CN103339144A - 半胱天冬酶-2抑制剂 - Google Patents
半胱天冬酶-2抑制剂 Download PDFInfo
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Abstract
本发明涉及新的化合物、药物组合物及其用途,其抑制促凋亡的半胱天冬酶-2,以预防和/或治疗其中涉及半胱天冬酶-2活性的疾病和损伤,特别是新生儿大脑缺血。
Description
发明领域
本发明是在医药生物学和化学的领域中,并且涉及新的化合物、药物组合物及其用途,其抑制促凋亡的(pro-apoptotic)半胱天冬酶-2,以预防和/或治疗其中涉及半胱天冬酶-2活性的疾病和损伤。
发明背景
在胚胎发生过程中出现了神经元细胞死亡,以除去过多的神经元来确保适当的突触前和突触后连接并且使得可以形成功能性的成熟大脑。除了涉及正常老化的有丝分裂后死亡,环境或遗传突变因素在急性损伤(例如,缺氧-缺血、中风、脊髓损伤、外伤)或慢性神经退行性疾病过程中也可以诱使成年人中的神经元死亡。与这些疾病相关的细胞死亡可能通过三种截然不同的机制发生,呈现出坏死、自体吞噬或凋亡的形态学和生物化学特征。生理和病理神经元死亡常常与有缺陷的凋亡调控有关,导致哺乳动物细胞中的这种活性细胞自杀机制的信号传输途径可以分成半胱氨酰基天冬氨酸盐-特异性蛋白酶(半胱天冬酶)-依赖性途径vs.半胱天冬酶-非依赖性途径。
神经元凋亡是可以分成连续阶段的活性细胞自杀机制,所述连续阶段包括启动、决定、执行和降解。这个事件级联通过特定机制的激活来驱动,所述机制涉及半胱氨酸-依赖性天冬氨酸盐-特异性蛋白酶(半胱天冬酶)和可以作为决定性(或放大器)调控细胞器的线粒体的激活。实际上,线粒体改变包括线粒体内膜电化学梯度的丢失和致凋亡(apoptogenic)因子(如,细胞色素c Smac/Diablo和凋亡诱导因子)的释放。一旦从线粒体释放出来,这些效应子引发半胱天冬酶-依赖性和/或半胱天冬酶-非依赖性细胞质和核分解。因此,线粒体因子结合半胱天冬酶引起凋亡的降解阶段,在吞噬作用前导致细胞收缩、核浓缩、凋亡体喷射和“吃掉我”信号的出现,如磷脂酰-丝氨酸移动至质膜的外部小叶。
迄今为止,在人体中已经鉴定出几种半胱天冬酶。特别地,存在两种类型的凋亡半胱天冬酶:启动子(顶端)半胱天冬酶和效应子(行刑者)半胱天冬酶。启动子半胱天冬酶(例如,半胱天冬酶-2、半胱天冬酶-8、半胱天冬酶-9、半胱天冬酶-10)分裂效应子半胱天冬酶的无活性前形式(pro-form),由此将其激活。效应子半胱天冬酶(例如,半胱天冬酶-2、半胱天冬酶-6、半胱天冬酶-7)随后分裂细胞内的其他蛋白底物,以引发凋亡过程。
现有技术中已经公开了几种半胱天冬酶抑制剂。WO2004/103389、WO2005/105829和WO2006/056487中已经报道了能够抑制半胱天冬酶-2活性的化合物。
特别地,五肽5-(2,6-二氟-苯氧基)-3(R,S)-{2(S)-[2(S)-(3-甲氧基羰基-2(S)-{3-甲基-2(S)-[(喹啉-2-羰基)-氨基]丁酰基氨基}-丙酰基氨基)-3-甲基-丁酰基氨基]-丙酰基氨基}-4-氧戊酸甲酯是选择性的半胱天冬酶-2抑制剂,公开于WO2005/105829中,目前正研发用于治疗新生儿脑损伤。
该化合物具有以下记录的通式:
现有技术中还引用为喹啉-2-羰基-(S)-Val-(S)-Asp(OMe)-(S)-Val-(S)-Ala-(R,S)-Asp(OMe)-CH2OC6H3(2,6-F2)或TRP601。
然而,对具有提高的特性的半胱天冬酶-2抑制剂仍然存在需求,特别是就药物动力学和ADME(吸附、分配、代谢和排泄)特性而言。
特别地,提供更有效的半胱天冬酶-2抑制剂用于治疗新生儿大脑缺血将是非常有利的,新生儿大脑缺血是早产儿神经发育损伤的主要诱因并且仍然是主要的未满足的医学需求。
发明概述
本发明涉及通式(I)的半胱天冬酶-2抑制剂
其中:
n是0或1;
A表示N、N(H)、O、S或N-O(即,N-氧化物)
分别地,当A是O或S时,与基团A相邻的…可以是单键,或当A是N(H)或N时,与基团A相邻的…可以是单或双键;
X,彼此相同或不同,独立地选自卤素原子,优选氟;
X1表示H或卤素原子,和
R1,彼此相同或不同,独立地选自H和直链或支链(C1-C4)烷基,优选选自H、甲基和乙基。
在第二个方面中,本发明提供了包含作为活性成分的通式(I)的化合物和任选一种或多种药物学上可接受赋形剂的药物组合物。
在第三个方面中,本发明提供了用作药物的通式(I)的化合物。
在第四个方面中,本发明提供了用于预防或治疗其中涉及半胱天冬酶-2活性的疾病(如,新生儿大脑损伤)的通式(I)的化合物。
在第五个方面中,本发明提供了通式(I)的化合物在制备用于预防或治疗其中涉及半胱天冬酶-2活性的疾病(如,新生儿大脑损伤)的药物中的用途。
在第六个方面中,本发明提供了用于预防或治疗其中涉及半胱天冬酶-2活性的疾病(如,新生儿大脑损伤)的方法,所述方法包括给药治疗有效量的通式(I)的化合物。
定义
除非另外限定,本文中所用的所有技术和科学术语具有本主题所属领域的技术人员通常理解的相同意思。
术语“卤素原子”包括氟、氯、溴和碘。
表述“直链或支链(C1-C4)烷基)”指的是其中组成的碳原子的数量在1至4个范围内的直链或支链烷基。特定的烷基实例是甲基、乙基、n-丙基、异丙基和t-丁基。
对于“剂量”,意思是待给药的药物的单位含量。
“用于治疗特定疾病的化合物的有效量”是足以改善,或在一些方式中,减轻疾病相关症状的含量。
术语“高水平的化学纯度”指的是其中如通过标准分析方法(如,薄层色谱(TLC)或高性能液相色谱(HPLC))测定的易检测杂质的总量低于5%的化合物,有利地低于2.5%,优选低于1.0,更优选低于0.5%w/w。
术语“预防”意思是用于降低疾病发作风险的方法。
术语“治疗”意思是用于获得有益或所需结果(包括临床结果)的方法。有益或所需临床结果可以包括,但不限于,减轻或改善一个或多个症状或病症、降低疾病的程度、稳定(即没有恶化)病况、预防疾病扩散、延迟或减缓疾病进展、改善或缓和病况以及好转(不管是部分的还是全部的),不管是可检测的或是不可检测的。术语还可以表示与如果没有接受治疗的预期存活相比延长的存活。
附图简述
图-TRP701vs.其他化合物的体外活性。
发明详述
本发明涉及通式(I)的半胱天冬酶-2抑制剂
当A是N并且…是双键时,本发明还包括喹啉环上相应的N-氧化物。
在本发明的优选实施方案中,A是N并且…是双键,因此形成喹啉环。
更优选,半胱天冬酶-2抑制剂是通式(II)的化合物,其中n=1
其中X、X1和R1中的每一个具有以上定义的含义。
此外,本发明包括其药物学上可接受的盐和/或溶剂化物。
药物学上可接受的盐包括其中存在酸性官能团时与合适的碱形成例如钠盐、钾盐、钙盐、镁盐、铵盐和胆碱盐的那些。
当A是N并且…是双键时,药物学上可接受的盐还包括通过将喹啉环的氮用作碱与强无机酸或有机酸形成例如盐酸盐和三氟甲烷磺酸盐的那些。
通式(I)的化合物是氨基酸序列缬氨酰-天冬氨酰-缬氨酰-丙氨酰-天冬氨酰的衍生物,并且含有不对称中心,所述不对称中心具有对应于L的绝对构型R或对应于D系列的S构型。
本发明包括光学立体异构体及其混合物。
优选,氨基酸残基缬氨酰和丙氨酰的不对称中心具有绝对构型(S),而天冬氨酰残基可以是(S)或(R,S)。
通式(II)的化合物的优选基团是其中R1是H,每个X是F,并且X1是H。
因此,在本发明的一个优选实施方案中,半胱天冬酶-2抑制剂是化合物2-喹啉羰基-(S)-缬氨酰-(S)-天冬氨酰-(S)-缬氨酰-(S)-丙氨酰基-(R,S)-天冬氨酰2,3,5,6-四氟苯酯。
通式(II)的化合物的另一个优选基团是其中R1是甲基,每个X是F,并且X1是H。
因此,在本发明的一个优选实施方案中,半胱天冬酶-2抑制剂是化合物5-(2,3,5,6-四氟-苯氧基)-3(R,S)-{2(S)-[2(S)-(3-甲氧基羰基-2(S)-{3-甲基-2(S)-[(喹啉-2-羰基)-氨基]-丁酰基氨基}-丙酰基氨基)-3-甲基-丁酰基氨基]-丙酰基氨基}-4-氧代-戊酸甲酯,下文中也用内部代码TRP701来引述。
所述化合物还可以称为2-喹啉羰基-(S)-缬氨酰-(S)-天冬氨酰(甲酯)-(S)-缬氨酰-(S)-丙氨酰-(R,S)-天冬氨酰(甲酯)2,3,5,6-四氟苯酯或喹啉-2-羰基-(S)-Val-(S)-Asp(OMe)-(S)-Val-(S)-Ala-(R,S)-Asp(OMe)-CH2OC6H(2,3,5,6-F4)。
通式(II)的化合物的另一个优选基团是其中R1是乙基,每个X是F,并且X1是H。
因此,在本发明的一个优选实施方案中,半胱天冬酶-2抑制剂是化合物2-喹啉羰基-(S)-缬氨酰-(S)-天冬氨酰(乙酯)-(S)-缬氨酰-(S)-丙氨酰-(R,S)-天冬氨酰(乙酯)2,3,5,6-四氟苯酯。
除非另外指出,本发明包括所有那些其中带有基团A的环在任何合适的自由位置,通过酰氨基被所述分子的残余部分取代的化合物,如通式(I)中所示。
本发明的化合物,是非常亲脂性的,可以容易地穿过血脑屏障并且扩散至大脑中。此外,末端苯氧基基团上更多卤素原子(特别是氟)的添加使得所得到的化合物与较少卤素原子的化合物(如TRP601)相比,具有更快速的作用发作。没有受到理论束缚,推测芳香环上的补充卤素原子甚至可以增强相关化合物的电子脱离原位,这随后使其更易于与半胱天冬酶-2的袋子中的活性位点的活性硫醇(SH)基团快速地相互作用。
可以通过已知方法来制备通式(I)的化合物。流程图1、2和3中记录了可以使用的一些方法,其中A、X、X1和R1具有以上所述的含义。
所用的条件和反应物公开于WO2005/105829中,按引用将其关于合成的教导并入本文中。
然而,所述的合成途径不应当看作是限制用于制备本发明化合物的合成方法的范围。
流程图涉及通式(I)的化合物的制备,其中n=1并且…是双键,但它们也可以用于制备其中n=0并且…是单键的化合物,相应地使用合适的中间体。
起始材料和反应物是已知的,或如果本身不可购得,可以根据已知的方法容易地制备。
有利地,以高水平的化学纯度来使用通式(I)的化合物,用于制备药物组合物,用于以任何便利的方式来给药。
可以通过主治医生来容易地确定本发明化合物的合适剂量,并且将取决于病人的类型、年龄、疾病性质和药物传送方式。约0.01mg至约5mg/kg,优选约0.1至3mg/kg,更优选约0.5至约2mg/kg体重数量级的剂量是有用的。
可以通过将合适剂量的通式(I)的化合物与一种或多种药物学上可接受的赋形剂混合来制备药物组合物。根据待治疗的医学疾病或病症的性质和病人的类型,可以将药物组合物配制成通过任何合适途径来传送,包括口服、静脉内、非肠道、吸入、鼻内、局部、皮下、肌内、直肠、腹膜内、脑室内、海马内或其他大脑内传送、用于机械传送的装置(如浸渍了本发明化合物的)的大脑内植入。合适的剂型包括本领域技术人员已知的所有那些,如片剂、胶囊、粉剂、持续释放制剂、膏剂、凝胶、霜剂、栓剂、滴眼液、经皮贴剂、糖浆、溶液、悬浮液、气雾剂、用于喷雾器的溶液、鼻喷雾等。
合适的已知赋形剂,包括载体、稀释剂、润湿剂、乳化剂、粘合剂、涂层、填充剂、助流剂、润滑剂、崩解剂、防腐剂、表面活性剂、pH缓冲物质等。在Handbook of Pharmaceutical Excipients(药物赋形剂手册),第5版,(2006),Rowe等编辑,Pharmaceutical Press中提供了赋形剂实例。
在优选的实施方案中,将组合物配制成用于通过静脉内、皮下、腹膜内或大脑内途径来传送。
在本发明的一些实施方案中,组合物可以配制成脂质体溶液或微悬浮液的形式。在其他实施方案中,可以配制成水溶液,任选pH-缓冲的水溶液的形式。
通式(I)的化合物在其中应当溶解的溶剂可以仅由水组成,或由水和与水混溶的助溶剂的混合物组成,所述助溶剂选自乙醇、丙二醇、聚乙二醇、聚丙二醇和甘油,或其混合物。
在优选的实施方案中,组合物可以配制成包含通式(II)的化合物的水溶液形式,任选pH缓冲的,其中R1是H,每个X是F,并且X1是H,或其盐,剂量为0.02至0.25mg/kg,更优选0.05至0.2mg/kg。
如果需要,组合物还可以包含一种或多种其他治疗剂,优选新生儿疾病治疗中常用的那些。
通式(I)的化合物可以用于预防性目的或用于多种涉及半胱天冬酶-2活性的疾病的治疗。
例如,所述化合物可以有利地用于预防、降低和治疗特征在于细胞死亡的病况,特别是缺氧-缺血(H-I)大脑损伤和中风-样状况大脑损伤:例如,完全的或病灶性的、瞬时的或长久性的、最初在大脑或心脏水平的成人或新生儿的H-I(伴有或未伴有缺氧/低血糖的缺血),伴有或未伴有再灌注,或MCAO(中脑动脉阻塞)。
优选,本发明的化合物用于治疗新生儿大脑损伤,包括围产期动脉中风(PAS)、围产期缺氧-缺血脑病(HIE)和早产儿中的脑室周围白质软化(leucomalacia)(白质损伤),更优选用于围产期缺氧-缺血脑病的治疗。
本发明的化合物还可以用于:
-预防和/或治疗慢性退行性疾病过程中的凋亡,例如,神经退行性疾病,包括阿尔茨海默氏病、亨廷顿氏病、帕金森病、多发性硬化、肌萎缩性脊髓侧索硬化症、脊髓延髓萎缩症、朊病毒疾病、痴呆,或
-预防和/或治疗视网膜周细胞凋亡、视网膜神经元凋亡青光眼、由局部缺血引起的视网膜损伤、糖尿病性视网膜病,或-预防和/或治疗癫痫症,或
-预防和/或治疗脊髓损伤过程中的凋亡,或预防和/或治疗由外伤性大脑损伤引起的凋亡、视网膜缺血或
-预防和/或治疗病灶性大脑缺血的病况过程中的凋亡或-提供大脑保护作用,或
-预防和/或治疗与自体免疫疾病和移植排斥相关的细胞毒性T细胞和自然杀伤细胞-介导的凋亡,或
-预防和/或治疗心脏细胞的细胞死亡,包括心力衰竭、心肌病、心脏的病毒感染或细菌感染、心肌缺血、心肌梗死和心肌缺血、冠状动脉旁路移植,或
-预防和/或治疗线粒体药物毒性,例如,作为化疗或HIV治疗的结果,或
-预防和/或治疗病毒感染或细菌感染过程中的细胞死亡,或
-预防和/或治疗炎症或炎性疾病、炎性肠病;脓毒症和脓毒性休克,或
-预防滤泡至卵母细胞阶段、卵母细胞至成熟卵阶段和精子(例如,冷冻和移植卵巢组织、人工受精的方法)的细胞死亡,或
-保持女性和男性在化疗后的生育力,或
-保持雌性和雄性动物的生育力,或预防和/或治疗黄斑变性和青光眼,或
-预防和/或治疗急性肝炎、慢性活动性肝炎、乙肝和丙肝,或
-预防和/或治疗脱发,并且所述脱发是由于男性型脱发、辐射、化疗或情绪压力引起的,或
-治疗或缓解皮肤伤害(由于暴露于高水平的辐射、热、燃烧、化学品、阳光和自体免疫疾病引起的),或
-预防骨髓发育异常综合症(MDS)中的骨髓细胞的细胞死亡,或-预防和/或治疗胰腺炎,或
-预防和/或治疗呼吸道综合症,或
-预防和/或治疗骨关节炎、类风湿性关节炎、牛皮癣、肾小球性肾炎、动脉粥样硬化和移植对宿主疾病,或
-预防和/或治疗与凋亡增加相关的病况。
通过以下实施例进一步说明了本发明。
实施例
实施例1-体外活性
根据以下实验方案,评价了2-喹啉羰基-(S)-缬氨酰-(S)-天冬氨酰(甲酯)-(S)-缬氨酰-(S)-丙氨酰-(R,S)-天冬氨酰(甲酯)2,3,5,6-四氟苯酯(TRP701)与其他化合物比较的体外半胱天冬酶-2抑制活性。
用最终100μl最终试验缓冲液(50mM HEPES,pH7.4,100mM NaCl,0.1%CHAPS,10mM DTT,1mM EDTA,10%甘油)中的抑制剂(0.001-2μM)将人重组半胱天冬酶-2(25-50U;BIOMOL,Plymouth,宾西法尼亚,USA)预培养30min,然后与200μM荧光半胱天冬酶底物(BIOMOL)Ac-VDVAD-AMC混合。使用稳态荧光方法,从剂量应答S形曲线测定了对应于抑制50%半胱天冬酶活性的浓度的IC50值。通过监控在405nm处激发时510nm处的发射,在荧光微平板阅读器上在37℃下2h后,测量了通过人重组半胱天冬酶-2对基于AMC的底物的分裂。
用于比较目的的化合物是:
TRP601(喹啉-2-羰基-(S)-Val-(S)-Asp(OMe)-(S)-Val-(S)-Ala-(R,S)-Asp(OMe)-CH2OC6H3(2,6-F2)),用编码MZ77027来识别;
rac-TRP601,即,外消旋TRP601,用编码BS03140来识别;
M3,其是化合物2-喹啉羰基-S-缬氨酸,结构上与TRP601相关的无活性化合物;和
TRP600(喹啉-2-羰基-(S)-Val-(S)-Asp(OMe)-(S)-Val-(S)-Ala-(R,S)-Ala((R,S)-CH2OC6H3(2,6-F2)),另一种结构上与TRP601相关的无活性化合物。
图中记录了剂量应答S形曲线。曲线是三次独立运行的平均。
TRP701显示出是选择性的半胱天冬酶-2抑制剂。还显示出能够抑制半胱天冬酶-2活性,具有与TRP601相似的IC50,即,大约60-90nM。
实施例2-对体内半胱天冬酶-2动力学的影响和病理状况时的大脑组织保护
通过便利的动物模型(即,其中半胱天冬酶-2在早期是有活性的)评价了半胱天冬酶-2的活化动力学以及基于组织学参数的功效。这样的模型可以比较2-喹啉羰基-(S)-缬氨酰-(S)-天冬氨酰(甲酯)-(S)-缬氨酰-(S)-丙氨酰-(R,S)-天冬氨酰(甲酯)2,3,4,5,6-五氟苯酯(TRP701)vs.TRP601的半胱天冬酶-2抑制功效和保护性作用。
这种新生儿中风(大脑缺血再灌注)模型引起同侧半影进展并且在48h时导致皮层损伤(梗塞)。这随后产生空腔。这个实验模型呈现出如临床综合症中所示的真实再灌注步骤,并且就大脑成熟和血脑屏障而言,与足月的人新生儿相关。损伤模式与出生时的完全足月的婴儿或在出生后数天/数月时发生的非常相似。
在7天大的大鼠幼仔(Wistar株系)中进行实验模型。按照之前所述的(Renolleau S等,Stroke.1998年7月;29(7):1454-60),在两种性别的P7Wistar大鼠中诱发了单侧短暂性病灶缺血。用水合氯醛(i.p.,350mg/kg)或气体麻醉将七天大的Wistar大鼠(Janvier,LeGenest-St-Isle,法国)麻醉。简而言之,在大脑静脉的下位,将左中脑动脉凝结,然后放置夹子,以闭塞左颈总动脉。50min后,移除夹子,并且通过显微镜验证颈动脉血流回复。在外科手术过程中,将体温保持在37-38℃。再灌注时(对应于缺血发作后1h)根据负责人限定的途径给药测试物质。重要地,载体和测试物质必须在幼仔内随机分配,以考虑和最小化幼仔之间的应答差异。然后将幼仔转移到培养箱(37℃)中直至恢复,然后返回其母鼠。
从再灌注至再灌注后48h将大鼠幼仔杀死,然后取出大脑。在再灌注后逐渐显示出梗塞损伤(苍白区),反映出同侧半球中的大脑损伤过程,并且在有效药物治疗的情况中应当减少。
为了确定半胱天冬酶-2活性动力学和确定中风后半胱天冬酶-2活性水平是否受到TRP701vs.TRP701治疗的改变,对大脑进行了酶试验。重要地,大脑中的半胱天冬酶-2体内抑制使得与大脑组织保护相关。为了继续进行,必须在只对应于受伤组织的缺血半球中测量半胱天冬酶-2活性。为了方便地测量任何的活性差异,就在斩首之后立即取出大鼠幼仔(缺血后24h)大脑。将对侧(CL)和同侧(IL,含有梗塞)半球快速冷冻并保存在-80℃。融化后,将同侧半球快速微切片,以专门获取半影区,根据再灌注后的时间,其或多或少呈现出明显的白色。在对侧对应物中也取出了相应区域,以测量内在半胱天冬酶活性(半胱天冬酶-2,C2;半胱天冬酶-3,C3;半胱天冬酶-9,C9)的极限。然后将每个组织在冰中快速处理。将样品(1-2mm3)置于含有当场补充了蛋白酶抑制剂:PMSF1mM,亮肽素1μg/ml,抑胃肽A1μg/ml,松胞菌素B1μM,木瓜凝乳蛋白酶10μg/ml,抗蛋白酶1μg/ml的800μl缓冲液B(HEPES10mM pH7.4,KCl42mM,MgCl25mM,DTT1mM,CHAPS0.5%,EDTA0.1mM)的玻璃管中。将试管置于冰浴中,并用玻璃Potter进行人工压碎。然后将压碎的组织在-80℃下至少保持24h,然后融化并消除碎片(10min,4℃,2000g)。将100μg上清液在缓冲液A中(特定的半胱天冬酶活性缓冲液)稀释并且在特定的可购得的用于半胱天冬酶-2(C2)、半胱天冬酶-3(C3)和半胱天冬酶-9(C9)的半胱天冬酶底物(50μM)的存在下,在37℃下培养2-3小时。通过分光光度计监控半胱天冬酶活性(λex=380nm;λem=465nm)。
为了确定TRP701的保护作用,在再灌注后48h杀死大鼠幼仔,并且取出大脑。然后将大脑在4%PFA中固定2天。在低温恒温器上切出50μm冠状大脑切片并且收集于明胶覆盖的载玻片上。可以选择从前纹状体至后海马(前囱+3mm至-6.5mm)的十八片切片,以相等的0.5mm间隔获取。使用成像分析仪在甲酚紫染色的切片上测量损伤区域,并且将各自冠状切片之间的距离用来计算梗塞体积和梗塞体积在同侧半球中的%(基于Cavalieri原理)。
Claims (16)
2.根据权利要求1的化合物,其中A是N并且…是双键。
3.根据权利要求2的化合物,是喹啉N-氧化物的形式。
4.根据权利要求1或2的化合物,具有通式(II)
其中R1,X和X1如权利要求1中所限定。
5.根据权利要求1至4任一项的化合物,其中X表示氟原子。
6.根据权利要求5的化合物,其中X1是H。
7.根据权利要求1至6任一项的化合物,其中R1是H。
8.根据权利要求1至6任一项的化合物,其中R1是甲基或乙基。
9.根据权利要求8的化合物,其是5-(2,3,5,6-四氟-苯氧基)-3(R,S)-{2(S)-[2(S)-(3-甲氧基羰基-2(S)-{3-甲基-2(S)-[(喹啉-2-羰基)-氨基]-丁酰基氨基}-丙酰基氨基)-3-甲基-丁酰基氨基]-丙酰基氨基}-4-氧代-戊酸甲酯。
10.一种药物组合物,其包含作为活性成分的如权利要求1至9任一项中限定的通式(I)的化合物,和任选一种或多种药物学上可接受的赋形剂。
11.根据权利要求10的药物组合物,其中活性成分的剂量为0.01mg至5mg/kg体重。
12.如权利要求1至9任一项中限定的通式(I)的化合物,用作药物。
13.如权利要求1至9任一项中限定的通式(I)的化合物,用于预防或治疗其中涉及半胱天冬酶-2活性的疾病。
14.根据权利要求13的化合物,其中疾病源自缺氧-缺血(H-I)大脑损伤。
15.根据权利要求13或14的化合物,其中疾病是新生儿大脑损伤。
16.根据权利要求15的化合物,其中疾病选自围产期动脉中风(PAS)、围产期缺氧-缺血脑病(HIE)和早产儿中的脑室周围白质软化。
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