CN102811992B - 抗利什曼原虫化合物以及抗利什曼原虫药 - Google Patents
抗利什曼原虫化合物以及抗利什曼原虫药 Download PDFInfo
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Abstract
一种抗利什曼原虫化合物,其由式(1)表示。
Description
技术领域
本发明涉及具有高抗利什曼原虫活性的抗利什曼原虫化合物以及抗利什曼原虫药。
背景技术
利什曼原虫症是因作为鞭毛型寄生原虫类的利什曼原虫属(Leishmania)的原虫感染而发病的感染症,利什曼原虫属的原虫是巨噬细胞的专性细胞内寄生体。利什曼原虫症被WHO指定为六大热带疾病之一。另外,利什曼原虫症是以作为吸血昆虫的雌性砂蝇为媒介的生物媒介的感染症,由于利什曼原虫在砂蝇吸血时侵入到皮肤、内脏等哺乳类宿主的体内而感染。已知利什曼原虫症的症状从轻症到危及生命的重症不等,但作为主要治疗药使用的5价的锑会引起严重的副作用。需要说明的是,两性霉素B(AmBisome)本来是作为抗真菌药使用的,其只不过是也可以用于利什曼原虫症的治疗。因此,需要副作用的风险低的新药。另外,作为抑制副作用的药,有两性霉素B,但存在药物价格高的问题。
另一方面,报道了来源于海藻的代谢物显示出抗利什曼原虫活性(例如,参考非专利文献1)。但是,该文献中,对于来源于海藻的何种化合物具有抗利什曼原虫活性,并没有进行化合物的特别指定。
现有技术文献
非专利文献
非专利文献1:Y.Freile-Pelegrin,D.Robledo,M.J.Chan-Bacab,B.O.Orrtega-Morales,“Antileishmanial propertie of tropical marine algaeextract”,Fitoterapia,(Holland),Elsevier,2008,79,p.374-377
发明内容
发明所要解决的问题
本发明人进行了深入的研究,结果发现,着眼于褐藻类墨角藻目马尾藻科山田马尾藻(Sargassum yamadae),进行提取物的分离后,具有高抗利什曼原虫活性,从而完成了本发明。
用于解决问题的方法
即,本发明涉及的抗利什曼原虫化合物由式(1)表示。
另外,本发明涉及的抗利什曼原虫化合物由式(2)表示。
另外,本发明涉及的抗利什曼原虫化合物由式(4)表示。
另外,本发明涉及的抗利什曼原虫化合物由式(5)表示。
另外,本发明涉及的抗利什曼原虫化合物由式(6)表示。
另外,本发明涉及的抗利什曼原虫药的特征在于,含有由式(1)、式(2)、式(4)~式(6)中的任意一个表示的化合物及其药理上允许的盐作为有效成分。
发明效果
根据本发明,可以提供显示高抗利什曼原虫活性的抗利什曼原虫化合物以及抗利什曼原虫药。
附图说明
图1是表示本发明的实施例涉及的化合物的分离操作(第1次)的顺序的图。
图2是表示本发明的实施例涉及的化合物的分离操作(第1次)的顺序的图。
图3是表示本发明的实施例涉及的化合物的分离操作(第1次)的顺序的图。
图4是表示本发明的实施例涉及的化合物的分离操作(第1次)的顺序的图。
图5是表示本发明的实施例涉及的化合物的分离操作(第1次)的顺序的图。
图6是表示本发明的实施例涉及的化合物的分离操作(第2次)的顺序的图。
图7是表示本发明的实施例涉及的化合物的分离操作(第2次)的顺序的图。
图8是表示本发明的实施例涉及的化合物的分离操作(第2次)的顺序的图。
图9是表示本发明的实施例涉及的体外抗利什曼原虫活性测定结果的图。
图10是表示本发明的实施例涉及的体内抗利什曼原虫活性测定结果的图。
图11是表示本发明的实施例涉及的体内抗利什曼原虫活性测定结果的图。
图12是表示本发明的实施例涉及的体内抗利什曼原虫活性测定结果的图。
具体实施方式
以下,参照附图,对本发明的实施方式涉及的抗利什曼原虫化合物以及抗利什曼原虫药进行说明。本发明涉及的抗利什曼原虫化合物由式(1)~(6)所示的化合物中的至少一种构成,本发明涉及的抗利什曼原虫药含有式(1)~(6)所示的化合物中的至少一种作为有效成分。
为了分离、纯化式(1)~(6)所示的化合物中的任意一种,对于褐藻等藻而言,考虑该化合物的物理化学性质,适当利用采集代谢物时通常使用的分离、纯化方法即可。例如,对于藻,通过有机溶剂、优选氯仿-甲醇的等量混合溶剂进行提取操作。然后,可以从所得到的提取液中再通过二氯甲烷等有机溶剂提取化合物,也可以使用各种色谱法而使化合物吸附、洗脱。另外,可以根据需要进一步进行纯化操作,从而分离、纯化具有期望纯度的化合物。色谱法中,可以使用惯用的无机和有机载体、例如硅胶、聚苯乙烯树脂等作为载体。
式(1)~(6)所示的化合物,作为例如医药品领域的抗原虫药、特别是抗利什曼原虫药有用。由式(1)~(6)的任意一种表示的化合物,可以单独使用,或者也可以与一般制剂上允许的添加剂一起混合而制成制剂。另外,作为给药方式,可以列举:使用片剂、颗粒剂、胶囊剂、丸剂、散剂、液体制剂、混悬剂、乳剂、糖浆剂、酏剂、浸膏剂等口服制剂的给药方式,或者使用注射剂、液体制剂、栓剂、软膏剂、贴剂、巴布剂、洗剂等非口服制剂的给药方式等,但没有特别制限,可以根据治疗目的等适当选择。
另外,在为片剂、颗粒剂、丸剂、胶囊剂、散剂的情况下,可以含有赋形剂、粘合剂、崩解剂、润滑剂等添加剂。作为赋形剂,可以列举:淀粉、羧甲基纤维素、白糖、糊精、玉米淀粉等。
作为粘合剂,可以列举:结晶纤维素、结晶纤维素/羧甲基纤维素钠、甲基纤维素、羟丙基纤维素、低取代羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯琥珀酸酯、羧甲基纤维素钠、乙基纤维素、羧甲基乙基纤维素、羟乙基纤维素、小麦淀粉、大米淀粉、玉米淀粉、土豆淀粉、糊精、预胶化淀粉、部分预胶化淀粉、羟丙基淀粉、支链淀粉、聚乙烯吡咯烷酮、甲基丙烯酸氨基烷酯共聚物E、甲基丙烯酸氨基烷酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物、聚乙烯醇缩醛二乙氨基乙酸酯、聚乙烯醇、阿拉伯胶、阿拉伯胶粉末、琼脂、明胶、白虫胶、黄蓍胶、精制白糖、聚乙二醇。
作为崩解剂,可以列举:结晶纤维素、甲基纤维素、低取代羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、小麦淀粉、大米淀粉、玉米淀粉、土豆淀粉、部分预胶化淀粉、羟丙基淀粉、羧甲基淀粉钠、黄蓍胶。
作为润滑剂,可以列举:小麦淀粉、大米淀粉、玉米淀粉、硬脂酸、硬脂酸钙、硬脂酸镁、含水二氧化硅、轻质无水硅酸、合成硅酸铝、干燥氢氧化铝凝胶、滑石粉、偏硅酸铝镁、磷酸氢钙、无水磷酸氢钙、蔗糖脂肪酸酯、蜡类、氢化植物油、聚乙二醇。
另外,在为液体制剂、糖浆剂、混悬剂、乳剂、酏剂的情况下,除了水、植物油等通常使用的惰性稀释剂之外,还可以含有着色剂、矫味剂、芳香剂等作为添加剂。
另外,在为注射剂的情况下,可以含有混悬液、乳浊液、用时溶解剂等添加剂。另外,在为软膏剂、栓剂的情况下,可以含有脂肪、脂肪油、羊毛脂、凡士林、石蜡、蜡、树脂、塑料、基剂、二醇类、高级醇、水、乳化剂、混悬化剂等作为添加剂。另外,在为巴布剂的情况下,可以含有甘油、水、水溶性高分子、吸水性高分子等作为添加物。另外,在为洗剂的情况下,可以含有溶剂、乳化剂、混悬化剂等作为添加剂。
本发明的抗利什曼原虫化合物,可以添加到食品、口香糖、饮料等中,也可以在所谓的特定保健用食品(例如,抗利什曼原虫食品)、补充剂等中含有。
需要说明的是,上述式(1)~(6)所示的化合物是包括这些化合物的药理上允许的盐的概念。即,本发明包括通过在人或动物的体内代谢而转变为上述化合物以及酰胺、从而显示出药理活性的生物化学前体物质。本发明中,药理上允许的盐是指将上述化合物用酸或碱进行处理而得到的盐,不具有显著的毒性,并且可以作为医药品使用的盐。作为这样的酸加成盐的例子,可以列举:利用盐酸、氢溴酸、硫酸、磷酸等无机酸、马来酸、富马酸、酒石酸、柠檬酸等有机酸等的加成盐,作为通过碱生成的盐,可以列举:利用氢氧化钠、氢氧化钾等碱金属氢氧化物、氢氧化钙、氢氧化镁等碱土金属氢氧化物、胍、三乙胺、二环己胺等有机碱形成的盐。
实施例
以下,使用实施例对本发明更加具体地进行说明。
1.式(1)~(6)所示的化合物的分离操作
(1)脂质成分的提取
将褐藻类墨角藻目马尾藻科山田马尾藻(Sargassumyamadae)(294.4g)在甲醇与氯仿的等量混合溶剂(1.4L)中浸渍1天,通过抽滤除去残渣,提取出脂质成分。进而,将该残渣在甲醇与氯仿的等量混合溶剂(1.4L)中浸渍1天,通过进行抽滤而提取出脂质成分。减压下除去溶剂,将所得到的提取物(31.2g)利用水和氯仿而分成二层,得到脂质成分(23.8g)。另外,山田马尾藻在采集后通过人工海水清洗,在恒温除湿室中干燥,粉碎后保存在-20℃下直到用于实验。
(2)第1次分离操作
在通过(1)所示的操作得到的脂质成分中,分取5.14g,如图1所示改变乙酸乙酯-己烷系溶剂的比例的同时,通过开放柱色谱法(φ7×45cm)分离出A~P这16个组分。
其中,如图2~5所示,对于组分E、K、N以及O,进一步通过开放柱色谱法、薄层色谱法、以及使用乙酸乙酯-己烷混合洗脱液的HPLC,分离出多种化合物。
如图2所示,对于组分E,进行薄层色谱法,得到多种组分。
其中,从组分f中得到式(5)所示的化合物。另外,对于组分e进行HPLC,在保留时间18分钟得到式(5)所示的化合物。另外,在图2~8中,在组分名的下方示出所得到的组分的质量(mg)。另外,在为上述式(1)~(6)所示的化合物中的任意一种的情况下,将该化合物的式子的编号用粗体示出。另外,对于进行HPLC时得到的组分,从上依次示出保留时间、所得到的化合物的质量(mg),并且在为上述式(1)~(6)所示的化合物中的任意一种的情况下,将该化合物的式子的编号用粗体示出。
另外,如图3所示,对于组分K,使用20%乙酸乙酯-己烷洗脱液进行HPLC,在保留时间28分钟得到马尾藻醌酸(sargaquinoic acid),在保留时间31分钟得到式(1)所示的化合物。另外,如图4所示,对于组分N,进行薄层色谱法以及使用20%乙酸乙酯-己烷洗脱液的HPLC,在HPLC中,在保留时间28分钟得到式(2)所示的化合物(HREIMS m/z 440.2560[M+].C27H36O5(△-0.3mmu))。另外,如图5所示,对于组分O,使用55%乙酸乙酯-己烷洗脱液进行HPLC,在保留时间28分钟得到式(3)所示的化合物(HREIMS m/z 440.2934[M+].C28H40O4(△+0.8mmu))。
(3)第2次分离操作
在通过上述脂质成分的提取操作得到的脂质成分中,对于在第1次分离操作中没有使用的剩余的18.6g,改变乙酸乙酯-己烷系溶剂的比例的同时,如图6所示通过开放柱色谱法(φ7×45cm)分离出A’~O’这15个组分。
如图7所示,合并所得到的组分中的组分C’以及组分D’,进行利用Sep-Pak的提取。对于使用0.5%乙酸乙酯-己烷混合洗脱液进行提取而得到的组分,使用1%乙酸乙酯-己烷洗脱液进行HPLC,在保留时间182分钟得到式(6)所示的化合物。另外,对于使用1%乙酸乙酯-己烷混合洗脱液进行提取而得到的组分,使用7%乙酸乙酯-己烷洗脱液进行HPLC,在保留时间108分钟得到式(5)所示的化合物。
另外,如图8所示,对于组分E’,进行薄层色谱法,进而使用20%乙酸乙酯-己烷混合洗脱液进行HPLC。在保留时间40分钟得到式(5)所示的化合物,在保留时间76分钟得到式(4)所示的化合物(EIMS m/z 408C27H36O3[M+],m/z 175[M-C16H25O])。
对于所得到的化合物,通过1H-NMR以及13C-NMR等进行分子结构的分析。将NMR光谱的数据示于下表。另外,式(1)所示的化合物的NMR数据与Bull.Chem.Soc.Jpn.,2008,81(9)1125-1130中发表的NMR数据一同示出,式(4)所示的化合物的NMR数据与结构类似的马尾藻色烯醇(sargachromenol)的NMR数据一同示出,式(5)以及式(6)所示的化合物的NMR数据与马尾藻醌酸(sargaquinoic acid)的NMR数据一同示出。
表1
式(1)所示的化合物的NMR数据
表2
式(2)所示的化合物的NMR数据
表3
式(3)所示的化合物的NMR数据
表4
式(4)所示的化合物的NMR数据
*:未检测到
表5
式(5)所示的化合物的NMR数据
*:未检测到
表6
式(6)所示的化合物的NMR数据
*:未检测到
由这些NMR数据可知,所得到的化合物分别由上述式(1)~式(6)表示。
2.抗利什曼原虫活性测定
(1)体外抗利什曼原虫活性测定
根据上述的顺序,对于分离出的式(1)~(6)所示的化合物,在下述所示的条件下进行生理活性测定。作为利什曼原虫,选择硕大利什曼原虫前鞭毛体(Leishmania.major promastigotes)(MHOM/UZ/91/PM2),使用导入了荧光蛋白egfp基因的L.major/egfp前鞭毛体,将上述化合物作为样品,在下述条件下求出生长抑制率。
(测定顺序)
在25℃下使用96孔板,在添加有10%胎牛血清、25mM Hepes缓冲液(MC Biomedicals Inc.,LLC)和10μg/mL衣霉素(SIGMA-ALDRICHinc.,美国)的199培养基(日水制药,东京,日本)中培养L.major/egfp前鞭毛体。接着,在96孔板(黑色微孔板,NUNC,丹麦)的各孔中加入L.major/egfp原虫100μL(1×106个细胞/mL)以及样品溶液100μL(溶解于DMSO中),使用低温培养箱(三洋,日本)在25℃下培养72小时。之后,使用荧光微孔板读取装置(Fluoroscan Ascent FL,大日本制药,大阪,日本),在激发光485nm、发射光538nm处测定了L.major/egfp前鞭毛体的荧光信号。另外,将使用两性霉素B作为标准物质时的生长抑制率设为100%,示出各试样的抑制率。
图9中示出测定的结果、所求出的生长抑制率。这些结果显示了,式(1)~(6)所示的化合物具有抑制利什曼原虫生长的生理活性特性。特别是,式(3)所示的化合物的生长抑制率与两性霉素B的生长抑制率大致相同。
(2)体内抗利什曼原虫活性测定
对于通过上述顺序分离出的式(3)所示的化合物,为了评价其在体内的抗利什曼原虫活性,使用利什曼原虫症小鼠模型考察治疗效果。
使6周龄的小鼠(Balb/C,雄性,1组6只)感染利什曼原虫L.majorPM2株1×107的培养前鞭毛体。从感染次日起,通过腹腔接种将式(3)所示的化合物以每个检体各200μg向小鼠给药。给药计划是1天1次、连续给药3周。另外,作为对照,对进行了两性霉素B给药的治疗组、未进行任何给药的治疗组也进行了测定。
将测量小鼠的溃疡尺寸的结果示于图10。另外,图11中示出小鼠血中的抗体值的变动。另外,图12中示出对使用从小鼠的血液中提取的DNA作为模板、通过以原虫基因作为目标而实施的PCR扩增后的DNA产物进行电泳的结果。即,图12中示出血中的原虫DNA的检测结果,在原虫DNA存在时,在310bp的位置观察到PCR产物。图12中的白色越深,表示原虫DNA以越高浓度存在。另一方面,在310bp为黑色的情况下,表示原虫DNA不存在。
由这些结果可知,式(3)所示的化合物在体内也显示出与两性霉素B同样的抗利什曼原虫活性。
Claims (6)
1.由式(1)表示的抗利什曼原虫化合物或其药理上允许的盐在制造抗利什曼原虫药中的应用,
2.一种抗利什曼原虫化合物,其由式(2)表示,
3.一种抗利什曼原虫化合物,其由式(4)表示,
4.由式(5)表示的抗利什曼原虫化合物或其药理上允许的盐在制造抗利什曼原虫药中的应用,
5.由式(6)表示的抗利什曼原虫化合物或其药理上允许的盐在制造抗利什曼原虫药中的应用,
6.一种抗利什曼原虫药,其特征在于,含有权利要求2或3所述的抗利什曼原虫化合物或其药理上允许的盐作为有效成分。
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