CN111902143A - 神经细胞内钙浓度上升抑制剂 - Google Patents
神经细胞内钙浓度上升抑制剂 Download PDFInfo
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- CN111902143A CN111902143A CN201980023844.9A CN201980023844A CN111902143A CN 111902143 A CN111902143 A CN 111902143A CN 201980023844 A CN201980023844 A CN 201980023844A CN 111902143 A CN111902143 A CN 111902143A
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- increase
- amine derivative
- cyclic amine
- intracellular calcium
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- A61K31/4164—1,3-Diazoles
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Abstract
课题在于,提供神经细胞内钙浓度上升抑制剂。本发明提供神经细胞内钙浓度上升抑制剂,其含有下述的化学式所代表的环状胺衍生物或其药理学上可接受的盐作为有效成分。
Description
技术领域
本发明涉及神经细胞内钙浓度上升抑制剂。
背景技术
神经细胞中细胞内钙作为细胞内信息传递的信使而在分化、增殖、生长、存活、细胞凋亡、基因转录、膜兴奋、神经传递因子释放、突触可塑性之类的细胞功能的调节中发挥极为重要的功能(非专利文献1和2)。
平常的细胞内钙浓度保持为几十~百nmol/L左右,与此相对地,如果对细胞施加各种各样的刺激,则其钙浓度上升至几百nmol/L~几十μmol/L,因该细胞内钙浓度上升而引起多种多样的生命应答。并且,如果必要的生命应答结束,则细胞内钙浓度恢复至平常水平。因此,为了使细胞的功能正常发挥功能,必不可少的是严格地控制经由多种多样的受体、离子通道等而向细胞内外流入或流出的细胞内钙的浓度。
神经细胞中,如果细胞内钙浓度上升,则产生作为神经细胞的最重要功能的兴奋性传递。如果因某种原因而导致无法严格控制神经细胞内的钙浓度,则导致异常的细胞内钙浓度上升,其结果是产生大量的神经疾病和神经紊乱。该异常的细胞内钙浓度上升用例如超过正常范围的细胞内钙浓度、超过正常范围的细胞内钙浓度上升持续时间的长度、或超过正常范围的单位时间的细胞内钙浓度上升次数表示。例如,癫痫据信是因大脑神经细胞的异常兴奋、具体而言是因单位时间的细胞内钙浓度上升次数异常增加而引起的疾病之一。已知作为其治疗药的加巴喷丁与存在于兴奋性神经的突触前的电位依赖性钙通道结合从而抑制细胞内钙流入,通过抑制兴奋性突触传递而发挥抗癫痫作用(非专利文献3)。因此,神经细胞内钙浓度上升抑制剂在因与神经细胞的细胞内钙浓度上升相伴的异常兴奋而引起的各种各样的神经疾病和障碍的预防或治疗中是有用的。
专利文献1和2中,公开了环状胺衍生物具有镇痛作用,但针对与神经细胞内钙浓度上升抑制相关的效果,没有任何公开或教导。
现有技术文献
专利文献
专利文献1:国际公开第2013/147160号
专利文献2:国际公开第2016/136944号
非专利文献
非专利文献1:Berridge、Neuron、1998年、第21卷、p.13-26
非专利文献2:Pchitskaya等人、Cell Calcium、2018年、第70卷、p.87-94
非专利文献3:Fink等人、British Journal of Pharmacology、2000年、第130卷、p.900-906。
发明内容
发明要解决的课题
本发明的目的在于,提供神经细胞内钙浓度上升抑制剂。
用于解决课题的手段
本发明人等为了解决上述课题而反复进行了深入研究,结果发现,环状胺衍生物或其药理学上可接受的盐对神经细胞内钙浓度上升具有显著的抑制效果。
即,本发明提供神经细胞内钙浓度上升抑制剂,其含有下述通式(I)所示的环状胺衍生物或其药理学上可接受的盐作为有效成分,
[化1]
[式中,A表示下述通式(IIa)、(IIb)或(IIc)所示的基团;
[化2]
R1表示羟基或氢原子;R2表示甲基、乙基、正丙基、异丙基、正丁基、二氟甲基或2,2,2-三氟乙基;R3表示氢原子、氟原子、溴原子或氯原子;R4各自独立地表示甲基或乙基;n表示1或2;在R1表示羟基的情况下,标记*的碳表示不对称碳]。
上述的环状胺衍生物中,A优选为通式(IIa)所示的基团,此时,R2优选为甲基、乙基、正丙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。通过限定于这些,能够提高神经细胞内钙浓度上升抑制作用。
上述的环状胺衍生物中,A优选为通式(IIb)所示的基团,此时,R2优选为甲基、乙基、正丙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。通过限定于这些,能够提高神经细胞内钙浓度上升抑制作用。
上述的环状胺衍生物中,A优选为通式(IIc)所示的基团,n为1或2,此时,R2优选为甲基、乙基、正丙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。通过限定于这些,能够提高神经细胞内钙浓度上升抑制作用。
上述的环状胺衍生物中,R1优选为氢原子,此时,R2优选为甲基、乙基、正丙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。通过限定于这些,能够进一步提高神经细胞内钙浓度上升抑制作用。
上述的环状胺衍生物中,R1优选为羟基,此时,R2优选为甲基、乙基、正丙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子,标记*的不对称碳的立体化学优选为S构型。通过限定于这些,能够进一步提高神经细胞内钙浓度上升抑制作用。
此外,本发明提供用于治疗或预防与神经细胞的异常兴奋关联的疾病的药物组合物,其包含上述的通式(I)所示的环状胺衍生物或其药理学上可接受的盐、和药理学上可接受的赋形剂等。
此外,本发明提供上述的通式(I)所示的环状胺衍生物或其药理学上可接受的盐,其用于与神经细胞的异常兴奋关联的疾病的治疗或预防。
此外,本发明提供上述的通式(I)所示的环状胺衍生物或其药理学上可接受的盐的用途,其用于治疗或预防与神经细胞的异常兴奋关联的疾病。
此外,本发明提供上述的通式(I)所示的环状胺衍生物或其药理学上可接受的盐在用于治疗或预防与神经细胞的异常兴奋关联的疾病的药物的制造中的用途。
此外,本发明提供治疗或预防与神经细胞的异常兴奋关联的疾病的方法,其包括:对需要治疗的患者施与治疗有效量的上述通式(I)所示的环状胺衍生物或其药理学上可接受的盐。
此外,本发明提供抑制神经细胞内钙浓度上升的方法,其包括:使有效量的上述通式(I)所示的环状胺衍生物或其药理学上可接受的盐与神经细胞接触。
此外,本发明提供抑制神经细胞内钙浓度上升的方法,其包括:将有效量的上述通式(I)所示的环状胺衍生物或其药理学上可接受的盐施与需要其的对象。
此外,上述的与神经细胞的异常兴奋关联的疾病不仅限于此,但可以举出例如阿尔兹海默病、帕金森病、亨廷顿舞踏病、克雅氏病、肌肉萎缩性侧索硬化症(ALS)、脊髄小脑变性症、脊髄小脑失调症、唐氏综合征、多发性硬化症、精神分裂症、抑郁病、躁狂病、焦虑性神经症、强迫症、惊恐障碍、双相障碍、大脑皮质基底节变性、进行性核上性麻痹、路易体痴呆症、额颞叶变性症、作为阿尔兹海默病的前病变的轻度认知障碍、额颞叶痴呆症、癫痫、酒精依赖症、药物依赖症、焦虑症状、不愉快的精神状态、情绪异常、循环性精神病、神经过敏症、自闭症、晕厥、成瘾、性欲下降等中枢神经疾病;头部外伤、脊髄损伤、脑水肿、知觉功能障碍、糖尿病性神经病、植物神经功能紊乱、鞭抽式损伤等中枢和末梢神经紊乱;老年性痴呆症、脑血管性痴呆症、健忘症等记忆障碍、脑出血、脑梗塞等和其后遗症·并发症;无症状性脑血管疾病、短暂性脑缺血发作、高血压性脑病、血脑屏障的紊乱等脑血管疾病、脑血管疾病的复发或后遗症;脑血管阻塞后的中枢功能减退症、脑循环·肾循环自动调节能力的障碍或异常;特发性正常压力脑积水症、阻塞性脑积水症、感染性或者代谢性的脑病等代谢异常症;视神经脊髄炎、边缘性脑炎等自身免疫疾病;神经上皮组织性肿瘤(神经胶质瘤、神经细胞性肿瘤等)、神经鞘性肿瘤(神经鞘瘤、神经纤维瘤等)、髄膜性肿瘤(髄膜瘤、其他间叶性肿瘤)、鞍区肿瘤、转移性肿瘤等肿瘤性疾病、睡眠障碍或瘙痒症。
本说明书包括作为本申请的优先权基础的日本专利申请第2018-066541号的公开内容。
发明的效果
本发明的环状胺衍生物或其药理学上可接受的盐能够抑制神经细胞内钙浓度上升。
具体实施方式
本说明书中使用的下述术语在没有特别限制的情况下,如下述的定义所述。
本发明的一个实施方式所涉及的环状胺衍生物的特征在于,为下述的通式(I)所示,
[化3]
[式中,A表示下述通式(IIa)、(IIb)或(IIc)所示的基团;
[化4]
R1表示羟基或氢原子;R2表示甲基、乙基、正丙基、异丙基、正丁基、二氟甲基或2,2,2-三氟乙基;R3表示氢原子、氟原子、溴原子或氯原子;R4各自独立地表示甲基或乙基;n表示1或2;在R1表示羟基的情况下,标记*的碳表示不对称碳]。
上述的环状胺衍生物中,A优选为通式(IIa)所示的基团,此时,R2优选为甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,A优选为通式(IIa)所示的基团,此时,R2优选为正丙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,A优选为通式(IIb)所示的基团,此时,R2优选为甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,A优选为通式(IIb)所示的基团,此时,R2优选为正丙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,A优选为通式(IIc)所示的基团,n为1或2,此时,R2优选为甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,A优选为通式(IIc)所示的基团,n为1或2,此时,R2优选为正丙基,R3优选为氢原子或氯原子。此外,在R1为羟基的情况下,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,R1优选为氢原子,此时,R2优选为甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。
上述的环状胺衍生物中,R1优选为氢原子,此时,R2优选为正丙基,R3选为氢原子或氯原子。
上述的环状胺衍生物中,R1优选为羟基,此时,R2优选为甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3优选为氢原子或氯原子。此外,标记*的不对称碳的立体化学优选为S构型。
上述的环状胺衍生物中,R1优选为羟基,此时,R2优选为正丙基,R3优选为氢原子或氯原子。此外,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIa)所示的基团,R1是氢原子,R2是甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R2优选为甲基、乙基或2,2,2-三氟乙基,R3优选为氢原子。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIa)所示的基团,R1是氢原子,R2是正丙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R3优选为氢原子。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIa)所示的基团,R1是羟基,R2是甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R3优选为氢原子或氯原子。此外,本实施方式中,R2优选为甲基、乙基或2,2,2-三氟乙基,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIa)所示的基团,R1是羟基,R2是正丙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIb)所示的基团,R1是羟基,R2是甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R2优选为甲基、乙基或2,2,2-三氟乙基,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIb)所示的基团,R1是羟基,R2是正丙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIc)所示的基团,n是1或2,R1是羟基,R2是甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R2优选为甲基、乙基或2,2,2-三氟乙基,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIc)所示的基团,n是1或2,R1是羟基,R2是正丙基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基。本实施方式中,R3优选为氢原子。此外,本实施方式中,标记*的不对称碳的立体化学优选为S构型。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIa)所示的基团,R1是羟基或氢原子,R2是正丙基、异丙基或正丁基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基,在R1为羟基的情况下,标记*的碳表示不对称碳。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIb)所示的基团,R1是羟基或氢原子,R2是正丙基、异丙基或正丁基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基,在R1为羟基的情况下,标记*的碳表示不对称碳。
本发明的另一实施方式所涉及的环状胺衍生物中,A是通式(IIc)所示的基团,R1是羟基或氢原子,R2是正丙基、异丙基或正丁基,R3是氢原子、氟原子、溴原子或氯原子,R4各自独立地是甲基或乙基,n是1或2,在R1为羟基的情况下,标记*的碳表示不对称碳。
上述的通式(I)所示的环状胺衍生物(以下称为“环状胺衍生物(I)”)的优选的具体例示于表1-1、表1-2和表1-3,但本发明不限于这些。
[表1-1]
[表1-2]
[表1-3]
应予说明,在环状胺衍生物(I)中存在镜像异构体、立体异构体等异构体的情况下,任一种异构体和它们的混合物包括在环状胺衍生物(I)中。此外,在环状胺衍生物(I)中存在镜像异构体、立体异构体等异构体的情况下,环状胺衍生物(I)可以是包含任一种异构体或它们的混合物的混合物。此外,在环状胺衍生物(I)中存在因构象而导致的异构体的情况下,任一种异构体和它们的混合物包括在环状胺衍生物(I)中。目标异构体可以通过公知的方法或以其为基准的方法而得到。例如,在环状胺衍生物(I)中存在镜像异构体的情况下,从环状胺衍生物(I)中拆分得到的一个镜像异构体也包括在环状胺衍生物(I)中。
目标镜像异构体可以通过公知的手段(例如使用光学活性的合成中间体,或者对最终产物的外消旋混合物使用公知的方法或以其为基准的方法(例如光学拆分))而得到。
此外,环状胺衍生物(I)中,包括环胺衍生物(I)的前药或其药理学上可接受的盐。环状胺衍生物(I)的前药是指在生物体内以酶或化学的方式转化为环状胺衍生物(I)的化合物。环状胺衍生物(I)的前药的活性本体是环状胺衍生物(I),但环状胺衍生物(I)的前药本身也可以具有活性。
作为环状胺衍生物(I)的前药,可以举出例如环状胺衍生物(I)的羟基被烷基化、磷酸化或硼酸化而得到的化合物。这些化合物可以按照公知的方法由环状胺衍生物(I)合成。
此外,环状胺衍生物(I)的前药可以是在公知文献(“医药品的开发”、广川书店、1990年、第7卷、p.163~198和Progress in Medicine、第5卷、1985年、p.2157~2161)中记载的生理的条件下变化为环状胺衍生物(I)的物质。
环状胺衍生物(I)可以被同位素标记,作为所标记的同位素,可以举出例如2H、3H、13C、14C、15N、15O和/或18O。
作为环状胺衍生物(I)的药理学上可接受的盐,可以举出例如盐酸盐、硫酸盐、磷酸盐或氢溴酸盐等无机酸盐、或草酸盐、丙二酸盐、枸橼酸盐、富马酸盐、乳酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、乙酸盐、三氟乙酸盐、马来酸盐、葡糖酸盐、苯甲酸盐、水杨酸盐、昔萘酸盐、帕莫酸盐、抗坏血酸盐、己二酸盐、甲磺酸盐、对甲苯磺酸盐或肉桂酸盐等有机酸盐。
环状胺衍生物(I)或其药理学上可接受的盐中,包括其水合物和溶剂化物。
在环状胺衍生物(I)或其药理学上可接受的盐中存在多晶型物的情况下,所有多晶型物和它们的混合物包括在环状胺衍生物(I)或其药理学上可接受的盐中。
环状胺衍生物(I)或其药理学上可接受的盐可以按照例如公知文献(国际公开第2013/147160号)或公知文献(国际公开第2016/136944号)中记载的方法来合成。
本说明书中,“细胞内钙浓度上升”是指细胞内的钙浓度以产生异常的神经细胞的兴奋性传递的程度上升,以例如超过正常的范围的细胞内钙浓度、超过正常的范围的细胞内钙浓度上升持续时间的长度、或超过正常的范围的单位时间的细胞内钙浓度上升次数作为指标来表示。
本说明书中,“细胞内钙浓度上升抑制”是指抑制所产生的异常的神经细胞的兴奋性传递、或维持不产生异常的神经细胞的兴奋性传递的状态,以例如正常的范围内的细胞内钙浓度、正常的范围内的细胞内钙浓度上升持续时间的长度、或正常的范围内的单位时间的细胞内钙浓度上升次数作为指标来表示。此外,“细胞内钙浓度上升抑制”还是指与不抑制细胞内钙浓度上升的情况相比,抑制10%以上、20%以上、30%以上、40%以上、50%以上、60%以上、70%以上、80%以上、90%以上或100%细胞内钙浓度上升。
此外,上述的与神经细胞的异常兴奋关联的疾病不仅限于此,但可以举出例如阿尔兹海默病、帕金森病、亨廷顿舞踏病、克雅氏病、肌肉萎缩性侧索硬化症(ALS)、脊髄小脑变性症、脊髄小脑失调症、唐氏综合征、多发性硬化症、精神分裂症、抑郁病、躁狂病、焦虑性神经症、强迫症、惊恐障碍、双相障碍、大脑皮质基底节变性、进行性核上性麻痹、路易体痴呆症、额颞叶变性症、作为阿尔兹海默病的前病变的轻度认知障碍、额颞叶痴呆症、癫痫、酒精依赖症、药物依赖症、焦虑症状、不愉快的精神状态、情绪异常、循环性精神病、神经过敏症、自闭症、晕厥、成瘾、性欲下降等中枢神经疾病;头部外伤、脊髄损伤、脑水肿、知觉功能障碍、糖尿病性神经病、植物神经功能紊乱、鞭抽式损伤等中枢和末梢神经紊乱;老年性痴呆症、脑血管性痴呆症、健忘症等记忆障碍、脑出血、脑梗塞等和其后遗症·并发症;无症状性脑血管疾病、短暂性脑缺血发作、高血压性脑病、血脑屏障的紊乱等脑血管疾病、脑血管疾病的复发或后遗症;脑血管阻塞后的中枢功能减退症、脑循环·肾循环自动调节能力的障碍或异常;特发性正常压力脑积水症、阻塞性脑积水症、感染性或者代谢性的脑病等代谢异常症;视神经脊髄炎、边缘性脑炎等自身免疫疾病;神经上皮组织性肿瘤(神经胶质瘤、神经细胞性肿瘤等)、神经鞘性肿瘤(神经鞘瘤、神经纤维瘤等)、髄膜性肿瘤(髄膜瘤、其他间叶性肿瘤)、鞍区肿瘤、转移性肿瘤等肿瘤性疾病、睡眠障碍或瘙痒症。
环状胺衍生物(I)或其药理学上可接受的盐可用作用于治疗或预防哺乳动物(例如小鼠、大鼠、仓鼠、兔、猫、狗、牛、羊、猴或人)、特别是人的与神经细胞的异常兴奋关联的疾病的药物。
在将环状胺衍生物(I)或其药理学上可接受的盐用作药物的情况下,可以将环状胺衍生物(I)或其药理学上可接受的盐直接作为药物、或配混作为药物可接受的载体,从而经口或非经口地施与。
作为将含有环状胺衍生物(I)或其药理学上可接受的盐作为有效成分的药物经口施与的情况下的剂型,可以举出例如片剂(包括糖衣片和膜包衣片)、丸剂、颗粒剂、散剂、胶囊剂(包括软胶囊剂和微胶囊剂)、糖浆剂、乳剂或混悬剂。此外,作为将含有环状胺衍生物(I)或其药理学上可接受的盐作为有效成分的药物非经口施与的情况下的剂型,可以举出例如注射剂、注入剂、点滴剂、栓剂、涂布剂或贴剂。进一步,还有效的是,将环状胺衍生物(I)或其药理学上可接受的盐与适当的基剂(例如丁酸的聚合物、乙醇酸的聚合物、丁酸-乙醇酸的共聚物、丁酸的聚合物与乙醇酸的聚合物的混合物或聚甘油脂肪酸酯)组合,制成缓释性制剂。
上述的剂型的制剂的制备可以按照在制剂领域中常规使用的公知的制造方法来进行。在该情况下,根据需要,可以含有在制剂领域中常规使用的赋形剂、粘合剂、润滑剂、崩解剂、甜味剂、表面活性剂、悬浮剂或乳化剂等而制造。
片剂的制备可以含有例如赋形剂、粘合剂、崩解剂或润滑剂而进行。丸剂和颗粒剂的制备可以含有例如赋形剂、粘合剂或崩解剂而进行。此外,散剂和胶囊剂的制备可以含有例如赋形剂而进行。糖浆剂的制备可以含有例如甜味剂而进行。乳剂或混悬剂的制备可以含有例如表面活性剂、悬浮剂或乳化剂而进行。
作为赋形剂,可以举出例如乳糖、葡萄糖、淀粉、蔗糖、微晶纤维素、甘草末、甘露醇、碳酸氢钠、磷酸钙或硫酸钙。
作为粘合剂,可以举出例如淀粉糊液、阿拉伯胶液、明胶液、黄蓍胶液、羧基甲基纤维素液、藻酸钠液或甘油。
作为崩解剂,可以举出例如淀粉或碳酸钙。
作为润滑剂,可以举出例如硬脂酸镁、硬脂酸、硬脂酸钙或精制滑石。
作为甜味剂,可以举出例如葡萄糖、果糖、转化糖、山梨糖醇、木糖醇、甘油或单糖浆。
作为表面活性剂,可以举出例如月桂基硫酸钠、聚山梨酯80、脱水山梨糖醇单脂肪酸酯或聚氧乙烯40硬脂酸酯。
作为悬浮剂,可以举出例如阿拉伯胶、藻酸钠、羧基甲基纤维素钠、甲基纤维素或膨润土。
作为乳化剂,可以举出例如阿拉伯胶、黄蓍胶、明胶或聚山梨酯80。
进一步,在将含有环状胺衍生物(I)或其药理学上可接受的盐作为有效成分的药物制备为上述的剂型的情况下,可以添加在制剂领域中常规使用的着色剂、保存剂、芳香剂、矫味剂、稳定剂或粘稠剂等。
含有环状胺衍生物(I)或其药理学上可接受的盐作为有效成分的药物的平均1天的施与量根据患者的状态或体重、化合物的种类或施与通路等而不同。例如,在对成人(体重约60kg)经口施与的情况下,优选将环状胺衍生物(I)或其药理学上可接受的盐以有效成分量计以1~1000mg的范围分为1~3次施与。在对成人(体重约60kg)非经口施与的情况下,如果为注射剂,则优选将环状胺衍生物(I)或其药理学上可接受的盐以有效成分量计以平均1kg体重0.01~100mg的范围通过静脉注射施与。
环状胺衍生物(I)或其药理学上可接受的盐为了补充或增强治疗或预防效果、或者减少施与量,也可以与其他药物适量配混或并用。环状胺衍生物(I)或其药理学上可接受的盐可以与其他药物同时施与,也可以以任意的顺序连续施与。作为其他药物,不仅限于此,但可以举出上述的与神经细胞的异常兴奋关联的疾病的治疗药。可以举出例如多奈哌齐、美金刚、加兰他敏、卡巴拉汀、恩他卡朋、左旋多巴、苄丝肼盐酸盐、卡比多巴、唑尼沙胺、金刚烷胺盐酸盐、溴隐亭甲磺酸盐、培高利特甲磺酸盐、卡麦角林、普拉克索盐酸盐水合物、罗替戈汀、他利克索盐酸盐、罗匹尼罗盐酸盐、阿扑吗啡盐酸盐水合物、司来吉兰盐酸盐、苯海索盐酸盐、比哌立登盐酸盐、异丙嗪盐酸盐、伊曲茶碱、屈昔多巴、利鲁唑、普罗瑞林酒石酸盐水合物、他替瑞林水合物、氯丙嗪、氟哌啶醇、舒必利、利培酮、哌罗匹隆、奧氮平、喹硫平、帕罗西汀、氟伏沙明、舍曲林、艾司西酞普兰、米那普仑、度洛西汀、米氮平、阿莫沙平、阿米替林、丙咪嗪、氯丙米嗪、度硫平、曲米帕明、去甲替林、洛非帕明、司普替林、马普替林、米塞林、碳酸锂、卡马西平、丙戊酸钠、拉莫三嗪、托非索泮、氯噻西泮、依替唑仑、劳拉西泮、阿普唑仑、溴西泮、地西泮、氯硝西泮、氯噁唑仑、氯氟䓬乙酯、氟托西泮、坦度螺酮枸橼酸盐、双硫仑、氨基氰、阿坎酸、丙戊酸、乙琥胺、苯巴比妥、卡马西泮、苯妥英、安贝氯铵、氯化腾喜龙、氯化乙酰胆碱、溴化新斯的明、舒更葡糖钠、新斯的明甲基硫酸盐、吡拉西坦、吡啶斯地明溴化物、氨甲酰甲胆碱氯化物、甲基硫酸新斯的明、阿托品硫酸盐水合物、普瑞巴林、依帕司他、美西律、阿司匹林、噻氯匹定盐酸盐、氯吡格雷硫酸盐、西洛他唑、华法林钾、达比加群酯甲磺酸盐、依度沙班对甲苯磺酸盐水合物、利伐沙班、阿哌沙班、异戊巴比妥、艾司佐匹克隆、艾司唑仑、夸西泮、苏沃雷生(Suvorexant)、司可巴比妥钠、佐匹克隆、唑吡坦酒石酸盐、右美托咪定盐酸盐、三唑仑、三氯福司钠、硝西泮、卤噁唑仑、苯巴比妥钠、氟硝西泮、氟西泮盐酸盐、溴替唑仑、溴戊酰脲、戊巴比妥钙、水合氯醛、咪达唑仑、雷美替胺、利马扎封盐酸盐、氯甲西泮或纳呋拉啡盐酸盐。
实施例
以下,基于实施例具体说明本发明,但本发明不限于这些。
作为受试化合物,使用表2所示的1-(4-(二甲基氨基)哌啶-1-基)-3-(1-乙基-1H-咪唑-2-基)-3-羟基丙-1-酮(以下称为“化合物1”)、(S)-1-(4-(二甲基氨基)哌啶-1-基)-3-羟基-3-(1-甲基-1H-咪唑-2-基)丙-1-酮(以下称为“化合物2”)、1-(4-(二甲基氨基)哌啶-1-基)-3-羟基-3-(1-(2,2,2-三氟乙基)-1H-咪唑-2-基)丙-1-酮(以下称为“化合物3”)和1-(4-(二甲基氨基)哌啶-1-基)-3-(1-甲基-1H-咪唑-2-基)丙-1-酮硫酸盐1水合物(以下称为“化合物4”),按照公知文献(国际公开第2013/147160号和国际公开第2016/136944号)中记载的方法合成。
[表2]
进一步,作为受试化合物,使用表3所示的1-((R)-3-(3-(二甲基氨基)哌啶-1-基)-3-羟基-3-(1-甲基-1H-咪唑-2-基)丙-1-酮(以下称为“化合物5”)、3-羟基-3-(1-甲基-1H-咪唑-2-基)-1-(4-(4-甲基哌嗪-1-基)哌啶-1-基)丙-1-酮(以下称为“化合物6”)、1-(4-(二甲基氨基)哌啶-1-基)-3-(1-丙基-1H-咪唑-2-基)-3-羟基丙-1-酮(以下称为“化合物7”)、1-((R)-3-(二甲基氨基)吡咯烷-1-基)-3-羟基-3-(1-甲基-1H-咪唑-2-基)丙-1-酮(以下称为“化合物8”)、3-(5-氯-1-甲基-1H-咪唑-2-基)-1-(4-(二甲基氨基)哌啶-1-基)-3-羟基丙-1-酮(以下称为“化合物9”)、1-(4-(二甲基氨基)哌啶-1-基)-3-(1-异丙基-1H-咪唑-2-基)-3-羟基丙-1-酮(以下称为“化合物10”)、1-(4-(二甲基氨基)哌啶-1-基)-3-(1-(2-甲氧基乙基)-1H-咪唑-2-基)-3-羟基丙-1-酮(以下称为“比较例1的化合物”)和1-(4-(二甲基氨基)哌啶-1-基)-3-(1-(3,3,3-三氟丙基)-1H-咪唑-2-基)-3-羟基丙-1-酮(以下称为“比较例2的化合物”)。
表3所示的受试物质之中,化合物5、化合物6和化合物8按照公知文献(国际公开第2013/147160号和国际公开第2016/136944号)中记载的方法合成。化合物7、化合物9和化合物10的化合物通过以下的实施例中记载的方法合成。针对比较例1的化合物和比较例2的化合物,通过以下的参考例中记载的方法合成。此外,它们的原料和中间体通过以下的参考例中记载的方法合成。应予说明,针对参考例化合物的合成中使用的化合物中未记载合成方法的物质,使用市售的化合物。
以下的记载中,NMR数据中所示的溶剂名表示测定中使用的溶剂。此外,400 MHzNMR谱使用JNM-AL400型核磁共振装置(日本电子公司制)测定。化学位移以四甲基硅烷作为基准,用δ(单位:ppm)表示,信号各自用s(单峰)、d(二重峰)、t(三重峰)、q(四重峰)、quint(五重峰)、sept(七重峰)、m(多重峰)、br(宽峰)、dd(双二重峰)、dt(双三重峰)、ddd(三二重峰)、dq(双四重峰)、td(三双重峰)、tt(三重三重峰)表示。ESI-MS谱使用AgilentTechnologies 1200 Series、G6130A(Agilent Technology公司制)测定。溶剂全部使用市售物质。快速柱色谱使用YFLC W-prep2XY(山善公司制)。
(参考例1)1-丙基-1H-咪唑-2-甲醛的合成:
[化5]
向1H-咪唑-2-甲醛(1.00g、10.4mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中添加1-碘丙烷(1.22mL、12.5mmol)和碳酸钾(2.16g、15.6mmol),在60℃下进行3小时搅拌。向反应液中添加水,用乙酸乙酯萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(硅胶、己烷/乙酸乙酯)纯化,得到黄色油状物形式的1-丙基-1H-咪唑-2-甲醛(0.786g、5.69mmol、55%)。
(参考例2) 5-氯-1-甲基-1H-咪唑-2-甲醛的合成:
[化6]
向(5-氯-1-甲基-1H-咪唑-2-基)甲醇(0.300g、2.05mmol)的二氯甲烷(20.0mL)溶液中,在0℃下添加戴斯马丁试剂(1.04g、2.46mmol),在该温度下进行3小时搅拌。向反应液中添加10%硫代硫酸钠水溶液和饱和碳酸氢钠水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(硅胶、己烷/乙酸乙酯)纯化,得到白色固体形式的5-氯-1-甲基-1H-咪唑-2-甲醛(0.235g、1.62mmol、79%)。
(参考例3)1-异丙基-1H-咪唑-2-甲醛的合成:
[化7]
向1H-咪唑-2-甲醛(1.00g、10.4mmol)的N,N-二甲基甲酰胺(10mL)溶液中添加2-碘丙烷(1.26mL、12.5mmol)和碳酸钾(2.16g、15.6mmol),在60℃下进行3小时搅拌。向反应液中添加水,用乙酸乙酯萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(硅胶、己烷/乙酸乙酯)纯化,得到黄色油状物形式的1-异丙基-1H-咪唑-2-甲醛(0.703g、5.09mmol、49%)。
(参考例4)1-(2-甲氧基乙基)-1H-咪唑-2-甲醛的合成:
[化8]
向1H-咪唑-2-甲醛(1.00g、10.4mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中,添加2-溴乙基甲基醚(1.20mL、12.5mmol)和碳酸钾(2.16g、15.6mmol)、碘化钠(0.468g、3.12mmol),在60℃下搅拌3小时。向反应液中添加水,用乙酸乙酯萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(硅胶、己烷/乙酸乙酯)纯化,得到白色固体形式的1-(2-甲氧基乙基)-1H-咪唑-2-甲醛(0.535g、3.47mmol、33%)。
(参考例5)1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛的合成:
[化9]
向1H-咪唑-2-甲醛(0.500g、5.20mmol)的N,N-二甲基甲酰胺(5.20mL)溶液中,添加1,1,1-三氟-3-碘丙烷(0.710mL、6.24mmol)和碳酸钾(1.08g、7.81mmol),在60℃下进行5小时搅拌。向反应液中添加水,用乙酸乙酯萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(硅胶、己烷/乙酸乙酯)纯化,得到无色油状物形式的1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛(0.0863g、0.449mmol、8.6%)。
(参考例6)比较例1的化合物的合成:
[化10]
向1-(4-二甲基氨基哌啶-1-基)乙酮(0.300g、1.76mmol)的四氢呋喃(6.00mL)溶液中,在-78℃下滴加二异丙基氨基锂的四氢呋喃溶液(2.0M、0.969mL、1.94mmol),在相同温度下进行1小时搅拌。向反应液中在相同温度下添加1-(2-甲氧基乙基)-1H-咪唑-2-甲醛(0.292g、2.12mmol)的四氢呋喃溶液(2.80mL),进行1小时搅拌后,在0℃下进一步进行1小时搅拌。向反应液中按顺序添加饱和氯化铵水溶液、碳酸钾水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(NH硅胶、氯仿/甲醇)纯化,得到无色油状物形式的比较例1的化合物(0.193g、0.594mmol、34%)。
(参考例7)比较例2的化合物的合成:
[化11]
向1-(4-二甲基氨基哌啶-1-基)乙酮(0.0760g、0.448mmol)的四氢呋喃(1.80mL)溶液中,在-78℃下滴加二异丙基氨基锂的四氢呋喃溶液(2.0M、0.246mL、0.492mmol),在相同温度下进行1小时搅拌。向反应液中在相同温度下添加1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛(0.0860g、0.448mmol)的四氢呋喃溶液(0.70mL),进行1小时搅拌后,在0℃下进一步进行1小时搅拌。向反应液中按顺序添加饱和氯化铵水溶液、碳酸钾水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(NH硅胶、氯仿/甲醇)纯化,得到无色油状物形式的比较例2的化合物(0.0845g、0.233mmol、52%)。
(实施例1)化合物7的合成:
[化12]
向1-(4-二甲基氨基哌啶-1-基)乙酮(0.300g、1.76mmol)的四氢呋喃(6.00mL)溶液中,在-78℃下滴加二异丙基氨基锂的四氢呋喃溶液(2.0M、0.969mL、1.94mmol),在相同温度下进行1小时搅拌。向反应液中在相同温度下添加1-丙基-1H-咪唑-2-甲醛(0.292g、2.12mmol)的四氢呋喃溶液(2.8mL),进行1小时搅拌后,在0℃下进一步进行1小时搅拌。向反应液中按顺序添加饱和氯化铵水溶液、碳酸钾水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(NH硅胶、氯仿/甲醇)纯化,得到无色油状物形式的化合物7(0.296g、0.960mmol、55%)。
(实施例2)化合物9的合成:
[化13]
向1-(4-二甲基氨基哌啶-1-基)乙酮(0.231g、1.36mmol)的四氢呋喃(5.10mL)溶液中,在-78℃下滴加二异丙基氨基锂的四氢呋喃溶液(2.0M、0.745mL、1.49mmol),在相同温度下进行1小时搅拌。向反应液中在相同温度下添加5-氯-1-甲基-1H-咪唑-2-甲醛(0.235g、1.63mmol)的四氢呋喃溶液(1.70mL),进行1小时搅拌后,在0℃下进一步进行1小时搅拌。向反应液中按顺序添加饱和氯化铵水溶液、碳酸钾水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(NH硅胶、氯仿/甲醇)纯化,得到无色油状物形式的化合物9(0.159g、0.505mmol、37%)。
(实施例3)化合物10的合成:
[化14]
向1-(4-二甲基氨基哌啶-1-基)乙酮(0.300g、1.76mmol)的四氢呋喃(6.00mL)溶液中,在-78℃下滴加二异丙基氨基锂的四氢呋喃溶液(2.0M、0.969mL、1.94mmol),在相同温度下进行1小时搅拌。向反应液中在相同温度下添加1-异丙基-1H-咪唑-2-甲醛(0.292g、2.12mmol)的四氢呋喃溶液(2.8mL),进行1小时搅拌后,在0℃下进一步进行1小时搅拌。向反应液中按顺序添加饱和氯化铵水溶液、碳酸钾水溶液,用氯仿萃取。将有机层用10%氯化钠水溶液洗涤后,用无水硫酸钠干燥、过滤,将滤液减压浓缩。将残渣用快速柱色谱(NH硅胶、氯仿/甲醇)纯化,得到无色油状物形式的化合物10(0.302g、0.979mmol、56%)。
[表3]
(实施例4)环状胺衍生物(I)或其药理学上可接受的盐对大鼠脊髄背根神经节(DRG)神经细胞的高钾诱发细胞内钙浓度上升的效果:
研究环状胺衍生物(I)或其药理学上可接受的盐对DRG神经细胞的高钾诱发细胞内钙浓度上升的抑制效果。
(1)DRG的采集
将SD大鼠(4~6周龄、雄性;日本チャールス·リバー)在麻醉下切开腹大动脉,通过放血而安乐死。切开后背部后,摘除脊柱并用冰冷。切取脊柱背侧,从脊柱腹侧去除脊髄后,用精密镊子摘除伴有神经纤维束的DRG(L4~L6)。使摘除的DRG浸渍在冰冷的Leibovitz's L-15培养基(Thermo Fisher Scientific)中,在实体显微镜下去除神经纤维束,分离DRG。
(2)DRG神经细胞的分散培养
将分离的DRG用眼科剪刀精细地切入切口后,用胶原蛋白酶A(Collagenase A,RocheMolecular Systems),在37℃下温育20分钟。以200×g、5分钟进行离心分离后,去除上清液,添加0.05%的Trypsin-EDTA(Thermo Fisher Scientific),在37℃下温育5分钟。添加含有1%青霉素-链霉素(Thermo Fisher Scientific)和10%胎牛血清(Thermo FisherScientific)的DMEM(Thermo Fisher Scientific),以200×g、5分钟进行离心分离后,去除上清液。去除上清液后,添加作为DRG神经培养培养基而制备的含有1%青霉素-链霉素和2%B-27(Thermo Fisher Scientific)的Neurobasal-A Medium(Thermo Fisher Scientific)后,用微量吸移管吸取,使细胞分散。分散后,通过70μm细胞筛(Greiner),以200×g、5分钟进行离心。离心分离后,去除上清液,添加培养基,将细胞悬浮。将该细胞悬浮液接种于预先包被有层连蛋白(Sigma-Aldrich)的聚赖氨酸包被35mm皿(松浪硝子工业),在37℃、5%CO2下培养过夜后,用于细胞内钙浓度变化测定。
(3)钙荧光色素的负载
作为荧光钙色素,使用Cal-520,AM(注册商标)(AAT Bioquest)。从在皿中培养的细胞中去除培养基,用灌流液洗涤2次后,添加制备为4μmol/L的Cal-520,AM溶液,在37℃、5%CO2下进行1~1.5小时培养。灌流液使用制备为pH7.4的包含NaCl(140mmol/L)、KCl(5mmol/L)、CaCl2·2H2O(1.2mmol/L)、MgCl2·6H2O(2mmol/L)、D(+)-葡萄糖(14mmol/L)和HEPES(10mmol/L)的水溶液。其后,将灌流液在皿中以10分钟、2mL/分钟进行灌流,由此进行洗涤。
(4)细胞内钙浓度变化的测定
细胞内钙浓度变化的测定通过利用分析软件来分析对负载有钙荧光色素的细胞的荧光强度变化用共焦点激光显微镜系统(Nikon Instech Co., Ltd.)拍摄得到的图像,从而进行。激光波长为488nm,图像以1分钟57~60张的间隔获取。
作为神经细胞的兴奋诱发,为了诱发因细胞膜的去极化而导致的细胞内钙浓度上升,进行使用高钾溶液的处理(以下称为“高钾处理”)。对细胞的高钾处理、和使用环状胺衍生物(I)或其药理学上可接受的盐(化合物1~10、比较例1的化合物和比较例2的化合物)的处理(以下称为“化合物处理”)通过溶液的灌流置换来进行。灌流速度用管泵控制为2mL/分钟。利用高钾处理的细胞内钙浓度上升诱发通过用制备为pH7.4的包含NaCl(125mmol/L或115mmol/L)、KCl(32.5mmol/L或30mmol/L)、CaCl2·2H2O(1.2mmol/L)、MgCl2·6H2O(2mmol/L)、D(+)-葡萄糖(14mmol/L)和HEPES(10mmol/L)的水溶液对细胞进行1分钟处理而进行。高钾处理以5分间隔进行8次。化合物处理通过下述方式进行:将化合物1~10、比较例1的化合物和比较例2的化合物以达到100mmol/L的方式溶解在蒸馏水(大塚制药工场)中后,将以达到30μmol/L的方式用灌流液稀释得到的溶液对细胞进行处理,从而进行。化合物处理从第3次的高钾处理开始3分钟前连续进行直至第8次的高钾处理结束后(以下将其称为“化合物处理组”)。作为对照,使用用灌流液稀释蒸馏水而得到的溶液的处理从第3次的高钾处理开始3分钟前连续进行直至第8次的高钾处理结束后(以下将其称为“溶剂处理组”)。但是,针对化合物5~10、比较例1的化合物和比较例2的化合物,利用高钾处理的细胞内钙浓度上升诱发通过用制备为pH7.4的包含NaCl(115mmol/L)、KCl(30mmol/L)、CaCl2·2H2O(1.2mmol/L)、MgCl2·6H2O(2mmol/L)、D(+)-葡萄糖(14mmol/L)和HEPES(10mmol/L)的水溶液对细胞进行1分钟处理而进行。
(5)图像分析和细胞内钙浓度上升抑制率的算出
所拍摄的图像通过ImageJ 1.51j8(National Institutes of Health)进行分析。随时间测定各细胞的亮度值,制作随时间变化亮度值曲线,算出各高钾处理时的随时间变化亮度值曲线下面积(AUC)。各细胞的反应率作为第7次和第8次的高钾处理时的AUC之和相对于第1次和第2次的高钾处理时的AUC之和的比例,通过以下的式1算出。接着,基于各细胞的反应率和溶剂处理组的全部细胞的反应率的平均值,通过以下的式2,算出各细胞的细胞内钙浓度上升抑制率。将各组的全部细胞的抑制率的平均值记作各组的抑制率,将溶剂处理组的细胞内钙浓度上升抑制率记作0%。
各细胞的反应率=第7次和第8次的高钾处理时的AUC之和÷第1次和第2次的高钾处理时的AUC之和×100···式1
各细胞的细胞内钙浓度上升抑制率(%)=(1-各细胞的反应率÷溶剂处理组的全部细胞的反应率的平均值)×100···式2。
化合物1~4对通过DRG神经细胞的高钾处理而诱发的细胞内钙浓度上升的抑制效果示于表4。表中的“抑制率”表示所算出的细胞内钙浓度上升抑制率(为平均值,各组的细胞数为106~262个)。表中的“化合物1”、“化合物2”、“化合物3”和“化合物4”是指利用各化合物的化合物处理组。表中的“#”和“###”表示与溶剂处理组相比有统计学上显著(#:p<0.05、###:p<0.001、Dunnet型多重比较检验)的差异。
[表4]
在任一化合物处理组中,与溶剂处理组相比,均显著抑制了细胞内钙浓度上升。即,明确了化合物1~4抑制DRG神经细胞的高钾诱发细胞内钙浓度上升。此外,通式(I)中,利用R1为羟基的化合物1~3的化合物处理组的神经细胞内钙浓度上升抑制率与利用R1为氢原子的化合物4的化合物处理组相比更强。
通过与上述相同的方法测定得到的化合物5~10、比较例1的化合物和比较例2的化合物的抑制效果示于表5(为平均值,各组的细胞数为60~250个)。表中的“化合物5”、“化合物6”、“化合物7”、“化合物8”、“化合物9”、“化合物10”、“比较例1的化合物”和“比较例2的化合物”是指利用各化合物的化合物处理组。表中的“###”表示与溶剂处理组相比有统计学上显著(###:p<0.001、Dunnet型多重比较检验)的差异。
[表5]
化合物5~10处理组中,抑制了细胞内钙浓度上升。其中,化合物5~8处理组中,与溶剂处理组相比,显著抑制了细胞内钙浓度上升。另一方面,比较例1的化合物处理组和比较例2的化合物处理组中,细胞内钙浓度上升未被抑制。
根据上文,显示环状胺衍生物(I)或其药理学上可接受的盐为神经细胞内钙浓度上升抑制剂。
工业实用性
本发明的环状胺衍生物(I)或其药理学上可接受的盐显著抑制神经细胞内钙浓度上升,因此可以用作对与神经细胞的异常兴奋关联的疾病的药物。
本说明书中引用的全部出版物、专利和专利申请通过直接引用的方式并入本说明书中。
Claims (10)
2.根据权利要求1所述的神经细胞内钙浓度上升抑制剂,其中,A是通式(IIa)所示的基团。
3.根据权利要求1所述的神经细胞内钙浓度上升抑制剂,其中,A是通式(IIb)所示的基团。
4.根据权利要求1所述的神经细胞内钙浓度上升抑制剂,其中,A是通式(IIc)所示的基团。
5.根据权利要求1所述的神经细胞内钙浓度上升抑制剂,其中,R1是氢原子。
6.根据权利要求1所述的神经细胞内钙浓度上升抑制剂,其中,R1是羟基。
7.根据权利要求1~6中任一项所述的神经细胞内钙浓度上升抑制剂,其中,R2是甲基、乙基、异丙基、正丁基或2,2,2-三氟乙基。
8.根据权利要求1~6中任一项所述的神经细胞内钙浓度上升抑制剂,其中,R2是正丙基。
9.根据权利要求1~6中任一项所述的神经细胞内钙浓度上升抑制剂,其中,R3是氢原子或氯原子。
10.根据权利要求1~4和6中任一项所述的神经细胞内钙浓度上升抑制剂,其中,标记*的不对称碳的立体化学是S构型。
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