AUC来确定。如已知的那样，有效量可能取决于多种因素诸如给药模式(例如，口服给药可能与静脉内给药相比需要更高的剂量来达到指定的血浆水平或AUC)；受试者的年龄、体重、体表面积、性别、健康状况和遗传因素；其他的施用药物；等。
在下面，除非另外指明，剂量以重量/Kg表示，是指在每次给药中每千克被治疗受试者的体重所给药的A3AR激动剂(例如，IB-MECA)的重量。例如，毫克/Kg和微克/Kg分别表示每千克被治疗受试者的体重给药试剂的毫克数和给药试剂的微克数。
有效量优选小于约1mg/kg体重，特别地小于约500μg/kg或甚至小于约200μg/kg体重或有时小于约100μg/kg体重或甚至小于约50μg/kg体重。对于IB-MECA，对于每天给药一次，有效量优选为每次剂量小于5mg(即，小于约70μg/kg体重的剂量，假定平均个体体重为约70kg)，对于每天给药两次，每次剂量小于约4mg(即，小于约57μg/kg体重)。对于每天给药一次或两次，IB-MECA 的剂量更优选为每次剂量小于约2mg和典型地每次剂量约0.1-1mg之间(以重量每体重计的相应剂量分别为约29μg/kg体重和约1.5-15μg/kg体重)。
A3AR激动剂对个体的给药可以与药学可接受载体一起用于形成适合于特定给药模式的剂型。所述剂型因此是在将施用于需要其的受试者的组合物中使用的A3AR激动剂的物理形式。
在口服给药的情况下，载体是对于制备适合于口服给药的剂型可接受的一种载体。在局部给药的情况下，载体是对于配制适合于局部给药的剂型可接受的一种载体，一个实例是眼部给药，例如，以滴眼剂的形式。
对于术语“药学可接受的载体”，其是指不与A3AR激动剂反应并且可以作为稀释剂或载体添加至制剂中或赋予制剂以形状或稠度(consistency)的任一种惰性的无毒材料。
口服制剂可以是丸剂、胶囊的形式，糖浆剂、乳剂、芳香粉的形式，和其他各种形式。有时基于所需的制剂形式选择载体。载体有时还可以具有改善活性成分向靶组织的递送或渗透的作用，用以改善药物的稳定性、减慢清除率、赋予缓释性，减少不需要的副作用等。载体还可以是稳定制剂的物质(例如，防腐剂)，用于为制剂提供可食用的风味等。载体可以是常规使用的任一种载体，并且仅受化学-物理因素和给药途径的限制，所述化学-物理因素诸如可溶性和缺少与A3AR激动剂的反应性。载体可以包括添加剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、增味剂和药理学相容的载体。另外，载体可以是辅料，所述辅料被定义为以可预测的方式影响活性成分的作用的物质。
适合于口服给药的载体的典型实例包括(a)在合适的液体诸如CremophorRH40或甲基纤维素(例如，Methocel A4M Premium)中的混悬液或乳液；(b)胶囊(例如，含有例如表面活性剂、润滑剂和惰性填料的普通的硬壳或软壳明胶型)、片剂、锭剂(其中活性物质在风味剂诸如蔗糖和阿拉伯胶或西黄蓍胶中，或活性物质在惰性基质诸如明胶和甘油中)和含片，每一种含有预定量的作为固体或颗粒的西黄蓍胶；(c)粉剂；(d)溶液，典型地当与增溶增强剂混合时；(e)脂质体制剂；以及其他载体。
A3AR激动剂，IB-MECA的口服给药形式的一个非限制性实例包括以片剂形式配制的下列成分和用量：
表1：IB-MECA片剂
局部制剂可以是适合于局部给药的任何形式，包括，但不限于，眼用乳剂或溶液(例如，滴眼剂)，眼用凝胶或眼用膏或油性洗剂。A3AR激动剂的局部给药还包括使用眼用贴剂，所述眼用贴剂在合适的含药层中携带A3AR激动剂，并且将被放置在眼睑的上部以及放置在眼用膜剂上，所述眼用膜剂是含有A3AR激动剂并且被置于下或上结膜囊中的装置(参见例如WO0059420)。
滴眼剂可以通过如下制备：将A3AR激动剂悬浮在无菌水溶液诸如盐水、缓冲溶液等中，或在使用前结合待溶解的粉末成分。需注意的是由于IB-MECA不溶于水，当制备包含IB-MECA的液体制剂时，可能需要使用乳化剂、表面活性剂、增溶增强剂等，以便在溶液中保留IB-MECA。
其他添加剂可以包含在滴眼剂中，诸如等渗剂(例如，氯化钠等)、缓冲剂(例如，硼酸、磷酸氢二钠、磷酸二氢钠等)、防腐剂(例如，苯扎氯铵、苄索氯铵、三氯叔丁醇等)、增稠剂(例如，糖类诸如乳糖、甘露醇、麦芽糖等；例如，透明质酸或其盐诸如透明质酸钠、透明质酸钾等；例如，粘多糖诸如硫酸软骨素等；例如，聚丙烯酸钠、羧乙烯基聚合物、交联的聚丙烯酸酯等)。
眼膏可以通过将A3AR激动剂混合至基质中来制备。用于眼膏的基质的实例包括矿脂、Selen 50、Plastibase(液体石蜡和聚乙烯的复合软膏基质)、聚乙二醇等，但不限于这些。
可以用在本制剂中的一些示例性眼用粘度增强剂包括：羧甲基纤维素钠；甲基纤维素；羟丙基纤维素；羟丙基甲基纤维素；羟乙基纤维素；聚乙二醇300；聚乙二醇400；聚乙烯醇；和聚维酮(providone)。
一些天然产品，诸如硅酸镁铝、藻酸盐、黄原胶、明胶、阿拉伯胶和西黄蓍胶，也可以用来增加眼用溶液的粘度。
渗透压是重要的，因为低渗滴眼剂导致角膜水肿，高渗滴眼剂导致角膜变形。理想的渗透压为大约300mOsM。渗透压可以通过在本领域专业技术人员已知的Remington：The Science和Practice of Pharmacy(雷明顿：药学技术和实践)中所述的方法来实现。
另外的给药途径可以包括，但不限于，或肠胃外给药(包括皮下、肌内和静脉内、动脉内、腹膜内和鼻内)及其他。
当在本文中使用时，形式“一”、“一个/种”、“所述”和“该”(″a″、″an″和″the″)包括单数以及复数指代物，除非上下文另外明确地指示。例如，术语“一A3AR激动剂”包括能够与A3AR特异性结合从而完全或部分激活所述受体的一种或多种化合物。
此外，当在本文中使用时，术语“包括/包含”意在指组合物包含所列举的活性剂，即A3AR激动剂，但不排除其他要素，诸如生理学可接受的载体和赋形剂以及其他活性剂。术语“基本上由......组成”用来限定这样的组合物，其包含所列举的要素但排除可能对葡萄膜炎的治疗具有实质重要性的其他要素。“由...... 组成”因此应当是指排除超过痕量要素的其他要素。由每一个这些过渡术语限定的实施方案包括在本发明的范围内。
此外，所有数值，例如，当提到构成包含A3AR激动剂作为活性成分的组合物的要素的量或范围时，是从所述值(+)或(-)变化至多达20％，有时至多达10％的近似值。要理解的是，即使不总是明确地说明，所有数值标示前均带有术语“大约”。
现在在以下根据本发明实施的实验描述中对本发明进行举例说明。要理解的是这些实施例意在是说明性的而非限制性的。显而易见的是，根据上述教导，这些实施例的许多变更和变化是可能的。因此，要理解的是在附带的权利要求的范围内，本发明可以另外地以比如下文具体所说明的那些更大量的可能方式实施。
一些非限制性实施例的描述
IB-MECA对葡萄膜炎发展的作用
材料和方法
使用的A3AR激动剂是临床等级的化合物，一般被称为1-脱氧-1-[6-[[(3-碘苯基)甲基]氨基]-9H-嘌呤-9-基]-N-甲基-D-呋喃核糖糖醛酰胺或N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)的化合物，所述化合物由Albany Molecular Research Inc，Albany，NY，USA根据药品临床试验管理规范(GMP)为Can-Fite BioPharma合成。10μM的IB-MECA的储备溶液在二甲基亚砜(DMSO)中制备，并且在RPMI培养基中制备进一步的稀释液。
实验性急性葡萄膜炎(EAU)通过用视网膜抗原感光器间受体类视黄醇结合蛋白(IRPB，每只小鼠200μg)在补充有结核分枝杆菌H37RA至2.5mg/ml的不完全弗氏佐剂中的乳液在大腿和尾巴的基部皮下注射免疫C57BL/6j小鼠来诱发。另外，腹膜内注射百日咳毒素(300ng/小鼠)。
使用IB-MECA(10μg/kg每盎司(Patent Office)，每天两次)的口服治疗在免疫后第7天开始。在免疫后第16天和第20天扩瞳后通过眼底镜检查对疾病强度进行评分。根据下列指定评分：0-无变化；0.5-痕量。少量的(1-2)非常小的周边局灶性病变，最小的血管炎/viritis；1-轻微的血管炎，＜5个小局灶性病变，≤1 个线性病变；2-多个(＞5个)脉络膜视网膜病变和/或浸润；严重的血管炎(大尺寸、厚壁、浸润)；很少的线性病变(＜5)。
在研究结束时，将刚摘除的眼睛在磷酸盐缓冲的戊二醛中固定，用苏木素和伊红染色，并进行病理学分析。基于眼中的细胞浸润、血管炎、肉芽肿形成、视网膜和脉络膜中的感光细胞损害以及视网膜剥离的程度以0-4的等级对组织学严重性进行评级。
为了探究IB-MECA对T细胞的抗原特异性应答的免疫效应，进行了体外抗原驱动的增殖测定。从来自载体组和IB-MECA治疗组两者的经IRBP免疫的小鼠中收集引流淋巴结(腹股沟和髂淋巴结)。在分级剂量的IRBP(0.2-20μg/ml)的存在下培养细胞48小时，并通过3[H]胸苷掺入测定法评价增殖。
结果
图1显示IB-MECA(在图中由代号CF101标识)治疗在免疫后第16天时和第20天时将眼底镜检查评分分别抑制了91％和49.4％。
此外，图2显示与载体治疗组相比，IB-MECA(在图中也由代号CF101标识)治疗抑制了病理学评分达53％，支持了眼底镜检查的观察结果。
在来自载体治疗动物的细胞中，观察到增加的对IRBP的T细胞应答，而来自IB-MECA治疗动物的细胞显示出对特定激动剂的中度反应，如图3中所示(IB-MECA在图中由代号CF101标识)。
总之，IB-MECA反转了EAU的临床和病理学评分的发展，并且抑制了相关的抗原特异性增殖反应。
Claims (24)
1.A3AR激动剂用于治疗受试者中的葡萄膜炎的用途。
2.权利要求1所述的用途，所述用途以适于将所述A3AR激动剂口服施用于所述受试者的剂型应用。
3.权利要求2所述的用途，所述用途以适于将所述A3AR激动剂一天两次口服施用的剂型应用。
4.权利要求1所述的用途，所述用途以适于将所述A3AR激动剂局部施用于所述受试者的剂型应用。
5.权利要求4所述的用途，所述用途以适于将所述A3AR激动剂局部施用于所述受试者眼部的剂型应用。
6.权利要求5所述的用途，其中所述A3AR激动剂以滴眼剂的形式配制。
7.权利要求1至6中任一项所述的用途，其中所述A3AR激动剂选自由下列各项组成的组：N6-2-(4-氨基苯基)乙基腺苷(APNEA)、N6-(4-氨基-3-碘苄基)腺苷-5′-(N-甲基糖醛酰胺)(AB-MECA)、N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)和2-氯-N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(Cl-IB-MECA)。
8.权利要求7所述的用途，其中所述A3AR激动剂是IB-MECA。
9.一种治疗葡萄膜炎的方法，所述方法包括向受试者施用一定量的A3腺苷受体(A3AR)激动剂，所述量有效地治疗或预防葡萄膜炎。
10.权利要求9所述的方法，其中所述A3AR激动剂通过口服施用。
11.权利要求10所述的方法，其中所述A3AR激动剂一天施用两次。
12.权利要求9所述的方法，其中所述A3AR激动剂对所述受试者局部施用。
13.权利要求12所述的方法，其中所述A3AR激动剂对所述受试者的眼睛局部施用。
14.权利要求13所述的方法，其中所述A3AR激动剂以滴眼剂的形式对所述受试者的眼睛施用。
15.权利要求9至14中任一项所述的方法，其中所述A3AR激动剂选自由下列各项组成的组：N6-2-(4-氨基苯基)乙基腺苷(APNEA)、N6-(4-氨基-3-碘苄基)腺苷-5′-(N-甲基糖醛酰胺)(AB-MECA)、N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)和2-氯-N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(Cl-IB-MECA)。
16.权利要求15所述的方法，其中所述A3AR激动剂是IB-MECA。
17.一种用于治疗葡萄膜炎的药物组合物，所述药物组合物包含作为活性成分的一定量的A3AR激动剂和生理学可接受的载体，该A3AR激动剂的量有效地治疗葡萄膜炎。
18.权利要求17所述的药物组合物，其中所述生理学可接受的载体适合于所述A3AR激动剂的口服施用。
19.权利要求18所述的药物组合物，其中所述A3AR激动剂的量适于一天两次口服施用。
20.权利要求17所述的药物组合物，其中所述生理学可接受的载体适合于所述A3AR激动剂的局部施用。
21.权利要求20所述的药物组合物，用于所述A3R激动剂对眼睛的局部施用。
22.权利要求21所述的药物组合物，为滴眼剂的形式。
23.权利要求17至22任一项所述的药物组合物，其中所述A3AR激动剂选自由下列各项组成的组：N6-2-(4-氨基苄基)乙基腺苷(APNEA)、N6-(4-氨基-3-碘苄基)腺苷-5′-(N-甲基糖醛酰胺)(AB-MECA)、N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)和2-氯-N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(Cl-IB-MECA)。
24.权利要求23所述的药物组合物，其中所述A3AR激动剂是IB-MECA。
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| US31004310P | 2010-03-03 | 2010-03-03 | |
| US61/310,043 | 2010-03-03 | ||
| PCT/IL2011/000193 WO2011107981A1 (en) | 2010-03-03 | 2011-02-27 | A3ar agonists for the treatment of uveitis |
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| EP (1) | EP2542242A1 (zh) |
| JP (1) | JP2013521274A (zh) |
| KR (1) | KR20130072189A (zh) |
| CN (1) | CN102905708A (zh) |
| CA (1) | CA2790869A1 (zh) |
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| CN108463463A (zh) * | 2016-01-14 | 2018-08-28 | 韩德株式会社 | 拮抗a3腺苷受体的化合物、其制备方法、及其医学用途 |
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| WO2006059327A1 (en) * | 2004-12-02 | 2006-06-08 | Can-Fite Biopharma Ltd. | A biological marker for inflammation |
| US20070099865A1 (en) * | 2004-07-28 | 2007-05-03 | Pnina Fishman | Treatment of dry eye conditions |
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| US5443836A (en) | 1993-03-15 | 1995-08-22 | Gensia, Inc. | Methods for protecting tissues and organs from ischemic damage |
| AU7331094A (en) | 1993-07-13 | 1995-02-13 | United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The | A3 adenosine receptor agonists |
| US5688774A (en) | 1993-07-13 | 1997-11-18 | The United States Of America As Represented By The Department Of Health And Human Services | A3 adenosine receptor agonists |
| AU1399297A (en) | 1996-01-24 | 1997-08-20 | Sumitomo Chemical Company, Limited | Dihalopropene compounds, their use as insecticides/acaricides and intermediates for their production |
| US6048865A (en) | 1997-07-29 | 2000-04-11 | Medco Research, Inc. | N6 -substituted-adenosine-5'-uronamides as adenosine receptor modulator |
| WO1999006053A1 (en) | 1997-07-29 | 1999-02-11 | Medco Research, Inc. | N6-substituted-adenosine-5'-uronamides as adenosine receptor modulators |
| US6329349B1 (en) | 1997-10-23 | 2001-12-11 | Trustees Of The University Of Pennsylvania | Methods for reducing ischemic injury of the heart via the sequential administration of monophosphoryl lipid A and adenosine receptor agents |
| US6217896B1 (en) | 1999-04-01 | 2001-04-17 | Uab Research Foundation | Conjunctival inserts for topical delivery of medication or lubrication |
| IL133680A0 (en) | 1999-09-10 | 2001-04-30 | Can Fite Technologies Ltd | Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist |
| JP2009519236A (ja) * | 2005-11-30 | 2009-05-14 | キャン−ファイト・バイオファーマ・リミテッド | Ａ３アデノシンレセプター抗体の治療的使用 |
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- 2011-02-27 CN CN2011800121918A patent/CN102905708A/zh active Pending
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- 2011-02-27 WO PCT/IL2011/000193 patent/WO2011107981A1/en active Application Filing
- 2011-02-27 KR KR1020127024527A patent/KR20130072189A/ko not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20070099865A1 (en) * | 2004-07-28 | 2007-05-03 | Pnina Fishman | Treatment of dry eye conditions |
| WO2006059327A1 (en) * | 2004-12-02 | 2006-06-08 | Can-Fite Biopharma Ltd. | A biological marker for inflammation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108463463A (zh) * | 2016-01-14 | 2018-08-28 | 韩德株式会社 | 拮抗a3腺苷受体的化合物、其制备方法、及其医学用途 |
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| CA2790869A1 (en) | 2011-09-09 |
| KR20130072189A (ko) | 2013-07-01 |
| WO2011107981A1 (en) | 2011-09-09 |
| US20130045943A1 (en) | 2013-02-21 |
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