CN1794992A - 治疗轻度认知缺损及预防或延缓阿尔茨海默病的方法 - Google Patents
治疗轻度认知缺损及预防或延缓阿尔茨海默病的方法 Download PDFInfo
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Abstract
本申请公开了式(Ⅰ)化合物或其药学上可接受的盐在制备用于治疗与年龄相关的认知减退或轻度认知缺损的药物中的用途，尤其是为了要预防或延缓阿尔茨海默病发病。
Description
本发明涉及应用方法及物质来治疗人体。尤其提供了治疗与年龄相关的认知减退和轻度认知缺损的方法，特别是为了预防或延缓阿尔茨海默病发病。
与年龄相关的认知减退和轻度认知缺损(MCI)是出现记忆缺失但不存在其它痴呆诊断标准的状态(Santacruz andSwagerty，AmericanFawssily PhJosician，63(2001)，703-13)。(另参见″The ICD-10Classification of Mental and Behavioural Disorders″，Geneva：WorldHealth Organisation，1992，64-5)。本文使用的与年龄相关的认知减退的特征是在至少六个月的持续时间内至少一种状态减退：记忆和学习、注意力和专心度、思维、语言以及视觉空间机能和至少一个标准偏差的分数低于标准化神经心理学测试例如MMSE的常模(norm)。
尤其可以是记忆进行性减退。在更严重的状况轻度认知缺损(MCI)中，记忆缺陷度超出了就患者年龄来说认为正常的范围但却没出现阿尔茨海默病。Petersen等人，Arch.Neurol.，56(1999)，303-8中描述了MCI和轻度AD的鉴别诊断。在该文章中，Petersen等人披露了患有MCI的患者典型地都经受着认知缺损进行性增加并在多数情况下发展成AD。Knopman等人，Mayo Clinic Proceedings，78(2003)，1290-1308提供了有关MCI鉴别诊断的其它信息。Tuokko等人在对中年以上个体的研究中发现，那些最初出现MCI的人在5年内发展成痴呆的危险性要增加3倍。
Grundman等人(I.Mol.Neurosci.，19(2002)，23-28)报道在MCI患者中海马体积低于基准是继发AD的预后指标。类似的，Andreasen等人(Acta Neurol.Scand，107(2003)47-51)报道高CSF水平的总tau蛋白(tau)、高CSF水平的磷酸化tau蛋白(phospho-tau)和低CSF水平的Aβ42都与增加由MCI发展为AD的危险性有关。
与年龄相关的认知减退和轻度认知缺损与显著的认知缺陷不同，认知缺陷有时是由大脑或全身性疾病和创伤例如中风、震荡，或脑下垂体主要断裂而引起的。
阿尔茨海默病(AD)是痴呆的最普遍形式。它的诊断记载于American Psychiatric Association(DSM-IV)出版的Diagnostic andStatistical Manual of Mental Disorders，第四版中(例如第139-143页)。阿尔茨海默病的诊断标准包括患者多重认知缺陷的发展，其可通过(1)记忆缺陷(获悉新信息或回忆以前获悉信息的能力受损)和(2)一个(或多个)下列认识障碍(a)失语症(语言障碍)、(b)运动不能症(进行运动活动的能力受损尽管运动机能未受损)、(c)认识不能(不能识别或鉴别物体尽管感觉功能未受损)和(d)执行机能障碍(例如规划、组织、排序、抽象)来证明。这样的认知缺陷不能认为是归因于以下任何一种情况：(1)引起记忆和认知进行性缺陷的其它中枢神经系统状况(例如脑血管疾病、帕金森病、亨延顿舞蹈病、硬脑膜下血肿、正常颅压脑积水、脑肿瘤)，(2)已知能引起痴呆的全身性状况(例如甲状腺机能减退、维生素B12或叶酸缺乏、烟酸缺乏、高血钙、神经梅毒、HIV感染)，(3)由物质诱导的状况。
阿尔茨海默病是一种神经变性疾病，其临床特征为记忆和一般认知功能进行性丧失，病理特征为患者的皮质和相连脑区域中的细胞外蛋白质斑块沉积。这些斑块主要包含β-淀粉体肽(Aβ)的纤维状聚集物。因此已有提议通过减少大脑中Aβ的负荷来作为治疗AD的对策。例如Carro等人，在NatureMedicine，8(2002)，1390-7中公开了在特定的啮齿类中皮下给予胰岛素样生长因子1(IGF-1)能降低大脑Aβ的负荷。然而，一些作者已经提出了质疑，即Aβ的沉积是否就是造成神经元损失(其通常是引起阿尔茨海默型痴呆的直接原因)的原因(参见例如Robinson and Bishop，Neurobiology of Aging，23(2002)，1051-72；以及New Scientist，Feb.12003，35-37)。
US 5,767,124、US 5,536,716、WO 94/13696和EP 0615977B公开了是生长激素促分泌剂的化合物，例如它们能在包括人在内的动物中刺激或增加生长激素的内源性释放。这个性质对促进食用动物(foodanimals)的生长是有用的，并且在人中能用于治疗以生长激素分泌不足为特征的生理或医学状况，和通过生长激素的合成作用能得以改善的医学状况。能被治疗的所列状况包括阿尔茨海默病。
US 4,902,680主张将生长激素给予阿尔茨海默病的晚期患者。
WO 00/13650公开了在大脑中，提高的生长激素水平能提供神经保护作用，尤其能拯救否则由于损伤而将死亡的神经元。打算将生长激素注射到脑中。
由于较多垂体后叶素异常而导致的大部分生长激素缺乏在成人中能导致认知缺损(Deijen等人，Psyclzoyaeuroendocrinology，21(1996)，313-22)，其能通过生长激素替代疗法而逆转(Deijen等人，ibid.，23(1998)，45-55；Soares等人，Arq.Neuropsiquiatr.，57(1999)，182-9；Rosen等人，Horm.Res.，43(1995)，93-99)。也已经有推测，在其它多数作用中，给予生长激素或其促分泌剂可能改善正常健康的中年以上个体的认知(参见例如，Merriam等人，Endocrine，7(1997)，49-52；Cummings and Merriam，Semin.Reprod.Endocrinol.，17(1999)，311-25)，但是用于这种目的的促分泌剂却没有产生真正的作用。然而，近期的出版物推断给予正常的年老个体生长激素或生长激素促分泌剂是没有临床益处的(Anawalt and Merriam，Endocriyaol.Metab.Clin.North Am.，30(2001)，647-69；Cummings and Merriam，Annu.Rev.Med.，54(2003)，513-33)。本发明不涉及正常的健康个体(例如无症状的个体)。
在上面提及的US5,767,124中公开的化合物已经在不同的治疗领域但非与年龄相关的认知减退或轻度认知缺损中成为一些临床试验的对象(参见例如，Murphy等人，J.Bone Miner.Res.，14，(1999)，1182-8；Chapman等人，J Clinical Endocrinology and Metabolism，81，(1996)，4249-57；ibid.，82，(1997)，3455-63；以及Svensson等人，ibid.，83，(1998)，362-9)。
根据本发明，在此提供了式I化合物：
或其药学上可接受的盐在制备用于治疗与年龄相关的认知减退或轻度认知缺损的药物中的用途。此治疗的有利结果是防止或延缓了阿尔茨海默病的发病。这种预防或延缓可以通过中断或减慢患者的认知减退，或者是中断或减慢认知缺损的进程来证明。
本发明的一个好处是所述的药物不需要通过注射给予。在一个优选的实施方案中，所述药物是适于口服给药的形式。
式I化合物可以被称为N-[1(R)-[(1，2-二氢-1-甲烷磺酰基螺[3H-吲哚-3，4′-哌啶]-1′-基)羰基]-2-(苯基甲氧基)乙基l-2-氨基-2-甲基丙酰胺。
就本发明的使用来说，比较有利的是式I化合物通过将药学上可接受的酸例如盐酸、硫酸、苯磺酸、甲苯磺酸、甲磺酸、富马酸、马来酸、琥珀酸、醋酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸与I中的伯胺基团相互作用而形成酸加成盐的形式。优选的是，式I化合物是甲磺酸盐的形式，其本身优选为是US 5,767,124中描述的多晶型中的一种。
US 5,767,124、EP 0615977B、US 6,028,196、US 6,046,333和WO96/33189中描述了式I化合物及其适宜的盐的合成。
本发明的方法可以增加Aβ从脑中的清除率，这可以通过脑脊液和/或血清中可溶性Aβ水平的改变来证明。另外(或再者)，显像技术例如磁共振影像学、正电子发射断层摄影术、单光子发射计算体层摄影术和多光子显微镜检查法，可以探测脑内Aβ的沉积量(参见例如Bacskai等人，J.Cereb.BloodFlowMetab.，22(2002)，1035-41)。
在一个特别的实施方案中，本发明提供了如上定义的化合物在制备用于预防或延缓痴呆发病的药物中的用途，其中所述的痴呆是在具有与年龄相关的认知减退或轻度认知缺损的患者中与阿尔茨海默病相关的痴呆。
本发明还提供了治疗与年龄相关的认知减退或轻度认知缺陷的方法，其包括给予有需要的患者治疗有效量的如上定义的式I化合物或其药学上可接受的盐。在一个特别的实施方案中，本发明还提供了预防、延缓或阻止任何其它与年龄相关的认知减退或是轻度认知缺损的进程，其包括给予有需要的患者治疗有效量的如上定义的式I化合物或其药学上可接受的盐。
本发明还提供了预防或延缓阿尔茨海默病发病的方法，其包括给予患有与年龄相关的认知减退或认知缺损的患者治疗有效量的如上定义的式I化合物或其药学上可接受的盐。
在一个特别的实施方案中，本发明还提供了预防或延缓与阿尔茨海默病有关的痴呆发病的方法，其包括给予患有与年龄相关的认知减退或认知缺损的患者治疗有效量的如上定义的式I化合物或其药学上可接受的盐。
在本发明的一个优选实施方案中，将式I化合物或其药学上可接受的盐给予具有轻度认知缺损的个体。
在本发明的另一个优选实施方案中，将式I化合物或其药学上可接受的盐给予呈现与年龄相关的认知减退的个体。
本发明的方法最适于预防、延缓或阻止不溶性Aβ在患有与年龄相关的认知减退或认知缺损的患者脑部的积聚。
本发明中使用的药物特别适合给予患有记忆功能缺损而没有其它能构成痴呆的症状例如失语症、运动不能、认识不能或执行功能紊乱的患者。这样的记忆功能缺损典型地不归咎于由垂体后叶素功能紊乱引起的全身或大脑疾病，例如中风或代谢性疾病。这样的患者尤其可以是55岁或更年长的人，特别是60岁或更年长的人，更好的是65岁或更年长的人。这样的患者可以具有对于他们的年龄来说是正常的生长激素分泌模式和水平。然而，这样的患者可以具有一种或多种发展为阿尔茨海默病的其它危险因素。这样的因素包括此疾病的家族史、此疾病的遗传易感、提高的血清胆固醇、成年发病的糖尿病、增高的总牛tau蛋白CSF水平、增高的磷酸化tau蛋白CSF水平和降低的Aβ42CSF水平。
在本发明的一个特别的实施方案中，式I化合物或其药学上可接受的盐被给予患有与年龄相关的认知减退或轻度认知缺损的患者，所述患者还有一种或多种发展成AD的危险因素，所述因素选自：此疾病的家族史、此疾病的遗传易感、提高的血清胆固醇、成年发病的糖尿病、增高的总tau蛋白CSF水平、增高的磷酸化tau蛋白CSF水平和降低的Aβ42CSF水平。
遗传易感(尤其对于早期发病的阿尔茨海默病)能在一个或多个APP、早老素-1和早老素-2基因中产生点突变。另外，与载脂蛋白E基因的ε4同种型纯合的个体发展为AD的危险性更高。
在用式I化合物或其药学上可接受的盐进行治疗之前、期间或之后，在常规间隔能有利地评定患者的认知减退或缺损程度，以便可以检测到其中的变化，例如认知减退的减缓或停止。本领域中有已知的用于这个目的各种神经心理试验，例如带有能调节年龄和教育标准的迷你-精神状态检查(MMSE)(Folstein等人，J.Psych.Res.，12(1975)，196-198，Anthony等人，Psychological Med.，12(1982)，397-408；Cockrell等人，Psychopharmacology，24(1988)，689-692；Crum等人，J.Am.Med.Assoc`n.18(1993)，2386-2391)。在成年人中，MMSE是认知状态的简单、定量测定法。它能用于筛选认知减退或缺损，以在给定的点及时评价认知减退或缺损的严重性，以在单独的额外时间中跟踪认知变化的进程，以及证明对治疗的个体应答。
本发明中适用的化合物典型地以药物组合物的形式给予，其中组合物包含式I化合物(或其药学上可接受的盐)和药学上可接受的载体。优选的是，这些组合物是单位剂量的形式例如片剂、丸剂、胶囊、粉剂、颗粒剂、无菌注射液或混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、经皮贴剂、自动注射器装置或拴剂，用于口服非胃肠道、鼻内、舌下或直肠给药，或用于通过吸入或吹入给药。将主要的活性成分典型地与药物载体进行混合以形成包含式I化合物或其药学上可接受盐的均匀制剂前(preformulation)组合物，载体例如有普通片剂成分如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁和磷酸二钙，或树胶、分散剂、混悬剂或表面活性剂例如去水山梨糖醇单油酸酯和聚乙二醇，以及其它的药物稀释剂例如水。当提及这些均匀的处方设计前组合物时，其指的是将活性成分均匀、全部地分散于组合物中，以便组合物可以容易地分成相等的有效单位剂型，例如片剂、丸剂和胶囊。然后将这个处方设计前组合物再分成上述单位剂型，例如包含0.1到约150mg活性成分。优选的单位剂型包含0.5到100mg，例如0.5、1、2、3、5、10、15、20、25、30、50、60或75mg的游离碱或与其等量的药学上可接受的盐。片剂或丸剂药物组合物能被包衣或另外混合以形成能提供长效作用优势的剂型。例如，片剂或丸剂能包含内部剂量和外部剂量成分，后者是包裹在前者上的。这两个成分能通过肠溶衣得以分隔，其中肠溶衣在胃中能抵抗崩解，并允许内部成分完整地通过进入十二指肠或延缓释放。许多物质都可用于这种肠衣层或包衣，这样的物质包括许多具有这种物质如虫胶、十六醇和醋酸纤维素的聚合酸以及聚合酸的混合物。
可以使药物组合物混合用于口服给药的液态形式包括水溶液、填充液体或凝胶的胶囊、适宜的调味糖浆、水或油性混悬液，带有食用油例如棉籽油、芝麻油、椰子油或花生油的调味乳液，以及酏剂和类似的药物赋形物。水性混悬液的适宜分散剂或混悬剂包括合成和天然的胶例如西黄蓍胶、阿拉伯胶、海藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚(乙二醇)、聚(乙烯吡咯烷酮)或明胶。
US 6,123,964中描述了式I化合物或其适宜的盐的药物制剂。
就本发明的使用来说，以上定义的化合物的最适宜剂量水平，根据安全性和有效性，可以依据发展成阿尔茨海默病的可察觉危险性而变化，和/或个别患者的其它具体因素而变化，并且可以通过本领域技术人员已知的方法测定。一般来说，可以预期的剂量是约0.01到5.0mg/kg每天，优选约0.05到2.5mg/kg每天，更优选约0.1到1.0mg/kg体重每天。
化合物可以以任何适宜的服用方法给予，例如每天1、2、3或4次，但优选每天给药一次或两次，最优选每日给药一次。所述的给药优选是口服给药。
化合物可以以规则的间隔延长给予一段时间，例如3个月、6个月、1年或更长，或是个体剩余的寿命。
式I化合物及其药学上可接受的盐尤其适于口服给予。因此，在本发明的方法和用途中，最适合的就是口服给予单位剂量的药物组合物。
在本发明的一个实施方案中，以总剂量相当于每天每人约25mg游离碱的量给予化合物N-[1(R)-[(1，2-二氢-1-甲烷磺酰基螺[3H-吲哚-3，4′-哌啶]-1′-基)羰基]-2-(苯基甲氧基)乙基]-2-氨基-2-甲基丙酰胺甲磺酸盐。在另两个实施方案中，以总量相当于每天10mg或5mg游离碱的量给予所述化合物。在这些实施方案中，优选的是日剂量以一次例如以一片或两片的形式给予。
如果情况需要，超过上面概括界限之外的其它服用方法和/或剂量水平也是可以的。
实施例
在以下实施例中，活性药物是如US 5,767,124中记载的以结晶形式制得的N-[1(R)-[(1，2-二氢-1-甲烷磺酰基螺[3H-吲哚-3，4′-哌啶]-1′-基)羰基]-2-(苯基甲氧基)乙基]-2-氨基-2-甲基丙酰胺甲磺酸盐。
实施例1-片剂(湿法制粒法)
以下制剂用于生产包衣片剂，每片均含有相当于25mg游离碱的量：
片芯
mg/片
活性药物 29.6
预凝胶化淀粉NF 113.0
磷酸氢钙，USP 174.0
微晶纤维素NF 57.0
硬脂酸镁极细粉NF 2.0
交联羧甲基纤维素钠NF 24.0
95％乙醇USP* --
纯水USP* -
片剂包衣
羟丙基甲基纤维素USP 3.2
羟丙基纤维素w/0.3％二氧化硅 3.2
二氧化钛USP 1.28
滑石粉USP纯 0.32
纯水USP* -
*制备期间除去
将活性药物、磷酸钙、预胶化淀粉、微晶纤维素和一半交联羧甲基纤维素钠混合，然后转移至制粒机中再简单混合。缓慢加25％乙醇/水的混合物，并进行制粒。将颗粒进行干燥、过筛，并与剩余的交联羧甲基纤维素钠混合，然后与硬脂酸镁混合。通过压制形成片剂，经片剂包衣成分的水混悬液喷雾形成薄膜衣。
通过适当调节成分的相对比例，经同样的步骤形成包含不同载药量例如10mg或5mg的片剂。
实施例2-片剂(滚压法)
以下制剂用于生产包衣片剂，每片均含有相当于25mg游离碱的量：
片芯
mg/片
活性药物 29.6
磷酸氢钙，USP 60.44
微晶纤维素NF 150.0
硬脂酸镁极细粉NF 2.56
交联羧甲基纤维素钠NF 7.5
片剂包衣
羟丙基甲基纤维素USP 3.125
羟丙基纤维素w/0.3％二氧化硅 3.125
二氧化USP 1.25
纯水USP* -
*制备期间除去
将活性药物、微晶纤维素和一部分硬脂酸镁混合，然后滚压，并将得到的压制物碾碎。将该碾碎的物质与交联羧甲基纤维素钠、磷酸钙和剩余的硬脂酸镁混合，然后压成片剂。用片剂包衣成分的水混悬液通过喷雾对片剂进行薄膜包衣。
通过适当调节成分的相对比例，经同样的步骤形成包含不同载药量的片剂。
实施例3-用于预防或延缓阿尔茨海默病发病的疗法
每天与水一同给予需要这种治疗的个体一片25mg的片剂(如实施例1或实施例2所述)。
实施例4-预防或延缓呈现轻度认知缺损的个体阿尔茨海默病发
病的疗法
用MMSE或类似的诊断仪器确定具有轻度认知缺损的个体。
每天与水一同给予所述个体一片25mg的片剂(如实施例1或实施例2所述)。
用MMSE或类似仪器定时监视个体的认知状态，并监视个体的痴呆临床症状。
Claims (11)
1.式I化合物
或其药学上可接受的盐在制备用于治疗需要这种治疗的患者与年龄相关的认知减退或轻度认知缺损的药物中的用途。
2.如权利要求1定义的式I化合物或其药学上可接受的盐在制备用于预防或延缓患有与年龄相关的认知减退或轻度认知缺损的患者阿尔茨海默病发病的药物中的用途。
3.如权利要求1定义的式I化合物或其药学上可接受的盐在制备用于预防或延缓患有与年龄相关的认知减退或轻度认知缺损的患者与阿尔茨海默病相关的痴呆发病的药物中的用途。
4.根据前述权利要求任一项的用途，其中所述患者是55岁或更年长的人。
5.根据前述权利要求任一项的用途，其中所述患者是60岁或更年长的人。
6.根据前述权利要求任一项的用途，其中所述患者是65岁或更年长的人。
7.根据前述权利要求任一项的用途，其中所述的患者还有一种或多种发展成阿尔茨海默病的危险因素，所述因素选自：此疾病的家族史、此疾病的遗传易感、提高的血清胆固醇、成年发病的糖尿病、增高的总tau蛋白CSF水平、增高的磷酸化tau蛋白CSF水平和降低的Aβ42CSF水平。
8.根据权利要求1-7任一项的用途，其中患者患有轻度认知缺损。
9.根据权利要求1-7任一项的用途，其中患者患有与年龄相关的认知减退。
10.如权利要求1定义的式I化合物或其药学上可接受的盐在制备用于预防、延缓或阻止患有与年龄相关的认知减退或轻度认知缺损的患者脑中不溶性Aβ积聚的药物中的用途。
11.根据前述权利要求任一项的用途，其中所述的药物适于口服给予。
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| GB0313772D0 (en) * | 2003-06-13 | 2003-07-23 | Merck Sharp & Dohme | Therapeutic treatment |
| US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7872009B2 (en) | 2005-11-21 | 2011-01-18 | Amgen Inc. | Beta-Secretase modulators and methods of use |
| AU2006316620B2 (en) | 2005-11-21 | 2011-03-03 | Amgen Inc. | Beta-secretase modulators and methods of use |
| US7838676B2 (en) | 2005-11-21 | 2010-11-23 | Amgen Inc. | Beta-secretase modulators and methods of use |
| CA2687608C (en) | 2007-05-25 | 2013-07-02 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| WO2008147547A1 (en) | 2007-05-25 | 2008-12-04 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
| US7803809B2 (en) | 2008-11-12 | 2010-09-28 | Amgen Inc. | Substituted pyrano [2,3-b] pyridinamine compounds as beta-secretase modulators and methods of use |
| PE20110805A1 (es) * | 2008-09-11 | 2011-11-09 | Amgen Inc | Compuestos con anillos espiro-triciclicos como moduladores de beta-secretasas y metodos de uso |
| US9296698B2 (en) | 2009-11-23 | 2016-03-29 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| EP2504330A1 (en) | 2009-11-23 | 2012-10-03 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| CA2788363A1 (en) | 2010-01-19 | 2011-07-28 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
| WO2011115938A1 (en) | 2010-03-15 | 2011-09-22 | Amgen Inc. | Spiro-tetracyclic ring compounds as beta - secretase modulators |
| US8497264B2 (en) | 2010-03-15 | 2013-07-30 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
| WO2012109165A1 (en) | 2011-02-07 | 2012-08-16 | Amgen Inc. | 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use |
| WO2013044092A1 (en) | 2011-09-21 | 2013-03-28 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
| US9725469B2 (en) | 2012-11-15 | 2017-08-08 | Amgen, Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
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| WO1994013696A1 (en) * | 1992-12-11 | 1994-06-23 | Merck & Co., Inc. | Spiro piperidines and homologs which promote release of growth hormone |
| AU5486396A (en) * | 1995-04-19 | 1996-11-07 | Merck & Co., Inc. | Process for the preparation of spiroindolines |
| US5767124A (en) * | 1995-10-27 | 1998-06-16 | Merck & Co., Inc. | Polymorphic forms of a growth hormone secretagogue |
| US6028196A (en) * | 1995-10-27 | 2000-02-22 | Merck & Co., Inc. | Process for the preparation of a growth hormone secretagogue |
| CA2253390A1 (en) * | 1996-05-07 | 1997-11-13 | Merck & Co., Inc. | Enhancement of sleep with a growth hormone secretagogue |
| US6046333A (en) * | 1996-10-25 | 2000-04-04 | Merck & Co., Inc. | Convergent process for the preparation of a growth hormone secretagogue |
| EP1109572A4 (en) * | 1998-09-03 | 2004-11-24 | Neuronz Ltd | NEUROPROTECTION |
| EP1258250B1 (en) * | 1999-12-28 | 2005-09-14 | Kaken Pharmaceutical Co., Ltd. | Nerve protective drugs |
| EP1149583A3 (en) * | 2000-04-13 | 2001-11-14 | Pfizer Products Inc. | Combinations of corticotropin releasing factor antagonists and growth hormone secretagogues |
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| CN104884052A (zh) * | 2012-12-31 | 2015-09-02 | 切萨联盟有限公司 | 4-羟基-2-甲基-5-(丙-2-亚基)环己-3-烯甲醛用于预防及治疗认知、神经退行性或神经元疾病 |
| CN104884052B (zh) * | 2012-12-31 | 2021-06-25 | 切萨联盟有限公司 | 4-羟基-2-甲基-5-(丙-2-亚基)环己-3-烯甲醛用于预防及治疗认知、神经退行性或神经元疾病 |
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| IS8004A (is) | 2005-08-29 |
| CA2518886A1 (en) | 2004-09-23 |
| WO2004080459A1 (en) | 2004-09-23 |
| KR20050109990A (ko) | 2005-11-22 |
| US20060241133A1 (en) | 2006-10-26 |
| MXPA05009850A (es) | 2005-12-06 |
| NO20054714D0 (no) | 2005-10-13 |
| JP2006520371A (ja) | 2006-09-07 |
| EP1605940A1 (en) | 2005-12-21 |
| AU2004218871A1 (en) | 2004-09-23 |
| BRPI0408295A (pt) | 2006-03-07 |
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