CN107708687A - 四氢‑N,N‑二甲基‑2,2‑二苯基‑3‑呋喃甲胺的对映体(ANAVEX2‑73)及其在治疗阿尔海默氏病和其他由σ1受体调节的疾病中的用途 - Google Patents
四氢‑N,N‑二甲基‑2,2‑二苯基‑3‑呋喃甲胺的对映体(ANAVEX2‑73)及其在治疗阿尔海默氏病和其他由σ1受体调节的疾病中的用途 Download PDFInfo
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Abstract
已经发现化合物(‑)‑四氢‑N,N‑二甲基‑2,2‑二苯基‑3‑呋喃甲胺盐酸盐((‑)ANAVEX2‑73、(‑)A2‑73、(‑)AE 73)显示出对于σ1受体的选择性,以及相比所述化合物的(+)对映体对于毒蕈碱M1乙酰胆碱受体更强的激动剂活性。公开了包含(‑)对映体的药物组合物,以及使用所述(‑)对映体治疗与σ1受体有关的疾病和治疗阿尔海默氏病的用途。还公开了使用所述(‑)对映体将细胞按σ受体类型分类的方法。
Description
发明领域
包含基本无的的药物制剂。本发明还包括通过施用治疗有效量的基本无的的方法,治疗需要这种治疗的受试者中的阿尔海默氏病的方法。
本发明还再包括通过将细胞暴露于可检测量的基本无的并确定σ受体结合水平的方法,将所述细胞按σ受体类型分类的方法。
背景技术
已经基于其药理学特征鉴定了两种σ受体亚型。已经克隆了 sigma-1(σ-1)受体(Hanner等,1996)。已经报道了σ-2受体是一个单独的分子实体(Langa等,2003)。已经报道了σ-1受体具有对bezomorphas阳性异构体如(+)-喷他佐辛和(+)-SKF-10,047 的高亲和力。已经报道了σ-2受体具有对ibogaine的高亲和力 (Vilner和Bowen,2000)。特别地,σ1受体激动剂也已被报道为具有抗抑郁作用。在这方面,σ1受体配体在几种动物模型中显示出明显的抗抑郁作用。例如,选择性σ1受体激动剂(+)-喷他佐辛、 (+)-SKF-10,047、igmesine、OPC14523、DTG或SA4503减少了强制游泳试验中的不动时间或在悬尾试验(tailsuspension test)中有效 (Ukai等1998,Matsuno等1996,Tottori等1997,Kinsora等1998)。美国专利号5,034,419描述了N-环烷基烷基胺,据报道其也是σ1受体激动剂。
首先报道在1996年克隆的σ-1受体是包含223个氨基酸的单个多肽跨膜蛋白。其主要位于内质网膜上。报道了σ-1受体在眼组织,包括角膜、晶状体和视网膜中表达。也已报道其在细胞存活中起作用 (Wang等,Exp Cell Research,Vol.312(8):1439-1446,2006);Hayashi等,Cell,Vol.131(3):596-610,2007年11月;Jiang 等,IOVS,Vol.47(12):5576-5582,2006)。
已报道了σ受体配体是神经保护性的。报道了σ受体配体 opipramol保护沙鼠免于缺血。此外,包括BMY-14802,卡拉米芬和氟哌啶醇在内的其它σ配体在体内模型中表现出与保护作用一致的性质 (Pontecorvo等,Brain Research Bulletin,Vol.26:461-465,1991)。报道了几种σ配体在体外抑制海马切片制备物中缺血诱导的谷氨酸释放(Lobner等,Neuroscience Letters,Vol.117:169-174,1990)。也已报道了σ-1受体激动剂(+)-喷他佐辛可以保护视网膜细胞免受应激(Dun等,IOVS,Vol.48(10):4785-4794,2007;Smith等,IOVS, Vol.49(9):4154-4161,2008)。
等已报道以sigma-2(σ-2)激动剂处理Jurkat T细胞通过激活的T细胞以剂量依赖的方式降低白细胞介素(IL)-2,肿瘤坏死因子(TNF)-α和环氧合酶(COX)-2的表达诱导。(“Inhibitory effects of sigma-2 receptor agonists on T lymphocyteactivation,”Front.Pharmacol,13 March 2013|doi:10.3389/fphar.2013.00023.)。报道的效应发生在转录水平,这是由于σ-2激动剂BD-737和CB-184降低了这些基因启动子的活性。那些免疫抑制作用可能归因于干扰转录因子的激活。核因子(NF)-κB或活化T细胞核因子(NFAT)介导的诱导转录被σ-2激动剂抑制。作者认为,这些效果对于σ-2激动剂是特异的,这是由于没有发现σ-1配体PRE-084[2-(4-吗啉乙基)1苯基环己烷羧酸酯]和BD-1063对T细胞活化的显著影响。作为非限制性实例,所报道的σ-2激动剂包括CB-64D,CB-184,BD-737和氟哌啶醇。
受体拮抗剂是一类受体配体或药物,其阻断或抑制激动剂介导的应答,而不是在结合受体时引发生物反应本身。在药理学中,拮抗剂对其同源受体具有亲和力但没有效力,并且结合将破坏相互作用并抑制受体的激动剂功能或逆转激动剂。拮抗剂通过与受体的活性(正位体=正确位置)位点或变构(=其他位置)位点结合来介导其作用,或者其可能在通常不参与受体活性的生物调节的独特结合位点相互作用。拮抗剂活性可能是可逆的或不可逆的,这取决于拮抗剂-受体复合物的寿命,其相应取决于拮抗剂-受体结合的性质。大多数药物拮抗剂通过与结构限定的受体结合位点上的内源配体或底物竞争来实现其效力。
激动剂或拮抗剂的竞争性(也称为可战胜性)将激动剂或拮抗剂在与内源性配体或激动剂/拮抗剂相同的结合位点(活性位点)可逆地结合受体,但不活化受体。激动剂和拮抗剂“竞争”受体上相同的结合位点。一旦结合,拮抗剂将阻止相反功能的分子结合。受体的活性水平将由每种分子对于该位点的相对亲和力及其相对浓度决定。高浓度的竞争性激动剂或拮抗剂将增加该分子占据的受体的比例,获得相同程度的结合位点占有率会需要较高浓度的分子。在使用竞争性拮抗剂的功能测定中,观察到激动剂剂量-反应曲线的平行向右移动,而没有改变最大反应。
术语“非竞争性”(有时称为非可克服拮抗剂)可用于描述两种不同的现象:一种其中激动剂或拮抗剂与受体的活性位点结合,一种其中激动剂/拮抗剂与受体的变构位点结合。虽然这两种现象的机制是不同的,但它们都被称为“非竞争性”,因为其每个的最终结果在功能上非常相似。与影响达到最大反应所必需的激动剂或拮抗剂的量但不影响该最大反应量级的竞争性不同,非竞争性激动剂或拮抗剂减少了任何量的激动剂或拮抗剂可以获得的最大反应量级。
σ1-不受任何特定理论的束缚,认为σ1受体通过NMDA受体以及释放神经递质如多巴胺和乙酰胆碱来调节神经传递。因此,提出σ1 受体在学习和记忆以及某些神经精神疾病中起作用。
拮抗剂-σ1拮抗剂被认为可用于治疗情感迟钝,快感缺乏,无意志或冷漠,和焦虑的精神分裂症相关症状。σ1拮抗剂也被认为可用于减弱作为关于精神药物副作用的口腔运动障碍和肌张力障碍反应。σ1拮抗剂也被认为可用作癌症抗增殖药物。
激动剂-σ1激动剂可用作抗抑郁药。特别注意的是具有低σ2亲和力的σ1激动剂在治疗缺血性脑/神经元损伤如局部缺血中的用途。也认为σ1激动剂可用于改善认知障碍,如神经递质功能受损(如乙酰胆碱)以及与年龄相关的认知障碍和焦虑相关损伤(包括导致后代学习缺陷的怀孕应激)所显示的。
σ2-σ2受体被认为可用作运动功能和癌症治疗的靶标。σ2受体在快速增殖的癌细胞中以高密度表达。
拮抗剂-σ2拮抗剂可用于治疗不可逆运动副作用,例如长期施用典型抗精神病药物后报道的那些。
参考Sigma Receptors:Chemistry,Cell Biology and Clinical Implications,Matsumo to等编,Springer;2007版(2014年11月 16日)。本出版物的教导和本文引用的所有参考文献通过引用的方式整体纳入。另外参考:
Nguyen等,“Role of sigma-1 receptors in neurodegenerative diseases”JPharmacol Sci,。2015年1月;127(1):17-29;
Guo等,“Sigma-2 receptor ligands:neurobiological effects”, Curr MedChem.2015;22(8):989-1003;
2014年10月20日提交的,名为“A19-144,A2-73and Certain AnticholinesteraseInhibitor Compositions and Method for Anti-Seizure Therapy”的USSN 62/065,833;
Crawford等,“Sigma-2 Receptor Agonists Activate a Novel ApoptoticPathway and Potentiate Antinoplastic Drugs in Breast Tumor Cell Lines”,CancerResearch,62,313-322,2002年1月 1日;
Rossi等,“A step forward in the sigma enigma:a role for chirality inthe sigmal receptor-ligand interaction?” Medicinal Chemistry Communication(影响因子:2.63).09/2014; 6(1);
Gant等的名为“Morphinan modulators of nmda receptors,sigmal receptors,sigma2 receptors,and/or a3b4nicotinic receptors”的美国公开号20110206780,其有2010年1月6目的优先权日。
Vamvakides等的名为“SYNTHESIS OF(+)AND(-)1 -(5,5-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N-DIMETHYLMETHANAMINE, (+)AND(-)1-(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N- DIMETHYLMETHANAMINE AND(+)AND(-)1-(2,2-DFFHENYLTETRAHYDROFURAN-3-YL)-N-METIHYLMETHANAMINE”的 WO2013008044阐述了手性分离方法。
名为“ANAVEX2-73FOR THE TREATMENT OF ALZHEIMER’S DISEASE”并与本文同日提交的美国专利申请。
名为“CRYSTAL FORMS OF tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride,PROCESSES OF MAKING SUCH FORMS,AND THEIRPHARMACEUTICAL COMPOSITIONS”并与本文同日提交的美国专利申请。
发明概述
包含基本无的的药物制剂。
本发明还包括通过施用治疗有效剂量的包含基本无的 的药物制剂来治疗性处置需要增强σ1受体刺激的受试者的方法。特别注意的是基本无的的药物制剂有约0.5至约100mg特别是1-20mg。
通过施用治疗有效量的基本无的的方法,治疗需要这种治疗的受试者中的阿尔海默氏病的方法
进一步注意的是通过将细胞暴露于可检测量的基本无的并确定σ受体结合水平的方法,将所述细胞按σ受体类型分类的方法。
发明详述
参考以下定义将更好地理解本发明:
A.ANAVEX2-73或A2-73应表示四氢-N,N-二甲基-2,2-二苯基-3- 呋喃甲胺盐酸盐。这在一些测试数据中列为AE 37。A2-73是被认为以低微摩尔范围内的亲和力结合毒蕈碱乙酰胆碱和σ-1受体的化合物。
B.ANAVEX19-144或A19-144应表示1-(2,2-二苯基四氢呋喃-3- 基)-N-甲基甲胺盐酸盐。A19-144是被认为以低微摩尔范围内的亲和力结合毒蕈碱乙酰胆碱和σ-1受体的化合物。
C.ANAVEX1-41或A1-41应表示四氢-N,N-二甲基-5,5-二苯基-3- 呋喃甲胺盐酸盐。这在一些测试数据中列为AE 14。A1-41在Villard 等的“Antiamnesic andNeuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41Against Amyloid b25-35-Induced Toxicity in Mice”,Neuropsychopharmacology, 1-15(2008)中报道。
D.术语“对映体”或“对映体的”是指与其次映像(minor image) 不能重叠,并因此是光学活性的分子,其中对映体在一个方向上旋转偏振光平面,并且其次映像在相反的方向旋转偏振光平面。
E.定义对映体形式不存在的形式或者形式不存在的形式的“基本无”应表示小于约2%(w/w)的排除形式,并优选地小于约1%,且更优选地小于约0.5%,以及在某些情况下小于约0.1%。
F.按σ1或2受体群的“分类”细胞应表示确定给定细胞群中细胞表面上的σ1或2受体的存在和/或密度。分类利用用作生物标志物的σ受体的差异群。生物标志物可用作定义细胞群体倾向的手段,如乳腺癌增殖的可能性。
测试方法在下面更充分地阐述:
Hashimoto等,“Sigma receptor ligands:possible application astherapeutic drugs and as radiopharmaceuticals”,Curr Pharm Des.2006;12(30):3857-76;
Mach RH等,“Sigma 2receptors as potential biomarkers of proliferationin breast cancer”,Cancer Res 1997;57:156-61;
Al-Nabulsi,I等,“Effect of ploidy,recruitment, environmental factors,and tamoxifen treatment on the expression of sigma-2receptors inproliferating and quiescent tumour cells”,Br J Cancer1999;81:925-33;和,
Wheeler KT等,“Sigma-2 receptors as a biomarker of proliferation insolidtumours”,BrJCancer2000;82:1223-32。
是σ1受体的选择性非竞争性激动剂,并且是比明显更强的激动剂。
本发明的药理学活性组合物可以根据Galenic药学的常规方法加工,以制备用于施用给受试者例如包括人的哺乳动物的药剂。
对几种化合物在各种体外受体结合和分离器官测定中的作用进行了研究。
1.材料和方法
1.1体外药理学:结合分析
1.1.1一般程序
1.1.2实验条件
一般来说,显示高于50%的抑制(或在基础条件下运行测试的刺激)的体外结果被认为代表测试化合物的显著效果。50%是进一步研究最常见的临界值(从浓度-反应曲线确定IC50或EC50值)。
显示20%至50%之间的抑制(或刺激)的结果表明弱至中度效果 (在某些测试中,其可以通过进一步测试来确认,这是因为其在可能发生更多实验间变化的范围内)。
显示低于20%的抑制(或刺激)的结果被认为是不显著的,并且主要归因于对照水平附近信号的变化。
低到中等负值没有真正的意义,并且归因于对照水平附近信号的变化。有时以高浓度测试化合物获得的高负值(≥50%)通常归因于测试化合物在测定中的非特异效果。
1.1.3结果分析与表达
与受体结合的具体配体被定义为在过量的未标记配体的存在下测定的总结合和非特异性结合之间的差异。
结果表示为在测试化合物存在下获得的对照特异性结合的百分比和对照特异性结合抑制的百分比。
个体和平均值在结果部分显示。
通过使用Hill方程式曲线拟合的竞争曲线的非线性回归分析来确定IC50值(引起对照特异性结合的半数最大抑制的浓度)和Hill系数(nH)。通过Cheng Prusoff方程(Ki=IC50/(1+(L/KD))计算抑制常数(Ki),其中L=测试中放射性配体的浓度,和KD=放射性配体对受体的亲和力)。
1.2体外药理:分离器官生物测定
1.2.1一般程序
1.2.2实验条件
将兔输精管的前列腺节段悬浮于含富氧(95%O2和5%CO2)和预温热(30℃)生理盐水溶液的20ml器官浴中,生理盐水溶液为以下组成的生理盐水溶液(mM):NaCl 118.0,KCl4.7,MgSO40.6,CaCl2 2.5,KH2PO41.2,NaHCO325和葡萄糖11.0(pH 7.4)。
在整个实验中还存在育亨宾(1μM)和纳洛酮(1μM)以分别阻断α2-肾上腺素和阿片受体。
将组织与用于等张力记录的力转换器连接。将其拉伸至1g的静息张力,然后使其平衡60分钟,期间其被反复清洗并且重新调整张力。此后,用恒定电流刺激器传送的方波脉冲(亚最大强度,1毫秒持续时间,0.1赫兹)进行电刺激。
实验使用具有八个器官浴,有多通道数据采集的半自动分离器官系统进行。
1.2.3实验方案
测试激动剂活性
将组织暴露于参比激动剂McN-A-343(1μM)的亚最大浓度以验证反应性并获得对照反应。在清洗和恢复初始抽搐收缩之后,将组织暴露于与组织保持接触的测试化合物或相同的激动剂,直到获得稳定的反应或最多15分钟。
如果获得激动剂样反应(抽搐收缩的抑制),则相对于测试化合物测试参比拮抗剂哌仑西平(0.1μM),以证实M1受体参与该反应。
拮抗剂活性测试
将组织暴露于参比激动剂McN-A-343(1μM)的亚最大浓度以获得对照反应。
在稳定McN-A-343诱导的反应后,将组织暴露于与组织保持接触的测试化合物或参比拮抗剂哌仑西平,直至获得稳定的反应或持续最多15分钟。如果发生,受试化合物的抽搐收缩幅度的恢复表明M1受体的拮抗剂活性。
1.2.4结果分析与表达
测量的参数是由化合物诱导的电诱发收缩幅度的最大变化。结果表示为对McN-A-343的对照反应的百分比(平均值)。
化合物
1.3测试化合物
F.W.:式分子量
*:分离器官的生物测试
结果
1.4体外药理:结合分析
测试化合物效果的平均值总结在表1-1中。
用测试化合物获得的个体数据报告在表1-2中。
每个参比化合物的IC50和Ki值列于表1-3中。每个在历史平均± 0.5log单位的可接受限度内。
1.5参比化合物
在每个实验中,与测试化合物同时测试各参比化合物,以评估测定的适合性。在几个浓度下进行了测试,并将数据与历史值进行了比较。根据相应的标准操作程序,如果满足适用性标准,则该测定结果有效。
表1-1
结果总结
表1-2
个体数据
表1-3
参比化合物数据
1.6体外药理:分离器官生物测定
所研究的(+)A1-41,(-)A1-41和(-)A2-73对兔输精管中的毒蕈碱M1受体的激动剂和拮抗剂活性的影响在表2-1中显示,其中也报道了参比化合物的那些。
在场刺激的兔输精管中,M1受体激动剂McN-A-343诱导了抽搐收缩幅度的浓度依赖性降低,其以浓度依赖性方式被拮抗剂哌仑西平逆转。
在未处理的组织中,(+)A1-41,(-)A1-41和(-)A2-73没有降低抽搐收缩幅度,而是引起了轻微到中度增加。
在先前被McN-A-343抑制的组织中,(+)A1-41,(-)A1-41和 (-)A2-73产生了浓度依赖性并几乎完全的抽搐收缩幅度恢复。
这些结果表明(+)A1-41,(-)A1-41和(-)A2-73在M1受体上表现为拮抗剂。
表2-1
研究的(+)AE 14,(-)AE 14和(-)AE 37对兔输精管中的毒蕈碱M1受体的激动剂和拮抗剂活性的影响
激动剂活性测试
拮抗剂活性测试
结果表示为对McN-A-343的对照反应的百分比(抽搐收缩幅度减小)(平均值;n=2)
实施例1
抗β淀粉样蛋白的神经保护
被诊断患有早期阿尔茨海默氏痴呆症的67岁男性用10mg基本无的治疗,每周一次,持续三年。其精神功能在此期间每季度被测试且未下降。在尸检中,其脑被发现含有老年斑,但淀粉样肽寡聚物含量非常低。
实施例2
抗氧化应激的神经保护
29岁的女性气球驾驶员,预计有缺氧应激,每日在气球升空前口服施用10mg口服基本无的持续5日。气球驾驶员没有氧气辅助上升到6000米而未受缺氧伤害。
实施例3
抗神经毒性神经保护
37岁的男性危险材料工程师,预测有神经毒性应激,每日暴露于破伤风毒素前口服施用1mg基本无的持续5日。工程师暴露于0.1ng/kg的所述神经毒素而未受损害。
实施例4
中风患者神经保护
57岁的男性进入急诊室并诊断为涉及大脑中动脉的缺血事件,症状发作少于1小时。立即,患者被静脉注射补充了1mg基本无的同时恢复受制区域的血液供应。认知和运动系统的日常测试显示身体或精神能力没有缺陷。此外,恢复后立即的CT/MRI成像显示受影响区域无损伤迹象,其被保持并被随后的成像和行为测试确认。
实施例5
抗淀粉样蛋白的神经保护
80岁的女性患者被诊断患有AD,并且每日用10mg基本无的治疗持续3年。患者的认知评分稳定,然后在接下来的几个月内缓慢而规律地增加。
给药信息/剂型:
注意对基本无的剂量约.01-100mg/ 日,优选0.5-10mg/目,更优选0.5-2mg/日。注意每两日给药一次(3 次一周)。AD是一种慢性疾病,因此,优选诊断后立即开始治疗。
特别注意本发明的方法,其包含施用基本无的在一些情况下,治疗性处置包括施用至少一种协同乙酰胆碱酯酶抑制剂(多奈哌齐,加兰他敏,利凡斯的明或美金刚),其中每种的至少一种所述治疗有效量或协同乙酰胆碱酯酶抑制剂的剂量与单独使用时的活性剂量相比为亚治疗的(sub-MAD)。使用基本无 的 或协同乙酰胆碱酯酶抑制剂。在这方面,参考Vamvakides等的,名为“ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORSCOMPOSITION AND METHOD FOR NEUROPROTECTION”的USSN 13/940,352,其教导通过引用的方式纳入本发明。
本发明的组合物单独或与常规赋形剂混合来组合使用,常规赋形剂即适用于肠胃外,肠内(例如口服或吸入)或局部应用的药学上可接受的有机或无机载体物质,其不与活性组合物有害反应。合适的药学上可接受的载体包括但不限于水,盐溶液,醇,阿拉伯胶,植物油,苄醇,聚乙二醇,明胶,碳水化合物如乳糖,直链淀粉或淀粉,硬脂酸镁,滑石粉,二氧化钛,硅酸,粘稠石蜡,香料油,脂肪酸酯,羟甲基纤维素,聚乙烯吡咯烷酮等。药物制剂可以灭菌,如果需要,与不会与活性组合物有害反应的助剂如润滑剂,防腐剂,稳定剂,润湿剂,乳化剂,用于影响渗透压的盐,缓冲液,着色剂,调味剂和/或芳香物质等混合灭菌。其也可以根据需要与其它活性剂例如维生素组合。
在本发明的一些实施方案中,剂型包括使用这种组合物的说明书。
对于胃肠外施用,特别合适的是可注射的无菌溶液,优选油性或水溶液,以及悬浮液,乳剂或植入物,包括栓剂。安瓿瓶,管和注射器盒是方便的单位剂型。
“单位剂型”是指单个药物施用实体。作为示例,单个片剂,胶囊,糖衣丸或锭剂,栓剂或注射器。
也用于肠胃外应用,特别适合的是片剂,糖衣丸,液体剂,滴剂,栓剂或胶囊剂。可以使用其中使用增甜载体的糖浆,酏剂等。也注意到舌下和口腔形式。
可以配制持续或定向释放组合物,例如脂质体或其中活性成分被可差异降解的包衣保护的那些,例如通过微胶囊化,多层包衣等。还可以冷冻干燥新组合物并使用获得的冻干物,例如用于注射用产品的制备。
Claims (10)
1.基本无Anavex2-73的Anevex2-73药物剂型。
2.权利要求1的药物剂型,其包含约0.5至约100mg的Anevex2-73。
3.权利要求2的药物剂型,其包含约1至约20mg的Anevex2-73。
4.本发明还包括通过施用治疗有效剂量的包含基本无A2-73的A2-73的药物制剂来治疗性处置需要增强σ1受体刺激的受试者的方法。
5.权利要求4的方法,其中所述治疗有效量包含约0.5至约100mg的Anevex2-73。
6.权利要求5的方法,其中所述治疗有效量包含约1至约20mg的Anevex2-73。
7.一种治疗受试者中的阿尔海默氏病的方法,所述受试者需要这种治疗,所述方法通过施用治疗有效量的基本无A2-73的A2-73。
8.权利要求7的方法,其中所述治疗有效量包含约0.5至约100mg的Anevex2-73。
9.权利要求8的方法,其中所述治疗有效量包含约1至约20mg的Anevex2-73。
10.一种将细胞按σ受体类型分类的方法,所述方法通过将细胞暴露于可检测量的基本无A2-73的A2-73,并确定σ受体结合水平。
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WO2014155138A1 (en) * | 2013-03-28 | 2014-10-02 | Alexandre Vamvakides | Optimization and therapeutic valorization of the symptomatic treatment of alzheimer's disease with rivastigmine, galantamine or donepezil, by selected aminotetrahydrofurans acting as mixed sigma-1 / muscarinic ligands |
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CN112105349A (zh) * | 2018-04-12 | 2020-12-18 | 阿纳韦克斯生命科学公司 | A2-73结晶多晶型物质组合物及其使用方法 |
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HK1247847A1 (zh) | 2018-10-05 |
US20230044710A1 (en) | 2023-02-09 |
JP2021152077A (ja) | 2021-09-30 |
EP3324956A1 (en) | 2018-05-30 |
CN116687906A (zh) | 2023-09-05 |
CA2986345A1 (en) | 2017-01-26 |
JP2023073373A (ja) | 2023-05-25 |
EP3324956A4 (en) | 2019-02-20 |
US11617734B2 (en) | 2023-04-04 |
WO2017013496A1 (en) | 2017-01-26 |
US20180169059A1 (en) | 2018-06-21 |
JP2018524306A (ja) | 2018-08-30 |
JP7429942B2 (ja) | 2024-02-09 |
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