CN110691593B - 脊髓小脑变性症预防或治疗剂 - Google Patents
脊髓小脑变性症预防或治疗剂 Download PDFInfo
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- CN110691593B CN110691593B CN201880035501.XA CN201880035501A CN110691593B CN 110691593 B CN110691593 B CN 110691593B CN 201880035501 A CN201880035501 A CN 201880035501A CN 110691593 B CN110691593 B CN 110691593B
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- atrophy
- cerebellar atrophy
- spinocerebellar
- cerebellar
- spinocerebellar degeneration
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Abstract
本发明的课题为提供脊髓小脑变性症的优异的预防或治疗剂。1‑(3‑(2‑(1‑苯并噻吩‑5‑基)乙氧基)丙基)氮杂环丁烷‑3‑醇或其盐具有抑制脑萎缩，特别是小脑萎缩的效果，可用于脊髓小脑变性症预防或治疗剂。通过施用1‑(3‑(2‑(1‑苯并噻吩‑5‑基)乙氧基)丙基)氮杂环丁烷‑3‑醇或其盐，可以预防或治疗在脊髓小脑变性症中观察到的小脑萎缩。
Description
技术领域
本发明涉及含有1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇或其盐作为活性成分的脊髓小脑变性症的预防或治疗剂。
背景技术
脊髓小脑变性症为以小脑性或脊髓后索性共济失调及痉挛性截瘫作为主要症状的神经变性疾病。脊髓小脑变性症可以大体分类为遗传性和非遗传性两种。作为遗传性的，可列举例如：遗传性橄榄脑桥小脑萎缩、遗传性皮质小脑萎缩、脊髓小脑变性症1型、脊髓小脑变性症2型、脊髓小脑变性症3型(马查多-约瑟夫病)、脊髓小脑变性症6型、脊髓小脑变性症31型、遗传性齿状核红核苍白球路易体萎缩、毛细血管扩张性共济失调、弗里德赖希共济失调，共济失调伴维生素E缺乏症(AVED)、Aprataxin缺乏症(早发性共济失调伴眼动失用症和低白蛋白血症/共济失调伴眼动失用症1型，EAOH/AOA1)、Senataxin缺乏症(共济失调伴眼动失用症2型，AOA2)、Charlevoix-Saguenay常染色体隐性遗传性痉挛性共济失调(Autosomal recessive spastic ataxia of Charlevoix-Saguenay，ARSACS)、遗传性痉挛性截瘫(Hereditary Spastic Paraplegia，HSP)等，作为非遗传性的，可列举例如：橄榄脑桥小脑萎缩、夏伊-德雷格综合征、纹状体黑质变性、皮质性小脑萎缩。虽然将初期症状为小脑性共济失调的称为橄榄脑桥小脑萎缩，为帕金森综合征的称为纹状体黑质变性症，体位性低血压等自主神经障碍显著的称为夏伊-德雷格综合征，但从都是进展则症状重叠、可见脑干和小脑萎缩及纹状体的异常等外观、组织病理学所见共通来看，它们也被总称为多系统萎缩。
作为药物疗法，对所有失调症状可使用促甲状腺素释放激素(TRH)或TRH衍生物。另外，作为针对各疾病的症状对症使用的药物，可列举：对于痛性肌肉痉挛的盐酸美西律，对于反复发作性的失调症状、眩晕症状的乙酰唑胺等。
已知1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇(以下称为“化合物A”)或其盐具有神经保护作用、神经再生促进作用及轴突生长作用，为作为中枢及外周神经疾病的治疗药有用的化合物(专利文献1)。另外，其给药量被记载为在口服施用的情况下，通常对于成人，可以每1天0.01～500mg以1次～分成多次进行施用(专利文献2)。
现有技术文献
专利文献
专利文献1：国际公开第2003/035647号公报
专利文献2：国际公开第2003/105830号公报
发明内容
发明要解决的问题
本发明的目的是提供脊髓小脑变性症的优异的预防或治疗剂。
解决问题的方法
在这样的情况下，本发明人发现化合物A或其盐具有抑制小脑萎缩的效果，从而完成了本发明。
根据本发明，提供以下发明。
(1)含有化合物A或其盐作为活性成分的脊髓小脑变性症预防或治疗剂。
(2)根据(1)所述的脊髓小脑变性症预防或治疗剂，其中，脊髓小脑变性症为遗传性橄榄脑桥小脑萎缩、遗传性皮质小脑萎缩、脊髓小脑变性症3型(马查多-约瑟夫病)、脊髓小脑变性症6型、脊髓小脑变性症31型或皮质性小脑萎缩。
(3)根据(1)或(2)所述的脊髓小脑变性症预防或治疗剂，其用于抑制患有脊髓小脑变性症的患者的小脑萎缩。
(4)根据(1)或(2)所述的脊髓小脑变性症预防或治疗剂，其用于改善患有脊髓小脑变性症的患者的共济失调。
(5)根据(1)或(2)所述的脊髓小脑变性症预防或治疗剂，其用于改善患有脊髓小脑变性症的患者的平衡障碍。
(6)根据(1)～(5)中任一项所述的脊髓小脑变性症预防或治疗剂，其以每次以化合物A计100mg～400mg、1天1次口服施用。
(7)根据(1)～(5)中任一项所述的脊髓小脑变性症预防或治疗剂，其以每次以化合物A计160mg或320mg、1天1次口服施用。
另外，根据本发明也提供以下发明。
(a)含有化合物A或其盐作为活性成分的药物组合物，用于预防或治疗脊髓小脑变性症。
(b)用于在脊髓小脑变性症的预防或治疗中使用的化合物A或其盐。
(c)预防或治疗脊髓小脑变性症的方法，包括向患者施用化合物A或其盐。
(d)化合物A或其盐用于制造脊髓小脑变性症预防或治疗剂的用途。
(e)含有化合物A或其盐作为活性成分的小脑萎缩抑制剂。
(f)用于在小脑萎缩的抑制中使用的化合物A或其盐。
(g)对患者施用化合物A或其盐而抑制小脑萎缩的方法。
(h)化合物A或其盐用于制造小脑萎缩抑制剂的用途。
发明的效果
通过施用化合物A或其盐，可以抑制脑萎缩特别是小脑的萎缩，可以预防或治疗脊髓小脑变性症。
附图说明
[图1]示出来自试验例1的52周的筛选的脑体积(全脑)的变化的图。“n.s.”指统计学上没有有意义的差异。
[图2]示出来自试验例1的52周的筛选的脑体积(海马)的变化的图。“n.s.”指统计学上没有有意义的差异。
具体实施方式
以下对本发明进行详细说明。
在本说明书中，如果没有特指，则各术语具有以下含义。
在本说明书中使用“～”示出的数值范围，意味着将“～”的前后记载的数值分别作为最小值及最大值而包含的范围。
化合物A是指1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇。
作为化合物A的盐，可列举通常已知的氨基等碱性基团或羟基或者羧基等酸性基团的盐。
作为碱性基团的盐，可列举例如：与盐酸、氢溴酸、硝酸及硫酸等无机酸的盐；与甲酸、乙酸、柠檬酸、乙二酸、富马酸、马来酸、琥珀酸、苹果酸、酒石酸、天冬氨酸、三氯乙酸及三氟乙酸等有机羧酸的盐；以及与甲磺酸、苯磺酸、对甲苯磺酸、均三甲苯磺酸及萘磺酸等磺酸的盐。
作为酸性基团的盐，可列举例如：与钠及钾等碱金属的盐；与钙及镁等碱土金属的盐；铵盐；以及与三甲胺、三乙胺、三丁胺、吡啶、N，N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己胺、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺及N，N′-二苄基乙二胺等含氮有机碱的盐等。
在上述盐中，作为优选的盐，可列举药理学上允许的盐，作为更优选的盐，可列举与马来酸的盐。
在化合物A或其盐中，在存在异构体(例如，光学异构体、几何异构体及互变异构体等)的情况下，本发明包括它们的全部异构体，另外，包括水合物、溶剂合物及全部晶形。
预防是指防止特定的疾病或由该疾病产生的1个以上的症状的发病。
治疗是指对于对象罹患的特定的疾病，减轻或改善由该疾病产生的1个以上的症状，以及延迟该疾病的进展。
本发明的实施方式中，预防是指阻止或者延迟脊髓小脑变性症的发生或进展。治疗是指阻止或延迟脊髓小脑变性症的进展。
在本发明的另外的实施方式中，预防是指阻止或者延迟小脑萎缩的发生或进展。治疗是指阻止或延迟小脑萎缩的进展。
轻度～中度阿尔茨海默型痴呆(AD)为，依照国立神经疾病脑卒中研究所/阿尔茨海默病相关疾病协会(National Institute of Neurological and CommunicativeDisorders and Stroke/the Alzheimer’s Disease and Related DisordersAssociations)(NINCDS-ADRDA)的诊断基准能够临床诊断为“基本确定的(probable)阿尔茨海默病”。
对“轻度～中度”的诊断而言，使用标准的基准，普通医生能够足以进行。例如，参考标准化的简易精神状态检查(Mini-Mental State Examination)(MMSE；0～30分的打分)的数值，临床诊断轻度～中度、中度、及中度～重度AD。MMSE(Folstein，Folstein andMcHugh，1975)为基于对患者的询问法的简便的认知功能检查。对于定向力、记忆、计算、注意力，语言功能等进行评价。合计打分为30分，得分越低，认知功能的障碍的程度越高。
在本发明的试验例中，将在试验开始(筛选)时间点的MMSE打分为12～22的患者定义为轻度～中度AD。需要说明的是，应该注意MMSE不是用于临床诊断AD的等级的唯一方法，而是简单的方法。
载脂蛋白E(ApoE)为构成脂蛋白，参与脂蛋白的识别及脂质代谢的载脂蛋白之一。在ApoE中存在ApoE2、ApoE3及ApoE4这3个亚型，报告称编码ApoE4的ApoE4基因型与脑内的淀粉样蛋白β蛋白的沉积量相关，及ApoE4基因型为AD的风险基因。
脑的结构变化虽然在正常的老化中也可以观察到，但小脑萎缩为对于脊髓小脑变性症特征性的器质性异常，引起共济失调等。
在本发明的实施方式中，作为脊髓小脑变性症，可列举例如：遗传性橄榄脑桥小脑萎缩、遗传性皮质小脑萎缩、脊髓小脑变性症1型、脊髓小脑变性症2型、脊髓小脑变性症3型(马查多-约瑟夫病)、脊髓小脑变性症6型、脊髓小脑变性症31型、遗传性齿状核红核苍白球路易体萎缩、毛细血管扩张性共济失调、弗里德赖希共济失调、共济失调伴维生素E缺乏症(AVED)、Aprataxin缺乏症(早发性共济失调伴眼动失用症和低白蛋白血症/共济失调伴眼动失用症1型，EAOH/AOA1)、Senataxin缺乏症(共济失调伴眼动失用症2型，AOA2)、Charlevoix-Saguenay常染色体隐性遗传性痉挛性共济失调(Autosomal recessivespastic ataxia of Charlevoix-Saguenay，ARSACS)、遗传性痉挛性截瘫(HereditarySpastic Paraplegia，HSP)、多系统萎缩(橄榄脑桥小脑萎缩、夏伊-德雷格综合征、纹状体黑质变性症)及皮质性小脑萎缩等，优选可列举：遗传性橄榄脑桥小脑萎缩、遗传性皮质小脑萎缩、脊髓小脑变性症3型(马查多-约瑟夫病)、脊髓小脑变性症6型、脊髓小脑变性症31型及皮质性小脑萎缩。
容积磁共振成像(Volumetric MRI(vMRI))能够实现脑结构体积的体内评价，提供萎缩速度的量度。
本发明中使用的化合物A或其盐可以通过本身公知的方法或将它们适当组合，以及专利文献1中记载的方法而制造。
本发明中使用的化合物A或其盐可以配合：赋形剂、粘合剂、崩解剂、崩解抑制剂、防结块及粘连剂、润滑剂、吸收·吸附载体、溶剂、增量剂、等渗剂、助溶剂、乳化剂、悬浮剂、增稠剂、包衣剂、吸收促进剂、凝胶化·凝固促进剂、光稳定剂、保存剂、防潮剂、乳化·悬浊·分散稳定剂、防着色剂、脱氧·抗氧化剂、矫味·矫臭剂、着色剂、起泡剂、消泡剂、安抚剂、抗静电剂、缓冲·pH调节剂等各种药物添加物，而制成口服制剂(片剂、胶囊剂、散剂、颗粒剂、细粒剂、丸剂、悬浮剂、乳剂、液剂、糖浆剂等)、注射剂、滴眼剂、经鼻剂或透皮剂等药物制剂。需要说明的是，作为患有AD的患者中的口服施用制剂优选为片剂。
上述药物利用通常的方法而制成制剂。
对化合物A的施用方法没有特别限定，根据制剂的形态、患者的年龄、性别、其它条件，患者的症状的程度而适当确定。
化合物A的给药量根据用法、患者的年龄、性别、疾病的形态、其它条件等而适当选择。
通常，对于成人，可以将以化合物A计1天40～500mg以1次～分成多次进行施用，更优选可以将以化合物A计1天100～400mg以1次～分成多次进行施用，进一步优选可以将以化合物A计1天160mg或320mg以1次进行施用。
在本发明中，化合物A或其盐的施用可以进一步包括基于乙酰胆碱酯酶抑制剂(AChEI)的施用的预防或治疗。作为AChEI，可列举：盐酸多奈哌齐、盐酸加兰他敏、酒石酸卡巴拉汀或盐酸他克林等。
在本发明中，对象可以在化合物A或其盐的施用前接受至少6个月期间的基于AChEI的施用的预备或治疗。
下面，通过试验例及制剂例说明本发明，但本发明并不限于这些。
作为试验化合物，使用了化合物A的马来酸盐。
试验例1在轻度到中度AD患者中的评价化合物A的有效性及安全性的2期多中心随机化双盲安慰剂对照试验
对象(选择基准)：从临床试验药物设计安排的42天前至进行设计安排，基于下述选择基准进行了患者的筛选。
·获得筛选的同意时为55岁以上且85岁以下，且为基本确定的(probable)AD的患者
·筛选时的MMSE打分为12～22的患者
·修改的Hachinski缺血量表(Modified Hachinski Ischemia Scale)打分为4以下的患者
·在基线前至少4个月期间及在基线前3个月期间以稳定的给药量，通过多奈哌齐盐酸盐或卡巴拉汀经皮系统接受了治疗的患者
·对于除了多奈哌齐盐酸盐或卡巴拉汀经皮系统以外还施用了美金刚的患者，在基线前至少4个月期间及在基线前3个月期间以稳定的给药量接受了美金刚的治疗的患者
·筛选时的脑MRI或CT与AD一致的患者
组的构成：将适合上述的患者(484名)随机分为下述3组，开始了试验。
(1)高用量施用组：224mg试验化合物(以化合物A计160mg)进行了1天1次口服施用4周之后，将448mg试验化合物(以化合物A计320mg)进行1天1次口服施用48周(158名)
(2)低用量施用组：224mg试验化合物(以化合物A计160mg)进行1天1次口服施用52周(166名)
(3)安慰剂施用组：将安慰剂进行1天1次口服施用52周(158名)
评价方法：
容积磁共振成像(Volumetric MRI)
在筛选及52周后利用vMRI扫描测定了对象的脑体积，将每个对象的全脑(全部脑)及海马的体积变化进行定量，根据从筛选起的变化而对脑萎缩进行了评价。
另外，每个对象的全脑及101个区域(布罗德曼的脑图(1～52)中，在左脑及右脑中各个存在的区域分开而分成101个区域)的体积变化进行定量，根据从筛选起的变化而对脑萎缩进行了评价。
统计分析：
将52周之后的全脑及海马体积的从基线的变化利用混合效应模型(Mixed-effectModel)，在高用量施用组和安慰剂组，及低用量施用组和安慰剂施用间进行了组间比较。在模型中，将施用组以固定效果、年龄、各脑体积(全部脑或海马)的基线，MMSE的基线及ApoE4基因型(阳性/阴性)作为协变量，包括临床试验实施设施作为变量效果。另外，将52周之后的全脑及101个区域的各体积的从基线的变化，在高用量施用组和安慰剂组，及低用量施用组和安慰剂施用间进行了组间比较。
结果：如下所示。
将来自在52周的筛选的基于vMRI扫描的脑体积的变化示于表1、图1及图2。
[表1]
对于来自52周的筛选的全部脑及海马体积的变化，与安慰剂施用组相比，在化合物A施用组中确认了体积的减少较少的倾向。对于相对于化合物A低用量施用组和安慰剂施用组的海马体积变化的效果的差为统计学有意义。
对于来自52周的筛选的基于vMRI扫描的各脑体积的变化，将在试验化合物的低用量施用组和安慰剂施用组的组间比较中，存在统计学有意义的差异的区域(P值＜0.05)的结果示于表2。
[表2]
在化合物A的低用量施用组中，与安慰剂施用组相比，在全脑及101个区域中，特别是确认了抑制小脑的体积减少的倾向(表2的编号1、2、4及8)。
另外，在化合物A的高用量施用组中，也确认了与低用量施用组相同的倾向。
制剂例1
在化合物A的马来酸盐174.03g中加入硬脂酸镁(硬脂酸镁，默克)0.9726g，混合了30分钟。将该混合粉末利用干式造粒机(TF-LABO(辊加压3MPa)，Freund产业)压缩成形，对成形而成的固态物进行整粒。向得到的整粒粉末60.0g中，分别利用网眼850μm的筛过筛而加入乳糖(Flowlac90，Meggle Japan)49.51g，结晶纤维素(Ceolus PH302，旭化成chemicals)16.50g及交联羧甲纤维素钠(primellose，DMV Japan)6.67g，混合了10分钟。向该混合粉末中加入硬脂酸镁0.6667g，混合了30分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵，在压片压约12kN下，利用压片机(HT-P18A，烟铁工所)进行压片，得到了250mg 1片的圆形裸片。利用包衣机：DRC-200(powrex)对裸片以包衣剂每1片8mg的比例进行包衣后，添加微量的棕榈蜡(抛光蜡-105，日本Wax)，得到了薄膜衣片(film coating tablet)。
制剂例2
向化合物A的马来酸盐53.70g中加入甘露醇(Parteck M200，默克)60.90g及交联羧甲纤维素钠3.60g，混合了10分钟。向该混合粉末中加入硬脂酸镁1.80g，混合了30分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵，在压片压约10kN条件压片，得到了250mg 1片的圆形的裸片。对裸片将包衣剂(欧巴代03F44057，00F440000(羟丙甲纤维素2910：71.5％、PEG 6000：14.166％、滑石：7.167％、氧化钛：7.067％、氧化铁：0.1％)，日本卡乐康)以每1片8mg的比例包衣之后，添加微量的棕榈蜡，得到了薄膜衣片。
制剂例3
向化合物A的马来酸盐1988.89g中加入硬脂酸镁11.11g，混合了30分钟。将该混合粉末利用干式造粒机压缩成形，对成形的固态物进行整粒。向得到的整粒粉末107.13g中加入甘露醇26.2lg、乙基纤维素(ETHOCEL100FP premium，Dow Chemical)7.50g、结晶纤维素(ceolus KG-1000，旭化成Chemicals)3.75g、交联聚维酮(Kollidon CL-SF，BASF)3.75g及交联羧甲纤维素钠0.75g，混合了30分钟。向该混合粉末中加入硬脂酸镁0.90g，混合了5分钟。将该混合粉末使用片剂径8.5mm的双弧面的杵，在压片压约7kN条件压片，得到了315mg1片的圆形的裸片。对裸片将包衣剂以每1片9mg的比例进行包衣后，添加微量的棕榈蜡，得到了薄膜衣片。
Claims (8)
1.1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇或其盐用于制备脊髓小脑变性症小脑萎缩的治疗剂的用途，其中，脊髓小脑变性症小脑萎缩为遗传性橄榄脑桥小脑萎缩症小脑萎缩、遗传性皮质小脑萎缩症小脑萎缩、脊髓小脑变性症1型小脑萎缩、脊髓小脑变性症2型小脑萎缩、脊髓小脑变性症3型小脑萎缩、脊髓小脑变性症6型小脑萎缩、脊髓小脑变性症31型小脑萎缩、遗传性齿状核红核苍白球路易体萎缩症小脑萎缩、毛细血管扩张性共济失调小脑萎缩、弗里德赖希共济失调小脑萎缩、Aprataxin缺乏症小脑萎缩、Senataxin缺乏症小脑萎缩、Charlevoix-Saguenay常染色体隐性遗传性痉挛性共济失调小脑萎缩、遗传性痉挛性截瘫小脑萎缩、多系统萎缩症小脑萎缩及皮质性小脑萎缩症小脑萎缩。
2.根据权利要求1所述的用途，其中，脊髓小脑变性症小脑萎缩为遗传性橄榄脑桥小脑萎缩症小脑萎缩、遗传性皮质小脑萎缩症小脑萎缩、脊髓小脑变性症3型小脑萎缩、脊髓小脑变性症6型小脑萎缩、脊髓小脑变性症31型小脑萎缩或皮质性小脑萎缩症小脑萎缩。
3.根据权利要求1所述的用途，其中，脊髓小脑变性症小脑萎缩为橄榄脑桥小脑萎缩症小脑萎缩、夏伊-德雷格综合征小脑萎缩或纹状体黑质变性症小脑萎缩。
4.根据权利要求1-3任一项所述的用途，其中所述治疗剂用于抑制患有脊髓小脑变性症的患者的小脑萎缩。
5.根据权利要求1-3任一项所述的用途，其中所述治疗剂用于改善患有脊髓小脑变性症的患者的共济失调。
6.根据权利要求1-3任一项所述的用途，其中所述治疗剂用于改善患有脊髓小脑变性症的患者的平衡障碍。
7.根据权利要求1-3任一项所述的用途，其中所述治疗剂以每次以1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇计100mg～400mg、1天1次口服施用。
8.根据权利要求1-3任一项所述的用途，其中所述治疗剂以每次以1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇计160mg或320mg、1天1次口服施用。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996003989A1 (fr) * | 1994-08-05 | 1996-02-15 | Suntory Limited | Remede contre la degenerescence spino-cerebelleuse |
| WO2006028277A1 (en) * | 2004-09-09 | 2006-03-16 | Shionogi & Co., Ltd. | A pharmaceutical composition for treating ataxia, multiple system atrophy or balance disorders |
| JP2008512344A (ja) * | 2004-09-09 | 2008-04-24 | 塩野義製薬株式会社 | 脊髄小脳変性症治療剤 |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2302808C (en) | 1997-09-05 | 2010-05-18 | Human Genome Sciences, Inc. | 50 human secreted proteins |
| GB9824207D0 (en) | 1998-11-04 | 1998-12-30 | Zeneca Ltd | Neurological disorders |
| BRPI0213393B8 (pt) | 2001-10-19 | 2021-05-25 | Fujifilm Toyama Chemical Co Ltd | derivados de éter alquílico, ou um de seus sais, processo para produzir um derivado de éter alquílico, derivado de alquil-amida, ou um de seus sais, e, composição farmacêutica |
| SI2389937T1 (sl) | 2002-06-14 | 2018-10-30 | Toyama Chemical Co., Ltd, | Farmacevtska sestava za izboljšanje možganske funkcije |
| AU2004229283B2 (en) | 2003-04-17 | 2009-02-05 | Toyama Chemical Co., Ltd. | Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof |
| SI2011796T1 (sl) * | 2006-04-26 | 2015-02-27 | Toyama Chemical Co., Ltd. | Induktor nevrogeneze ali terapevtska uäśinkovina proti nevropatiji, vsebujoäśa derivat alkilnega etra ali sol le-tega |
| US8119625B2 (en) * | 2006-04-26 | 2012-02-21 | Toyama Chemical Co., Ltd. | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
| NZ587532A (en) | 2008-03-04 | 2012-07-27 | Vernalis R&D Ltd | Azetidine derivatives for inhibition of faah activity |
| FR2934596B1 (fr) | 2008-07-30 | 2015-04-10 | Trophos | Nouveaux derives de l'oxime de cholest-4-en-3-one, compositions pharmaceutiques les renfermant, et procede de preparation |
| US20110262442A1 (en) * | 2009-11-06 | 2011-10-27 | Adenios, Inc. | Compositions for treating cns disorders |
| CN104159583B (zh) * | 2012-02-22 | 2018-04-13 | 富山化学工业株式会社 | 含有1‑(3‑(2‑(1‑苯并噻吩‑5‑基)乙氧基)丙基)氮杂环丁烷‑3‑醇或其盐的固体药物组合物 |
| AU2013292519B2 (en) | 2012-07-19 | 2017-12-07 | Drexel University | Sigma receptor ligands for modulating cellular protein homeostasis |
| EP2903980B1 (en) | 2012-10-01 | 2017-07-19 | F. Hoffmann-La Roche AG | Benzimidazoles as cns active agents |
| LT3100725T (lt) * | 2014-01-31 | 2020-08-10 | Fujifilm Toyama Chemical Co., Ltd. | Reabilitacijos poveikį po nervo pažeidimo sustiprinanti priemonė, apimanti alkileterio darinį arba jo druską |
| WO2015163318A1 (ja) | 2014-04-25 | 2015-10-29 | レジリオ株式会社 | アルツハイマー病の治療剤を含む、神経細胞の軸索の機能不全が関与する疾患の治療剤 |
| WO2015188368A1 (en) | 2014-06-13 | 2015-12-17 | Merck Sharp & Dohme Corp. | Pyrrolo[2,3-c]pyridines as imaging agents for neurofibrilary tangles |
| WO2016051799A1 (ja) | 2014-10-01 | 2016-04-07 | 学校法人同志社 | ２－アミノヒドロキノン誘導体及びタウ凝集阻害剤 |
| SG11201705727TA (en) | 2015-02-02 | 2017-08-30 | Ucb Biopharma Sprl | 9h-pyrrolo-dipyridine derivatives |
| US20160324851A1 (en) | 2015-05-07 | 2016-11-10 | Axovant Sciences, Ltd. | Methods of treating a neurodegenerative disease |
| EP3308782B1 (en) | 2015-06-11 | 2022-01-19 | Toyama Chemical Co., Ltd. | Sigma-receptor binding agent |
| KR102703879B1 (ko) | 2015-12-25 | 2024-09-05 | 후지필름 도야마 케미컬 가부시키가이샤 | 1-(3-(2-(1-벤조티오펜-5-일)에톡시)프로필)아제티딘-3-올 또는 그 염을 포함하는 정제 |
| WO2018221732A1 (ja) | 2017-06-02 | 2018-12-06 | 富山化学工業株式会社 | アミロイドβ蛋白質量減少剤 |
| JPWO2018221728A1 (ja) | 2017-06-02 | 2020-04-02 | 富士フイルム富山化学株式会社 | アルツハイマー型認知症予防または治療剤 |
| NZ759585A (en) * | 2017-06-02 | 2022-02-25 | Fujifilm Toyama Chemical Co Ltd | Agent for preventing or treating brain atrophy |
| WO2018221731A1 (ja) | 2017-06-02 | 2018-12-06 | 富山化学工業株式会社 | タウオパチー予防または治療剤 |
| US11548878B2 (en) | 2017-10-30 | 2023-01-10 | Fujifilm Toyama Chemical Co., Ltd. | Emopamil binding protein binding agent and use thereof |
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- 2018-06-01 JP JP2019521349A patent/JP7133547B2/ja active Active
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996003989A1 (fr) * | 1994-08-05 | 1996-02-15 | Suntory Limited | Remede contre la degenerescence spino-cerebelleuse |
| WO2006028277A1 (en) * | 2004-09-09 | 2006-03-16 | Shionogi & Co., Ltd. | A pharmaceutical composition for treating ataxia, multiple system atrophy or balance disorders |
| JP2008512344A (ja) * | 2004-09-09 | 2008-04-24 | 塩野義製薬株式会社 | 脊髄小脳変性症治療剤 |
Non-Patent Citations (2)
| Title |
|---|
| 朴钟源 ; 宋琳 ; 江新梅 ; .脊髓小脑性共济失调的分型进展.中风与神经疾病杂志.2008,(04),全文. * |
| 李欣 ; .脊髓小脑性共济失调患者10例分析.中国实用医药.2008,(10),全文. * |
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| ZA201907974B (en) | 2022-03-30 |
| WO2018221730A1 (ja) | 2018-12-06 |
| SG11201911515QA (en) | 2020-01-30 |
| IL270910B2 (en) | 2024-03-01 |
| JPWO2018221730A1 (ja) | 2020-04-09 |
| RU2728717C1 (ru) | 2020-07-30 |
| BR112019024881A2 (pt) | 2020-06-16 |
| US11660287B2 (en) | 2023-05-30 |
| CA3067455C (en) | 2021-11-23 |
| CN110691593A (zh) | 2020-01-14 |
| IL270910B1 (en) | 2023-11-01 |
| US20200085787A1 (en) | 2020-03-19 |
| KR20190138696A (ko) | 2019-12-13 |
| EP3632430A1 (en) | 2020-04-08 |
| AU2018277981B2 (en) | 2021-04-08 |
| IL270910A (en) | 2020-01-30 |
| CA3067455A1 (en) | 2018-12-06 |
| JP7133547B2 (ja) | 2022-09-08 |
| MX2019014302A (es) | 2022-07-05 |
| AU2018277981A1 (en) | 2019-12-19 |
| NZ759647A (en) | 2022-02-25 |
| EP3632430A4 (en) | 2020-06-10 |
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