CN110612102A - 含有吡唑并喹啉衍生物的路易氏体病治疗剂 - Google Patents
含有吡唑并喹啉衍生物的路易氏体病治疗剂 Download PDFInfo
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Abstract
本发明提供一种针对路易氏体病的治疗剂，该治疗剂包含式(I)所表示的(S)‑7‑(2‑甲氧基‑3,5‑二甲基吡啶‑4‑基)‑1‑(四氢呋喃‑3‑基)‑1H‑吡唑并[4,3‑c]喹啉‑4(5H)‑酮或其药学上可接受的盐。
Description
技术领域
本发明涉及一种路易氏体型痴呆症及帕金森氏痴呆症的治疗剂，该治疗剂包含具有磷酸二酯酶9(PDE9)抑制作用的吡唑并喹啉衍生物或其药学上可接受的盐作为有效成分。
背景技术
路易氏体型痴呆症(Dementia with Lewy bodies，DLB)、帕金森氏症(Parkinsondisease，PD)是主要由α-突触核蛋白(α-Synuclein)构成的异常包涵体(路易氏体)出现于神经元内，引起神经元的变性和丧失的进行性神经退化性疾病。大量路易氏体分布于大脑皮质引发认知功能损害等的发展，并且大量路易氏体分布于脑干引发帕金森氏症的发展。此外，还发现幻视、幻觉、妄想、抑郁症状等精神症状，以及睡眠障碍、自主神经症状。当帕金森氏症发病前或发病1年以内产生痴呆症时，诊断为路易氏体型痴呆症，以及当痴呆症发病之前帕金森氏症已存在1年或多年时，诊断为帕金森氏痴呆症(Parkinsondisease withdementia，PDD)。如此，根据例如认知功能损害或帕金森氏症的出现时间顺序和程度的差异，而给出不同的诊断，即为路易氏体型痴呆症、帕金森氏痴呆症、或帕金森氏症。但这些疾病在病理学上视为同一疾病，统称为路易氏体病(Lewy body disease，LBD)。路易氏体型痴呆症的特征在于，在脑SPECT或FDG PET中，于阿兹海默症中可见于扣带后回和顶颞联合区的血流降低和糖代谢异常，还可见于除扣带后回和顶颞联合区之外的包含视觉区的枕叶中。若实施对脑内多巴胺神经系统进行功能评价的多巴胺转运体(DAT)造影，则不仅于帕金森氏症，而且于帕金森氏症出现前的路易氏体型痴呆症中也观察到脑内纹状体的DAT摄取降低(参见非专利文献1)。还报告了，于路易氏体型痴呆症和帕金森氏症中，作为乙酰胆碱能神经起点的内核的梅纳特基底核(basal nucleus of Meynert)的神经元发生变性或丧失，并且于海马区或皮质观察到重度的乙酰胆碱能神经系统障碍(参见非专利文献2、3和4)。
目前并不存在对路易氏体型痴呆症和帕金森氏症的脑病变进展过程本身加以修饰的根本性疗法，而实施根据症状的对症治疗。对于帕金森症状，例如使用利用L-DOPA的多巴胺替代疗法、手术疗法等。针对于认知功能损害，批准多奈哌齐(donepezil)唯一用于路易氏体型痴呆症的适应症，并且批准卡巴拉汀(rivastigmine)唯一用于帕金森氏痴呆症的适应症，并且这些药对于认知功能和精神症状(幻觉、妄想、冷漠、抑郁症状、行为症状)的改变也显示出效果(参见非专利文献5、6、7和8)。然而，据报告，乙酰胆碱酯酶抑制剂会使帕金森症状恶化(参见非专利文献9)，并且当从副作用和耐受性方面考虑无法使用乙酰胆碱酯酶抑制剂时，目前并不存在其他有效的疗法。将作为5-HT2A反向激动剂的匹莫范色林(Pimavanserin)批准作为帕金森氏症患者所经历的幻觉和妄想等精神症状的治疗药(参见非专利文献10)。但与奥氮平(olanzapine)、喹硫平(quetiapine)、利培酮(risperidone)等非典型抗精神病药一样，黑框警告指示当用于治疗老年人痴呆症的精神症状时则死亡风险会提高。如上所述，目前不存在对于路易氏体型痴呆症或帕金森氏症的认知功能损害和精神症状充分令人满意的疗法，因此开发出有效的药剂是期待已久的。
能够利用对其施用东莨菪碱或6-OHDA(6-羟基多巴胺)的动物作为路易氏体病中可见的认知功能损害的动物模型。东莨菪碱为蕈毒碱受体抑制剂，其阻断乙酰胆碱能神经系统的转导。乙酰胆碱能神经系统与记忆、注意力等相关，并且对其施用东莨菪碱的健康受试者或动物表现出类似痴呆症的健忘症状，利用用于治疗路易氏体病的认知功能损害的药剂可以使该症状有所减轻(参见非专利文献11和12)。6-OHDA是使多巴胺能神经及去甲肾上腺素能神经选择性地变性的神经毒素。通过使用6-OHDA和选择性去甲肾上腺素再摄取抑制剂(例如地昔帕明(desipramine))，使6-OHDA可特异性地作用于多巴胺能神经是可能的。对其施用6-OHDA的动物表现出认知功能损害，利用用于治疗路易氏体病的认知功能损害的药剂可以使该症状有所减轻(参见非专利文献13)。
式(I)所表示的化合物(以下称为化合物(I))或其药学上可接受的盐显示出PDE9抑制作用，并预期其对于阿兹海默型痴呆症是有效的(专利文献1)。虽然有报告显示，PDE9抑制剂于使用患有东莨菪碱诱发认知功能损害的大鼠的新奇物识别实验中显示出认知功能改善效果(参见非专利文献14)，但并未知晓显示出认知功能改善效果的吡唑并喹啉衍生物。
引证文献清单
专利文献
专利文献1：美国专利号8563565
非专利文献
非专利文献1：McKeith等人,Neurology[神经学],65,1863-1872页2005
非专利文献2：Shimada等人,Neurology[神经学],卷73,273-278页,2009
非专利文献3：Tiraboschi等人,Neurology[神经学]54(2000)407-411
非专利文献4：Perry等人,NeuroReport[神经报告],卷5,747-749页(1994)
非专利文献5：Mori等人,Ann.Neurol[神经病学年鉴],卷72,41-52页(2012)
非专利文献6：Dubois等人,Movement Disorders[运动障碍],卷27,1230-1238页(2012)
非专利文献7：Bergman等人,Clin.Neuropharmacol.[临床神经药理学],卷25,107-110页(2002)
非专利文献8：McKeith等人,Lancet[柳叶刀],卷356,2031-2036页(2000)
非专利文献9：Bourke等人,Ann.Pharmacother.[药物治疗学年鉴]卷32,610-611页(1998)
非专利文献10：Cummings等人,Lancet[柳叶刀]2014,卷383,533-540页
非专利文献11：Snyder等人,Alzheimer's&Dementia[阿尔茨海默氏痴呆]1(2005)126-135
非专利文献12：Sambeth等人,European Journal of Pharmacology[欧洲药理学杂志],卷572(2007)151-159页
非专利文献13：Kadowaki等人,Psychopharmacology[精神药理学](2013),230,345-352页
非专利文献14：Hutson等人,Neuropharmacology[神经药理学],61(2011)665-676页
发明内容
技术问题
本发明的目标在于提供一种在动物模型中显示出抗痴呆症作用且具有作为路易氏体病治疗剂的潜在用途的化合物或其药学上可接受的盐。
问题的解决方案
本发明者等人为了实现上述目标，使用东莨菪碱诱发认知功能损害大鼠模型进行深度研究，结果发现，式(I)所表示的吡唑并喹啉衍生物或其药学上可接受的盐具有抑制由东莨菪碱诱发的认知功能损害的效果。本发明者等人还发现通过使用6-OHDA模型进行评价，可确认对路易氏体病的认知功能改善效果，从而完成了本发明。
具体地，本发明涉及以下<1>至<4>。
<1>一种针对路易氏体型痴呆症或帕金森氏痴呆症的治疗剂，该治疗剂包含(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮
或其药学上可接受的盐。
<2>一种用于治疗路易氏体型痴呆症或帕金森氏痴呆症的方法，该方法包括将(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮
或其药学上可接受的盐向有需要的患者施用。
<3>(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮或其药学上可接受的盐，
用于在治疗路易氏体型痴呆症或帕金森氏痴呆症中使用。
<4>(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮或其药学上可接受的盐
用于制造针对路易氏体型痴呆症或帕金森氏痴呆症的治疗剂的用途。
发明的有利效果
本发明的吡唑并喹啉衍生物或其药学上可接受的盐于作为路易氏体病的动物模型的东莨菪碱诱发认知功能损害大鼠模型中显示出抑制由东莨菪碱诱发的认知功能损害的效果。另外，预期本发明之吡唑并喹啉衍生物或其药学上可接受的盐于作为路易氏体病的动物模型的6-OHDA模型中显示出抑制认知功能损害的效果。因此，本发明的化合物或其药学上可接受的盐具有作为路易氏体病治疗剂的潜在用途。
具体实施方式
以下，对本发明的内容进行详细说明。
如本文中所使用的“药学上可接受的盐”没有特别限制，只要它是与本发明的化合物形成的盐即可，并且其具体实例包括酸加成盐，例如无机酸的盐、有机酸的盐和酸性氨基酸的盐。
在如本文中所使用的“药学上可接受的盐”的上下文中，除非另外特别说明，对形成的盐中酸分子数/1分子上述化合物没有特别限制，只要该盐以酸与上述化合物的适当比例形成即可。在一个实施例中，每1分子上述化合物中，酸分子数为约0.1至约5；在另一个实施例中，每1分子上述化合物中，酸分子数为约0.5至约2；并且在又另一个实施例中，每1分子上述化合物中，酸分子数为约0.5、约1或约2。
无机酸的盐的具体实例包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐和磷酸盐；有机酸的盐的具体实例包括乙酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、乳酸盐、硬脂酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐和苯磺酸盐。
酸性氨基酸的盐的具体实例包括天冬氨酸盐和谷氨酸盐。
[制备]
本发明的药物组合物可通过将药学上可接受的添加剂与化合物(I)或其药学上可接受的盐进行混合而制造。本发明的药物组合物可根据已知方法，例如日本药典第十六修订版的制剂通则(General Rulesfor Preparations of the Japanese Pharmacopoeia,16th Edition)中记载的方法进行制造。
本发明的药物组合物可根据其剂型以适当方式对患者进行施用。
化合物(I)或其药学上可接受的盐的剂量根据症状的严重程度、年龄、性别、体重、剂型和盐的种类、疾病的具体种类等而有所不同；但通常在成人中，以单一给药或多次分开给药的形式，每天经口施用约30μg至10g，在一个实施例中，施用100μg至5g，以及在另一个实施例中，施用100μg至1g；并且以单一给药或多次分开给药的形式，每天通过注射施用约30μg至1g，在一个实施例中，施用100μg至500mg，以及在另一个实施例中，施用100μg至300mg。
实例
化合物(I)例如可通过专利文献1中所述的方法进行制造。
(药理学测试实例)
本发明者等人为了确认对于路易氏体病的认知功能改善效果，进行了或可进行以下试验。
[测试实例1]使用东莨菪碱诱发认知功能损害大鼠的新奇物识别实验(NovelObject Recognition Test)
为了确认对于由乙酰胆碱神经系统障碍诱发的认知功能损害的改善效果，实施使用东莨菪碱诱发认知功能损害大鼠的新奇物识别实验。新奇物识别实验是基于相较于熟悉的物体而对新奇物花更多时间探索的啮齿类自发性行为特性的认知功能评价试验系统。将Ennacer等Behavioural Brain Research[脑行为研究],31(1988)47-51页中记载的试验方法加以部分改良后实施。
材料及方法
对6周龄的雄性Long Evans大鼠(动物繁殖研究所(Institute for AnimalReproduction))进行试验。于试验前2天，每天进行一次使大鼠适应实验程序的操作。在适应操作中，向大鼠施用媒介物，其后将大鼠放入至空的试验装置(40cm×30cm×H 45cm)内，使之探索3分钟，并使该大鼠进入休息室(13cm×30cm×H 45cm)中1分钟左右，其后使大鼠再次返回空的试验装置内并放置5分钟。
于试验日当天，进行获得试验(T1)。将化合物(I)于T1前2小时通过使用0.5％甲基纤维素的0.01M盐酸溶液作为媒介物而经口施用。将东莨菪碱(和光纯药工业株式会社(Wako Pure Chemical Industries,Ltd.))于T1前30分钟通过使用0.7mg/kg剂量的盐水作为媒介物而皮下施用。T1中，使大鼠于空的试验装置内适应3分钟后，将其转移到休息室中。于试验装置中设置2个相同物体，其后使大鼠再次返回试验装置内，使之自由探索2个相同物体5分钟。其后，使大鼠返回饲养笼中。2小时后进行保持试验(retention trial，T2)。将大鼠放入至空的试验装置内3分钟使之适应后，将其转移到休息室内。将T1中使用过的一个物体(“熟悉的”物体)与T1中未使用的一个物体(“新奇”物)放置于试验装置中后，使大鼠再次返回试验装置内，使之自由探索这些物体3分钟。于每次实验后利用浸渍于乙醇中的湿巾对物体进行擦拭以不使气味作为线索残留。T1与T2期间的大鼠行为利用数字摄录像机进行拍摄，使用秒表手动测量各物体的总探索时间。将大鼠的鼻靠近物体2cm以内且鼻朝向物体的行为定义为探索行为。
于新奇物识别实验中，将T2期间的新奇物探索百分比视为反映区分熟悉的物体与新奇物的健忘指数。新奇物探索百分比根据以下等式算出。
新奇物探索百分比(％)＝N/(N+F)×100
F：熟悉的物体探索时间
N：用于探索新奇物的时间
将T1或T2期间用于物体探索的总时间为10秒以下的大鼠、或T1期间用于探索任一物体的时间百分比为总探索时间的70％以上或30％以下的大鼠自数据分析中排除。
结果以平均值±标准误差表示。未经东莨菪碱处理的正常对照组与经东莨菪碱处理的疾病对照组间的差异利用非配对t检验进行分析(具有显著差异：*)。使用邓尼特多重比较测试(Dunnett's multiple comparison test)分析疾病对照组与单一药剂处理组的差异(具有显著差异：#)。将p<0.05判断为具有统计学显著差异。统计分析通过使用GraphPad Prism 5.04或6.02版进行。
结果
T2中，疾病对照组的大鼠与正常对照组的大鼠相比，显示出新奇物探索百分比显著降低。这意味着东莨菪碱诱发了大鼠的记忆力损害。化合物(I)以3.3mg/kg及10mg/kg显示出新奇物探索百分比的显著改善效果。
[表1]
[测试实例2]使用6-OHDA模型的新奇物识别实验及物体位置识别试验(ObjectLocation Recognition Test)
路易氏体病的临床前疾病模型的实例包括通过修饰路易氏体病相关基因或导入路易氏体病相关物质而制作的细胞模型或动物模型(例如α-突触核蛋白转基因、使用AAV载体过表达α-突触核蛋白、Parkin敲除、DJ-1敲除、和注入α-突触核蛋白聚集体的模型)；反映出路易氏体病患者中鉴定的神经系统障碍的药剂施用模型(例如6-OHDA、MPTP、百草枯、鱼藤酮、LPS、和皂草毒素的神经毒素施用模型，以及东莨菪碱等神经松弛药施用模型)；源自患者iPS细胞的神经元模型。针对路易氏体病的药剂的效果可通过使用这些临床前疾病模型确认。
此处示出可使用6-OHDA模型确认对路易氏体病的治疗效果。
使用雄性SD大鼠来制作6-OHDA模型。将大鼠于麻醉下固定于脑定位装置，使颅骨露出后将套管插入至脑内。使用显微注射泵，花数分钟注入溶解于含有抗坏血酸的盐水中的6-OHDA。为了保护去甲肾上腺素能神经，于6-OHDA注入前施用地昔帕明。于脑内同一部位插入套管而制作未经6-OHDA处理的大鼠。手术数天后，进行新奇物识别实验或物体位置识别试验。通过将Ennacer等Behavioural Brain Research[脑行为研究],31(1988)47-51页中记载的试验方法加以部分改良后进行新奇物识别实验。通过将Dix Behavioural BrainResearch[脑行为研究]99(1999)191-200页中记载的试验方法加以部分改良后进行物体位置识别试验。物体位置识别实验是基于啮齿类自发性行为特性的认知功能评价试验系统，其中当物体周围的环境发生变化时，即使物体是熟悉的物体，啮齿类探索行为也会增加。
在两个实验中，均在试验日前进行使啮齿类适应实验程序的操作。在适应操作中，向大鼠施用媒介物，使之自由探索空的试验装置(40cm×30cm×H 45cm)一定时间(数分钟至数个十分钟)。
于试验日当天，在获得试验(T1)之前经口施用化合物(I)。在两个试验中，均在T1期间使大鼠自由探索设置于试验装置内的2个相同物体一定时间(数分钟)。使大鼠返回饲养笼中，其后进行保持试验(T2)。于新奇物识别实验的T2中，于试验装置内设置T1中使用过的一个物体(“熟悉的”物体)和T1中未使用的一个物体(“新奇”物)，并使大鼠自由探索这些物体一定时间(数分钟)。于物体位置识别试验的T2中，将T1中出现的2个相同物体中的1个变更到新位置，设置于试验装置内。使大鼠自由探索这些物体一定时间(数分钟)。在两个试验中，于每次实验后利用浸渍于乙醇中的湿巾对物体进行擦拭以不使气味作为线索残留。T1与T2期间的大鼠行为利用数字摄录像机进行拍摄，使用秒表手动测量各物体的总探索时间。将大鼠的鼻靠近物体2cm以内且鼻朝向物体的行为定义为探索行为。
于新奇物识别实验中，将T2期间的新奇物探索百分比视为反映区分熟悉的物体与新奇物的健忘指数。于物体位置识别实验中，将T2期间的新位置探索百分比视为反映区分熟悉的位置与新位置的健忘指数。新奇物探索百分比及新位置物体探索百分比根据以下等式算出。
新奇物探索百分比(％)＝NO/(NO+FO)×100
FO：用于探索熟悉的物体的时间
NO：用于探索新奇物的时间
新位置物体探索百分比(％)＝Nl/(Nl+Fl)×100
Fl：用于探索熟悉的位置处的物体的时间
Nl：用于探索新位置处的物体的时间
将新奇物探索百分比或新位置物体探索百分比进行组间比较，确认化合物(I)的效果。
Claims (4)
1.一种针对路易氏体型痴呆症或帕金森氏痴呆症的治疗剂，该治疗剂包含式(I)所表示的(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮
或其药学上可接受的盐。
2.一种用于治疗路易氏体型痴呆症或帕金森氏痴呆症的方法，该方法包含将式(I)所表示的(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮
或其药学上可接受的盐向有需要的患者施用。
3.式(I)所表示的(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮或其药学上可接受的盐，
用于在治疗路易氏体型痴呆症或帕金森氏痴呆症中使用。
4.式(I)所表示的(S)-7-(2-甲氧基-3,5-二甲基吡啶-4-基)-1-(四氢呋喃-3-基)-1H-吡唑并[4,3-c]喹啉-4(5H)-酮或其药学上可接受的盐
用于制造针对路易氏体型痴呆症或帕金森氏痴呆症的治疗剂的用途。
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| US201762513727P | 2017-06-01 | 2017-06-01 | |
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| PCT/JP2018/020650 WO2018221551A1 (ja) | 2017-06-01 | 2018-05-30 | ピラゾロキノリン誘導体を含有するレビー小体病治療剤 |
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| IL270394B (en) | 2017-06-01 | 2022-08-01 | Eisai R&D Man Co Ltd | A therapeutic agent for dementia that combines a pyrazoloquinoline derivative and memantine |
| AU2018276565A1 (en) | 2017-06-01 | 2019-11-07 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil |
| KR20200010211A (ko) | 2017-06-01 | 2020-01-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Pde9 저해제를 포함하는 약제학적 조성물 |
| US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100210839A1 (en) * | 2002-08-23 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Selective phosphodiesterase 9a inhibitors as medicaments for improving cognitive processes |
| CN103930423A (zh) * | 2011-10-07 | 2014-07-16 | 卫材R&D管理有限公司 | 吡唑并喹啉衍生物 |
| CN105121440A (zh) * | 2013-04-05 | 2015-12-02 | 卫材R&D管理有限公司 | 吡唑并喹啉衍生物的盐及其晶体 |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5318759A (en) | 1976-08-02 | 1978-02-21 | Nisshin Oil Mills Ltd | Method of making fried beancurd |
| JPH05132484A (ja) | 1991-04-26 | 1993-05-28 | Otsuka Pharmaceut Factory Inc | ピラゾロキノリン及びピラゾロナフチリジン誘導体 |
| DE69518075T2 (de) | 1994-05-24 | 2001-03-22 | Hoffmann La Roche | Tricyclische dicarbonylderivate |
| DE19642591A1 (de) | 1996-10-15 | 1998-04-16 | Basf Ag | Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung |
| HN2002000317A (es) | 2001-11-02 | 2003-05-21 | Pfizer | Inhibidores de pde9 para tratamiento de trastornos cardiovasculares |
| AU2003250539A1 (en) | 2002-08-07 | 2004-02-25 | Mitsubishi Pharma Corporation | Dihydropyrazolopyridine compounds |
| DE102004004142A1 (de) | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Cyclylmethyl- und 6-Alkylmethyl-substituierte Pyrazolopyrimidine |
| RU2426734C2 (ru) | 2003-10-03 | 2011-08-20 | Зм Инновейтив Пропертиз Компани | Пиразолопиридины и их аналоги |
| US20060035920A1 (en) | 2004-05-28 | 2006-02-16 | Millennium Pharmaceuticals, Inc. | Chk-1 inhibitors |
| JP2006045118A (ja) | 2004-08-04 | 2006-02-16 | Mochida Pharmaceut Co Ltd | 新規ピラゾロキノロン誘導体 |
| AU2006289838B2 (en) | 2005-09-15 | 2011-08-18 | Aska Pharmaceutical Co., Ltd. | Heterocyclic compound, and production process and use thereof |
| ES2566774T3 (es) | 2006-12-13 | 2016-04-15 | Aska Pharmaceutical Co., Ltd. | Derivado de quinoxalina |
| AU2007332439A1 (en) | 2006-12-13 | 2008-06-19 | Aska Pharmaceutical Co., Ltd. | Therapeutic agent for urinary tract disease |
| GEP20125405B (en) | 2007-05-11 | 2012-02-27 | Pfizer | Amino-heterocyclic compounds |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| EP2334684B1 (en) | 2008-09-08 | 2017-08-02 | Boehringer Ingelheim International GmbH | Pyrazolopyrimidines and their use for the treatment of cns disorders |
| TWI404721B (zh) | 2009-01-26 | 2013-08-11 | Pfizer | 胺基－雜環化合物 |
| AU2010219598A1 (en) | 2009-03-05 | 2011-09-22 | Astellas Pharma Inc. | Quinoxaline compounds |
| DK2414363T3 (da) | 2009-03-31 | 2014-01-27 | Boehringer Ingelheim Int | 1-heterocyklyl-1,5-dihydro-pyrazol[3,4-d]pyrimidin-4-on-derivater og anvendelse af disse som PDE9A-modulatorer. |
| US8880976B2 (en) | 2009-09-25 | 2014-11-04 | Stmicroelectronics, Inc. | Method and apparatus for encoding LBA information into the parity of a LDPC system |
| SG187081A1 (en) | 2010-08-12 | 2013-03-28 | Boehringer Ingelheim Int | 6-cycloalkyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a inhibitors |
| CA2810696C (en) | 2010-09-07 | 2018-09-18 | Astellas Pharma Inc. | Pyrazoloquinoline compound |
| US20130040971A1 (en) | 2011-02-14 | 2013-02-14 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of cns disorders |
| PL2573073T3 (pl) | 2011-09-26 | 2015-04-30 | Sanofi Sa | Pochodne pirazolochinolinonu, ich wytwarzanie i ich zastosowanie terapeutyczne |
| JP6042060B2 (ja) | 2011-09-26 | 2016-12-14 | サノフイ | ピラゾロキノリノン誘導体、その調製および治療上の使用 |
| BR112015024075B1 (pt) | 2013-04-05 | 2022-05-03 | Eisai R&D Management Co., Ltd | Compostos de piridinilpirazoloquinolina |
| KR20200010211A (ko) | 2017-06-01 | 2020-01-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Pde9 저해제를 포함하는 약제학적 조성물 |
| AU2018276565A1 (en) | 2017-06-01 | 2019-11-07 | Eisai R&D Management Co., Ltd. | Dementia therapeutic agent combining pyrazoloquinoline derivative and donepezil |
| IL270394B (en) | 2017-06-01 | 2022-08-01 | Eisai R&D Man Co Ltd | A therapeutic agent for dementia that combines a pyrazoloquinoline derivative and memantine |
-
2018
- 2018-05-30 JP JP2019521251A patent/JP7269875B2/ja active Active
- 2018-05-30 KR KR1020197033124A patent/KR20200010220A/ko not_active Application Discontinuation
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100210839A1 (en) * | 2002-08-23 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Selective phosphodiesterase 9a inhibitors as medicaments for improving cognitive processes |
| CN103930423A (zh) * | 2011-10-07 | 2014-07-16 | 卫材R&D管理有限公司 | 吡唑并喹啉衍生物 |
| CN105121440A (zh) * | 2013-04-05 | 2015-12-02 | 卫材R&D管理有限公司 | 吡唑并喹啉衍生物的盐及其晶体 |
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| KR20200010220A (ko) | 2020-01-30 |
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| ES2961554T3 (es) | 2024-03-12 |
| RU2019135690A (ru) | 2021-07-13 |
| BR112019023552A2 (pt) | 2020-06-02 |
| AU2018278422A1 (en) | 2019-11-21 |
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