CN108290887A - 用于治疗睡眠相关的呼吸病症的作为task-1和task-2通道阻断剂的2-苯基-3-(哌嗪子基甲基)咪唑并[1,2-a]吡啶衍生物 - Google Patents
用于治疗睡眠相关的呼吸病症的作为task-1和task-2通道阻断剂的2-苯基-3-(哌嗪子基甲基)咪唑并[1,2-a]吡啶衍生物 Download PDFInfo
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- CN108290887A CN108290887A CN201680072084.7A CN201680072084A CN108290887A CN 108290887 A CN108290887 A CN 108290887A CN 201680072084 A CN201680072084 A CN 201680072084A CN 108290887 A CN108290887 A CN 108290887A
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Abstract
本申请公开了作为TASK‑1和TASK‑3通道的选择性阻断剂的2‑苯基‑3‑(哌嗪子基甲基)咪唑并[1,2‑a]吡啶衍生物,其用于治疗和/或预防呼吸病症,包括睡眠相关的呼吸病症诸如阻塞性和中枢性睡眠呼吸暂停和打鼾。
Description
本申请涉及新型的2-苯基-3-(哌嗪子基(piperazino)甲基)咪唑并[1,2-a]吡啶衍生物、其制备方法、其单独或组合地用于治疗和/或预防疾病的用途,和其用于制备用于治疗和/或预防疾病,特别是用于治疗和/或预防呼吸病症,包括睡眠相关的呼吸病症诸如阻塞性和中枢性睡眠呼吸暂停和打鼾的药物的用途。
钾通道是参与大量不同生理过程的几乎普遍存在的膜蛋白。其也包括神经元和肌肉细胞的膜电位和电兴奋性的调节。钾通道分为三种主要群组,其区别在于跨膜结构域的数目(2、4或6)。其中两个孔形成结构域被四个跨膜结构域侧接(flankiert)的钾通道的群组被称为K2P通道。功能上,K2P通道基本上独立于时间和电压地介导K+背景电流,并且对于维持静息膜电位的贡献至关主要。K2P通道家族包括15个成员,其基于序列、结构和功能的相似性被分成6个亚家族: TWIK、TREK、TASK、TALK、THIK和TRESK。
特别感兴趣的是TASK (TWIK-相关的酸敏感性K+通道)亚家族的TASK-1 (KCNK3或K2P3.1)和TASK-3 (KCNK9或K2P9.1)。功能上,这些通道的特征在于,在维持电压非依赖性动力学期间,“泄露”或“背景”电流流经它们,其中它们通过增加或降低其活性而响应于多种生理和病理影响。TASK通道的特征是对细胞外pH值的变化的敏感反应:在酸性pH值下,通道被抑制,而在碱性pH值下,它们被活化。
TASK-1主要在中枢神经系统和心血管系统中表达。TASK-1的相关表达可以在大脑、脊髓神经节、舌下神经和三叉神经的运动神经元、心脏、颈动脉球、肺动脉、主动脉、肺、胰腺、胎盘、子宫、肾、肾上腺、小肠和胃以及在T淋巴细胞上得到证实。TASK-3主要在中枢神经系统中表达。TASK-3的相关表达可以在大脑、舌下神经和三叉神经的运动神经元和颈动脉球的神经上皮细胞和肺以及在T淋巴细胞上得到证实。在心脏、胃、睾丸组织和肾上腺中发现较少的表达。
TASK-1和TASK-3通道在呼吸调节中发挥作用。这两种通道在脑干的呼吸中枢的呼吸神经元中表达,尤其是在产生呼吸节律的神经元(具有Bötzinger前复合物的腹呼吸群)和去甲肾上腺素能蓝斑以及中缝核的血清素能神经元中。由于pH依赖性,在此该TASK通道具有感受器的功能,其将细胞外的pH值变化转化成相应的细胞信号[Bayliss 等人,Pflugers Arch. 467, 917-929 (2015)]。TASK-1和TASK-3也在颈动脉球中表达,所述颈动脉球是一种外周化学感受器,其测量血液的pH、O2和CO2含量并将信号传递给脑干中的呼吸中枢以调节呼吸。已显示TASK-1基因敲除小鼠对缺氧和常氧性高碳酸血症具有减少的通气反应(呼吸频率和呼吸容量增加)[Trapp 等人, J. Neurosci. 28, 8844-8850 (2008)]。此外,已证实在舌下神经(第12颅神经)的运动神经元中,TASK-1和TASK-3通道具有保持上呼吸道开放的重要作用[Berg 等人, J. Neurosci. 24, 6693-6702 (2004)]。
在被麻醉的猪中的睡眠呼吸暂停模型中,鼻内施用在纳摩尔范围内阻断TASK-1通道的钾通道阻断剂导致咽部呼吸肌群的缩陷性(Kollapsibilität)的抑制和上呼吸道负压反射的敏化。推测鼻内施用钾通道阻断剂使上呼吸道中的机械感受器去极化,并且通过负压反射的活化而导致上呼吸道肌群的活性增加,由此稳定上呼吸道并防止缩陷。由于上呼吸道的这种稳定作用,TASK通道阻断对于阻塞性睡眠呼吸暂停以及对于打鼾可能是非常重要的[Wirth 等人, Sleep 36, 699-708 (2013); Kiper 等人, Pflugers Arch. 467,1081-1090 (2015)]。
阻塞性睡眠呼吸暂停(OSA)是一种睡眠相关的呼吸病症,其特征在于上呼吸道阻塞的反复发作。当吸入时,通过两种相反力的一起作用确保上呼吸道的通畅。上呼吸道肌群的扩张作用抵消使管腔收缩的负腔内压力。横隔膜和其它辅助性呼吸肌肉的主动收缩在呼吸道中产生负压,由此构成呼吸的驱动力。上呼吸道的稳定性决定性地由上呼吸道的扩张肌肉的协调和收缩性质决定。
颏舌肌在阻塞性睡眠呼吸暂停的发病机制中发挥决定性作用。在扩张性补偿机制的意义上,颏舌肌的活性随着咽部压力的减小而增加。由舌下神经支配,它驱使舌头向前和向下,由此拓宽咽部气道[Verse 等人, Somnologie 3, 14-20 (1999)]。上呼吸道的扩张肌肉的张力尤其通过鼻/咽部的机械感受器/牵张受体来调节[Bouillette 等人, J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]。在睡眠中具有严重睡眠呼吸暂停的患者中,通过上气道的局部麻醉,可以观察到颏舌肌的活性的额外降低[Berry 等人, Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]。患有阻塞性睡眠呼吸暂停的患者由于心血管病症诸如高血压、心肌梗死和中风具有高死亡率和发病率[Vrints 等人, Acta Clin. Belg. 68, 169-178 (2013)]。
在中枢性睡眠呼吸暂停的情况下,由于脑功能受损和呼吸调节受损的缘故,存在呼吸驱动的间断性抑制。中枢性呼吸病症导致机械性呼吸停止,即在这些发作期间,没有呼吸活动;包括横隔膜在内的所有呼吸肌肉都暂时地静止。在中枢性睡眠呼吸暂停的情况下,没有上呼吸道的阻塞。
在原发性打鼾的情况下,同样没有上呼吸道的阻塞。然而,由于上呼吸道的收缩的缘故,被吸入和呼出的空气的流速增加了。这与松弛的肌群组合在一起导致口腔和咽部的软组织在空气流中扑动。这种轻微的震动产生了典型的打鼾噪声。
阻塞性打鼾(上气道阻力综合征、重度打鼾、呼吸功能不全综合征)是由睡眠期间上呼吸道的反复部分阻塞导致的。这导致呼吸道阻力增加,由此增加呼吸功,伴随相当大的胸内压力波动。在吸气期间,胸内负压发展可以达到如同由于阻塞性睡眠呼吸暂停期间的完全呼吸道阻塞而出现的值。对心脏、循环和睡眠质量的病理生理学影响相当于阻塞性睡眠呼吸暂停中的那些。发病机制如在阻塞性睡眠呼吸暂停中那样被推测为睡眠时的吸气期间咽部扩张肌肉的反射机制受损。通常,阻塞性打鼾是阻塞性睡眠呼吸暂停的初始阶段[Hollandt 等人, HNO 48, 628-634 (2000)]。
此外,TASK通道也似乎在神经元的细胞凋亡中发挥作用。在髓鞘少突胶质细胞糖蛋白(MOG)诱导的自身免疫性脑脊髓炎的动物模型(一种多发性硬化的动物模型)中,TASK-1基因敲除小鼠显示减少的神经元变性。通过预防神经元凋亡,TASK通道的抑制似乎起保护神经的作用,并且因此可能有益于治疗神经变性病症[Bittner 等人, Brain 132, 2501-2516 (2009)]。
此外已经描述了,T淋巴细胞表达TASK-1和TASK-3通道,并且这些通道的抑制导致T淋巴细胞刺激后的减少的细胞因子产生和增殖。TASK通道对T淋巴细胞的选择性抑制改善了多发性硬化动物模型中的疾病进程。因此,TASK通道的阻断对于自身免疫性病症的治疗也可能是重要的[Meuth 等人, J. Biol. Chem. 283, 14559-14579 (2008)]。
TASK-1和TASK-3也在心脏中表达[Rinné 等人, J. Mol. Cell. Cardiol. 81,71-80 (2015)]。由于TASK-1在神经刺激传导系统和心房中的特别大量地表达,该通道可能在触发刺激传导紊乱或室上心律不齐中起作用。在心脏中,TASK-1似乎有助于背景电流,其本身有助于静息电位维持、动作电位持续时间和复极化[Kim 等人, Am. J. Physiol. 277, H1669-1678 (1999)]。在人心肌细胞上显示了,TASK-1离子电流的阻断导致动作电位延长[Limberg 等人, Cell. Physiol. Biochem. 28, 613-624 (2011)]。再者,对于TASK-1基因敲除小鼠而言证实了延长的QT时间[Decher 等人, Cell. Physiol. Biochem. 28,77-86 (2011)]。TASK通道的抑制因此对于心律不齐,特别是心房颤动的治疗而言可能是重要的。
在某些血管中,TASK通道也似乎在血管紧张性的调节中发挥作用。在肺和肠系膜动脉的平滑肌中可以发现TASK-1的相关表达。在人肺动脉的平滑肌细胞的研究中显示了TASK-1在肺血管紧张性的调节中发挥作用。TASK-1可能参与缺氧和酸中毒诱导的肺血管收缩[Tang 等人, Am. J. Respir. Cell. Mol. Biol. 41, 476-483 (2009)]。
在肾上腺皮质的肾小球细胞中,TASK-1在钾传导性中发挥作用[Czirjak 等人,Mol. Endocrinol. 14, 863-874 (2000)]。
有可能地,TASK通道也在凋亡和肿瘤发生中发挥重要作用。在乳腺癌、结肠癌和肺癌活组织检查以及在转移的前列腺癌和在黑色素瘤细胞中已经发现,TASK-3大量过度表达[Mu 等人, Cancer Cell 3, 297-302 (2003); Kim 等人, APMIS 112, 588-594 (2004);Pocsai 等人, Cell. Mol. Life Sci. 63, 2364-2376 (2006)]。在TASK-3通道的点突变——其关闭通道功能——同时取消肿瘤形成作用(增殖、肿瘤生长、凋亡抗性) [Mu 等 人, Cancer Cell 3, 297-302 (2003)]。TASK-3和TASK-1在鼠类成纤维细胞系(C8细胞)中的过度表达抑制细胞内的凋亡途径[Liu 等人, Brain Res. 1031, 164-173 (2005)]。因此,TASK通道的阻断对于各种癌症疾病的治疗而言也可能是重要的。
因此,本发明的目的是提供作为TASK-1和TASK-3通道的强效和选择性阻断剂并且本身特别适合于治疗和/或预防呼吸病症,包括睡眠相关的呼吸病症诸如阻塞性和中枢性睡眠呼吸暂停和打鼾以及其它病症的新型物质。
US 2002/0022624-A1描述了各种氮杂吲哚衍生物,其中包括用于治疗CNS病症的作为P物质拮抗剂的咪唑并[1,2-a]吡啶。WO 2004/035578-A1公开了可用于治疗各种病症的已知作为NO合酶抑制剂的3-(氨基甲基)咪唑并[1,2-a]吡啶衍生物。WO 2009/143156-A2要求保护作为GABAA受体调节剂的2-苯基咪唑并[1,2-a]吡啶衍生物,其同样适用于治疗CNS病症。WO 2011/113606-A1和WO 2012/143796-A2公开了适用于治疗细菌感染或炎性病症的二环咪唑衍生物。EP 2 671 582-A1公开了二环咪唑衍生物和其作为T型钙通道抑制剂的治疗用途可能性。WO 2012/130322-A1描述了2,6-二芳基-3-(哌嗪子基甲基)咪唑并[1,2-a]吡啶衍生物,其由于其HIF-1抑制活性而特别适用于治疗炎性和过度增殖性病症。WO2014/187922-A1公开了作为葡萄糖转运体(GLUT)的抑制剂的各种2-苯基-3-(哌嗪子基甲基)咪唑并[1,2-a]吡啶衍生物,其可以用于治疗炎性、增殖性、代谢性、神经性和/或自身免疫性病症。
此外,化学文摘(Chemical Abstracts)的多种{4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮衍生物被索引编入作为"化学药品库(Chemical Library)”物质而无参考文献,特别是化合物
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环丙基)甲酮 [CAS 登记号1327935-11-4],
(3-氯苯基){4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮 [CAS登记 号1300380-37-3],
(4-乙基苯基){4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮 [CAS登 记号1296556-17-6],
苯基{4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮 [CAS登记号 1062372-04-6]
和
环丙基{4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮 [CAS登记号 950099-20-4]。
迄今为止尚未具体描述所提及的化合物的医学治疗应用。
下文列出的其它(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-哌嗪-1-基)甲酮衍生物同样被化学文摘以各自给定的录入日期(ED)索引编入作为“化学药品库”物质而没有给出参考文献:
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-甲氧基苯基)-甲酮 [CAS登记号1899197-66-0, ED 2016年4月28日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环己基) 甲酮 [CAS 登记号1899359-25-1, ED 2016年4月28日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(四氢呋喃-2-基)-甲酮 [CAS登记号1899359-35-3, ED 2016年4月28日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-甲基苯基)-甲酮[CAS登记号1906559-37-2, ED 2016年5月9日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(3-甲氧基苯基)-甲酮 [CAS登记号1906734-00-6, ED 2016年5月9日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(3-氟苯基)甲酮[CAS登记号1906738-71-3, ED 2016年5月9日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(3-甲基苯基)-甲酮[CAS登记号1907498-96-7, ED 2016年5月10日],
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环丁基)甲酮 [CAS 登记号1907503-77-8, ED 2016年5月10日],
和
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮[CAS登记号1907618-99-8, ED 2016年5月10日]。
同样尚未具体描述这些化合物的医学治疗应用。
本发明提供了通式(I)的化合物及其盐、溶剂合物和盐的溶剂合物
其中
R1代表卤素、氰基、(C1-C4)-烷基、环丙基或环丁基
和
R2代表(C4-C6)-环烷基,其中环-CH2-基团可以被-O-代替
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、溴、氰基、(C1-C3)-烷基或(C1-C3)-烷氧基,
其中(C1-C3)-烷基和(C1-C3)-烷氧基可以被氟取代至多三次,
R4代表氢、氟、氯、溴或甲基,
R5代表氢、氟、氯、溴或甲基
和
R6代表氢、(C1-C3)-烷氧基、环丁基氧基、氧杂环丁烷-3-基氧基、四氢呋喃-3-基氧基或四氢-2H-吡喃-4-基氧基,
其中(C1-C3)-烷氧基可以被氟取代至多三次。
本发明的化合物为式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,式(I)所涵盖的下面提及的式的化合物及其盐、溶剂合物和盐的溶剂合物,以及式(I)所涵盖的下面作为实施例所提及的化合物及其盐、溶剂合物和盐的溶剂合物(如果式(I)所涵盖的下面提及的化合物尚未为盐、溶剂合物和盐的溶剂合物的话)。
在本发明的上下文中优选的盐为本发明的化合物的生理上可接受的盐。也涵盖本身不适合于药学应用,但可以例如用于分离、纯化或储存本发明的化合物的盐。
本发明的化合物的生理上可接受的盐包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘二磺酸、甲酸、乙酸、三氟乙酸、丙酸、琥珀酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、苯甲酸和扑酸的盐。
在本发明的上下文中,溶剂合物被描述为以固体或液体的形式通过与溶剂分子配位形成络合物的那些本发明的化合物的那些形式。水合物是一种具体形式的溶剂合物,其中和水配位。在本发明的上下文中优选的溶剂合物是水合物。
取决于其结构,本发明的化合物可以以不同的立体异构形式存在,即以构型异构体或者任选地构象异构体的形式(对映异构体和/或非对映异构体,包括在阻转异构体的情况中的那些)。因此,本发明包括对映异构体和非对映异构体及其各自的混合物。立体异构统一组分可以以已知的方式从这样的对映异构体和/或非对映异构体混合物中分离出来;色谱方法优选用于此目的,特别是非手性或手性相上的HPLC色谱法。
如果本发明的化合物可以互变异构形式出现,则本发明包括所有的互变异构形式。
本发明还包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体在这里理解为指这样的化合物:其中本发明化合物中的至少一个原子已被替换为具有相同的原子序数,但原子质量与通常或主要存在于自然界中的原子质量不同的另一个原子。可并入本发明化合物的同位素的实例是氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的那些,诸如2H(氘)、3H (氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明的化合物的特定的同位素变体,特别是已被并入一个或多个放射性同位素的那些可能是有益的,例如用于活性物质在体内的分布的作用机制的检查;由于相对容易制备和可检测性,尤其是用3H或14C同位素标记的化合物适用于此目的。此外,作为化合物的更大代谢稳定性的结果,同位素例如氘的并入可以导致特定的治疗益处,例如在体内的半衰期延长或所需的活性剂量减少;这样的本发明的化合物的改变可能因此也可能构成本发明的优选实施方案。本发明的化合物的同位素变体可以通过本领域技术人员已知的常用方法来制备,例如通过下文进一步描述的方法和实施例中描述的规程,其中采用各自试剂和/或起始化合物的相应的同位素变体。
本发明另外还包括本发明的化合物的前药。术语“前药”在这里是指本身可为生物活性或非活性,但在体内停留时间过程中例如通过代谢或水解路线转化为本发明化合物的化合物。
在本发明的情况下,除非另有规定,否则取代基和基团的定义如下:
在本发明的上下文中,(C1-C4)-烷基代表具有1-4个碳原子的直链或支化的烷基。例子包括: 甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
在本发明的上下文中,(C1-C3)-烷基代表具有1-3个碳原子的直链或支化的烷基。例子包括: 甲基、乙基、正丙基和异丙基。
在本发明的上下文中,(C1-C3)-烷氧基代表具有1-3个碳原子的直链或支化的烷氧基。 例子包括: 甲氧基、乙氧基、正丙氧基和异丙氧基。
在本发明的上下文中,(C4-C6)-环烷基代表具有4-6个碳原子的单环饱和环烷基。例子包括: 环丁基、环戊基和环己基。
在本发明的上下文中,卤素包括氟、氯、溴和碘。优选氟、氯或溴。
在本发明的上下文中,对于出现多次的所有基团,其含义是彼此独立的。当本发明的化合物中的基团被取代时,所述基团可以单或多取代,除非另有规定。优选是被一个取代基或被两个相同或不同的取代基取代。特别优选是被一个取代基取代。
在本发明的上下文中优选式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表氟、氯、溴、甲基、异丙基、叔丁基或环丙基
和
R2代表环丁基、环戊基或环己基
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、氰基、(C1-C3)-烷基、(C1-C3)-烷氧基或三氟甲氧基,
R4代表氢、氟或氯,
R5代表氢、氟、氯、溴或甲基
和
R6代表氢或(C1-C3)-烷氧基,其可以被氟取代至多三次。
本发明的一个特定实施方案涉及式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表氯或溴。
本发明的另一个特定实施方案涉及式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表甲基、异丙基、叔丁基或环丙基。
本发明的另一个特定实施方案涉及式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R2代表环丁基、环戊基或环己基。
本发明的另一个特定实施方案涉及式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R2代表式(a)的苯基
其中*标记与毗邻羰基连接的键,
R3代表氟、氯、氰基、(C1-C3)-烷基或(C1-C3)-烷氧基
和
R4代表氢、氟或氯。
本发明的另一个特定实施方案涉及式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R2代表式(b)的吡啶基
其中*标记与毗邻羰基连接的键,
R5代表氢、氯或溴
和
R6代表(C1-C3)-烷氧基,其可以被氟取代至多三次。
在本发明的上下文中,特别优选的是式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表氯、溴、异丙基或环丙基
和
R2代表环丁基、环戊基或环己基
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、氰基、甲基、异丙基、甲氧基或乙氧基,
R4代表氢、氟或氯,
R5代表氢、氯或溴
和
R6代表甲氧基、二氟甲氧基、三氟甲氧基或异丙氧基。
不论各自给出的基团组合如何,在基团的各个组合或优选组合中各自给出的基团定义也任意地被其它组合的基团定义替代。
非常特别优选上述优选范围中两个或更多个的组合。
本发明还提供了用于制备根据本发明的式(I)的化合物的方法,其特征在于在合适的还原剂的存在下使式(II)的化合物
其中R1具有上面给出的含义
[A] 与式(III)的化合物反应
其中R2具有上面给出的含义,
或
[B] 与式(IV)的被保护的哌嗪衍生物反应
其中PG代表合适的氨基保护基,例如叔丁氧基羰基、苄氧基羰基或(9H-芴-9-基甲氧基)羰基,
以首先得到式(V)的化合物
其中PG和R1具有上面给出的含义,
然后移除保护基PG,并然后使所得式(VI)的化合物与式(VII)的羧酸通过活化(VII)中的羧酸功能而反应
其中R1具有上面给出的含义
其中R2具有上面给出的含义,
或与相应的式(VIII)的酰氯反应
其中R2具有上面给出的含义
并将所得的式(I)的化合物任选地用适当的(i)溶剂和/或(ii)酸转化成它们的溶剂合物、盐和/或盐的溶剂合物。
用于这样的目的的用作方法步骤[A] (II) + (III) → (I)和[B] (II) + (IV)→ (V) [还原性胺化]的合适还原剂是常用的碱金属硼氢化物诸如硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠;优选使用三乙酰氧基硼氢化钠。在这些反应中可以有利地添加酸,诸如特别是乙酸,和/或脱水剂,例如分子筛或原甲酸三甲酯或原甲酸三乙酯。
用于这些反应的合适溶剂尤其是醇,诸如甲醇、乙醇、正丙醇或异丙醇,醚诸如二异丙基醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,极性非质子溶剂诸如乙腈或N,N-二甲基甲酰胺(DMF)或此类溶剂的混合物;优选使用四氢呋喃。反应通常在0℃至+50℃的温度范围进行。
用作化合物(IV)中的保护基PG的可以是常规的氨基保护基,诸如叔丁氧基羰基(BOC)、苄氧基羰基(Z)或(9H-芴-9-基甲氧基)羰基(Fmoc);优选使用叔丁氧基羰基(BOC)。方法步骤[B] (V) → (VI)中的保护基的移除是通过已知的方法进行的。因此,叔丁氧基羰基通常通过在惰性溶剂如二乙醚、1,4-二噁烷、二氯甲烷或乙酸中用强酸如氯化氢、溴化氢或三氟乙酸处理而移除。在苄氧基羰基作为保护基团的情况下,这优选通过在合适的钯催化剂(如活性炭上的钯)的存在下通过氢解除去。(9H-芴-9-基甲氧基)羰基通常借助仲胺碱如二乙胺或哌啶移除[参见,例如,T.W. Greene和P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; P.J. Kocienski, Protecting Groups,第3版, Thieme, 2005]。
方法步骤[B](VI) + (VII) → (I)[酰胺形成]是通过已知的方法借助于缩合剂或活化剂进行的。合适的此类试剂是例如碳二亚胺如N,N'-二乙基-、N,N'-二丙基-、N,N'-二异丙基-、N,N'-二环己基碳二亚胺(DCC)或N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC),光气衍生物如N,N'-羰基二咪唑(CDI)或氯甲酸异丁酯,1,2-噁唑鎓化合物如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸盐或2-叔丁基-5-甲基异噁唑鎓高氯酸盐,酰基氨基化合物如2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉,α-氯烯胺如1-氯-N,N,2-三甲基丙-1-烯-1-胺,1,3,5-三嗪衍生物如4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉鎓氯化物,磷化合物如正丙烷膦酸酐(PPA)、氰基膦酸二乙酯、二苯基磷酰叠氮化物(DPPA)、双(2-氧代-3-噁唑烷基)磷酰氯、苯并三唑-1-基氧基三(二甲基氨基)鏻六氟磷酸盐或苯并三唑-1-基氧基三(吡咯烷基)鏻六氟磷酸盐(PyBOP),或脲鎓化合物如O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU)、O-(1H-6-氯苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TCTU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HBTU)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU)或2-(2-氧代-1-(2H)-吡啶基)-1,1,3-四甲基脲鎓四氟硼酸盐(TPTU),所述试剂任选与其它助剂,如1-羟基苯并三唑(HOBt)或N-羟基琥珀酰亚胺(HOSu),以及作为碱的碱金属碳酸盐,例如碳酸钠或碳酸钾,或叔胺碱如三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉(NMM)、N-甲基哌啶(NMP)、吡啶或4-N, N-二甲基氨基吡啶(DMAP)组合。所用的优选的缩合剂或活化剂是1-氯-N,N,2-三甲基丙-1-烯-1-胺与作为碱的吡啶、或O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU)与N,N-二异丙基乙基胺。
经由羰基氯(VIII)的替代性的方法[(VI) + (VIII) → (I)]通常在碱诸如碳酸钠、碳酸钾、三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉(NMM)、N-甲基哌啶(NMP)、吡啶、2,6-二甲基吡啶、4-N,N-二甲基氨基吡啶 (DMAP)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)或1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)的存在下进行;优选使用三乙胺或N,N-二异丙基乙基胺。
用于这些酰胺形成反应的合适惰性溶剂是例如醚如二乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷、1,2-二甲氧基乙烷或双(2-甲氧乙基)醚,烃如苯、甲苯、二甲苯、戊烷、己烷或环己烷,卤代烃如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、三氯乙烯或氯苯,或极性非质子溶剂如丙酮、甲乙酮、乙酸乙酯、乙腈、丁腈、吡啶、二甲亚砜(DMSO)、N,N-二甲基甲酰胺(DMF)、N,N'-二甲基亚丙基脲(DMPU)或N-甲基吡咯烷酮(NMP);也可以使用此类溶剂的混合物。优选使用二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺或它们的混合物。反应一般在-20℃至+60℃的温度范围内进行,优选在0℃至+40℃下进行。
在方法步骤[B] (VI) + (VII) → (I)和(VI) + (VIII) → (I)中,胺化合物(VI)也可以盐的形式使用,例如作为盐酸盐或三氟乙酸盐。在这样的情况下,在相应增加量的各自使用的辅助碱的存在下进行反应。
上述方法可以在标准、升高或降低的压力下进行(例如在0.5至5巴的范围内);一般而言,各自在大气压下操作。
式(II)的化合物本身可以通过文献已知的方法如下制备: 在碱的影响下使2-氨基吡啶 (IX)
与式(X)的苯乙酮衍生物缩合
其中R1具有上面给出的含义
且
X代表合适的离去基如氯、溴或碘,
以得到式(XI)的2-苯基咪唑并[1,2-a]吡啶
其中R1具有上面给出的含义
并且然后用N,N-二甲基甲酰胺和三氯氧磷的混合物将其甲酰化以得到(II)。
缩合反应(IX) + (X) → (XI)通常在醇溶剂诸如甲醇、乙醇、正丙醇、异丙醇或正丁醇,在醚诸如二乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷、1,2-二甲氧基乙烷或双(2-甲氧基乙基)醚,或在偶极非质子溶剂如N,N-二甲基甲酰胺(DMF)、N,N'-二甲基亚丙基脲(DMPU)或N-甲基吡咯烷酮(NMP)中在+20℃至+120℃范围内的温度下进行;优选地,所用溶剂是乙醇。
适用于该反应的碱特别是碱金属碳酸氢盐或-碳酸盐,例如碳酸氢钠或碳酸氢钾或碳酸锂、碳酸钠、碳酸钾或碳酸铯,或氧化铝;优选使用碳酸氢钠。任选地,如果反应温度相应增加,也可以在不添加碱的情况下进行反应。
区域选择性甲酰化(XI) → (II)在Vilsmaier-Haack反应的常规条件下通过用N, N-二甲基甲酰胺和三氯氧磷的预形成的混合物(其以大过量使用并且与此同时也用作溶剂)处理(XI)来进行。该反应通常在0℃至+100℃的温度范围内进行。
式(III)、(IV)、(VII)、(VIII)、(IX)和(X)的化合物是市售的或本身描述在文献中,或者它们可以通过本领域技术人员熟悉和文献已知的方法以简单的方式由其它市售的化合物起始来制备。各种详细规程和进一步的参考文献也可以在实验部分中在起始化合物和中间体的制备部分中找到。
根据本发明的化合物的制备可以例如由以下反应方案例示:
方案1
本发明的化合物具有有价值的药理性质并可用于预防和治疗人和动物的疾病。
根据本发明的化合物是强效且选择性的TASK-1和TASK-3通道阻断剂并且因此适用于治疗和/或预防病症和病理过程,特别是由TASK-1和/或TASK-3的活化或由活化的TASK-1和/或TASK-3导致的那些,以及以继发性方式由TASK-1和/或TASK-3造成的损害诱发的病症。
在本发明的上下文中,这特别包括来自呼吸病症和睡眠相关的呼吸病症的组的病症,诸如阻塞性睡眠呼吸暂停(成人和儿童中)、原发性打鼾、阻塞性打鼾(上气道阻力综合征、重度打鼾、呼吸功能不全综合征)、中枢性睡眠呼吸暂停、混合型睡眠呼吸暂停、陈-施呼吸、婴儿期的原发性睡眠呼吸暂停、早产儿呼吸暂停、由于使用药物或使用其它物质引起的中枢性睡眠呼吸暂停、肥胖通气不足综合征、被破坏的中枢性呼吸驱动、婴儿猝死、原发性肺泡通气不足综合征、术后缺氧和呼吸暂停、肌肉性呼吸病症、长期通气后的呼吸病症、高山适应期间的呼吸病症、具有缺氧和高碳酸血症的急性和慢性肺疾病、睡眠相关的非阻塞性肺泡通气不足和先天性中枢性肺泡通气不足综合征。
根据本发明的化合物还可用于治疗和/或预防神经变性病症,诸如痴呆、具有路易小体的痴呆、阿尔茨海默病、帕金森病、亨廷顿氏病、皮克病、威尔逊氏病、进行性核上性麻痹、皮质基底节变性、tau蛋白病变(Silberkornkrankheit)、第17染色体的额颞叶痴呆和帕金森综合征、多系统萎缩、脊髓小脑共济失调、肯尼迪型脊髓延髓肌萎缩、弗立特里希氏共济失调、齿状核红核苍白球丘脑下部核萎缩、肌萎缩性侧索硬化、原发性侧索硬化、脊髓性肌萎缩症、克罗伊茨费尔特-雅各布病和克罗伊茨费尔特-雅各布病的变体、婴儿神经轴索性营养不良、伴有脑铁积聚的神经变性、伴有泛素蛋白酶体系统的额颞叶变性和伴有神经源性丝氨酸蛋白酶抑制剂包涵体的家族性脑病。
此外,根据本发明的化合物可用于治疗和/或预防中枢神经系统(CNS)的神经炎症和神经免疫病症,例如多发性硬化(播散性脑脊髓炎)、横贯性脊髓炎、视神经脊髓炎、急性播散性脑脊髓炎、视神经炎、脑膜炎、脑炎、脱髓鞘疾病以及中枢神经系统中的炎性血管改变。
此外,根据本发明的化合物适用于治疗和/或预防癌症疾病,例如皮肤癌、乳腺癌、肺癌、结肠癌和前列腺癌。
此外,根据本发明的化合物适用于治疗和/或预防心律失常和心律不齐,例如房性和室性心律失常,传导缺陷如第一至第三度房室传导阻滞,室上性快速性心律失常、心房颤动、心房扑动、心室颤动、心室扑动、室性快速性心律失常、尖端扭转型室性心动过速、房性和室性早搏、房室交界性早搏、病态窦房结综合征、晕厥和房室结折返性心动过速。
根据本发明的化合物可以用于治疗和/或预防的其它心血管病症是例如心力衰竭、冠心病、稳定和不稳定型心绞痛、高血压、肺动脉高压(PAH)和其它形式的肺高压(PH)、肾性高血压、外周和心血管病症、沃-帕-怀综合征、急性冠脉综合征(ACS)、自身免疫性心脏病(心包炎、心内膜炎、肺泡炎、主动脉炎、心肌病)、拳师犬心肌病、动脉瘤、休克如心源性休克、感染性休克和过敏性休克,以及血栓栓塞症和缺血,如心肌缺血、心肌梗死、中风、心脏肥大、短暂性和缺血性发作、先兆子痫、炎性心血管病症、冠状动脉和外周动脉的痉挛、水肿形成如肺水肿、脑水肿、肾水肿或心力衰竭引起的水肿、外周循环障碍、再灌注损伤、动脉和静脉血栓、微量白蛋白尿、心肌机能不全、血管内皮功能障碍、微血管和大血管损伤(血管炎),以及例如在溶栓治疗、经皮腔内血管成形术(PTA)、经皮腔内冠状动脉血管成形术(PTCA)、心脏移植和旁路手术后防止再狭窄。
在本发明的上下文中,术语“心力衰竭”包括急性和慢性形式的心力衰竭,也包括其特定或相关的疾病类型,如急性失代偿性心力衰竭、右心衰竭、左心衰竭、全心衰竭、缺血性心肌病、扩张性心肌病、肥大性心肌病、特发性心肌病、先天性心脏缺陷、心脏瓣膜缺损、与心脏瓣膜缺损相关的心力衰竭、二尖瓣狭窄、二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣狭窄,三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、复合型心脏瓣膜缺损、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心衰、酒精性心肌病、心脏贮积性病症(Speichererkrankung)和舒张期和收缩期心衰。
本发明的化合物还可用于治疗和/或预防伴有间歇性或持久性特征的不同严重程度的哮喘性病症(难治性哮喘、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、药物或粉尘诱导的哮喘)、各种形式的支气管炎(慢性支气管炎、传染性支气管炎、嗜酸细胞性支气管炎)、支气管扩张、肺炎、农民肺及相关病症、咳嗽和感冒(慢性炎性咳嗽、医源性咳嗽)、鼻粘膜炎症(包括药物相关的鼻炎、血管运动性鼻炎和季节性变应性鼻炎,例如花粉热)和息肉。
本发明的化合物也适用于治疗和/或预防肾脏病症,特别是肾功能不全和肾衰竭。在本发明的上下文中,术语“肾功能不全”和“肾衰竭”包括其急性和慢性表现以及潜在的或相关的肾脏病症,如肾灌注不足、透析中低血压、梗阻性尿路病、肾小球病变、肾小球肾炎、急性肾小球肾炎、肾小球硬化、肾小管间质疾病、肾病如原发性和先天性肾病、肾炎、免疫性肾病如肾移植排斥和免疫复合物引起的肾脏病症、由毒性物质诱导的肾病、造影剂引起的肾病、糖尿病和非糖尿病性肾病、肾盂肾炎、肾囊肿、肾硬化、高血压性肾硬化和肾病综合征,其可诊断性地具有以下特征,例如异常降低的肌酐和/或水排泄、异常升高的尿素、氮、钾和/或肌酐的血浓度、肾酶例如谷氨酰合成酶的活性改变、尿同渗容摩或尿量的改变、尿微量白蛋白升高、大量蛋白尿、肾小球和小动脉损伤、肾小管扩张、高磷血症和/或需要透析。本发明还包括本发明化合物用于治疗和/或预防肾功能不全后遗症,例如高血压、肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钾血症、低钠血症)和骨骼和碳水化合物代谢紊乱的用途。
此外,本发明的化合物适用于治疗和/或预防泌尿生殖系统的病症,例如良性前列腺综合征(BPS)、良性前列腺增生症(BPH)、良性前列腺肥大(BPE)、膀胱出口梗阻(BOO)、下泌尿道综合征(LUTS)、神经源性膀胱过度活动症(OAB)、失禁如混合性尿失禁、急迫性尿失禁、压力性尿失禁或溢流性尿失禁(MUI、UUI、SUI、OUI)、盆腔疼痛以及勃起功能障碍和女性性功能障碍。
根据本发明的化合物还适用于治疗和/或预防炎性病症和自身免疫性病症,例如类风湿性病症、炎性眼病、慢性阻塞性肺病(COPD)、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、α-1抗胰蛋白酶缺乏症(AATD)、肺气肿(如香烟烟雾引起的肺气肿)、囊性纤维化(CF)、脓毒症(SIRS)、多器官功能衰竭(MODS、MOF)、肾脏炎性病症、慢性肠炎(IBD、克罗恩病、溃疡性结肠炎)、胰腺炎、腹膜炎、膀胱炎、尿道炎、前列腺炎、附睾炎(Epidimytitis)、卵巢炎、输卵管炎和外阴阴道炎,也用于治疗和/或预防内脏器官如肺、心、肾、骨髓以及尤其是肝脏的纤维化病症、皮肤纤维化和眼睛的纤维化病症。在本发明的上下文中,术语“纤维化病症”特别是包括如下病症,诸如肝纤维化、肝硬化、肺纤维化、心内膜心肌纤维化、肾病、肾小球肾炎、间质性肾纤维化、糖尿病引起的纤维化损害、骨髓纤维化、腹膜纤维化和类似的纤维化病症、硬皮病、硬斑病、瘢痕疙瘩、增生性瘢痕、痣、糖尿病视网膜病变、增生性玻璃体视网膜病变和结缔组织病症(如结节病)。本发明的化合物同样可用于促进伤口愈合、用于控制术后瘢痕形成(例如青光眼手术后)和对于老化或角化皮肤的美容性用途。
此外,根据本发明的化合物可用于治疗和/或预防动脉硬化、脂质代谢病症和血脂异常(低脂蛋白血症、高甘油三酯血症、高脂血症、合并型高脂血症、高胆固醇血症、无β脂蛋白血症、谷甾醇血症)、黄瘤症、脂肪肝、丹吉尔病、脂肪过多( 多脂)、肥胖(肥胖病)、代谢病症(代谢综合征、高血糖、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病、妊娠期糖尿病、高胰岛素血症、胰岛素抵抗、葡萄糖不耐受和糖尿病后遗症如视网膜病变、肾病和神经病变)、贫血如溶血性贫血,特别是血红蛋白病如镰状细胞贫血和地中海贫血、巨幼细胞性贫血、缺铁性贫血、由于急性失血引起的贫血、排量贫血和再生障碍性贫血、胃肠道和腹部病症(舌炎、牙龈炎、牙周炎、食道炎、嗜酸性粒细胞性胃肠炎、肥大细胞增多症、克罗恩病、结肠炎、直肠炎、肛门瘙痒症、腹泻、腹腔疾病、肝炎、肝纤维化、肝硬化、胰腺炎和胆囊炎)、中枢神经系统病症(中风、癫痫、抑郁症)、免疫病症、甲状腺病症(甲亢)、皮肤病症(银屑病、痤疮、湿疹、神经性皮炎、多种形式的皮炎、角膜炎、大疱病、血管炎、蜂窝组织炎、脂膜炎、红斑狼疮、红斑、淋巴瘤、皮肤癌、斯威特综合征、韦伯-克里斯汀综合征、瘢痕形成、疣形成、冻疮)、炎性眼部病症(结节病、睑缘炎、结膜炎、虹膜炎、葡萄膜炎、脉络膜炎、眼炎)、病毒性病症(由流感病毒、腺病毒和冠状病毒如HPV、HCMV、HIV、SARS引起)、骨骼、关节和骨骼肌的病症、动脉炎性变化(多种形式的动脉炎如动脉内膜炎、动脉中层炎、动脉周围炎、全身动脉炎、风湿性动脉炎、变形性动脉炎、颞动脉炎、颅动脉炎、巨细胞动脉炎和肉芽肿性动脉炎和霍顿综合征以及Churg-Strauss综合征和高安动脉炎)、穆-韦二氏综合征、菊地氏病、多软骨炎、硬皮病和具有炎性或免疫性组分的其它病症,如白内障、恶病质、骨质疏松症、痛风、失禁、麻风病、塞扎莱综合征和副肿瘤综合征,用于器官移植后的排斥反应和伤口愈合和血管生成,特别是在慢性伤口的情况下。
由于其性质特点,根据本发明的化合物优选适用于治疗和/或预防呼吸病症,特别是睡眠相关的呼吸病症诸如阻塞性和中枢性睡眠呼吸暂停以及原发性和阻塞性打鼾,用于治疗和/或预防心律失常和心律不齐,也用于治疗和/或预防神经变性、神经炎性和神经免疫病症。
上述充分表征的人类疾病也可以类似病因发生在其它哺乳动物中,并且同样可以用本发明的化合物治疗。
在本发明的上下文中,术语“治疗”包括抑制、阻滞、妨碍、缓解、减轻、限制、减少、防止、排斥或治愈疾病、病痛、病症、损伤或健康问题、此类状态和/或此类状态的症状的发展、过程或进展。这里使用的术语“疗法”与术语“治疗”同义。
术语“防止”、“预防”和“排除”在本发明的上下文中被同义地使用,指的是避免或减少感染、经历、遭受或患有疾病、病痛、病症、损伤或健康问题、或此类状态和/或材料状态的症状的发展或进展的风险。
治疗或预防疾病、病痛、病症、损伤或健康问题可以是部分的或完全的。
本发明因此进一步提供了本发明的化合物用于治疗和/或预防病症,尤其是上述病症的用途。
本发明进一步提供了本发明的化合物用于制备用于治疗和/或预防病症,尤其是上述病症的药物的用途。
本发明进一步提供了用于治疗和/或预防病症,尤其是上述病症的药物,其包含至少一种本发明的化合物。
本发明进一步提供了本发明的化合物在用于治疗和/或预防病症,尤其是上述病症的方法中的用途。
本发明进一步提供了使用有效量的至少一种本发明化合物治疗和/或预防病症,尤其是上述病症的方法。
本发明的化合物可以单独使用,或者如果需要,可以与一种或多种其它药理活性物质组合使用,只要这种组合不导致不良和不可接受的副作用。因此,本发明还提供了包含至少一种本发明的化合物和一种或多种其它活性物质的药物,其特别是用于治疗和/或预防上述病症的药物。适用于该目的的组合活性物质的优选实例包括:
• 呼吸刺激剂,例如,作为实例且优选的是,茶碱、多沙普仑、尼可刹米或咖啡因;
• 精神刺激化合物,例如,作为实例且优选的是,莫达非尼或阿莫非尼;
• 苯丙胺和苯丙胺衍生物,例如,作为实例且优选的是,苯丙胺、甲基苯丙胺或哌醋甲酯;
• 5-羟色胺再摄取抑制剂,例如,作为实例且优选的是,氟西汀、帕罗西汀、西酞普兰、依他普仑、舍曲林、氟伏沙明或曲唑酮;
• 5-羟色胺前体,例如,作为实例且优选的是,L-色氨酸;
• 选择性5-羟色胺去甲肾上腺素再摄取抑制剂,例如,作为实例且优选的是,文拉法辛和度洛西汀;
• 去甲肾上腺素能和特异性5-羟色胺能抗抑郁剂,例如,作为实例且优选的是,米氮平;
• 选择性去甲肾上腺素再摄取抑制剂,例如,作为实例且优选的是,瑞波西汀;
• 三环抗抑郁剂,例如,作为实例且优选的是,阿米替林、普罗替林、多虑平、曲米帕明、丙咪嗪、氯米帕明或地昔帕明;
• α2肾上腺素能激动剂,例如,作为实例且优选的是,氯压定;
• GABA激动剂,例如,作为实例且优选的是,巴氯芬;
• α拟效感神经药,例如,作为实例且优选的是,赛洛唑啉、羟甲唑啉、苯肾上腺素、萘甲唑啉、四氢唑啉或曲马唑啉;
• 糖皮质激素类,例如,作为实例且优选的是,氟替卡松、布地奈德、倍氯米松、莫米松、替可的松或曲安西龙;
• 大麻素受体激动剂;
• 碳酸酐酶抑制剂,例如,作为实例且优选的是,乙酰唑胺,醋甲唑胺或双氯非那胺;
• 阿片样物质和苯二氮卓类受体拮抗剂,例如,作为实例且优选的是,氟马西尼、纳洛酮或纳曲酮;
• 胆碱酯酶抑制剂,例如,作为实例且优选的是,新斯的明、吡啶斯的明、毒扁豆碱、多奈哌齐、加兰他敏或利斯的明;
• N-甲基-D-天冬氨酸和谷氨酸拮抗剂,例如,作为实例且优选的是,金刚烷胺、美金刚或沙贝鲁唑;
• 烟碱受体激动剂;
• 白三烯受体拮抗剂,例如,作为实例且优选的是,孟鲁司特或Tripelukast;
• 多巴胺受体拮抗剂,例如,作为实例且优选的是,Dromperidon、甲氧氯普胺或苯甲酰胺-、丁酸酚酮-或吩噻嗪-衍生物;
• 食欲抑制剂,例如,作为实例且优选的是,西布曲明、托吡酯、芬特明、脂肪酶抑制剂或大麻素受体拮抗剂;
• 质子泵抑制剂,例如,作为实例且优选的是,泮托拉唑、奥美拉唑、艾美拉唑、兰索拉唑或雷贝拉唑;
• 有机硝酸酯和NO供体,例如硝普钠、硝酸甘油、单硝酸异山梨酯、二硝酸异山梨酯、吗多明或SIN-1和吸入的NO;
• 抑制环单磷酸鸟苷(cGMP)和/或环单磷酸腺苷(cAMP)降解的化合物,例如磷酸二酯酶(PDE) 1、2、3、4和/或5的抑制剂,尤其是PDE 5 抑制剂如西地那非、伐地那非、他达拉非、乌地那非、达生他非、阿伐那非、米罗那非或罗地那非;
• 可溶性鸟苷酸环化酶(sGC)的NO-和血红素-非依赖性活化剂,诸如特别是WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462和WO 02/070510中所述的化合物;
• 可溶性鸟苷酸环化酶(sGC)的NO-非依赖性但血红素依赖性刺激剂,诸如特别是利奥西呱、威利西呱和WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647和WO 2012/059549中所述的化合物;
• 前列环素类似物和IP受体激动剂,作为实例且优选的是伊洛前列素、贝前列素、曲罗尼尔、依前列醇或Selexipag;
• 内皮素受体拮抗剂,作为实例且优选的是波生坦、达卢生坦、安立生坦或西他生坦;
• 抑制人中性粒细胞弹性蛋白酶(HNE)的化合物,作为实例且优选的是西维来司他或DX-890 (Reltran);
• 抑制细胞外基质降解和改变的化合物,作为实例且优选的是基质金属蛋白酶(MMPs)的抑制剂,尤其是基质降解酶、胶原酶、明胶酶和蛋白聚糖酶(在该上下文中,特别是MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11和MMP-13)和金属弹性蛋白酶(MMP-12)的抑制剂;
• 阻断5-羟色胺与其受体的结合的化合物,作为实例且优选的是5-HT2B受体的拮抗剂诸如PRX-08066;
• 生长因子、细胞因子和趋化因子的拮抗剂,作为实例且优选的是TGF-β、CTGF、IL-1、IL-4、IL-5、IL-6、IL-8、IL-13和结合素类的拮抗剂;
• Rho激酶抑制化合物,作为实例且优选的是法舒地尔、Y-27632、SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;
• 影响心脏能量代谢的化合物,作为实例且优选的是依托莫司、二氯乙酸盐、雷诺嗪或曲美他嗪;
• 抑制信号转导级联的化合物,作为实例且优选的是来自激酶抑制剂的群组,特别是来自酪氨酸激酶-和/或丝氨酸/苏氨酸-激酶抑制剂的群组,作为实例且优选的是尼达尼布、达沙替尼、尼洛替尼、波舒替尼、瑞戈非尼、索拉非尼、舒尼替尼、西地尼布、阿昔替尼、替拉替尼、伊马替尼、布伐替尼、帕唑帕尼、伐他拉尼、吉非替尼、埃罗替尼、拉帕替尼、卡纽替尼、来妥替尼、培利替尼、司马沙尼或坦度替尼;
• 抗阻塞剂,其例如用于治疗慢性阻塞性肺病(COPD)或支气管哮喘,作为实例且优选的是来自吸入或全身给药的β-肾上腺素能受体激动剂(β模拟物)和吸入给药的抗毒蕈碱能物质的群组;
• 抗炎、免疫调节、免疫抑制和/或细胞毒性剂,作为实例且优选的是来自以下的群组:全身或吸入给药的皮质类固醇以及富马酸二甲酯、芬戈莫得、醋酸格拉默、β-干扰素类、那他珠单抗、特立氟胺、米托蒽醌、免疫球蛋白类、乙酰半胱氨酸、孟鲁司特、泰鲁司特、硫唑嘌呤、环磷酰胺、羟基脲、阿奇霉素、干扰素-γ、吡非尼酮或依那西普;
• 抗纤维化剂,例如,作为实例且优选的是,溶血磷脂酸受体 1 (LPA-1) 拮抗剂、CTGF抑制剂、IL-4 拮抗剂、IL-13 拮抗剂、TGF-β 拮抗剂或吡非尼酮;
• 抗血栓剂,作为实例且优选的是来自血小板聚集抑制剂、抗凝血剂和致纤溶作用(profibrinolytisch)物质的群组;
• 降压活性物质,作为实例且优选的是来自钙拮抗剂、血管紧张素AII 拮抗剂、ACE 抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α受体阻断剂、β受体阻断剂、盐皮质激素受体拮抗剂和利尿剂的群组; 和/或
• 改变脂质代谢的活性物质,例如且优选来自以下的群组:甲状腺受体激动剂、胆固醇合成抑制剂如作为实例且优选的是HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂、ACAT 抑制剂、CETP 抑制剂、MTP 抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、脂肪酶抑制剂、聚合胆汁酸吸附剂、胆汁酸再吸收抑制剂和脂蛋白(a)拮抗剂。
在本发明的一个优选的实施方案中,本发明的化合物与β-肾上腺素能受体激动剂组合施用,其作为实例且优选的是沙丁胺醇、异丙肾上腺素、奥西那灵、特布他林、非诺特罗、福莫特罗、瑞普特罗、柳丁氨醇或沙美特罗。
在本发明的一个优选的实施方案中,本发明的化合物与抗毒蕈碱能物质组合施用,其作为实例且优选的是溴化异丙托品、噻托溴铵或氧托溴铵。
在本发明的一个优选的实施方案中,本发明的化合物与皮质类固醇组合施用,其作为实例且优选的是泼尼松、泼尼松龙、甲泼尼龙、曲安西龙, 地塞米松、倍他米松、倍氯米松、氟尼缩松、布地奈德或氟替卡松。
抗血栓剂优选被理解为表示来自以下群组的化合物:血小板聚集抑制剂、抗凝血剂和致纤溶作用物质。
在本发明的一个优选的实施方案中,本发明的化合物与血小板聚集抑制剂组合施用,其作为实例且优选的是阿司匹林、氯吡格雷、噻氯匹定或双嘧达莫。
在本发明的一个优选的实施方案中,本发明的化合物与凝血酶抑制剂组合施用,其作为实例且优选的是希美加群、美拉加群、达比加群、比伐卢定或克赛。
在本发明的一个优选的实施方案中,本发明的化合物与GPIIb/IIIa拮抗剂组合施用,其作为实例且优选的是替罗非班或阿昔单抗。
在本发明的一个优选的实施方案中,本发明的化合物与因子Xa抑制剂组合施用,其作为实例且优选的是利伐沙班、阿哌沙班、非得沙班、雷扎沙班、磺达肝素、依达肝素、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV803、SSR-126512或SSR-128428。
在本发明的一个优选的实施方案中,本发明的化合物与肝素或低分子量(LMW)肝素衍生物组合施用。
在本发明的一个优选的实施方案中,本发明的化合物与维生素K拮抗剂组合施用,其作为实例且优选的是香豆素。
降压剂优选被理解为表示来自以下群组的化合物:钙拮抗剂、血管紧张素AII 拮抗剂、ACE 抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻断剂、β-受体阻断剂、盐皮质激素受体拮抗剂和利尿剂。
在本发明的一个优选的实施方案中,本发明的化合物与钙拮抗剂组合施用,其作为实例且优选的是硝苯地平、氨氯地平、维拉帕米或地尔硫卓。
在本发明的一个优选的实施方案中,本发明的化合物与α-1-受体阻断剂组合施用,其作为实例且优选的是哌唑嗪。
在本发明的一个优选的实施方案中,本发明的化合物与β-受体阻断剂组合施用,其作为实例且优选的普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、阿普洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、美替洛尔、纳多洛尔、甲吲洛尔、卡拉洛尔、索他洛尔、美托洛尔、倍他洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维地洛、阿达洛尔、兰地洛尔、奈必洛尔、依泮洛尔或布新洛尔。
在本发明的一个优选的实施方案中,本发明的化合物与血管紧张素AII拮抗剂组合施用,其作为实例且优选的是洛沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦。
在本发明的一个优选的实施方案中,本发明的化合物与ACE抑制剂组合施用,其作为实例且优选的是依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、奎诺普利、培多普利或川多普利。
在本发明的一个优选的实施方案中,本发明的化合物与内皮素拮抗剂组合施用,其作为实例且优选的是波生坦、达卢生坦、安立生坦或西他生坦。
在本发明的一个优选的实施方案中,本发明的化合物与肾素抑制剂组合施用,其作为实例且优选的是阿利吉仑、SPP-600或SPP-800。
在本发明的一个优选的实施方案中,本发明的化合物与盐皮质激素受体拮抗剂组合施用,其作为实例且优选的是螺内酯、依普利酮或芬尼酮。
在本发明的一个优选的实施方案中,本发明的化合物与利尿剂组合施用,其作为实例且优选的是呋塞米、布美他尼、托拉塞米、苄氟噻嗪、氯噻嗪、氢氯噻嗪、氢氟噻嗪、甲氯噻嗪、泊利噻嗪、三氯噻嗪、氯噻酮、吲达帕胺、美托拉宗、喹乙宗、醋唑磺胺、醋唑磺胺、双氯非那胺、醋甲唑胺、甘油、异山梨醇、甘露醇、阿米洛利或氨苯蝶啶。
脂质代谢调节剂优选被理解为表示来自以下群组的化合物: CETP 抑制剂、甲状腺受体激动剂、胆固醇合成抑制剂诸如HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂、ACAT抑制剂、MTP 抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、聚合胆汁酸吸附剂、胆汁酸再吸收抑制剂、脂肪酶抑制剂和脂蛋白(a)拮抗剂。
在本发明的一个优选的实施方案中,本发明的化合物与CETP抑制剂组合施用,其作为实例且优选的是托塞曲匹(CP-529 414)、JJT-705或CETP疫苗(Avant)。
在本发明的一个优选的实施方案中,本发明的化合物与甲状腺受体激动剂组合施用,其作为实例且优选的是D-甲状腺素、3,5,3'-三碘甲腺原氨酸(T3)、CGS 23425或阿昔替罗(CGS 26214)。
在本发明的一个优选的实施方案中,本发明的化合物与他汀类的HMG-CoA还原酶抑制剂组合施用,其作为实例且优选的是洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀或匹伐他汀。
在本发明的一个优选的实施方案中,本发明的化合物与角鲨烯合成抑制剂组合施用,其作为实例且优选的是BMS-188494或TAK-475。
在本发明的一个优选的实施方案中,本发明的化合物与ACAT抑制剂组合施用,其作为实例且优选的是阿伐麦布、甲亚油酰胺、帕替麦布、依鲁麦布或SMP-797。
在本发明的一个优选的实施方案中,本发明的化合物与MTP抑制剂组合施用,其作为实例且优选的是英普他派、BMS-201038、R-103757或JTT-130。
在本发明的一个优选的实施方案中,本发明的化合物与PPAR-γ激动剂组合施用,其作为实例且优选的是吡格列酮或罗格列酮。
在本发明的一个优选的实施方案中,本发明的化合物与PPAR-δ激动剂组合施用,其作为实例且优选的是GW 501516或BAY 68-5042。
在本发明的一个优选的实施方案中,本发明的化合物与胆固醇吸收抑制剂组合施用,其作为实例且优选的是伊泽替米贝、替奎安或帕马苷。
在本发明的一个优选的实施方案中,本发明的化合物与脂肪酶抑制剂组合施用,其作为实例且优选的是奥利司他。
在本发明的一个优选的实施方案中,本发明的化合物与聚合胆汁酸吸附剂组合施用,其作为实例且优选的是消胆胺、考来替泊、考来索凡、考来胶或考来替米。
在本发明的一个优选的实施方案中,本发明的化合物与胆汁酸再吸收抑制剂组合施用,其作为实例且优选的是ASBT (= IBAT) 抑制剂,例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在本发明的一个优选的实施方案中,本发明的化合物与脂蛋白(a)拮抗剂组合施用,其作为实例且优选的是吉卡宾(Gemcarbene)钙(CI-1027)或烟酸。
特别优选的是根据本发明的化合物与一种或多种其它活性物质的组合,所述活性物质选自呼吸刺激剂、精神刺激化合物、5-羟色胺再摄取抑制剂、去甲肾上腺素能、5-羟色胺能和三环抗抑郁药、sGC刺激剂、盐皮质激素受体拮抗剂、抗炎药、免疫调节剂、免疫抑制剂和细胞毒性药物。
如果需要,根据本发明的物质也可以与一种或多种医疗技术设备或辅助设备一起使用,只要这不导致不必要的和不可接受的副作用。适用于这种组合应用的医疗设备和辅助设备例如且优选的是:
• 用于呼吸道正压通气的设备,作为实例且优选的是CPAP (持续性正压通气) 设备、BiPAP (双向正压通气) 设备和IPPV (间歇性正压通气) 设备;
• 舌下神经的神经刺激器;
• 口腔内辅助设备,作为实例且优选的是突出牙套;
• 鼻用一次性阀;
• 鼻用支架。
本发明进一步提供了药物,其包含至少一种本发明的化合物与通常一种或多种惰性、无毒性、药学上合适的赋形剂,以及其用于上述目的的用途。
本发明的化合物可以全身地和/或局部地发挥作用。为此目的,它们可以以合适的方式给药,例如口服、肠胃外、肺、肺内(吸入)、鼻、鼻内、咽、舌、舌下、含服、直肠、真皮、经皮、结膜、耳道,或作为植入物或支架。
本发明的化合物可以以适合于这些给药途径的给药形式给药。
口服给药的合适的给药形式是按照现有技术工作的并以快速和/或改进的方式释放本发明化合物的那些,并且其含有晶体和/或无定形和/或溶解形式的本发明化合物,例如片剂(未包衣或包衣片剂,例如具有控制本发明化合物的释放的耐胃液或延迟溶解或不溶性包衣)、在口腔中迅速崩解的片剂或薄膜/圆片、薄膜/冻干物、胶囊(例如硬或软明胶胶囊)、糖衣片、颗粒剂、丹剂、粉末剂、乳剂、混悬剂、气雾剂或溶液剂。
胃肠外给药可以绕过再吸收步骤(例如,静脉内、动脉内、心内、椎管内或腔内)或包括再吸收(例如,吸入、肌内、皮下、皮内、经皮或腹膜内)。适用于肠胃外给药的给药形式包括溶液剂、混悬剂、乳剂、冻干物或无菌粉末剂形式的注射和输注制剂。
对于其它给药途径,合适的例子是可吸入药物形式(包括粉末吸入器、雾化器、计量气雾剂)、滴鼻剂、鼻用溶液剂或喷雾剂、喉咙喷雾剂、舌、舌下或含服给药的片剂、薄膜/圆片或胶囊、栓剂、耳或眼制剂、阴道胶囊、水混悬剂(洗液、摇动混合物)、亲脂性混悬剂、软膏、乳膏、经皮治疗系统(例如贴片)、乳状物、糊剂、泡沫、喷粉、植入物或支架。
优选口服、静脉内、鼻内和咽部给药。
根据一个实施方案,进行鼻内给药。根据一个实施方案,借助于滴鼻剂或鼻喷雾剂进行鼻内给药。根据一个实施方案,借助于鼻喷雾剂进行鼻内给药。
本发明的化合物可以转化为所提及的给药形式。这可以以本身已知的方式通过与惰性、无毒、药学上合适的赋形剂混合来完成。这些赋形剂包括载体物质(例如微晶纤维素、乳糖、甘露醇)、溶剂(例如液体聚乙二醇)、乳化剂和分散或润湿剂(例如十二烷基硫酸钠、聚氧脱水山梨糖醇油酸酯(Polyoxysorbitanoleat))、粘合剂(例如聚乙烯吡咯烷酮)、合成和天然聚合物(例如白蛋白)、稳定剂(例如抗氧剂,例如抗坏血酸)、着色剂(例如无机颜料,例如氧化铁)和风味和/或气味校正剂。
一般而言,已发现在胃肠外给药的情况下,施用约0.001至1mg/kg,优选约0.01至0.5mg/kg体重以获得有效的结果是有利的。在口服给药的情况下,剂量为约0.01至100mg/kg,优选约0.01至20mg/kg,最优选为0.1至10mg/kg体重。
根据一个实施方案,在鼻内给药的情况下,剂量为每天约0.1μg至500μg。根据另一个实施方案,在鼻内给药的情况下,剂量为每天约1μg至250μg。根据另一个实施方案,在鼻内给药的情况下,剂量为每天约1μg至120μg。根据另一个实施方案,在睡前每天一次鼻内给药约0.1 µg至500 µg每天,或约1 µg至250 µg每天,或约1 µg至120 µg每天的剂量。根据一个实施方案,每天给药一次约0.1 µg至500 µg每天,或约1 µg至250 µg每天,或约1 µg至120 µg每天的剂量,在每种情况下每个鼻孔给药一半。根据一个实施方案,在睡前每天一次给药约0.1 µg至500 µg每天,或约1 µg至250 µg每天,或约1 µg至120 µg每天的剂量,在每种情况下每个鼻孔给药一半。
尽管如此,任选地可能需要偏离所述量,更确切地说根据体重、给药途径、个体对活性物质的反应、制剂的性质和给药发生的时间或间隔。因此,在某些情况下,小于上述最小量可能是足够的,而在其它情况下,必须超过所提到的上限。在给药量更大的情况下,可能值得推荐的是在一天内将它们分成几个单独的剂量。
下面的实施例说明了本发明。本发明不限于这些实施例。
A. 实施例
缩写和简称:
abs. 纯
Ac 乙酰基
aq. 水性、水溶液
Boc 叔丁氧基羰基
br. 宽(于NMR信号中)
Bsp. 实施例
Bu 丁基
c 浓度
ca. 约
cat. 催化的
CI 化学电离(在MS中)
d 双峰(在NMR中)
d 天
DCI 直接化学电离(在MS中)
dd 双重双峰(在NMR中)
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
dq 双重四峰(在NMR中)
dt 双重三峰(在NMR中)
d. Th. 理论值的(在化学产率中)
EI 电子碰撞电离(在MS中)
eq. 当量
ESI 电喷雾电离(在MS中)
Et 乙基
h 小时
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐
HOBt 1-羟基-1H-苯并三唑水合物
HPLC 高压、高效液相色谱法
iPr 异丙基
konz. 浓缩的(在溶液的情况下)
LC 液相色谱
LC-MS 液相色谱-偶联的质谱
Lit. 文献(参考)
m 多重峰(在NMR中)
Me 甲基
min 分钟
MS 质谱
NMR 核磁共振光谱
Ph 苯基
Pr 丙基
q 四重峰(在NMR中)
quant. 定量(在化学产率中)
RP 反相(反相,在HPLC中)
RT 室温
Rt 保留时间(在HPLC、LC-MS中)
s 单峰(在NMR中)
t 三重峰(在NMR中)
tBu 叔丁基
TFA 三氟乙酸
THF 四氢呋喃
UV 紫外光谱
v/v (溶液的)体积/体积比
zus. 共同。
LC-MS和HPLC方法:
方法1 (LC-MS):
仪器: Waters Acquity SQD UPLC系统; 柱: Waters Acquity UPLC HSS T3 1.8 µm,50 mm x 1 mm; 流动相 A: 1 l水+ 0.25 ml 99%甲酸, 流动相 B: 1 l 乙腈 + 0.25 ml99%甲酸; 梯度: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; 温度: 50℃; 流速: 0.40 ml/min; UV 检测: 208-400 nm。
方法2 (LC-MS):
MS 仪器: Thermo Scientific FT-MS; UHPLC 仪器: Thermo Scientific UltiMate3000; 柱: Waters HSS T3 C18 1.8 µm, 75 mm x 2.1 mm; 流动相 A: 1 l水+ 0.01%甲酸, 流动相 B: 1 l 乙腈 + 0.01%甲酸; 梯度: 0.0 min 10% B → 2.5 min 95% B →3.5 min 95% B; 温度: 50℃; 流速: 0.90 ml/min; UV 检测: 210-300 nm。
方法3 (LC-MS):
MS 仪器: Waters Micromass QM; HPLC 仪器: Agilent 1100 Serie; 柱: AgilentZORBAX Extend-C18 3.5 µm, 50 mm x 3.0 mm; 流动相 A: 1 l水+ 0.01 mol碳酸铵, 流动相 B: 1 l 乙腈; 梯度: 0.0 min 98% A → 0.2 min 98% A → 3.0 min 5% A → 4.5min 5% A; 温度: 40℃; 流速: 1.75 ml/min; UV 检测: 210 nm。
方法4 (LC-MS):
MS 仪器: Waters Micromass Quattro Micro; HPLC 仪器: Waters UPLC Acquity;柱: Waters BEH C18 1.7 µm, 50 mm x 2.1 mm; 流动相 A: 1 l水+ 0.01 mol甲酸铵,流动相 B: 1 l 乙腈; 梯度: 0.0 min 95% A → 0.1 min 95% A → 2.0 min 15% A →2.5 min 15% A → 2.51 min 10% A → 3.0 min 10% A; 温度: 40℃; 流速: 0.5 ml/min; UV 检测: 210 nm。
方法5 (LC-MS):
仪器: Agilent MS Quad 6150+HPLC Agilent 1290; 柱: Waters Acquity UPLC HSST3 1.8 µm, 50 mm x 2.1 mm; 流动相 A: 1 l水+ 0.25 ml 99%甲酸, 流动相 B: 1 l 乙腈 + 0.25 ml 99%甲酸; 梯度: 0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A →3.0 min 5% A; 流速: 1.20 ml/min; 温度: 50℃; UV 检测: 205-305 nm。
方法6 (制备型HPLC):
仪器: Abimed Gilson 305; 柱: Reprosil C18 10 µm, 250 mm x 30 mm; 流动相A: 水, 流动相 B: 乙腈; 梯度: 0-3 min 10% B, 3-27 min 10% B → 95% B, 27-34.5min 95% B, 34.5-35.5 min 95% B → 10% B, 35.5-36.5 min 10% B; 流速: 50 ml/min; 室温; UV 检测: 210 nm。
其它细节:
下面的1H NMR信号的耦合模式的描述是由所涉信号的视觉外观来指导的,并且不一定对应于严格的、物理上正确的解释。一般来说,所说的化学位移是指所涉信号的中心;在宽多重峰的情况下,通常给出一个区间。
如果给出的话,熔点和熔点范围是未修正的。
在其中反应产物通过搅拌提取(ausrühren)、搅拌或重结晶得到的情况下,常常可以通过色谱分离从各自母液分离更多量的产物。然而,除非仅能在这一步骤中分离出大部分的总产率,否则下文将省略对这种色谱法的描述。
对于其制备未在下文中明确描述的所有反应物或试剂而言,它们从通常可获取的来源商业购买。对于其制备同样未在下文中描述并且不能从市场上获得或者是从通常不可获得的来源获得的所有其它反应物或试剂,可参考描述了它们的制备的公开的文献。
起始化合物和中间体:
实施例1A
2-(4-氯苯基)咪唑并[1,2-a]吡啶
将10.95 g (130 mmol)的碳酸氢钠加入到20 g (85.65 mmol) 2-溴-1-(4-氯苯基)乙酮和8.87 g (94.22 mmol)吡啶-2-胺在200 ml乙醇中的溶液中,并在80℃下搅拌5小时。然后将混合物首先冷却至室温,然后冷却至0℃(冰浴)。将所得沉淀物过滤掉,并用乙醇/水混合物(2:1)反复洗涤。然后将固体在真空中在40℃干燥过夜。这得到19.8g目标产物,其未经进一步纯化地用于后续反应。
1H-NMR (400 MHz, DMSO-d 6, δ/ppm): 6.87-6.94 (m, 1H), 7.23-7.29 (m,1H), 7.50 (d, 2H), 7.58 (d, 1H), 7.99 (d, 2H), 8.43 (s, 1H), 8.53 (d, 1H)。
LC-MS (方法1): Rt = 0.58 min; m/z = 229/231 (M+H)+。
类似于实施例1A,由在每种情况下所示的起始物质制备下列化合物:
实施例7A
2-(4-叔丁基苯基)咪唑并[1,2-a]吡啶
将1 g (5.67 mmol) 1-(4-叔丁基苯基)乙酮、1.23 g (13.05 mmol)吡啶-2-胺和1.728 g (6.81 mmol)碘的混合物在120℃的温度搅拌2小时。然后加入15 ml水和8.51 ml1 N氢氧化钠水溶液,并将混合物在100℃搅拌另一小时。冷却至室温后,加入约100 ml水和约100 ml 乙酸乙酯。分离各相后,将有机相用水洗涤两次,经硫酸镁干燥,过滤并在真空中浓缩至干。将获得的残余物施加于硅胶上并通过硅胶上的柱色谱法(Biotage 100 g KP-sil; 流速: 100 ml/ min; 流动相梯度: 1.3 min 环己烷/乙酸乙酯 92:8 → 在13 min内环己烷/乙酸乙酯34:66 → 2.6 min 环己烷/乙酸乙酯 34:66)纯化。这得到970 mg(3.87 mmol,理论值的68% )目标化合物。
1H-NMR (400 MHz, DMSO-d 6, δ/ppm): 1.32 (s, 9H), 6.88 (t, 1H), 7.19-7.26 (m, 1H), 7.46 (d, 2H), 7.57 (d, 1H), 7.88 (d, 2H), 8.34 (s, 1H), 8.51(d, 1H)。
LC-MS (方法1): Rt = 0.72 min; m/z = 251 (M+H)+。
实施例8A
2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-甲醛
将300 ml DMF冷却至0℃。然后缓慢地逐滴加入44 ml (470.08 mmol)三氯氧磷。然后将反应溶液缓慢地温热至室温并在该温度搅拌另一小时。然后逐份添加43 g (188.03mmol) 2-(4-氯苯基)咪唑并[1,2-a]吡啶。在此期间,将反应溶液温热至35℃。在加入已经结束后,将反应混合物加热至80℃并在该温度搅拌2小时。冷却至室温后,将溶液缓慢地加至3升冰-水中。将所得固体抽吸滤出,用水反复洗涤并在高真空干燥室中在40℃干燥过夜。这得到39.6 g (154.27 mmol,理论值的82%)目标产物。
1H-NMR (400 MHz, DMSO-d 6, δ/ppm): 7.37 (t, 1H), 7.63 (d, 2H), 7.78 (t,1H), 7.90-7.99 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H)。
LC-MS (方法1): Rt = 0.97 min; m/z = 257/259 (M+H)+。
类似于实施例8A,由在各情况中所示的起始物质制备下述化合物:
实施例15A
4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-甲酸叔丁酯
在氩气下且在室温,将1 g (3.90 mmol) 2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-甲醛溶解于20 ml THF中,并加入1.45 g (7.79 mmol)哌嗪-1-甲酸叔丁酯和0.45 ml (7.79mmol)乙酸。随后,逐份加入2.48 g (11.69 mmol)三乙酰氧基硼氢化钠,并将反应混合物在室温搅拌过夜。在反应已经结束后,缓慢地且小心地滴加水(气体逸出),然后加入乙酸乙酯。分离出有机相并将水相用乙酸乙酯萃取两次。将合并的有机相经硫酸镁干燥,过滤并在真空中在旋转蒸发器上浓缩至干。将所得残余物施加于硅胶上并通过硅胶上的柱色谱法(流动相: 环己烷/乙酸乙酯 2:1)纯化。这得到1.27 g (2.97 mmol, 76% 理论的)目标化合物。
1H-NMR (400 MHz, DMSO-d 6 , δ/ppm): 1.38 (s, 9H), 2.31-2.44 (m, 4H),3.22-3.32 (m, 4H, 被水信号部分地隐藏), 3.99 (s, 2H), 6.98 (t, 1H), 7.31 (t,1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.92 (d, 2H), 8.56 (d, 1H)。
LC-MS (方法1): Rt = 0.85 min; m/z = 427/429 (M+H)+。
类似于实施例15A,由在各情况中所示的起始物质制备下述化合物:
实施例22A
2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐
在搅拌下,将41.11 ml 氯化氢于二噁烷中的4 M溶液加至2.34 g (5.48 mmol) 4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-甲酸叔丁酯,并将混合物在室温搅拌3小时。然后将获得的固体抽吸滤出,用二乙醚反复洗涤并在高真空下在40℃干燥。这得到2.48 g目标产物,其未经进一步纯化地用于后续反应中。
LC/MS (方法1): Rt = 0.35 min; m/z = 327/329 (M+H)+。
类似于实施例22A, 由在各情况中所示的起始物质制备下述化合物:
实施例29A
2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶
将8.60 g (19.36 mmol) 2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐溶解于83 ml THF中,加入13.5 ml (97 mmol)三乙胺并在室温搅拌2小时。然后将水和乙酸乙酯加至反应溶液中。分离出有机相后,将水相用二氯甲烷萃取十次。将合并的有机相经硫酸镁干燥,过滤并在旋转蒸发器上在真空中浓缩至干。这得到3.15 g (8.48 mmol,理论值的44%)标题产物,其未经进一步纯化地用于后续反应中。
1H-NMR (400 MHz, DMSO-d 6 , δ/ppm): 2.29-2.43 (m, 4H), 2.61-2.75 (m,4H), 3.95 (s, 2H), 6.98 (t, 1H), 7.31 (t, 1H), 7.60 (d, 1H), 7.67 (d, 2H),7.85 (d, 2H), 8.54 (d, 1H)。
LC-MS (方法2): Rt = 0.59 min; m/z = 371/373 (M+H)+。
类似于实施例29A,由所示起始物质制备以下化合物:
实施例:
实施例1
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环戊基)甲酮
合成方法1
将100 mg (0.27 mmol) 2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶和35µl (0.32 mmol)环戊烷甲酸溶解于2 ml DMF中,并加入133 mg (0.35 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)和94 µl (0.54 mmol) N,N-二异丙基乙基胺。将混合物在室温搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到61 mg (0.13 mmol,理论值的48%)标题化合物。
LC-MS (方法1): Rt = 0.81 min; m/z = 467/469 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.42-1.77 (m, 8H), 2.35-2.46 (m,4H), 2.87-2.99 (m, 1H), 3.36-3.50 (m, 4H), 4.00 (s, 2H), 6.98 (t, 1H), 7.32(t, 1H), 7.61 (d, 1H), 7.67 (d, 2H), 7.86 (d, 2H), 8.58 (d, 1H)。
实施例2
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环戊基)甲酮
合成方法2
将150 mg (0.38 mmol) 2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐溶解于2 ml DMF中,并加入261 µl (1.50 mmol) N,N-二异丙基乙基胺。将混合物在室温搅拌30 min。然后加入47 mg (0.41 mmol)环戊烷甲酸和214 mg (0.56 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU),并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到110mg (0.26 mmol,理论值的69%)标题化合物。
LC-MS (方法1): Rt = 0.80 min; m/z = 423/425 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.42-1.78 (m, 8H), 2.34-2.46 (m,4H), 2.88-2.99 (m, 1H), 3.37-3.50 (m, 4H), 4.01 (s, 2H), 6.98 (t, 1H), 7.32(t, 1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.92 (d, 2H), 8.58 (d, 1H)。
实施例3
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮
合成方法3
将46 mg (0.30 mmol) 6-甲氧基吡啶-2-甲酸溶解于1.5 ml DMF中,加入124 mg(0.33 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)并在室温搅拌30 min。然后加入100 mg (0.25 mmol) 2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐和0.13 ml (0.75 mmol) N,N-二异丙基乙基胺,并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到81 mg (0.15 mmol,理论值的60%)标题化合物。
LC-MS (方法1): Rt = 0.74 min; m/z = 462/464 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.42-2.48 (m, 2H), 2.48-2.59 (m,2H, 被DMSO信号部分地隐藏), 3.37-3.47 (m, 2H), 3.55-3.67 (m, 2H), 3.80 (s,3H), 4.04 (s, 2H), 6.89 (d, 1H), 6.98 (t, 1H), 7.15 (d, 1H), 7.32 (t, 1H),7.53 (d, 2H), 7.61 (d, 1H), 7.80 (t, 1H), 7.92 (d, 2H), 8.58 (d, 1H)。
实施例4
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮
合成方法4
将1.77 g (3.98 mmol) 2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐溶解于30 ml 二氯甲烷中,加入2.77 ml (15.90 mmol) N,N-二异丙基乙基胺并在室温搅拌30 min。在将反应溶液冷却至0℃后,滴加0.52 ml (4.37 mmol)2-氟苯甲酰氯,然后将混合物温热至室温并在该温度继续搅拌过夜。加入水后,将溶液在分液漏斗中振摇并分离各相。将有机相经硫酸镁干燥,过滤并在真空中在旋转蒸发器上浓缩至干。将所得残余物施加于硅胶上并通过硅胶上的柱色谱法(Biotage; 流动相: 环己烷/乙酸乙酯 4:1)纯化。这得到1.42 g (2.88 mmol,理论值的72%)目标化合物。
LC-MS (方法1): Rt = 0.74 min; m/z = 493/495 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.36-2.45 (m, 2H), 2.47-2.59 (m,2H, 被DMSO信号隐藏), 3.13-3.23 (m, 2H), 3.56-3.68 (m, 2H), 4.03 (s, 2H), 6.98(t, 1H), 7.23-7.41 (m, 4H), 7.44-7.53 (m, 1H), 7.60 (d, 1H), 7.67 (d, 2H),7.85 (d, 2H), 8.58 (d, 1H)。
实施例5
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(3-甲氧基苯基)甲酮
合成方法5
将100 mg (0.27 mmol) 2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶溶解于3 ml二氯甲烷中,加入56 µl (0.40 mmol)三乙胺和1.65 mg (0.01 mmol) 4-N,N-二甲基氨基吡啶并然后将混合物冷却至0℃。然后在搅拌下滴加45 µl (0.30 mmol) 3-甲氧基苯甲酰氯,然后将混合物温热回到室温并在该温度继续搅拌过夜。在加入水和二氯甲烷后,将所得水相用二氯甲烷再萃取三次。将合并的有机相经硫酸镁干燥,过滤并在真空中在旋转蒸发器上浓缩至干。将获得的残余物溶解于乙腈中。过一小会儿后,从溶液中沉淀出固体,将固体抽吸滤出,用乙腈重复洗涤,然后在真空下在40℃干燥。这得到51 mg标题化合物。将获得的母液在旋转蒸发器上浓缩,并将残余物通过制备型HPLC (方法6)分离成其组分。这得到另外23 mg标题化合物。总计,获得74 mg (0.14 mmol,理论值的54%)标题化合物。
LC-MS (方法1): Rt = 0.81 min; m/z = 505/507 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.35-2.56 (m, 4H, 被DMSO信号部分地隐藏), 3.22-3.38 (m, 2H, 被水信号部分地隐藏), 3.47-3.66 (m, 2H), 3.77 (s,3H), 4.02 (s, 2H), 6.86-6.94 (m, 2H), 6.95-7.03 (m, 2H), 7.28-7.38 (m, 2H),7.60 (d, 1H), 7.67 (d, 2H), 7.85 (d, 2H), 8.58 (d, 1H)。
实施例6
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氯-5-氟苯基)甲酮
合成方法6
将47 mg (0.27 mmol) 2-氯-5-氟苯甲酸置于1 ml 二氯甲烷中,加入100 mg (0.27mmol) 2-(4-溴苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶并在室温搅拌30 min。然后加入0.07 ml (0.81 mmol)吡啶和0.06 ml (0.43 mmol) 1-氯-1-二甲基氨基-2-甲基-1-丙烯(溶解于3 ml 二氯甲烷中),并将混合物在室温进一步搅拌过夜。然后将反应混合物浓缩并将残余物通过制备型HPLC (方法6)分离成其组分。这得到76 mg (0.14 mmol,理论值的52%)标题化合物。
LC-MS (方法1): Rt = 0.86 min; m/z = 527/529 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.38-2.46 (m, 2H), 2.46-2.57 (m,2H, 被DMSO信号隐藏), 3.06-3.16 (m, 2H), 3.53-3.66 (m, 2H), 4.03 (s, 2H), 6.98(t, 1H), 7.26-7.36 (m, 3H), 7.53-7.62 (m, 2H), 7.67 (d, 2H), 7.84 (d, 2H),8.57 (d, 1H)。
实施例7
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮
合成方法7
将100 mg (0.25 mmol) 2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐溶解于1.5 ml DMF中,并加入0.17 ml (1.00 mmol)N,N-二异丙基乙基胺。将混合物在室温搅拌30 min。然后加入39 mg (0.28 mmol) 2-氟苯甲酸和143 mg (0.38 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU),并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到76mg (0.17 mmol,理论值的68%)标题化合物。
LC-MS (方法1): Rt = 0.77 min; m/z = 449/451 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.35-2.44 (m, 2H), 2.44-2.58 (m,2H, 被DMSO信号部分地隐藏), 3.12-3.23 (m, 2H), 3.54-3.68 (m, 2H), 4.03 (s,2H), 6.98 (t, 1H), 7.23-7.41 (m, 4H), 7.44-7.56 (m, 3H), 7.60 (d, 1H), 7.91(d, 2H), 8.58 (d, 1H)。
实施例8
(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(环己基)甲酮
合成方法8
将45 mg (0.35 mmol) 环己烷甲酸溶解于1.5 ml DMF中,加入184 mg (0.48 mmol)2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)并在室温搅拌30min。然后加入100 mg (0.32 mmol) 2-(4-氟苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶和0.11 ml (0.64 mmol) N,N-二异丙基乙基胺,并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到75 mg (0.17 mmol,理论值的53%)标题化合物。
LC-MS (方法1): Rt = 0.75 min; m/z = 421 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 1.06-1.36 (m, 5H), 1.52-1.73 (m,5H), 2.34-2.47 (m, 4H), 2.47-2.58 (m, 1H, 被DMSO信号隐藏), 3.36-3.48 (m, 4H),3.99 (s, 2H), 6.97 (td, 1H), 7.26-7.35 (m, 3H), 7.60 (d, 1H), 7.89-7.96 (m,2H), 8.57 (d, 1H)。
根据上述合成方法1-8,也由在各情况中所示的起始物质制备以下化合物:
实施例67
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)[6-(三氟甲氧基)吡啶-2-基]甲酮
将75 mg (0.36 mmol) 6-(三氟甲氧基)吡啶-2-甲酸溶解于1.8 ml DMF中,加入148mg (0.39 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)并在室温搅拌30 min。然后加入120 mg (0.30 mmol) 2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐和0.16 ml (0.90 mmol) N,N-二异丙基乙基胺,并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到112 mg (0.22 mmol,理论值的73%)标题化合物。
LC-MS (方法2): Rt = 1.55 min; m/z = 516/518 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.44 (br. t, 2H), 2.55 (br. t,2H), 3.37 (br. t, 2H), 3.61 (br. s, 2H), 4.05 (s, 2H), 6.98 (td, 1H), 7.32(ddd, 1H), 7.38 (d, 1H), 7.53 (d, 2H), 7.58-7.65 (m, 2H), 7.91 (d, 2H), 8.14(t, 1H), 8.58 (d, 1H)。
实施例68
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(3-氟-6-甲氧基吡啶-2-基)甲酮
将62 mg (0.36 mmol) 3-氟-6-甲氧基吡啶-2-甲酸溶解于1.8 ml DMF中,加入148 mg(0.39 mmol) 2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)并将混合物在室温搅拌30 min。然后加入120 mg (0.30 mmol) 2-(4-氯苯基)-3-(哌嗪-1-基甲基)咪唑并[1,2-a]吡啶二盐酸盐和0.16 ml (0.90 mmol) N,N-二异丙基乙基胺,并将混合物在室温进一步搅拌过夜。然后将反应混合物通过制备型HPLC (方法6)直接分离成其组分。这得到118 mg仍然污染的标题化合物,将其通过另一次制备型HPLC (方法6)再纯化。这得到91 mg (0.19 mmol,理论值的63%)标题化合物。
LC-MS (方法2): Rt = 1.36 min; m/z = 480/482 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 2.42 (br. t, 2H), 2.47-2.59 (m,2H, 被DMSO信号部分地隐藏), 3.23 (br. t, 2H), 3.62 (br. s, 2H), 3.79 (s, 3H),4.05 (s, 2H), 6.90-7.02 (m, 2H), 7.32 (ddd, 1H), 7.53 (d, 2H), 7.61 (d, 1H),7.77 (t, 1H), 7.92 (d, 2H), 8.59 (d, 1H)。
实施例69
(4-{[2-(4-环丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮
将100 mg (0.20 mmol) (4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮溶解于8 ml甲苯和0.4 ml水中。然后将35 mg (0.41 mmol)环丙基硼酸、151 mg (0.71 mmol)磷酸钾、4.6 mg (0.02 mmol)乙酸钯(II)和11 mg (0.04 mmol)三环己基膦依次加入至反应溶液中。然后将反应溶液加热至80℃并在该温度搅拌过夜。冷却至室温后,将反应混合物首先通过硅藻土过滤,然后通过制备型HPLC (方法6)分离成其组分。这得到41 mg (0.09 mmol,理论值的43%)标题化合物。
LC-MS (方法2): Rt = 1.36 min; m/z = 455 (M+H)+。
1H-NMR (400 MHz, DMSO-d 6 ): δ [ppm] = 0.68-0.76 (m, 2H), 0.94-1.03 (m,2H), 1.13-1.35 (m, 1H), 1.60-1.85 (m, 1H), 1.91-2.01 (m, 1H), 2.40 (br. s,2H), 3.18 (br. s, 2H), 3.61 (br. s, 2H), 4.02 (s, 2H), 6.95 (td, 1H), 7.17(d, 2H), 7.23-7.33 (m, 3H), 7.37 (td, 1H), 7.44-7.52 (m, 1H), 7.58 (d, 1H),7.74 (d, 2H), 8.55 (d, 1H)。
根据上述合成方法7,也由在各情况中所示的起始物质制备以下化合物:
B. 药理效力的评估
如本领域技术人员已知的那样,本发明的化合物的药理活性可通过体外和体内研究来证实。下面的应用实施例描述了本发明的化合物的生物作用,而并非将本发明限制于这些实施例。
B-1. 通过有爪蟾卵母细胞中的双电极电压钳制术进行人TASK-1和TASK-3通道的 体外电生理分析
如在它处以示例性方式描述那样,选择爪蟾卵母细胞[Decher 等人, FEBS Lett. 492,84-89 (2001)]。随后,向卵母细胞注射0.5-5 ng编码TASK-1或TASK-3的cRNA溶液。对于卵母细胞中表达的通道蛋白的电生理分析,使用双电极电压钳制术 [Stühmer, Methods Enzymol. 207, 319-339 (1992)]。测量如所述那样[Decher 等人, FEBS Lett. 492, 84-89(2001)]在室温(21-22℃)通过在2 kHz记录并以0.4 kHz过滤的Turbo TEC 10CD扩增器(NPI)进行。物质施用是通过重力驱动的灌注系统进行的。在此,卵母细胞存在于测量室中并暴露于10 ml/min的溶剂流。通过使用蠕动泵抽吸溶液,对测量室中的水平进行监测并调节。
下表1A显示了通过本发明的代表性实施例在该测试中测定的人TASK-1和TASK-3通道的半数最大抑制(IC50值):
表1A
从表1A中的数据明显可以看出,TASK-1和TASK-3二者都被阻断了。因此,表1A中的结果证实了根据本发明的化合物作为双重TASK-1/3 抑制剂的作用机制。
为了对比,也在该测试中就对人TASK-1和TASK-3通道的抑制而言研究了一些其它{4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮衍生物(其可以视为结构上最接近的现有技术[参见WO 2014/187922-A1中所述的化合物,其为葡萄糖转运体(GLUT)的抑制剂])。对于这些化合物所获得的结果列在下表1B中:
表1B
因此,根据该测试,表1B中列出的现有技术的对比化合物具有就TASK-1和TASK-3通道而言显著更低(低了约1-3个数量级)的抑制活性。
B-2. 重组TASK-1和TASK-3的体外抑制
使用稳定转染的CHO细胞进行对重组TASK-1和TASK-3通道的抑制的研究。在此,根据下述参考文献中详细描述的方法[Whiteaker等人, Validation of FLIPR membranepotential dye for high-throughput screening of potassium channel modulators,J. Biomol. Screen. 6 (5), 305-312 (2001); Molecular Devices FLIPR ApplicationNote: Measuring membrane potential using the FLIPR® membrane potential assaykit on Fluorometric Imaging Plate Reader (FLIPR®) systems, http://www.moleculardevices.com/reagents-supplies/assay-kits/ion-channels/flipr-membrane-potential-assay-kits]在电压敏感性染料的存在下通过施用40 mM 氯化钾测试根据本发明的化合物。将测试物质的活性确定为它们抑制重组细胞中由40 mM 氯化钾诱导的去极化的能力。可以阻断该去极化的一半的浓度被称为IC50。
下表2A列出了来自该测定的针对本发明的实施例确定的IC50值(一些是作为来自多次独立单独测定的平均值):
表2A
从表2A中的数据中明显可以看出,TASK-1和TASK-3二者都被阻断了。因此,表2A中的结果证实了根据本发明的化合物作为双重TASK-1/3 抑制剂的作用机制。
为了对比,也在该测试中就对重组TASK-1和TASK-3通道的抑制而言研究了一些其它{4-[(2-苯基咪唑并[1,2-a]吡啶-3-基)甲基]哌嗪-1-基}甲酮衍生物(其可以视为结构上最接近的现有技术[参见WO 2014/187922-A1中所述的化合物,其为葡萄糖转运体(GLUT)的抑制剂])。对于这些化合物所获得的结果列在下表2B中:
表2B
因此,在该测试中,在表2B中列出的来自现有技术的对比化合物不具有对于TASK-1的显著活性,其最多可以被认为是非特异性的,并且对于TASK-3仅具有弱至同样不显著的抑制活性。
B-3. 猪中的阻塞性睡眠呼吸暂停动物模型
通过使用负压,可以引起麻醉的、自发性呼吸的猪的上呼吸道缩陷和由此带来的阻塞。[Wirth 等人, Sleep 36, 699-708 (2013)]。
将德国兰德拉斯猪(Deutsche Landschweine)用于该模型。将猪麻醉和切开气管。将各一个插管插入气管的前部和尾部。使用T形头(T-Stück),将前部插管一方面连接到产生负压的装置,另一方面连接到尾部插管。使用T形头,将尾部插管与前部插管和与通过绕过上呼吸道而允许自主呼吸的管连接。通过适当的关闭和打开管,由此在当上呼吸道被分离并连接到用于产生负压的装置时,猪有可能从正常的鼻呼吸改变成通过尾部插管的呼吸。通过肌电图(EMG)记录颏舌肌的肌肉活动。
在某些时间点,通过使猪通过尾部插管呼吸并向上呼吸道施加-50、-100和-150cm水柱(cm H2O)的负压,测试上呼吸道的缩陷。由此使上呼吸道缩陷,其表现为管系统中的空气流中断和压力降。该测试是在施用测试物质之前和在施用测试物质后一定时间间隔进行的。适当有效的测试物质可以防止该吸气期中的呼吸道的缩陷。
在从鼻呼吸转换成通过尾部插管的呼吸之后,不能测量麻醉的猪的颏舌肌的EMG活性。作为进一步的测试,然后确定EMG活性重新开始时的负压。如果测试物质是有效的,这个阈值推移至更正向的值。该研究同样是在施用测试物质之前和在施用测试物质后一定时间间隔进行的。测试物质的施用可以是鼻内、静脉内、皮下、腹膜内或胃内。
C. 药物组合物的实施例
可以如下将本发明的化合物转化成药物制剂:
片剂:
组成:
100 mg本发明的化合物、50 mg乳糖(一水合物)、50 mg玉米淀粉(天然)、10 mg聚乙烯吡咯烷酮(PVP 25)(BASF公司, Ludwigshafen, 德国)和2 mg硬脂酸镁。
片剂重212 mg。直径8 mm,曲率半径12 mm。
生产:
将本发明的化合物、乳糖和淀粉的混合物用PVP在水中的5%溶液(w/w)进行造粒。在干燥后,将颗粒与硬脂酸镁混合5分钟。将该混合物通过传统压片机压制(片剂的规格见上)。用于压制的引导值为15 kN的压制力。
口服施用的混悬剂:
组成:
1000 mg本发明的化合物、1000 mg乙醇 (96%)、400 mg of Rhodigel® (黄原胶,FMC公司, Pennsylvania, USA)和99 g水。
10 ml口服混悬剂对应于100 mg本发明的化合物的单剂量。
生产:
将Rhodigel悬浮在乙醇中;将本发明的化合物添加到悬浮液中。在搅拌下加入水。搅拌约6 h,直至Rhodigel溶胀完成。
用于口服施用的溶液剂:
组成:
500 mg本发明的化合物、2.5 g聚山梨酯和97 g聚乙二醇400。20 g口服溶液剂对应于100 mg本发明的化合物的单剂量。
生产:
在搅拌下将本发明的化合物悬浮在聚乙二醇和聚山梨酯的混合物中。继续搅拌操作直至本发明化合物完全溶解。
静脉注射溶液剂:
将本发明的化合物以低于饱和溶解度的浓度溶解在生理上可接受的溶剂(例如等渗盐水溶液、5%葡萄糖溶液和/或30% PEG 400溶液)中。该溶液进行无菌过滤,并分配到无菌和无热原的注射容器中。
用于鼻腔施用的溶液剂:
将本发明的化合物以低于饱和溶解度的浓度溶解在生理上可接受的溶剂(例如纯化水、磷酸盐缓冲液、柠檬酸盐缓冲液)中。该溶液可含有用于等渗、用于保存、用于调节pH值、用于改善溶解度和/或用于稳定化的其它添加剂。
Claims (11)
1.式(I)的化合物及其盐、溶剂合物和盐的溶剂合物
其中
R1代表卤素、氰基、(C1-C4)-烷基、环丙基或环丁基
和
R2代表(C4-C6)-环烷基,其中环-CH2-基团可以被-O-代替
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、溴、氰基、(C1-C3)-烷基或(C1-C3)-烷氧基,
其中(C1-C3)-烷基和(C1-C3)-烷氧基可以被氟取代至多三次,
R4代表氢、氟、氯、溴或甲基,
R5代表氢、氟、氯、溴或甲基
和
R6代表氢、(C1-C3)-烷氧基、环丁基氧基、氧杂环丁烷-3-基氧基、四氢呋喃-3-基氧基或四氢-2H-吡喃-4-基氧基,
其中(C1-C3)-烷氧基可以被氟取代至多三次。
2.根据权利要求1的式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表氟、氯、溴、甲基、异丙基、叔丁基或环丙基
和
R2代表环丁基、环戊基或环己基
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、氰基、(C1-C3)-烷基、(C1-C3)-烷氧基或三氟甲氧基,
R4代表氢、氟或氯,
R5代表氢、氟、氯、溴或甲基
和
R6代表氢或(C1-C3)-烷氧基,其可以被氟取代至多三次。
3.根据权利要求1或2的式(I)的化合物及其盐、溶剂合物和盐的溶剂合物,其中
R1代表氯、溴、异丙基或环丙基
和
R2代表环丁基、环戊基或环己基
或
代表式(a)的苯基或式(b)的吡啶基
其中*标记与毗邻羰基连接的键并且
R3代表氟、氯、氰基、甲基、异丙基、甲氧基或乙氧基,
R4代表氢、氟或氯,
R5代表氢、氯或溴
和
R6代表甲氧基、二氟甲氧基、三氟甲氧基或异丙氧基。
4.用于制备如权利要求1-3中定义的式(I)的化合物的方法,其特征在于在合适的还原剂的存在下使式(II)的化合物
其中R1具有在权利要求1-3中给出的含义,
[A] 与式(III)的化合物反应
其中R2具有在权利要求1-3中给出的含义,
或
[B] 与式(IV)的被保护的哌嗪衍生物反应
其中PG代表合适的氨基保护基,例如叔丁氧基羰基、苄氧基羰基或(9H-芴-9-基甲氧基)羰基,
以首先得到式(V)的化合物
其中PG和R1具有上面给出的含义,
然后移除保护基PG并然后使所得式(VI)的化合物与式(VII)的羧酸通过活化(VII)中的羧酸功能而反应
其中R1具有上面给出的含义,
其中R2具有在权利要求1-3中给出的含义,
或与相应的式(VIII)的酰氯反应
其中R2具有在权利要求1-3中给出的含义,
并将如此所得的式(I)的化合物任选地用适当的(i)溶剂和/或(ii)酸转化成它们的溶剂合物、盐和/或盐的溶剂合物。
5.如权利要求1-3中的任一项定义的化合物,其用于治疗和/或预防疾病。
6.如权利要求1-3中的任一项定义的化合物,其用于治疗和/或预防呼吸病症、睡眠相关的呼吸病症、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律失常、心律不齐、神经变性病症、神经炎性病症和神经免疫病症的方法。
7.如权利要求1-3中的任一项定义的化合物用于制备用于治疗和/或预防呼吸病症、睡眠相关的呼吸病症、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律失常、心律不齐、神经变性病症、神经炎性病症和神经免疫病症的药物的用途。
8.药物,其包含如权利要求1-3中的任一项定义的化合物与一种或多种惰性、无毒性、药学上合适的赋形剂的组合。
9.药物,其包含如权利要求1-3中的任一项定义的化合物与一种或多种其它活性物质的组合,所述活性物质选自呼吸刺激剂、精神刺激化合物、5-羟色胺再摄取抑制剂、去甲肾上腺素能、5-羟色胺能和三环抗抑郁药、sGC刺激剂、盐皮质激素受体拮抗剂、抗炎药、免疫调节剂、免疫抑制剂和细胞毒性药物。
10.如权利要求8或9中定义的药物,其治疗和/或预防呼吸病症、睡眠相关的呼吸病症、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律失常、心律不齐、神经变性病症、神经炎性病症和神经免疫病症。
11.通过施用有效量的至少一种如权利要求1-3中的任一项定义的化合物或如权利要求8-10中的任一项定义的药物治疗和/或预防人和动物中的呼吸病症、睡眠相关的呼吸病症、阻塞性睡眠呼吸暂停、中枢性睡眠呼吸暂停、打鼾、心律失常、心律不齐、神经变性病症、神经炎性病症和神经免疫病症的方法。
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PCT/EP2016/079973 WO2017097792A1 (de) | 2015-12-10 | 2016-12-07 | 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridin-derivate als blocker der task-1 und task-2 kanäle zur behandlung von schlafbedingten atemstörungen |
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CN113194924A (zh) * | 2018-11-27 | 2021-07-30 | 拜耳公司 | 制备包含task-1和task-3通道抑制剂的药物剂型的方法及其在呼吸障碍治疗中的用途 |
CN114507695A (zh) * | 2022-02-17 | 2022-05-17 | 四川大学华西医院 | 一种用于调控神经元活性的重组载体和方法 |
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TW202216141A (zh) | 2020-07-06 | 2022-05-01 | 德商拜耳廠股份有限公司 | 用以治療睡眠呼吸終止之α2-腎上腺素受體C亞型(α-2C)拮抗劑與TASK1/3通道阻斷劑的組合 |
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- 2016-12-07 WO PCT/EP2016/079973 patent/WO2017097792A1/de active Application Filing
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CN113166166A (zh) * | 2018-11-20 | 2021-07-23 | 拜耳公司 | 用于治疗睡眠呼吸中止的α2-肾上腺素受体亚型C(α-2C)拮抗剂 |
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EA201891374A1 (ru) | 2018-11-30 |
ECSP18043573A (es) | 2018-06-30 |
CU20180056A7 (es) | 2018-10-04 |
CO2018005905A2 (es) | 2018-07-10 |
KR20180088462A (ko) | 2018-08-03 |
WO2017097792A1 (de) | 2017-06-15 |
JP2018536693A (ja) | 2018-12-13 |
CL2018001511A1 (es) | 2018-09-21 |
PH12018501235A1 (en) | 2019-02-04 |
US20190062326A1 (en) | 2019-02-28 |
GEAP202014824A (en) | 2020-01-27 |
CA3007724A1 (en) | 2017-06-15 |
IL259374A (en) | 2018-07-31 |
CA3007724C (en) | 2023-10-17 |
SV2018005704A (es) | 2018-09-10 |
MX2018007040A (es) | 2018-08-15 |
HK1254853A1 (zh) | 2019-07-26 |
TW201734012A (zh) | 2017-10-01 |
DOP2018000142A (es) | 2018-06-30 |
UY37013A (es) | 2017-06-30 |
SG11201804449WA (en) | 2018-06-28 |
GEP20207104B (en) | 2020-05-11 |
US10759794B2 (en) | 2020-09-01 |
NI201800066A (es) | 2019-03-14 |
EP3386979A1 (de) | 2018-10-17 |
AU2016365676A1 (en) | 2018-06-07 |
EP3386979B1 (de) | 2020-07-29 |
TN2018000193A1 (en) | 2019-10-04 |
BR112018011783A2 (pt) | 2018-12-04 |
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