CN101151034B - 含有前列腺素F2α衍生物作为有效成分的视网膜神经细胞保护剂 - Google Patents
含有前列腺素F2α衍生物作为有效成分的视网膜神经细胞保护剂 Download PDFInfo
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Abstract
本发明的课题在于找出前列腺素F2α衍生物的新医药用途。前列腺素F2α衍生物在大鼠胎儿视网膜神经细胞中浓度依赖性地抑制谷氨酸诱发的视网膜神经细胞死亡、即前列腺素F2α衍生物直接作用于视网膜神经细胞，显示保护作用。因此，前列腺素F2α衍生物对与视网膜神经细胞损伤相关的眼疾病的预防或治疗是有用的。
Description
技术领域
本发明涉及含有前列腺素F2α衍生物作为有效成分的视网膜神经细胞保护剂。
背景技术
视网膜是由内界膜、神经纤维层、神经节细胞层、内丛状层、内颗粒层、外丛状层、外颗粒层、外界膜、视细胞层及视网膜色素上皮层这样10层构成的、厚度为0.1～0.5mm的组织，其中，存在视细胞、双极细胞、神经节细胞、水平细胞、无长突细胞及苗勒细胞的视网膜神经细胞群。
视网膜神经细胞在将光刺激转化为电信号、传递给脑的视觉信息的接受与传达中发挥重要作用。
详细叙述该传递机制如下：从眼睛进入的视觉信息被视细胞电信号化，经由水平细胞、双极细胞及/或无长突细胞后，传达至神经节细胞。然后，该电信号经由作为包括神经节细胞轴突的视神经纤维束的视神经被传达至脑。
如果该视网膜神经细胞因各种原因受到损害，则无法维持视网膜神经细胞的恒常性(通过视网膜血流循环向视网膜神经细胞供给氧和营养的功能等)，阻碍视觉信息向脑传递。例如，众所周知在视网膜血管阻塞症、糖尿病性视网膜症、缺血性视神经症、青光眼、黄斑变性症、视网膜色素变性症、Leber病等各种视网膜疾病中发生视网膜神经细胞的功能破坏(非专利文献1)。
最近，人们已经逐渐认识到视网膜缺血导致视网膜神经细胞死亡是损害视网膜神经细胞的原因之一，关于视网膜缺血导致的视网膜神
经细胞死亡，报道了下述内容：
1)视网膜缺血导致视网膜神经细胞死亡的机制与脑缺血时的脑神经细胞死亡的机制相类似；
2)短期的视网膜缺血选择性地损伤视网膜内层(内丛状层)；
3)视网膜缺血时能确认谷氨酸的过剩游离；
4)通过将谷氨酸等兴奋性氨基酸注射入玻璃体内引起视网膜神经细胞死亡；
5)视网膜的N-甲基-D-天冬氨酸(NMDA)受体介导的过剩刺激促进钙(Ca)流入细胞内，结果通过一氧化氮(NO)的诱导引发细胞损伤等(专利文献1、非专利文献2)。
根据上述内容，认为谷氨酸神经毒性抑制药、NMDA受体阻断药、NO合成抑制药等药物对由视网膜神经细胞损伤引起的眼疾病的治疗是有用的，现在，正在进行各种研究。
例如，专利文献2公开了含有作为β阻断药之一的尼普洛尔(nipradilol)为有效成分的视网膜神经细胞保护剂；专利文献3公开了含有白细胞介素1受体拮抗蛋白为有效成分的视神经节细胞保护剂；专利文献4公开了含有盐酸溴莫尼定等α1受体阻断药为有效成分的视神经节细胞保护剂；非专利文献3公开了作为前列腺素衍生物之一的拉坦前列素(latanoprost)的神经保护作用等。
另一方面，在专利文献5、专利文献6、专利文献7、专利文献8、专利文献9、专利文献10、专利文献11、专利文献12、专利文献13、专利文献14及专利文献15中，作为具有降眼压作用的青光眼治疗剂，公开了前列腺素F2α衍生物。专利文献5公开了天然的前列腺素F2α衍生物；专利文献6公开了拉坦前列素相关化合物；专利文献7公开了比马前列胺(bimatoprost)相关化合物；专利文献8公开了曲伏前列素(travoprost)相关化合物；专利文献9公开了单氟前列腺素F2α衍生物；专利文献10及专利文献11公开了二氟前列腺素F2α衍生物；另外，专利文献12公开了具有多取代芳氧基的含氟前列腺素F2α衍生物；专利文献13公开了醚型二氟前列腺素F2α衍生物；专利文献14公开了二氟
前列腺素F2α酰胺衍生物。
但是，所有专利文献中都完全没有记载含氟前列腺素F2α衍生物的视网膜神经细胞保护作用。
非专利文献1：Brain Res Bull.，62(6)，447-453(2004)
专利文献1：特开2003-146904号公报
非专利文献2：Nature Rev.，2，448-459(2003)
专利文献2：特开2001-072591号公报
专利文献3：国际公开第01/056606号说明书
专利文献4：国际公开第03/004058号说明书
非专利文献3：Experimental Eye Res.，72，479-486(2001)
专利文献5：特开昭59-1418号公报
专利文献6：特表平3-501025号公报
专利文献7：特表平8-501310号公报
专利文献8：特开平10-182465号公报
专利文献9：国际公开第98/12175号说明书
专利文献10：欧州专利申请公开第850926号说明书
专利文献11：特开2004-002462号公报
专利文献12：特开平10-259179号公报
专利文献13：特开2002-293771号公报
专利文献14：特开2003-321442号公报
发明内容
找出前列腺素F2α衍生物(特别是含氟前列腺素F2α)的新医药用途是非常有趣的课题。
本发明人等为找出前列腺素F2α衍生物的新医药用途而进行了深入研究，结果发现前列腺素F2α衍生物在大鼠胎儿视网膜神经细胞中浓度依赖性地抑制谷氨酸诱发的视网膜神经细胞死亡，即，前列腺素F2α衍生物直接作用于视网膜神经细胞显示保护作用，从而完成了本发明。
本发明涉及含有前列腺素F2α衍生物为有效成分的视网膜神经细胞保护剂。
本发明还涉及视网膜神经细胞的保护方法、与视网膜神经细胞损伤相关的眼疾病的预防或治疗方法。
本发明的“前列腺素F2α衍生物”表示由前列腺烷酸骨架衍生的前列腺素F2α相关化合物。
具体而言可以举出以下述前列腺素F2α衍生物或其盐为有效成分的视网膜神经细胞保护剂，即特开平59-1418中公开的天然的前列腺素F2α衍生物、特表平3-501025中公开的拉坦前列素相关化合物(但为不包括拉坦前列素的拉坦前列素相关化合物或其盐)、特表平8-501310中公开的比马前列胺相关化合物(优选为比马前列胺或其盐)、特开平10-182465中公开的曲伏前列素相关化合物(优选为曲伏前列素或其盐)、国际公开第98/12175号说明书、欧州专利申请公开第850926号说明书、特开2004-002462号公报、特开平10-259179号公报、特开2002-293771号公报、特开2003-321442号公报等公开的含氟前列腺素F2α衍生物等。
可以优选举出含有“含氟前列腺素F2α衍生物”为有效成分的视网膜神经细胞保护剂，该“含氟前列腺素F2α衍生物”表示具有1个或多个氟原子的前列腺素F2α衍生物。
具体而言，可以举出含有国际公开第98/12175号说明书、欧州专利申请公开第850926号说明书、特开2004-002462号公报、特开平10-259179号公报、特开2002-293771号公报、特开2003-321442号公报等公开的含氟前列腺素F2α衍生物为有效成分的视网膜神经细胞保护剂。
可以较优选举出含有上述欧州专利申请公开第850926号说明书、特开2004-002462号公报、特开平10-259179号公报、特开2002-293771号公报及特开2003-321442号等公报中记载的15，15-二氟前列腺素F2α衍生物为有效成分的视网膜神经细胞保护剂。
更优选举出作为含氟前列腺素F2α衍生物含有下述通式(1)表示
的15，15-二氟前列腺素F2α衍生物或其盐为有效成分的视网膜神经细胞保护剂。
[式中，R表示羟烷基、甲酰基、羧基、烷氧基羰基、芳氧基羰基、氨基羰基、烷基氨基羰基或芳基氨基羰基，R为该芳氧基羰基或该芳基氨基羰基时，其芳基部分可以具有取代基。以下相同。]
此处，本说明书中规定的各基团或用语含义如下。
“卤素”表示氟、氯、溴或碘。
“烷基”表示碳原子数为1～6个的直链或支链的烷基。作为具体例，可以举出甲基、乙基、正丙基、正丁基、正戊基、正己基、异丙基、异丁基、仲丁基、叔丁基、异戊基等。
“烷氧基”表示碳原子数为1～6个的直链或支链的烷氧基。作为具体例，可以举出甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正己氧基、异丙氧基、异丁氧基、仲丁氧基、叔丁氧基、异戊氧基等。
“芳基”表示碳原子数为6～14个的单环式或2环式或3环式的缩合多环式芳香族烃。作为具体例，可以举出苯基、萘基、蒽基、菲基等。
“芳氧基”表示碳原子数为6～14个的单环式或2环式或3环式的缩合多环式芳香族烃氧基。作为具体例，可以举出苯氧基、萘氧基、蒽氧基、菲氧基等。
“烷氨基”表示碳原子数为1～12个的单或二烷基氨基。具体而言，可以举出甲氨基、乙氨基、二甲氨基、二己氨基等。
“芳氨基”表示碳原子数为6～28个的单或二芳基氨基。作为具体例，可以举出苯氨基、萘氨基、甲基苯氨基、乙基苯氨基、二苯氨基、二蒽氨基等。
R为“芳氧基羰基”或“芳氨基羰基”时，其芳基部分可以具有取代基。作为取代基，优选选自卤原子、烷基、卤代烷基及烷氧基的原子或基团，取代基数优选为1～3个。
作为更优选的含氟前列腺素F2α衍生物，可以举出上述通式(1)中，R表示羧基或其盐或烷氧基羰基的15，15-二氟前列腺素F2α衍生物。
作为特别优选的含氟前列腺素F2α衍生物，可以举出上述通式(1)中R表示羧基或其盐或异丙氧基羰基的15，15-二氟前列腺素F2α衍生物。
另外，作为其他优选的化合物，可以举出上述国际公开第98/12175号说明书中记载的15-单氟前列腺素F2α衍生物。
上述前列腺素F2α衍生物可以与盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸等无机酸、乙酸、富马酸、马来酸、琥珀酸、柠檬酸等有机酸、锂、钠、钾等碱金属、钙、镁等碱土类金属、铵等形成盐，上述盐也包含在本发明中。
本发明的“视网膜神经细胞”表示参与视觉信号向脑的传递的神经细胞。具体而言，表示视细胞、水平细胞、双极细胞、视神经节细胞、无长突细胞等。
本发明的“眼疾病”表示与视网膜神经细胞损伤相关的眼疾病。具体而言，表示视野异常、视网膜血管阻塞症、糖尿病性视网膜症、缺血性视神经症、青光眼、黄斑变性症、视网膜色素变性症、Leber病等，优选表示视野异常、视网膜血管阻塞症、糖尿病性视网膜症、缺血性视神经症、黄斑变性症、视网膜色素变性症、Leber病。
本发明的视网膜神经细胞保护剂可以经口给与或非经口给与。作为给药剂型，可以举出滴眼剂、眼软膏、注射剂、片剂、胶囊剂、颗粒剂、散剂等，特别优选滴眼剂。上述剂型可以使用常用的技术、例如特开平59-1418、特表平3-501025、特表平8-501310、特开平10-182465、国际公开第98/12175号说明书、欧州专利申请公开第850926号说明书、特开2004-002462号公报、特开平10-259179号公
报、特开2002-293771号公报、特开2003-321442号公报、国际公开第02/22131号说明书等公开的技术进行制剂化。
例如，滴眼剂可以根据需要使用氯化钠、浓甘油等等渗剂、磷酸钠、乙酸钠等缓冲剂、聚氧乙烯失水山梨糖醇单油酸酯、硬脂酸聚烃氧40酯、聚氧乙烯氢化蓖麻油等表面活性剂、柠檬酸钠、依地酸钠等稳定剂、苯扎氯铵、对羟基苯甲酸酯等防腐剂等进行制剂化。pH只要在眼科用制剂允许的范围内即可，没有特别问题，优选在pH4～8的范围内。
眼软膏可以根据需要使用白色凡士林、液体石蜡等常用的基剂进行制剂化。
另外，片剂、胶囊剂、颗粒剂、散剂等口服制剂可以根据需要使用乳糖、结晶纤维素、淀粉、植物油等增量剂、硬脂酸镁、滑石等润滑剂、羟丙基纤维素、聚乙烯吡咯烷酮等粘合剂、羧甲基纤维素钙、低取代羟丙基甲基纤维素等崩解剂、羟丙基甲基纤维素、聚乙二醇、硅树脂等包衣剂、明胶被膜等被膜剂等进行制剂化。
给药量可以根据症状、年龄、剂型等适当选择，滴眼剂可以1天1次～数次滴眼0.00001～1％(w/v)、优选0.0001～1％(w/v)。口服制剂通常可以1天1次～数次给与0.01～5000mg、优选0.1～1000mg。
在下述药理试验项中详细地说明，研究了前列腺素F2α衍生物对使用了大鼠胎儿视网膜神经细胞的谷氨酸诱发视网膜神经细胞死亡的效果。结果为前列腺素F2α衍生物浓度依赖性地抑制了谷氨酸诱发视网膜神经细胞死亡。即，前列腺素F2α衍生物具有视网膜神经细胞保护作用，对于与视网膜神经细胞损伤相关的眼疾病的预防或治疗是有用的。
附图说明
[图1]是表示使用添加谷氨酸的受试化合物时各浓度的生存率的图。
具体实施方式
以下给出本发明的制剂例及药理试验结果。需要说明的是，下述例子用于更好地理解本发明，并不限定本发明的范围。
[制剂例]
以下给出含有本发明的前列腺素F2α衍生物的通常的制剂例。
1)滴眼剂100ml中
前列腺素F2α衍生物 10mg
浓甘油 2500mg
聚山梨醇酯80 2000mg
磷酸二氢钠二水合物 200mg
灭菌精制水 适量
1N盐酸或1N氢氧化钠 适量
pH 6.0
通过适当改变前列腺素F2α衍生物和添加剂的种类以及量可以得到所希望的滴眼剂。
2)眼软膏 100g中
前列腺素F2α衍生物 0.1g
液体石蜡 20g
白色凡士林 77.9g
精制羊毛脂 2g
通过适当改变前列腺素F2α衍生物和添加剂的种类以及量可以得到所希望的眼软膏。
[药理试验]
为了找出前列腺素F2α衍生物的新医药用途，使用大鼠胎儿视网膜神经细胞，评价研究前列腺素F2α衍生物对谷氨酸诱发的视网膜神经细胞死亡的视网膜神经细胞保护作用。
需要说明的是，使用16-苯氧基-15-脱氧-15，15-二氟-17，18，19，20-四去甲前列腺素F2α作为受试化合物的前列腺素F2α衍生物。
(1)分离培养视网膜神经细胞
将妊娠SD大鼠在全身麻醉下进行剖腹，将子宫转移至装有Hanks’s平衡盐溶液(Hanks’s Balanced Salt Solution、HBSS)的皿中。从子宫摘出大鼠胎儿，取出大鼠胎儿的眼球。在实体显微镜下从该眼球中摘出视网膜，用医科用手术刀切细。进一步将视网膜切细至细胞水平，通过尼龙筛(No.305 NBC工业(株)制)除去细胞块，将透过物在1000rpm下离心4分种。除去上清液，在残留的细胞中加入适量的含有10％胎牛血清(fetal bovine serum、FBS)的改性Eagle’s培养基(Modified Eagle’s Medium、MEM)，使其混悬。用血细胞计数板计数细胞数后，加入含有10％FBS的MEM培养基，得到细胞数0.8×106 细胞/ml的细胞悬浊液。将细胞悬浊液分别以80μl播种在聚乙二亚胺涂布后的塑料盘中，在培养器(37℃·5％CO2)中静置。以细胞播种日为培养第一日，在偶数日进行培养基交换。另外，使用含有10％FBS的MEM培养基至第4天为止，第8天以后使用含有10％马血清(HorseSerum、HS)的MEM培养基。其中，为除去增殖性细胞，在第6天使用6ml含有阿糖胞苷(Ara-C)的培养基(在含有10％FBS的MEM培养基中有1.5×10-5M)。
(2)制备含有受试化合物的含有HS的MEM培养基
将2mg受试化合物溶解在100％乙醇中，用含HS的MEM培养基依次稀释制备含有0.1nM、1nM、10nM及100nM受试化合物的含有HS的MEM培养基。
(3)制备含有受试化合物不含血清的MEM培养基
将2mg受试化合物溶解在100％乙醇中，用不含血清的MEM培养基依次稀释，制备含有0.1nM、1nM、10nM及100nM的受试化合物不含血清的MEM培养基。
(4)评价细胞死亡
培养第10日，将播种·培养细胞的塑料盘转移至含有受试化合物含有HS的MEM培养基中，培养24小时(37℃·5％CO2)。将塑料盘转移至含有1mM谷氨酸不含血清的MEM培养基中，培养10分钟后，转移至含有受试化合物不含血清的MEM培养基中，培养1小时(37℃·5％CO2)。将细胞用1.5％锥虫蓝液染色10分钟后，加入10％福尔马林固定液固定细胞。用生理盐水清洗后，在倒立型显微镜下计数染色细胞及非染色细胞。
另外，使用含有HS的MEM培养基代替上述含有受试化合物含有HS的MEM培养基，使用不含血清的MEM培养基代替含有受试化合物不含血清的MEM培养基，除此之外，实施与上述相同的试验作为基剂给与组。
另外，使用含有HS的MEM培养基代替上述含有受试化合物含有HS的MEM培养基，使用不含血清的MEM培养基代替含有受试化合物不含血清的MEM培养基，并且不用含有谷氨酸不含血清的MEM培养基实施处理，除此之外，实施与上述相同的试验作为无处理组。
生存率基于下述计算式计算。
(5)结果及讨论
根据图1所示，用谷氨酸处理的视网膜神经细胞在基剂添加组中可见生存率为约40％的细胞死亡，使用含有受试化合物的含HS的MEM培养基(0.1nM～100nM)作为培养基时，浓度依赖性地抑制谷氨酸诱发的视网膜神经细胞死亡，确认了视网膜神经细胞保护作用。
Claims (1)
1.作为15，15-二氟前列腺素F2α衍生物的下述通式(1)表示的化合物或其盐在制备视野异常、视网膜血管阻塞症、糖尿病性视网膜症、缺血性视神经症、黄斑变性症、视网膜色素变性症、Leber病的预防剂或治疗剂中的应用，
式中，R表示羧基或其盐或烷氧基羰基。
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- 2006-03-31 KR KR1020077023372A patent/KR101396731B1/ko active IP Right Grant
- 2006-03-31 US US11/887,037 patent/US20090234005A1/en not_active Abandoned
- 2006-03-31 WO PCT/JP2006/306826 patent/WO2006106915A1/ja active Application Filing
- 2006-03-31 CA CA2602573A patent/CA2602573C/en active Active
- 2006-03-31 SI SI200631410T patent/SI1864666T1/sl unknown
- 2006-03-31 RU RU2007140309/15A patent/RU2414904C2/ru active
- 2006-03-31 CN CN201110176745A patent/CN102293774A/zh active Pending
- 2006-03-31 EP EP06730774A patent/EP1864666B1/en active Active
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2007
- 2007-10-29 NO NO20075464A patent/NO339794B1/no not_active IP Right Cessation
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2011
- 2011-09-02 US US13/199,598 patent/US9138438B2/en active Active
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- 2012-10-16 CY CY20121100958T patent/CY1113473T1/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1140057A (zh) * | 1995-03-10 | 1997-01-15 | 株式会社·R-技术上野 | 前列腺烷酸化合物治疗视神经障碍 |
| CN1187486A (zh) * | 1996-12-26 | 1998-07-15 | 旭硝子株式会社 | 二氟前列腺素衍生物及其使用 |
Non-Patent Citations (5)
| Title |
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| Filippo Drago, et.al..Latanoprost experts neuroprotective activity in vitro and invivo.Experimental eye research72.2001,72479-486. * |
| JP特开平9-87179A 1997.03.31 |
| Kayoko Hayami et al.photoreceptor protection against constant light-induceddamage by isopropyl unoprostone, a prosaglandin F2 alphametabolite-related compound.Ophthalmic research33.2001,33203-209. * |
| KayokoHayamietal.photoreceptorprotectionagainstconstantlight-induceddamagebyisopropylunoprostone a prosaglandin F2 alphametabolite-related compound.Ophthalmic research33.2001 |
| 说明书第2页第1-11段以及第34页末段. |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2414904C2 (ru) | 2011-03-27 |
| US20090234005A1 (en) | 2009-09-17 |
| CY1113473T1 (el) | 2016-06-22 |
| US20120010288A1 (en) | 2012-01-12 |
| KR20070116632A (ko) | 2007-12-10 |
| CN101151034A (zh) | 2008-03-26 |
| DK1864666T3 (da) | 2012-10-29 |
| CA2602573C (en) | 2013-10-08 |
| NO20075464L (no) | 2007-12-18 |
| NO339794B1 (no) | 2017-01-30 |
| PL1864666T3 (pl) | 2013-02-28 |
| EP1864666A1 (en) | 2007-12-12 |
| WO2006106915A1 (ja) | 2006-10-12 |
| US9138438B2 (en) | 2015-09-22 |
| PT1864666E (pt) | 2012-09-06 |
| KR101396731B1 (ko) | 2014-05-19 |
| EP1864666B1 (en) | 2012-08-15 |
| SI1864666T1 (sl) | 2012-10-30 |
| EP1864666A4 (en) | 2008-04-02 |
| ES2389500T3 (es) | 2012-10-26 |
| RU2007140309A (ru) | 2009-05-10 |
| CN102293774A (zh) | 2011-12-28 |
| CA2602573A1 (en) | 2006-10-12 |
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Address after: Tokyo, Japan, Japan Co-patentee after: Santen Pharmaceutical Co., Ltd. Patentee after: AGC Corporation Address before: Tokyo, Japan, Japan Co-patentee before: Santen Pharmaceutical Co., Ltd. Patentee before: Asahi Glass Co., Ltd. |