CN105934245A - 多发性硬化症的治疗剂或预防剂 - Google Patents
多发性硬化症的治疗剂或预防剂 Download PDFInfo
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Abstract
本发明的目的在于,提供以非类固醇系的低分子化合物作为有效成分的多发性硬化症的治疗剂或预防剂。本发明提供多发性硬化症的治疗剂或预防剂,其含有以下述为代表的环己烷衍生物或其药理学上可允许的盐作为有效成分。
Description
技术领域
本发明涉及多发性硬化症的治疗剂或预防剂。
背景技术
多发性硬化症的特征在于,覆盖脑、脊髓、视神经等神经纤维的髓鞘被破坏而出现的脱髄,是在反复再发和缓解的同时损害逐渐加剧的疾病。症状因病变部位而异,已知的是,表现出视力障碍、四肢麻痹、感觉障碍、行走障碍等各种神经症状(非专利文献1)。
作为多发性硬化症的治疗药,在急性期的治疗中使用肾上腺皮质激素(类固醇),为了预防再发而使用干扰素β-1b和干扰素β-1a(非专利文献2)。
另外,已知的是:在多发性硬化症中,凝固体系亢进,作为凝血酶抑制剂的水蛭素在多发性硬化症的病态模型中改善症状(非专利文献3)。
作为具有凝血酶抑制活性的低分子化合物,虽然在专利文献1中有所报告,但并未示出其对于多发性硬化症的有用性,具体的药效数据完全没有记载。
另一方面,关于下述通式所示的环己烷衍生物,已知其作为镇痛药和神经源性疼痛治疗药(专利文献2)、纤维肌肉痛症治疗药(专利文献3)、蓄尿障碍治疗药(专利文献4)、阿尔茨海默病治疗药(专利文献5)和神经障碍性疼痛治疗药(专利文献6)是有效的。
[化1]
[式中,A表示取代或未取代的1,5-二芳基-1H-吡唑-3-基或4,5-二芳基噁唑-2-基等,R4表示氟原子或羟基等,R5和R6各自独立地表示氢原子、羟基或羧基等。]。
现有技术文献
专利文献
专利文献1:国际公开第2011/126903号
专利文献2:国际公开第2010/050577号
专利文献3:国际公开第2011/125836号
专利文献4:国际公开第2011/125838号
专利文献5:国际公开第2011/136318号
专利文献6:国际公开第2012/015027号
非专利文献
非专利文献1:荒浪等人、细胞工学、第30卷、第10号、2011年、p1060-1063
非专利文献2:吉良等人、《多发性硬化症治疗指导方针2010》、2010年、p.11-15
非专利文献3:Ham等人、Nature、第451卷、2008年、p.1076-1081。
发明内容
发明要解决的问题
然而,在多发性硬化症的治疗和预防中,若使用类固醇则可观察到急性期症状的缓和,其效果是一过性的,难以进行长期治疗。另外,关于多发性硬化症的再发预防中使用的干扰素β-1b和干扰素β-1a,由于其是生物学制剂,因此是昂贵的药剂,无法期待其对所有患者均具备治疗效果,还已知其对一部分患者是无效的(非专利文献1和2)。
因而,本发明的目的在于,提供以非类固醇系的低分子化合物作为有效成分的多发性硬化症的治疗剂或预防剂。
用于解决问题的方案
本发明人等为了解决上述课题而重复进行了深入研究,结果发现,环己烷衍生物或其药理学上可允许的盐对于多发性硬化症具备优异的治疗效果和预防效果。
即,本发明提供多发性硬化症的治疗剂或预防剂,其含有下述通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分。
[化2]
[式中,A为通式(IIa)或(IIb)所示的取代基,
[化3]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基、碳原子数1~4的烷氧基或氰基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、甲氧基羰基、乙氧基羰基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,R7和R8各自独立地为氢原子或氟原子,Y为氧原子或硫原子,Z为氮原子或次甲基。]。
另外,本发明提供多发性硬化症的治疗剂或预防剂,其含有下述通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分。
[化4]
[式中,A为通式(IIc)或(IId)所示的取代基,
[化5]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基或碳原子数1~4的烷氧基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,Y为氧原子或硫原子,Z为氮原子或次甲基。]。
上述环己烷衍生物中,优选的是,R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基或碳原子数1~4的烷氧基,R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,R7和R8为氢原子。
上述环己烷衍生物中,R1和R2各自独立地更优选为三氟甲基、甲基或甲氧基,进一步优选的是,R3为氢原子,R4为羟甲基或羟基,R5和R6各自独立地为氢原子、氟原子、三氟甲基、羧基、甲氧基、羟基或乙酰氧基(或者任选一同形成氧代基团)。
发明的效果
本发明的多发性硬化症的治疗剂或预防剂能够显著地抑制多发性硬化症的症状恶化,能够有效地治疗或预防多发性硬化症。
附图说明
图1是髓磷脂少突胶质细胞糖蛋白诱发小鼠实验性自身免疫性脑脊髓炎模型中的、化合物3为30mg/kg时抑制神经症状得分上升的效果的示意图。
图2是髓磷脂少突胶质细胞糖蛋白诱发小鼠实验性自身免疫性脑脊髓炎模型中的、化合物3为3mg/kg和10mg/kg时抑制神经症状得分上升的效果的示意图。
图3是蛋白脂质蛋白诱发小鼠实验性自身免疫性脑脊髓炎模型中的、化合物3抑制神经症状得分上升的效果的示意图。
图4是化合物3对凝血酶活性的作用的示意图。
具体实施方式
本发明的多发性硬化症的治疗剂或预防剂的特征在于,其含有下述通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分。
[化6]
[式中,A为下述通式(IIa)或(IIb)所示的取代基,
[化7]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基、碳原子数1~4的烷氧基或氰基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、甲氧基羰基、乙氧基羰基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,R7和R8各自独立地为氢原子或氟原子,Y为氧原子或硫原子,Z为氮原子或次甲基。]。
另外,本发明的多发性硬化症的治疗剂或预防剂的特征在于,其含有下述通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分。
[化8]
[式中,A为通式(IIc)或(IId)所示的取代基,
[化9]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基或碳原子数1~4的烷氧基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,Y为氧原子或硫原子,Z为氮原子或次甲基。]。
“碳原子数1~4的烷基”表示碳原子数1~4的直链状、分枝状或环状的烷基,可列举出例如甲基、乙基、正丙基、异丙基、环丙基、环丙基甲基、正丁基、仲丁基或叔丁基。
“碳原子数1~4的烷氧基”表示碳原子数1~4的直链状、分枝状或环状的烷基氧基,可列举出例如甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、正丁氧基、仲丁氧基或叔丁氧基。
“碳原子数1~3的卤代烷基”表示碳原子数1~3的直链状烷基上的一部分或全部氢原子被卤素原子(卤素原子表示氟原子、氯原子、溴原子或碘原子)取代的基团,可列举出例如单氯甲基、单氟甲基、二氟甲基、三氟甲基、三氯甲基或五氟乙基。
作为“碳原子数2~5的烷基羰基氧基”,可列举出例如乙酰氧基、乙酰基氧基、丙酰氧基、异丙酰氧基、丁酰氧基、异丁酰氧基或戊酰氧基。
上述通式(I)中,作为A,优选为通式(IIa),作为Y,优选为氧原子,作为Z,优选为次甲基。
上述通式(I)中,作为R1,优选为氢原子、氯原子、三氟甲基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基,更优选为三氟甲基、甲基或甲氧基,进一步优选为甲基。
上述通式(I)中,作为R2,优选为氢原子、氯原子、三氟甲基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基,更优选为甲氧基。
上述通式(I)中,作为R3,优选为氢原子,作为R4,优选为羟甲基或羟基,更优选为羟基。
上述通式(I)中,作为R5,优选为氢原子、氟原子、三氟甲基、羧基、甲氧基、乙氧基、正丙氧基、异丙氧基、羟基、乙酰氧基、丙酰氧基、丁酰氧基或异丁酰氧基,更优选为氢原子、羟基或羧基,进一步优选为羟基。
上述通式(I)中,作为R6,优选为氢原子、氟原子、三氟甲基、羧基、甲氧基、乙氧基、正丙氧基、异丙氧基、羟基、乙酰氧基、丙酰氧基、丁酰氧基或异丁酰氧基,更优选为氢原子或羟基,进一步优选为氢原子。另外,R5与R6任选一同形成氧代基团。
另外,上述通式(I)中,作为R7和R8,优选为氢原子。
将上述通式(I)所示的环己烷衍生物(以下记作环己烷衍生物(I))中的优选具体例示于表1-1~表1-4,但本发明不限定于它们。
需要说明的是,环己烷衍生物(I)或其药理学上可允许的盐存在手性碳时,所有的对映异构体和它们的混合物均涵盖于环己烷衍生物(I)或其药理学上可允许的盐。
进而,环己烷衍生物(I)或其药理学上可允许的盐存在立体异构体时,所有的立体异构体和它们的混合物均涵盖于环己烷衍生物(I)或其药理学上可允许的盐。
作为“药理学上可允许的盐”,可列举出例如盐酸盐、硫酸盐、磷酸盐或氢溴酸盐等无机酸盐;草酸盐、丙二酸盐、柠檬酸盐、富马酸盐、乳酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、醋酸盐、三氟醋酸盐、马来酸盐、葡糖酸盐、苯甲酸盐、抗坏血酸盐、甲磺酸盐、对甲苯磺酸盐或肉桂酸盐等有机酸盐;钠盐、钾盐、钙盐、镁盐或铵盐等无机碱盐或甲胺盐、二乙胺盐、三甲胺盐、三乙胺盐、吡啶嗡盐、三乙醇胺盐、乙二胺盐或胍盐等有机碱盐。进而,环己烷衍生物(I)或其药理学上可允许的盐可以形成水合物或溶剂合物,结晶多形体也涵盖于此。
环己烷衍生物(I)或其药理学上可允许的盐例如可以按照公知文献(国际公开第2010/050577号)所述的方法进行合成。
环己烷衍生物(I)或其药理学上可允许的盐对于多发性硬化症的治疗或预防是有效的,其可以使用病态模型进行评价。作为病态模型,可列举出例如实验性自身免疫性脑脊髓炎模型(Journal of Neuroscience Research、2006年、第84卷、p.1225-1234、International Immunology、1997年、第9卷、p.1243-1251)。实验性自身免疫性脑脊髓炎模型是通过用髓磷脂少突胶质细胞糖蛋白(以下记作MOG)或蛋白脂质蛋白(以下记作PLP)或它们的部分肽使实验动物产生免疫,从而引发由中枢神经系的脱髄导致的后肢麻痹等神经障碍的动物模型。由于该症状和病理所见的人的类似性而广泛用于研究多发性硬化症的治疗剂或预防剂的药效。对于治疗或预防多发性硬化症的有效性,可以使用上述实验性自身免疫性脑脊髓炎模型,例如以多发性硬化症的特征指标即神经症状得分的降低作为指标来进行评价。
环己烷衍生物(I)或其药理学上可允许的盐对于凝血酶活性的作用可以使用体外试验来评价。作为体外试验,可列举出例如测定凝血酶的蛋白酶活性的方法。作为评价凝血酶的蛋白酶活性的方法,可列举出例如利用荧光共振能量移动(FRET)来测定由凝血酶带来的基质切断的方法(Advanced Functional Materials、第20卷、第18号、2010年、p.3175-3182)。
上述多发性硬化症的治疗剂或预防剂可用作对于哺乳动物(例如小鼠、大鼠、仓鼠、兔、猫、狗、牛、羊、猴或人)有效且优异地治疗和预防多发性硬化症的医药品。
作为上述多发性硬化症的治疗剂或预防剂的投与形态,可以将环己烷衍生物(I)或其药理学上可允许的盐直接经口或非经口地投与,或者,配合医药上可允许的载体后,经口或非经口地投与。
作为将含有环己烷衍生物(I)或其药理学上可允许的盐的制剂进行经口投与时的剂型,可列举出例如片剂(包括糖衣片、包膜包衣片)、丸剂、颗粒剂、散剂、胶囊剂(包括软胶囊剂、微胶囊剂)、糖浆剂、乳剂或悬浮剂,另外,作为非经口投与时的剂型,可列举出例如注射剂、注入剂、点滴剂或栓剂。另外,与适当的基剂(例如丁酸的聚合物、羟基乙酸的聚合物、丁酸-羟基乙酸的共聚物、丁酸的聚合物与羟基乙酸的聚合物的混合物、或者聚甘油脂肪酸酯)组合而制成缓释性制剂也是有效的。
含有环己烷衍生物(I)或其药理学上可允许的盐的上述剂型的制剂制备可以按照制剂领域中通常使用的公知制造方法来进行。此时,根据需要可以含有制剂领域中通常使用的赋形剂、结合剂、润滑剂、崩解剂、甜味剂、表面活性剂、悬浮剂、乳化剂等来制造。
含有环己烷衍生物(I)或其药理学上可允许的盐的片剂的制备可以通过含有赋形剂、结合剂、崩解剂、润滑剂等来进行,丸剂和颗粒剂的制备可以通过含有赋形剂、结合剂、崩解剂等来进行。另外,散剂和胶囊剂的制备可通过含有赋形剂等来进行,糖浆剂的制备可通过含有甜味剂等来进行,乳剂或悬浮剂的制备可通过含有表面活性剂、悬浮化剂、乳化剂等来进行。
作为上述赋形剂,可列举出例如乳糖、葡萄糖、淀粉、蔗糖、微晶纤维素、甘草粉末、甘露糖、碳酸氢钠、磷酸钙或硫酸钙。
作为上述结合剂,可列举出例如淀粉糊液、阿拉伯树胶液、明胶液、黄蓍胶液、羧甲基纤维素液、藻酸钠液或甘油。
作为上述崩解剂,可列举出例如淀粉或碳酸钙。
作为上述润滑剂,可列举出例如硬脂酸镁、硬脂酸、硬脂酸钙或精制滑石。
作为上述甜味剂,可列举出例如葡萄糖、果糖、转化糖、山梨糖醇、木糖醇、甘油或单糖浆。
作为上述表面活性剂,可列举出例如月桂硫酸钠、聚山梨酯80、山梨糖醇酐单脂肪酸酯或聚乙二醇40硬脂酸酯。
作为上述悬浮化剂,可列举出例如阿拉伯树胶、藻酸钠、羧甲基纤维素钠、甲基纤维素或皂土。
作为上述乳化剂,可列举出例如阿拉伯树胶、黄蓍胶、明胶或聚山梨酯80。
进而,将含有环己烷衍生物(I)或其药理学上可允许的盐的制剂制备成上述剂型时,可以添加在制剂领域中通常使用的着色剂、保存剂、芳香剂、矫味剂、稳定剂、粘稠剂等。
上述制剂的单日投与量因患者的状态、体重、化合物的种类、投与路径等而异,例如,在经口投与的情况下,若为成人(体重约为60kg),则优选在1mg~1000mg的范围内分1~3次进行投与,在非经口投与的情况下,若为注射剂,则优选在平均1kg体重为0.01~100mg的范围内通过静脉注射来投与。
上述多发性硬化症的治疗剂或预防剂也可以与其它多发性硬化症的治疗剂或预防剂、或者针对多发性硬化症患者的痉挛、挛缩等症状的治疗剂或预防剂组合使用。
作为其它多发性硬化症的治疗剂或预防剂,可列举出例如肾上腺皮质甾醇(强的松龙、甲基强的松龙等)、免疫抑制剂(芬戈莫德、氨甲蝶呤、硫唑嘌呤、环磷酰胺、环孢霉素A、他克莫司、咪唑立宾、来氟米特等)、干扰素制剂(干扰素α、干扰素β-1b、干扰素β-1a等)、共聚物I、免疫球蛋白、米托蒽醌、醋酸格拉替雷、T细胞受体疫苗、粘着分子抑制剂、镇痛剂(吲哚美辛、双氯芬酸等)或肌肉松弛剂(替扎尼定、乙哌立松、氟喹酮、巴氯芬、地西泮、丹曲林钠等)。
作为针对多发性硬化症患者的痉挛、挛缩等症状的治疗剂或预防剂,可列举出例如抗痉挛剂(卡马西平、苯妥英、氯硝西泮、阿米替林等)。
实施例
以下,基于实施例来具体说明本发明,但本发明不限定于它们。
(MOG诱发小鼠实验性自身免疫性脑脊髓炎模型中的环己烷衍生物(I)或其药理学上可允许的盐为30mg/kg时的评价)
评价了环己烷衍生物(I)或其药理学上可允许的盐对于MOG诱发小鼠实验性自身免疫性脑脊髓炎模型的神经症状得分上升的作用。小鼠实验性自身免疫性脑脊髓炎模型通过部分变更Journal of Neuroscience Research、2006年、84卷、p.1225-1234所述的方法来制作。
将包含浓度调整为4mg/mL的MOG的部分合成肽(MOG35-55;CS Bio社)的PBS溶液与Freund的完全辅助剂等量混合,将由此得到的MOG35-55投与液在C57BL/6J系小鼠(雄、7周龄)(Charles River Laboratories International, Inc.)的侧腹部两侧的皮内共计接种0.1mL(单侧0.05mL)。进而,在接种MOG35-55投与液的当天和两天后,向小鼠腹腔内投与浓度调整为1μg/mL的百日咳毒素(Sigma公司)200μL。
作为被检化合物,使用下述化学式所示的1-(1-(4-甲氧基苯基)-5-对甲苯基-1H-吡唑-3-基)环己烷-顺式-1,4-二醇(以下记作化合物3),按照公知文献(国际公开第2010/050577号)所述的方法进行合成。
[化10]
另外,下述化学式所示的比较对照化合物1通过使用三氟醋酸等对公知文献(国际公开第2008/105383号)所述的参考例99(N-Boc保护体)进行脱Boc化来合成,下述化学式所示的比较对照化合物2基于公知文献(国际公开第2010/050577号)所述的比较例2的合成方法来合成。
[化11]
[化12]
自接种MOG35-55投与液的3天前起,以30mg/kg的用量1天2次、连续16天对小鼠经口投与化合物3。需要说明的是,使化合物3悬浮于0.5%甲基纤维素溶液后使用。将对小鼠投与化合物3的组记作化合物3投与组。溶剂投与组同样地投与了0.5%甲基纤维素溶液。
在接种MOG35-55投与液的13天后,针对神经症状得分进行评分(0:正常、1:尾巴松弛或后肢衰弱、2:尾巴松弛和后肢衰弱、3:后肢部分麻痹、4:后肢完全麻痹、5:频死状态)。评分方法使用了Current Protocols in Immunology(John Wiley & Sons.Inc、2000年、p.15.1.1-15.1.20)记载的方法。
将结果示于图1。纵轴表示神经症状得分(平均值±标准误差、n=10)。横轴的“溶剂”表示对接种了MOG35-55投与液的小鼠经口投与0.5%甲基纤维素溶液的组(溶剂投与组),“化合物3”表示对接种了MOG35-55投与液的小鼠以30mg/kg的用量1天2次经口投与化合物3的组(化合物3投与组)。
通过接种MOG35-55投与液,溶剂投与组的神经症状得分上升至2.8。与此相对,化合物3投与组显著抑制神经症状得分的上升。利用化合物3抑制神经症状恶化的抑制率为85.7%。
另外,针对比较对照化合物1和比较对照化合物2也同样地进行评价。即,自接种MOG35-55投与液的3天前起,以30mg/kg的用量1天2次、连续16天对小鼠经口投与悬浮于0.5%甲基纤维素溶液的比较对照化合物1或比较对照化合物2,在接种MOG35-55投与液的13天后,针对神经症状得分进行评分。通过比较对照化合物1和比较对照化合物2抑制神经症状恶化的抑制率分别为3.3%和6.5%。
由该结果可明确:环己烷衍生物(I)或其药理学上可允许的盐对于多发性硬化症显示出显著的神经症状抑制效果。
(MOG诱发小鼠实验性自身免疫性脑脊髓炎模型中的环己烷衍生物(I)或其药理学上可允许的盐为3mg/kg和10mg/kg时的评价)
评价了环己烷衍生物(I)或其药理学上可允许的盐对于MOG诱发小鼠实验性自身免疫性脑脊髓炎模型的神经症状得分上升的作用。
将包含浓度调整为4mg/mL的MOG的部分合成肽(MOG35-55;CS Bio社)的PBS溶液与Freund的完全辅助剂等量混合,将由此得到的MOG35-55投与液在C57BL/6J系小鼠(雄、10周龄)(Charles River Laboratories International, Inc.)的侧腹部两侧的皮内共计接种0.1mL(单侧0.05mL)。进而,在接种MOG35-55投与液的当天和两天后,向小鼠腹腔内投与浓度调整为1μg/mL的百日咳毒素(Sigma公司)200μL。作为被检化合物,使用了化合物3。
在接种MOG35-55投与液的2天后,分别以3mg/kg和10mg/kg的用量1天2次、连续12天对小鼠经口投与化合物3。需要说明的是,使化合物3悬浮于0.5%甲基纤维素溶液后使用。将对小鼠投与化合物3的组记作化合物3投与组。溶剂投与组同样地投与了0.5%甲基纤维素溶液。
在接种MOG35-55投与液的14天后,针对神经症状得分进行评分(0:正常、1:尾巴松弛或后肢衰弱、2:尾巴松弛和后肢衰弱、3:后肢部分麻痹、4:后肢完全麻痹、5:频死状态)。评分方法使用了Current Protocols in Immunology(John Wiley & Sons.Inc、2000年、p.15.1.1-15.1.20)记载的方法。
将结果示于图2。纵轴表示神经症状得分(平均值±标准误差、n=8)。横轴的“溶剂”表示对接种了MOG35-55投与液的小鼠经口投与0.5%甲基纤维素溶液的组(溶剂投与组),“化合物3”表示对接种了MOG35-55投与液的小鼠以3mg/kg和10mg/kg的用量1天2次经口投与化合物3的组(化合物3投与组)。
通过接种MOG35-55投与液,溶剂投与组的神经症状得分上升至1.3。与此相对,通过投与3mg/kg和10mg/kg的化合物3,神经症状得分的上升明显受到抑制,神经症状恶化的抑制率分别为53.8%和61.5%。
由该结果可明确:环己烷衍生物(I)或其药理学上可允许的盐自3mg/kg的用量起对于多发性硬化症显示出显著的神经症状抑制效果。
(PLP诱发小鼠实验性自身免疫性脑脊髓炎模型中的环己烷衍生物(I)或其药理学上可允许的盐的评价)
评价了环己烷衍生物(I)或其药理学上可允许的盐对于PLP诱发小鼠实验性自身免疫性脑脊髓炎模型的神经症状得分上升的作用。小鼠实验性自身免疫性脑脊髓炎模型通过部分变更International Immunology、1997年、第9卷、p.1243-1251所述的方法来制作。
将包含浓度调整为2mg/mL的PLP的部分合成肽(PLP139-151;国产化学株式会社)的PBS溶液与Freund的完全辅助剂等量混合,将由此得到的PLP139-151投与液在SJL系小鼠(雌、6周龄)(Charles River Laboratories International, Inc.)的侧腹部两侧的皮内共计接种0.1mL(单侧0.05mL)。进而,在接种PLP139-151投与液的当天和两天后,向小鼠腹腔内投与浓度调整为1μg/mL的百日咳毒素(Sigma公司)200μL。作为被检化合物,使用了化合物3。
在接种PLP139-151投与液的2天后,以10mg/kg的用量1天2次、连续7天对小鼠经口投与化合物3。需要说明的是,使化合物3悬浮于0.5%甲基纤维素溶液后使用。将对小鼠投与化合物3的组记作化合物3投与组。溶剂投与组同样地投与了0.5%甲基纤维素溶液。
在接种PLP139-151投与液的9天后,针对神经症状得分进行评分(0:正常、1:尾巴松弛或后肢衰弱、2:尾巴松弛和后肢衰弱、3:后肢部分麻痹、4:后肢完全麻痹、5:频死状态)。评分方法使用了Current Protocols in Immunology(John Wiley & Sons.Inc、2000年、p.15.1.1-15.1.20)记载的方法。
将结果示于图3。纵轴表示神经症状得分(平均值±标准误差、n=8)。横轴的“溶剂”表示对接种了PLP139-151投与液的小鼠经口投与0.5%甲基纤维素溶液的组(溶剂投与组),“化合物3”表示对接种了PLP139-151投与液的小鼠以10mg/kg的用量1天2次经口投与化合物3的组(化合物3投与组)。
通过接种PLP139-151投与液,溶剂投与组的神经症状得分上升至1.1。与此相对,化合物3投与组显著抑制神经症状得分的上升。通过化合物3抑制神经症状恶化的抑制率为66.4%。
由该结果可明确:环己烷衍生物(I)或其药理学上可允许的盐对于多发性硬化症显示出显著的神经症状抑制效果。
(相对于凝血酶活性的效果)
使用应用了荧光共振能量移动(FRET)的Anaspec公司的SensoLyte(注册商标)520凝血酶活性检测试剂盒,评价环己烷衍生物(I)或其药理学上可允许的盐对于凝血酶活性的作用。
被检化合物溶解于二甲基亚砜(以下记作DMSO)后,用试剂盒附带的检测缓冲液稀释至DMSO最终浓度达到0.5~1%后进行使用。向384孔的黑色板(Corning公司)的各孔中添加被检化合物(最终浓度为0.1nmol/L~30μmol/L)和用检测缓冲液稀释的凝血酶(最终浓度为300ng/mL),在室温下培养10分钟。需要说明的是,设置未添加凝血酶且未添加被检化合物的孔、以及添加凝血酶且未添加被检化合物的孔。进而,添加用检测缓冲液稀释的5-FAM/QXL 520凝血酶基质(最终浓度为300nmol/L),在室温下培养2小时后,测定用485nm激发时的520nm荧光值。
作为被检化合物,使用了环己烷衍生物(I)或其药理学上可允许的盐中包含的化合物3。另外,作为阳性对照,使用了作为选择性凝血酶抑制剂的阿加曲班。
由下式1算出凝血酶活性抑制率(%),回归至S型曲线(可变斜率),算出被检化合物的凝血酶活性抑制的IC50值。
凝血酶活性抑制率(%)=(1-((添加凝血酶且添加被检化合物时的荧光值)-(未添加凝血酶且未添加被检化合物时的荧光值))/((添加凝血酶且未添加被检化合物时的荧光值)-(未添加凝血酶且未添加被检化合物时的荧光值)))×100 ・・・式1
将结果示于图4。纵轴表示凝血酶活性抑制率(%)(平均值±标准误差、n=4)。横轴表示被检化合物浓度(nmol/L)。
其结果:阿加曲班的IC50值为3.0nmol/L,与此相对,化合物3的最大浓度即30μmol/L时的凝血酶活性抑制率为17.2%。
由该结果可明确:环己烷衍生物(I)或其药理学上可允许的盐不会抑制凝血酶活性。
产业上的可利用性
本发明的环己烷衍生物或其药理学上可允许的盐会显著抑制多发性硬化症的症状恶化,因此,可用作多发性硬化症的治疗剂或预防剂。
Claims (6)
1.多发性硬化症的治疗剂或预防剂,其含有通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分,
[化1]
式(I)中,A为通式(IIa)或(IIb)所示的取代基,
[化2]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基、碳原子数1~4的烷氧基或氰基,
R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,
R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、甲氧基羰基、乙氧基羰基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,
R7和R8各自独立地为氢原子或氟原子,
Y为氧原子或硫原子,
Z为氮原子或次甲基。
2.多发性硬化症的治疗剂或预防剂,其含有通式(I)所示的环己烷衍生物或其药理学上可允许的盐作为有效成分,
[化3]
式(I)中,A为通式(IIc)或(IId)所示的取代基,
[化4]
R1和R2各自独立地为氢原子、氯原子、碳原子数1~3的卤代烷基、碳原子数1~4的烷基或碳原子数1~4的烷氧基,
R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,
R5和R6各自独立地为氢原子、氟原子、碳原子数1~3的卤代烷基、羧基、碳原子数1~4的烷氧基、羟基或碳原子数2~5的烷基羰基氧基,或者任选一同形成氧代基团,
Y为氧原子或硫原子,
Z为氮原子或次甲基。
3.根据权利要求1或2所述的多发性硬化症的治疗剂或预防剂,其中,R1和R2各自独立地为三氟甲基、甲基或甲氧基。
4.根据权利要求1~3中任一项所述的多发性硬化症的治疗剂或预防剂,其中,R3为氢原子。
5.根据权利要求1~4中任一项所述的多发性硬化症的治疗剂或预防剂,其中,R4为羟甲基或羟基。
6.根据权利要求1~5中任一项所述的多发性硬化症的治疗剂或预防剂,其中,R5和R6各自独立地为氢原子、氟原子、三氟甲基、羧基、甲氧基、羟基或乙酰氧基,或者任选一同形成氧代基团。
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JP5783042B2 (ja) * | 2010-03-31 | 2015-09-24 | 東レ株式会社 | 蓄尿障害の治療剤又は予防剤 |
CN102858748B (zh) * | 2010-04-28 | 2015-06-17 | 东丽株式会社 | 阿尔茨海默病的治疗剂或预防剂 |
AU2011283462B9 (en) | 2010-07-30 | 2014-09-18 | Toray Industries, Inc. | Therapeutic agent or prophylactic agent for neuropathic pain |
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MX2016009932A (es) | 2017-01-11 |
WO2015115509A1 (ja) | 2015-08-06 |
JPWO2015115509A1 (ja) | 2017-03-23 |
CA2933018C (en) | 2021-10-26 |
US20170231960A1 (en) | 2017-08-17 |
EP3100726A1 (en) | 2016-12-07 |
US10130608B2 (en) | 2018-11-20 |
US20170000767A1 (en) | 2017-01-05 |
JP6447496B2 (ja) | 2019-01-09 |
CN105934245B (zh) | 2019-04-09 |
EP3100726A4 (en) | 2017-06-14 |
BR112016016674A2 (pt) | 2017-08-08 |
CA2933018A1 (en) | 2015-08-06 |
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