CN106456641A - 眼后段疾病的预防或治疗剂 - Google Patents
眼后段疾病的预防或治疗剂 Download PDFInfo
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Abstract
本发明涉及眼后段疾病的预防或治疗剂，所述眼后段疾病的预防或治疗剂含有式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐(以下，也称为“本化合物”)作为有效成分。
Description
技术领域
本发明涉及眼后段疾病的预防或治疗剂，所述眼后段疾病的预防或治疗剂含有3-氨基-2-氧代吡咯烷衍生物，特别是式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐(以下，也称为“本化合物”)作为有效成分。
[化学式1]
背景技术
所谓眼后段疾病，通常是指玻璃体、视网膜、脉络膜、巩膜或视神经中的疾病，这些疾病与新生血管显现紧密相关。即，对于老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜静脉阻塞症、葡萄膜炎等眼后段疾病而言，新生血管显现的亢进是病态形成及病态发展的主要的要因，已知抑制血管新生对于这些疾病的治疗是有用的(非专利文献1、非专利文献2)。
另一方面，已报道式(1b)表示的化合物具有抑制CCR-2及CCR-5受体的活性，表明该化合物对炎症性疾病、过敏性疾病、自身免疫性疾病、癌症及/或循环系统疾病的治疗是有用的(专利文献1)。
[化学式2]
但是，没有针对3-氨基-2-氧代吡咯烷衍生物，特别是式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐(本化合物)对眼后段疾病的预防或治疗的效果进行研究的报道。
[化学式3]
现有技术文献
专利文献
专利文献1：国际公开2011/046916号小册子
非专利文献
非专利文献1：日眼会誌(日眼会志)，103，923-947(1999)
非专利文献2：新図説臨床眼科講座第5巻「網膜硝子体疾患」(新图说临床眼科讲座第5卷“视网膜玻璃体疾病”)，P.184-189，232-237(2000)。
发明内容
发明所要解决的课题
本发明的课题在于提供含有3-氨基-2-氧代吡咯烷衍生物作为有效成分的眼后段疾病的预防或治疗剂。
解决课题所用的手段
本申请的发明人为了探索含有3-氨基-2-氧代吡咯烷衍生物作为有效成分的眼后段疾病的预防或治疗剂进行了深入研究，结果发现式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐在视网膜、脉络膜这样的眼后段组织中具有优异的血管新生抑制作用及血管透过性亢进抑制作用，发现本化合物对眼后段疾病具有优异的预防或治疗效果，从而完成了本发明。
[化学式4]
即，本发明涉及以下内容。
本发明为眼后段疾病的预防或治疗剂，所述眼后段疾病的预防或治疗剂含有式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分。
[化学式5]
[式(1)中，
R1及R2相同或不同，表示氢原子、低级烷基、或被卤素原子取代的低级烷基；
R3表示氢原子、卤素原子、低级烷基、或被卤素原子取代的低级烷基；
R4表示氢原子、低级烷基、或被卤素原子取代的低级烷基；
R5表示未取代或被R6取代的含氮双环式芳香环基；
R6表示卤素原子、低级烷基、或被卤素原子取代的低级烷基。]
此外，本发明的其他实施方式为含有上式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，上述式(1)中，
R1及R2相同或不同，表示氢原子或低级烷基；
R3表示氢原子或低级烷基；
R4表示氢原子或低级烷基
R5表示式(2a)、(2b)或(2c)：
[化学式6]
R6表示低级烷基或被卤素原子取代的低级烷基。
其中，式(2a)、(2b)或(2c)中的·表示R5与所键合的氮原子的键合位点。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，上述式(1)表示的化合物为式(1’)表示的化合物。
[化学式7]
此外，本发明的其他实施方式为含有上述式(1)或式(1’)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，上述式(1)或式(1’)中，
R1表示氢原子；
R2表示叔丁基；
R3表示甲基；
R4表示氢原子；
R5表示式(2b)；
R6表示叔丁基。
其中，式(2b)中的·为R5与所键合的氮原子的键合位点。
[化学式8]
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，该眼后段疾病为玻璃体、视网膜、脉络膜、巩膜或视神经中的疾病。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，眼后段疾病为选自由老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜色素变性症、增殖性玻璃体视网膜病、视网膜动脉阻塞症、视网膜静脉阻塞症、葡萄膜炎、Leber氏病、早产儿视网膜病变、视网膜脱落、视网膜色素上皮脱落、中心性浆液性脉络膜视网膜病变、中心性渗出性脉络膜视网膜病变、息肉状脉络膜血管病变、多发性脉络膜炎、新生血管黄斑病、视网膜动脉瘤、视网膜血管瘤样增生、所述疾病导致的视神经损伤、青光眼导致的视神经损伤及缺血性视神经损伤组成的组中的至少1种。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂，其中，眼后段疾病为选自由老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜静脉阻塞症及葡萄膜炎组成的组中的至少1种。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的脉络膜血管新生抑制剂。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂、或者抑制剂，其施予方式为滴眼施予、玻璃体内施予、结膜下施予、结膜囊内施予、特农囊(Tenon’scapsule)下施予或口服施予。
此外，本发明的其他实施方式为含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂、或者抑制剂，其剂型为滴眼剂、眼软膏、插入剂、贴剂、注射剂、片剂、细粒剂或胶囊剂。
进而，本发明还涉及以下内容。
本发明的其他实施方式为用于眼后段疾病的预防或治疗的上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐。
本发明的其他实施方式为上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐在制造用于预防或治疗眼后段疾病的药物中的应用。
本发明的其他实施方式为用于预防或治疗眼后段疾病的药物组合物，其含有治疗有效量的上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐及添加剂。
本发明的其他实施方式为用于预防或治疗眼后段疾病的方法，所述方法包括施予有效量的上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐。
发明的效果
根据本发明，能够提供含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分的眼后段疾病的预防或治疗剂。
具体实施方式
以下详细说明本发明。
所谓“卤素原子”表示氟原子、氯原子、溴原子或碘原子。
所谓“低级烷基”，表示碳原子数为1～8个的直链或支链的烷基，优选碳原子数为1～6个的直链或支链的烷基。作为具体例，可举出甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、异丙基、异丁基、仲丁基、叔丁基、异戊基等。
所谓“被卤素原子取代的低级烷基”，表示被1个或多个(例如，2个或3个)卤素原子取代的低级烷基，优选被3个卤素原子取代的低级烷基。作为具体例，可举出三氟甲基等。需要说明的是，存在多个卤素原子的情况下，这些卤素原子可以相同或不同。
所谓“含氮双环式芳香环基”，表示至少1个环原子为氮原子的双环式芳香环，例如，优选环原子为8个、9个或10个、且含有1个、2个、3个或4个氮原子作为环原子的芳香环。作为具体例，可举出喹啉基、异喹啉基、噌啉基、吡唑并[1,5-α]吡啶基、咪唑并[1,2-α]吡啶基、喹喔啉基、喹唑啉、苯并三唑基、吲哚基、吲唑基、吡唑并[1,5-α][1,3,5]三嗪、嘧啶并[5,4-d]嘧啶等。
本发明的眼后段疾病的预防或治疗剂中所包含的化合物，可按照有机合成化学领域中的通常的方法进行制造。例如，可按照国际公开2011/046916号小册子等中记载的方法进行制造。此外，该化合物的几何异构体(顺式-反式异构体)、光学异构体(对映异构体、非对映异构体)或互变异构体也可以通过柱色谱法、HPLC等通常的方法来分离、纯化。
本发明的眼后段疾病的预防或治疗剂所包含的化合物为式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐。
[化学式9]
上述式(1)表示的化合物存在几何异构体(顺式-反式异构体)、光学异构体(对映异构体、非对映异构体)或互变异构体时，这些异构体也包含在该式(1)表示的化合物的范围内。此外，该式(1)表示的化合物也可以是选自其几何异构体(顺式-反式异构体)、光学异构体(对映异构体、非对映异构体)及互变异构体的组中的1种或2种以上的异构体的混合物。
上述式(1)中，R1及R2相同或不同，表示氢原子、低级烷基、或被卤素原子取代的低级烷基。
上述式(1)中，R3表示氢原子、卤素原子、低级烷基、或被卤素原子取代的低级烷基。
上述式(1)中，R4表示氢原子、低级烷基、或被卤素原子取代的低级烷基。
上述式(1)中，R5表示未取代或被R6取代的含氮双环式芳香环基。
上述式(1)中，R6表示卤素原子、低级烷基、或被卤素原子取代的低级烷基。
以下示出各取代基的优选例。
上述式(1)中，对于R1及R2而言，优选相同或不同，为氢原子或低级烷基，更优选的是，R1为氢原子、R2为低级烷基，特别优选的是，R1为氢原子、R2为叔丁基。
上述式(1)中，R3优选为低级烷基，特别优选为甲基。
上述式(1)中，R4优选为氢原子。
上述式(1)中，R5优选为式(2a)、(2b)或(2c)，特别优选为式(2b)。其中，式(2a)、(2b)或(2c)中的·为R5与所键合的氮原子的键合位点。
[化学式10]
[化学式11]
R6优选为低级烷基或被卤素原子取代的低级烷基，更优选为叔丁基或三氟甲基，最优选为叔丁基。
上述式(1)优选为式(1’)：
[化学式12]
作为上述式(1)或式(1’)表示的化合物的具体例，可举出式(1a)表示的N-((1R,2S,5R)-2-((S)-3-((6-(叔丁基)嘧啶并[5,4-d]嘧啶-4-基)氨基)-2-氧代吡咯烷-1-基)-5-(叔丁基氨基)环己基)乙酰胺(以下，也称为“化合物1a”)、其对映异构体及非对映异构体、和它们的混合物(例如，外消旋混合物、非对映异构体混合物等)。
[化学式13]
作为上述式(1)或式(1’)表示的化合物的具体例，可举出式(1b)表示的N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-3-(7-叔丁基吡唑并[1,5-α][1,3,5]三嗪-4-基氨基)-2-氧代吡咯烷-1-基)环己基)乙酰胺(以下，也称为“化合物1b”)、其对映异构体及非对映异构体、和它们的混合物(例如，外消旋混合物、非对映异构体混合物等)。
[化学式14]
作为上述式(1)或式(1’)表示的化合物的具体例，可举出式(1c)表示的N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-((6-(三氟甲基)喹唑啉-4-基)氨基)吡咯烷-1-基)环己基)乙酰胺(以下，也称为“化合物1c”)、其对映异构体及非对映异构体、和它们的混合物(例如，外消旋混合物、非对映异构体混合物等)。
[化学式15]
所谓上述式(1)、(1’)、(1a)、(1b)或(1c)表示的化合物的“药学上容许的盐”，例如，可举出与无机酸形成的盐或与有机酸形成的盐。作为无机酸，例如可举出盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸等。作为有机酸，例如可举出乙酸、富马酸、马来酸、琥珀酸、柠檬酸、酒石酸、己二酸、葡糖酸、葡庚糖酸、葡糖醛酸、对苯二甲酸、甲磺酸、乳酸、马尿酸、1,2-乙二磺酸、羟乙基磺酸、乳糖酸、油酸、亚甲基双羟萘酸(Pamoic acid)、多聚半乳糖醛酸、硬脂酸、鞣酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、硫酸月桂酯、硫酸二甲酯、萘磺酸、磺基水杨酸等。
上述式(1)、(1’)、(1a)、(1b)或(1c)表示的化合物可以为水合物或溶剂合物的形态。
上述式(1)、(1’)、(1a)、(1b)或(1c)表示的化合物存在多晶型及多晶型组(多晶型体系)时，这些多晶型体及多晶型组(多晶型体系)也包含在本化合物的范围内。这里，所谓多晶型组(多晶型体系)，是指根据这些结晶的制造、结晶、保存等的条件及状态(需要说明的是，该状态中也包括制剂化后的状态)，晶型发生各种变化时各阶段的晶型及该过程整体。
本发明中，眼后段疾病是指玻璃体、视网膜、脉络膜、巩膜或视神经中的疾病。作为眼后段疾病，优选为选自由老年黄斑变性(渗出型老年黄斑变性、萎缩型老年黄斑变性、初期老年黄斑变性)、糖尿病视网膜病、糖尿病黄斑水肿、视网膜色素变性症、增殖性玻璃体视网膜病、视网膜动脉阻塞症、视网膜静脉阻塞症、葡萄膜炎、Leber氏病、早产儿视网膜病变、视网膜脱落、视网膜色素上皮脱落、中心性浆液性脉络膜视网膜病变、中心性渗出性脉络膜视网膜病变、息肉状脉络膜血管病变、多发性脉络膜炎、新生血管黄斑病、视网膜动脉瘤、视网膜血管瘤样增生、所述疾病导致的视神经损伤、青光眼导致的视神经损伤及缺血性视神经损伤组成的组中的至少1种，特别优选为选自由老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜静脉阻塞症及葡萄膜炎组成的组中的至少1种。
将本化合物用于眼后段疾病的治疗时，可以口服地或非口服地施予至患者，作为施予方式，可举出口服施予、对眼的局部施予(滴眼施予、结膜囊内施予、玻璃体内施予、结膜下施予、特农囊下施予等)、静脉内施予、经皮施予等。作为将本化合物局部施予至眼时使用的优选剂型，可使用滴眼剂或眼软膏剂，或者可使用注射剂、尤其是结膜下施予剂、特农囊施予剂或玻璃体内施予剂。含有本化合物作为有效成分的制剂，可根据需要与药学上容许的添加剂一同制剂化为适于施予的剂型。作为适于口服施予的剂型，例如可举出片剂、胶囊剂、颗粒剂、散剂等，作为适于非口服施予的剂型，例如可举出注射剂、滴眼剂、眼软膏、贴剂、凝胶、插入剂等。上述剂型可采用该领域中广泛应用的通常的技术进行制备。进而，为了更有效地发挥本发明的治疗效果的持续作用，也可以制成眼内植入(implant)用制剂、微球等DDS化的制剂。
例如，片剂可适宜地选择使用赋形剂、崩解剂、粘合剂、润滑剂、包衣剂、矫味剂等进行制备。作为赋形剂，例如可举出乳糖、葡萄糖、D-甘露糖醇、无水磷酸氢钙、淀粉、蔗糖等。作为崩解剂，例如可举出羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮(crospovidone)、淀粉、部分α化淀粉、低取代羟丙基纤维素等。作为粘合剂，例如可举出羟丙基纤维素、乙基纤维素、阿拉伯胶、淀粉、部分α化淀粉、聚乙烯吡咯烷酮、聚乙烯醇等。作为润滑剂，例如可举出硬脂酸镁、硬脂酸钙、滑石、含水二氧化硅、氢化油等。作为包衣剂，例如可举出精制白砂糖、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮等。作为矫味剂，例如可举出柠檬酸、阿斯巴甜、抗坏血酸、薄荷醇等。
例如，注射剂可根据需要选择使用等渗剂、缓冲剂、表面活性剂、增稠剂等进行制备。作为等渗剂，例如可举出氯化钠等。作为缓冲剂，例如可举出磷酸钠等。作为表面活性剂，例如可举出聚氧乙烯山梨糖醇酐单油酸酯等。作为增稠剂，例如可举出甲基纤维素等。
例如，滴眼剂可根据需要选择使用等渗剂、缓冲剂、表面活性剂、稳定剂、防腐剂等来进行制备，pH只要在眼科制剂容许的范围内即可，但通常优选在4～8的范围内。作为等渗剂，例如可举出氯化钠、浓甘油等。作为缓冲剂，例如可举出磷酸钠、乙酸钠等。作为表面活性剂，例如，可举出聚氧乙烯山梨糖醇酐单油酸酯、硬脂酸-40-聚烃氧基酯(polyoxyl40stearate)、聚氧乙烯氢化蓖麻油等。作为稳定剂，例如可举出柠檬酸钠、乙二胺四乙酸钠等。作为防腐剂，例如可举出苯扎氯铵、对羟基苯甲酸酯等。
例如，眼软膏可使用白凡士林、液体石蜡等广泛使用的基质进行制备。
例如，插入剂可如下进行制备，即，将生物降解性聚合物、例如羟丙基纤维素、羟丙基甲基纤维素、羧基乙烯聚合物、聚丙烯酸等生物降解性聚合物与本发明化合物一同粉碎混合，将该粉末压缩成型，由此来制备；根据需要，可以使用赋形剂、粘合剂、稳定剂、pH调节剂。
例如，眼内植入用制剂可使用生物降解性聚合物、例如聚乳酸、聚羟基乙酸、乳酸·羟基乙酸共聚物、羟丙基纤维素等生物降解性聚合物进行制备。
本化合物的施予量可根据剂型、应施予的患者的症状的轻重、年龄、体重、眼球容积、医生的判断等适当地改变，口服施予时，通常可以对成人每1日一次或分数次施予0.01～10000mg、优选0.1～5000mg、更优选0.5～2500mg；注射剂的情况下，通常可以对成人一次或分数次施予0.0001～2000mg。此外，滴眼剂或插入剂的情况下，可以1日一次或数次施予有效成分浓度为0.000001～10％(w/v)、优选为0.00001～1％(w/v)、更优选为0.0001～0.1％(w/v)的制剂。进而，贴剂的情况下，可以对成人贴敷含有0.0001～2000mg本发明化合物的贴剂，眼内植入用制剂的情况下，可以在成人眼内植入含有0.0001～2000mg本发明化合物的眼内植入用制剂。
[实施例]
以下示出药理试验的结果及制剂例，但这些例子是用于更好地理解本发明的，并不限定本发明的范围。
[药理试验1]
使用激光诱导大鼠脉络膜血管新生模型(Invest.Ophthalmol.Vis.Sci.,40(2),459-466(1999))，评价了本化合物的有用性。
(氪激光诱导大鼠脉络膜血管新生模型动物的制作方法)
以1mL/kg的量对大鼠肌肉内施予5％(W/V)盐酸氯胺酮注射液与2％盐酸赛拉嗪注射液的混合液(7：1)，将其全身麻醉，向眼内滴入0.5％(W/V)托吡卡胺-0.5％盐酸苯肾上腺素滴眼液，使其散瞳后，利用氪激光光凝固装置进行光凝固。光凝固如下进行：在眼底后局部处，避开粗的视网膜血管，使焦点对准视网膜深层，每眼8处，呈散在状实施(凝固条件：点尺寸100μm，输出功率100mW，凝固时间0.1秒)。光凝固后，进行眼底照相，确认激光照射部位。
(试验化合物)
本药理试验中，作为本化合物，使用了按照国际公开2011/046916号小册子中记载的合成方法合成的上述化合物1b。
(药物施予方法)
将化合物1b混合在1％(W/V)甲基纤维素液(使甲基纤维素溶解于精制水中进行制备)中使其成为20mg/mL，在从光凝固手术日开始包括手术日在内的7天期间，以100mg/kg的用量1日2次口服施予含有化合物1b的施予液。需要说明的是，对基质施予组同样地施予1％(W/V)甲基纤维素液。
(评价方法)
在光凝固后第7日，以1mL/kg的量对大鼠肌肉内施予5％(W/V)盐酸氯胺酮注射液与2％盐酸赛拉嗪注射液的混合液(7：1)，将其全身麻醉，向眼内滴入0.5％(W/V)托吡卡胺-0.5％盐酸苯肾上腺素滴眼液，使其散瞳后，从阴茎静脉注入0.1mL的10％荧光素溶液，进行荧光眼底造影。通过荧光眼底造影，将没有观察到荧光渗漏的点判断为阴性(无血管新生)，将观察到了荧光渗漏的点判断为阳性。此外，存在两处可观察到若干的荧光渗漏的光凝固部位时，判定为阳性(有血管新生)。然后，按照式1，由相对于8处激光照射的点而言的阳性点数算出脉络膜血管新生发生率(％)，按照式2算出评价药物的抑制率(％)。化合物1b的结果示于表1。需要说明的是，各施予组的例数为7例或8例。
[式1]：
脉络膜血管新生发生率(％)＝(阳性点数/光凝固部位总数)×100
[式2]：
抑制率(％)＝{(A0-AX)/A0}×100
A0：基质施予组的脉络膜血管新生发生率
AX：药物施予组的脉络膜血管新生发生率
[表1]
| 组构成 | 抑制率(％) |
| 化合物1b 100mg/kg | 66.6 |
由表1可知，化合物1b在激光诱导大鼠脉络膜血管新生模型动物中抑制脉络膜血管新生。以上结果表明，本化合物对眼后段疾病具有优异的预防或治疗效果。
[制剂例]
给出制剂例更具体地说明本发明的药剂，但本发明并不限于这些制剂例。
处方例1滴眼剂
100mL中
向灭菌精制水中加入本发明化合物及除此以外的上述成分，将其充分混合，制备滴眼液。通过改变本化合物的添加量，可制备浓度为0.05％(w/v)～1％(w/v)的滴眼剂。
处方例2眼软膏
100g中
本化合物 0.3g
液体石蜡 10.0g
白凡士林 适量
向均匀熔融的白凡士林及液体石蜡中加入本化合物，将其充分混合后，缓慢冷却，由此制备眼软膏。通过改变本化合物的添加量，可制备浓度为0.05％(w/v)～1％(w/v)的眼软膏。
处方例3片剂
100mg中
将本化合物、乳糖在混合机中混合，向该混合物中加入羧甲基纤维素钙及羟丙基纤维素进行造粒，将所得到的颗粒干燥后进行整粒，向该整粒颗粒中加入硬脂酸镁进行混合，用压片机压片。此外，通过适当改变本化合物、羧甲基纤维素钙及羟丙基纤维素的添加量，可制备100mg中的本化合物的含量为0.1mg～50mg的片剂。
处方例4注射剂或玻璃体内施予剂
10mL中
向灭菌精制水中加入本化合物及除此以外的上述成分，充分混合使其溶解或悬浮，制备注射剂。通过适当改变本化合物及除此以外的上述成分的添加量，可制备10ml中的本化合物的含量为2mg～200mg的注射剂。如此制备的注射剂可作为用于眼内施予的注射剂(例如玻璃体内施予剂)进行施予。
Claims (10)
1.眼后段疾病的预防或治疗剂，其含有式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分，
[化学式16]
式(1)中，
R1及R2相同或不同，表示氢原子、低级烷基、或被卤素原子取代的低级烷基；
R3表示氢原子、卤素原子、低级烷基、或被卤素原子取代的低级烷基；
R4表示氢原子、低级烷基、或被卤素原子取代的低级烷基；
R5表示未取代或被R6取代的含氮双环式芳香环基；
R6表示卤素原子、低级烷基、或被卤素原子取代的低级烷基。
2.如权利要求1所述的预防或治疗剂，其中，式(1)中，
R1及R2相同或不同，表示氢原子或低级烷基；
R3表示氢原子或低级烷基；
R4表示氢原子或低级烷基；
R5表示式(2a)、(2b)或(2c)：
[化学式17]
R6表示低级烷基或被卤素原子取代的低级烷基。
3.如权利要求1或2所述的预防或治疗剂，其中，式(1)表示式(1’)：
[化学式18]
4.如权利要求1～3中任一项所述的眼后段疾病的预防或治疗剂，其中，式(1)或式(1’)中，
R1表示氢原子，
R2表示叔丁基；
R3表示甲基；
R4表示氢原子；
R5表示式(2b)：
[化学式19]
R6表示叔丁基。
5.如权利要求1～4中任一项所述的预防或治疗剂，其中，眼后段疾病为玻璃体、视网膜、脉络膜、巩膜或视神经中的疾病。
6.如权利要求1～4中任一项所述的预防或治疗剂，其中，眼后段疾病为选自由老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜色素变性症、增殖性玻璃体视网膜病、视网膜动脉阻塞症、视网膜静脉阻塞症、葡萄膜炎、Leber氏病、早产儿视网膜病变、视网膜脱落、视网膜色素上皮脱落、中心性浆液性脉络膜视网膜病变、中心性渗出性脉络膜视网膜病变、息肉状脉络膜血管病变、多发性脉络膜炎、新生血管黄斑病、视网膜动脉瘤、视网膜血管瘤样增生、所述疾病导致的视神经损伤、青光眼导致的视神经损伤及缺血性视神经损伤组成的组中的至少1种。
7.如权利要求6所述的预防或治疗剂，其中，眼后段疾病为选自由老年黄斑变性、糖尿病视网膜病、糖尿病黄斑水肿、视网膜静脉阻塞症及葡萄膜炎组成的组中的至少1种。
8.脉络膜血管新生抑制剂，其含有上述式(1)表示的化合物、其对映异构体或非对映异构体、或者其药学上容许的盐作为有效成分。
9.如权利要求1～8中任一项所述的预防或治疗剂、或者抑制剂，其中，施予方式为滴眼施予、玻璃体内施予、结膜下施予、结膜囊内施予、特农囊下施予或口服施予。
10.如权利要求1～9中任一项所述的预防或治疗剂、或者抑制剂，其剂型为滴眼剂、眼软膏、插入剂、贴剂、注射剂、片剂、细粒剂或胶囊剂。
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| CN101568532A (zh) * | 2006-07-28 | 2009-10-28 | 百时美施贵宝公司 | 作为趋化因子受体活性调节剂的环状衍生物 |
| CN102648201A (zh) * | 2009-10-13 | 2012-08-22 | 百时美施贵宝公司 | N-((1r,2s,5r)-5-(叔丁基氨基)-2-((s)-3-(7-叔丁基吡唑并[1,5-a][1,3,5]三嗪-4-基氨基)-2-氧代吡咯烷-1-基)环己基)乙酰胺，趋化因子受体活性的双重调节剂，晶形及方法 |
| CN103380115A (zh) * | 2010-12-16 | 2013-10-30 | 阿勒根公司 | 作为趋化因子受体调节剂的硫衍生物 |
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| US7629351B2 (en) * | 2006-07-28 | 2009-12-08 | Bristol-Myers Squibb Company | N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino) pyrrolidin-1-yl)cyclohexyl)acetamide and other modulators of chemokine receptor activity, crystalline forms and process |
| JP6087836B2 (ja) * | 2011-01-11 | 2017-03-01 | ディメリックス バイオサイエンス プロプライアタリー リミテッド | 併用療法 |
| WO2014133072A1 (ja) * | 2013-02-28 | 2014-09-04 | 参天製薬株式会社 | テトラヒドロピラニルアミノシクロペンチルカルボニルテトラヒドロピリドピリジン誘導体を有効成分として含有する後眼部疾患の予防または治療剤 |
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- 2015-07-17 SG SG11201700331RA patent/SG11201700331RA/en unknown
- 2015-07-17 MA MA040320A patent/MA40320A/fr unknown
- 2015-07-17 CN CN201580033445.2A patent/CN106456641A/zh active Pending
- 2015-07-17 BR BR112017000991A patent/BR112017000991A2/pt not_active Application Discontinuation
- 2015-07-17 WO PCT/JP2015/070477 patent/WO2016010130A1/ja active Application Filing
- 2015-07-17 MX MX2017000580A patent/MX2017000580A/es unknown
- 2015-07-17 CA CA2955862A patent/CA2955862A1/en not_active Abandoned
- 2015-07-17 US US15/326,728 patent/US20170202845A1/en not_active Abandoned
- 2015-07-17 EP EP15821760.4A patent/EP3170500A4/en not_active Withdrawn
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| CN101568532A (zh) * | 2006-07-28 | 2009-10-28 | 百时美施贵宝公司 | 作为趋化因子受体活性调节剂的环状衍生物 |
| CN102648201A (zh) * | 2009-10-13 | 2012-08-22 | 百时美施贵宝公司 | N-((1r,2s,5r)-5-(叔丁基氨基)-2-((s)-3-(7-叔丁基吡唑并[1,5-a][1,3,5]三嗪-4-基氨基)-2-氧代吡咯烷-1-基)环己基)乙酰胺，趋化因子受体活性的双重调节剂，晶形及方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| US20170202845A1 (en) | 2017-07-20 |
| KR20170029513A (ko) | 2017-03-15 |
| EA201790231A1 (ru) | 2017-05-31 |
| JP2016029037A (ja) | 2016-03-03 |
| WO2016010130A1 (ja) | 2016-01-21 |
| CA2955862A1 (en) | 2016-01-21 |
| TW201625255A (zh) | 2016-07-16 |
| EP3170500A1 (en) | 2017-05-24 |
| MA40320A (fr) | 2017-05-24 |
| SG11201700331RA (en) | 2017-02-27 |
| EP3170500A4 (en) | 2018-03-14 |
| MX2017000580A (es) | 2017-09-01 |
| BR112017000991A2 (pt) | 2018-07-24 |
| PH12017500106A1 (en) | 2017-05-22 |
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