CN115335058A - 神经细胞变性抑制剂 - Google Patents
神经细胞变性抑制剂 Download PDFInfo
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- CN115335058A CN115335058A CN202180024013.0A CN202180024013A CN115335058A CN 115335058 A CN115335058 A CN 115335058A CN 202180024013 A CN202180024013 A CN 202180024013A CN 115335058 A CN115335058 A CN 115335058A
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- phenyl
- alkyl
- triazin
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Abstract
Description
技术领域
本发明涉及一种包含用于治疗运动神经元疾病或痴呆的化合物的药剂(药物、药物组合物)。
背景技术
真核生物基因组含有各种重复序列,并且最近,位于C9orf72基因非翻译区的六碱基重复序列“GGGGCC”(以下也称为G4C2重复)作为肌萎缩侧索硬化(以下也称为“ALS”)与额颞叶痴呆(以下也称为“FTD”)之间的联系已经引起注意。
ALS是一种典型的运动神经元疾病,特征为上运动神经元和下运动神经元的选择性变性,其中大约10%的患者是散发性的,并且大约90%的患者是家族性的。到目前为止,已经广泛开展基于在家族性患者中发现的基因突变的研究,并且最近,将C9orf72基因的G4C2重复序列的异常扩增鉴定为在家族性和散发性ALS患者中最常观察到的基因异常。另一方面,FTD的特征为大脑额叶和颞叶的变性,并且是在年龄65岁以下的痴呆患者中第二最常见的疾病,并且据报道,FTD中最常观察到的基因异常也是C9orf72基因的G4C2重复序列的异常扩增(非专利文献1和2)。
已知由具有异常扩增的G4C2重复序列的C9orf72基因转录的RNA容易聚集,并且包裹核蛋白以生成核聚集体(以下称为RNA团簇(RNA foci))(非专利文献1和2)。还已知的是,上述RNA通过重复相关的非ATG翻译(以下称为RAN翻译)被翻译成二肽重复蛋白(以下称为DPR),并且DPR生成细胞内包涵物(非专利文件3、4和5)。RNA团簇和DPR由于它们的细胞毒性被认为是这些疾病中神经变性的主要原因(非专利文件6),并且认为有效抑制它们的生成可以预防这些疾病的发作或有效抑制发作后的病理进展。
到目前为止,各种模型***已被用于搜寻可以抑制RNA团簇和/或DPR的生成的基因。例如,通过使用在复眼中表达异常扩增的G4C2重复序列的果蝇模型进行筛选,将FUS(负责ALS6的基因)鉴定为其过表达抑制RNA翻译和复眼神经变性的基因(专利文件1)。另外,还已经开发了C9orf72基因的反义寡核苷酸,并已经报道其可抑制RNA团簇的生成并且有效抑制神经元死亡(例如,非专利文件7)。
然而,尚未报道可以有效抑制由G4C2重复序列引起的RNA团簇和/或DPR的生成的小分子化合物。
文献列表
专利文献
专利文献1:JP 2018-193309
非专利文献
非专利文献1:DeJesus-Hernandez,M.等人,Neuron 72,245-56(2011)
非专利文献2:Renton,A.E.等人,Neuron 72,257-68(2011)
非专利文献3:Ash,P.E.等人,Neuron 77,639-46(2013)
非专利文献4:Mori,K.等人,Science 339,1335-8(2013)
非专利文献5:Zu,T.等人,Proc Natl Acad Sci U S A 110,E4968-77(2013)
非专利文献6:J.Chew等人,Science,348,1151-1154(2015)
非专利文献7:D.Sareen等人,Sci.Transl.Med.,5,208ra149,doi:10.1126/scitranslmed.3007529(2013)
发明内容
本发明要解决的问题
本发明旨在找到能够有效抑制RNA团簇和DPR的生成的化合物,所述RNA团簇和DPR的生成被认为是运动神经元疾病和以FTD为代表的痴呆中的神经变性的原因,并且旨在提供可用于上述疾病的预防或治疗的药剂(药物、药物组合物)。
解决问题的手段
为了解决上述的问题,本发明人已经进行了广泛研究,并且首次发现被具有异常扩增的G4C2重复序列的ALS患者来源的iPS细胞的Lhx3、Ngn2和Isl1基因过表达诱导分化的运动神经元自发生成RNA团簇和DPR,从而导致神经变性。本发明人已经开发通过表达所述三种基因诱导分化的方法,作为能够在短时间内以高同步性诱导分化为运动神经元的方法(WO 2014/148646,以及K.Imamura等人,Science Translational Medicine 2017,9,eaaf3962)。
然后,本发明人已经使用上述运动神经元筛选小分子化合物,并且发现七种化合物对RNA团簇和DPR的生成具有极好的抑制作用,即,它们可以是用于由重复序列异常扩增引起的运动神经元疾病和/或痴呆的预防或治疗的药剂,从而完成本发明。
因此,本发明提供以下内容。
[1]一种神经元变性抑制剂(以下也称为“本发明的药剂”),其包含由式(I)表示的化合物
其中
R1是由式(a-1)或(a-2)表示的基团
其中
R11和R12各自独立地是氢原子或C1-6烷基,
R13是氢原子、氰基、C1-6烷基-羰基或C1-6烷氧基-羰基,并且
R14是C1-6烷基、C3-8环烷基或C6-14芳基,
R2是由式(b-1)-(b-3)表示的基团
其中
R21是C1-6烷基、任选地被一个或多个卤素原子取代的C6-14芳基或任选地被一个或多个卤素原子取代的C7-16芳烷基,
R22各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,并且
n是0、1或2,
R3各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,
m是0、1或2,并且
L是C1-3亚烷基,
或其盐。
[2]根据上述[1]的神经元变性抑制剂,其中
R11和R12两者是氢原子,
R13是氢原子或C1-6烷氧基-羰基,
R14是C1-6烷基,
R21是C1-6烷基或任选地被一个或多个卤素原子取代的C7-16芳烷基,
R22是卤素原子,
n是0或1,
m是0,并且
L是亚甲基。
[3]根据上述[1]的神经元变性抑制剂,其中由式(I)表示的化合物或其盐选自
(1)4-(4-氟-2-甲氧基苯基)-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺、
(2)1-(3-{[4-(2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺、
(3)1-(3-{[4-(4-氯-2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺、
(4)1-[3-({4-[2-(苄氧基)苯基]-1,3,5-三嗪-2-基}氨基)苯基]甲磺酰胺、
(5)4-{2-[(3,4-二氯苯基)甲氧基]苯基}-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺、
(6){[(3-{[4-(2,3-二氢-1,4-苯并二噁英-5-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯、
(7){[(3-{[4-(2,3-二氢-1-苯并呋喃-7-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯,
和其盐。
[4]根据上述[1]-[3]中任一项的神经元变性抑制剂,其是用作用于预防或治疗运动神经元疾病或痴呆的药剂。
[5]根据上述[4]的神经元变性抑制剂,其中所述运动神经元疾病或痴呆是涉及六核苷酸重复序列的异常扩增的运动神经元疾病或痴呆。
[6]根据上述[4]或[5]的神经元变性抑制剂,其中所述运动神经元疾病是肌萎缩侧索硬化。
[7]根据上述[4]或[5]的神经元变性抑制剂,其中所述痴呆是额颞叶痴呆。
[8]一种用于抑制哺乳动物中神经元变性的方法,所述方法包括向所述哺乳动物施用有效量的如在上述[1]-[3]中任一项所定义的化合物或盐。
[9]一种用于预防或治疗哺乳动物中神经元变性疾病的方法,所述方法包括向所述哺乳动物施用有效量的如在上述[1]-[3]中任一项所定义的化合物或盐。
[10]一种如在上述[1]-[3]中任一项所定义的化合物或盐,其用于在预防或治疗神经元变性疾病中使用。
[11]如在上述[1]-[3]中任一项所定义的化合物或盐用于制造用于预防或治疗神经元变性疾病的药剂的用途。
发明效果
根据本发明,可以提供一种药剂,其对在涉及C9orf72基因的G4C2重复序列的异常扩增的神经变性疾病中RNA团簇和DPR的生成具有极好的抑制作用,并且可以用于预防或治疗上述疾病。
附图说明
[图1]
图1是在由ALS7(C9orf72)细胞分化的运动神经元中使用荧光探针可视化的RNA团簇的荧光显微图像。
具体实施方式
下面详细解释本发明。
本发明提供一种神经元变性抑制剂,其包含由下式(I)表示的化合物或其盐(以下也称为“化合物(I)”)作为活性成分。
其中
R1是由式(a-1)或(a-2)表示的基团
其中
R11和R12各自独立地是氢原子或C1-6烷基,
R13是氢原子、氰基、C1-6烷基-羰基或C1-6烷氧基-羰基,并且
R14是C1-6烷基、C3-8环烷基或C6-14芳基,
R2是由式(b-1)-(b-3)表示的基团
其中
R21是C1-6烷基、任选地被一个或多个卤素原子取代的C6-14芳基或任选地被一个或多个卤素原子取代的C7-16芳烷基,
R22各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,并且
n是0、1或2,
R3各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,
m是0、1或2,并且
L是C1-3亚烷基。
以下详细解释了如本文所用使用的每个取代基的定义。除非另有说明,否则每个取代基具有以下定义。
如本文所用,“卤素原子”的例子包括氟、氯、溴和碘。
如本文所用,“C1-6烷基”的例子包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基和2-乙基丁基。
如本文所用,“C3-8环烷基”的例子包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基和金刚烷基。
如本文所用,“C6-14芳基”的例子包括苯基、1-萘基、2-萘基、1-蒽基、2-蒽基和9-蒽基。
如本文所用,“C7-16芳烷基”的例子包括苄基、苯乙基、萘基甲基和苯基丙基。
如本文所用,“C1-6烷氧基”的例子包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和己氧基。
如本文所用,“C1-6烷基-羰基”的例子包括乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、3-甲基丁酰基、2-甲基丁酰基、2,2-二甲基丙酰基、己酰基和庚酰基。
如本文所用,“C1-6烷氧基-羰基”的例子包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、仲丁氧羰基、叔丁氧羰基、戊氧羰基和己氧羰基。
如本文所用,“C1-3亚烷基”的例子包括-CH2-、-(CH2)2-、-(CH2)3-、-CH(CH3)-、-CH2CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2-和-CH(C2H5)-。
以下详细解释了式(I)中的每个符号的定义。
R1是由式(a-1)或(a-2)表示的基团
R11和R12各自独立地是氢原子或C1-6烷基,R13是氢原子、氰基、C1-6烷基-羰基或C1-6烷氧基-羰基,并且R14是C1-6烷基、C3-8环烷基或C6-14芳基。
R11和R12两者优选地是氢原子。
R13优选地是氢原子或C1-6烷氧基-羰基(例如乙氧羰基),特别优选地是氢原子。
R14优选地是C1-6烷基(例如甲基),特别优选甲基。
R1优选地是由式(a-2)表示的基团。
R2是由式(b-1)-(b-3)表示的基团
R21是C1-6烷基、任选地被一个或多个卤素原子取代的C6-14芳基或任选地被一个或多个卤素原子取代的C7-16芳烷基,R22各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,并且n是0、1或2。
R21优选地是C1-6烷基(例如甲基)或任选地被一个或多个卤素原子(例如氯原子)取代的C7-16芳烷基(例如苄基),更优选地是C1-6烷基(例如甲基),特别优选地是甲基。
R22优选地是卤素原子(例如,氟原子、氯原子),特别优选地是氟原子。
n优选地是0或1,特别优选是1。
R2优选地是由式(b-1)表示的基团。
R3各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基。
m是0、1或2。
m优选地是0。
L是C1-3亚烷基。
L优选地是亚甲基。
化合物(I)的优选实施方案包括以下化合物。
化合物(I)其中
R1是由式(a-1)或(a-2)表示的基团,
R11和R12两者是氢原子,
R13是氢原子或C1-6烷氧基-羰基(例如乙氧羰基),
R14是C1-6烷基(例如甲基),
R2是由式(b-1)-(b-3)表示的基团,
R21是C1-6烷基(例如甲基)或任选地被一个或多个卤素原子(例如氯原子)取代的C7-16芳烷基(例如苄基),
R22是卤素原子(例如,氟原子、氯原子),
n是0或1,
m是0,并且
L是亚甲基。
化合物(I)的具体例子包括以下化合物。
(1)4-(4-氟-2-甲氧基苯基)-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺(化合物编号1)、
(2)1-(3-{[4-(2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺(化合物编号2)、
(3)1-(3-{[4-(4-氯-2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺(化合物编号3)、
(4)1-[3-({4-[2-(苄氧基)苯基]-1,3,5-三嗪-2-基}氨基)苯基]甲磺酰胺(化合物编号4a、4b)、
(5)4-{2-[(3,4-二氯苯基)甲氧基]苯基}-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺(化合物编号5)、
(6){[(3-{[4-(2,3-二氢-1,4-苯并二噁英-5-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯(化合物编号6)、
(7){[(3-{[4-(2,3-二氢-1-苯并呋喃-7-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯(化合物编号7),
和其盐。
当化合物(I)是盐时,它优选地是药学上可接受的盐。此类盐的例子包括与无机碱形成的盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性氨基酸形成的盐和与酸性氨基酸形成的盐。
所述与无机碱形成的盐的优选例子包括碱金属盐,如钠盐、钾盐等;碱土金属盐,如钙盐、镁盐等;铝盐;和铵盐。
所述与有机碱形成的盐的优选例子包括与以下形成的盐:三甲胺、三乙胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇[三(羟甲基)甲胺]、叔丁胺、环己胺、苄胺、二环己胺和N,N-二苄基乙二胺。
所述与无机酸形成的盐的优选例子包括与以下形成的盐:盐酸、氢溴酸、硝酸、硫酸和磷酸。
所述与有机酸形成的盐的优选例子包括与以下形成的盐:甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸和对甲苯磺酸。
所述与碱性氨基酸形成的盐的优选例子包括与以下形成的盐:精氨酸、赖氨酸和鸟氨酸。
所述与酸性氨基酸形成的盐的优选例子包括与以下形成的盐:天冬氨酸和谷氨酸。
当化合物(I)作为游离形式获得时,可以根据本身已知的方法将其转化为目标盐。当化合物(I)作为盐获得时,可以根据本身已知的方法将其转化为目标游离形式或其他盐。
如本文所用术语“神经元变性”是指神经突萎缩、神经突断裂、神经突消失、细胞体萎缩、细胞体破碎和细胞体消失的任何一种或多种异常的发生。通常,神经元变性可以用细胞死亡(实际上,作为存活神经元数量的反面)作为指标来检测和评价。
此外,对于由具有六(或三)核苷酸单元的重复序列的异常扩增引起的神经变性,神经变性可以使用由从所述重复序列转录的RNA组成的RNA团簇或通过所述RNA的RAN翻译生成的DPR作为指标来检测和评价。RNA团簇和DPR二者都可以通过熟知的常规的方法来检测和定量。
对于RNA团簇,例如,使用含有与重复序列互补的序列的寡核苷酸(优选用荧光等标记的)作为探针通过FISH(荧光原位杂交)方法分析神经元,并且RNA团簇可以作为存在于神经元核内的荧光信号点(例如,具有0.60μm或更大的直径的点)来检测。RNA团簇的生成水平可以通过测量每个神经元或每个单位区域(例如,观察视野区域、观察视野中的核染色区域等)的点的数量来定量地评价。
例如,可以通过使用针对可能从六(或三)核苷酸重复序列生成的DPR的抗体通过熟知并且常规的免疫技术(例如,ELISA方法)分析神经元来源的裂解物或提取物来对DPR进行检测和定量。可替代地,通过使用上述抗体对神经元进行免疫染色,DPR可以作为抗体阳性点来检测和定量。
在一个实施方案中,使用源自ALS患者的iPS细胞的运动神经元,由某化合物(测试化合物)对运动神经元的细胞变性抑制率可以使用下式来计算。
测试化合物的运动神经元变性抑制活性=((X-C)/(T-C))x 100
X:培养开始后y天在测试化合物组中的运动神经元的数量,
C:培养开始后y天在DMSO组中的运动神经元的数量,
T:培养开始后x天运动神经元的数量
这里,x选自在受试者中发生自发的细胞死亡之前的任一天,并且y选自在受试者中发生自发的细胞死亡期间的任一天。
因为化合物(I)对由G4C2重复序列的异常扩增引起的RNA团簇和DPR的生成有极好的抑制作用,本发明的药剂可以适宜作为用于预防或治疗涉及重复序列异常扩增的神经变性疾病的药剂使用。此外,因为认为在由六(或三)核苷酸重复序列生成RNA团簇和DPR的过程中存在非序列依赖性的共同机制,所以预期本发明的药剂作为用于预防或治疗涉及六(或三)核苷酸异常扩增的所有神经变性疾病的药剂。所述神经变性疾病包括运动神经元疾病和痴呆。
运动神经元疾病的例子包括肌萎缩侧索硬化(ALS)、进行性延髓麻痹、进行性肌萎缩、原发性侧索硬化、进行性假性延髓麻痹、脊髓性肌萎缩、帕金森病、多***萎缩、亨廷顿病、脊髓小脑变性、强直性肌营养不良、脆性x综合征相关疾病、眼咽肌病、富克斯角膜内皮营养不良、球形切开术肌萎缩(spherotomy muscular atrophy)等。如本文所用,这些疾病有时称为“运动神经元疾病”。在这些疾病中,肌萎缩侧索硬化、球形切开术肌萎缩、强直性肌营养不良、帕金森病、亨廷顿病、脆性x综合征相关疾病和脊髓性肌萎缩特别优选地例示为根据本发明的药剂的目标运动神经元疾病。
痴呆的例子包括额颞叶痴呆(FTD)、路易体痴呆等,并且FTD是特别合适的目标痴呆疾病。
用于所述预防或治疗的药剂可用于上述疾病,无论它们是散发性的还是家族性的。
用于所述预防或治疗的药剂可以用作用于在哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、绵羊、猴、人等)中预防或治疗上述疾病的药剂。
本发明的药剂可以含有化合物(I)的一个种类,或可以组合含有化合物(I)的两个或更多个种类。
化合物(I)具有更好的体内动力学(例如,血浆药物半衰期、大脑内可转移性、代谢稳定性),显示低毒性(例如,作为药物在急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、药物相互作用、致癌性等方面更好)。将化合物(I)直接用作药剂或药物组合物与药学上可接受的载体等混合,以安全地口服或肠胃外施用到哺乳动物(例如,人、猴、牛、马、猪、小鼠、大鼠、仓鼠、兔子、猫、狗、绵羊和山羊)。“肠胃外”的例子包括静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、大脑内、直肠内、***内、腹膜内和肿瘤内施用、施用至肿瘤附近等以及直接施用至病灶。
尽管化合物(I)的剂量根据施用途径、症状等变化,例如,当向患有肌萎缩侧索硬化的患者(成年,体重40-80kg,例如,60kg)口服施用化合物(I)时,其剂量是例如0.001-1000mg/kg体重/天,优选是0.01-100mg/kg体重/天,更优选是0.1-10mg/kg体重/天。这个量可以每天以1至3份施用。
根据本身作为药物制剂生产方法(例如,在日本药典(Japanese Pharmacopoeia)中描述的方法等)已知的方法,本发明的药剂可以使用单独的化合物(I)或作为含有化合物(I)和药学上可接受的载体的药物组合物的化合物(I)。本发明的药剂(药物、药物组合物)可以以例如以下的形式安全地口服或肠胃外(例如,静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、大脑内、直肠内、***内、腹膜内施用,以及施用至病灶)施用,片剂(包括糖衣片、膜衣片、舌下片、口腔崩解片、颊片等)、丸剂、散剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、液体剂、乳剂、混悬剂、控释制剂(例如,速释制剂、缓释制剂、缓释微胶囊)、气雾剂、膜剂(例如,口腔崩解膜剂、口腔粘膜粘性膜剂)、注射剂(例如,皮下注射剂、静脉内注射剂、肌内注射剂、腹膜内注射剂)、点滴注射剂、透皮吸收型制剂、软膏剂、洗剂、粘性制剂、栓剂(例如,直肠栓剂、***栓剂)、团粒剂、鼻用制剂、肺用制剂(吸入剂)、滴眼剂等。
作为前述“药学上可接受的载体”,可以使用常规地用作制备材料(起始材料)的各种有机或无机载体。例如,赋形剂、润滑剂、粘合剂、崩解剂等用于固体制剂,并且溶剂、增溶剂、悬浮剂、等渗性剂、缓冲液、舒缓剂等用于液体制剂。必要时,也可以使用制备添加剂,如防腐剂、抗氧化剂、着色剂、甜味剂等。
赋形剂的例子包括乳糖、蔗糖、D-甘露糖醇、淀粉、玉米淀粉、结晶纤维素和轻质无水硅酸。
润滑剂的例子包括硬脂酸镁、硬脂酸钙、滑石粉和胶态二氧化硅。
粘合剂的例子包括结晶纤维素、蔗糖、D-甘露糖醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、明胶、甲基纤维素和羧甲基纤维素钠。
崩解剂的例子包括淀粉、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠和L-羟丙基纤维素。
溶剂的例子包括注射用水、醇、丙二醇、Macrogol、芝麻油、玉米油和橄榄油。
增溶剂的例子包括聚乙二醇、丙二醇、D-甘露糖醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠和柠檬酸钠。
悬浮剂的例子包括表面活性剂,如硬脂基三乙醇胺、月桂基硫酸钠、月桂基氨基丙酸、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等;以及亲水性聚合物,如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等。
等渗性剂的例子包括葡萄糖、D-山梨糖醇、氯化钠、甘油和D-甘露糖醇。
缓冲液的例子包括缓冲溶液,如磷酸盐、乙酸盐、碳酸盐和柠檬酸盐。
舒缓剂的例子包括苄醇。
防腐剂的例子包括对羟基苯甲酸酯、氯丁醇、苄醇、苯乙醇、脱氢乙酸和山梨酸。
抗氧化剂的例子包括亚硫酸盐、抗坏血酸和α-生育酚。
虽然药物组合物(配制品)根据剂型、施用方法、载体等而改变,但它可以根据常规方法通过以通常为制剂总量0.01%-100%(w/w)、优选0.1%-95%(w/w)的比例添加化合物(I)来产生。
化合物(I)可以单独地或以其两种或更多的组合用作药剂(药物、药物组合物)。如本文所用,除非另有说明,化合物(I)也包括其多种的组合。
此外,化合物(I)可以与其他活性成分(以下简称为伴随药物)组合使用。
伴随药物的例子包括以下。苯二氮(benzodiazepine)(氯氮卓(chlordiazepoxide)、***(diazepam)、氯氮卓钾(potassium clorazepate)、劳拉西泮(lorazepam)、氯硝西泮(clonazepam)、阿普***(alprazolam)等)、L型钙通道抑制剂(普瑞巴林(pregabalin)等)、三环或四环抗抑郁药(盐酸丙咪嗪(imipramine hydrochloride)、盐酸阿米替林(amitriptyline hydrochloride)、盐酸地昔帕明(desipramine hydrochloride)、盐酸氯米帕明(clomipramine hydrochloride)等)、选择性血清素再吸收抑制剂(马来酸氟伏沙明(fluvoxamine maleate)、盐酸氟西汀(fluoxetine hydrochloride)、氢溴酸西酞普兰(citalopram hydrobromide)、盐酸舍曲林(sertraline hydrochloride)、盐酸帕罗西汀(paroxetine hydrochloride)、草酸艾司西酞普兰(escitalopram oxalate)等)、血清素-去甲肾上腺素再吸收抑制剂(盐酸文拉法辛(venlafaxine hydrochloride)、盐酸度洛西汀(duloxetine hydrochloride)、盐酸去甲文拉法辛(desvenlafaxine hydrochloride)等)、去甲肾上腺素再吸收抑制剂(甲磺酸瑞波西汀(reboxetine mesylate)等)、去甲肾上腺素-多巴胺再吸收抑制剂(盐酸安非他酮(bupropion hydrochloride)等)、米氮平(mirtazapine)、***唑酮(trazodone hydrochloride)、盐酸奈法唑酮(nefazodonehydrochloride)、盐酸安非他酮(bupropion hydrochloride)、马来酸司普替林(setiptiline maleate)、5-HT1A激动剂(盐酸丁螺环酮(buspirone hydrochloride)、枸橼酸坦度螺酮(tandospirone citrate)、盐酸奥莫佐坦(osemozotan hydrochloride)等)、5-HT3拮抗剂(氰美马嗪(Cyamemazine)等)、心脏非选择性β抑制剂(盐酸普奈洛尔(propranolol hydrochloride)、盐酸氧烯洛尔(oxprenolol hydrochloride)等)、组胺H1拮抗剂(盐酸羟嗪(hydroxyzine hydrochloride)等)、精神***症的治疗药物(氯丙嗪(chlorpromazine)、氟哌啶醇(haloperidol)、舒必利(sulpiride)、氯氮平(clozapine)、盐酸三氟拉嗪(trifluoperazine hydrochloride)、盐酸氟奋乃静(fluphenazinehydrochloride)、奥氮平(olanzapine)、富马酸喹硫平(quetiapine fumarate)、利培酮(risperidone)、阿立哌唑(aripiprazole)等)、CRF拮抗剂、其他抗焦虑药物(甲丙氨酯(meprobamate)等)、速激肽拮抗剂(MK-869、沙瑞度坦(saredutant)等)、对促代谢型谷氨酸受体起作用的药剂、CCK拮抗剂、β3肾上腺素拮抗剂(盐酸阿米拜龙(amibegronhydrochloride)等)、GAT-1抑制剂(盐酸噻加宾(tiagabine hydrochloride)等)、N型钙通道抑制剂、碳酸酐酶II抑制剂、NMDA甘氨酸部分激动剂、NMDA拮抗剂(盐酸美金刚(memantine)等)、外周苯二氮受体激动剂、加压素拮抗剂、加压素V1b拮抗剂、加压素V1a拮抗剂、磷酸二酯酶抑制剂、阿片样物质拮抗剂、阿片样物质激动剂、尿苷、烟酸受体激动剂、甲状腺激素(T3、T4)、TSH、TRH、MAO抑制剂(硫酸苯乙肼(phenelzine sulfate)、硫酸反苯环丙铵(tranylcypromine sulfate)、吗氯贝胺(moclobemide)等)、5-HT2A拮抗剂、5-HT2A反向激动剂、COMT抑制剂(恩他卡朋(entacapone)等)、双相障碍的治疗药物(碳酸锂、丙戊酸钠、拉莫三嗪(lamotrigine)、利鲁唑(riluzole)、非尔氨酯(felbamate)等)、***素CB1拮抗剂(利莫那班(rimonabant)等)、FAAH抑制剂、钠通道抑制剂、抗ADHD药物(盐酸哌甲酯(methylphenidate hydrochloride)、盐酸甲基***(methamphetamine hydrochloride)等)、酒精中毒的治疗药物、自闭症的治疗药物、慢性疲劳综合征的治疗药物、痉挛的治疗药物、纤维肌痛综合征的治疗药物、头痛的治疗药物、失眠的治疗药物(依替***(etizolam)、佐匹克隆(zopiclone)、***仑(triazolam)、唑吡坦(zolpidem)、雷美替胺(ramelteon)、因地普隆(indiplon)等)、戒烟的治疗药物、重症肌无力的治疗药物、脑梗死的治疗药物、躁狂症的治疗药物、睡眠过度的治疗药物、疼痛的治疗药物、心境恶劣的治疗药物、植物神经性共济失调的治疗药物、男性和女性性功能障碍的治疗药物、偏头痛的治疗药物、病态赌徒的治疗药物、不宁腿综合征的治疗药物、物质成瘾的治疗药物、酒精相关综合征的治疗药物、肠易激综合征的治疗药物、阿尔茨海默病的治疗药物(多奈哌齐(donepezil)、加兰他敏(galanthamine)、盐酸美金刚、利凡斯的明(rivastigmine)等)、帕金森病的治疗药物(左旋多巴(levodopa)、卡比多巴(carbidopa)、苄丝肼(benserazide)、司来吉兰(selegiline)、唑尼沙胺(zonisamide)、恩他卡朋(entacapone)、金刚烷胺(amantadine)、他利克索(talipexole)、普拉克索(pramipexole)、阿朴***(apomorphine)、卡麦角林(cabergoline)、溴隐亭(bromocriptine)、伊曲茶碱(istradefylline)、苯海索(trihexyphenidyl)、异丙嗪(promethazine)、培高利特(pergolide)等)、亨廷顿病的治疗药物(盐酸氯丙嗪(chlorpromazine hydrochloride)、氟哌啶醇、利血平(reserpine)等)、戈谢病(Gaucher's disease)的治疗药物(伊米苷酶(imiglucerase)、他立苷酶α(taliglucerase alfa)、维拉苷酶α(velaglucerase alfa)、依鲁司他(eliglustat)、麦格司他(miglustat)等)、ALS的治疗药物(利鲁唑(riluzole)等、神经营养因子等)、多发性硬化的治疗药物(分子靶向药物,如芬戈莫德(fingolimod)、干扰素β1b、那他珠单抗等)、抗癫痫药物(苯妥英(phenytoin)、卡马西平(carbamazepine)、***(phenobarbital)、扑米酮(primidone)、唑尼沙胺(zonisamide)、丙戊酸钠(sodium valproate)、乙琥胺(ethosuximide)、***、硝西泮(nitrazepam)、氯硝西泮(clonazepam)、氯巴占(clobazam)、加巴喷丁(gabapentin)、托吡酯(topiramate)、拉莫三嗪、左乙拉西坦(levetiracetam)、司替戊醇(stiripentol)、卢非酰胺(rufinamide)等)、血脂异常的治疗药物如降胆固醇药物(他汀系列(普伐他汀钠(pravastatin sodium)、阿托伐他汀(atorvastatin)、辛伐他汀(simvastatin)、瑞舒伐他汀(rosuvastatin)等)、贝特类(氯贝丁酯(clofibrate)等)、角鲨烯合成酶抑制剂)、由痴呆引起的异常行为的治疗药物或漫游症的抑制药(镇静药、抗焦虑药等)、细胞凋亡抑制剂、抗肥胖药、糖尿病的治疗药物、高血压的治疗药物、低血压的治疗药物、风湿病的治疗药物(DMARD)、抗癌剂、甲状旁腺的治疗药物(PTH)、钙受体拮抗剂、性激素或其衍生物(孕酮、***、苯甲酸***等)、神经元分化促进剂、神经再生促进剂、非甾体抗炎药(美洛昔康(meloxicam)、替诺昔康(tenoxicam)、吲哚美辛(indomethacin)、布洛芬(ibuprofen)、塞来昔布(celecoxib)、罗非昔布(rofecoxib)、阿司匹林(aspirin)等)、类固醇(***(dexamethasone)、醋酸可的松(cortisoneacetate)等)、抗细胞因子药物(TNF抑制剂、MAP激酶抑制剂等)、抗体药物、核酸或核酸衍生物、适配体药物等。
通过将化合物(I)和伴随药物组合,可以实现更好的作用,如
(1)如与化合物(I)或伴随药物的单一施用相比,可以减少剂量,
(2)可以根据患者的病情(轻症、重症等)选择待与化合物(I)组合的药物,
(3)可以通过选择与化合物(I)具有不同作用和机制的伴随药物来设定更长的治疗期,
(4)可以通过选择与化合物(I)具有不同作用和机制的伴随药物来设计持续的治疗效果,
(5)可以通过化合物(I)和伴随药物的组合使用来提供协同作用,等等。
下文将组合使用的化合物(I)和伴随药物称为“本发明的组合药剂”。
当使用本发明的组合药剂时,化合物(I)和伴随药物的施用时间不受限制,并且化合物(I)或其药物组合物和伴随药物或其药物组合物可以同时施用至施用对象,或者可以在不同的时间施用。伴随药物的剂量可以根据临床使用的用量来确定,并且可以根据施用对象、施用途径、疾病、组合等适当选择。
本发明的伴随药物的施用方式没有特别限制,并且在施用中组合化合物(I)和伴随药物是足够的。这种施用方式的例子包括以下方法:
(1)施用通过同时加工化合物(I)和伴随药物获得的单一制剂,(2)通过相同的施用途径同时施用分开产生的化合物(I)和伴随药物的两个种类的制剂,(3)通过相同的施用途径以交错方式施用分开产生的化合物(I)和伴随药物的两个种类的制剂,(4)通过不同的施用途径同时施用分开产生的化合物(I)和伴随药物的两个种类的制剂,(5)通过不同的施用途径以交错方式(例如,按化合物(I)和伴随药物的顺序或按相反的顺序施用)施用分开产生的化合物(I)和伴随药物的两个种类的制剂等。
本发明的组合药剂展现低毒性。例如,化合物(I)或(和)前述伴随药物可以根据已知方法与药理学上可接受的载体组合以制备药物组合物,如片剂(包括糖衣片和膜衣片)、散剂、颗粒剂、胶囊剂(包括软胶囊)、液体剂、注射剂、栓剂和缓释剂。这些组合物可以安全地口服或非口服施用(例如,局部施用、直肠施用、静脉内施用)。注射可以是静脉内、肌内、皮下施用或通过器官内施用或直接施用至病灶。
能用于产生本发明的组合药剂的药理学上可接受的载体的例子包括与上述载体类似的那些。
本发明的组合药剂中化合物(I)与伴随药物的混合比率可以根据施用对象、施用途径、疾病等适当地选择。
例如,本发明的组合药剂中化合物(I)的含量根据制剂的形式而不同,并且基于制剂,通常为约0.01wt%至约100wt%,优选约0.1wt%至约50wt%,进一步优选约0.5wt%至约20wt%。
本发明的组合药剂中伴随药物的含量根据制剂的形式而不同,并且基于制剂,通常为约0.01至约100wt%,优选约0.1至约50wt%,进一步优选约0.5至约20wt%。
实施例
下面通过参考实施例、实验实施例对本发明进行详细解释,这些实施例、实验实施例不应被解释为限制性的,并且本发明可以在本发明的范围内改变。
在以下实验实施例中使用的测试化合物如下。
表1
4-(4-氟-2-甲氧基苯基)-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺(化合物编号1)描述于WO 2012/160034的实施例2。
1-(3-{[4-(2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺(化合物编号2)在WO 2011/116951中描述为化合物B1。
1-(3-{[4-(4-氯-2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺(化合物编号3)在WO 2011/116951中描述为化合物B6。
1-[3-({4-[2-(苄氧基)苯基]-1,3,5-三嗪-2-基}氨基)苯基]甲磺酰胺(化合物编号4b)和其三氟乙酸盐(化合物编号4a)在WO 2011/116951中描述为化合物B13。
4-{2-[(3,4-二氯苯基)甲氧基]苯基}-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺(化合物编号5)描述于WO 2012/160034的实施例61。
{[(3-{[4-(2,3-二氢-1,4-苯并二噁英-5-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯(化合物编号6)描述于WO 2012/160034的实施例37。
{[(3-{[4-(2,3-二氢-1-苯并呋喃-7-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯(化合物编号7)描述于WO 2012/160034的实施例33。
实验实施例1
使用在K.Imamura等人,Science Translational Medicine 2017,9,eaaf3962中描述的ALS7(C9orf72)细胞系,检查了本发明中使用的化合物对RNA团簇的作用。所述细胞系是通过将四环素诱导的Lhx3、Ngn2和Isl1基因引入从具有C9orf72基因的G4C2重复序列的异常扩增的家族性ALS患者建立的iPS细胞系中制备的稳定细胞系。因此,ALS7(C9orf72)细胞是在将四环素或其衍生物添加到培养基中后,可迅速(约7天内)分化为运动神经元,并且分化后,自发延续到细胞死亡(参见上述文献)的ALS细胞模型。此外,本发明者已经发现,RNA团簇和DPR的生成在细胞死亡前自发发生。
将ALS7(C9orf72)细胞使用iPS细胞维持培养基在饲养细胞(丝裂霉素处理的SNL细胞)上培养,所述iPS细胞维持培养基由灵长类ES细胞培养基(ReproCell,RCHEMD001A)、4ng/ml hbFGF(Wako,060-04543)、50μg/ml G418(Nacalai,09380-86)和青霉素-链霉素(Thermo Fisher Scientific,15140-122)组成。
将ALS7(C9orf72)细胞接种在测定板上的方法如下。
将人工基膜(BD Falcon,D2650)用由DMEM/F-12(1:1)(Thermo FisherScientific,11330-057)、N2补充物(Thermo Fisher Scientific,17502-048)、青霉素-链霉素(Thermo Fisher Scientific,15140-122)、10ng/ml重组人BDNF(PeproTech,450-02)、10ng/ml重组人GDNF(PeproTech,450-10)、10ng/ml重组人NT-3(PeproTech,450-03)、1μM视黄酸(Sigma,R2625)、1μg/ml多西环素(Clontech,631311)、1μM SAG(Enzo life sciences,ALX-270-426-M001)和10μM Y-27632(Wako,253-00513)组成的测定培养基稀释20倍,然后用稀释的溶液涂布384孔板(CellCarrier-384Ultra,PerkinElmer,6057300)。
然后将ALS7(C9orf72)细胞悬浮在测定培养基中,并且以1x104个细胞/孔接种在人工基膜涂布的测定板上。
从ALS7(C9orf72)细胞分化的运动神经元中的RNA团簇的荧光染色方法如下。
对于根据在先前部分所述的方法接种在测定板上的ALS7(C9orf72)细胞,在接种四天后将不含Y-27632的测定培养基添加到所述板中,并且培养细胞。在接种后七天,将以预定浓度含有测试化合物的测定培养基(视黄酸、多西环素、SAG、无Y-27632)通过培养基交换添加到板中,并且在添加测试化合物后一天,将PFA(Wako,163-20145)添加到板中以固定细胞。在将用PBS(Wako,045-29795)洗涤重复三次后,将冰冷的甲醇(Wako,131-01826)添加到板中,并且允许板在室温下静置10分钟。将DNA探针[5'-(Cy3)-CCCGGCCCCCCCCGGCCCCCCGGG-3'(SEQ ID NO:1),SIGMA genosys,定制合成]在80℃变性75s,在由50%甲酰胺(Wako,066-02301)、2xSSC(Nippon Gene,319-90015)、50mM磷酸钠(TEKNOVA,P2070)、10%硫酸葡聚糖(SIGMA,D8906-100G)、0.1mg/mL酵母tRNA(INVITRON,15401029)和无核糖核酸酶水(QIAGEN,129112)组成的杂合缓冲液中制备至2μg/μL,并且添加到板中,并且允许板在37℃下静置16至24h以使探针与RNA团簇结合。将由50%甲酰胺、1xSSC和无核糖核酸酶水组成的洗涤缓冲液添加到板中,并且允许板在37℃下静置30分钟,然后用PBS洗涤。将用PBS稀释5000倍的Hoechst(invitrogen,H3569)添加到板中,并且允许板在室温下静置20分钟以将细胞核染色,然后用PBS洗涤。
通过用高含量分析仪分析上述处理的板(测量Cy3荧光)来检测细胞核中的RNA团簇。使用的高含量分析仪是来自PerkinElmer的Opera phoenix。图1显示了通过Opera获取的典型图像。
检测测试化合物活性的方法如下。
作为阴性对照,使用在补充有DMSO(而不是测试化合物)的测定培养基中培养的细胞(被诱导从ALS7(C9orf72)分化的运动神经元)。因为在一些情况下细胞分层并且细胞核相互重叠,所以使用核染色面积作为细胞数量的指标。通过用细胞核中RNA团簇的数量除以核染色面积来校正细胞数量的变化。
将测试化合物减少阴性对照中RNA团簇数量的程度定义为测试化合物的RNA团簇抑制活性,其通过下式来计算。
测试化合物的RNA团簇抑制活性
=100-X/C×100
X:测试化合物组中每个恒定核区域的RNA团簇数量,
C:DMSO组中每个恒定核区域的RNA团簇数量
在1、3和10μmol/l的测试化合物浓度下的活性在下表2中示出。
[表2]
如在表2中所示出的,当用任何所述化合物处理时,有效抑制了在ALS7(C9orf72)细胞来源的运动神经元中自发的RNA团簇生成。特别地,化合物编号1、4a、4b和5-7在1-10μM的广泛浓度范围内将RNA团簇生成抑制40%或更多。
因此,显示根据本发明的化合物可以有效抑制由G4C2重复序列的异常扩增引起的RNA团簇生成。
实验实施例2
接下来,检查在本发明中使用的化合物对RAN翻译的作用。在通过RAN翻译生成的DPR中,通过电化学发光***(Meso Scale Diagnostics)测量聚GP水平。
将ALS7(C9orf72)细胞以与实验实施例1中相同的程序接种在测定板上。接种后四天,将不含Y-27632的测定培养基添加到板中,并且培养细胞直至接种后七天,并且将以预定浓度含有测试化合物的测定培养基(视黄酸、多西环素、SAG、无Y-27632)通过培养基交换添加到板中。添加测试化合物后两天,去除培养基,并且使细胞在由8M尿素(Wako,219-00175)、4%CHAPS(Dojindo,349-04722)和30mM Tris-HCl(pH 8.0,Nippon Gene,312-90061)组成的尿素缓冲液中裂解。将细胞裂解物添加到多阵列384孔板(Meso ScaleDiagnostics,L21XB-4)中,并且将板在室温下用板振荡仪(Azwan,DM-301)以700rpm摇动,然后允许板在4℃下静置过夜。去除细胞裂解物,将由5%阻断剂A(Meso ScaleDiagnostics,R93AA-1)和1xTBS-T{含有0.05%Tween-20(Bio-Rad,170-6531)的TBS(Bio-Rad,170-6435)}组成的阻断缓冲液添加到板中,并将板在室温下用板振荡仪以700rpm摇动1h,然后用由0.05%Tween-20和PBS(Wako,162-18547)组成的洗涤缓冲液洗涤三次。将用含有1%阻断剂A的1xTBS-T稀释10,000倍的C9RANT抗体(Novus Biologicals,NBP2-25018)添加到板中,并且将板在4℃下用板振荡仪以700rpm摇动2h,然后允许板在4℃下静置过夜。在用洗涤缓冲液洗涤三次后,将用含有1%阻断剂A的1xTBS-T稀释500倍的SULFO-TAG山羊抗兔抗体(Meso Scale Diagnostics,R32AB-1)添加到板中,并且将板在室温下用板振荡仪以700rpm摇动2h。在用洗涤缓冲液洗涤三次后,将含有表面活性剂的2xMSD读取缓冲液T(MesoScale Diagnostics,R92TC-1)添加到板中,并且通过Meso SECTOR S600(Meso ScaleDiagnostics)测量源自C9RANT抗体的信号。
检测测试化合物活性的方法如下。
作为阴性对照,使用在补充有DMSO(而不是测试化合物)的测定培养基中培养的细胞。
将测试化合物减少阴性对照中的聚GP水平的程度定义为测试化合物的RAN翻译抑制活性,其通过下式来计算。
测试化合物的RAN翻译抑制活性
=100-X/C×100
X:测试化合物组中的聚GP水平,
C:DMSO组中的聚GP水平
在1、3和10μmol/l的测试化合物浓度下的活性在下表3中示出。
[表3]
如在表3中示出的,当用任何所述化合物处理时,有效地抑制了ALS7(C9orf72)细胞来源的运动神经元中的聚GP生成。
因此,显示根据本发明的化合物可以有效抑制由G4C2重复序列的异常扩增引起的RAN翻译。
实验实施例3
为了检查测试化合物的细胞毒性,测量了细胞内ATP水平。
将ALS7(C9orf72)细胞以与实验实施例1中相同的程序接种在测定板上。接种后四天,将不含Y-27632的测定培养基添加到板中,并且培养细胞直至接种后七天,并且将以预定浓度含有测试化合物的测定培养基(视黄酸、多西环素、SAG、无Y-27632)通过培养基交换添加到板中。添加测试化合物后24h或48h,去除培养基,并且进行CellTiter-Glo发光细胞活力测定(Promega,G7570)。
检测测试化合物的细胞毒性的方法如下。
作为阴性对照,使用在补充有DMSO(而不是测试化合物)的测定培养基中培养的细胞。
将对测试化合物处理的细胞中的细胞内ATP水平的作用程度定义为测试化合物与阴性对照相比的ATP水平,其通过下式来计算。
测试化合物与阴性对照相比的ATP水平=X/C×100
X:测试化合物组中的ATP水平,
C:DMSO组中的ATP水平
当细胞内ATP水平小于阴性对照中的细胞内ATP水平的0.5倍或大于阴性对照中的细胞内ATP水平的1.5倍时,将其判定为细胞毒性的。在1、3和10μmol/l的测试化合物浓度下的细胞内ATP水平在下表4中示出。
[表4]
如在表4中所示出的,当用任何所述化合物处理时,ALS7(C9orf72)细胞来源的运动神经元中的细胞内ATP水平的范围在阴性对照中的细胞内ATP水平的0.5至1.5倍内。即使在处理每种化合物48小时时,所述水平也在上述范围内。因此,认为根据本发明的化合物的细胞毒性是足够低的。特别地,对于化合物1、6和7,即使在1-10μM的浓度范围内处理48小时,细胞内ATP水平仍维持在阴性对照的80%或更多。因此,认为细胞毒性是极低的。
如根据这些结果清楚地,显示在具有足够低细胞毒性的浓度范围内,根据本发明的化合物可以有效抑制由G4C2重复序列的异常扩增引起的RNA团簇和RAN翻译。
可以预期与化合物编号1至7同样地,在下表5中示出的参考实施例1至30的化合物也可以抑制RNA团簇和RAN翻译,。
[表5-1]
[表5-2]
[表5-3]
[表5-4]
[表5-5]
制剂实施例
含有本发明的化合物作为活性成分的药剂可以例如通过以下配方来产生。
1.胶囊
将上述(1)、(2)和(3)的总量与5mg(4)共混并且粒化,并且添加5mg剩余的(4)。将全部混合物密封在明胶胶囊中。
2.片剂
将上述(1)、(2)和(3)的总量、20mg(4)和2.5mg(5)共混并且粒化,并且添加10mg剩余的(4)和2.5mg剩余的(5),并且使混合物压缩成形得到片剂。
工业实用性
根据本发明的化合物可以有效抑制由G4C2重复序列的异常扩增引起的神经变性疾病(例如,ALS或FTD)中RNA团簇的生成和通过RAN翻译的DPR的生成,并且可以预防或治疗此类疾病。一些神经变性疾病是因由不同的六(或三)核苷酸序列组成的重复序列的异常扩增所致,并且在任何情况下,认为RNA团簇和DPR的生成是导致神经变性的主要细胞毒性。并且,已经有人提出,在RNA团簇和DPR的生成过程中存在非序列依赖性的共同机制。
因此,预期根据本发明的化合物可以作为如下药剂做出贡献,所述药剂不仅用于预防或治疗由G4C2重复序列的异常扩增引起的神经变性疾病,而且用于预防或治疗由核苷酸重复序列的异常扩增引起的所有神经变性疾病。
本申请基于2020年3月27日在日本提交的专利申请号2020-058414,所述申请的内容全部涵盖在本文中。
序列表
<110> 国立大学法人京都大学(Kyoto University)
<120> 神经细胞变性抑制剂
<130> 093115
<150> JP2020-058414
<151> 2020-03-27
<160> 1
<170> PatentIn 3.5版
<210> 1
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> DNA探针
<400> 1
ccccggcccc ggccccggcc ccgg 24
Claims (11)
1.一种包含由式(I)表示的化合物的神经元变性抑制剂
其中
R1是由式(a-1)或(a-2)表示的基团
其中
R11和R12各自独立地是氢原子或C1-6烷基,
R13是氢原子、氰基、C1-6烷基-羰基或C1-6烷氧基-羰基,并且
R14是C1-6烷基、C3-8环烷基或C6-14芳基,
R2是由式(b-1)-(b-3)表示的基团
其中
R21是C1-6烷基、任选地被一个或多个卤素原子取代的C6-14芳基或任选地被一个或多个卤素原子取代的C7-16芳烷基,
R22各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,并且
n是0、1或2,
R3各自独立地是卤素原子、氰基、C1-6烷基或C1-6烷氧基,
m是0、1或2,并且
L是C1-3亚烷基,
或其盐。
2.根据权利要求1所述的神经元变性抑制剂,其中
R11和R12两者是氢原子,
R13是氢原子或C1-6烷氧基-羰基,
R14是C1-6烷基,
R21是C1-6烷基或任选地被一个或多个卤素原子取代的C7-16芳烷基,
R22是卤素原子,
n是0或1,
m是0,并且
L是亚甲基。
3.根据权利要求1所述的神经元变性抑制剂,其中由式(I)表示的化合物或其盐选自:
(1)4-(4-氟-2-甲氧基苯基)-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺、
(2)1-(3-{[4-(2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺、
(3)1-(3-{[4-(4-氯-2-甲氧基苯基)-1,3,5-三嗪-2-基]氨基}苯基)甲磺酰胺、
(4)1-[3-({4-[2-(苄氧基)苯基]-1,3,5-三嗪-2-基}氨基)苯基]甲磺酰胺、
(5)4-{2-[(3,4-二氯苯基)甲氧基]苯基}-N-{3-[(S-甲磺酰亚胺基)甲基]苯基}-1,3,5-三嗪-2-胺、
(6){[(3-{[4-(2,3-二氢-1,4-苯并二噁英-5-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯、
(7){[(3-{[4-(2,3-二氢-1-苯并呋喃-7-基)-1,3,5-三嗪-2-基]氨基}苯基)甲基](甲基)氧代-λ6-亚磺酰基}氨基甲酸乙酯,
和其盐。
4.根据权利要求1至3中任一项所述的神经元变性抑制剂,其用作用于预防或治疗运动神经元疾病或痴呆的药剂。
5.根据权利要求4所述的神经元变性抑制剂,其中所述运动神经元疾病或痴呆是涉及六核苷酸重复序列的异常扩增的运动神经元疾病或痴呆。
6.根据权利要求4或5所述的神经元变性抑制剂,其中所述运动神经元疾病是肌萎缩侧索硬化。
7.根据权利要求4或5所述的神经元变性抑制剂,其中所述痴呆是额颞叶痴呆。
8.一种用于抑制哺乳动物中神经元变性的方法,所述方法包括向所述哺乳动物施用有效量的如在权利要求1至3中任一项所定义的化合物或盐。
9.一种用于预防或治疗哺乳动物中神经元变性疾病的方法,所述方法包括向所述哺乳动物施用有效量的如在权利要求1至3中任一项所定义的化合物或盐。
10.一种如在权利要求1至3中任一项所定义的化合物或盐,其用于在预防或治疗神经元变性疾病中使用。
11.如在权利要求1至3中任一项所定义的化合物或盐用于制造用于预防或治疗神经元变性疾病的药剂的用途。
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EP4129293A4 (en) | 2024-04-03 |
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