CN101305003A - 用于治疗精神病和神经变性疾病的作为nAChR胆碱能配体的(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-杂芳基)-胺 - Google Patents
用于治疗精神病和神经变性疾病的作为nAChR胆碱能配体的(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-杂芳基)-胺 Download PDFInfo
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- CN101305003A CN101305003A CNA2006800416171A CN200680041617A CN101305003A CN 101305003 A CN101305003 A CN 101305003A CN A2006800416171 A CNA2006800416171 A CN A2006800416171A CN 200680041617 A CN200680041617 A CN 200680041617A CN 101305003 A CN101305003 A CN 101305003A
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Abstract
本发明涉及游离碱或酸加成盐形式的式(I)化合物，在式(I)中，n代表0、1、2、3、4或5，R彼此独立代表羟基、氰基、硝基、卤素、烷基、烷氧基、烷基羰基、烷氧基羰基、烷基胺、二烷基胺、烷基羰基胺、烷基氨基甲酸酯，Y代表下列基团(Ia)之一，本发明还涉及它们的制备方法、含有它们的药用组合物以及它们在制备用于治疗精神病和神经变性疾病和/或延缓其进程的药物中的用途。
Description
本发明涉及新的1-氮杂-双环壬烷衍生物、它们的制备方法、它们作为药物的用途以及含有它们的药用组合物。
更特别地讲，本发明在第一方面提供了游离碱或酸加成盐形式的式(I)化合物：
其中
n代表0、1、2、3、4或5，
R彼此独立代表羟基、氰基、硝基、卤素、烷基、烷氧基、烷基羰基、烷氧基羰基、烷基胺、二烷基胺、烷基羰基胺、烷基氨基甲酸酯，
Y代表下列基团之一：
除非另有说明，上下文中使用的通用术语优选在本公开的上下文中具有如下含义：
本文中使用的术语“未取代的或取代的”是指各个基团可以被一个和多个(优选为不超过3个，特别是一个或两个)取代基取代。所述取代基优选选自氨基、C1-C4烷基氨基、二(C1-C4烷基)-氨基、C3-C5环烷基氨基、二(C3-C5)环烷基氨基、N-C1-C4烷基-N-C3-C5环烷基氨基、卤素、C1-C4烷基、C4-C6环烷基、羟基、C1-C4烷氧基、C3-C5环烷基氧基、C1-C4烷氧基C1-C4烷氧基、二(C1-C4烷基)-氨基C1-C4烷氧基、氨基甲酰基、N-C1-C4烷基-氨基甲酰基、N，N-二(C1-C4烷基)-氨基甲酰基、硝基、氰基、羧基、C1-C4烷氧基羰基、C1-C4烷酰基、C1-C4烷酰氧基、苯甲酰基、脒基、胍基、脲基、巯基、C1-C4烷硫基、吡啶基、苯基、苯氧基、C1-C4烷氧基苯基、苯硫基、苯基-C1-C4烷硫基、C1-C4烷基磺酰基、苯基磺酰基、C1-C4烷基苯基磺酰基、C1-C4链烯基、C1-C4烷酰基、与环上相邻C-原子连接的C1-C4亚烷二氧基以及被下列基团取代的C1-C4烷基：卤素、羟基、C1-C4烷氧基、硝基、氰基、羧基、C1-C4烷氧基羰基、C1-C4烷酰基或C1-C4烷酰氧基。
术语“C5-C10芳基”、“C5-C10杂芳基”是指所有的未取代或被以上提供的取代基取代的芳香族基团，优选未取代或被一个或多个选自卤素、CN或烷基的取代基取代，该烷基可以是未取代的或被卤素取代，例如三氟甲基；或被C1-C4烷氧基取代，或是与例如苯并[1，3]间二氧杂环戊烯或2，3-二氢苯并[1，4]二噁烯和/或另外的杂环基的环稠合。C5-C10杂芳基是其中一个或多个碳原子被杂原子代替的芳香族杂环体系。优选含有一个、两个或三个杂原子的5-9元环体系。上述的C5-C10芳基或C5-C10杂芳基基团的实例包括苯基、萘基、异苯并呋喃基、噻吩基、吲哚基。
术语“烷基”代表直链或支链烷基，优选代表直链或支链C1-7烷基，特别优选代表直链或支链C1-4烷基；例如甲基；乙基；正或异丙基；正、异、仲或叔丁基；正戊基；正己基；正庚基；正辛基；正壬基；正癸基；正十一烷基和正十二烷基，特别优选为甲基、乙基、正丙基和异丙基。
“烷氧基”、“烷氧基烷基”、“烷氧基羰基”、“烷氧基羰基烷基”和“卤代烷基”各自的烷基部分应该与上述的“烷基”定义具有相同的含义。烷氧基特别为C1-C4烷氧基，尤其是甲氧基、乙氧基或正丙氧基。
“杂原子”是除了碳和氢以外的原子，优选为氮(N)、氧(O)或硫(S)。
“卤素”代表氟、氯、溴或碘，优选代表氟、氯或溴并且特别优选代表氯。
由于式I化合物及其盐中存在不对称碳原子，所以该化合物可以以光学活性形式存在或以光学异构体混合物的形式存在，例如以外消旋混合物的形式存在。所有的旋光异构体和包括外消旋混合物的旋光异构体混合物均包含在本发明内。
式(I)化合物以游离形式或酸加成盐形式存在。在本说明书中，除非另外说明，术语例如“式(I)化合物”应理解为包含该化合物的所有形式，例如游离碱或酸加成盐形式。也包括不适合作为药用但可以用于例如游离式(I)化合物的分离或纯化的盐，例如苦味酸盐或高氯酸盐。对于治疗用途而言，只能采用药学上可接受的盐或游离化合物(当以药物制剂的形式应用时)，所以优选之。
式(I)化合物可以以各种异构体的形式存在，例如酮-烯醇互变异构体。在本说明书中，除非另外说明，术语例如“式(I)化合物”应理解为包含该化合物的所有形式，例如酮或烯醇形式或其任何的混合物。
鉴于游离形式的新化合物和盐(包括可以例如在纯化或鉴别新化合物中用作中间体的那些盐)形式的该化合物的紧密关系，如果适当并且有利时，当上下文提及任何游离化合物时应被理解为也是指其相应的盐。
当采用化合物、盐等的复数形式时，也包括单数形式的化合物、盐等。
式(I)以及相应的中间体化合物中存在的优选的取代基、优选的数值范围或优选的基团范围定义如下。这些取代基、优选的数值范围或优选的基团范围独立地、共同地或以任何组合或亚组合优选为：
n优选代表0或1。
n特别优选代表0。
R优选代表羟基、C1-C4烷基、C1-C4烷基羰基氨基。
本发明优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-嘧啶-2-基]-胺：
本发明另外优选的化物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[6-(1H-吲哚-5-基)-吡啶-3-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-4-基)-吡啶-2-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-4-基)-嘧啶-2-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[6-(1H-吲哚-5-基)-哒嗪-3-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-6-基)-吡啶-2-基]-胺：
本发明另外优选的化合物为如下所示的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-3-基]-胺：
在另外的方面，本发明也提供了制备式(I)化合物的方法。
第一种方法包括下列步骤：
i)使式(VIII)化合物：
R-Y-Z (VIII)
其中R代表
Y代表下列基团之一：
Z代表离去基团，例如Cl、Br、I或甲苯磺酸酯基(tosylate)
与式(IX)反应：
XB(OR)2 (IX)
其中X代表吲哚基，该基团适当的被Rn取代(例如5-吲哚基、4-吲哚基、5-1，3-二氢-吲哚-2-酮基)，其中R代表H或C1-C4烷基，或者两个RO与它们所连接的硼原子一起形成杂环，
ii)回收如此获得的游离碱或酸加成盐形式的式(I)化合物，
iii)任选通过已知的方法分离立体异构体，例如手性HPLC色谱方法。
第二种方法包括下列步骤：
i)使式(X)化合物：
与式(XI)化合物反应：
其中R和n如式(I)所定义，并且
ii)回收如此获得的游离碱或酸加成盐形式的式(I)化合物，
iii)任选通过已知的方法分离立体异构体，例如手性HPLC色谱方法。
原料为已知的，或者可以通过众所周知的方法获得。
下面的考虑因素应用于以上描述的各个反应步骤：
a)原料中的一个或多个官能团，例如羧基、羟基、氨基或巯基可能需要保护基团的保护。采用的保护基团可能已经存在于前体中并且保护有关的官能团不发生不希望的副反应，例如酰化、醚化、酯化、氧化、溶剂分解以及类似的反应。保护基团的特征在于例如在类似生理环境的条件下，它们容易被裂除，即无需进行不希望的副反应即可裂除，通常通过溶剂分解、还原、光解或也可以通过酶的活性除去，并且它们不存在于终产物中。技术人员已知或可以容易地确定哪些保护基团适合上下文中提及的反应。各保护基团对各官能团的保护、保护基团本身以及它们的除去反应在例如标准参考文献中已有描述，例如J.F.W.McOmie，“有机化学中的保护基团(Protective Groups in Organic Chemistry)”，Plenum Press，London andNew York 1973；T.W.Greene，“有机合成中的保护基团(Protective Groupsin Organic Synthesis)”，Wiley，New York 1981；“肽(The Peptides)”，第3卷(主编：E.Gross和J.Meienhofer)，Academic Press，London and NewYork 1981；“有机化学方法(Methoden der organischen Chemie)”，HoubenWeyl，第4版，第15/I卷，Georg Thieme Verlag，Stuttgart 1974；H.-D.Jakubke和H.Jescheit，“氨基酸、肽和蛋白(
Peptide，Proteine)”，Verlag Chemie，Weinheim，Deerfield Beach，and Basel 1982以及Jochen Lehmann，“碳水化合物：单糖及其衍生物(Chemie derKohlenhydrate：Monosaccharide und Derivate)”，Georg Thieme Verlag，Stuttgart 1974。
b)酸加成盐可以按照已知的方式从游离碱制备，反之亦然。另外，可以应用任选的旋光纯原料。用于本发明的适当的酸加成盐包括例如盐酸盐。
c)立体异构体混合物，例如非对映异构体混合物，可以按照众所周知的方式通过适当的分离方法分离为其相应的异构体。非对映异构体混合物例如可以通过分级结晶、色谱、溶剂分配以及类似的方法分离为其单一的非对映异构体。该分离可以在原料化合物阶段或以式I化合物本身进行。对映体可以通过非对映异构体盐的形成进行分离，例如通过与对映体纯的手性酸形成盐，或通过色谱的方法例如通过HPLC，采用具有手性配体的色谱底物。另外，可以应用旋光纯的原料。
d)用于进行上述方法的适当的稀释剂特别地为惰性有机溶剂。它们特别包括脂肪族、脂环族或芳香族的有机溶剂，任选：卤化烃，例如挥发油、苯、甲苯、二甲苯、氯苯、二氯苯、石油醚、己烷、环己烷、二氯甲烷、氯仿、四氯化碳；醚，例如乙醚、二异丙醚、二噁烷、四氢呋喃或乙二醇二甲醚或乙二醇二乙醚；酮，例如丙酮、丁酮或甲基异丁酮；腈，例如乙腈、丙腈或丁腈；酰胺，例如N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基-甲酰苯胺、N-甲基-吡咯烷酮或六甲替磷酰三胺；酯，例如乙酸甲酯或乙酸乙酯；亚砜，例如二甲基亚砜；醇，例如甲醇、乙醇、正或异丙醇、乙二醇单甲醚、乙二醇单乙醚、二乙二醇单甲醚、二乙二醇单乙醚。另外，可以应用稀释剂的混合物。根据原料、反应条件和辅助剂，水或包含水的稀释剂可能是适合的。也可能采用一种原料同时作为稀释剂。
e)反应温度可以在相对宽的范围内变动。通常，该方法在温度为0℃至150℃之间进行，优选为10℃至120℃之间。脱质子化反应可以在相对宽的温度范围内进行。通常，该方法在温度为-150℃至+50℃之间进行，优选为-75℃至0℃之间。
f)反应通常在大气压下进行。但是，本发明的方法也可能在升压或减压下进行，通常在0.1bar至10bar之间。
g)原料通常可以以近似等摩尔量应用。但是，也可能采用一种组分相对较大过量。反应通常在反应辅助剂的存在下在适当的稀释剂中进行，并且反应混合物通常在需要的温度下搅拌数小时。
h)根据以上方法处理反应混合物并且纯化由此获得的化合物可以根据已知的方法进行(参看制备实施例)。
本发明化合物在体外和动物试验中显示出有价值的药理学性质，因此可用作药物。
因此，本发明化合物为nAChR的胆碱能配体。另外本发明优选的化合物显示出选择性nAChRα7活性。申请人发现本发明化合物特别为受体的激动剂、部分激动剂、拮抗剂或受体变构调节剂。
由于其药理学性质，预期本发明的化合物可用于治疗不同的疾病或病症：CNS相关疾病；PNS相关疾病；与炎症相关的疾病；疼痛和由药物滥用引起的戒断症状。与CNS相关的疾病或病症包括广泛性焦虑症、认知障碍、学习和记忆缺陷以及功能障碍、阿尔茨海默病(AD)、前期AD、老年轻度认知功能损害(MCI)、遗忘型MCI、年龄相关性记忆损害、注意力缺失和过动症(ADHD)、帕金森病、亨廷顿病、ALS、朊病毒神经变性障碍例如克-雅综合征和库鲁病、吉勒德拉图雷综合征、精神病、抑郁和抑郁性障碍、躁狂症、躁狂抑郁、精神分裂症、精神分裂症中的认知缺陷、强迫症、惊恐症、进食障碍、发作性睡眠、伤害感觉、AIDS-痴呆、老年性痴呆、与年龄相关的轻度认知功能障碍、孤独症、诵读困难、迟发性运动疾病、癫痫以及惊厥性疾病、创伤后精神紧张性疾病、短暂缺氧、假性痴呆、经前期综合征、晚黄体期综合征(late luteal phase syndrome)、慢性疲劳综合征以及时差反应。另外，本发明的化合物可以用于治疗内分泌疾病，例如甲状腺毒症、嗜铬细胞瘤、高血压和心律失常以及心绞痛、异常高动力、早泄和勃起困难。另外，本发明的化合物可以用于治疗炎性疾病(Wang等，Nature 2003，421，384；de Jonge等，Nature Immunology 2005，6，844；Saeed等，JEM 2005，7，1113)，疾病或病症包括炎性皮肤病、类风湿性关节炎、术后肠梗阻、克隆病、炎性肠病、溃疡性结肠炎、脓毒病、纤维肌痛综合征、胰腺炎和腹泻。本发明的化合物还可以用于治疗由于成瘾物质的使用而引起的戒断症状，该成瘾性物质如海洛因、可卡因、烟草、尼古丁、阿片类、苯并二氮杂类和酒精。最后，本发明的化合物可以用于治疗疼痛，例如由偏头痛、手术后疼痛、幻肢痛引起的疼痛或与癌症相关的疼痛。疼痛可以包括炎性或神经性疼痛、中枢疼痛、慢性头痛、与糖尿病性神经病、治疗后神经痛或周围神经损伤相关的疼痛。
另外，可以治疗的变性眼病包括直接或间接涉及视网膜细胞变性的眼病，包括通常的局部缺血性视网膜病变、眼前部缺血性视神经病变、所有形式的视神经炎、年龄相关的黄斑变性(AMD)(其干性形式(干性AMD)和湿性形式(湿性AMD))、糖尿病性视网膜病变、囊样黄斑水肿(CME)、视网膜脱离、视网膜色素变性、斯塔加特病、贝斯特卵黄样视网膜变性、莱伯先天性黑矇病以及其他的遗传性视网膜变性、病理性近视、早产儿视网膜病变以及莱伯遗传性视神经病。
已经发现含有至少一种烟碱-α7受体激动剂和至少一种选自(a)传统抗精神病药物和(b)非典型精神病药物的化合物的联合应用的效果大于精神病治疗中联合应用药物的相加效果。尤为特别的是，本文所公开的联合应用可以用于治疗精神分裂症，该病对于采用联合应用的配对药物中任何一种的单一治疗都是难以治愈的。
因此，本发明涉及联合应用，例如联合的制剂或药用组合物，它含有至少一种烟碱-α7受体激动剂和至少一种选自(a)传统抗精神病药物和(b)非典型精神病药物的化合物，其中活性成分均为游离形式或可药用盐形式，它还任选含有至少一种可药用载体，所述成分可以同时、分别或顺序使用。
本文中所用术语“精神疾病”包括但不限于精神分裂症、焦虑症、抑郁症和双相障碍。优选采用本公开联合应用治疗的精神疾病为精神分裂症，更优选为采用联合应用的配对药物中任何一种的单一治疗都是难以治愈的精神分裂症。
本文中使用的术语“传统抗精神病药”包括但不限于氟哌啶醇、氟非那嗪、替沃噻吨和氟哌噻吨。
本文中使用的术语“非典型抗精神病药”包括但不限于氯氮平、利司培酮、奥氮平、喹硫平、齐拉西酮和阿利哌唑。
另一方面，本发明的化合物用作诊断试剂和/或PET配体，例如鉴定和定位各种组织中的烟碱受体。本发明的适当的同位素标记物作为组织病理学标记物、显像剂和/或生物学标记(下文中的“标记物”)对于nAChR的选择性标记显示出有价值的性质。更特别地，本发明的物质可以用作体外或体内标记nAChRα7受体的标记物。特别地，适当的同位素标记的本发明的化合物可以用作PET标记物。该PET标记物采用一个或多个选自11C、13N、15O、18F的原子标记。
因此，本发明的物质用于例如确定作用于nAChR的药物的受体占据水平，或用于由nAChR失调或功能障碍引起的疾病的诊断，以及监控药物对于此类疾病治疗的效力。
根据上述，本发明提供了用作神经造影标记物的本发明的物质。
另一方面，本发明提供了包含本发明物质的组合物，该组合物用于在体内和体外标记与nAChR有关的脑和周围神经系统结构。
另一方面，本发明提供了在体内和体外标记与nAChR有关的脑和周围神经系统结构的方法，该方法包括将脑组织与本发明的物质接触。
本发明的方法可以包括目的在于确定本发明的物质是否标记了靶结构的另外的步骤。所述的另外的步骤可以通过应用正电子成像术(PET)或单光子发射计算机化断层显像(SPECT)或任何可以检测放射性辐射的仪器来观察靶结构而实现。
特别的是，本发明的物质为α7烟碱乙酰胆碱受体(nAChRα7)激动剂。
在功能分析中，本发明的物质对nAChRα7显示出很高的亲和力，如以下试验所示：
a)对nAChRα7的亲和力的功能分析采用稳定表达nAChRα7的大鼠垂体细胞系进行。简言之，试验前72小时在黑色96孔板上接种重组表达nAChRα7的GH3细胞，在37℃潮湿环境(5％CO2/95％空气)中培养。在试验当天通过轻弹该板将介质除去，在2.5mM丙磺舒(Sigma)存在下用100μL含有荧光钙敏感染料的生长介质代替该介质。将细胞在37℃潮湿环境(5％CO2/95％空气)中培养1小时。轻弹该板除去过量的Fluo-4，用Hepes缓冲盐溶液(以mM计：NaCl 130、KCl 5.4、CaCl2 2、MgSO4 0.8、NaH2PO40.9、葡萄糖25、Hepes 20，pH7.4；HBS)洗涤两次，当适合时用100μL含有拮抗剂的HBS补充。在拮抗剂存在下，将培养持续3至5分钟。然后将板放入成像板读数仪并记录荧光信号。在此分析中，本发明的化合物显示出pEC50值为约5至约9。在该试验中优选部分激动剂和高效激动剂。
b)为了评价本发明的化合物对人神经元nAChRα4β2的拮抗剂活性，采用稳定表达人α4β2亚型的人上皮细胞系进行类似的功能分析(Michelmore等，Naunyn-Schmiedeberg’s Arch.Pharmacol.(2002)366，235)。在该分析中，本发明优选的化合物显示出对于nAChRα7亚型的选择性。
c)为了评价本发明的化合物对“神经节亚型“(α3β4)、肌型烟碱受体(α1β1γδ)和5-HT3受体的拮抗剂活性，采用稳定表达人神经节亚型的人上皮细胞系、内源性表达肌型人烟碱受体的细胞系或内源性表达鼠科动物5-HT3受体的细胞系进行如a)项下描述的类似的功能试验(Michelmore等，Naunyn-Schmiedeberg’s Arch.Pharmacol.(2002)366，235)。在nAChRα3β4、肌亚型的烟碱受体以及5-HT3受体上显示出较小活性或无活性的化合物是特别优选的。
在S.Leonard等Schizophrenia Bulletin 22，431-445(1996)中描述的感觉门控缺陷的小鼠模型(DBA/2-小鼠)中，本发明化合物在浓度为约10至约40μM时诱导了显著的感觉门控。
本发明的化合物在啮齿动物的注意力试验中显示出注意力增加(Robbins，J.Neuropsychiatry Clin.Neurosci.(2001)13，326-35)，该实验也称为5-选择系列反应时间试验(5-CSRTT)。在该试验中，大鼠必须观察包含5个孔的墙。当光闪出现在其中一个孔时，大鼠必须在5秒钟内做出将鼻子伸进正确的孔的反应，从而接受传递至对面上的饲料器(feeder)中的食物小球作为奖励。
在小鼠和大鼠的社会认知试验中，本发明的化合物也显示出学习/记忆加强作用(Ennaceur和Delacour，Behav.Brain Res.(1988)31，47-59)。
因此，本发明的化合物用于预防和治疗(包括缓解和预防)多种疾病，特别是上述的那些疾病。nAChRα7激动剂在神经变性中的用途在文献例如Wang等，J.Biol.Chem.275，5626-5632(2000)中被证明。
对于以上和其它疾病的治疗，本发明的化合物(活性成分)的适当的剂量当然取决于例如宿主、给药方式和待治疗疾病的性质和严重程度以及所应用的本发明的具体物质的相对效果而变化。例如，需要的活性成分的量可以根据已知的体外和体内技术为基础确定，确定特定的活性成分在血浆中的浓度应该保持可接受的治疗有效水平多长时间。通常，口服日剂量约0.01至约30.0mg/kg可以在动物中获得满意的结果。对于人类而言，口服日剂量范围为约0.7至约1400mg/天，例如约50至约200mg(对于70kg的人而言)，方便地每天一次给药或分剂量每天不超过4次给药或以缓释的形式给药。因此，适当的口服剂型包含与适当的可药用稀释剂或载体混和的约1.75或2.0至约700或1400mg本发明的化合物。
药物组合物含有例如约0.1％至约99.9％，优选为约20％至约60％的活性成分。
含有本发明化合物的组合物的实例包括例如范围为0.1％至1％(例如0.5％)的式I化合物的盐或游离的式I化合物的固体分散物、水溶液(例如含有增溶剂的水溶液)、微乳和混悬剂。该组合物可以通过适当的缓冲液缓冲至pH范围为例如3.5至9.5，例如pH4.5。
本发明的化合物也可以在商业上用作研究性化学试剂。
根据本发明的用途，式I化合物和/或其可药用盐可以作为活性成分单独给药，或者与一种或多种式I和/或其可药用盐的其它活性成分联合给药，或者特别地与通常特别地用于治疗本文中所述疾病或另外的其他疾病的其他活性成分联合给药，该给药通过任何常规方式(例如口服)给药，例如以片剂、胶囊剂或鼻喷雾剂的形式给药，或经胃肠外给药，例如以注射溶液剂或混悬剂的形式给药。应用于该联合给药中的其它的活性成分优选选自苯并二氮杂
类、选择性5-羟色胺再摄取抑制剂(SSRI)、选择性5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)、传统抗精神病药、非典型抗精神病药、丁螺环酮、卡马西平、奥卡西平、加巴喷丁和普瑞巴林。
适用于本发明的SSRI特别选自氟西汀、氟伏沙明(fuvoxamine)、舍曲林、帕罗西汀、西酞普兰和依他普仑。适用于本发明的SNRI特别选自文拉法辛和度洛西汀。本文中使用的术语“苯并二氮杂
类”包括但不局限于氯硝西泮、地西泮和劳拉西泮。本文中使用的术语“传统抗精神病药”包括但不局限于氟哌啶醇、氟非那嗪、替沃噻吨和氟哌噻吨。本文中使用的术语“非典型抗精神病药”指的是氯氮平、利司培酮、奥氮平、喹硫平、齐拉西酮和阿利哌唑。
丁螺环酮可以以游离形式或作为盐(如其盐酸盐)给药，例如以商标BusparTM或BesparTM的商购形式给药。它可以如US 3,717,634所述进行制备和给药。氟西汀可以例如以其例如商标ProzacTM的商购盐酸盐形式给药。它可以如CA 2002182所述进行制备和给药。帕罗西汀((3S，4R)-3-[(1，3-苯并间二氧杂环戊烯-5-基氧基)甲基]-4-(4-氟苯基)哌啶)可以例如以商标PaxilTM的商购形式给药。它可以如US 3,912,743所述进行制备和给药。舍曲林可以例如以商标ZoloftTM的商购形式给药。它可以如US 4,536,518所述进行制备和给药。氯硝西泮可以例如以商标AntelepsinTM的商购形式给药。地西泮可以例如以商标Diazepam DesitinTM的商购形式给药。劳拉西泮可以例如以商标TavorTM的商购形式给药。西酞普兰可以以游离形式或作为盐(如其氢溴酸盐)例如以商标CipramilTM的商购形式给药。依地普仑可以例如以商标CipralexTM的商购形式给药。它可以如AU623144所述进行制备和给药。文拉法辛可以例如以商标TrevilorTM的商购形式给药。度洛西汀可以例如以商标CymbaltaTM的商购形式给药。它可以如CA1302421所述进行制备和给药。卡马西平可以例如以商标TegretalTM或TegretolTM的商购形式给药。奥卡西平可以例如以商标TrileptalTM的商购形式给药。奥卡西平在文献中是众所周知的[参见例如Schuetz H.等，Xenobiotica(GB)，16(8)，769-778(1986)]。加巴喷丁可以例如以商标NeurontinTM的商购形式给药。氟哌啶醇可以例如以商标HaloperidolSTADATM的商购形式给药。氟非那嗪可以例如以其例如商标ProlixinTM的商购二盐酸盐形式给药。替沃噻吨可以例如以商标NavaneTM的商购形式给药。它可以如US 3,310,553所述进行制备。氟哌噻吨可以例如以商标EmergilTM的商购例如二盐酸盐形式或例如以商标DepixolTM的商购例如癸酸盐形式给药。它可以如BP 925,538所述进行制备。氯氮平可以例如以商标LeponexTM的商购形式给药。它可以如US 3,539,573所述进行制备。利司培酮可以例如以商标RisperdalTM的商购形式给药。奥氮平可以例如以商标ZyprexaTM的商购形式给药。喹硫平可以例如以商标SeroquelTM的商购形式给药。齐拉西酮可以例如以商标GeodonTM的商购形式给药。它可以如GB 281,309所述进行制备。阿利哌唑可以例如以商标AbilifyTM的商购形式给药。它可以如US 5,006,528所述进行制备。
通过代码、通用名或商品名鉴别的活性成分的结构可以来自于标准目录“The Merck Index”的现行版本或来自于数据库，例如PatentsInternational(例如IMS World Publications)。其相应的内容引入本文作为参考。本领域中任何技术人员完全能够鉴别活性成分，并且根据这些文献也能够制备并且在体外和体内的标准试验模型上试验药物的适应证和性质。
在联合给药的情况下，根据本发明可以按照众所周知的方法制备分别给药的联合成分的药物组合物和/或那些以固定组合给药的药物组合物(即包含至少两种联合成分的单一盖伦制剂组合物)，所述组合物为那些适合肠道给药(例如口服或直肠)和胃肠外给药于哺乳动物(包括人)的药物组合物，该药物组合物含有治疗有效量的至少一种药理学上有活性的联合成分，可以单独含有该成分或者还含有一种或多种可药用的载体，特别是适合肠道或胃肠外给药的载体。除非另外说明，当应用的联合成分作为单一药物以商购的形式应用时，其剂量和给药方式可以根据不同商购药物包装说明提供的信息实施以产生本文中描述的有益疗效。
肠道或胃肠外给药的联合治疗的药物制剂是例如那些单位剂型的药物制剂，例如糖包衣片、片剂、胶囊剂或栓剂，还包括安瓿剂。除非另外说明，它们按照众所周知的方法制备，例如通过常规的混合、制粒、糖包衣、溶解或冻干方法制备。值得关注的是包含于每种剂型的各个剂量中的联合成分的单位含量本身不需要与有效量相等，因为需要的有效量可以用单剂量单位代替，也可以通过给予两个或多个剂量单位达到。
特别地，治疗有效量的每种联合成分可以同时或相继以及以任何顺序给药，并且各组分可以分别给药(例如以固定的时间间隔或可变的时间间隔相继给药)，或以固定的组合给药。例如根据本发明治疗(包括缓解)疾病的方法可以包括(i)给予游离或可药用盐形式的联合成分(a)(本发明化合物)，和(ii)以共同治疗有效量(优选为以协同有效量，例如以与本文所述量一致的日剂量)同时或以任何顺序相继给予游离或可药用盐形式的联合成分(b)(例如不同的本发明化合物或不同结构式的活性成分)。各个联合成分可以在治疗过程中的不同时间分别给药或以分开的或单一组合形式同时给药。另外，术语“给药”也包括采用联合成分的前体药物，该前体药物在体内转化为联合的成分。因此，本发明包括所有的此类同时和/或交互治疗的模式，术语“给药”也作如此解释。
采用的联合成分的有效剂量可以例如取决于采用的具体化合物或药物组合物、给药方式、待治疗疾病和/或待治疗疾病的严重程度。因此，根据多种因素选择剂量方案，所述因素包括给药途径以及患者肾和肝的代谢功能。普通的医师、临床医师或兽医可以容易地确定或处方预防、缓解、对抗或抑制疾病所需要的有效量的单一活性成分。在产生疗效而无毒性的范围内获得活性成分的最佳精确浓度需要基于对于靶点的活性成分利用度的动力学的研究方案而定。
根据前述，本发明也提供了：
(1)式I化合物和/或其盐，用于诊断或治疗哺乳动物，特别是人；特别用作α7受体激动剂，例如用于治疗(包括缓解)任何一种或多种疾病，特别是任何一种或多种上下文中列出的具体的病症。
(2)药物组合物，它含有作为活性成分的式I化合物和/或其可药用盐以及可药用稀释剂或载体。
(2’)药物组合物，用于治疗或预防其中α7受体活化作用起作用的或涉及α7受体活化作用的和/或涉及α7受体活性的病症，特别是上下文中所述的任何一种或多种疾病，该药物组合物含有作为活性成分的式I化合物和/或其可药用盐以及可药用稀释剂或载体。
(3)在需要此类治疗的个体中治疗疾病(特别是上文中列出的任何一种或多种具体的疾病)的方法，该方法包括给予药物有效量的式I化合物或其可药用盐。
(3’)用于治疗或预防其中α7受体活化作用起作用的或涉及α7受体活化作用的和/或涉及α7受体活性的疾病的方法，该方法包括给予需要的哺乳动物治疗有效量的式I化合物和/或其可药用盐。
(4)式I化合物和/或其可药用盐在制备用于治疗和预防其中α7受体活化作用起作用的或涉及α7受体活化作用的和/或涉及α7受体活性的疾病或病症(特别是上文中提及的一种或多种疾病)的药物中的用途。
(5)上文中定义的方法，该方法包括联合应用，例如同时或相继给予治疗有效量的式I的α7激动剂和/或其可药用盐以及第二种药物活性化合物和/或其可药用盐，所述的第二种药物活性化合物和/或其盐特别用于治疗上文或下文中列出的任何一种或多种具体的疾病。
(6)组合产品，该组合产品包括治疗有效量的式I的α7激动剂和/或其可药用盐以及第二种药物活性化合物和/或其可药用盐，所述的第二种药物活性化合物特别用于治疗上文中列出的任何一种或多种具体的疾病。
下列实施例用于说明本发明而非限制本发明的范围。
采用下面的缩略语：
AcOEt 乙酸乙酯
aq. 含水的
EtOH 乙醇
FC 快速色谱
HV 高真空
MeOH 甲醇
m.p. 熔点
MTBE 甲基叔丁基醚
NHMDS 六甲基二硅氮烷钠
rt 室温
soln. 溶液
THF 四氢呋喃
温度以摄氏度测定。除非另外说明，反应在室温下进行。最终产物、中间体和原料的结构通过标准分析方法确定，例如微量分析和光谱学特征分析(例如MS、IR、NMR)。
根据Frank D.King等，J.Med.Chem.(1993)36，683的方法制备(4SR，5RS)-1-氮杂-双环[3.3.1]壬-4-基胺。
实施例1(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺
将2.59g(10.9mmol)2，5-二溴吡啶、1.57g(16.4mmol)叔-丁醇钠、0.20g的Pd2(dba)3和0.38g的xantphos溶于40ml无水甲苯中，采用1.53g(10.9mmol)(rac.)-1-氮杂-双环[3.3.1]壬-4-基胺的10ml甲苯溶液处理。加热至95℃60分钟后，将反应混合物倒在冰上，用AcOEt稀释。将水相用AcOEt萃取，合并的有机相用水和盐水洗涤，经粉末碳酸钠干燥并蒸发。残留物经中压硅胶色谱层析纯化，采用AcOEt/MeOH/NEt3 50∶45∶5洗脱，得到2.09g的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-(5-溴-吡啶-2-基)-胺，为米色粉末。MS(ES+)：m/e＝296/298(MH+)。
向配有搅拌棒的微波小瓶中装入148mg(0.5mmol)(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-(5-溴-吡啶-2-基)-胺、98mg(0.61mmol)吲哚-5-硼酸和29.7mg四(三苯膦)钯，旋紧瓶盖，吹入氩气排空后。加入9ml甲苯，然后加入1ml的EtOH和1ml的2M Na2CO3溶液，将混合物在微波反应器(Initiator Exp，Biotage)中于120℃照射45分钟。反应混合物经hyflo过滤，用AcOEt稀释。水相用AcOEt萃取，合并的有机相用水和盐水洗涤，经硫酸钠干燥并蒸发。残留物经中压硅胶色谱层析纯化，采用AcOEt/MeOH/NEt3 50∶45∶5洗脱，得到泡沫状物，采用戊烷研磨后得到73mg的(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺，为米色粉末。MS(ES+)：m/e＝333(MH+)。
制备性对映体分离：
柱：Chiralpak AD 20um；5×(75×21.2mm)
洗脱剂：正-己烷∶CHCl3∶MeOH 50∶25∶25+0.1％二乙胺
流速：40ml/分钟
检测器：UV 254nm
峰1：9-13分钟；峰2：17-30分钟。
分析测定：
柱：Chiralpak AD 10um；4.6×250mm)
洗脱剂：正-己烷∶CHCl3∶MeOH 50∶25∶25+0.1％二乙胺
流速：1.5ml/分钟
检测器：UV 254nm
峰1：6.65分钟＝(4R，5S)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺；峰2：19.12分钟＝(4S，5R)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺
实施例2(软胶囊制备)
5000粒软明胶胶囊制备如下，每一粒含有0.05g作为活性成分的前面实施例中所述的式I化合物之一：
将250g粉碎的活性成分悬浮于2升(丙二醇月桂酸酯，Gattefossé S.A.，Saint Priest，France)，在湿的粉碎机中研磨，得到的粒子大小为约1-3μm。然后采用胶囊填充机将0.419g份的混合物填充到软明胶胶囊中。
Claims (20)
1.游离碱或酸加成盐形式的式(I)化合物：
其中：
n代表0、1、2、3、4或5，
R彼此独立代表羟基、氰基、硝基、卤素、烷基、烷氧基、烷基羰基、烷氧基羰基、烷基胺、二烷基胺、烷基羰基胺、烷基氨基甲酸酯，
Y代表下列基团之一：
2.权利要求1的式(I)化合物，其中n代表0。
3.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-吡啶-2-基]-胺。
4.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-嘧啶-2-基]-胺。
5.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[6-(1H-吲哚-5-基)-吡啶-3-基]-胺。
6.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-4-基)-吡啶-2-基]-胺。
7.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-4-基)-嘧啶-2-基]-胺。
8.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[6-(1H-吲哚-5-基)-哒嗪-3-基]-胺。
9.(4SR，5RS)-(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-6-基)-吡啶-2-基]-胺。
10.制备权利要求1的式(I)化合物或其盐的方法，该方法包括下列步骤：
i)使式(VIII)化合物：
R-Y-Z (VIII)，
其中R代表：
Y代表下列基团之一：
且Z代表离去基团，例如Cl、Br、I或甲苯磺酸酯基，
与式(IX)化合物反应：
XB(OR)2 (IX)
其中X代表吲哚基，该基团适当的被Rn取代(例如5-吲哚基、4-吲哚基、5-1，3-二氢-吲哚-2-酮基)，其中R代表H或C1-C4烷基，或者两个RO基团与它们所连接的硼原子一起形成杂环，
ii)回收如此获得的游离碱或酸加成盐形式的式(I)化合物，
iii)任选通过已知的方法分离立体异构体，例如手性HPLC色谱方法。
11.制备权利要求1的式(I)化合物或其盐的方法，该方法包括下列步骤：
i)使式(X)化合物：
与式(XI)化合物反应：
其中R和n如权利要求1所定义，并且
ii)回收如此获得的游离碱或酸加成盐形式的式(I)化合物，
iii)任选通过已知的方法分离立体异构体，例如手性HPLC色谱方法。
12.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物，用作药物。
13.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物，用于预防、治疗精神病和神经变性疾病和/或延缓精神病和神经变性疾病的进程。
14.药用组合物，该组合物含有游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物以及药用载体或稀释剂。
15.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物的用途，作为预防、治疗精神病和神经变性疾病和/或延缓精神病和神经变性疾病的进程的药物。
16.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物在制备用于预防、治疗精神病和神经变性疾病和/或延缓精神病和神经变性疾病的进程的药物中的用途。
17.在需要此类治疗的患者中预防、治疗精神病和神经变性疾病和/或延缓精神病和神经变性疾病的进程的方法，该方法包括给予此类患者治疗有效量的游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物。
18.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物，用于预防、治疗其中nAChRα7的活化起作用或与nAChRα7的活化有关的精神病和神经变性疾病和/或延缓此类疾病的进程。
18.游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物的用途，作为预防、治疗其中nAChRα7的活化起作用或与nAChRα7的活化有关的精神病和神经变性疾病和/或延缓此类疾病的进程的药物。
19.在需要此类治疗的患者中预防、治疗其中nAChRα7的活化起作用或与nAChRα7的活化有关的精神病和神经变性疾病和/或延缓此类疾病的进程的方法，该方法包括给予此类患者治疗有效量的游离碱或药学上可接受的酸加成盐形式的权利要求1的化合物。
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| PCT/EP2006/012022 WO2007068475A1 (en) | 2005-12-16 | 2006-12-14 | (1-aza-bicyclo[3.3.1] n0n-4-yl)-[5-(ih-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenerative disorders |
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| TW200813067A (en) | 2006-05-17 | 2008-03-16 | Astrazeneca Ab | Nicotinic acetylcholine receptor ligands |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102573842A (zh) * | 2009-07-23 | 2012-07-11 | 诺瓦提斯公司 | 氮杂双环烷基衍生物或吡咯烷-2-酮衍生物的用途 |
| US10537539B2 (en) | 2009-09-22 | 2020-01-21 | Novartis Ag | Use of nicotinic acetylcholine receptor alpha 7 activators |
| US11096916B2 (en) | 2009-09-22 | 2021-08-24 | Novartis Ag | Use of nicotinic acetylcholine receptor alpha 7 activators |
| CN103442701A (zh) * | 2011-01-27 | 2013-12-11 | 诺瓦提斯公司 | 烟碱乙酰胆碱受体α7激活剂的用途 |
| CN105246485A (zh) * | 2013-01-15 | 2016-01-13 | 诺华有限公司 | α7烟碱型乙酰胆碱受体激动剂的应用 |
| CN105263492A (zh) * | 2013-01-15 | 2016-01-20 | 诺华有限公司 | α7烟碱型乙酰胆碱受体激动剂在治疗发作性睡病中的应用 |
| CN105263492B (zh) * | 2013-01-15 | 2018-04-10 | 诺华有限公司 | α7烟碱型乙酰胆碱受体激动剂在治疗发作性睡病中的应用 |
| CN105246485B (zh) * | 2013-01-15 | 2019-03-15 | 诺华有限公司 | α7烟碱型乙酰胆碱受体激动剂的应用 |
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