CN101365430B - 用于治疗干眼病的腺苷a3受体激动剂 - Google Patents
用于治疗干眼病的腺苷a3受体激动剂 Download PDFInfo
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- CN101365430B CN101365430B CN2006800475697A CN200680047569A CN101365430B CN 101365430 B CN101365430 B CN 101365430B CN 2006800475697 A CN2006800475697 A CN 2006800475697A CN 200680047569 A CN200680047569 A CN 200680047569A CN 101365430 B CN101365430 B CN 101365430B
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- A61K31/706—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及的治疗干眼的方法和组合物。该方法包括给显示干眼的眼科临床症状和迹象的个体提供A3腺苷受体(A3AR)激动剂。优选将A3AR激动剂局部或口服施用于患者。
Description
发明领域
本发明涉及用于治疗干眼的化合物和方法。
发明背景
眼前部的泪液膜在维持角膜的完整性，保护免于感染和保护视敏度方面发挥着重要作用。而这些功能严格依赖于泪液膜结构的稳定性、弹性和/或构成。可替代地，泪液膜缺乏或丧失可能会导致角膜上皮不希望地干燥、角膜溃疡和穿孔、感染疾病的发病率提高，并最终导致严重的视力缺损和失明。
干眼疾病通常称作综合征或疾病；已知它还有很多的术语。干燥性角结膜炎(KCS)或更常见的干燥性角膜炎会涉及一定程度干燥的任何眼睛。
在干眼中，由于泪液异常高速的蒸发或由于不能产生足够的泪液，眼睛会变得干燥。
在全世界，有无数的个体患有干眼综合症。这种导致泪液膜机能障碍的异常情况可以细分为四大类：(a)含水泪液缺乏，这是干眼状态最常见的原因，起源于泪腺障碍并包括自身免疫性疾病、先天性无泪、麻痹性分泌补足或排泄管阻塞；(b)粘蛋白缺乏，这是在很多的结膜瘢痕形成性疾病例如Stevens-Johnson综合症、沙眼、类天疱疮、热和化学性烧伤以及维生素A缺乏中观测到的；(c)液体异常，它是在眼睑发炎(例如，慢性睑炎)时发生的；和(d)眼睑功能降低[Holly，F.J.，Tear film physiology.Internat.Ophthalmol.Clin.27：2-6(1987)]。
一线的治疗剂通常是作为人工泪液发挥作用的滴眼剂，优选不含防腐剂。大多数的人工泪液是水凝胶，其增加眼睛表面的含水量并给予一些暂时的缓解。这些溶液和软膏给予一些暂时的缓解，但是几乎不能阻止或逆转任何的所损伤的情况。近来引导人工泪液的产品是基于蓖麻油乳剂(Refresh Endura泪)。
此外，应用于闭合的眼睑的皮肤上的热的湿敷布也用于减少由于蒸发而导致的泪液损失。
对于角膜发炎的干眼的更严重情况，有时会给予抗炎剂例如局部用类固醇(在滴眼剂中)。一个例子包括蓖麻油和环孢霉素的组合(Restasis)。
也可以使用干眼的口服药物。例如已知在SalagenTM或西维美林中的活性成分或在EvoxacTM中的活性成分能够刺激泪腺中的特异性受体，导致泪液的分泌增加。
其他治疗方法包括泪点塞和泪点关闭器(其阻止了泪液从泪小管流下到鼻中)，和食品补充剂，例如商业销售的麻子油补充剂(ω-3补充剂，TheraTears)。
发明简述
根据第一个方面，本发明提供一种治疗个体干眼疾病的方法，包括给所述个体施用一定量的A3腺苷受体(A3AR)激动剂，该量有效地改善个体的干眼症状。
根据一个实施方案，本发明提供一种治疗个体干眼综合症的方法，包括给所述个体施用A3腺苷受体(A3AR)激动剂。
根据第二个方面，本发明提供一种治疗干眼综合症的药物组合物，包含一定量的A3AR激动剂作为活性成分和生理学可接受的载体，一定量的所述A3AR激动剂有效地改善个体的干眼症状。
根据第三个方面，本发明提供A3AR激动剂在制备治疗干眼疾病的药物组合物中的应用。
示例性实施方案的详述
干眼综合症包括一大群不同的疾病过程，其产生了干燥性角结膜炎(KCS)的目标性的临床征兆。干眼综合症的经典原型是
综合症，但也有很多其他的KCS的原因，包括瘢痕形成性结膜疾病例如沙眼和类天疱疮、导致的特异性干眼检查物的非瘢痕形成性综合症，和非典型综合症，例如角膜软化症，其中眼睛症状性或客观地干燥，但是反常的是，泪液产生是正常的。
干眼的主要症状是痒或砂粒感，似乎眼睛中有什么东西。其他症状可以包括眼睛痒或炙热；产生过量的泪液，然后是非常干燥的时期；眼睛的粘性排出物；及眼睛的疼痛和发红。有时干眼的个体感觉眼睑沉重或模糊、视力改变或降低，尽管视力损失并不常见。
干眼的一些个体会有沿着它们面颊流下的泪液。这是因为眼睛可能产生较少的脂质和泪液膜的粘蛋白层，粘蛋白层有助于将泪液保留在眼睛中。当这发生时，泪液不能足够长时间地停留在眼睛中彻底地湿润眼睛。
本发明提供了一种治疗干眼病，特别是干眼综合症的方法，包括给显示一种或多种干眼症状和征兆的个体提供一定量的A3腺苷受体(A3AR)激动剂，该量可以有效地治疗干眼病。
如所理解的，尽管参考上面的方法在下面的详述中描述了本发明，但应当理解的是，用于所述治疗的包含A3AR激动剂的组合物也包括在本发明内。
在本发明的全文中，术语“干眼病”是指导致干眼症状现象的任何疾病或综合症。它包括已经存在的疾病和伪干眼病，即，有发生干眼综合症的高度诱因的疾病。干眼综合症可以是导致干眼的另一种潜在疾病例如Sjogren′s综合症、绝经或类风湿性关节炎的结果。干眼也可以是炎症例如眼睑炎或眼中杂物的并发症。干眼还可以是感染或药物的副作用，或暴露于毒素、化学品或其他可以导致干眼症状或疾病的结果。
本文使用的可以与术语“干眼征兆”互换使用的术语“干眼症状”是指个体患病眼睛的正常功能或结构的任何感觉或改变。患者可以感觉并且可以作为干眼综合症的指示的征兆的非限制性例子包括，干眼感、砂粒感、眼睛的痒感、眼睛炙热、眼睛刺痛或瘙痒、多泪、眼痛、眼睛发红、视力模糊、视力降低。
本文使用的术语“治疗”以及类似用语是指获得期望的药理学和生理学效应。该效应可以预防性的，即预防或部分预防干眼疾病、症状或情况和/或可以是治疗性的，即部分或完全治愈干眼综合症导致的疾病、情况、症状或不利效应。本文使用的术语“治疗”包括在哺乳动物，特别是人中对疾病的任何治疗，包括(a)在容易发生干眼综合症但尚未诊断出患有该病的个体中预防干眼综合症发生，即导致在容易发生干眼综合症但并未感觉或显示干眼综合症症状的个体不会发生干眼综合症的临床症状；(b)抑制干眼综合症，即，阻止或减轻干眼综合症或其临床症状的发生；或(c)缓解干眼综合症，即，导致干眼综合症和/或其症状或情况退化。
本发明的全文中的术语“A3腺苷受体激动剂”(A3AR激动剂)是能够与A3AR特异性结合并由此完全或部分活化所述受体的任意分子。因此，A3AR激动剂是一种通过结合并活化A3AR而显示其主要作用的分子。这就是说，在一定剂量下施用时，它基本上仅结合并活化A3AR。在一个优选的实施方案中，A3AR激动剂对人A3AR的亲和力(Ki)的范围是小于100nM，典型地小于50nM，优选小于20nM，更优选小于10nM，理想地小于5nM。特别优选的A3AR激动剂对人A3R的Ki小于2nM，期望地小于1nM。
应当注意的是，一些A3AR激动剂也会与其他受体以较低的亲和力(即Ki较高)相互作用并活化所述受体。在本发明的全文中，如果其与A3AR的亲和力是与其他任何腺苷受体(即，A1、A2a和A2b)的至少3倍(即，其与A3AR的Ki小至少3倍)，优选10倍，希望地至少20倍，最优选至少50倍，那么就认为该分子是A3AR激动剂(即，通过结合并活化A3AR来显示其主要作用的分子)。
A3AR激动剂与人A3AR的亲和力，以及与其他的人腺苷受体的相对亲和力可以通过很多试验例如结合试验来测定。结合试验的例子包括提供含有受体的膜，并测定A3AR激动剂置换结合的放射性激动剂的能力；在功能性试验中，根据具体情况使用显示各种人腺苷受体的细胞并测定A3AR激动剂活化或使下游信号事件失活的能力例如通过提高或降低cAMP水平来影响所测定的腺苷酸环化酶；等等。显然，如果增加A3AR激动剂的施用水平使得其血液水平达到接近A1、A2a和A2b腺苷受体的Ki的水平，那么在这样施用后除了会活化A3AR，还会发生这些受体的活化。因此，优选以一定剂量施用A3AR激动剂，以使获得的血液水平仅仅主要使A3AR活化。
一些腺苷A3AR激动剂的性质及它们的制备方法在文献中有详细描述，特别是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和本申请人的共待决专利申请号09/700,751(对应于WO 01/19360)，将它们全部通过参考引入本文。
下面的实例是在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行所指出的：
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(hydrazido)-N6-(3-碘苄基)-9-甲基腺嘌呤；
N6-(3-碘苄基)-2-甲氨基-9-甲基腺嘌呤；
2-二甲氨基-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-甲硫基腺嘌呤；
N6-(3-碘苄基)-9-甲基-2-(4-吡啶基硫)腺嘌呤；
(1S，2R，3S，4R)-4-(6-氨基-2-苯基乙基氨基-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-甲基氨甲酰基)环戊-1β-基)]-N6-(3-碘苄基)-腺嘌呤；
2-氯-9-(2′-氨基-2′，3′-二去氧-β-D-5′-甲基-阿糖-furonamido)-N6-(3-碘苄基)腺嘌呤；
2-氯-9-(2′，3′-二去氧-2′-氟-β-D-5′-甲基-阿糖furonamido)-N6-(3-碘苄基)腺嘌呤；
9-(2-乙酰基-3-去氧-β-D-5-甲基-呋喃核糖酰氨基(ribofuronamido))-2-氯-N6(3-碘苄基)腺嘌呤；
2-氯-9-(3-去氧-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-去氧-β-D-5-甲基-呋喃核糖酰氨基)-N6-(3-碘苄基)腺嘌呤；
2-氯-9-(3，5-1，1，3，3-三异丙基二硅氧基-β-D-5-呋喃核糖基(ribofuranosyl))-N6-(3-碘苄基)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-去氧-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-去氧-N，4-二甲基-β-D-呋喃核糖苷糖醛酰胺(ribofuranosiduronamide)；
2-氯-9-(2，3-二去氧-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′-二去氧-β-D-5′-甲基-阿糖-furonamido)-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-去氧-N-甲基-β-D-呋喃核糖苷糖醛酰胺；
N6-[3-(L-脯氨酰氨基)苄基]腺苷-5′-N-甲基糖醛酰胺(uronamide)；
N6-[3-(β-丙氨酰氨基)苄基]腺苷-5′-N-甲基糖醛酰胺；
N6-[3-(N-T-Boc-β-丙氨酰氨基)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′-二去氧赤呋喃糖苷基)-N6-[(3-β-丙氨酰氨基)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′-去氧-6′-硫代-L-阿糖胞苷基)腺嘌呤；和
2-氯-(6′-硫代-L-阿糖胞苷基)腺嘌呤。
在US 5,773,423的第6栏第39行到第7栏的第14行，具体公开了包括下式的化合物：
其中
X1是RaRbNC(＝O)，其中Ra和Rb可以相同或不同，选自氢、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选自氢、卤素、C1-C10烷氧基、氨基、C2-C10烯基和C2-C10炔基；和
R5选自R-和S-1-苯乙基、未取代的苄基和在一个或多个位置被选自C1-C10烷基、氨基、卤素、C1-C10卤代烷基、硝基、羟基、乙酰氨基、C1-C10烷氧基和硫的取代基取代的苄基。
更具体的化合物包括上式中其中Ra和Rb可以相同或不同选自氢和C1-C10烷基的那些，特别是当R2是氢或卤素，特别是氢时的那些化合物。
其他具体的化合物是其中Ra是氢和R2是氢，特别是当R5是未取代的苄基时的那些化合物。
更具体的化合物是那些化合物，其中Rb是C1-C10烷基或C3-C10环烷基，特别是C1-C10烷基，更特别地是甲基。
特别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，R5是R-或S-1-苯基乙基或在一个或多个位置被选自卤素、氨基、乙酰氨基、C1-C10卤代烷基和硫的取代基取代的苄基，其中硫衍生物是盐，例如三乙基铵盐。
在US 5,773,423中公开的特别优选的化合物的例子是IB-MECA。此外，在这篇文献中特别提到的那些化合物，其中R2是式Rd-C＝C-的C2-C10亚烯基，其中Rd是C1-C8烷基。同时具体公开了其中R2不是氢的那些化合物，特别是其中R2是卤素、C1-C10烷基氨基、或C1-C10烷基硫的那些，更特别地，另外当Ra是氢时，Rb是C1-C10烷基，和/或R5是取代的苄基。
这些具体公开的化合物包括2-氯-N6-(3-碘苄基)-9-[5-(甲基氨基)-β-D-呋喃核糖基]-腺嘌呤、N6-(3-碘苄基)-2-甲氨基-9-[5-(甲基氨基)-β-D-呋喃核糖基]-腺嘌呤和N6-(3-碘苄基)-2-甲硫基-9-[5-(甲基氨基)-β-D-呋喃核糖基]-腺嘌呤。
此外，US 5,773,423在第7栏第60行到第8栏第6行公开了具有下式的作为修饰的黄嘌呤-7-肌苷的A3AR激动剂：
其中
X是O；
R6是RaRbNC(＝O)，其中Ra和Rb可以相同或不同，选自氢、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，选自C1-C10烷基、R-和S-1-苯基乙基、未取代的苄基和在一个或多个位置被选自C1-C10烷基、氨基、卤素、C1-C10卤代烷基、硝基、羟基、乙酰氨基、C1-C10烷氧基和硫的取代基取代的苄基；和
R9选自卤素、苄基、苯基和C3-C10环烷基。
WO 99/06053在实施例中公开了化合物19-33：
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-苯基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-乙酰基-苯基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-((R)-α-苯基乙基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-((S)-α-苯基乙基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(5-甲基-异噁唑-3-基-氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(1，3，4-噻二唑-2-基-氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-(4-正丙氧基-苯基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；
N6-二-(4-硝基苯基氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺；和
N6-二-(5-氯-吡啶-2-基-氨甲酰基)-腺苷-5′-N-乙基糖醛酰胺。
根据本发明的一个实施方案，A3AR激动剂是通过结合并活化腺苷A3AR而发挥其主要作用的化合物，它是一种落在通式(I)的范围内的嘌呤衍生物：
其中，
-R11代表烷基、羟基烷基、羧基烷基或氰基烷基或下列通式(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可以相同或不同，选自氢、烷基、氨基、卤代烷基、氨基烷基、BOC-氨基烷基和环烷基，或者结合在一起形成包含2到5个碳原子的杂环；和
-Rg选自烷基、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、烷基酰氨基或羟基烷基；
-X13和X14独立地代表氢、羟基、酰氨基、氨基、叠氮基、卤素、烷基、烷氧基、羧基、三价氮基、硝基、三氟基、芳基、烷芳基、硫、硫酯、硫醚、-OCOPh、-OC(＝S)OPh或X13和X14都是与＞C＝S连接形成五元环的氧，或者X12和X13形成式(III)的环：
其中R′和R″独立地代表烷基；
-R12选自氢、卤素、烷基醚、氨基、酰肼基、烷基氨基、烷氧基、硫烷氧基、吡啶基硫、烯基；炔基、硫、和烷基硫；和
-R13是式-NR15R16的基团，其中
-R15是氢原子或选自烷基、取代的烷基或芳基-NH-C(Z)-的基团，其中Z是O、S、或Re具有上述含义的NRa；其中当R15是氢时，那么
-R16选自R-和S-1-苯基乙基、苄基、苯基乙基或者未取代或在一个或多个位置被选自烷基、氨基、卤素、卤代烷基、硝基、羟基、乙酰氨基、烷氧基和磺酸及其盐的取代基取代的苯胺；苯并二噁烷甲基、糠基、L-丙基丙氨酰-氨基苄基、β-丙氨酰氨基-苄基、T-BOC-β-丙氨酰氨基苄基、苯基氨基、氨甲酰基、苯氧基或环烷基；或R16是下式的基团：
或者当R15是烷基或芳基-NH-C(Z)-时，那么R16选自杂芳基-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。
根据一个优选的实施方案，A3AR激动剂是通式(IV)的核苷衍生物：
其中X1、R2′和R5如上定义，及所述化合物的生理学可接受的盐。
形成本发明的化合物的部分取代基的非环碳水化合物基团(例如，烷基、烯基、炔基、烷氧基、芳烷基、烷芳基、烷基胺等等)可以是有支链或无支链的，优选包含1或2到12个碳原子。
当涉及本发明使用的化合物的“生理学可接受的盐”时，它是指在制药工业中常用的任何无毒性的碱金属、碱土金属和铵盐，包括通过本领域已知的方法制备的钠、钾、锂、钙、镁、钡、铵盐和鱼精蛋白锌盐。该术语也包括无毒性的酸加成盐，它一般是通过本发明的化合物与适当的有机或无机酸反应而制备的。酸加成盐是保持了游离碱的生物有效性和性质，并且没有毒性或其他不期望的性质的那些盐。例子包括，特别是来自无机酸，盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等等的酸。有机酸包括，特别是，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、羟乙酸、葡糖酸、丙酮酸、琥珀酸、水杨酸和芳基磺酸例如对甲苯磺酸。
可以根据本发明的通式(IV)使用的A3AR激动剂的具体例子包括但不限于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)。IB-MECA是根据本发明最优选的化合物。
根据另一个实施方案，A3AR激动剂可以是腺苷的氧化衍生物，例如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。
本发明上下文中的术语“有效量”或“有效......的量”是指防止或减轻了患者干眼症状时的A3AR激动剂的量。根据本发明，可以容易地确定“有效量”，通过给受式患者施用不同量的A3AR激动剂，然后绘出作为量的函数的生理学应答(例如，积分的“SS指标”集合了数种的治疗有益效果)。可替代地，有时也可以通过在适当动物模型中进行试验来确定有效量，然后用很多常规方法中的一种来推广至人；或者通过测定随着时间的血浆浓度或血浆浓度曲线下面积(AUC)，并计算有效剂量以得到可比较的血浆浓度或AUC。如人们所知，有效量可以取决于很多因素例如施用方式(例如，口服需要比静脉施用更高的剂量，以得到给定的血浆水平或AUC)；患者的年龄、体重、体表面积、性别、健康情况和遗传因子；施用的其他药物；等等。
下文中，除非另有说明，剂量用重量/kg表示，是指每次施用中所治疗患者的每kg体重所施用的A3AR激动剂(例如，IB-MECA)的重量。例如mg/Kg和微克/Kg分别是指所治疗患者的每kg体重所施用的药剂的毫克数和微克数。
有效量优选是小于约1mg/kg体重，特别是小于约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。至于IB-MECA，当每日1次施用时，有效量优选每剂量小于5mg(即每剂量小于约70μg/kg体重，假定个体的平均体重是约70kg)，当每日2次施用时，每剂量小于约4mg(即小于约57μg/kg体重)。对于每日1或2次施用时，IB-MECA的剂量更优选是每剂量小于约2mg，典型地每剂量是约0.1-1mg(对应于每kg体重的重量表示的对应剂量分别是约29μg/kg和约1.5-15μg/kg体重)。
A3AR激动剂可以与药学可接受的载体一起施用于个体。在口服的情况中，载体是口服可接受的。在局部施用(一个例子是眼部施用)的情况中，载体是局部施用可接受的。
术语“药学可接受的载体”是指任一的惰性、无毒性物质，它不会与A3AR激动剂反应，可以加入到制剂中作为稀释剂或载体，或使制剂成型或具有稠度。
口服可以是丸剂、胶囊，糖浆、芳香粉末的形式，及其他各种形式。有时根据制剂的所需形式来选择载体。有时载体也具有下列的效果：改善活性成分递送或渗透到靶组织中，改善药物的稳定性，减缓清除速率，给予缓释性质，减小不期望的副作用等等。载体也可以是稳定制剂的物质(例如，防腐剂)，提供具有可食用香味的制剂。载体可以是通常能够使用的任意载体，限制仅仅在于化学-物理考虑，例如溶解性和不与A3AR激动剂反应，和施用途径。载体可以包括添加剂、着色剂、稀释剂、缓冲剂、崩解剂、湿润剂、防腐剂、香味剂、和药理学相容的载体。此外，载体可以是佐剂，其定义为以可预测方式影响活性成分作用的物质。
适合口服的载体的典型例子包括(a)液体溶液，其中将有效量的活性物质溶解于稀释剂例如水、盐水、天然汁、醇、糖浆等等中；(b)胶囊(例如普通的硬或软壳明胶型，包含例如表面活性剂、润滑剂和惰性填充剂)、片剂、锭剂(其中活性物质在香味剂例如蔗糖和阿拉伯胶或西黄蓍胶中或活性物质在惰性基质例如明胶和甘油中)和含片，分别包含预定量的固体或颗粒状的西黄蓍胶；(c)粉末；(d)在适当液体中的混悬液；(e)适当的乳剂；(f)脂质体制剂；及其他。
局部用制剂可以是适合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性洗剂。A3AR激动剂的局部施用也包括使用眼用贴剂和眼用嵌入剂，其中贴剂在适当的含药层中载有A3AR激动剂并置于眼睑的上部，其中嵌入剂是包含A3AR激动剂的装置并置于结膜囊的下方或上方的器械(参见例如WO0059420)。
可以通过将A3AR激动剂溶解于无菌的水溶液例如盐水、缓冲溶液等等中，或通过在使用前将粉末组合物溶解来制备滴眼剂。在滴眼剂中可以包括其他添加剂例如等张剂(例如，氯化钠等等)，缓冲剂(例如，硼酸、磷酸一氢钠、磷酸二氢钠等等)，防腐剂(例如苯扎氯铵、苄索氯铵、三氯叔丁醇等等)，增稠剂(例如，糖例如乳糖、甘露醇、木糖醇等等；例如，透明质酸或其盐例如透明质酸钠、透明质酸钾等等；例如，粘多糖例如硫酸软骨素等等；例如，聚丙烯酸钠、羧乙烯基聚合物、交联聚丙烯酸酯等等)。
可以通过将A3AR激动剂混入到基质中来制备眼用软膏。眼用软膏的基质的例子包括凡士林油、selen 50、Plastibase、聚乙二醇等等，但并不限于此。
可以在本发明制剂中使用的一些示例性的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。
也可以使用一些天然产物，例如硅酸镁铝、海藻酸盐、呫吨胶、明胶、阿拉伯胶和西黄蓍胶来增强眼用溶液的粘度。
张度是重要的，因为低张的滴眼剂会导致角膜水肿，而高张的滴眼剂会导致角膜变形。理想的张度是约300mOsM，可以通过Remington：The Science and Practice of Pharmacy中所述的本领域已知的方法来达到张度。
本文使用的形式“一种”和“所述(该)”，除非上下文另有明确的说明，包括单数和复数。例如，术语“一种A3AR激动剂”包括一种或多种能够与A3AR特异性结合并完全或部分活化所述受体的激动剂。
此外，本文使用的术语“包含”意欲是指该组合物包括所列举的活性剂，即A3AR激动剂，但并不排除其他要素，例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”是用于定义包括所列举的要素但排除对干眼综合症的治疗具有本质重要性的其他药物的组合物。这样“由.......组成”是指排除超过痕量要素的其他要素。这些可互换的术语的每一个所定义的实施方案在本发明的范围内。
此外，所有的数值，例如当涉及组成包含A3AR激动剂作为活性成分的组合物的各要素的量或范围时，其表示的是近似值，可以在指定值的(+)或(-)高达20％，有时高达10％的范围内变化。应当理解的是，尽管并不总是明确指出，但所有的数值表示前面都是有术语“约”的。
现在将在根据本发明进行的试验的下面详述中示例本发明。应当理解的是，这些实施例意欲是解释的性质而不是进行限定。显然，根据上述教导，本发明的很多变更和改变都是可能的。因此，应当理解的是，在附属的权利要求范围内，本发明可以以下文所述的具体方式以外的无数可能的方式实施。
实施例：
IB-MECA在类风湿性关节炎患者中改善了干眼症状
药物：
所使用的A3AR激动剂是临床级的化合物，传统上称作1-脱氧-1-[6-[[(3-碘苯基)甲基]氨基]-9H-嘌呤-9-基]-N-甲基-D-呋喃核糖醛酰胺或称作N6-(3-碘苯基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)，它是由Can-Fite BioPharma合成的，符合Albany Molecular ResearchInc，Albany，NY，USA的优良临床试验规范(GMP)。
将IB-MECA配制成椭圆形的软凝胶胶囊。该胶囊包含在CremophorRH 40和Miglyol 812中的IB-MECA溶液。该胶囊包含0.1，1或4mg剂量的IB-MECA，每种胶囊类型的确切组成如下表1-3所示：
表1：0.1mg IB-MECA软凝胶胶囊的组成
| 成分 | 胶囊 | ％W/W |
| IB-MECA | 0.105mg | 0.021 |
| Polyoxyl 45蓖麻油，USP(Cremophor RH 40) | 326.495mg | 65.299 |
| Miglyol 812 | 173.400mg | 34.680 |
表2：1mg IB-MECA软凝胶胶囊的组成
| 成分 | 胶囊 | ％W/W |
| IB-MECA | 1.05mg | 0.210 |
| Polyoxyl 45蓖麻油，USP(Cremophor RH 40) | 325.975mg | 65.195 |
| Miglyol 812 | 172.975mg | 34.595 |
表3：4mg IB-MECA软凝胶胶囊的组成
| 成分 | 胶囊 | ％W/W |
| IB-MECA | 4.2mg | 0.84 |
| Polyoxyl 45蓖麻油，USP(Cremophor RH 40) | 324.4mg | 64.88 |
| Miglyol 812 | 171.4mg | 34.28 |
方法：
将含IB-MECA的胶囊给患者每天口服2次。所有患者均患类风湿性关节炎(RA)，并在临床研究的框架内给予IB-MECA，其中所述临床研究的目的是研究IB-MECA在这些患者中改变RA疾病症状的效果。患者随机接受上述三种剂量中的一种剂量的胶囊。患者接受IB-MECA 12周。
所治疗患者中的4个也患有干性角膜炎，并检查了IB-MECA对于它们的干眼症状的效果。
结果：
表1概述了CF101治疗RA患者的结果。具体来说，下面是4个患RA 8±2年的年龄为58±4岁的患者。在基线时，患者具有较高水平的类风湿因子，即313±120IU/ml(0＜正常＜40)，并患干眼5±1.6年。在用CF101治疗6.25±1.1个月后，观测到了在Schirmer′s试验中从8.5±1.4mm改善为15.6±2.9mm。
表1-CF101治疗对于RA患者的效果
Claims (7)
1.A3腺苷受体(A3AR)激动剂在制备治疗干眼疾病的药物组合物中的应用，所述A3腺苷受体(A3AR)激动剂选自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(C1-IB-MECA)。
2.权利要求1的应用，用于治疗干眼综合症。
3.权利要求1的应用，用于制备口服的药物组合物。
4.权利要求1的应用，用于制备局部施用的药物组合物。
5.权利要求4的应用，用于制备局部施用于眼睛的药物组合物。
6.权利要求1的应用，其中所述A3腺苷受体(A3AR)激动剂选自N6-(3-碘苄基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)。
7.权利要求1的应用，其中所述干眼疾病包括选自异物感、炙热、痒、刺激、发红、眼痛、视力模糊、视力降低和多泪的眼科临床症状，且所述组合物用于改善所述症状。
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| ES2531828T3 (es) | 2008-03-31 | 2015-03-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Derivados de purina como agonistas selectivos de los receptores A3 de adenosina |
| US8916570B2 (en) | 2008-03-31 | 2014-12-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | A3 adenosine receptor agonists and antagonists |
| JP5431476B2 (ja) | 2008-08-01 | 2014-03-05 | アメリカ合衆国 | Ａ３アデノシン受容体アンタゴニストおよびａ３アデノシン受容体部分アゴニスト |
| US9181253B2 (en) | 2008-08-01 | 2015-11-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Adenosine receptor agonists, partial agonists, and antagonists |
| CA2761499A1 (en) * | 2009-05-17 | 2010-11-25 | Can-Fite Biopharma Ltd. | A3 adenosine receptor agonists for the reduction of intraocular pressure |
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| CN1250369A (zh) * | 1997-02-06 | 2000-04-12 | 印斯拜尔药品股份有限公司 | 用嘌呤能受体激动剂治疗干眼病的方法 |
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| JPH10158188A (ja) * | 1996-11-29 | 1998-06-16 | Senju Pharmaceut Co Ltd | 角膜治療用組成物 |
| IL133680A0 (en) * | 1999-09-10 | 2001-04-30 | Can Fite Technologies Ltd | Pharmaceutical compositions comprising an adenosine receptor agonist or antagonist |
| AU2003276988B2 (en) * | 2002-09-27 | 2009-11-05 | Bioenvision, Inc. | Methods and compositions for the treatment of autoimmune disorders using clofarabine |
| JPWO2005121320A1 (ja) * | 2004-06-10 | 2008-04-10 | 協和醗酵工業株式会社 | 幹細胞自己複製促進剤 |
| DK1778239T3 (da) * | 2004-07-28 | 2013-12-02 | Can Fite Biopharma Ltd | Adenosin-a3-receptor-agonister til behandling af sygdomme forbundet medtørre øjne, herunder sjögrens syndrom |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1250369A (zh) * | 1997-02-06 | 2000-04-12 | 印斯拜尔药品股份有限公司 | 用嘌呤能受体激动剂治疗干眼病的方法 |
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|---|---|
| JP2009524647A (ja) | 2009-07-02 |
| KR20080090517A (ko) | 2008-10-08 |
| CA2622975A1 (en) | 2007-08-02 |
| EP1976494A1 (en) | 2008-10-08 |
| AU2006336834B2 (en) | 2009-12-10 |
| JP2013032396A (ja) | 2013-02-14 |
| CN101365430A (zh) | 2009-02-11 |
| JP5185139B2 (ja) | 2013-04-17 |
| BRPI0621052A2 (pt) | 2012-07-17 |
| IL191271A (en) | 2014-03-31 |
| IL191271A0 (en) | 2009-08-03 |
| WO2007086044A1 (en) | 2007-08-02 |
| CA2622975C (en) | 2011-05-03 |
| AU2006336834A1 (en) | 2007-08-02 |
| KR101037095B1 (ko) | 2011-05-26 |
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