CN105452222B - 包含苯氧基哌啶核结构的h3拮抗剂 - Google Patents
包含苯氧基哌啶核结构的h3拮抗剂 Download PDFInfo
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- CN105452222B CN105452222B CN201480011655.7A CN201480011655A CN105452222B CN 105452222 B CN105452222 B CN 105452222B CN 201480011655 A CN201480011655 A CN 201480011655A CN 105452222 B CN105452222 B CN 105452222B
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Abstract
本发明涉及通式(I)的新的组胺H3(H3)受体亚型选择性配体和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物。本发明还涉及包含所述化合物的药物组合物和这些化合物作为用于治疗和/或预防需要调节H3受体的病症的药物的用途。本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合
Description
发明领域
本发明涉及通式(I)的新的组胺H3(H3)受体亚型选择性配体和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物。本发明还涉及包含所述化合物的药物组合物和这些化合物作为用于治疗和/或预防需要调节H3受体的病症的药物的用途。本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合。
发明背景
很早之前已经知道组胺在变态反应的介导中具有关键作用，且其调节胃酸分泌。在脑中组胺不仅调节基本自身稳定功能，而且还调节更高级的脑功能例如学习和认知功能、醒－睡周期、食物摄取。
组胺能神经元源于下丘脑的乳头结节核，并通过组胺能神经通路将投射送至脑的大多数部位。
组胺是与调节生理功能有关的重要的生物胺，其生物作用由命名为H1、H2、H3和H4的4种受体介导，它们的分类基于其序列差异、信号发放性质和药理学性质(Haas和Panula,Nat Rev Neurosci(2003) 4:121–130；Leurs等,Nat Rev Drug Discov(2005)4:107-120；Esbenshade等,Br J Pharmacol(2008)154(6):1166-1181)。
H1和H2受体是已知的药物靶点。H1受体在过敏反应中的重要作用众所周知，H1受体拮抗剂应用广泛。H2受体的主要功能是胃酸分泌的调节。H4受体的作用尚未完全研究清楚。根据临床前证据，它们可以涉及炎症性过程和痛觉。
组胺H3受体作为自身受体控制组胺合成和释放(Arrang等, Nature(1983)302:832-837)，且作为异身受体在乙酰胆碱和其他神经递质(去甲肾上腺素、5-羟色胺、多巴胺)的释放的调节中起关键作用 (Schlicker等,Naunyn Schmiedebergs Arch Pharmacol(1988) 337:588-590；Schlicker等,J Neural Transm Gen Sect(1993)93:1-10；Schlicker等,Naunyn Schmiedebergs Arch Pharmacol(1989) 340:633-638；Clapham和Kilpatrick,Br J Pharmacol(1992) 107:919-923；Blandina等,Br J Pharmacol(1996)119:1656-1664)。
组胺H3受体拮抗剂/反相激动剂作为自身受体和异身受体通过调节H3受体的功能在食物摄取的调节和体重控制中具有举足轻重的作用(Passani等,J Pharmacol Exp Ther(2011)336,24-29)。
组胺H3受体拮抗剂在脑中引起组胺和其它单胺的合成和释放。根据该机制它们增强醒觉状态、改善认知功能、使前庭反射正常化。组胺H3受体反相激动剂增加组胺的突触释放(synaptic release)，其通过激活突触后H1受体增强醒觉状态。不仅促认知作用可能通过H3自身受体介导，而且通过H3异身受体调节的其他递质系统(诸如胆碱能神经元，其在认知中起重要作用)也受到影响(Khateb等,Neuroscience (1995)69(2):495-506；Lin等,JNeurosci(1996)16(4):1523-1537；Passani等,Trends Pharmacol Sci(2004)25:618-625；Jones,Trends Pharmacol Sci(2005)26:578-586；Bonaventure等,Biochem Pharmacol(2007)73:1084-1096；Ligneau等,Biochem Pharmacol (2007)73:1215-1224；Parmentier等,Biochem Pharmacol(2007) 73:1157-1171；Haas等,Physiol Rev(2008)88:1183-1241)。
自从发现组胺H3受体后(Arrang等,Nature(1983)302:832-837)，已经记载众多H3反相激动剂或拮抗剂(Berlin等,J Med Chem(2011) 54:26-53；等,ExpertOpin.Ther.Patents(2010) 20:1147-1169；Raddatz等,Cur Top Med Chem(2010)10:153-169)。尽管一些化合物已经进展到临床阶段，但没有一种获得治疗性的应用，仅有一种化合物，替洛利生(1-{3-[3-(4-氯苯基)丙氧基]丙基}哌啶)，已经开始在发作性睡病适应症中进行3期临床试验,(Kuhne等,Expert Opin Investig(2011)20:1629-1648)。将组胺H3受体反相激动剂或拮抗剂化合物作为药物推向市场主要缺陷如下:(等,ExpertOpin.Ther.Patents(2010)20:1147-1169)
磷脂质病:在组胺H3受体反相激动剂或拮抗剂的结构中有一个或二个碱性氮。磷脂质病最可能由二碱基的性质引起，但在一碱基化合物的情况中，也可以发生磷脂质病(Ratcliffe Curr Med Chem(2009) 16:2816-2823)。二碱基的JNJ-5207852由于其引起磷脂质病被驳回 (Bonaventure等,Biochem Pharmacol(2007)73:1084-1096)。
心血管副作用，其与hERG钾通道相互作用:ABT-239(Hancock, BiochemPharmacol(2006)71:1103-1113)
高血浆蛋白结合:ABT-239(Hancock,Biochem Pharmacol(2006) 71:1103-1113)
基因毒性:A-331440(Hancock等,Basic Clin Pharmacol Toxicol (2004)95:144-152)
药物动力学性质不佳:JNJ-5207852(Bonaventure等,Biochem Pharmacol(2007)73:1084-1096)。螺[苯并吡喃-2,4’-哌啶]衍生物，其在结构上与本发明的化合物最相近，但它们的结构柔性少得多，其口服生物利用度差，因此它们应当进一步优化。(Dandu等,Bioorg Med Chem Lett(2012)22:2151-2153)
CYP酶相互作用:NNC 38-1202(Peschke等,Bioorg Med Chem (2004)12:2603-2616)
从潜在的组胺H3受体反相激动剂或拮抗剂除去不期望的性质不是容易的任务，鉴于尽管若干组胺H3受体反相激动剂或拮抗剂已经在不同适应症中进行了临床研究，但没有一种获批。(Kuhne等,Expert Opin Investig(2011)20:1629-1648)
组胺H3反相激动剂和拮抗剂的潜在的治疗应用包括多种适应症，例如神经变性疾病和认知缺陷的治疗选项。
用于阿尔茨海默病(属于神经变性疾病)的对症治疗的药物疗法主要有两种类型，其中之一是使用乙酰胆碱酯酶酶抑制剂药物(例如多奈哌齐、雷司替明、加兰他敏、他克林)，而另一种是使用NMDA受体拮抗剂(美金刚)。临床试验显示乙酰胆碱酯酶抑制剂与美金刚组合施用并不优于单一疗法。迄今为止批准的用于单一疗法的药物的功效是有限的，它们在改善认知功能方面仅具有微弱功效，且该功效局限于治疗法的前6-12个月，此外乙酰胆碱酯酶抑制剂仅在30-40％的治疗患者中有效。常见的副作用为恶心、呕吐、食欲不振和更频繁的排便。
由阿尔茨海默病引起的认知功能障碍的改善代表重要的未满足的医学需求；对新的药物有高度需求(Gerald和Ockert,Nat Rev Drug Discov(2013)12(1):19-20.；Molino等,(2013)ScientificWorldJournal 2013:925702；McGleenon等,(1999)Br J ClinPharmacol 48(4):471-480)。
已经试验了通过与具有不同作用机制的药物共施用改善了乙酰胆碱酯酶抑制剂的功效。
在最近的临床试验中已经试验了组胺H3反相激动剂或拮抗剂化合物与乙酰胆碱酯酶抑制剂的共施用。在三种候选药物的情况中，在主要终点没有改善，因此停止了它们的进一步开发(NCT01181310； Cho等,Psychopharmacology(2011)218(3):513-524；NCT00420420； Egan等,Curr Alzheimer Res(2012)9(4):481-490；NCT01266525； Kirkesseli等,J Nutr Health Aging(2013)17(9):804)。
事实仍然是对于阿尔茨海默病的治疗没有满意的单一疗法或组合疗法。
发明概述
本发明的目标为合成新结构的、化学可变的、选择性的和类药的 H3拮抗剂和反相激动剂。
令人惊讶地发现含苯氧基-哌啶核结构的合成的化合物以高亲和性和选择性结合于H3受体，其是类药分子，即它们具有可接受的药物动力学性质，例如它们的吸收良好，它们可以穿越血脑屏障，它们没有心血管副作用，它们不引起磷脂质病，它们没有遗传毒性和不与 CYP酶相互作用。
使用组胺H3受体配体可以治疗多种疾病，其中H3配体可以为拮抗剂或反相激动剂。
本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗与神经变性疾病(例如阿尔茨海默病、皮克病)或年龄相关的学习和精神障碍有关的认知功能障碍、或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD) 或亨廷顿病)、精神障碍(例如例如情感性分裂症或精神分裂症)、睡眠障碍(例如例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如例如高脂血症、糖尿病)、头晕和癫痫。
此外，本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗焦虑症(例如例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如例如激动或抑郁)和其它中枢神经系统障碍(例如精神分裂症)。
此外，本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗例如变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明的化合物以高亲和性和选择性结合于H3受体(与其他组胺受体H1、H2和H4相比)。
发明详述
本发明涉及通式(I)的化合物
其中
R1、R2彼此独立地表示氢原子，或
C1-C6烷基基团，或
C3-C7环烷基基团，或
R1和R2与相邻的碱性氮原子一起形成4-10元的一或二环的饱和的杂环基团，其任选地包含一个或两个氧原子和/或硫原子，且这些杂环基团任选地被一个或两个卤素原子、氧代基团、C1-C6烷基基团及其组合取代；
R3表示:
氢原子、-C(＝O)R4、-C(＝O)-OR4、-C(＝O)-NR4R5基团，
其中R4和R5彼此独立地表示氢原子、C1-C6直链或支链的烷基基团或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代，
和/或其盐和/或立体异构体和/或非对映异构体和/或水合物和/或溶剂化物和/或多晶型物变型。
如本文使用的术语“C1-C6烷基”是指包含1-6个碳原子的支链或直链的烷基基团。
如本文使用的术语“C3-C7环烷基”是指包含3至7个碳原子的碳环基团。
如本文使用的术语“卤素”单独或作为另一个基团的部分是指氟、氯、溴和碘原子。
有机酸和无机酸均可用于形成酸加成盐。适合的无机酸包括但不限于氢氯酸、硫酸、硝酸和磷酸。一价有机酸的代表包括但不限于甲酸、乙酸、丙酸和不同的丁酸(酪酸)、缬草酸(戊酸)和羊油酸(己酸)。二价有机酸的代表包括但不限于草酸、丙二酸、马来酸、富马酸和琥珀酸。还可以使用其他有机酸，例如羟基羧酸，例如柠檬酸、酒石酸或芳族羧酸类，例如苯甲酸或水杨酸、以及脂肪族和芳族的磺酸，例如甲磺酸、萘磺酸和对甲苯磺酸。
优选的酸加成盐为这样的酸加成盐，这些酸加成盐的酸成分自身是药学上可接受的和在施用剂量上不具有治疗效果，以及其对活性成分的效果没有不利影响。这些酸加成盐为药学上可接受的酸加成盐。药学上不可接受的酸加成盐在所期望的式(I)化合物的纯化和/或分离中可以是有益的，并因此也将其包括在本发明的范围内。
一些通式(I)的化合物
-其中R1、R2和R3的含义如上文所述–可以具有几何异构体、立体异构体和/或非对映异构体形式。这些化合物及其混合物也包括在本发明的范围内。
本发明的优选的化合物为那些式(I)的化合物：其中R1和R2与相邻的氮原子一起形成5-元的任选地被取代的杂环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R1和 R2与相邻的氮原子一起形成2-甲基-吡咯烷环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R1和 R2与相邻的氮原子一起形成2-(R)-甲基-吡咯烷环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R3的含义为–C(＝O)R4，其中R4的含义为C1-C6直链或支链的烷基基团或 C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
本发明的优选的通式(I)的化合物为以下化合物:
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1- 基)-甲酮盐酸盐
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1- 基]-乙酮盐酸盐
环丁基-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-基]-甲酮盐酸盐
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-甲酰胺
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐
本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合。本发明的组合优选地包含作为乙酰胆碱酯酶抑制剂的多奈哌齐、加兰他敏、他克林或雷司替明。
本发明的通式(I)的化合物可以根据下文的反应方案合成(基团的含义如上文对式(I)所述，PG表示用于仲胺的保护的保护基团)
步骤A:
将式(II)的中间体、优选含叔丁氧基羰基保护基团的化合物 (Waterson等,WO2006064218A1(2006)；实施例1和7；Ishii等, EP1849773A1(2007)实施例29)，与式(III)的中间体、优选1-氯-3-(1- 哌啶基)-丙烷(Buchanan等,Bioorg.Med.Chem.Let.(2011)21:2394-2399；Sann等,Tetrahedron(2007)63:12903-12911)或 (2R)-1-(3-氯丙基)-2-甲基吡咯烷(Nakamura等,WO2010090347A1 (2010))在惰性溶剂、优选在乙腈或N,N-二甲基甲酰胺中在有机或无机碱(优选K2CO3)的存在下进行反应。
步骤B
将式(IA)的中间体的保护基团裂解。将优选使用的叔丁氧羰基保护基团用酸、优选用吸附在有机溶剂中的氯化氢裂解。盐形成:将得到的式(IB)的化合物溶于极性溶剂中，加入等摩尔量的酸，并通过蒸发除去溶剂。
步骤C
可以根据以下方法将式(IB)的中间体转化为式(I)的烷基胺、羧酰胺(carboxamides)、脲或氨基甲酸酯，且在给定情况下形成盐:
步骤C1，羧酰胺:
将式(IB)的中间体与适合的羧酸在偶联剂的存在下反应，或与适合的羧酰氯(carboxylic acid chloride)在碱的存在下、在惰性溶剂中反应。
步骤C2，脲:
将式(IB)的中间体与适合的氨基甲酰氯在碱的存在下、在惰性溶剂中反应。
步骤C3，氨基甲酸酯:
将式(IB)的中间体与适合的碳酰氯在碱的存在下、在惰性溶剂中反应。
步骤C4，盐的形成:
将在步骤C1、C2、C3中任一项中得到的式(I)的化合物溶于极性溶剂中，加入等摩尔量的酸，并通过蒸发除去溶剂，或将沉淀的结晶滤出。
本发明涉及药物组合物，其包含治疗有效量的式(I)的化合物和/ 或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物，和/或这些化合物与乙酰胆碱酯酶抑制剂及一种或多种药学上可接受的载体的组合。
本发明优选地涉及药物组合物，其包含治疗有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/ 或水合物和/或溶剂化物，和/或这些化合物与乙酰胆碱酯酶抑制剂和一种或多种药学上可接受的载体的组合，其用于治疗和/或预防需要调节组胺H3受体的和/或强化调节胆碱能系统的病症。
本发明的药物组合物最优选地包含具有H3受体拮抗剂或反相激动剂效应的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合。
本发明还涉及药物组合物，其包含式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合，其将有效治疗和 /或预防与年龄相关的认知功能障碍、学习和精神障碍(例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明还涉及式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合在制备药物中的用途。
本发明还提供式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合在制备药物中的用途，所述药物用于治疗和/或预防与年龄相关的认知功能障碍、学习和精神障碍(例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明还提供治疗和/或预防需要调节组胺H3受体功能的病症的方法，其包括向待治疗的哺乳动物–包括人–施用有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物本身或其药物组合物。
本发明还提供了治疗和/或预防需要调节组胺H3受体功能的病症的方法，所述病症例如与年龄相关的认知功能障碍、学习和精神障碍 (例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的病症(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎，所述方法包括向待治疗受试者施用有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物本身或其药物组合物。
本发明的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物可以通过任何适宜的方法施用，例如口服、胃肠外、口腔、舌下、鼻、直肠或经皮施用。
通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合还可以通过多种途径和剂型施用。所述组合的活性成分可以组合地或单独地配制为药物组合物，且所述组合物可以以单次剂量或多倍剂量施用。通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合同时或相继被施用。
本发明的组合优选地包含作为乙酰胆碱酯酶抑制剂的多奈哌齐、加兰他敏、他克林或雷司替明。
用于口服施用的本发明的药物组合物可以是液体或固体形式，例如糖浆剂、混悬剂或乳剂、片剂、膜片剂、糖锭剂和胶囊剂。
混悬液或液体组合物可以在适合的液体载体，例如水性溶剂例如水、乙醇或甘油中或在非水溶剂例如聚乙二醇或油中包含活性成分。所述制剂还可包含一种或多种助悬剂、防腐剂、矫味剂和着色剂或其组合。
以片剂的固体形式存在的组合物可以使用常规用于制备固体制剂的任何适合的药物载体制备。所述载体的实例包括硬脂酸镁、淀粉、乳糖、蔗糖、纤维素等。
以胶囊的固体形式存在的组合物可以使用常规的胶囊化方法制备。例如使用标准载体制备包含活性成分的球粒，然后将其填充至硬的明胶胶囊；或者使用任何适合的药物载体、例如水性胶、纤维素、硅酸盐或油类制备分散体系或混悬体系，并将得到的分散体系或混悬体系随后填充至软的明胶胶囊中。
用于肠胃外施用的组合物可以以液体或混悬剂形式配制，其除了包含本发明的式(I)的化合物之外，还包含无菌水性载体或胃肠外可接受的油、例如聚乙二醇、聚乙烯吡咯烷、卵磷脂、花生油或芝麻油。或者，可以将得到的溶液冻干，并将冻干物在即将施用前再溶于适合的溶剂中。
用于鼻施用的组合物可以以气雾剂、滴剂、凝胶剂和粉剂的形式配制。用于口腔或舌下施用的本发明的化合物可以以片剂、糖锭剂和软锭剂的形式制备，其中将活性成分与载体、例如糖和阿拉伯胶、黄蓍胶或明胶和甘油等一起配制。
用于直肠施用的组合物可以方便地以包含常用的栓剂成分，例如可可酯的栓剂的形式配制。
用于经皮施用的组合物包括软膏剂、凝胶剂和贴剂。
上述成分和不同的施用途径仅仅是代表性的。本领域熟知的其他材料以及处理技术也可以使用。
在所有类型的组合物的情况中，药学上可接受的本发明的式(I)的化合物–其中R1和R2的含义如上文所述–和/或其几何异构体和/或立体异构体和/或非对映异构体和/或药学上可接受的盐和/或水合物和/ 或溶剂化物可以正常地以每日剂量方案(用于成人患者)每日1至4次地施用，其中每个剂量单位可包含0.05(或优选0.005)至2000mg式(I) 的化合物(以游离碱计算)。本发明的化合物可以适合地在一段连续治疗的时间施用，例如一周或更多。
实施例
通过以下非限制性实施例说明本发明。
通过NMR和质谱测定所有中间体和最终产物的结构。
实施例1
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
在氮气下将4.2g(14.3mmol)4-(4-羟基苯氧基)哌啶-1-甲酸叔丁酯、3.7g(18.7mmol)N-(3-氯丙基)-哌啶和5.9g(42.9mmol)K2CO3于50ml N,N-二甲基甲酰胺中的混合物在50℃搅拌16小时。在冷却至室温后将沉淀的固体物质滤出，用乙腈洗涤，并将滤液在真空下浓缩。将残余物经柱色谱法(使用100g硅胶和作为洗脱剂的乙酸乙酯: 乙醇＝9:1的混合物)纯化，得到3.15g(53％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.40s(9H,H3-18,H3-18’,H3-18”)； 2.31br(4H,H2-2,H2-2’)；3.15t br(2H,Hax-14,Hax-14’)；3.91t(2H, H2-7)4.38tt(1H,H-12)；6.82m(2H,H-9,H-9’)；6.89m(2H,H-10, H-10’)
13CNMR(100MHz,DMSO-d6):28.0(C-18,C-18’,C-18”)；40.9 (C-14,C-14’)；54.3(C-2,C2’)；66.4(C-7)；72.8(C-12)；115.3(C-9,C-9’)； 117.4(C-10,C-10’)
MS:m/z:[M+H]+＝419
实施例2
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
向2.5g(6mmol)4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1甲酸叔丁酯(实施例1)于20ml乙酸乙酯中的搅拌的溶液中加入25ml含 21w/w％氯化氢的乙酸乙酯，保持温度低于10℃。使该混合物放置回温至室温，并在该温度搅拌16小时。将沉淀的结晶滤出，并接连用乙酸乙酯和乙醚洗涤，得到2.16g(92％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):2.80br(2H,Hx-2,Hx-2’)；3.03 ddd(2H,Hx-14,Hx-14’)；3.99t(2H,H2-7)；4.51tt(1H,H-12)；6.88 m(2H,H-9,H-9’)；6.95m(2H,H-10,H-10’)；9.14br(2H,NH2 +-15)； 10.50br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6):40.3(C-14,C-14’)；52.0(C-2, C-2’)；65.5(C-7)；69.8(C-12)；115.5(C-9,C-9’)；117.4(C-10,C-10’)
MS:m/z:M·+＝318
实施例3
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)在20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌20分钟，并滴加0.11ml(1.5 mmol)乙酰氯。将该反应混合物在室温搅拌16小时，然后用20ml8 w/w％NaHCO3水溶液洗涤，将水相用20ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入10ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.33g (83％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):2.01s(3H,H3-17)；3.43d(2H, Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.46tt(1H,H-12)；6.87m(2H,H-9, H-9’)；10.47br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6):21.2(C-17)；52.1(C-2,C-2’)；65.4 (C-7)；72.6(C-12)；115.5(C-9,C-9’)
MS:m/z:M·+＝360
实施例4
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌20min，并逐滴加入0.17ml(1.5 mmol)环丁基甲酰氯(cyclobutyl carboxylic acidchloride)。将该反应混合物在室温搅拌16小时，然后用20ml 8w/w％NaHCO3水溶液洗涤，将水相用20ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入10ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.28g(64％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):1.71m(2H,Hx-4,Hx-19)；3.34m (1H,H-17)；3.43d(2H,Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.45tt(1H, H-12)；6.86m(2H,H-9,H-9’)；10.32br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6):36.4(C-17)；52.0(C-2,C-2’)；65.4 (C-7)；72.6(C-12)；115.4(C-9,C-9’)；171.8(C-16)
MS:m/z:[M+H]+＝401
实施例5
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1- 基)-甲酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于10ml N,N-二甲基甲酰胺中的冰冷却的溶液中加入0.46ml(3.25mmol)三乙胺，将该混合物搅拌10min，然后加入0.48 g(1.25mmol)HBTU和0.13g(1.25mmol)1-甲基-环丙烷-甲酸。将该反应混合物在室温搅拌16小时，然后加入15ml 8w/w％NaHCO3水溶液，将该混合物用3x8ml二氯甲烷萃取，并将合并的有机相用10ml 水洗涤，经Na2SO4干燥，过滤，并浓缩。经柱色谱法使用15g硅胶并使用乙酸乙酯:乙醇＝1:1的混合物作为洗脱剂纯化残余物。将纯化的碱形式的标题化合物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.23g(53％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.53m(2H,Hx-18,Hx-18’)；0.78 m(2H,Hy-18,Hy-18’)；1.22s(3H,H3-19)；1.40m(1H,Hx-4)；2.86br (4H,Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.47tt(1H,H-12)；6.86m(2H, H-9,H-9’)；10.06br(1H,NH+-1)
MS:m/z:[M+H]+＝401
实施例6
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)在20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.14ml(1.5 mmol)氯甲酸乙酯。将该反应混合物在室温搅拌16小时，然后用3x20 ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入4ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.34g(80％) 为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.18t(3H,H3-18)；1.40m(1H, Hax-4)；2.88q br(2H,Hax-2,Hax-2’)；3.99t(2H,H2-7)；4.04q(2H, H2-17)；4.43tt(1H,H-12)；6.87m(2H,H-9,H-9’)；10.04br(1H, NH+-1)
MS:m/z:M·+＝390
实施例7
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.35 ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.12ml (1.5mmol)异氰酸乙酯。将该反应混合物在室温搅拌16小时，然后用 3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩，得到0.28 g(72％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.00t(3H,H3-19)；1.37m(2H, H2-4)；2.31br(4H,H2-2,H2-2’)；3.91t(2H,H2-7)；4.36tt(1H,H-12)；6.47t(1H,NH-17)；6.82m(2H,H-9,H-9’)
MS:m/z:M·+＝389
实施例8
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.35 ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.18g (1.5mmol)甲基乙基异氰酸酯(methyl ethyl isocyanate)。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于15ml乙酸乙酯中，并加入 8ml含21w/w％氯化氢的乙酸乙酯，将该混合物浓缩，并将残余物用乙醚研磨，得到0.34g(77％)为结晶物质的标题化合物。
1HNMR(800MHz,DMSO-d6):1.05t(3H,H3-19)；1.37m(2H, H2-4)；2.72s(3H,H3-17)；2.87q br(2H,Hax-2,Hax-2’)；3.10q(2H, H2-18)；3.98t(2H,H2-7)；4.39tt(1H,H-12)；6.86m(2H,H-9,H-9’)
MS:m/z:M·+＝403
实施例9
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁基酯
将4.3g(14.7mmol)4-(4-羟基苯氧基)哌啶-1-甲酸叔丁酯、3.1g (19.1mmol)(2R)-1-(3-氯丙基)-2-甲基吡咯烷、5.3g(38.2mmol) K2CO3和50ml N,N-二甲基甲酰胺的混合物在氮气下在50℃搅拌16h。将该反应混合物冷却至室温，将沉淀的固体物质过滤，用乙腈洗涤，并将滤液在真空下浓缩。将残余物经柱色谱法使用100g硅胶并使用乙酸乙酯:乙醇＝4:1的混合物作为洗脱剂纯化，得到2.4g(39％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.99d(3H,H3-6)；1.40s(9H, H3-20,H3-20’,H3-20”)；2.24sex(1H,H-5)；3.93t(2H,H2-9)；4.38tt (1H,H-14)；6.83m(2H,H-11,H-11’)
MS:m/z:M·+＝418
实施例10
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
向2.3g(5.5mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯(实施例9)于20ml乙酸乙酯中的搅拌的溶液中加入25ml含21w/w％氯化氢的乙酸乙酯，保持温度低于10℃。将该混合物放置回温至室温，并在该温度搅拌16小时。将沉淀的结晶滤出，并接连用乙酸乙酯和乙醚洗涤，得到1.76g(82％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.36br(3H,H3-6)；1.92m(2H, H2-3)；4.01t(2H,H2-9)；4.51tt(1H,H-14)；6.89m(2H,H-11,H-11’)； 9.12br(2H,NH2 +-17)；10.52br(1H,NH+-1)
MS:m/z:M·+＝318
实施例11
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1- 基]-乙酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌20分钟，并滴加0.11 ml(1.5mmol)乙酰氯。将该反应混合物在室温搅拌16小时，然后用 20ml 8w/w％NaHCO3水溶液洗涤，将水相用3x10ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，用乙酸乙酯和乙醚连续洗涤，得到0.37g(82％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.39d(3H,H3-6)；2.01s(3H, H3-19)；4.01t(2H,H2-9)；4.46tt(1H,H-14)；6.87m(2H,H-11,H-11’)； 10.37br(1H,NH+-1)
MS:m/z:[M+H]+＝361
实施例12
环丁基-[4-(4-{3-[(2R)-2-甲基吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-基]-甲酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌20分钟，并逐滴加入0.17ml(1.5mmol)环丁基甲酰氯。将该反应混合物在室温搅拌16h，然后用20ml 8w/w％NaHCO3水溶液洗涤，将水相用3x10ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.17g(39％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.36br(3H,H3-6)；1.73m(1H, Hx-21)；2.09m(2H,Hx-20,Hx-20’)；4.00t(2H,H2-9)；4.45tt(1H,H-14)； 6.87m(2H,H-11,H-11’)；10.06br(1H,NH+-1)
MS:m/z:M·+＝400
实施例13
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在10ml N,N-二甲基甲酰胺中的冰冷却的溶液中加入0.46ml(3.25mmol)三乙胺，将该混合物搅拌10分钟，然后加入0.48g(1.25mmol)HBTU和0.13g(1.25mmol)1-甲基-环丙烷-甲酸。将该反应混合物在室温搅拌16小时，然后加入20ml 8w/w％ NaHCO3水溶液，将该混合物用3x10ml二氯甲烷萃取，并将合并的有机相用10ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将残余物经柱色谱法(使用15g硅胶并用乙酸乙酯:乙醇＝1:1的混合物作为洗脱剂)纯化。将纯化的碱形式的标题化合物溶于10ml乙酸乙酯中，
并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.15g(34％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.53m(2H,Hx-20,Hx-20’)；0.79 m(2H,Hy-20,Hy-20’)；1.22s(3H,H3-21)；1.37br(3H,H3-6)；4.00t(2H, H2-9)；4.47tt(1H,H-14)；6.88m(2H,H-11,H-11’)；10.43br(1H, NH+-1)
MS:m/z:M·+＝400
实施例14
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.14ml(1.5mmol)氯甲酸乙酯。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入4ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.32g(75％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.18t(3H,H3-20)；1.38d(3H, H3-6)；4.01m(2H,H2-9)；4.04q(2H,H2-19)；4.43tt(1H,H-14)；6.88 m(2H,H-11,H-11’)；9.98br/10.43br(1H,NH+-1)
MS:m/z:M·+＝390
实施例15
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-甲酰胺
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)于20ml二氯甲烷中的冰冷却的溶液中加入0.35ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.12ml(1.5mmol)异氰酸乙酯。将该反应混合物在室温搅拌16 小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将残余物用乙醚研磨，得到0.27g(69％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.99d(3H,H3-6)；1.00t(3H, H3-21)；2.23sex(1H,H-5)；3.03m(2H,H2-20)；3.93t(2H,H2-9)；4.36 tt(1H,H-14)；6.46t(1H,NH-19)；6.83m(2H,H-11,H-11’)
MS:m/z:M·+＝389
实施例16
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)于20ml二氯甲烷中的冰冷却的溶液中加入0.35ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.18ml(1.5mmol)甲基乙基异氰酸酯。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，加入4ml含21w/w％氯化氢的乙酸乙酯，将该混合物浓缩，并将残余物用乙醚研磨，得到 0.28g(64％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.06t(3H,H3-21)；1.37d(3H, H3-6)；2.73s(3H,H3-22)；4.01t(2H,H2-9)；3.11q(2H,H2-20)；4.39 tt(1H,H-14)；6.88m(2H,H-11,H-11’)；9.60br(1H,NH+-1)
MS:m/z:M·+＝403
实施例17
组胺H3拮抗剂的评估
可以根据以下程序测定本发明的化合物对大鼠组胺H3受体的体外亲和力。
膜制备
如Witte等人(British Journal of Pharmacol.1-14,2006)之前的记载来制备大鼠组胺H3受体膜。将雄性Sprague-Dawley大鼠断头，将它们的脑取出，并分离皮层。通过搅拌匀浆器(Ultra-Turrax)将得到的组织在Tris-EDTA缓冲液(50mM Tris-HCl，pH 7.4，5mMEDTA， 2μg/ml抑酶肽，1mM苄脒,2μg/ml亮抑蛋白酶肽,1μg/ml胃蛋白酶抑制剂)中匀化。将该匀浆在4℃以40000g离心20min。通过重复上述匀化和离心步骤将膜球粒进一步纯化。通过将该球粒以1:10的比例在Tris-EDTA缓冲液(50mM Tris-HCl，pH 7.4，5mM EDTA)中再次匀化得到最终的膜制剂。将由此得到的膜制剂分成等分试样，速冻，并在-80℃存储直至使用。通过罗氏蛋白质定量法使用牛血清白蛋白 (BSA)做为标准品测定蛋白质含量。
体外结合测定
在至少两个独立的实验中，使用结合缓冲液(50mM Tris-HCl、pH 7.4、5mMMgCl2)、大鼠H3膜(140μg蛋白质/管)和作为放射性配体的N-α-[甲基-3H]甲基组胺二盐酸盐(1nM)在至少5种浓度进行受体结合测定，每种浓度两个平行的样品。在10μM噻普酰胺的存在下测定非特异性结合。在25℃将样品以0.50ml的最终体积温育30分钟。通过在0.5％聚乙烯亚胺(PEI)中预浸渍至少2小时的 GF/BTM玻璃纤维过滤器快速过滤来终止结合反应。将滤板用0.5ml 冰冷的洗涤缓冲液(50mM Tris-HCl，pH 7.4，5mM MgCl2，10μg/ml 皂苷(saponine))洗涤9次。将滤板在50℃干燥45分钟，并将40μl Microscint20(Packard)闪烁混合物加入各孔中。通过TopCount (Packard)闪烁计数器测定过滤器放射性。
数据分析
在至少两个平行实验中测定本发明的化合物的配体替代。将特异性放射性配体结合定义为总的结合与非特异性的结合之间的差异，所述结合在过量的未标记配体或用于特异性替代放射性配体的测试化合物的存在下测定。结果表示为在测试化合物的存在下得到的特异性结合的抑制百分比。从浓度-替代曲线通过S型曲线拟合(使用GraphPad Prism软件4.0)计算IC50值。使用Cheng-Prusoff等式(Cheng YC和 Prusoff WH(1973)BiochemPharmacol 22:3099-3108)计算抑制常数 (Ki值)。
Ki值
通过下表说明本发明的化合物在大鼠H3受体的亲和力。
其中符号的含义为
++Ki<10nM
+Ki<10-50nM
实施例18a-f
药物组合物的制备
a)片剂
将0.01-50w/w％式(I)的活性成分、15-50w/w％乳糖、15-50w/w％土豆淀粉、5-15w/w％聚乙烯吡咯烷酮、1-5w/w％滑石粉、0.01-3w/w％硬脂酸镁、1-3w/w％胶态二氧化硅和2-7w/w％超支链淀粉 (ultraamylopectin)混合，然后通过湿制粒法造粒，并压缩为片剂。
b)糖锭剂、膜包衣片剂
将根据上述方法制备的片剂通过由肠-或胃溶解膜(entero-or gastrosolventfilm)组成的层或由糖和滑石粉组成的层进行包衣。将糖锭剂通过蜂蜡和巴西棕榈蜡的混合物抛光。
c)胶囊
将0.01-50w/w％式(I)的活性成分、1-5w/w％十二烷基硫酸钠、 15-50w/w％淀粉、15-50w/w％乳糖、1-3w/w％胶态二氧化硅和0.01-3 w/w％硬脂酸镁彻底混合，将该混合物过筛，并填充至硬明胶胶囊中。
d)混悬剂
成分:0.01-15w/w％式(I)的活性成分、0.1-2w/w％氢氧化钠、0.1-3 w/w％柠檬酸、0.05-0.2w/w％尼泊金(4-羟基苯甲酸甲酯钠)、0.005-0.02 w/w％对羟苯甲酸丙酯、0.01-0.5w/w％聚羧乙烯(聚丙烯酸)、0.1-5w/w％的96％乙醇、0.1-1w/w％矫味剂、20-70w/w％山梨醇(70％水溶液)和 30-50w/w％蒸馏水。
在剧烈搅拌下向尼泊金和柠檬酸在20ml蒸馏水中的溶液少量多次地加入聚羧乙烯，并将该溶液放置10-12小时。然后在搅拌下加入于1ml蒸馏水中的氢氧化钠和山梨醇的水溶液，最后加入乙醇覆盆子香料(ethanolic raspberry flavor)。向该载体中少量多次地加入活性成分，并用沉浸式匀浆器混悬。最后用蒸馏水将该混悬液填充至所需的最后体积，将该混悬糖浆剂通过胶体磨设备。
e)栓剂
对各栓剂将0.01-15w/w％式(I)的活性成分和1-20w/w％乳糖彻底混合，然后将50-95w/w％豚脂前栓剂(pro suppository)(例如 Witepsol 4)熔化，冷却至35℃，并用匀浆器将活性成分和乳糖的混合物混合在其中。将得到混合物以冷却形式成型。
f)冻干粉末安瓿瓶组合物
用注射用重蒸馏水制备5％甘露醇或乳糖溶液，并将该溶液过滤以得到灭菌溶液。还用注射用重蒸馏水制备0.01-5％式(I)的活性成分的溶液，并将该溶液过滤以得到灭菌溶液。将这两个溶液在无菌状态下混合，以每份1ml将其填充入安瓿瓶中，将安瓿瓶内的物质冻干，并将安瓿瓶在氮气下密封。在施用前将安瓿瓶内的物质溶于无菌水或 0.9％(生理学)无菌氯化钠水溶液中。
本发明不限于本文公开的特定实施方案的范围，因为这些实施方式旨在说明本发明的若干方面。任何等同的实施方式旨在包括在本发明的范围内。事实上，除本文所示和所述的那些之外，本发明的各种修饰对于本领域技术人员将是显而易见的。所述修饰也旨在落入本发明的范围内。
实施例19
同时施用的组胺H3拮抗剂和乙酰胆碱酯酶抑制剂的评估
额叶前皮质和海马这两个脑区域在认知过程中起重要作用。组胺 (HA)和乙酰胆碱(ACh)均是在认知中起重要作用的递质。中枢胆碱能系统和组胺能系统的功能减退被认为是以痴呆为特征的认知缺陷的致病原因之一。通过大脑微透析技术在有意识的、自由移动的雄性 Wistar大鼠(4-6只动物/组)的额叶前皮质和海马中使用组胺H3拮抗剂和乙酰胆碱酯酶抑制剂(AChEIs)单独和同时治疗后研究HA和ACh 的细胞外水平的变化。
将微透析探针植入中间的额叶前皮质(MPFC)和海马(HC)，并用人工的无AChEI的脑脊髓液(aCSF)灌注。
通过手术植入的导管将本研究中检验的化合物在1％羟基丙基-甲基纤维素(HPMC)和5％聚氧乙烯(8)-脱水山梨醇-单油酸酯(Tween 80) 中施用于胃中。
收集30-分钟的样品，并通过高灵敏度和选择性的与质谱/质谱联用的液相色谱(LC-MS/MS)分析方法追踪细胞外ACh和组胺HA的暂时变化。
以相对于基态水平(药物治疗前得到的)的百分比变化表达神经递质水平，且效果以基线曲线上面积(AOBC)给出。
通过ANOVA/post hoc邓肯检验进行结果的统计评估。
结果
使用H3拮抗剂的治疗在MPFC和HC中均导致细胞外HA水平明确增加，然而它们仅产生中等增强的ACh释放。另一方面，AChE 抑制剂治疗后证实两个区域中的细胞外ACh水平均明确增加。该结果与公布的使用AChEI的数据吻合良好(Cerbai等,Eur.J.Pharmacol.(2007)572:142-150；Scali等,J Neural Transm.(2002) 109(7-8):1067-80；Kosasa等,Jpn.J.Pharmacol.(1999)81:216-222)。
0.5和1mg/kg的剂量的化合物11的单独治疗在两个区域中均产生细胞外HA水迅速和明确的增加(图1.)。无论哪种剂量施用后均没有观测到ACh水平的显著变化。(图2.)
然而，令人惊讶地，H3拮抗剂显著增强AChEIs诱导的ACh上升，而同时保留它们对HA水平的正面作用。在额叶前皮质和海马中均发现该现象。
例如，在同时施用多奈哌齐、原型AChEI和化合物11后在两个区域中均观测到明确的和超相加的应答。0.5mg/kg多奈哌齐和0.5 mg/kg化合物11或1mg/kg化合物11的同时施用在MPFC和HC中均产生细胞外ACh的超相加的增加。该加强作用在0.5mg/kg的化合物11剂量更明确(图2)，然而由化合物11引起的HA释放不会由于多奈哌齐而改变(数据未显示)。
因为两种化合物之间不存在药物动力学相互作用(即在单独或同时施用后多奈哌齐和化合物11的血浆和脑水平不变化)，所以观测到的ACh水平的增强是意料之外的，且属于AChE抑制和H3受体拮抗的有益的药效重合。
这些结果显示具有组胺H3拮抗作用的化合物可具有有益的和有效的认知改善作用，且其单独(显著的HA增加和微小的ACh增加)或与AChEIs组合作为“添加”疗法(超相加的ACh增加和显著的HA 应答)，代表对于不同起因的痴呆的一种治疗选择。
Claims (48)
1.通式(I)的化合物
和/或其盐
其中
R1和R2与相邻的碱性氮原子一起形成被取代的5-元的杂环基团，且所述杂环基团任选地被一个或两个C1-C6烷基基团取代；
R3表示:
-C(＝O)R4、-C(＝O)-OR4、-C(＝O)-NR4R5基团，
其中R4和R5彼此独立地表示氢原子、C1-C6直链或支链的烷基基团或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
2.根据权利要求1的通式(I)的化合物，其中R1和R2与相邻的氮原子一起形成2-甲基-吡咯烷环。
3.根据权利要求1的通式(I)的化合物，其中R1和R2与相邻的氮原子一起形成2-(R)-甲基-吡咯烷环。
4.根据权利要求1-3中任意一项的通式(I)的化合物，其中R3的含义是–C(＝O)R4，其中R4的含义为C1-C6直链或支链的烷基基团，或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
5.化合物，其选自：
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-乙酮盐酸盐
环丁基-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐。
6.药物组合物，其包含治疗有效量的作为活性成分的权利要求1-5中任意一项所要求保护的化合物和/或盐及一种或多种药学上可接受的辅料。
7.根据权利要求6的药物组合物在制备用于治疗和/或预防需要调节组胺H3功能的病症的药物中的用途。
8.根据权利要求7的用途，其特征在于包含化合物，其具有组胺H3受体拮抗剂或反相激动剂效应。
9.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防与神经变性疾病有关的认知功能障碍、或年龄相关的学习和精神障碍、或由于一般医学病症导致的其它的认知障碍、精神障碍、睡眠障碍、进食障碍、肥胖、与肥胖相关的代谢紊乱、头晕、癫痫、焦虑症、心境障碍、中枢神经系统失调、变态反应、充血、低血压、炎性痛、酒精滥用、肠易激综合征和骨关节炎。
10.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防心血管疾病。
11.根据权利要求9的用途，其特征在于神经变性疾病为阿尔茨海默病或皮克病。
12.根据权利要求9的用途，其特征在于由于一般医学病症导致的其它的认知障碍为注意缺陷多动症或亨廷顿病。
13.根据权利要求9的用途，其特征在于精神障碍为情感性分裂症或精神分裂症。
14.根据权利要求9的用途，其特征在于睡眠障碍为发作性睡病、睡眠过度或白天睡眠过多。
15.根据权利要求9的用途，其特征在于与肥胖相关的代谢紊乱为高脂血症或糖尿病。
16.根据权利要求9的用途，其特征在于焦虑症为泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍。
17.根据权利要求9的用途，其特征在于心境障碍为情感低落或带有情感低落和焦虑的适应障碍。
18.根据权利要求9的用途，其特征在于中枢神经系统失调为激动或抑郁。
19.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防精神分裂症。
20.根据权利要求9的用途，其特征在于充血为鼻充血。
21.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防神经病性疼痛。
22.权利要求1-5中任意一项所要求保护的化合物和/或其盐在制备用于治疗和/或预防需要调节组胺H3功能的病症的药物组合物中的用途。
23.根据权利要求22的用途，其特征在于制备的药物组合物包含具有组胺H3受体拮抗剂或反相激动剂效应的化合物。
24.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防与神经变性疾病有关的认知功能障碍、或年龄相关的学习和精神障碍、或由于一般医学病症导致的其它的认知障碍、精神障碍、睡眠障碍、进食障碍、肥胖、与肥胖相关的代谢紊乱、头晕、癫痫、焦虑症、心境障碍、中枢神经系统失调、变态反应、充血、低血压、炎性痛、酒精滥用、肠易激综合征和骨关节炎。
25.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防心血管疾病。
26.根据权利要求24的用途，其特征在于神经变性疾病为阿尔茨海默病或皮克病。
27.根据权利要求24的用途，其特征在于由于一般医学病症导致的其它的认知障碍为注意缺陷多动症或亨廷顿病。
28.根据权利要求24的用途，其特征在于精神障碍为情感性分裂症或精神分裂症。
29.根据权利要求24的用途，其特征在于睡眠障碍为发作性睡病、睡眠过度或白天睡眠过多。
30.根据权利要求24的用途，其特征在于与肥胖相关的代谢紊乱为高脂血症或糖尿病。
31.根据权利要求24的用途，其特征在于焦虑症为泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍。
32.根据权利要求24的用途，其特征在于心境障碍为情感低落或带有情感低落和焦虑的适应障碍。
33.根据权利要求24的用途，其特征在于中枢神经系统失调为激动或抑郁。
34.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防精神分裂症。
35.根据权利要求24的用途，其特征在于充血为鼻充血。
36.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防神经病性疼痛。
37.根据权利要求1的通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合。
38.根据权利要求37的组合，其中通式(I)的化合物为权利要求2中所定义。
39.根据权利要求37的组合，其中通式(I)的化合物为权利要求3中所定义。
40.根据权利要求37-39中任意一项的组合，其中通式(I)的化合物为权利要求4中所定义。
41.根据权利要求37-39中任意一项的组合，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
42.根据权利要求40的组合，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
43.根据权利要求37-42中任意一项的组合用于制备药物组合物的用途。
44.药物组合物，其包含权利要求1中所要求保护的通式(I)的化合物和乙酰胆碱酯酶抑制剂及一种或多种药学上可接受的辅料。
45.根据权利要求44的药物组合物，其特征在于包含权利要求2-4中任意一项中所定义的通式(I)的化合物。
46.根据权利要求44-45中任意一项的药物组合物，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
47.权利要求37-42中任意一项所要求保护的组合在制备用于治疗和/或预防需要调节组胺H3受体和胆碱能系统的病症的药物中的用途。
48.权利要求44-46中任意一项的药物组合物在制备用于治疗和/或预防需要调节组胺H3受体和胆碱能系统的病症的药物中的用途。
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| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
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| CN1972914A (zh) * | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | 作为组胺h3受体配合体的非咪唑杂环化合物 |
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- 2014-03-06 US US14/770,111 patent/US9994525B2/en active Active
- 2014-03-06 TW TW103107713A patent/TW201522311A/zh unknown
- 2014-03-06 JP JP2015560835A patent/JP6584960B2/ja active Active
- 2014-03-06 DK DK14712780.7T patent/DK2964613T3/en active
- 2014-03-06 WO PCT/IB2014/059489 patent/WO2014136075A1/en active Application Filing
- 2014-03-06 ES ES14712780.7T patent/ES2688055T3/es active Active
- 2014-03-06 HU HUE14712780A patent/HUE039801T2/hu unknown
- 2014-03-06 PL PL14712780T patent/PL2964613T3/pl unknown
-
2018
- 2018-09-12 CY CY181100943T patent/CY1120680T1/el unknown
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
| CN1468227A (zh) * | 2000-08-08 | 2004-01-14 | ����-������ҩƷ��˾ | 非咪唑芳氧基烷基胺 |
| CN1972914A (zh) * | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | 作为组胺h3受体配合体的非咪唑杂环化合物 |
Non-Patent Citations (2)
| Title |
|---|
| 4-Phenoxypiperidines: Potent, Conformationally Restricted, Non-Imidazole Histamine H3 Antagonists;Curt A. Dvorak，等;《J. Med. Chem》;20050205;第48卷;第2230页Scheme1 * |
| A New Class of Diamine-Based Human Histamine H3 Receptor Antagonists: 4-(Aminoalkoxy)benzylamines;Richard Apodaca，等;《J. Med. Chem》;20030723;第46卷;第3939页Scheme2-3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP1300139A2 (en) | 2014-09-29 |
| AR095040A1 (es) | 2015-09-16 |
| PT2964613T (pt) | 2018-11-08 |
| CY1120680T1 (el) | 2019-12-11 |
| SI2964613T1 (sl) | 2018-10-30 |
| US9994525B2 (en) | 2018-06-12 |
| JP2016510067A (ja) | 2016-04-04 |
| CN105452222A (zh) | 2016-03-30 |
| US20160009645A1 (en) | 2016-01-14 |
| EA201591645A1 (ru) | 2015-12-30 |
| RS57627B1 (sr) | 2018-11-30 |
| WO2014136075A1 (en) | 2014-09-12 |
| LT2964613T (lt) | 2018-10-25 |
| PL2964613T3 (pl) | 2018-12-31 |
| EP2964613A1 (en) | 2016-01-13 |
| EA029311B1 (ru) | 2018-03-30 |
| TW201522311A (zh) | 2015-06-16 |
| DK2964613T3 (en) | 2018-11-12 |
| ES2688055T3 (es) | 2018-10-30 |
| HRP20181560T1 (hr) | 2018-12-28 |
| HUE039801T2 (hu) | 2019-02-28 |
| JP6584960B2 (ja) | 2019-10-02 |
| EP2964613B1 (en) | 2018-07-18 |
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