CN101378739B - 药物的硝基氧基衍生物用于治疗肌肉营养不良症的应用 - Google Patents

药物的硝基氧基衍生物用于治疗肌肉营养不良症的应用 Download PDF

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CN101378739B
CN101378739B CN200780004219.7A CN200780004219A CN101378739B CN 101378739 B CN101378739 B CN 101378739B CN 200780004219 A CN200780004219 A CN 200780004219A CN 101378739 B CN101378739 B CN 101378739B
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muscular dystrophy
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E·克莱门蒂
G·科素
S·布鲁尼利
E·翁吉尼
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Abstract

本发明涉及释放一氧化氮的化合物用于延缓或逆转肌肉营养不良症，例如Duchenne型营养不良症和Becker型营养不良症的用途。

Description

药物的硝基氧基衍生物用于治疗肌肉营养不良症的应用
本发明涉及释放一氧化氮的化合物用于延缓或逆转肌肉营养不良症，例如Duchenne营养不良症和Becker营养不良症的用途。
肌肉营养不良症是由骨骼肌纤维的进行性退化引起的。存在于质膜或内膜中的几种蛋白质中的一种的缺乏都增加在收缩过程中损伤的可能性，并最终导致纤维退化，并伴随严重的带有免疫活性细胞渗入的局部炎症。
肌肉营养不良症包括一组遗传的、渐进的肌肉疾病，临床上通过骨骼肌衰弱的选择性分布加以识别。肌肉营养不良症的最普通的类型是Duchenne营养不良症和Becker营养不良症，每一种都是由肌营养不良蛋白基因变异的遗传性导致的，该基因位于Xp21基因部位。其它的营养不良症包括但不限于肢带肌肉营养不良症、面肩胛肱骨(兰-代二氏)肌肉营养不良症、先天性肌肉营养不良症、强直性肌营养不良症、和Emery-Dreifuss肌肉营养不良症。
在最严重的情形中，例如Duchenne肌肉营养不良症，再生能力已经耗尽，并且骨骼肌渐进地被脂肪和纤维组织所替代。这种情况导致患者表现出进行性的衰弱，并最终由于呼吸和/或心脏衰竭而死亡。
Duchenne肌肉营养不良症的症状差不多都出现在男性中，并大约在3-7岁的年龄开始，大多数患者在10-12岁被迫使用轮椅，许多人在20岁年龄左右由于呼吸并发症而死亡。
在尝试的可能治疗Duchenne肌肉营养不良症的不同的药物中，只有皮质类固醇类药物，例如强的松、泼尼松龙和地夫可特，显示出提供暂时改善的可能性。这种改善主要因降低渐进速度或稳定肌肉力量和功能而产生。皮质类固醇在治疗上还可以导致副作用；因此还没有对它们在标准治疗上的用途形成一致意见。
皮质类固醇，例如强的松，被认为通过阻断免疫细胞的活化和渗透而发挥作用，免疫细胞的活化和渗透是由疾病引起的肌肉纤维损伤形成的。
采用皮质类固醇作为肌肉营养不良症的药物进行长期治疗会引起副作用，例如骨质疏松症、高血压和皮质醇增多综合征、体重增加、白内障、身材矮小症、胃肠道综合征、在使用泼尼松龙情况下的行为改变和在使用地夫可特的情况下的体重增加和白内障。
Bredt D.S.在Proc.Natl.Acad.Sci.USA 95(1998)，14592-14593中报导了由肌肉NO合成酶产生的在结构和功能上与在肌纤维膜上的营养不良症基因相关联的一氧化氮(NO)，通过血管扩张调节，并因此在运动期间提供氧，增加肌原纤维中的葡萄糖摄取及调节与细胞能量代谢有关的酶的活性，来参与骨骼肌的生理学发展和功能。
EP 759899描述了非甾体抗炎药物NSAIDs的硝基氧基衍生物。该文献中报导的药理学数据显示了这些化合物与相应的母体药物相比，具有良好的抗炎、止痛和抗凝血活性以及增加的胃肠耐受性。该文献没有报导这些化合物具有治疗肌肉退化性疾病的活性。
WO 2004/105754描述了他汀类的硝基衍生物，其具有较强的抗炎、抗凝血和抗血小板活性。该文献报导了他汀类的硝基衍生物能够用于治疗或预防心血管疾病和外周血管疾病以及与内皮机能有关的所有疾病，例如糖尿病患者的血管并发症和动脉粥样硬化。该文献同样没有报导这些化合物具有治疗肌肉退化性疾病的活性。
WO 00/53191披露了一氧化氮(NO)、NO供体、NO活性抑制剂或NO生成调节剂在治疗肌肉疾病，包括Duchenne营养不良症、Becker营养不良症、肢带肌肉营养不良症、面肩胛肱骨(兰-代二氏)肌肉营养不良症、先天性肌肉营养不良症、强直性肌营养不良症和Emery-Dreifuss肌肉营养不良症方面的用途。
该文献特别披露了关于用地夫可特、地夫可特+L-NAME(一种NOS酶抑制剂)或地夫可特+L-精氨酸(一种NO供体)处理的mdx营养不良症小鼠的研究结果。在实验中，从处理的动物中收集胫骨前肌的肌肉组织和膈膜，并评估中央核化指标(CNI)，该指标用于测量肌肉损伤的有用的指标。结果显示向地夫可特添加NO供体没有改善mdx小鼠的肌肉状况，并且L-NAME只增加了地夫可特对膈膜的有益效果。作者的结论是实验结果表明L-NAME或其它NOS抑制剂可以用于在施用中改善类固醇的效果。
因此，有鉴定能够减缓肌肉纤维损伤和延迟患有肌肉营养不良症患者的肌力丧失开始，但比普通治疗引起更低程度的骨骼肌退化萎缩的治疗剂的需要。
特别令人惊奇和意想不到的是，发现可释放一氧化氮的通式M-X-Y-ONO2的化合物，其中M是NSAID或他汀类治疗剂的残基，能够有效地延缓或逆转(治疗)肌肉营养不良症。而且，它们还具有诱发更少副作用的优点，它们能够很好地被患者耐受并因此可以被用于长期的治疗。
本发明的一个目的是式(Ia)的释放一氧化氮的药物或其对映异构体或非对映异构体用于治疗肌肉营养不良症的应用，
M-X-Y-ONO2
(Ia)
其中在式(Ia)中，M、X和Y具有如下含义：
M是选自以下结构的残基：
Figure G2007800042197D00031
其中RA是氢原子或-C(O)CH3，
Figure G2007800042197D00051
Figure G2007800042197D00061
Figure G2007800042197D00071
X是-O-、-S-或-NR1-，其中R1是H或者是直链或支链的C1-C6烷基；
Y是具有如下定义的二价基团：
a)
-直链或支链的C1-C20亚烷基，优选C1-C10亚烷基，其任选地被一个或多个取代基取代，所述取代基选自：卤素原子、羟基、-ONO2或T，其中T是-OC(O)(C1-C10烷基)-ONO2或-O(C1-C10烷基)-ONO2；更优选Y是C1-C10亚烷基；
-C5-C7的亚环烷基，其任选地被直链或支链的C1-C10烷基，优选是CH3取代；
Figure G2007800042197D00081
其中n是0-20的整数，优选n是0-5的整数，更优选n是0；
n1是1-20的整数，优选n1是1-5的整数，更优选n1是1；
条件是：当Y选自b)或c)下提及的二价基团时，式(I)的-ONO2基团被连接在-(CH2)n 1-上；
Figure G2007800042197D00082
其中X1＝-OCO-或-COO-和R2是H或CH3；
na是1-20的整数；优选n是1-5的整数；
n2是0-2的整数；
e)
其中Y1＝-CH2-CH2-(CH2)n 2-；或-CH＝CH-(CH2)n 2-；
X1、na、n2和R2的定义同上；
Figure G2007800042197D00091
其中na和R2的定义同上，R3是H或-COCH3；
条件是：当Y选自如d)-f)下所提及的二价基团时，-式(I)的ONO2被连接在-(CH2)na上；
条件是：当X是-NR1-时，其中R1如上定义，Y不能是f)；
其中X2是-O-或-S-；
n3是1-6的整数，优选是1-4的整数，和R2的定义同上。
本发明的一个优选的具体实施方式包括式(Ib)的释放一氧化氮的药物在治疗肌肉营养不良症中的应用；式(Ib)的化合物公知是2-(乙酰氧基)苯甲酸3-(硝基氧基甲基)苯基酯。
Figure G2007800042197D00101
本发明的另一个优选的具体实施方式包括式(IIIb)的释放一氧化氮的药物或其对映异构体在延缓或反转肌肉营养不良症中的应用；式(IIIb)的化合物公知是2-氟-α-甲基-4[1，1′-联苯基]4-乙酸4-硝基氧基丁基酯。
本发明的另一个优选的具体实施方式包括通式(Ia)的释放一氧化氮的药物在治疗肌肉营养不良症中的应用，其中在式(Ia)中M选自：
X是氧原子，
Y选自：
-直链的C1-C10亚烷基，；
Figure G2007800042197D00121
其中n是0-5的整数；并且
n1是1-5的整数，更优选n1是1。
另一个具体实施方式是释放一氧化氮的药物在治疗肌肉营养不良症中的应用，其中药物选自：
Figure G2007800042197D00122
其为公知的[1S-[1α(βS*，δS*)，2α，6α，8β-(R*)，8aα]]-1，2，6，7，8，8a-六氢-β，δ，6-三羟基-2-甲基-8-(2-甲基-1-氧代丁氧基)-1-萘庚酸4-(硝基氧基)丁基酯或称为普伐他汀4-(硝基氧基)丁基酯；
其为公知的[1S-[1α(βS*，δS*)，2α，6α，8β-(R*)，8aα]]-1，2，6，7，8，8a-六氢-β，δ，6-三羟基-2-甲基-8-(2-甲基-1-氧代丁氧基)-1-萘庚酸4-(硝基氧基甲基)苯甲基酯或称为普伐他汀4-(硝基氧基甲基)苯甲基酯；
Figure G2007800042197D00131
其为公知的(βR，δR)-2(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸3-(硝基氧基)丁基酯或称为阿伐他汀3-(硝基氧基)丁基酯；
其为公知的(βR，δR)-2(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸3-(硝基氧基甲基)苯甲基酯或称为阿伐他汀3-(硝基氧基甲基)苯甲基酯。
给药的剂量依据例如年龄、体重、症状、需要的治疗效果、给药途径和治疗持续时间而决定。对于成年人，口服给药通常每人每次1mg至1000mg，每天若干次，和非胃肠道给药(优选静脉给药)通常1mg至100mg，每天若干次，或在1-24小时内持续给药。
如上所述，所用的剂量依据于各种情况。因此，会有剂量低于或高于上述特定的范围的情况。
本发明的化合物可以以例如固体组合物、液体组合物或其它供口服给药、注射、涂敷或栓剂等非胃肠道给药的形式给药。
式(Ia)的释放一氧化氮的药物，其中M选自式(I)-(XXIV)的残基并且X如上定义，其常规合成被描述在EP 7559899中。
式(Ib)的2-(乙酰氧基)苯甲酸3-(硝基氧基甲基)苯甲基酯的合成被描述在EP 1194397中。
式(Ia)的释放一氧化氮的化合物，其中M选自式(XXXIV)-(XXXIX)的残基，其常规合成以及普伐他汀4-(硝基氧基)丁基酯的合成被描述在WO2004/105754中。
实施例1
肌肉营养不良症模型(α-肌聚糖不足的小鼠)。
对照动物模型：参照Duclos F.等人的J Cell Biol.1998Sep 21；142(6)：1461-71
实验化合物是：
-式(Ib)的2-乙酰氧基苯甲酸3-(硝基氧基甲基)苯基酯；
-式(XXXVb)的普伐他汀4-(硝基氧基)丁基酯；
-式(IIIb)的2-氟-α-甲基-4[1，1′-联苯基]4-乙酸4-硝基氧基丁基酯；
-泼尼松龙作为皮质类固醇药物参照。
将四组无α-肌聚糖(SG)的C57BL/6小鼠用2-乙酰氧基苯甲酸3-(硝基氧基甲基)苯甲酸酯(化合物Ib)(100mg/kg)、普伐他汀4-(硝基氧基)丁基酯(化合物XXXVb)(12mg/kg)，2-氟-α-甲基-4[1，1′-联苯基]4-乙酸4-硝基氧基丁基酯(化合物IIIb)(30mg/kg)、泼尼松龙(3mg/kg)或载剂处理，每天通过食物给予。
在标注的时间点(范围从20-80天)上通过自由转轮检测法测定骨骼肌的功能。24小时后处死动物，对组织进行分离并从组织学上分析其特征。在使用AzanMallory技术染色后对渗入进行评估；在苏木紫染色区域测定坏死纤维；应用可商购的试剂盒对转轮检测前24小时取得的血液样本测定肌酸激酶(SampaolesiM.，et al Science 301，487-492，2003)。数据被报告在表1中。
自由转轮运动：应用自主的转轮运动作为运动范例，以避免任何由于强迫的单调运动的应激而会影响生理变化。将小鼠在装备了磁性计数器的聚碳酸酯转轮中单独圈养24小时，输出端是一个计速器，允许将每天的转数定量。数据被报告在表2中。
肌酸激酶活性测量：采用肌酸激酶试剂(Sigma)，根据制造商的说明书，对对照和药物处理动物的血清肌酸激酶活性进行定量和动态检测。从2-7个月大的小鼠尾部收集血液，在13,000rpm转速下离心10分钟得到血清，检测前在-80℃下贮存。数据被报告在表1中。
组织学：分离未处理的和药物处理的小鼠的膈膜和胫骨前肌并置于Killik冷冻介质中，快速冷冻并使用恒冷切片机按肌肉纤维横向切成8μm厚的片。切片既可用苏木紫和曙红，也可用Azan Mallory染色，以评估炎症渗入物和坏死纤维的数量(18-10片组织)。数据被报告在表1中。
结果显示测定的化合物(Ib)、(XXXVb)和(IIIb)在降低这些动物局部组织学、功能学和生物化学改变方面有显著的效果。特别地，处理的动物炎症渗入物显著减少，纤维坏死几乎不可察觉(表1)。肌酸激酶的血浆水平、肌肉损伤的标志在处理过的动物中都显著下降；一贯地，它们在自由转轮测试中表现显著地更好(表2)。
总而言之，数据显示本发明的化合物对比泼尼松龙有更好的效果，泼尼松龙是选择用该病理学的药物。
表1
Figure G2007800042197D00151
**P＜0.01；*P＜0.05，相对于对照
表2
Figure G2007800042197D00161
**P＜0.01；*P＜0.05，相对于对照

Claims (3)

1.式(Ia)的释放一氧化氮的化合物或其对映异构体或非对映异构体在制备用于治疗肌肉营养不良症的药物中的应用，
M-X-Y-ONO2
(Ia)
其中在式(Ia)中，M、X和Y具有如下含义：
M是选自以下结构的残基：
Figure FSB0000114722750000011
Figure FSB0000114722750000021
X是-O-；
Y是是直链或支链的C1-C10亚烷基。
2.根据权利要求1所述的应用，其中M是以下残基：
Figure FSB0000114722750000031
3.根据权利要求1所述的应用，其中式(Ia)的化合物是式(IIIb)的2-氟-α-甲基-4[1，1′-联苯基]4-乙酸4-硝基氧基丁基酯
Figure FSB0000114722750000032
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