CN111372921B - 小分子化合物 - Google Patents
小分子化合物 Download PDFInfo
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- CN111372921B CN111372921B CN201880070789.4A CN201880070789A CN111372921B CN 111372921 B CN111372921 B CN 111372921B CN 201880070789 A CN201880070789 A CN 201880070789A CN 111372921 B CN111372921 B CN 111372921B
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Abstract
本发明涉及使用新型化合物6‑氯‑3‑(2,4‑二氯‑5‑甲氧基苯基)‑2‑巯基‑7‑甲氧基喹唑啉‑4(3H)‑酮及其衍生物治疗与线粒体功能障碍相关的癌症以及其它疾病的组合物和方法,所述其它疾病包括但不限于神经退行性疾病、脑损伤和某些非神经性病症。
Description
相关申请的交叉引用
本申请要求于2017年9月13日提交的美国临时专利申请第62/558,323号的优先权,所述申请通过引用整体并入本文中。
发明背景
线粒体是真核细胞中的标志性细胞器,其对于确保许多基本的生理过程(如细胞能量产生、氧化还原平衡、细胞Ca2+浓度缓冲以及承载重要的生物合成途径)是必需的(Wallace 2005)。它们还通过参与细胞凋亡通路来控制细胞命运,所述细胞凋亡通路是在主要疾病病况(如癌症和神经退行性疾病)中关键的通路(Hedskog等人,2012)。细胞内线粒体的形状、体积、数量和分布受到严格控制(Cahill等人,2006)。这些参数严重影响线粒体的功能,特别是在神经肌肉系统中,其中线粒体采用策略性细胞内分布,大概是为了满足高局部能量需求。因此,维持健康的线粒体群体对于细胞和生物体健康是必需的。为了实现这一目的,细胞已经发展了涉及复杂的质量控制系统的机制,以去除受损的线粒体,或更新它们。这些过程的缺陷可导致受损线粒体的积累并最终导致疾病病况(Pickrell和Youle2015)、(Rugarli和Langer 2012)。
线粒体功能障碍可以以多种方式影响细胞功能(Stepien等人,2017)、(Pieczenik和Neustadt 2007)。首先,作为细胞动力装置,线粒体提供ATP的关键来源。线粒体功能障碍将导致细胞能量缺乏和细胞活力维持受损。其次,线粒体拥有参与氧化磷酸化的电子传输链。该过程产生活性氧(ROS),其在碱性条件下可提供一些信号传导功能,但有缺陷的线粒体在电子转移过程中是低效的,导致ROS产生升高,这可引起对所有必需大分子(蛋白质、核酸、脂质等)的损伤。此类氧化损伤与疾病(尤其是那些与年龄相关的疾病)有着广泛的联系(Kauppila等人,2017)。第三,线粒体是维持细胞钙稳态的重要细胞器(Paillusson等人,2016)。它们摄取从细胞内储存库(尤其是ER)释放的钙,或摄取由兴奋产生的钙。功能障碍的线粒体可改变细胞钙稳态并引起诸如ER应激的病况,其与多种疾病病况相关(Malhotra和Kaufman 2011)。此外,线粒体钙对于TCA循环和电子传输链中的某些酶的活性是必需的(Glancy和Balaban 2012)。因此,改变的线粒体钙稳态可导致线粒体能量缺乏。最后,作为细胞生存和细胞死亡的守卫,线粒体调节凋亡性细胞死亡和坏死性细胞死亡(Galluzzi等人,2016)。因此,在最极端的情况下,涉及这些通路的干扰可能触发不合时宜的细胞死亡并引起退行性疾病。相反地,缺乏适当的细胞死亡可导致不适当的组织生长和癌症的发展,其通常以改变的线粒体代谢为特征。
因此不足为奇的是,许多主要的人类疾病与线粒体功能障碍相关,其中许多代表紧急的未满足的医疗需求。这些范围从癌症(Wallace 2012)和神经退行性疾病(如阿尔茨海默氏病、帕金森氏病和ALS)(de Moura等人,2010)、(Lleonart等人,2017)、(Ganguly等人,2017)至脑损伤(如中风、癫痫、神经性疼痛、创伤性脑损伤、脊髓损伤、动脉瘤、蛛网膜下腔出血)(Dawson和Dawson 2017)、(Areti等人,2016)、(Sui等人,2013)、(Zsurka和Kunz2015)、(Cahill等人,2006)、(Hiebert等人,2015)、(Arun等人,2016),以及某些非神经性病症(例如脓毒病、急性肾损伤、心肾综合征、心脏缺血-再灌注损伤、肺动脉高压、慢性阻塞性肺病和血管收缩)(Stepien等人,2017)、(Lesnefsky等人,2017)、(Emma等人,2016)、(Lerner等人,2016)、(Sutendra和Michelakis 2014)、(Ratliff等人,2016)。然而,通过其有缺陷的线粒体导致各种疾病病况的确切机制仍有待阐明,并且仍有待观察是否可开发新的线粒体药物来治疗许多破坏性和普遍性疾病。
发明概述
本文公开了用于治疗或预防与线粒体功能障碍相关的疾病的组合物。所述组合物包括CPT-2008(即,6-氯-3-(2,4-二氯-5-甲氧基苯基)-2-巯基-7-甲氧基喹唑啉-4(3H)-酮),其药学上可接受的盐或其衍生物。
本文还公开了用于预防或治疗与线粒体功能障碍相关的疾病的方法。所述方法包括向有此需要的对象(例如在人或其它哺乳动物中)施用有效量的CPT-2008或含有有效量的CPT-2008或其衍生物的组合物。
本公开的方面包括但不限于所附权利要求和以下示例性实施方案:
1.式I的化合物:
或其药学上可接受的盐。
2.用于治疗与线粒体功能障碍相关的疾病或病况的药物组合物,所述组合物包含实施方案1所述的式I的化合物、其药学上可接受的盐或其衍生物,以及药学上可接受的载体。
3.用于治疗与线粒体功能障碍相关的疾病或病况的方法,所述方法包括给予有此需要的对象有效量的实施方案1所述的化合物或有效量的实施方案2所述的组合物。
4.如实施方案3所述的方法,其中所述有效量是治疗有效量。
5.如实施方案3所述的方法,其中所述有效量是预防有效量。
6.如实施方案3所述的方法,其中所述疾病是癌症。
7.如实施方案6所述的方法,其中所述癌症是T急性淋巴母细胞性白血病(T-ALL)、小细胞肺癌(SCLC)、非小细胞肺癌(NSCL)、成胶质细胞瘤、结肠直肠癌、乳腺癌或卵巢癌。
8.如实施方案3所述的方法,其中所述疾病是神经退行性疾病。
9.如实施方案8所述的方法,其中所述神经退行性疾病是帕金森氏病、阿尔茨海默氏病、肌萎缩性侧索硬化症或亨廷顿氏病。
10.如实施方案3所述的方法,其中所述病况是脑病况。
11.如实施方案10所述的方法,其中所述脑病况是中风、癫痫、神经性疼痛、创伤性脑损伤、脊髓损伤、动脉瘤或蛛网膜下腔出血。
12.如实施方案3所述的方法,其中所述疾病或病况是非神经性病症。
13.如实施方案14所述的方法,其中所述非神经性病症是脓毒病、急性肾损伤、心肾综合征、心脏缺血-再灌注损伤、肺动脉高压、慢性阻塞性肺病或血管收缩。
14.如实施方案3所述的方法,其中所述病况是由线粒体功能障碍引起的人衰老。
尽管公开了多个实施方案,但是本发明的其它实施方案对于本领域的技术人员而言将从以下详细描述中变得显而易见,所述详细描述显示并描述了本发明的说明性实施方案。如将认识到的,本发明能够在各种明显的方面进行修改,所有这些都不脱离本发明的精神和范围。因此,附图和详细描述在本质上被认为是说明性的而不是限制性的。
附图简述
图1显示了化学合成CPT-2008的路径。
图2显示了CPT-2008的化学结构。
图3显示了CPT-2008在Molt-4T-ALL模型中的功效。
图4显示了CPT-2008在Jurkat T细胞白血病模型中的功效。
图5显示了CPT-2008在NCI-H82 SCLC模型中的功效。
图6显示了CPT-2008在U118MG成胶质细胞瘤模型中的功效。
图7显示了CPT-2008在T98G成胶质细胞瘤模型中的功效。
图8显示了CPT-2008在NCI-H446 SCLC模型中的功效。
图9显示了CPT-2008在MCF7乳腺癌模型中的功效。
图10显示了CPT-2008在HCT-116结直肠癌模型中的功效。
图11显示了CPT-2008在A549 NSCLC模型中的功效。
图12显示了CPT-2008在NCI-H1299 NSCLC模型中的功效。
图13显示了CPT-2008在A2780卵巢癌模型中的功效。
图14显示了CPT-2008对人GBM细胞中线粒体钙的影响。将用DMSO媒介物(对照)或用含有CPT-2008的DMSO处理的GBM细胞用Rhod-2AM染色以探测线粒体钙(mito-Ca2+)水平。CPT-2008升高了mito-Ca2+。
图15显示了CPT-2008对人GBM细胞中线粒体ROS的影响。将用DMSO媒介物(对照)或用含有CPT-2008的DMSO处理的GBM细胞用Mito-SOX染色以探测线粒体ROS水平。CPT-2008显著升高了线粒体ROS水平。
图16显示了CPT-2008对GBM细胞中线粒体形态的影响。针对TOM-20对用DMSO(对照)或用含有CPT-2008的DMSO处理的GBM细胞进行免疫染色以揭示线粒体形态。注意,CPT-2008诱导线粒体尺寸减小。
图17显示了CPT-2008对人GBM细胞中线粒体膜电位的影响。将用DMSO媒介物或用含有CPT-2008的DMSO处理的GBM细胞用TMRM染色以探测线粒体膜电位。CPT-2008显著降低线粒体膜电位。
图18显示了CPT-2008抑制人GBM细胞自我更新的作用。对照:用DMSO媒介物处理的细胞;CPT-2008:用20μM CPT-2008处理的细胞。注意,虽然DMSO处理的GBM细胞形成了指示癌症干细胞自我更新的神经球,但CPT-2008处理的细胞丧失这种能力。
图19A显示了用媒介物或依达拉奉治疗的大鼠(上图)和用CPT-2008处理的大鼠(下图)中脑组织梗死的水平。
图19B显示了用依达拉奉或CPT-2008治疗的大鼠的脑组织梗死区。通过Dunnett检验后的单向方差分析,相对于媒介物,*P<0.05,**P<0.01,***P<0.001。
图20显示了在施用CPT-2008后紫杉醇处理的小鼠中的爪缩回阈值(PWT)测量。通过未配对t检验,相对于媒介物组,*p<0.05,**p<0.01。
图21A显示了对斯普拉格-杜勒大鼠口服施用和静脉内施用后,CPT-2008的血浆浓度。
图21B显示了对斯普拉格-杜勒大鼠口服施用和静脉内施用后,CPT-2008的脑浓度。
发明详述
I.发明领域
本发明通常涉及治疗与线粒体功能障碍相关的疾病的组合物和方法。具体地,本发明涉及使用CPT-2008或其衍生物改变线粒体活性氧(ROS)生成、电子传输链活性、线粒体形态或线粒体活性治疗以下疾病的方法:癌症、神经退行性疾病(包括帕金森氏病、阿尔茨海默氏病、ALS、亨廷顿氏病)、脑损伤(包括中风、癫痫、神经性疼痛、创伤性脑损伤、脊髓损伤、动脉瘤、蛛网膜下腔出血)和某些非神经性病症(包括脓毒病、急性肾损伤、心肾综合征、心脏缺血-再灌注损伤、肺动脉高压、慢性阻塞性肺病、血管收缩)。
II.定义
如本文中所使用的,“CPT-2008”是指6-氯-3-(2,4-二氯-5-甲氧基苯基)-2-巯基-7-甲氧基喹唑啉-4(3H)-酮,即具有式C16H11Cl3N2O3S和式I的结构的化合物:
如本文中所使用的,术语“治疗”是指对旨在治愈、改善、稳定或预防疾病、病理学病况或病症的患者进行的医学管理。该术语包括积极治疗,即,特异性针对疾病、病理学病况或病症的改善的治疗,并且还包括因果治疗,即,针对相关疾病、病理学病况或病症的病因的消除的治疗。此外,该术语包括姑息治疗,即,设计用于减轻症状而不是治愈疾病、病理学病况或病症的治疗;预防性治疗,即,涉及最小化或部分或完全抑制相关疾病、病理学病况或病症的发展的治疗;以及支持性治疗,即,用于补充针对相关疾病、病理学病况或病症的改善的另一种特定治疗的治疗。在各个方面,该术语涵盖对对象(包括哺乳动物(例如人))的任何治疗,并且包括:(i)防止疾病在可能易患该疾病但尚未被诊断出患有该疾病的对象中发生;(ii)抑制疾病,即阻止其发展;或(iii)缓解疾病,即引起疾病的消退。在一个方面,对象是哺乳动物(如灵长类动物),并且在另一方面,对象是人。术语“对象”还包括驯养动物(例如猫、狗等)、牲畜(例如牛、马,猪、绵羊、山羊等)和实验室动物(例如小鼠、兔、大鼠、豚鼠、果蝇等)。
如本文中所使用的,术语“预防(prevent/preventing)”是指阻止、避免、消除、预先防止、停止或妨碍一些事情发生,特别是通过提前动作。应当理解,本文中所使用的是减少、抑制或防止,除非另外特别指出,否则也清楚地公开了其它两个单词的使用。
如本文中所使用的,术语“诊断的”意指已经由技术人员(例如医生)进行身体检查,并且发现患有可以通过本文所公开的化合物、组合物或方法诊断或治疗的病况。
如本文中所使用的,短语“被鉴定为需要治疗病症”等是指基于治疗病症的需要选择对象。例如,可以基于技术人员的早期诊断将对象鉴定为需要治疗病症(例如,与阿尔茨海默氏病相关的病症),然后对该病症进行治疗。在一个方面,考虑鉴定可以由与进行诊断的人不同的人来执行。在另一个方面,还考虑给药可以由随后进行给药的人进行。
如本文中所使用的,术语“施用(administering/administration)”是指向对象提供药物制剂的任何方法。此类方法是本领域技术人员熟知的,包括但不限于口服施用、透皮施用、吸入施用、鼻施用、局部施用、阴道内施用、眼部施用、耳内施用、脑内施用、直肠施用、舌下施用、口腔施用和肠胃外施用,其包括可注射的,诸如静脉内施用、动脉内施用、肌内施用和皮下施用。施用可以是连续的或间歇的。在各个方面,制剂可以治疗性地施用;即,施用以治疗现有的疾病或病况。在其它各个方面,制剂可以预防性地施用;即,施用用于预防疾病或病况。
如本文所使用的术语“接触”是指将所公开的化合物与细胞、靶受体或其它生物实体以化合物可直接(即与靶标本身相互作用)或间接(即通过与靶标活性所依赖的另一种分子、辅因子、因子或蛋白质相互作用)影响靶标(例如,受体、转录因子、细胞等)的活性的方式集合在一起。
如本文中所使用的,术语“有效量(effective amount/amount effective)”是指足以实现所期望的结果或对不期望的病况具有影响的量。例如,“治疗有效量”是指足以实现所期望的治疗结果或对不期望的症状具有影响但通常不足以引起不良副作用的量。对于任何特定患者的具体治疗有效剂量水平将取决于多种因素,包括正在治疗的病症和病症的严重程度;所用的具体组合物;患者的年龄、体重、总体健康状况、性别和饮食;给药时间;给药途径;所用的特定化合物的排泄率;治疗的持续时间;与所使用的特定化合物以及医学领域中熟知的类似因素组合或同时使用的药物。例如,以低于实现所期望的治疗效果所需那些剂量的水平开始化合物的剂量并逐渐增加剂量直至实现所期望的效果,这在本领域技术范围内。如果期望,可以将有效的日剂量分成多个剂量用于给药目的。因此,单剂量组合物可以含有这样的量或其约数以构成日剂量。剂量可以在任何禁忌症的情况下由单独的医生调整。剂量可以变化,并且可以以每天一次或多次剂量施用而施用一天或数天。对于给定种类的药物产品的适当剂量,可以在文献中找到指导。在其它各个方面,制剂可以以“预防有效量”施用;也就是说,有效预防疾病或病况的量。
“药学上可接受的赋形剂或载体”是指可以任选地包括在本发明的组合物中并且不会对患者引起显著的不良毒理学作用的赋形剂。“药学上可接受的盐”包括但不限于氨基酸盐、用无机酸制备的盐(如氯化物、硫酸盐、磷酸盐、二磷酸盐、溴化物和硝酸盐,或由前述任一种的相应无机酸形式制备的盐,例如盐酸盐等)、或用有机酸制备的盐(如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、乙基琥珀酸盐、柠檬酸盐、乙酸盐、乳酸盐、甲磺酸盐、苯甲酸盐、抗坏血酸盐、对甲苯磺酸盐、棕榈酸盐、水杨酸盐和硬脂酸盐,以及丙酸酯十二烷基硫酸盐、葡庚糖酸盐和乳糖醛酸盐)。类似地,含有药学上可接受的阳离子的盐包括但不限于钠、钾、钙、铝、锂和铵(包括取代的铵)。
如本文中所使用的,术语“取代的”预期包括有机化合物的所有可允许的取代基。在广义上,可允许的取代基包括有机化合物的无环的和环状的、支链的和无支链的、碳环的和杂环的以及芳香族和非芳香族取代基。对于适当的有机化合物,可允许的取代基可以是一个或多个并且相同或不同的。为了本公开的目的,杂原子(如氮)可以具有氢取代基和/或满足杂原子的化合价的本文所述的有机化合物的任何可允许的取代基。本公开不旨在以任何方式受有机化合物的可允许取代基的限制。此外,术语“取代”或“用........取代”包括隐含的条件,即此类取代符合被取代的原子和取代基的允许的化合价,并且该取代产生稳定的化合物,例如,不自发地经历转化(如,通过重排、环化、消除等)的化合物。还预期,在某些方面,除非明确相反地指示,否则个别取代基还可以任选地被取代(即,进一步被取代或未被取代)。
如本文中所使用的,术语“衍生物”和“类似物”是指具有衍生自母体化合物的结构的结构的化合物(例如,本文所公开的化合物),并且其结构与本文所公开的那些结构充分相似并且基于该相似性,本领域技术人员将预期展现出与所要求保护的化合物相同或相似的活性和效用,或诱导作为前体,与所要求保护的化合物相同或相似的活性和效用。
本文可将范围表示为从“约”一个特定值,和/或至“约”另一个特定值。当表达这样的范围时,另一方面包括从一个特定值和/或至另一个特定值。类似地,当通过使用先行词“约”将值表示为近似值时,将理解,具体值形成另一方面。将进一步理解的是,每个范围的端点相对于另一端点都是重要的,并且独立于另一端点。还应理解,存在本文所公开的许多值,并且除了值本身之外,每个值在本文中还被公开为“约”该特定值。例如,如果公开了值“10”,则还公开了“约10”。还应理解,还公开了两个特定单元之间的每个单元。例如,如果公开了10和15,则还公开了11、12、13和14。
在说明书和最终权利要求书中提及的组合物中特定元素或组分的重量份表示组合物或制品中所述元素或组分与表达重量份的任何其它元素或组分之间的重量关系。因此,在含有2重量份的组分X和5重量份的组分Y的化合物中,X和Y以2:5的重量比存在,并且以这种比率存在,而不管化合物中是否含有另外的组分。
除非特别相反地说明,否则组分的重量百分比(wt.%)是基于其中包括该组分的制剂或组合物的总重量的。
如本文中所使用的,术语“任选的”或“任选地”意指随后所描述的事件或情况可以发生或可以不发生,并且该描述包括其中所述事件或情况发生的情况和它不发生的情况。
III.新药物及其组合物
本文提供了含有CPT-2008以及一种或多种药学上可接受的载体或其它赋形剂的药物组合物。药物组合物可以通过药学和药物递送领域中熟知的任何方法制备。通常,制备组合物的方法包括使活性成分与含有一种或多种辅助成分的载体缔合的步骤。药物组合物通常通过将活性成分与液体载体或细分散的固体载体或两者均匀地和紧密地缔合,然后,如果需要,将产物成型为所期望的制剂来制备。组合物可以方便地制备和/或包装成单位剂型。
药物组合物可以是无菌可注射水性或油性溶液和混悬液的形式。无菌可注射制剂可以使用无毒的肠胃外可接受的媒介物(包括水、林格氏溶液和等渗氯化钠溶液)和可接受的溶剂(如1,3-丁二醇)配制。此外,无菌不挥发性油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸(如油酸)可用于注射剂的制备。
水性混悬液含有活性成分与适于制备水性混悬液的赋形剂的混合物。此类赋形剂包括但不限于:悬浮剂,如羧甲基纤维素钠、甲基纤维素、油基-丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂,如卵磷脂、聚氧乙烯硬脂酸酯和聚乙烯脱水山梨糖醇单油酸酯;和防腐剂,如,乙基,正丙基和对羟基苯甲酸酯。
油性混悬液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性混悬液可以含有增稠剂,例如蜂蜡,硬石蜡或鲸蜡醇。这些组合物可以通过添加抗氧化剂(如抗坏血酸)来保存。
可分散的粉末和颗粒(适于通过添加水来制备水性混悬液)可含有与分散剂、润湿剂、混悬剂或它们的组合混合的活性成分。还可以存在另外的赋形剂。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油(例如橄榄油或花生油)、或矿物油(例如液体石蜡)、或这些的混合物。合适的乳化剂可以是天然存在的树胶(如阿拉伯树胶或黄蓍胶);天然存在的磷脂(如大豆卵磷脂);衍生自脂肪酸和己糖醇酐的酯或偏酯(如脱水山梨糖醇单油酸酯);和所述偏酯与环氧乙烷的缩合产物(如聚氧乙烯脱水山梨醇单油酸酯)。
含有CPT-2008的药物组合物也可以是适于口服使用的形式。用于口服施用的合适的组合物包括但不限于片剂、糖锭、锭剂、水性或油性混悬液、可分散的粉末或颗粒、乳剂、硬或软胶囊、糖浆、酏剂、溶液、口腔贴剂、口服凝胶、口香糖、咀嚼片、泡腾粉末和泡腾片。用于口服施用的组合物可以根据本领域技术人员已知的任何方法配制。此类组合物可以含有选自以下的一种或多种试剂:甜味剂、调味剂、着色剂、抗氧化剂和防腐剂,以提供药学上精致和可口的制剂。
片剂通常含有与无毒的药学上可接受的赋形剂混合的活性成分,所述赋形剂包括:惰性稀释剂(如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨醇、乳糖、磷酸钙和磷酸钠);制粒剂和崩解剂(如玉米淀粉和海藻酸);粘合剂(如聚乙烯吡咯烷酮(PVP)、纤维素、聚乙二醇(PEG)、淀粉、明胶和阿拉伯树胶;和润滑剂(如硬脂酸镁、硬脂酸和滑石粉)。片剂可以是通过已知的技术未包衣的或包衣的、肠溶或其它方式,以延迟在胃肠道中的崩解和吸收,从而在较长的时间内提供持续的作用。例如,可以使用时间延迟材料(如单硬脂酸甘油酯或二硬脂酸甘油酯)。片剂也可根据已知技术用半透膜和任选的聚合物渗透剂包衣以形成用于控制释放的渗透泵组合物。
可以将用于口服施用的组合物配制成硬明胶胶囊,其中活性成分与惰性固体稀释剂(如碳酸钙、磷酸钙或高岭土)混合,或配制成软明胶胶囊,其中活性成分与水或油介质(如花生油、液体石蜡或橄榄油)混合。
CPT-2008的透皮递送可以通过离子电渗疗法贴剂等来实现。该化合物也可以以栓剂的形式施用,用于药物的直肠给药。可以通过将药物与合适的非刺激性赋形剂混合来制备这些组合物,所述赋形剂在常温下是固体,但在直肠温度下是液体,因此将在直肠中融化以释放药物。此类材料包括可可脂和聚乙二醇。
在一些实施方案中,药物组合物包括CPT-2008和一种或多种另外的活性剂。在一些实施方案中,提供了含有CPT-2008和用于治疗神经性疾病的一种或多种其它活性剂的药物组合物。此类活性剂的实例包括但不限于胆碱酯酶抑制剂(例如,多奈哌齐、多奈哌齐/美金刚、加兰他敏、卡巴拉汀、他克林等)、α-7烟碱受体调节剂(例如,α-7激动剂,诸如encenicline和APN1125)、血清素调节剂(例如,idalopirdine、RVT-101、西酞普兰、依他普仑、氟西汀、氟伏沙明、帕罗西汀、舍曲林等)、NMDA调节剂(例如,NMDA受体拮抗剂,如美金刚)、Aβ-靶向疗法(例如,吡格列酮、begacestat、阿托伐他汀、辛伐他汀、依他唑酯、tramiprosate等)、ApoE靶向疗法(例如,类维生素AX受体激动剂)、σ靶向疗法(例如,亚甲蓝(methylthioninium)、无色亚甲蓝等)和抗炎药(例如,NSAID,如阿扎丙宗、双氯芬酸、布洛芬、吲哚美辛、酮洛芬、萘丁美酮、萘普生、吡罗昔康或舒林酸)。
在一些实施方案中,提供了含有CPT-2008以及用于治疗癌症的一种或多种其它活性剂的药物组合物。此类活性剂的实例包括但不限于血管生成抑制剂(例如,贝伐单抗、兰尼单抗等)、免疫检查点抑制剂(例如,CTLA-4抗体、OX40抗体、PD-L1抗体、PD1抗体或BY55抗体)、蒽环类(例如阿霉素、道诺霉素等)、铂类(例如,顺铂、奥沙利铂、卡铂等)、抗代谢物(例如,5-氟尿嘧啶、甲氨蝶呤等)、激酶抑制剂(例如,埃罗替尼、吉非替尼等)、核苷类似物(例如,吉西他滨、阿糖胞苷等)以及紫杉烷类(例如,紫杉醇、多西他赛等)。
IV.用于治疗线粒体疾病和病况的方法
CPT-2008及其组合物可用于治疗与线粒体功能障碍相关的疾病和病况。此类疾病包括但不限于癌症、神经退行性疾病、脑病况和非神经性病症。
在一些实施方案中,提供了其中疾病或病况是神经退行性疾病的方法。神经退行性疾病的实例包括但不限于帕金森氏病、阿尔茨海默氏病、肌萎缩性侧索硬化症和亨廷顿氏病。
在一些实施方案中,提供了其中疾病或病况是脑病况的方法。脑病况的实例包括但不限于中风、癫痫、神经性疼痛、创伤性脑损伤、脊髓损伤、动脉瘤和蛛网膜下腔出血。
在一些实施方案中,提供了其中疾病或病况是非神经性病症的方法。非神经性病症的实例包括但不限于脓毒病、急性肾损伤、心肾综合征、心脏缺血-再灌注损伤、肺动脉高压、慢性阻塞性肺病和血管收缩。在一些实施方案中,病况是由线粒体功能障碍引起的人衰老。
还提供了用于例如在患有癌症的个体中减少癌细胞增殖例如从而治疗癌症的方法和组合物。癌症是指涉及不受调节的细胞生长的疾病组。在癌症中,细胞增殖(即分裂)不可控制地形成恶性肿瘤,并侵入身体的附近部分。癌症也可通过淋巴系统或血流转移,即扩散到身体的更远部分。治疗可以在完全或部分预防癌症或其症状方面是预防性的和/或可以在部分或完全治愈癌症和/或归因于癌症的副作用方面是治疗性的。
癌症的治疗可以包括:(a)防止癌症在可能易患癌症但尚未诊断出患有癌症的对象中发生;(b)抑制癌症,即阻止其发展;或(c)减轻癌症,即引起癌症消退。治疗剂可以在癌症发作之前、期间或之后施用。其中治疗稳定或减轻患者的不希望的临床症状的正在进行的癌症的治疗是特别令人感兴趣的。此类治疗理想地在受影响组织中功能完全丧失之前进行。在癌症的症状性阶段期间,并且在一些情况下在癌症的症状性阶段之后,将期望地施用对象治疗。术语“个体”、“对象”、“宿主”和“患者”在本文中可互换使用,并且是指需要诊断、治疗或疗法的任何哺乳动物对象,特别是人。在一些情况下,主题方法和组合物减少例如抑制癌症的增殖。在一些情况下,主题方法和组合物减少例如抑制癌症的转移。
在一些实施方案中,所述癌症是Notch相关的癌症;也就是说,癌症与活性Notch信号传导相关,即至少部分由于活性Notch信号传导。“Notch”意指进化上保守的单程跨膜受体,其通过短程细胞-细胞相互作用影响多种细胞命运决定(Artavanis-Tsakonas和Muskavitch 2010)。Notch蛋白(秀丽隐杆线虫(C.elegans)中的cLIN-12和cGLP-1、果蝇(Drosophila)中的Notch、哺乳动物中的Notch1-4)由具有29-36个表皮生长因子(EGF)重复的用于配体结合的细胞外结构域(NECD)、跨膜结构域和具有转录活性的细胞内结构域(NICD)组成。“活性Notch信号传导”意指Notch蛋白在癌细胞中是有活性的(例如,它是激活的Notch),或组成型活性的Notch(例如,Notch蛋白已经被突变使得Notch蛋白或其结构域总是有活性的)。Notch相关癌症的实例包括血液恶性肿瘤,例如急性淋巴母细胞性白血病(T-ALL);乳腺肿瘤,例如乳腺癌;脑肿瘤,例如多形性成胶质细胞瘤(GBM);肺癌;和肠癌(Artavanis-Tsakonas和Muskavitch 2010)。通过在癌细胞中(例如在肿瘤活组织检查切片或细胞涂片中)检测导致组成型活性Notch的Notch突变,可以容易地将癌症鉴定为Notch相关的癌症。已经鉴定了导致组成型活性Notch信号传导的许多突变,其可以通过例如本领域已知的染色体扩散或PCR来检测。可替代地,癌症可以通过检测Notch信号传导的下游效应子的上调活性(例如,非典型Notch信号传导蛋白的上调活性,例如,与非癌细胞相比,PINK1表达增加、mTORC2信号传导增加(Akt磷酸化增加)和呼吸链复合物组装增加)被鉴定为Notch相关的癌症。
Notch蛋白通过典型通路和非典型通路调节细胞活性。在典型的Notch通路信号传导中,Notch配体(包含以下三个基序的跨膜蛋白:DSL(Delta、Serrate、LAG-2)、DOS(Delta和OSM-11样)和EGF重复)与来自相邻细胞的Notch胞外结构域的EGF重复结合。配体-Notch相互作用允许α-分泌酶/金属蛋白酶家族(ADAM10/Kuzmanian、ADAM17/TACE)的成员切割Notch的胞外结构域,导致Notch的胞内结构域被γ-分泌酶(由早老素(PS)、呆蛋白(nicastrin,NCT)、Aph-1、Pen-2等组成的多亚单位蛋白酶复合物)连续的细胞质切割。释放的胞内结构域转移到核中,在核中它通过其RAM结构域与DNA结合转录因子CSL(脊椎动物中的“CBF1/RBPjk”、果蝇中“无毛的抑制因子”、秀丽隐杆线虫中的“Lag-1”)相互作用,并作为CSL、主导控制样蛋白(Mastermind-like proteins)(脊椎动物中的“MAML1”、果蝇中的“主导控制(Mastermind)”、秀丽隐杆线虫中的“Lag-3”)和其它辅因子(如CBP/p300),用于转录激活Notch靶基因(Kopan和Ilagan2009)。在没有游离胞内结构域Notch的情况下,CSL作为序列特异性阻抑物起作用。因此,介导典型Notch信号传导的基因(即,“典型的Notch信号传导基因”)将包括编码γ-分泌酶复合物CSL的多肽(脊椎动物中的“CBF1/RBPjk”、果蝇中“无毛的抑制因子”、秀丽隐杆线虫中的“Lag-1”)的基因、编码主导控制样蛋白(Mastermind-like proteins)(脊椎动物中的“MAML1”、果蝇中的“主导控制(Mastermind)”、秀丽隐杆线虫中的“Lag-3”)的基因和CBP/p300基因。
Notch也可以通过非经典通路发出信号。非典型Notch信号传导是CSL非依赖性的并且可以是配体依赖性的或非依赖性的(Kopan和Ilagan2009)。尽管一些基因受到非经典Notch功能的影响,但在大多数情况下,非经典Notch信号传导的介体是未知的。非典型Notch功能的最好的研究和保守作用是Wnt/β-连环蛋白信号传导的调节。在该非典型Notch信号传导通路中,Notch结合并滴定专性Wnt信号传导组分活性β-连环蛋白的水平(Takebe等人,2011)。因此,活性β-连环蛋白活性可用作非典型Notch信号的有用读出。其它研究的非典型Notch信号传导通路包括通过NF-κB的信号传导、通过JNK通路的信号传导和通过HES1和MCK的信号传导(Andersen等人,2012)。
最近,发现mTORC2、Akt和促进线粒体发育或功能的蛋白(例如PINK1、线粒体呼吸链复合物蛋白、线粒体分裂蛋白和线粒体生物发生蛋白)介导非典型Notch信号传导(Lee等人,2013)。例如,线粒体呼吸链复合物I的多肽(例如,75kD亚基,ND-75)、线粒体分裂蛋白发动蛋白1样蛋白(Drp1)和线粒体生物发生蛋白过氧化物酶体增殖物激活受体γ共激活物1-α(PGC-1α)。重要的是,非典型Notch信号传导途径中的许多这些基因编码调节线粒体功能的蛋白质(Lee等人,2013)。如工作实例中所公开的,CPT-2008有效靶向Notch促进的癌细胞增殖,例如T-ALL(Molt-4、Jurkat细胞系)和成胶质细胞瘤(T98G、U118MG细胞系)的增殖。
作为神经元发育和功能的重要调节剂,Notch信号深入地参与了大脑发育,功能和维持的许多方面。失调的Notch信号传导涉及脑肿瘤、中风、神经退行性变、神经性疼痛、外伤性脑损伤、抑郁症和神经精神性病症的发病机理(Mathieu等人,2013;Zhang等人,2018;Alfred和Vaccari,2018)。Notch信号传导的结果与上下文高度相关的事实表明,非经典Notch功能可能是一种规范而不是例外。已经证明对典型Notch信号传导的有效抑制对于临床使用而言毒性太大的事实,主要是由于不需要的靶上效应(Andersson和Lendahl,2014),这表明用于调节超过典型通路的Notch信号传导的扩展方法将增加治疗选择的可用范围。因此,预期通过非经典通路抑制异常Notch激活,CPT-2008将对广泛的脑疾病和病况具有治疗价值。
在一些实施方案中,提供了用于治疗T急性淋巴母细胞性白血病(T-ALL)、小细胞肺癌(SCLC)、非小细胞肺癌(NSCL)、成胶质细胞瘤、结肠直肠癌、乳腺癌和/或卵巢癌的方法。
CPT-2008可以在本文提供的方法中以任何合适的剂量施用。通常,CPT-2008将以约0.1毫克至约1000毫克/千克对象体重(即,约0.1-1000mg/kg)范围内的剂量施用。CPT-2008的剂量可以是例如约0.1-1000mg/kg、或约1-500mg/kg、或约25-250mg/kg、或约50-125mg/kg。CPT-2008的剂量可以是约0.1-1mg/kg、或约1-50mg/kg、或约50-100mg/kg、或约100-150mg/kg、或约150-200mg/kg、或约200-250mg/kg、或约250-300mg/kg、或约350-400mg/kg、或约450-500mg/kg、或约500-550mg/kg、或约550-600mg/kg、或约600-650mg/kg、或约650-700mg/kg、或约700-750mg/kg、或约750-800mg/kg、或约800-850mg/kg、或约850-900mg/kg、或约900-950mg/kg、或约950-1000mg/kg。CPT-2008的剂量可以是约1、2、3、4、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、85、90、95、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950或1000mg/kg。CPT-2008可以使用合适的媒介物(包括上述任何组合物)经口、局部、肠胃外、静脉内、腹膜内、肌内、病灶内、鼻内、皮下或鞘内施用。可替代地,CPT-2008可经由栓剂或经由植入缓释装置(例如,微型渗透泵)施用。
剂量可以根据患者的需要、所治疗的疾病或病况的严重程度和所施用的具体制剂而变化。向患者施用的剂量应足以在患者中产生有益的治疗应答。剂量的大小还将由在特定患者中伴随药物施用的任何不良副作用的存在、性质和程度来确定。对于特定情况,确定合适的剂量在典型执业医生的技能范围内。总剂量可以分开并在适于治疗疾病或病况的时间段内分次施用。
CPT-2008的施用可以进行一段时间,其将根据具体病症的性质、其严重性和患者的总体状况而变化。施用可以例如每小时、每2小时、每3小时、每4小时、每6小时、每8小时、或每天两次(包括每12小时)、或其任何介于中间的间隔。施用可以每天进行一次、或每36小时或每48小时进行一次、或每月或数月进行一次。在治疗后,可以监测患者他或她的病况的变化和病症的症状的减轻。CPT-2008的剂量可以在患者对特定剂量水平没有显著应答的情况下增加,或者如果观察到症状的减轻,或者如果在特定剂量下观察到不可接受的副作用,则可以降低剂量。给药方案可以由两个或多个不同的间隔组组成。例如,给药方案的第一部分可以以每日、每日、每隔一天或每第三天多次向对象施用。给药方案可以从每隔一天、每隔三天、每周、每两周或每月向对象给药开始。给药方案的第一部分可以进行例如多达30天(如7、14、21或30天)。每周、每14天或每月施用具有不同间隔施用的给药方案的随后的第二部分可以任选地遵循,持续4周直至两年或更长,如4、6、8、12、16、26、32、40、52、63、68、78或104周。可替代地,如果症状缓解或通常改善,则剂量可维持或保持在低于最大量。如果病况或症状恶化,则可恢复第一给药方案直到观察到改善,并且可以再次实施第二给药方案。该循环可以根据需要重复多次。
V.实施例
提出以下实施例以向本领域普通技术人员提供如何制备和评估本文所要求保护的化合物、组合物、制品、装置和/或方法的完整公开和描述,并且旨在纯粹是本发明的示例,并且不旨在限制发明人将其视为他们的发明的范围。然而,根据本公开,本领域技术人员应当理解,在不脱离本发明的精神和范围的情况下,可以对所公开的具体实施方案进行许多改变,并且仍然获得相同或类似的结果。
已经进行了努力以确保关于数字(例如,量、温度等)的准确性,但应考虑一些误差和偏差。除非另有说明,份数为重量份,温度为℃或为环境温度,压力为大气压或接近大气压。
实施例1:CPT-2008的合成
采用会聚性合成方法制备CPT-2008,其中分别制备两个片段(化合物3和化合物5)并组合以制备如下所述的最终产物(图1)。最终产物具有式为C16H11Cl3N2O3S,分子量为417.69g/摩尔,并且通过HPLC和LCMS/1H NMR测定的纯度大于95%。
CPT-2008的化学合成涉及以下步骤。
化合物2的制备。在冰浴中向含有化合物1(50g,276mmol)的CHCl3(600mL)的溶液中加入SO2Cl2(26mL,331mmol),并在回流下搅拌4小时。将反应混合物浓缩以得到粗产物,将其通过用PE/EA=1:1(200mL)研磨来纯化以得到呈白色固体的所期望的产物(36g,61%的产率)。1HNMR(400MHz,DMSO-d6)δ:7.64(1H,s),6.48(1H,s),3.81(3H,s),3.75(3H,s)。
化合物3的制备。将含有化合物2的混合物(26g,167mmol)的NaOH(13.4g,0.334mmol)的水(400mL)溶液在室温下搅拌过夜,之后通过TLC观察到完全反应。用2N HCl酸化反应,并过滤,用水洗涤,以及干燥以得到所期望的白色固体产物(30g,90%的产率)。1HNMR(400MHz,DMSO-d6)δ:7.62(1H,s),6.44(1H,s),3.80(3H,s)。
化合物5的制备。向含有化合物4(28.7g,149mmol)的二恶烷(300mL)的溶液中加入二氯硫化碳(19.5mL,253mmol),并将混合物在回流下搅拌2h。通过TLC观察到完全反应,并将反应混合物浓缩以得到黄色固体的粗产物(35g,100%的产率)。1HNMR(400MHz,CDCl3)δ:7.41(1H,s),6.76(1H,s),3.88(3H,s)。
CPT-2008的制备。向含有化合物5(35g,149mmol)和化合物3(30g,149mmol)的混合物的2-丙醇(500mL)中加入NaOMe(402mg,7.4mmol),并将混合物在回流下搅拌过夜。将反应物浓缩,并将所得残余物悬浮于DCM(200mL)中并过滤。用DCM(50mL)洗涤滤饼以得到白色固体产物(21.5g,经两步产率为34%)。1HNMR(400MHz,DMSO-d6)δ:13.21(1H,s),7.93(1H,s),7.79(1H,s),7.43(1H,s),7.12(1H,s),3.98(3H,s),3.82(3H,s);ESILC-MS:Rt=1.730min,418.8[M+1]+。
实施例2.CPT-2008在细胞培养物中的抗肿瘤活性。
(a)试剂和材料
CellTiter-Glo发光细胞活力测定试剂盒获自Promega。RPMI 1640获自Invitrogen。胎牛血清(FBS)获自Corning。L-谷氨酰胺获自Invitrogen。100×青霉素-链霉素获自HyClone。0.05%胰蛋白酶-EDTA(T-E)获自Invitrogen。DPBS获自Corning。DMSO获自Sigma。黑色384孔板获自Greiner。96孔V底板获自Axygen。
(b)实验程序
细胞接种(第“-1”天):根据供应商推荐的信息调整8种贴壁细胞系的细胞密度。将50μL细胞接种在四个384孔板中,并将50μL DPBS加入到边缘孔中。
化合物制备(第0天):将所有测试化合物溶解在DMSO中并储存在氮气柜中。测试化合物的储备浓度为120mM。参考化合物的储备浓度为10mM。用DMSO稀释参考化合物紫杉醇以提供400μM的储备溶液。
用测试化合物处理细胞(第0天):使用ECHO液体处理系统(Labcyte Inc.)将测试化合物(125nL,在DMSO中)加入孔中并连续稀释三倍,在每个系列中提供最大浓度为300μM的10个剂量。将等体积的不含测试化合物的DMSO转移至孔板中的对照行。
细胞接种(第0天):根据供应商推荐的信息调整两种悬浮细胞系的细胞密度。将50μL细胞接种在384孔板中。向边缘孔中加入50μL DPBS。
使用上述程序,参考化合物紫杉醇的最高浓度为1μM,并且跨越孔板的DMSO浓度为0.25%(v/v)。
测定(第3天):在用化合物处理细胞72小时后,将板在室温下平衡大约30分钟。向每个孔中加入25μL CellTiter Glo试剂,并且在10分钟后使用ENVISION荧光板读数器(PerkinElmer)测量每个孔中的发光。
(c)数据分析方法
计算公式:抑制%=(最大值-样品值)/最大值*100。
通过Prism用S形剂量应答(可变斜率)模型拟合曲线,并通过4参数逻辑模型或S形剂量应答模型产生曲线,
Y=底部+(顶部-底部)/(1+10^((logEC50-x)*Hill斜率(HillSlope)))。
(d)结果
CPT-2008在癌症的多种细胞模型中展示出有效的抗肿瘤活性。为了评估CPT-2008的抗肿瘤活性,在72小时孵育后在各种人癌细胞系中测量化合物的生长抑制作用。在测定中,所有细胞系都满足在初始细胞铺板期间贴壁/混合细胞的存活力大于90%和悬浮细胞的存活力大于85%的标准。该测定中的所有细胞板满足变异系数(CV)<10%的标准。所记录的紫杉醇参考化合物的数据与历史公开的数据一致。
细胞系包括以下癌症模型:T-ALL(T急性淋巴母细胞性白血病)模型(Molt-4)、T细胞白血(Jurkat)、小细胞肺癌(SCLC:NCH-H82和NCI-H446)、非小细胞肺癌(NSCLC:NCI-H1299和A549)、成胶质细胞瘤(T98G和U118MG)、乳腺癌(MCF7)、卵巢癌(A2780)和结肠直肠癌(HCT116)。CPT-2008在NCI-H82、NCI-H446、Jurkat和A2780癌细胞系中展示出在nM范围内的IC50。在其它细胞系中,它在低μM范围内展示IC50。这些结果表明CPT-2008在人肿瘤细胞培养模型中具有有效的抗肿瘤活性。
CPT-2008影响线粒体功能。CPT-2008对大范围的癌症模型的功效表明其作用机制是独特的,靶向癌细胞增殖所需的一般细胞机制。鉴于线粒体在维持癌细胞(尤其是癌症干细胞)中的重要作用,接下来研究了CPT-2008对人类成胶质细胞瘤(GBM)细胞中的许多线粒体参数的影响。首先,研究CPT-2008对线粒体ROS水平的影响。为此目的,使用mito-SOX染料。Mito-SOX可以特异性地监测线粒体ROS水平。如图15中所示的,CPT-2008引起GBM细胞中线粒体ROS的显著增加。还使用TRM染料测量CPT-2008对线粒体膜电位的影响,所述线粒体膜电位是确定线粒体健康和活性的关键因素。如图17中所示的,CPT-2008诱导GBM细胞中线粒体膜电位的显著降低。还使用Rhod-2AM染料测量CPT-2008对线粒体钙稳态的影响,所述Rhod-2AM染料特异性地监测线粒体钙水平。如图14中所示的,CPT-2008引起线粒体钙的增加。还使用线粒体外膜标志物Tom20的免疫染色测量CPT-2008对线粒体形态的影响。如图16中所示的,CPT-2008诱导线粒体的显著片段化,导致与对照细胞中的长的和管状的线粒体相反的小的和圆形的线粒体。总之,这些结果表明CPT-2008影响线粒体功能。最后,测试CPT-2008对GBM细胞自我更新的影响。如图18中所示的,如通过在培养物中形成神经球的能力所测量的,CPT-2008显著抑制GBM细胞的自我更新。
实施例3.CPT-2008在体内中风模型中提供了改善的保护作用。
依达拉奉(3-甲基-1-苯基-2-吡唑啉-5-酮)是种活性氧(ROS)清除剂,在日本被批准用于治疗中风和ALS,并且在美国被批准用于治疗ALS。比较CPT-2008预防大鼠大脑中动脉闭塞(MCOA)模型脑损伤的功效与依达拉奉的功效。给斯普拉格-杜勒大鼠施用媒介物、依达拉奉(6mg/kg)或CPT-2008(25-100mg/kg),并评估梗死脑组织的水平。在本研究中,大鼠经历大脑中动脉闭塞(MCAO)1.5h,然后再灌注24h。在灌注后0h和8h腹膜内给予CPT-2008,并且分别通过Lona评分量表和TTC染色评估行为缺陷和脑损伤。如图19A和图19B中所示的,在用CPT-2008治疗后死亡脑组织的水平降低表明CPT-2008优于依达拉奉。据信CPT-2008的改善的益处部分是由于防止脑组织线粒体中ROS的形成。
实施例4.CPT-2008在化学诱导的神经性疼痛模型中展现出功效。
估计30-40%的接受化学疗法的癌症患者经历外周神经性疼痛,即神经炎症诱导的衰弱性副作用,其导致患者早期停止治疗或服用较低的剂量。在紫杉醇治疗的大鼠中研究CPT-2008在减轻神经性疼痛中的效果。紫杉醇治疗8天后,将斯普拉格-杜勒大鼠再饲养几天。在第22天,将16只大鼠随机分成两组。一组给予媒介物,另一组以100mg/kg经由腹膜内注射CPT-2008给药。疼痛(机械性异常性疼痛)测试对象使用如Xie(“Activation ofnotch signaling mediates the induction and maintenance of mechanicalallodynia in a rat model of neuropathic pain.”Molecular Medicine Reports 12:639-644,2015)所述的爪缩回测试(PWT)进行评估。在1.5h、3h和4.5h时,测量大鼠在给药测试化合物后的爪缩回阈值。如图20中所示的增加的阈值所表明的,向紫杉醇治疗的动物施用CPT-2008降低了疼痛敏感性。
实施例5.CPT-2008药代动力学性质的研究。
通过IV或PO向斯普拉格杜勒大鼠施用CPT-2008。在安乐死后通过在给药后5min、15min、30min、1h、2h、4h、8h、24h吸入二氧化碳经由心脏穿刺收集血液样品(约1mL)。将血液样品置于含有肝素钠的管中并在4℃下以3500rpm离心10分钟以从样品中分离血浆。离心后,将所得血浆转移至标记的试管中,并在-80℃冷冻保存待进行生物分析。在动物通过吸入二氧化碳安乐死后,在每个时间点收集每个研究的动物的脑。收集,切除整个组织,然后将其放入每只动物每个组织的一个管中。将组织样品置于干冰上,然后在-80℃下储存直至生物分析。
如图21A和21B中所示的,发现CPT-2008有效地穿过血脑屏障。CPT-2008在大鼠体内所测量的血浆生物利用度为94.5%。所测量的脑生物利用度为38.97%,其中在脑血浆、大脑、小脑和脑干中检测到药物。在比格犬中,CPT-2008在不同脑区(左脑、右脑、小脑和脑干)中的浓度达到1.5至2μM,其在许多癌细胞系中接近或高于化合物的EC50值。该化合物在微粒体和肝细胞中也展现出优异的稳定性。例如,所测量的半衰期在人微粒体中约为3.6小时,在人肝细胞中约为94.3小时(3.9天)。
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尽管为了清楚理解的目的,已经通过说明和实施例的方式详细描述了上述发明,但是本领域技术人员将理解,在所附权利要求的范围内可以实施某些改变和修改。此外,本文提供的每个参考文献通过引用整体并入本文,其程度如同每个参考文献单独通过引用并入本文。在本申请与本文提供的参考文献之间存在冲突的情况下,以本申请为准。
Claims (14)
1.式I的化合物:
或其药学上可接受的盐。
2.用于治疗与线粒体功能障碍相关的疾病或病况的药物组合物,所述组合物包含权利要求1所述的式I的化合物、其药学上可接受的盐,以及药学上可接受的载体。
3.有效量的权利要求1所述的化合物或有效量的权利要求2所述的组合物在制备用于治疗有此需要的对象的与线粒体功能障碍相关的疾病或病况的药物中的用途。
4.如权利要求3所述的用途,其中所述有效量是治疗有效量。
5.如权利要求3所述的用途,其中所述有效量是预防有效量。
6.如权利要求3所述的用途,其中所述疾病是癌症。
7.如权利要求6所述的用途,其中所述癌症是T急性淋巴母细胞性白血病(T-ALL)、小细胞肺癌(SCLC)、非小细胞肺癌(NSCL)、成胶质细胞瘤、结肠直肠癌、乳腺癌或卵巢癌。
8.如权利要求3所述的用途,其中所述疾病是神经退行性疾病。
9.如权利要求8所述的用途,其中所述神经退行性疾病是帕金森氏病、阿尔茨海默氏病、肌萎缩性侧索硬化症或亨廷顿氏病。
10.如权利要求3所述的用途,其中所述病况是脑病况。
11.如权利要求10所述的用途,其中所述脑病况是中风、癫痫、神经性疼痛、创伤性脑损伤、脊髓损伤、动脉瘤或蛛网膜下腔出血。
12.如权利要求3所述的用途,其中所述疾病或病况是非神经性病症。
13.如权利要求12所述的用途,其中所述非神经性病症是脓毒病、急性肾损伤、心肾综合征、心脏缺血-再灌注损伤、肺动脉高压、慢性阻塞性肺病或血管收缩。
14.如权利要求3所述的用途,其中所述病况是由线粒体功能障碍引起的人衰老。
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