CN101501026B - 含有烷基醚衍生物或其盐的蛋白激酶c活性促进剂 - Google Patents
含有烷基醚衍生物或其盐的蛋白激酶c活性促进剂 Download PDFInfo
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- CN101501026B CN101501026B CN2007800291310A CN200780029131A CN101501026B CN 101501026 B CN101501026 B CN 101501026B CN 2007800291310 A CN2007800291310 A CN 2007800291310A CN 200780029131 A CN200780029131 A CN 200780029131A CN 101501026 B CN101501026 B CN 101501026B
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Abstract
本发明公开了蛋白激酶C活性促进剂,其特征在于,含有由以下通式表示的苯并噻吩烷基醚衍生物或其盐,在通式中,R1和R2可相同或不同,各自表示一个或多个选自以下的基团:氢原子,卤原子,烷基,芳基,芳烷基,烷氧基,芳氧基,烯基,氨基,杂环基,任选被保护的氨基,羟基,羧基,氧代基团等;R3表示烷基氨基,氨基,羟基等;并且m和n可相同或不同,各自表示1-6的整数。该蛋白激酶C促进剂可用于治疗或预防多种与蛋白激酶C有关的疾病。
Description
技术领域
本发明涉及优异的含有烷基醚衍生物或其盐的蛋白激酶C活性促进剂。
背景技术
在哺乳动物中,蛋白激酶C(以下简称“PKC”)是由12类同工酶构成的家族,并且已知是参与信号转导的丝氨酸-苏氨酸激酶。除此之外,已知PKC参与调节多种细胞功能,如突触传递,离子流活化,分泌,细胞周期控制,分化,增殖,肿瘤生成,转移与细胞凋亡。具有PKC活性促进作用的化合物(以下简称“PKC活性促进剂”)已知例如在肝硬化动物模型中对葡萄糖代谢紊乱具有改善作用(非专利文献1)和抗赘生物作用(非专利文献2)。PKC活性促进剂作为对抗多种疾病的治疗剂已经引起广泛的关注,所述疾病为例如在肝硬化患者中的葡萄糖代谢作用紊乱,和赘生物性疾病如肿瘤。
例如,已知亮氨酸是PKC活性促进剂(非专利文献3)。在肝硬化患者的支链氨基酸补充(替代)疗法中使用的支链氨基酸(特别是亮氨酸与异亮氨酸)通过PI3激酶活化PKC,促进葡萄糖被骨骼肌吸收,以及改善肝硬化大鼠模型中的葡萄糖代谢紊乱(非专利文献1)。
例如,苔藓抑素与尼地吗啉也是已知的PKC活性促进剂。苔藓抑素与PKC结合(非专利文献4),在体外活化PKC同功酶(非专利文献5),并且显示抗赘生物作用(非专利文献6)。
本申请中所述的烷基醚衍生物据报道具有神经保护作用,神经再生作用,和轴突长出促进作用(专利文献1)。然而,迄今为止完全未知它们促进PKC活性。
专利文献1:WO 03/035647
非专利文献1:Am.J.Physiol.Gastrointest.Liver.Physiol.,2005,第288卷,第G1292-1300页
非专利文献2:Curr.Cancer Drug Targets,2004,第4卷,第125-146页
非专利文献3:Biochem.Biophys.Res.Commun.,2002,第299卷,第5期,第693-696页
非专利文献4:Biochem.Pharmacol.,1992,第43卷,第9期间,第2007-2014页
非专利文献5:Mol.Pharmacol.,1994,第46卷,第2期,第374-379页
非专利文献6:Rev.Physiol.Biochem.Pharmacol.,2001,第142卷,第1-96页
发明内容
发明要解决的课题
本发明要解决的技术问题是需要优异的具有更少副作用的PKC活性促进剂。
解决课题的手段
在上述背景下,本发明人发现由通式[1]表示的苯并噻吩烷基醚衍生物及其盐显示了PKC活性促进作用,并且因此可用作PKC活性促进剂,从而完成了本发明。
[式1]
在上式中,R1和R2可相同或不同,各自表示一个或多个选自以下的基团:氢原子,卤原子,任选被取代的烷基,芳基,芳烷基,烷氧基,芳氧基,烷基硫基,芳基硫基,烯基,烯氧基,氨基,烷基磺酰基,芳基磺酰基,氨基甲酰基或杂环基,任选被保护的氨基,羟基或羧基,硝基,和氧代基;R3表示任选被取代的烷基氨基或任选被保护的氨基或羟基;并且m和n可相同或不同,各自表示1-6的整数。
发明效果
本发明的由通式[1]表示的烷基醚衍生物或其盐显示PKC活性促进作用,并且可用于治疗或预防多种涉及PKC的疾病,所述疾病为例如在肝硬化患者中的葡萄糖代谢紊乱,和赘生物性疾病如肿瘤。
附图说明
图1:在培养细胞中测量PKC活性试验中的Western印迹法的结果。
具体实施方式
下面更详细地描述本发明。
除非另有说明,本说明书中使用的术语具有以下给出的含义。
″卤原子″是指氟原子,氯原子,溴原子或碘原子;″烷基″是指直链或支链的C1-12烷基如甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,己基,庚基和辛基;″低级烷基″是指直链或支链的C1-6烷基如甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基和己基;″烯基″是指C2-12烯基如乙烯基,丙烯基,丁烯基,戊烯基,己烯基,庚烯基和辛烯基;″低级烯基″是指C2-6烯基如乙烯基,丙烯基,丁烯基,戊烯基和己烯基;″酰基烷基″是指酰基C1-6烷基如乙酰基甲基,苯甲酰基甲基,对硝基苯甲酰基甲基,对溴苯甲酰基甲基,对甲氧基苯甲酰基甲基和1-苯甲酰基乙基;″酰氧基烷基″是指酰氧基C1-6烷基如乙酰氧基甲基,丙酰氧基甲基和新戊酰氧基甲基;″芳基硫基烷基″是指芳基硫基C1-6烷基如苯基硫基(sulfenyl)甲基和2-(对硝基苯基硫基)乙基;″芳基磺酰基烷基″是指芳基磺酰基C1-6烷基如对甲苯磺酰基乙基;″含氮杂环烷基″是指含氮杂环C1-6烷基如邻苯二甲酰亚胺基甲基和琥珀酰亚胺基甲基;″环烷基″是指C3-8环烷基如环丙基,环丁基,环戊基和环己基;″烷基硫基烷基″是指C1-6烷基硫基C1-6烷基如甲基硫基甲基,乙基硫基甲基和丙基硫基甲基;″烷氧基烷基″是指C1-6烷基氧基C1-6烷基如甲氧基甲基和1-乙氧基乙基;和″芳烷基氧基烷基″是指芳基C1-6烷基氧基C1-6烷基如苄氧基甲基和苯乙基氧基甲基;
″烷氧基″是指直链或支链的C1-12烷基氧基如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,戊氧基,己氧基,庚氧基和辛氧基;″低级烷氧基″是指直链或支链的C1-6烷基氧基如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,戊氧基和己氧基;″烯氧基″是指C2-12烯氧基如乙烯基氧基,丙烯基氧基,丁烯基氧基,戊烯基氧基,己烯基氧基,庚烯基氧基和辛烯基氧基;
″烷基硫基″是指C1-12烷基硫基如甲基硫基,乙基硫基,丙基硫基,异丙基硫基,丁基硫基,异丁基硫基,叔丁基硫基,戊基硫基,己基硫基,庚基硫基和辛基硫基;和″低级烷基硫基″是指C1-6烷基硫基如甲基硫基,乙基硫基,丙基硫基,异丙基硫基,丁基硫基,异丁基硫基,叔丁基硫基,戊基硫基和己基硫基;
″芳基″是指苯基,萘基,茚满基或茚基;″芳氧基″是指苯基氧基,萘基氧基,茚满基氧基或茚基氧基;″芳烷基″是指芳基C1-6烷基如苄基,二苯甲基,三苯甲基和苯乙基;″芳基硫基″是指苯基硫基,萘基硫基,茚满基硫基或茚基硫基;
″酰基″是指甲酰基,C2-12烷酰基如乙酰基,异戊酰基,丙酰基和新戊酰基,芳基C1-6烷基羰基如苄基羰基,和芳酰基如苯甲酰基和萘甲酰基;″烷基氧基羰基″是指直链或支链的C1-12烷基氧基羰基如甲氧基羰基,乙氧基羰基,1,1-二甲基丙氧基羰基,异丙氧基羰基,2-乙基己氧基羰基,叔丁氧基羰基和叔戊氧基羰基;″芳烷基氧基羰基″是指芳基C1-6烷基氧基羰基如苄氧基羰基和苯乙基氧基羰基;″芳氧基羰基″是指基团如苯基氧基羰基;″杂环氧基羰基″是指基团如2-糠基氧基羰基和8-喹啉基氧基羰基;
″烷基磺酰基″是指C1-12烷基磺酰基如甲基磺酰基,乙基磺酰基, 丙基磺酰基,异丙基磺酰基,丁基磺酰基,异丁基磺酰基,仲丁基磺酰基,叔丁基磺酰基,戊基磺酰基,己基磺酰基,庚基磺酰基和辛基磺酰基;″低级烷基磺酰基″是指C1-6烷基磺酰基如甲基磺酰基,乙基磺酰基和丙基磺酰基;″芳基磺酰基″是指基团如苯基磺酰基,对甲苯磺酰基和萘基磺酰基;
″烷基氨基″是指单C1-6烷基氨基或二C1-6烷基氨基如甲基氨基,乙基氨基,丙基氨基,异丙基氨基,丁基氨基,二甲基氨基,二乙基氨基,二异丙基氨基和二丁基氨基;
″杂环基″是指含有至少一个选自氮原子、氧原子和硫原子的5元或6元稠环或桥环的杂环基,例如,吡咯烷基,哌啶基,哌嗪基,高哌嗪基,高哌啶基,吗啉基,硫代吗啉基,四氢喹啉基,四氢异喹啉基,奎宁环基,咪唑啉基,吡咯基,咪唑基,吡唑基,吡啶基,嘧啶基,喹啉基,喹嗪基,噻唑基,四唑基,噻二唑基,吡咯啉基,吡唑啉基,吡唑烷基,嘌呤基,呋喃基,噻吩基,苯并噻吩基,吡喃基,异苯并呋喃基,噁唑基,异噁唑基,苯并呋喃基,吲哚基,苯并咪唑基,苯并噁唑基,苯并异噁唑基,苯并噻唑基,喹喔啉基,二氢喹喔啉基,2,3-二氢苯并噻吩基,2,3-二氢苯并吡咯基,2,3-4H-1-硫杂萘基,2,3-二氢苯并呋喃基,苯并[b]二噁烷基,咪唑并[2,3-a]吡啶基,苯并[b]哌嗪基,色烯基,异噻唑基,异噁唑基,恶二唑基,哒嗪基,异吲哚基,异喹啉基,1,3-苯并二噁烷基(dioxonyl)和1,4-苯并二噁烷基;
″含氧杂环基″是指基团如2-四氢吡喃基和2-四氢呋喃基;″含硫杂环基″是指基团如四氢噻喃基;″被取代的甲硅烷基″是指基团如三甲基甲硅烷基,三乙基基甲硅烷基和三丁基甲硅烷基;″烷基甲硅烷基烷基″是指C1-6烷基甲硅烷基C1-6烷基如2-(三甲基甲硅烷基)乙基。
氨基保护基包括所有的可被用作氨基的保护基的基团,例如,由W.Greene等在Protective Groups in Organic Synthesis,第3版,第494-615页,1999,John Wiley & Sons,Inc.中描述的基团。具体例子包括酰基,烷基氧基羰基,芳烷基氧基羰基,芳氧基羰基,芳 烷基,烷氧基烷基,芳烷基氧基烷基,芳基硫基,烷基磺酰基,芳基磺酰基和被取代的甲硅烷基。
羟基保护基包括所有的可被用作羟基的保护基的基团,例如,由W.Greene等在Protective Groups in Organic Synthesis,第3版,第17-245页,1999,John Wiley & Sons,Inc.中描述的基团。具体例子包括酰基,烷基氧基羰基,芳烷基氧基羰基,杂环氧基羰基,烷基,烯基,芳烷基,含氧杂环基,含硫杂环基,烷氧基烷基,芳烷基氧基烷基,烷基磺酰基,芳基磺酰基和被取代的甲硅烷基。
羧基保护基包括所有的可被用作羧基的保护基的基团,例如,由W.Greene等在Protective Groups in Organic Synthesis,第3版,第369-453页,1999,John Wiley & Sons,Inc.中描述的基团。具体例子包括烷基,烯基,芳基,芳烷基,酰基烷基,芳基硫基烷基,芳基磺酰基烷基,含氧杂环基,烷基甲硅烷基烷基,酰氧基烷基,含氮杂环烷基,环烷基,烷氧基烷基,芳烷基氧基烷基,烷基硫基烷基和被取代的甲硅烷基。
用于R1和R2处的烷基,芳基,芳烷基,烷氧基,芳氧基,烷基硫基,芳基硫基,烯基,烯氧基,氨基,烷基磺酰基,芳基磺酰基,氨基甲酰基和杂环基的取代基的例子,和用于R3处的烷基氨基的取代基的例子是选自以下的基团:卤原子,低级烷基,环烷基,芳基,低级烷氧基,芳氧基,低级烷基硫基,芳基硫基,低级烯基,低级烷基磺酰基,芳基磺酰基,烷基氨基,任选被保护的氨基,任选被保护的羟基,任选被保护的羧基,酰基,杂环基等。
通式[1]化合物的盐可以是在碱性基团如氨基处形成的盐或在酸性基团如羟基或羧基处形成的盐。
在碱性基团处形成的盐的例子包括无机酸的盐,所述无机酸如盐酸,氢溴酸,硝酸和硫酸;有机酸的盐,所述有机酸如甲酸,乙酸,柠檬酸,草酸,富马酸,马来酸,琥珀酸,苹果酸,酒石酸,天冬氨酸,三氯乙酸和三氟乙酸;和磺酸的盐,所述磺酸如甲磺酸,苯磺酸,对甲苯磺酸,均三甲苯磺酸和萘磺酸。
在酸性基团处形成的盐的例子包括碱金属如钠和钾的盐;碱土金属如钙和镁的盐;铵盐;含氮有机碱的盐,所述含氮有机碱为如三甲胺,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-苯乙基胺,1-ephenamine和N,N′-二苄基乙二胺。
在上述盐中,优选可药用的盐。
当通式[1]的烷基醚衍生物及其盐具有异构体如光学异构体、几何异构体和互变异构体时,本发明涵盖了所有的这些异构体。本发明还涵盖了水合物,溶剂合物和所有可能的晶形。
下面列举的化合物优选作为本发明的通式[1]的烷基醚衍生物及其盐。
优选R1是氢原子的化合物。
优选R2是氢原子、卤原子或烷氧基的化合物,更优选R2是氢原子的化合物。
优选R3是羟基的化合物。
优选m是2的化合物。
优选n是2或3的化合物,更优选n是3的化合物。
进一步优选R1和R2是氢原子、R3是羟基、m是2且n是3的化合物。
进一步优选通式[1]的烷基醚衍生物或其盐是1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇(以下简称“T-817”)或其盐的化合物,并且最优选T-817的马来酸盐(以下简称“T-817MA”)。
本发明的通式[1]的烷基醚衍生物或其盐具有PKC活性促进作用,并且含有通式[1]的烷基醚衍生物或其盐的药物可用于治疗或预防PKC活性增强能发挥效果的疾病。
本发明中使用的通式[1]的烷基醚衍生物或其盐可通过公知方法、已知方法的适当组合或通过专利文献1中所述的方法制备。
本发明中使用的通式[1]的烷基醚衍生物或其盐可被制成药物产品,如口服药物(片剂,胶囊,粉剂,颗粒剂,微粒剂,丸剂,混悬 剂,乳剂,溶液剂,糖浆剂等),注射剂,滴眼剂等,通过与以下的各种药物添加剂配合来实现,如赋形剂、粘合剂、崩解剂、崩解抑制剂、结块和粘结抑制剂、润滑剂、吸收/吸附载体、溶剂、增量剂、等渗剂、增溶剂、乳化剂、助悬剂、增稠剂、包覆剂、吸收促进剂、胶凝化/凝固促进剂、光稳定剂、防腐剂、干燥剂、乳化/悬浮/分散稳定剂、防变色剂、脱氧剂/抗氧化剂、调味剂、着色剂、起泡剂、消泡剂、无痛化剂、抗静电剂和缓冲剂/pH调节剂等。
以上的药物产品通过常规方法制备。
固体经口药物产品如片剂、粉剂和颗粒剂可通过常规方法如下制备:添加用于固体药物产品的药物添加剂,例如,赋形剂如乳糖,蔗糖,氯化钠,葡萄糖,淀粉,碳酸钙,高岭土,结晶纤维素,无水磷酸氢钙、部分α化淀粉,玉米淀粉和藻酸;粘合剂如单糖浆,葡萄糖溶液,淀粉溶液,凝胶溶液,聚乙烯醇,聚乙烯醚,聚乙烯吡咯烷酮,羧甲基纤维素,虫胶,甲基纤维素,乙基纤维素,藻酸钠,***树胶,羟丙基甲基纤维素,羟丙基纤维素,水和醇;崩解剂如干淀粉,藻酸,琼脂粉末,淀粉,交联聚乙烯吡咯烷酮,交联羧甲基纤维素钠,羧甲基纤维素钙和淀粉羟基乙酸钠;崩解抑制剂如硬脂醇,硬脂酸,可可脂和氢化油;结块和粘结抑制剂如硅酸铝,磷酸氢钙,氧化镁,滑石和无水硅酸;润滑剂如巴西棕榈蜡,轻质硅酸酐,硅酸铝,硅酸镁,氢化油,氢化植物油衍生物,芝麻油,白蜡,二氧化钛,无水氢氧化铝凝胶,硬脂酸,硬脂酸钙,硬脂酸镁,滑石,磷酸氢钙,十二烷基硫酸钠和聚乙烯醇;吸收促进剂如季铵盐,十二烷基硫酸钠,脲和酶;吸收/吸附载体如淀粉,乳糖,高岭土,皂土,无水硅酸,水合二氧化硅,偏硅酸镁铝和胶质硅酸。
在片剂的情况中,如果需要,它们可被制成普通的包衣片,如糖包衣片,明胶包衣片,胃溶包衣片,肠溶包衣片和水溶性薄膜包衣片。
胶囊通过与多种上述的药物产品混合并被填充入硬明胶胶囊、软胶囊等中进行制备。
水系或油系混悬剂、溶液剂、糖浆剂和酏剂也可使用多种用于液 体药物产品的上述添加剂来制备,所述添加剂为例如溶剂、增量剂、等渗剂、增溶剂、乳化剂、助悬剂和增稠剂。
注射剂可通过常规方法使用用于液体药物产品的药物添加剂制备,所述添加剂为例如稀释剂如水,乙醇,聚乙二醇,丙二醇,柠檬酸,乙酸,磷酸,乳酸,乳酸钠,硫酸和氢氧化钠;pH调节剂和缓冲剂如柠檬酸钠,乙酸钠和磷酸钠;稳定剂如焦亚硫酸钠,乙二胺四乙酸,巯基乙酸和硫羟乳酸;等渗剂如食盐,葡萄糖,甘露糖醇和甘油;增溶剂如羧甲基纤维素钠,丙二醇,苯甲酸钠,苯甲酸苄酯,尿烷,乙醇胺和甘油;无痛化剂如葡萄糖酸钙,氯代丁醇,葡萄糖和苄基醇;和局部麻醉剂。
滴眼剂可通过常规方法与例如以下的物质适当地进行配合而制备,所述物质为例如氯代丁醇,脱氢醋酸钠,苯扎氯铵,氯化十六烷基吡啶鎓,苯乙醇,对羟基苯甲酸甲酯和苄索氯铵;缓冲剂如硼砂,硼酸和磷酸二氢钾;增稠剂如甲基纤维素,羟乙基纤维素,羧甲基纤维素,羟丙甲基纤维素,聚乙烯醇,羧甲基纤维素钠和硫酸软骨素;增溶剂如聚山梨酯80和聚氧乙烯氢化蓖麻油60;稳定剂如依地酸钠和亚硫酸氢钠;和等渗剂如氯化钠,氯化钾和甘油。
对于上述药物产品的给予方法没有特殊限制;考虑到剂型,患者的年龄、性别和其它状况,以及症状的严重程度来进行确定。
本发明的药物产品中的活性成分的剂量可以根据给药方案、患者的年龄和性别、疾病的类型以及其它状况适当地进行确定。然而,通常,对成人可以分一次或多次给予0.1~500mg/天。
实施例
以下借助试验例和制剂例来描述本发明。然而,这些例子不以任何方式限制本发明的范围。
在这些试验中,T-817MA用作供试物质。
试验例1:在培养细胞中的PKC活性促进作用。
可适当地根据Etcheberrigaray等人(Proceedings of theNational Academy of Sciences of the United States of America (美国科学院论文集),2004,第101卷,第30期,第11141-11146页)的方法测定PKC活性。当被活化时,PKC从细胞质向膜转移。将膜级分中的PKC水平/细胞质级分中的PKC水平作为PKC活化的指标。在本试验中,测量了PKC的已知同工酶PKCε的活性。
培养细胞的制备根据Hirata等(J.Pharmacol.Exp.Ther.,2005,第314卷,第1期,第252-259页)的方法进行。
Wistar/ST大鼠的18日胎龄的胎儿中取得大脑皮质,在含有0.25%胰蛋白酶和40Kunitz单位/mL的DNA酶I的磷酸盐缓冲生理盐水(以下简称″PBS″)中在37℃下温育20分钟。然后,加入胎牛血清(由JRH Co.制造)和Dulbecco改良Eagle培养基(以下简称″DMEM″)的等量混合液,通过移液管分散细胞悬浮液。将该悬浮液通过镜头纸过滤,在1000rpm下离心5分钟,通过移液管将细胞再次分散在含有10%胎牛血清的DMEM中。然后将细胞以4×105个细胞/mL的密度接种在已涂有聚L-赖氨酸的60mm组织培养皿中的5mL培养基中并进行培养。从培养开始算起的第2天,向各皿中加入50μL的1mmol/L的AraC溶液。在24小时后,将培养基换成含有10%胎牛血清的5mL DMEM。
在从培养开始算起的第8天,向细胞中加入T-817MA至T-817的最终浓度为0.1μmol/升。添加之后,将细胞在0(未处理)、1、2和4小时用PBS洗涤。然后,使用细胞刮棒将细胞集聚于提取缓冲液(20mmol/L的Tris-HCl,pH 7.5,2mmol/L的EDTA,2mmol/L的EGTA,5mmol/L的DTT,0.32mmol/L的蔗糖,和1/100体积的蛋白酶抑制剂鸡尾酒(由SIGMA制造))中。将细胞提取液进行超声处理,并将在12000xg下离心20分钟获得的上清液作为细胞质级分。向粒状沉淀中加入含有1%Triton X-100的提取缓冲液。在超声处理后,将其置于冰上达45分钟,将其再次在12000xg下离心20分钟,并将获得的上清液作为膜级分。测定了在细胞质级分和膜级分中的蛋白质浓度,并且使用提取缓冲液或含有Triton X-100的提取缓冲液将各样品的蛋白质含量调节到某一恒定水平。然后将这些样品用含有2-巯基乙醇(由WakoPure Chemical Industries Ltd.制造)的电泳用缓冲液稀释并在10% 聚丙烯酰胺凝胶中进行SDS-PAGE(40mA,30分钟),在完成SDS-PAGE后,将凝胶上的蛋白质转移到PVDF膜(150mA,90分钟)上。将该膜在含有5%脱脂乳的PBST(含有0.1%吐温20的PBS)中振摇60分钟。然后,将该膜浸没在含有抗小鼠PKCε抗体(由BD TransductionLaboratories制造,稀释500倍)的PBS中静置90分钟。然后,将该膜用PBST洗涤后,将其在含有HRP-标记的抗小鼠IgG抗体(由GEHealthcare Bio-Sciences制造,稀释2500倍)的PBST中振摇90分钟。然后,用PBST洗涤后,该膜用ECL plus试剂(由GE HealthcareBio-Sciences制造)处理,并通过Lumino图像分析仪检测发出的荧光。比较各样品的PKCε带。结果如图1所示。
用T-817MA对细胞进行处理,在2和4小时后,显示出PKCε从细胞质向膜转移。PKC从细胞质向膜的转移可被看作活化指标。因此,证实了T-817MA具有PKCε的活性促进作用。
制剂例1
将50mg T-817MA、20mg乳糖、25mg玉米淀粉和40mg Avicel PH101(微晶纤维素,由旭化成制造)的混合物用聚乙烯吡咯烷酮K30的5%水溶液掺混。在60℃干燥该混合物后,将其与10mg的Kollidon CL(交联聚乙烯吡咯烷酮,由BASF Co.,Ltd.制造)、10mg Avicel PH302(微晶纤维素,由旭化成制造)、18mg轻质硅酸酐和2mg硬脂酸镁的混合物混合,并制成直径为7mm的圆形片,每片重175mg并含有50mg的T-817MA。
制剂例2
将50mg T-817MA、20mg乳糖和53mg玉米淀粉的混合物使用聚乙烯吡咯烷酮K30的5%水溶液掺混并在60℃干燥。然后,将其与7mgKollidon CL(交联聚乙烯吡咯烷酮,由BASF Co.,Ltd.制造)、18mgAvicel PH302(微晶纤维素,由旭化成制造)和2mg硬脂酸镁的混合物混合。将150mg的该混合物填充到4号明胶胶囊的每个胶囊中以制备药物胶囊。
工业实用性
本发明的烷基醚衍生物或其盐显示PKC活性促进作用,并且可用于治疗或预防多种涉及PKC的疾病,所述疾病为例如在肝硬化患者中的葡萄糖代谢紊乱,和赘生物性疾病如肿瘤。
Claims (1)
1.苯并噻吩烷基醚衍生物或其盐在制备用于治疗或预防在肝硬化患者中的葡萄糖代谢紊乱、或赘生物性疾病的药物中的应用,
所述苯并噻吩烷基醚衍生物是1-(3-(2-(1-苯并噻吩-5-基)乙氧基)丙基)氮杂环丁烷-3-醇。
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CN103917529B (zh) | 2011-11-11 | 2016-08-17 | 辉瑞大药厂 | 2-硫代嘧啶酮类 |
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US8173633B2 (en) | 2012-05-08 |
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EP2048145A1 (en) | 2009-04-15 |
WO2008016107A1 (fr) | 2008-02-07 |
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CY1111691T1 (el) | 2015-10-07 |
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