CN100423723C - 多发性硬化症的治疗剂 - Google Patents
多发性硬化症的治疗剂 Download PDFInfo
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- CN100423723C CN100423723C CNB2004800393344A CN200480039334A CN100423723C CN 100423723 C CN100423723 C CN 100423723C CN B2004800393344 A CNB2004800393344 A CN B2004800393344A CN 200480039334 A CN200480039334 A CN 200480039334A CN 100423723 C CN100423723 C CN 100423723C
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- alkyl
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- methyl
- adenosine
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Abstract
A3腺苷受体激动剂在制备用于治疗患有多发性硬化症个体的药物组合物中的用途。优选口服施用该组合物。还公开了治疗多发性硬化症的药物组合物,该药物组合物包括有效量的A3腺苷受体激动剂和药学上可接受的载体。
Description
发明领域
本发明涉及在多发性硬化症治疗中有益的化合物和方法。
发明背景
多发性硬化症(MS)是中枢神经***(CNS),特别是“白质”组织的一种慢性的,渐进性变性疾病。它被认为是以导致慢性神经痛障碍(neuralgic disturbance)的CNS发炎和脱髓鞘为特征的自身免疫性疾病。通过免疫***产生抗髓磷脂蛋白例如包围脊髓的髓磷脂碱性蛋白(MBP)抗原的自身抗体。
实验性自身免疫性脑脊髓炎(EAE)是通常的使用的MS动物模型。在野生型动物例如啮齿类动物中它可以通过接种来诱发,或在遗传感性品系动物中自发产生。
腺苷受体分为四种主要种类:A1,A2a,A2b和A3。A3腺苷受体属于Gi蛋白联合细胞表面受体的家族成员。受体活化导致其内在化和随后抑制腺苷酸环化酶的活性,cAMP形成和蛋白激酶A(PKA)表达,导致各种信号通路启动(1,2)。当用cAMP活化时PKA含有由母体分子解离的催化亚单位PKAc。
美国专利第5,506,214号(Beutler)公开了用含有取代的腺嘌呤衍生物例如2-氯代-2′-脱氧腺苷(CdA)的治疗剂治疗患有MS的患者。CdA治疗显示可显著改善病情(disease condition)。如在Siddiqi,S.M.等人,(1995)J.Me d.Chem.38:1174-1188中所述认为CdA是推定的A1受体部分激动剂,不同腺苷受体的CdA的Ki值是对于A1受体为7.4μM,对于A2a受体为20μM和对于A3受体为207μM。
美国专利申请第20020094974号(Castelhano,等人)公开了新的N-6取代的7-脱氮嘌呤(deazapurine)衍生物,其为A3腺苷受体拮抗剂。这些化合物可用于治疗与A3腺苷受体有关的疾病包括神经障碍例如MS。
发明概述
本发明是基于意外的发现,即施用A3腺苷受体激动剂(A3RAg)减轻了多发性硬化症的症状。
因此,根据一个实施方案,本发明涉及在受治疗的人中治疗多发性硬化症(MS)的方法,包括给需要这样治疗的个体施用有效量的A3RAg。
术语:“多发性硬化症”(MS)在本发明的上下文中指CNS的炎性疾病,其中部分丧失神经绝缘髓鞘(insulating myelin sheath),这引起不同的病理症状。MS包括各种疾病类型,例如复发/缓解型MS(RRMS),继发渐进型MS(SPMS),渐进复发型MS(PRMS)和原发渐进型MS(PPMS)。
术语“治疗”或“神经痛保护”在本发明的上下文中指疾病临床症状的任何改善和/或MS患者退化率或复发率的减少,以及患者健康(well being)的任何改善。例如,改善可通过以下的一项或多项来显示:肌无力的减少,肌肉痉挛的减少,痉挛状态的减少,平衡的改善和记忆力的改善。
术语“腺苷A3受体激动剂”(A3RAg)在本发明的上下文中指能够与腺苷A3受体(″A3R″)特异性结合的任何分子,由此完全地或部分地活化所述受体。因此A3RAg是通过结合和活化A3R来发挥其主要作用的分子。这意味着以其施用剂量其主要与A3R结合并且只活化A3R。在优选的实施方案中,A3RAg与人腺苷A3受体的亲合力(Ki)在小于100nM,通常小于50nM,优选小于20nM,更优选小于10nM,理想地小于5nM的范围内。Ki越低,活化A3R并由此达到治疗效果的有效A3RAg剂量(可使用的)越低。因此通常可优选与人A3R的Ki小于2nM,甚至小于1nM的A3RAg。
应该注意的是某些A3RAg还可以与其他具有低亲合力(即更高的Ki)的受体相互作用,并活化其它具有低亲合力的受体。如果其与A3R的亲合力比与任何其它腺苷受体(即A1,A2a和A2b)的亲合力大至少3倍(即其与A3R的Ki低至少3倍),优选10倍,理想地是20倍,最优选至少50倍,则可以认为在本发明的上下文中该分子是A3RAg(即通过结合和活化A3R来发挥其主要作用的分子)。
A3RAg与人A3R的亲合力以及与其它人腺苷受体(A1,A2a和A2b)的相对亲合力可以通过许多试验,例如结合试验来测定。结合试验的实例包括提供具有受体的膜或细胞和测量A3Rag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个人腺苷受体的细胞和测量A 3RAg活化或使下游信号事件失活的能力例如通过增加或减少cAMP水平影响测定的腺苷酸环化酶;等。显然,如果增加施用的A3RAg水平以致于其血液水平达到接近A1,A2a和A2b腺苷受体的Ki的水平,则在这样的施用后除活化A 3R外还会使这些受体发生活化。因此优选以这样的剂量施用A3RAg以使将获得的血液水平仅主要使A3R活化。
特别是在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和WO 99/06053,WO97/27173中对某些腺苷A3受体激动剂的特性和它们的制备方法有详细描述,将它们全部引入本文作为参考。
根据本发明的一个实施方案,A3RAg是通过结合和活化A3R发挥其主要作用的化合物,是属于通式(I)范围内的嘌呤衍生物:
其中,
-R1表示烷基,羟基烷基,羧基烷基或氰基烷基或以下通式(II)的基团:
其中:
-Y表示氧,硫或CH2;
-X1表示H,烷基,RaRbNC(=O)-或HORc,其中
-Ra和Rb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,和环烷基或其相互连接形成包含二至五个碳原子的杂环,和
-Rc选自烷基,氨基,卤代烷基,氨基烷基,BOC-氨基烷基,和环烷基;
-X2是H,羟基,烷基氨基,烷基酰氨基或羟基烷基;
-X3和X4独立表示氢,羟基,氨基,酰氨基,叠氮基,卤素,烷基,烷氧基,羧基,次氮基(nitrilo),硝基,三氟基,芳基,烷芳基,硫基,硫代酯,硫醚,-OCOPh,-OC(=S)OPh或X3和X4都是与>C=S连接形成5元环的氧,或X2和X3形成式(III)的环:
其中R′和R″独立地表示烷基;
-R2选自氢,卤素,烷基醚,氨基,酰肼基(hydrazido),烷基氨基,烷氧基,硫代烷氧基,吡啶基硫基,链烯基;炔基,硫基,和烷基硫基;和
-R3是式-NR4R5的基团,其中
-R4是氢原子或选自烷基、取代的烷基或芳基-NH-C(Z)-,Z是O、S、或NRa,Ra具有上文的含义;其中当R4是氢时,
-R5选自在一个或多个位置用选自烷基,氨基,卤素,卤代烷基,硝基,羟基,乙酰氨基,烷氧基,和磺酸或其盐的取代基未取代或取代的R-和S-1-苯基乙基,苯甲基,苯乙基,或酰基苯胺(anilide)基;苯并二噁烷甲基(benzodioxanemethyl),fururyl,L-丙基丙氨酰-氨基苯甲基,β-丙氨酰氨基-苯甲基,T-BOC-β-丙氨酰氨基苯甲基,苯基氨基,氨基甲酰基,苯氧基或环烷基;或R5是下式的基团:
或当R4是烷基或芳基-NH-C(Z)-时,R5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表示氧,硫(sulfor)或胺;或以上化合物生理上可接受的盐。
根据一个优选的实施方案,A3RAg是通式(IV)的核苷衍生物及所述化合物生理上可接受的盐:
其中X1,R2和R5如上定义。
形成本发明化合物取代基一部分的非环状碳水化合物基团(例如烷基,链烯基,炔基,烷氧基,芳烷基,烷芳基,烷基胺,等等)是支链或非支链的,优选地包含1或2至12个碳原子。
当提及本发明所使用的化合物的“生理上可接受的盐”时是指在制药工业中通常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,钡铵盐和鱼精蛋白锌盐。该术语还包括无毒的酸加成盐,通常通过将本发明的化合物与适宜的有机酸或无机酸反应来制备。酸加成盐保持游离碱的生物作用和性质,并且无毒或没有其他不需要的作用。实例包括由无机酸衍生的酸,特别包括盐酸,氢溴酸,硫酸,硝酸,磷酸,偏磷酸等。有机酸特别包括酒石酸,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,琥珀水杨酸和芳基磺酸,例如对甲苯磺酸。
根据本发明的通式(IV)可以使用的A3RAg的具体实施例包括但是不限于,N6-2-(4-氨基苯基)乙基腺苷(APNEA),N6-(4-氨基-3-碘代苯甲基)腺苷-5′-(N-甲基糖醛酰胺(uronamide))(AB-MECA),N6-(3-碘代苯甲基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)以及2-氯代-N6-(3-碘代苯甲基)-腺苷-5′-N-甲基糖醛酰胺(Cl-IB-MECA)。
根据另一个实施方案,A3RAg可以是腺苷的氧化物衍生物,例如N6-苯甲基腺苷-5′-N-烷基糖醛酰胺-N1-氧化物或N6-苯甲基腺苷-5′-N-二烷基糖醛酰胺-N1-氧化物,其中2-嘌呤位可以用烷氧基,氨基,链烯基,炔基或卤素取代。
可将所述A3RAg和药学上可接受的载体一起给患者施用。在口服施用的情况下,载体是可为口服施用所接受的载体。
就术语“药学上可接受的载体”而言,它是指任何惰性,无毒的材料,它们不与A3RAg发生反应,可以作为稀释剂或载体加入到制剂中或使制剂成型或均匀。口服制剂可以是丸剂,胶囊,糖浆,芳香粉末以及其它各种形式。通常根据所需的制剂形式选择载体。载体通常还可以具有改善活性成分对目标组织的递送或渗透,改善药物稳定性,延缓清除率,赋予缓释特性,减少不希望的副作用等作用。载体还是可以使制剂稳定的物质(例如防腐剂),给制剂提供适合食用香味的物质等。载体可以是通常使用的那些,且只是受限于理化方面的考虑如溶解度并缺乏与A3RAg的反应性,以及施用途径。载体可以包括添加剂,着色剂,稀释剂,缓冲剂,崩解剂,润湿剂,防腐剂,芳香剂以及药理学相容的载体。此外,载体可以是佐剂,根据定义其是以可预料的方式影响活性成分作用的物质。载体的典型实例包括(a)液体溶液,其中将有效量的活性物质溶解在稀释剂例如水,生理盐水,天然果汁,醇,糖浆等中;(b)胶囊(例如普通的硬壳或软壳明胶类型的胶囊,其含有例如,表面活性剂,润滑剂,以及惰性填充剂),片剂,锭剂(其中活性物质是在调味剂,例如蔗糖以及***胶或黄蓍胶中或活性物质是在惰性基质例如明胶以及甘油中),以及糖锭,各自包含预定量的固体或颗粒形式的A3Rag;(c)粉末;(d)在适宜液体中的混悬液;(e)适宜的乳剂;(f)脂质体制剂;及其他。
术语“有效量”在本发明上下文中指使患者从MS病理症状产生神经痛保护的A3RAg的量。根据本发明,可以容易地通过给多个受试者施用不同量的A3RAg然后以生理反应(例如组合多种治疗有益效果的综合″MS指数”)作为用量的函数作图来测定“有效量”。可选地,通常还可以通过在适当的动物模型中进行试验然后使用多种换算方法中的一种外推至人类来确定有效量;或通过测量血浆浓度或经时血浆浓度曲线下面积(AUC)和计算产生相当的血浆浓度或AUC的有效剂量来确定有效量。公知地,有效量取决于各种因素例如施用方式(例如,口服施用可能需要比静脉内施用更高的剂量以达到特定的血浆水平或AUC);受治疗者的年龄,体重,体表面积,性别,健康状况以及遗传因素;其它施用药物;等等。
在下文,除非另外指明,以重量/Kg表示剂量,表示每次施用时受治疗者每公斤体重施用的A3RAg(例如IB-MECA或Cl-IB-MECA)的重量。例如,mg/Kg和微克/Kg分别表示受治疗者每公斤体重施用毫克级的药剂和微克级的药剂。
在小鼠中,有效量通常小于大约1000微克/Kg,优选小于大约500微克/Kg。代表性的剂量在大约1微克/Kg至大约200微克/Kg的范围内,优选的剂量在大约5微克/Kg至大约150微克/Kg的范围内。在人中相应的有效量为在小鼠中观察到的人相当的量,可根据下文所阐明的方法进行测定。
术语“人相当的”指在人中产生与当给小鼠(mouse)或大鼠(rat)施用0.001-1mg/Kg剂量的A3RAg时相同效果的剂量。众所周知,该剂量取决于很多参数且可根据很多参数例如体重,体表面积,活性剂的吸收速率,活性剂的清除率,代谢速率及其他参数来确定。
可根据下文所阐明的多种换算准则来计算人相当的量;或人相当的量可是这样的剂量以使血浆水平与在小鼠中以上文所述剂量施用后的血浆水平相似;或是产生与在小鼠中以所述剂量范围所产生的总暴露相似的总暴露(即作为时间函数的所述活性剂血浆水平的AUC曲线下面积)的剂量。
众所周知,通过使用本领域已知的可能的换算方程可将给大鼠施用的Xmg/Kg的量换算为在另一个物种(特别是人)中相当的量。换算方程的实例如下:
换算I:
物种 | 体重(Kg) | 体表面积(m<sup>2</sup>) | Km因子 |
小鼠 | 0.2 | 0.0066 | 3.0 |
大鼠 | 0.15 | 0.025 | 5.9 |
人类儿童 | 20.0 | 0.80 | 25 |
成人 | 70.0 | 1.60 | 37 |
体表面积依赖性剂量换算:大鼠(150g)对于人(70Kg)是1/7大鼠剂量。这是指,例如在大鼠中0.001-1mg/Kg相当于在人中为大约0.14-140微克/Kg。假定平均人体重为70Kg,转化为人的绝对剂量为大约0.01至大约10mg。
换算II:
以下换算系数为:小鼠=3,大鼠=67。用换算系数乘动物体重使人剂量当量由mg/Kg变为mg/m2。
物种 | 体重(Kg) | BSA(m<sup>2</sup>) |
人 | 70.00 | 1.710 |
小鼠 | 0.02 | 0.007 |
大鼠 | 0.15 | 0.025 |
狗 | 8.00 | 0.448 |
根据这个方程,与在大鼠中0.001-1mg/Kg相当的人的量是0.16-64μg/Kg;即体重大约70Kg的人的绝对剂量为大约0.011至大约11mg,与换算I中所指示的范围相似。
换算III:
另一个可选的换算方法是通过调整剂量得到与给动物施用后所达到的血浆水平或AUC相同的血浆水平或AUC。例如,根据口服施用IB-MECA后在小鼠中所进行的测量和根据在给健康男性志愿者提供IB-MECA的临床研究中的人中所进行的此类的测量可以推导出在小鼠中1微克/Kg-1,000微克/Kg的剂量相当于大约0.14-140微克/Kg的人的剂量,即对于70Kg的个体总剂量为0.01-10mg。
应该注意的是除所述治疗方法之外,在本发明的范围内还包括治疗多发性硬化症的药物组合物,该药物组合物包括有效量的如上文定义的A3RAg和药学上可接受的载体;以及所述A3RAg用于制备用于给患有多发性硬化症和需要神经痛防护治疗的受治疗者施用的药物组合物的用途。可以理解,在药物组合物中有效量取决于预定的治疗方案和需要的治疗剂量。例如,剂量是每天1mg,需要的施用方案是每天一次,则在药物组合物中活性剂的量将是1mg。如果打算将该日剂量以每天2次施用,则在药物组合物中活性剂的量将是0.5mg。
现在在以下根据本发明所进行的试验的描述中将对本发明进行举例说明。应该理解这些实施例是旨在说明而不是限制。显然根据上文教导这些实施例的许多修改和变化是可能的。因此,应该理解在附加的权利要求的范围内除了本文以下所具体描述的方法外本发明还可以以无数种可能的方法实施。
附图简述
为了理解本发明以及明白实际如何实施,现在将仅通过非限制性的实施例,比照附图,对优选的实施方案进行描述,其中:
图1是表示患有EAE的大鼠临床症状作为时间函数的曲线图,用A3RAgIB-MECA(CF101)进行治疗(□)或没有进行治疗(◆)。
本发明详述
实施例I
材料和方法
IB-MECA,由Albany Molecular Research,Albany,New York,USAon beha lf of Can-Fite BioPharma,Ltd.,Israel在临床优良生产实践(cGMP)条件下作为临床级别的材料来制备(该材料命名为CF101)。制备在DMSO中的10μM储备液,用RPMI介质进一步稀释。
诱发实验性自身免疫性脑脊髓炎(EAE)
通过在雌性Lewis大鼠(8周龄)尾部的基部给每只大鼠皮内注射如下组成的乳剂来诱发EAE:由豚鼠得到的100μg髓磷脂碱性蛋白(MBP)(M2295;Sigma),0.1ml完全弗氏佐剂(CFA;F5506,Sigma),和0.2mg结核分支杆菌(Mycobacterium tuberculosis)H37 Ra(M.tuberculosis,3114,Difco)。将乳液两等份注射到大鼠每个后肢的内侧足垫(medial footpad)中。在疾病诱发后第7天开始施用CF101处理的PBS溶液(10μg/kg,PO,BID(一天两次))。对照接受PBS。
将发生临床EAE症状的大鼠分为以下几类:0,没有神经病学症状;1,尾紧张丧失和全尾麻痹;2,后肢无力;3,后肢麻痹;4,四肢麻痹;5,临近死亡
结果
在免疫后的10天内免疫大鼠发生急性单相EAE,持续5天。值得注意的是与对照组相比在CF101治疗组中临床得分非常低。CF101组和对照组之间的最大临床得分差异显著,使用Student’s t检验P<0.01,在治疗组中疾病的严重程度显著减轻。
Claims (3)
1. A3腺苷受体激动剂(A3RAg)用于制备用于给患有多发性硬化症和需要神经痛防护治疗的受治疗者施用的药物组合物的用途,
其中所述A3RAg是在通式(I)范围内的化合物:
其中,
-R1表示烷基,羟基烷基,羧基烷基或氰基烷基或以下通式(II)的基团:
其中:
-Y表示氧、硫或CH2;
-X1表示H、烷基、RaRbNC(=O)-或HORc-,其中
-Ra和Rb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、和环烷基或其相互连接形成包含二至五个碳原子的杂环,和
-Rc选自烷基、氨基、卤代烷基、氨基烷基、BOC-氨基烷基、和环烷基;
-X2是H、羟基、烷基氨基、烷基酰氨基或羟基烷基;
-X3和X4独立表示氢、羟基、氨基、酰氨基、叠氮基、卤素、烷基、烷氧基、羧基、次氮基、硝基、三氟基、芳基、烷芳基、硫基、硫代酯、硫醚、-OCOPh、-OC(=S)OPh或X3和X4是与>C=S连接形成5元环的氧、或X2和X3形成式(III)的环:
其中R′和R″独立地表示烷基;
-R2选自氢、卤素、烷基醚、氨基、酰肼基、烷基氨基、烷氧基、硫代烷氧基、吡啶基硫基、链烯基;炔基、硫基、和烷基硫基;和
-R3是式-NR4R5的基团,其中
-R4是氢原子或选自烷基、取代的烷基或芳基-NH-C(Z)-的基团,Z是O,S,或NRa,Ra具有上文的含义;其中R4是氢时,
-R5选自在一个或多个位置用选自烷基、氨基、卤素、卤代烷基、硝基、羟基、乙酰氨基、烷氧基、和磺酸或其盐的取代基未取代或取代的R-和S-1-苯基乙基、苯甲基、苯乙基、或酰基苯胺基;苯并二噁烷甲基、fururyl、L-丙基丙氨酰-氨基苯甲基、β-丙氨酰氨基-苯甲基、T-BOC-β-丙氨酰氨基苯甲基、苯基氨基、氨基甲酰基、苯氧基或环烷基;或R5是下式的基团:
或当R4是烷基或芳基-NH-C(Z)-时,R5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表示氧、硫或胺;或以上化合物生理上可接受的盐。
2. 根据权利要求1的用途,其中所述药物组合物用于口服施用。
3. 权利要求1的用途,其中所述A 3RAg选自N6-2-(4-氨基苯基)乙基腺苷(APNEA),N6-(4-氨基-3-碘代苯甲基)腺苷-5′-(N-甲基糖醛酰胺)(AB-MECA),N6-(3-碘代苯甲基)-腺苷-5′-N-甲基糖醛酰胺(IB-MECA)以及2-氯代-N6-(3-碘代苯甲基)-腺苷-5′-N-甲基糖醛酰胺(C1-IB-MECA)。
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