CN102427819A - 用于减小眼内压的a3腺苷受体激动剂 - Google Patents
用于减小眼内压的a3腺苷受体激动剂 Download PDFInfo
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- CN102427819A CN102427819A CN2010800212202A CN201080021220A CN102427819A CN 102427819 A CN102427819 A CN 102427819A CN 2010800212202 A CN2010800212202 A CN 2010800212202A CN 201080021220 A CN201080021220 A CN 201080021220A CN 102427819 A CN102427819 A CN 102427819A
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- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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Abstract
本公开提供了A3R激动剂诸如IB-MECA用于减小受试者(优选地人类受试者)眼内压(IOP)的用途。同样地,本发明提供了利用所述A3R激动剂来减小受试者IOP的药物组合物和方法。
Description
发明领域
本发明涉及用于减小受试者眼内压(IOP)的组合物、方法和用途。
发明背景
眼内压(IOP)是眼科学中重要的参数。增加的IOP或眼高压是青光眼的最重要的风险因素。同样,两只眼间压力的不同经常是有临床意义的,并且潜在地与某种类型的青光眼以及虹膜炎或视网膜脱离有关。
IOP可以由于以下因素而变高:解剖学问题、眼睛的炎症、遗传因素、作为来自药物治疗的副作用或其他因素。IOP通常随年龄增加而增加并且受遗传影响。其中IOP增加的病症有时候也可以与其他病症诸如干眼综合症有关。
然而,若干出版物显示通过在A3AR增加IOP的同时使用据发现降低IOP的A3AR拮抗药,A3AR可以用于调节IPO[Mortimer M.Civan等人Am J Physiol Cell Physiol(美国生理学和细胞生理学杂志)279:440-451,2000年;Current Eye Research(现代眼科研究)30:747-754,2005年;Investigative Ophthalmology & Visual Science(研究眼科学和视觉科学)卷43(9)2002年;British Journal of Pharmacology(英国药理学杂志)134:241-245,2001年;Acta Physiol(生理学学报),187:345-352 2006年]。
发明概述
根据本发明,令人惊奇的发现向人类受试者施用A3腺苷受体(A3AR)激动剂N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide)(IB-MECA)导致眼内压(IOP)的降低。
因此,根据第一方面,本发明提供A3AR激动剂在(i)制备用于减小具有升高的IOP的受试者(尤其是是人类受试者)的IOP的药物组合物中的用途,或在(ii)用于减小具有IOP的受试者的升高的IOP中的用途。
根据第二方面,本发明提供A3腺苷受体(A3AR)激动剂在制备用于减小具有IOP的受试者的IOP的药物组合物中的用途。
根据第三方面,本发明提供用于减小受试者尤其是人类受试者的IOP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激动剂和生理学上可接受的载体,所述A3AR激动剂的量有效减小具有IOP的受试者的IOP。
根据第四方面,本发明提供一种方法,所述方法包括向具有IOP的受试者施用一定量的A3AR激动剂,所述量有效减小具有IOP的受试者的IOP。
虽然本发明一般可以用于降低受试者的IOP,但是它尤其适用于治疗具有升高的IOP的受试者从而将IOP减小到较低的水平,优选地到统计学上显著的较低水平。
示例实施方案详述
通过一个实施方案,本发明提供了一种方法,所述方法包括向例如被诊断出具有升高的IOP的受试者提供一定量的A3腺苷受体(A3AR)激动剂,所述量的A3AR激动剂有效将IOP减小到与治疗前水平相比至少统计学上显著的更低水平,以及优选地到被认为代表正常眼压的水平。
如所理解的,尽管在以下详述中关于以上方法描述本发明,要理解如上文和下文所定义的用于在所述治疗中使用的包含所述A3AR激动剂的组合物;以及用途同样涵盖在本发明的范围中。
在本发明的上下文中术语“升高的IOP”是指高于临床上被认为是健康受试者的正常IOP水平的IOP。如可以被理解的,所述正常IOP和因此可以被认为是升高的IOP可以根据各种人口统计学因素和其他因素而不同。例如,鉴于IOP某种程度上是年龄依赖性的,所以被认为是正常的以及因此可以被认为是升高的IOP的也可以是年龄依赖性的。此外所述正常IOP的定义以及因此升高的IOP的定义可以取决于遗传、人口统计学和多种其他因素。
升高的IOP的病症包括但不限于青光眼、导致IOP升高的眼的炎性病症、归因于解剖学问题的IOP增加的病症、由其他药物的副作用产生的增加的IOP以及其他病症。本文所使用的术语“治疗(treating)”或“治疗(treatment)”等是指获得所需要的药理学和生理学效应。所述效应在防止或部分地防止IOP水平的增加方面可以是预防性的,和/或在降低IOP水平方面可以是治疗性的。本文所使用的术语“治疗”覆盖对哺乳动物(尤其是人)的疾病的任何治疗,并且包括:(a)防止IOP升高在可能易于患有IOP升高但是还未被诊断出具有IOP升高的个体中发生;或(b)在某些实施方案中,降低被诊断出具有升高的IOP的受试者的IOP水平。
在一些实施方案中,所述治疗是指对被诊断出具有干燥性角膜结膜炎(KCS)(也被称为干眼综合症)的受试者的IOP的治疗。
在本发明的上下文中,术语“A3腺苷受体激动剂”(A3AR激动剂)是指能够特异地结合到A3AR从而全面地或部分地激活所述受体的任何分子。因此所述A3AR激动剂是通过结合和激活A3AR来发挥其主要作用的分子。这意味着在其被施用的剂量下它基本上只结合并激活A3AR。在优选实施方案中,A3AR激动剂具有的对人A3AR的结合亲和力(Ki)在小于100nM,典型地在小于50nM,优选地在小于20nM,更优选地在小于10nM并且理想地在小于5nM的范围内。尤其优选的是A3AR激动剂对人A3R的Ki小于2nM以下并且合乎需要地小于1nM。
应当注意某些A3AR激动剂也可以较低的亲和力(即较高的Ki)与其他受体相互作用并激活其他受体。在本发明的上下文中,如果分子对A3AR的亲和力比对任何其他腺苷受体(例如A1、A2a和A2b)的亲和力大至少2倍(例如它对A3AR的Ki低至少2倍),优选地9倍,合乎需要地大19倍以及最优选地至少大49倍,则它将被认为是A3AR激动剂(即通过结合和激活A3AR来发挥其主要作用的分子)。
A3AR激动剂对人A3AR的亲和力以及它对其他人腺苷受体的相对亲和力可以通过许多测定诸如结合测定法(binding assay)来确定。结合测定法的实例包括提供包含受体的膜并测量所述A3AR激动剂取代结合的放射性激动剂的能力;在功能测定中利用显示各种人腺苷受体的细胞并测量所述A3AR激动剂(视情况而定)激活或失活下游信号传导事件的能力,所述下游信号传导事件诸如通过cAMP水平的增加或减少测量到的对腺苷酸环化酶的作用等。明显地,如果增加A3AR激动剂的施用水平以致它的血液水平达到与A1、A2a和A2b腺苷受体的Ki的水平近似的水平,则除了A3AR的激活以外这些受体的激活可以在这样的施用后发生。因此A3AR激动剂优选地以一定的剂量施用,所述剂量使得达到一定的血液水平,所述血液水平使得基本上只有A3AR将被激活。
根据本发明的实施方案,所述A3AR激动剂是通过结合和激活腺苷A3AR来发挥其主要作用的化合物。
一些A3AR激动剂是落在通式(I)范围内的嘌呤衍生物:
其中,
-R11代表烷基、羟烷基、羧烷基或氰基烷基或具有下述通式(II)的基团:
其中:
-Y代表氧、硫或CH2;
-X11代表H、烷基、ReRfNC(=O)-或HORg-,其中
-Re和Rf可以是相同的或不同的并且选自由以下各项组成的组:氢、烷基、氨基、卤烷基、氨烷基、BOC-氨烷基和环烷基或结合在一起从而形成包含二至五个碳原子的杂环;以及
-Rg选自由以下各项组成的组:烷基、氨基、卤烷基、氨烷基、BOC-氨烷基和环烷基;
-X12是H、羟基、烷基氨基、烷基酰胺基或羟烷基;
-X13和X14独立地代表氢、羟基、氨基、酰胺基、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X14两者是氧,所述氧与>C=S相连从而形成五元环,或者X12和X13形成具有结构式(III)的环:
其中R′和R″独立地代表烷基;
-R12选自由以下各项组成的组:氢、卤代、烷基醚、氨基、酰肼基、烷基氨基、烷氧基、硫代烷氧基、吡啶基硫代、烯基;炔基、硫代和烷基硫代;以及
-R13是具有结构式-NR15R16的基团,其中
-R15是氢原子或从以下各项中选出的基团:烷基、取代烷基或芳基-NH-C(Z)-,其中Z是O、S或NRa,其中Re具有上述含义;其中当R15是氢时,则
-R16选自由以下各项组成的组:R-和S-1-苯乙基、苄基、苯乙基或酰苯胺基团,所述酰苯胺基团是未取代的或在一个或多个位置中被选自由以下各项组成的组的取代基取代:烷基、氨基、卤代、卤烷基、硝基、羟基、乙酰胺基、烷氧基和磺酸或其盐;苯并二噁烷甲基、糠基(fururyl)、L-丙基丙胺酰-氨基苄基、β-丙胺酰氨基-苄基、T-BOC-β-丙胺酰氨基苄基、苯基氨基、氨基甲酰基、苯氧基或环烷基;或者R16是具有下列结构式(IV)的基团:
或者当R15是烷基或烷基-NH-C(Z)-时,则,R16选自由以下各项组成的组: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代表氧、硫或胺;
或以上化合物的生理学可接受的盐。
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,详细描述了某些腺苷A3AR激动剂的性质和它们的制备方法,这些专利申请通过引用合并于本文中。
示例的A3AR激动剂(公开在US 5,688,774中第4栏的67行-第6栏的16行;第5栏的40-45行;第6栏的21-42行;第7栏的1-11行;第7栏的34-36行;以及第7栏的60-61行中):
N6-(3-碘苄基)-9-甲基腺嘌呤;
N6-(3-碘苄基)-9-羟基乙基腺嘌呤;
R-N6-(3-碘苄基)-9-(2,3-二羟基丙基)腺嘌呤;
S-N6-(3-碘苄基)-9-(2,3-二羟基丙基)腺嘌呤;
N6-(3-碘苄基腺嘌呤-9-基)乙酸;
N6-(3-碘苄基)-9-(3-氰基丙基)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-酰肼基-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-阿糖基-糠醛酰胺基(furonamido))-N6-(3-碘苄基)腺嘌呤;
2-氯-9-(2′,3′-二脱氧-2′-氟-β-D-5′-甲基-阿糖基糠醛酰胺基)-N6-(3-碘苄基)腺嘌呤;
9-(2-乙酰基-3-脱氧-β-D-5-甲基-核糖糠醛酰胺基)-2-氯-N6(3-碘苄基)腺嘌呤;
2-氯-9-(3-脱氧-2-甲烷磺酰基-β-D-5-甲基-核糖糠醛酰胺基)-N6-(3-碘苄基)腺嘌呤;
2-氯-9-(3-脱氧-β-D-5-甲基-核糖糠醛酰胺基)-N6-(3-碘苄基)腺嘌呤;
2-氯-9-(3,5-1,1,3,3-四异丙基二硅氧基-β-D-5-呋喃核糖基)-N6-(3-碘苄基)腺嘌呤;
2-氯-9-(2′,3′-O-硫代羰基-β-D-5-甲基-核糖糠醛酰胺基)-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-核糖糠醛酰胺基)-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-核糖呋喃糖苷糖醛酰胺(uronamide);
2-氯-9-(2,3-二脱氧-β-D-5-甲基-核糖糠醛酰胺基)-N6苄基腺嘌呤;
2-氯-9-(2′-叠氮基-2′,3′-二脱氧-β-D-5′-甲基-阿糖基-糠醛酰胺基)-N6-苄基腺嘌呤;
2-氯-9-(β-D-赤呋喃糖苷)-N6-(3-碘苄基)腺嘌呤;
N6-(苯并二噁烷甲基)腺苷;
1-(6-糠基氨基-9H-嘌呤-9-基)-1-脱氧-N-甲基-β-D-核糖呋喃糖苷糖醛酰胺;
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-核糖呋喃糖苷-5′-N-甲基糖醛酰胺;
6-(O-苯基羟基氨基)嘌呤-9-β-核糖呋喃糖苷-5′-N-甲基糖醛酰胺;
9-(β-D-2′,3′-二脱氧赤呋喃糖基)-N6-[(3-β-丙氨酰基氨基)苄基]腺苷;
9-(β-D-赤呋喃糖苷)-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-阿糖基)腺嘌呤;以及
2-氯-(6′-硫代-L-阿糖基)腺嘌呤。
公开在US 5,773,423中的其他示例的A3AR激动剂是具有结构式(V)的化合物:
其中
X1是RaRbNC(=O),其中Ra和Rb可以是相同的或不同的并且选自由以下各项组成的组:氢、C1-C10烷基、氨基、C1-C10卤烷基、C1-C10氨烷基、和C3-C10环烷基;
R2选自由以下各项组成的组:氢、卤代、C1-C10烷氧基(alkyoxy)、氨基、C2-C10烯基和C2-C10炔基;以及
R5选自由以下各项组成的组:R-和S-1-苯乙基,未取代的苄基,和一个或多个位置中被选自由以下各项组成的组的取代团取代的苄基:C1-C10烷基、氨基、卤代、C1-C10卤烷基、硝基、羟基、乙酰胺基、C1-C10烷氧基和磺基。
更多的具体化合物包括具有以上结构式的那些,其中Ra和Rb可以是相同的或不同的并且选自由以下各项组成的组:氢和C1-C10烷基,特别是当R2是氢或卤代时,尤其是当是氢时。
另外的具体化合物是那些化合物其中Ra是氢而R2是氢,特别是当R5是未取代的苄基时。
更多具体化合物是这样的化合物,其中Rb是C1-C10烷基或C3-C10环烷基,特别地C1-C10烷基,且更特别地甲基。
尤其具体的是那些化合物,其中Ra是氢,Rb是C1-C10烷基或C3-C10环烷基,且R5是R-或S-1-苯乙基或在一个或多个位置中被选自由以下各项组成的组的取代团取代的苄基:卤代、氨基、乙酰胺基、C1-C10卤烷基和磺基,其中所述磺基衍生物是盐,诸如三乙铵盐。
US 5,773,423中公开的那些中尤其优选的化合物的实例是IB-MECA。此外,在此公开书中特别地提到了那些化合物,在那些化合物中R2是具有结构式Rd-C=C-的C2-C10亚链烯基,其中Rd是C1-C8烷基。还具体地提到那些化合物,其中R2是除氢外的其他基团,特别是那些,其中R2是卤代、C1-C10烷基氨基或C1-C10烷基硫代,并且更优选地是,当另外地Ra是氢,Rb是C1-C10烷基,和/或R5是取代的苄基时。
这些具体地公开的化合物包括2-氯-N6-(3-碘苄基)-9-[5-(甲基酰胺基)-β-D-呋喃核糖基]-腺嘌呤、N6-(3-碘苄基)-2-甲基氨基-9-[5-(甲基酰胺基)-β-D-呋喃核糖基]-腺嘌呤和N6-(3-碘苄基)-2-甲基硫代-9-[5-(甲基酰胺基)-β-D-呋喃核糖基]-腺嘌呤。
US 5,773,423中进一步公开的示例的A3AR激动剂是具有结构式(VI)的经修饰的黄嘌呤-7-核糖核苷:
其中
X是O;
R6是RaRbNC(=O),其中Ra和Rb可以是相同的或不同的并且选自由以下各项组成的组:氢、C1-C10烷基、氨基、C1-C10卤烷基、C1-C10氨烷基和C3-C10环烷基;
R7和R8可以是相同的或不同的并且选自由以下各项组成的组:C1-C10烷基、R-和S-1-苯乙基、未取代的苄基和在一个或多个位置中被选自由以下各项组成的组的取代团取代的苄基:C1-C10烷基、氨基、卤代、C1-C10卤烷基、硝基、羟基、乙酰胺基、C1-C10烷氧基和磺基;以及
R9选自由以下各项组成的组:卤代、苄基、苯基和C3-C10环烷基。
WO 99/06053在实施例19-33中公开了选自以下的化合物:
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-磺酰胺基-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-异噁唑-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-n-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;以及
N6-二-(5-氯-吡啶-2-基-氨基甲酰基)-腺苷-5′-N-乙基糖醛酰胺。
可以根据通式(I至III)被采用的A3AR激动剂的具体的实例包括但不限于: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)。根据本发明IB-MECA是最优选的化合物。
根据另一个实施方案,所述A3AR激动剂可以是腺苷的氧化物衍生物,诸如N6-苄基腺苷-5′-N-烷基糖醛酰胺-N1-氧化物或N6-苄基腺苷-5′-N-二烷基糖醛酰胺-N1-氧化物,其中2-嘌呤位置可以被烷氧基、氨基、烯基、炔基或卤素取代。
形成具有结构式(I)、(II)或(III)的化合物的取代基的一部分的非环状碳水化合物基团(例如烷基、烯基、炔基、烷氧基、芳烷基、烷芳基、烷基胺等)是有支链的或无支链的,优选地包含1个或2个至12个碳原子。
当提到本发明所采用的化合物的“生理学可接受的盐”时,其是指通常在制药工业中使用的任何无毒的碱金属盐、碱土金属盐和铵盐,包括通过本领域已知方法制备的钠盐、钾盐、锂盐、钙盐、镁盐、钡盐铵盐和精蛋白锌盐。该术语也包括无毒的酸加成盐,所述无毒的酸加成盐一般通过将本发明的化合物与合适的有机或无机酸反应而制备。所述酸加成盐是保持游离碱的生物有效性和定性性质的那些以及没有毒性或另外的不需要的性质的那些。实例包括(尤其是)来源于无机酸、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、苯乙酸、扁桃酸、乙醇酸、葡萄糖酸、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…有效的量”是指防止患者IOP升高或减小患者IOP水平(统计学上显著的减小),特别是减小升高的IP的A3AR激动剂的量。根据本发明,通过将不同量的A3AR激动剂施用于多名测试受试者并且之后将生理反应(例如结合治疗有益作用中几种的综合“SS指标(SS index)”)作为所述量的函数绘图,所述“有效量”可以容易地被确定。备选地,所述有效量有时也可以通过以下方式确定:在合适的动物模型上进行实验然后使用多种转换方法中的一种推延至人;或通过测量血浆浓度或血浆浓度随时间变化的曲线下面积(AUC)并计算有效剂量以致产生相当的血浆浓度或AUC。如已知的,所述有效量可以取决于多种因素诸如给药模式(例如,相比静脉内施用,口服施用可能要求更高的剂量以达到指定的血浆水平或AUC);受试者的年龄、体重、身体表面积、性别、健康状况和遗传因素;其他被施用的药物等。
在下文中,除非另外标明,剂量以重量/Kg标明,其是指在每次施用中经治疗的受试者的每千克体重的被施用的A3AR激动剂(例如IB-MECA)的重量。例如,mg/Kg和微克/Kg分别表示经治疗的受试者的每千克体重的被施用药剂的毫克数和被施用药剂的微克数。
所述有效量优选地小于大约1mg/kg体重,特别地小于大约500μg/kg或甚至小于大约200μg/kg体重或有时小于大约100μg/kg体重或甚至小于大约小于50μg/kg体重。至于IB-MECA,对于一日一次的给药,所述有效量优选地是每剂量小于5mg(假定平均个体重量是大约70kg,即小于大约70μg/kg体重的剂量),而对于一日两次的给药,每剂量小于大约4mg(即,小于大约57μg/kg体重)。对于一日一次或一日两次给药,IB-MECA的剂量更优选地是每剂量小于大约2mg并且典型地是每剂量在大约0.1~1mg之间(按体重以重量计,相应的剂量分别是大约29μg/kg和大约1.5-15μg/kg体重)。至于Cl-IB-MECA,对于一日一次或一日两次给药,所述有效量优选地是每剂量小于40mg(假定平均个体重量是大约70kg,即小于大约570μg/kg体重的剂量)。对于一日一次或一日两次给药,Cl-IB-MECA的剂量更优选地是每剂量小于大约30或小于大约20mg(按体重以重量计,相应的剂量分别是大约430μg/kg和大约285μg/kg体重)。
所述A3AR激动剂可以和药用载体一起施用于个体。在口服施用的情况中,所述载体是对于口服施用可接受的。在局部施用的情况中,所述载体是对于局部施用例如眼部施用可接受的。
术语“药用载体”是指任何一种惰性的无毒材料,所述惰性的无毒材料不与所述A3AR激动剂反应并且可以作为稀释剂或载体添加到制剂中或给予所述制剂形状或稠度。
口服制剂可以是药丸、胶囊、糖浆、芳香粉的形式和其他多种形式。所述载体有时基于所需要的制剂形式来选择。为了改进活性成分的稳定性、为了减慢活性成分的清除率、为了赋予活性成分的缓慢释放性质、为了减小不需要的副作用等,所述载体有时还可以具有改进所述活性成分递送或穿透到目靶组织的作用。为了向所述制剂提供食用调味剂等,所述载体还可以是稳定所述制剂的物质(例如防腐剂)。所述载体可以是任何常规使用的那些并且只受化学-物理考虑因素的限制,所述因素诸如溶解性和缺少与A3AR激动剂的反应性,以及受给药途径的限制。所述载体可以包含添加剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、调味剂和药理学相容载体。此外,所述载体可以是辅药,所述辅药根据定义是以可预知的方式影响所述活性成分的作用的物质。
适用于口服施用的载体的典型实例包括(a)液体溶液,其中有效量的活性物质溶解在稀释剂中,所述稀释剂诸如水、盐水、天然果汁、醇类、糖浆等;(b)胶囊(例如包含例如表面活性剂、润滑剂和惰性填料的普通硬壳或软壳明胶型胶囊)、药片、锭剂(其中所述活性物质在调味剂中,所述调味剂诸如蔗糖和***胶或黄蓍胶(tragacanth),或者所述活性物质是惰性基质诸如明胶和甘油)和糖锭剂,每种包含预定量的黄蓍胶作为固体或颗粒;(c)散剂(powder);(d)在合适液体中的悬浮液;(e)合适的乳剂;(f)脂质体制剂;及其他载体。
典型制剂可以是适于局部施用的任何形式,包括但不限于眼用溶液(例如滴眼剂)、眼用凝胶或眼用软膏或油状洗液。所述A3AR激动剂的局部施用还包括使用在合适的含药层中含有A3AR激动剂并被放置于眼睑上部的眼用贴剂,以及使用眼用***物,所述眼用***物是包含所述A3AR激动剂并被放入至下或上结膜囊中的装置(见例如WO00/59420)。
滴眼剂可以通过将A3AR激动剂溶解在无菌水溶液诸如盐水、缓冲溶液等中来制备,或者通过在使用前将待溶解的粉末组合物合并来制备。其他添加剂可以包含在所述滴眼剂中,所述添加剂诸如等渗剂(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、氯代丁醇等)、增稠剂(例如,糖诸如乳糖、甘露醇(mahnitol)、麦芽糖等;例如,透明质酸或它的盐诸如透明质酸钠、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、羧基乙烯基聚合物、交联聚丙烯酸酯等)。
眼用软膏可以通过将A3AR激动剂混合到基质中来制备。用于眼用软膏的基质的实例包括但不限于矿脂、selen 50、Plastibase、聚乙二醇等。
可以用于本制剂中的一些示例性眼用增粘剂包括: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)。
一些天然产物诸如硅酸镁铝(veegum)、海藻酸盐、黄原胶、明胶、***胶和黄蓍胶,也可以用于增加眼用溶液的粘度。
张力是重要的因为低渗滴眼剂导致角膜水肿,而高渗滴眼剂导致角膜变形。理想的张力是大约300mOsM。可以通过本领域技术人员已知的在Remington:The Science and Practice of Pharmacy(雷明顿:药学科学和实践)中描述的方法来获得所述张力。
本发明还提供包含一种或多种A3R激动剂和使用所述A3R激动剂的用法说明书的包装(试剂盒),所述用法说明书与本文公开的本发明方法保持一致。
如本文所用,形式“一个(a)”、“一种(an)”和“所述(the)”包括单数以及复数指代物,除非上下文明显指示不是。例如,术语“一种A3AR激动剂”包括能够特异性结合所述A3AR从而完全或部分激活所述受体的一种或多种化合物。
此外,如本文所用,术语“包括(comprising)”意在表明所述组合物包括所列举的活性药剂,例如A3AR激动剂,但是不排除其他成分,诸如生理学可接受的载体和赋形剂以及其他活性药剂。术语“基本上由…组成(consisting essentially of)”用于定义这样的组合物,所述组合物包含所列举的成分但是不包括对于减小IOP可能具有实质显著性的其他成分。因此“由…组成(consisting of)”应当是指不包括超过痕量成分的其他成分。由这些转换术语中的每个限定的实施方案在本发明的范围内。
此外,所有数值是近似值,所述近似值在所规定的值的基础上变化达(+)20%或(-)20%,有时达10%,例如当提及构成包含所述A3AR激动剂作为活性成分的组合物的成分的量或范围时。要理解这一点,即使不一定明确地规定在所有的数值指示前加上术语“大约”。
本发明现在将在以下对根据本发明实施的实验的描述中举例说明。要理解这些实施例意在具有说明的性质而非限制的性质。显然,根据以上教导,这些实施例的很多修饰和变化是可能的。因此要理解在所附权利要求的范围内,除了如在下文中具体描述的以外,本发明可以别的众多的可能方式实施。
非限制性实施例:
在患干眼综合症的患者中进行临床研究。所述患者接受剂量为1mg剂量的IB-MECA或安慰剂的口服施用,每日两次。令人惊奇的,除了一些干眼症状的改善以外,研究总体上显示了IB-MECA在减小测试受试者的IOP中的作用,并且特别地减小具有升高的IOP的患者的IOP的作用。
活性成分和制剂
所用A3AR激动剂是通常被称为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(ribofuranuronamide)或N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)的临床等级的化合物,所述化合物由Can-Fite BioPharma合成,根据由Albany Molecular ResearchInc(Albany,纽约,美国)制定的良好药品临床试验管理规范(goodclinical practice)(GMP)进行。
在本研究的第一期中,初始将IB-MECA制成口服软胶囊(“IB-MECA胶囊”)。每个所述胶囊包含具有下面表1中所示的组成的IB-MECA在克列莫佛(Cremophor)RH 40和Miglyol 812中的溶液:
表1-IB-MECA胶囊
在本研究的第二期中,将IB-MECA制成片剂形式(“IB-MECA片剂”),每个所述片剂包含下面表2中所示的成分:
表2-IB-MECA片剂
方法:
(a)研究设计
此研究是在18岁及以上年龄的被诊断为具有中度至重度干燥性角膜结膜炎(KCS)的成年男性和女性中进行的2期、随机化、双盲、安慰剂对照、平行分组研究。患者随机地口服接受1mg IB-MECA或匹配的安慰剂,每日两次,持续12周。长达4周的筛查期包括在12周治疗期前的2周准备期,紧接着12周治疗期后的2周随访期。
一些患者接受IB-MECA胶囊或匹配的安慰剂而其他接受IB-MECA片剂或匹配的安慰剂。对于每种被施用制剂的患者数目的分项数字在下面的表3中显示:
表3-治疗组
*No.可评价患者的数目
(b)患者纳入标准
将参与本研究的合格患者是符合以下规定的年龄在18岁及以上的被诊断为具有中度至KCS的成年男性和女性:
(1)以下眼部症状中至少1项的得分≥2,其中0=没有症状而4=非常严重/妨碍正常活动:畏光、视力模糊、异物感、酸痛或疼痛、瘙痒、烧伤、干燥;以及
(2)在任一只眼中,ST(在不麻醉的条件下)<7mm/5min;以及
(3)阳性的FS,其被定义为在任一只眼中角膜点状荧光素染色的得分≥1,其中0=没有症状而3=严重。在整个试验期间除了8次/天的未做防腐处理的人工泪液(REFRESH)以外禁止在本研究的过程中使用局部眼部治疗。也禁止在眼周涂抹化妆品。
(c)患者的排除标准
如果患者患有明显累及全身非外分泌腺的综合症、Stevens-Johnson综合症,烧伤后眼损伤或除KCS外的需要局部治疗的慢性眼病,则他们被排除出本研究。接受以下药物给药的患者也被排除:在筛查随访前的3个月内接受了局部环孢霉素滴眼剂施用或全身环孢霉素施用;包括甲氨蝶呤和生物制剂的疾病缓解药物(disease-modifying drugs),所述疾病缓解药物的剂量在筛查随访前的3个月内已经改变了或在试验期间预期会改变;每日口服>10mg***(prednisone)或等效物的皮质类固醇;或在筛查随访前的2周内以及整个研究期间接受了局部类固醇施用。另外的排除标准包括眼部单纯疱疹病毒感染;伴随地或在3个月内使用隐形眼镜;持续的眼内炎症或感染;超过轻度的活动性睑缘炎;近期进行了泪点堵塞手术;上皮下角膜瘢痕形成;感觉丧失的或神经营养性角膜;存在无法控制的哮喘或具有无法控制的哮喘病史、存在无法控制的动脉性高血压或症状性低血压或具有无法控制的动脉性高血压或症状性低血压的病史;显著的心律不齐或传导阻滞、充血性心力衰竭或有临床意义的心脏病的任何其他证据;在筛查心电图(ECG)上的有临床意义的其他发现;血红蛋白水平<9.0gm/L;血小板计数<125,000/mm3;白细胞(WBC)计数<3500/mm3;血清肌酸酐水平在实验室正常限度外;肝氨基转移酶水平超过正常实验室上限的2倍;已知或怀疑具有免疫缺陷或人免疫缺陷病毒阳性;根据研究者的判断,妊娠、计划妊娠、哺乳或不适当避孕;药物或酒精依赖史;严重的药物或碘过敏或敏感史;之前接受过CF101;在过去的5年内有恶性肿瘤(除皮肤的基底细胞癌外)病史;根据研究者的判断,会损害患者安全、限制患者完成研究的能力和/或损害研究目标的显著的急性或慢性医学、眼部或精神疾病;同时或在30天内参与了另一个研究性药物或疫苗临床试验;或将使研究评估混乱或危及患者安全的其他病症。
(d)研究终点
本研究的终点是与KCS有关的测量。然而,测量其他的参数,包括IOP。
结果
在第一次治疗(“基线”)前以及在12周治疗期结束时(“第12周”)测量患者(接受片剂的那些以及接受胶囊的那些)的IOP。结果显示在下面的表4中:
表4-IB-MECA有效性
如可见的,所述IB-MECA治疗组相比所述安慰剂组显示了更显著的IOP减小(6.07%变化率的减小相对于安慰剂组中的1.95%;p<0.05)。这导致下述结论:IB-MECA以及其他A3AR激动剂是用于减小IOP的潜在药物。
Claims (26)
1.A3腺苷受体(A3AR)激动剂用于减小受试者眼内压(IOP)的用途。
2.权利要求1所述的用途,所述用途用于减小具有升高的IOP的受试者的IOP。
3.权利要求1或2所述的用途,其中所述受试者是人类受试者。
4.权利要求1-3中任一项所述的用途,其中所述A3R激动剂经口服施用。
5.权利要求4所述的用途,其中所述A3R激动剂每日施用两次。
6.权利要求1-3中任一项所述的用途,其中所述A3R激动剂经局部施用。
7.权利要求6所述的用途,其中将所述A3R激动剂施用到眼部。
8.权利要求1-6中任一项所述的用途,其中所述A3RAg选自由以下各项组成的组: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)。
9.权利要求7所述的用途,其中所述A3Rag是IB-MECA。
10.用于减小受试者IOP的方法,所述方法包括将有效减小IOP的量的A3腺苷受体(A3AR)激动剂施用于所述受试者。
11.权利要求10所述的方法,其中所述受试者是人类受试者。
12.权利要求10或11所述的方法,其中所述受试者具有升高的IOP。
13.权利要求10-12中任一项所述的方法,所述方法包括所述A3R激动剂的口服施用。
14.权利要求13所述的方法,其中所述A3R激动剂每日施用两次。
15.权利要求10-12中任一项所述的方法,所述方法包括所述A3R激动剂的局部施用。
16.权利要求15所述的方法,其中将所述A3R激动剂施用到眼部。
17.权利要求10-16中任一项所述的方法,其中所述A3RAg选自由以下各项组成的组: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)。
18.权利要求17所述的方法,其中所述A3Rag是IB-MECA。
19.用于减小患者IOP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激动剂和生理学上可接受的载体,所述A3AR激动剂的量有效减小IOP。
20.权利要求19所述的药物组合物,其中所述受试者是人类受试者。
21.权利要求19或20所述的组合物,其中所述载体适用于所述A3R激动剂的口服施用。
22.权利要求9所述的组合物,所述组合物被配制成适于每日施用两次的剂型。
23.权利要求19-22中任一项所述的组合物,其中所述载体适用于所述A3R激动剂的局部施用。
24.权利要求23所述的组合物,所述组合物被配制成将所述A3R激动剂施用到眼部。
25.权利要求19-24中任一项所述的组合物,其中所述A3RAg选自由以下各项组成的组: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)。
26.权利要求25所述的组合物,其中所述A3RAg是IB-MECA。
Applications Claiming Priority (3)
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IL198787 | 2009-05-17 | ||
IL19878709 | 2009-05-17 | ||
PCT/IL2010/000393 WO2010134067A1 (en) | 2009-05-17 | 2010-05-16 | A3 adenosine receptor agonists for the reduction of intraocular pressure |
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CN102427819A true CN102427819A (zh) | 2012-04-25 |
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CN2010800212202A Pending CN102427819A (zh) | 2009-05-17 | 2010-05-16 | 用于减小眼内压的a3腺苷受体激动剂 |
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US (1) | US8557790B2 (zh) |
EP (1) | EP2432475A1 (zh) |
JP (1) | JP5849044B2 (zh) |
KR (1) | KR20120022919A (zh) |
CN (1) | CN102427819A (zh) |
AU (1) | AU2010250759B2 (zh) |
CA (1) | CA2761499A1 (zh) |
IL (1) | IL216114A (zh) |
MX (1) | MX2011012229A (zh) |
WO (1) | WO2010134067A1 (zh) |
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WO2007002139A2 (en) * | 2005-06-22 | 2007-01-04 | The Trustees Of The University Of Pennsylvania | Neuroprotection of retinal ganglion cells |
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US20090012035A1 (en) * | 2007-06-29 | 2009-01-08 | Government Of The United States Of America, Represented By The Secretary, Depa | Dendrimer conjugates of agonists and antagonists of the gpcr superfamily |
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CN101410114A (zh) * | 2006-01-26 | 2009-04-15 | 美国政府卫生与公共服务部 | A3腺苷受体别构调节剂 |
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2010
- 2010-05-16 AU AU2010250759A patent/AU2010250759B2/en not_active Ceased
- 2010-05-16 US US13/320,715 patent/US8557790B2/en not_active Expired - Fee Related
- 2010-05-16 CN CN2010800212202A patent/CN102427819A/zh active Pending
- 2010-05-16 JP JP2012510440A patent/JP5849044B2/ja not_active Expired - Fee Related
- 2010-05-16 KR KR1020117026858A patent/KR20120022919A/ko not_active Application Discontinuation
- 2010-05-16 WO PCT/IL2010/000393 patent/WO2010134067A1/en active Application Filing
- 2010-05-16 EP EP10726312A patent/EP2432475A1/en not_active Withdrawn
- 2010-05-16 MX MX2011012229A patent/MX2011012229A/es not_active Application Discontinuation
- 2010-05-16 CA CA2761499A patent/CA2761499A1/en not_active Abandoned
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US20040167094A1 (en) * | 2002-11-19 | 2004-08-26 | Can-Fite Biopharma Ltd. | A3AR agonists for the treatment of inflammatory arthritis |
CN101072554A (zh) * | 2004-11-08 | 2007-11-14 | 坎-菲特生物药物有限公司 | 对于加速性骨再吸收的治疗 |
WO2007002139A2 (en) * | 2005-06-22 | 2007-01-04 | The Trustees Of The University Of Pennsylvania | Neuroprotection of retinal ganglion cells |
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Also Published As
Publication number | Publication date |
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CA2761499A1 (en) | 2010-11-25 |
WO2010134067A1 (en) | 2010-11-25 |
KR20120022919A (ko) | 2012-03-12 |
IL216114A (en) | 2015-07-30 |
US20120065155A1 (en) | 2012-03-15 |
EP2432475A1 (en) | 2012-03-28 |
AU2010250759A1 (en) | 2011-12-08 |
JP2012526798A (ja) | 2012-11-01 |
US8557790B2 (en) | 2013-10-15 |
MX2011012229A (es) | 2011-12-08 |
AU2010250759B2 (en) | 2013-03-14 |
IL216114A0 (en) | 2012-01-31 |
JP5849044B2 (ja) | 2016-01-27 |
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