CN103025744A - 作为α-7烟碱乙酰胆碱受体配体前药的氮杂二环胺N-氧化物化合物 - Google Patents
作为α-7烟碱乙酰胆碱受体配体前药的氮杂二环胺N-氧化物化合物 Download PDFInfo
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- CN103025744A CN103025744A CN2011800323479A CN201180032347A CN103025744A CN 103025744 A CN103025744 A CN 103025744A CN 2011800323479 A CN2011800323479 A CN 2011800323479A CN 201180032347 A CN201180032347 A CN 201180032347A CN 103025744 A CN103025744 A CN 103025744A
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- base
- pyridyl
- pyrimidyl
- alkyl
- compound
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- 239000000651 prodrug Substances 0.000 title abstract description 6
- 239000003446 ligand Substances 0.000 title abstract description 4
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- 238000000034 method Methods 0.000 claims abstract description 18
- -1 pyrazolyl oxazolyl Chemical group 0.000 claims description 150
- 125000004076 pyridyl group Chemical group 0.000 claims description 49
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
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Abstract
本公开大体涉及式I的化合物包括其盐,以及使用所述化合物的组合物和方法。所述化合物为烟碱α7受体的配体、激动剂和部分激动剂的前药且可用于治疗各种中枢神经系统病症,特别是情感障碍及神经变性病症。
Description
相关申请的交叉引用
本专利申请要求2010年4月30日提交的美国临时专利申请61/329,765的权益。
技术领域
本公开大体涉及式I的化合物包括其盐,以及使用所述化合物的组合物和方法。所述化合物为烟碱α7受体的配体、激动剂和部分激动剂的前药且可用于治疗各种中枢神经系统病症,特别是情感障碍(affective disorder)及神经变性病症(neurodegenerative disorder)。
背景技术
精神分裂症(schizophrenia)为严重精神病症,其影响约1%的人口。其进行性病程对精神及社交功能造成重大损伤且经常导致出现其它病理。经常出现家族性易感性,认为遗传及环境因素二者均很重要。据估计,仅在美国,该疾病每年的直接及间接费用即为数百亿美元。
精神分裂症患者的自杀风险增加(约10%终生风险)。其所有原因死亡率增加2.5倍,从而使预期寿命降低20%。疾病的发作可引发一系列不健康的生活方式因素及行为,这提高出现各种病症的风险并由此提高死亡风险。
精神分裂症最常在青春期末期或成人期早期发作,且可在整个生命中复发。该疾病的特征在于三个独特的症状域的表现:阳性、阴性及认知。精神病或阳性症状包括妄想、幻觉、思维障碍及偏执狂。阴性症状包括负性情感、社交回避及兴趣缺失。认知功能障碍包括注意力、工作记忆及执行功能的缺陷。然而,尚未完全理解精神分裂症的病理生理学,大多数专家相信,其为多因素病症,其中生物、遗传及环境因素均有影响。当前大多数疗法均以多巴胺能系统为靶标且因此已有人提出,多巴胺能神经传递过度为精神分裂症中至少某些方面的基础。此理论由以下发现得到进一步证实:提高多巴胺含量的药物引发与该疾病中的阳性症状类似的精神病。同样,对精神分裂症患者脑的死后分析显示,D2多巴胺受体数量增加。尽管在过去十年间已引入对若干种其它神经递质受体具有活性的较新抗精神病药物(称作非典型抗精神病药),但所述药物仍均具有针对D2多巴胺受体的效能。当前使用的所有药物也具有重大限制。尽管所述药物一般在大多数患者中可降低阳性症状,但其对减轻常见且最常使人虚弱的阴性症状及认知缺陷几乎无作用。另外,抗精神病药物具有多种不期望的限制性副作用。
烟碱为少数对认知功能具有正面效应的药物之一。许多精神分裂症患者吸烟;患者吸烟的比率为一般人群的2-4倍,且高达90%的已住院精神分裂症患者吸烟。此吸烟习惯已被称作一种自我给药形式。
烟碱乙酰胆碱(nicotinic acetylcholine)受体(nAChR’s)为五聚配体门控离子通道,其在中枢及周围神经系统中广泛表达。所述通道为快速脱敏的钙通道,其在开放时提高Ca++离子的细胞内浓度。尽管存在12种单个受体,但脑中最丰富的烟碱受体为α4β2及α7。已将α4β2复合物确定为“高亲和性”烟碱位点。同五聚α7受体选择性结合天然产物α-金环蛇毒素,从而使其可相对容易地定位及测量。α7受体主要在皮质、海马及皮质下边缘区域表达且一般存在于突触前。α7nAChRs在涉及学习及记忆的区域中的定位促使使用敲除小鼠及药理学处理进行研究。其参与感觉门控、记忆及神经元可塑性。已显示α7激动剂可提高神经递质在啮齿类动物中的释放,所述神经递质包括多巴胺、5-羟色胺、谷氨酸盐及GABA。已显示选择性结合α7受体的化合物(诸如α7激动剂及部分激动剂)可在正常及老年动物中改善学习及记忆功能,逆转东莨菪碱(scopolamine)诱导的记忆缺陷,逆转NMDA拮抗剂诱导的认知缺陷,逆转药理学诱导的门控缺陷(例如安非他命(amphetamine)诱导的门控中断),且具有一些抗焦虑特性。预期本发明α7激动剂可用于治疗精神分裂症及与精神分裂症有关的认知障碍。
阿尔茨海默病(Alzheimer’s disease)为进行性神经变性病症,其造成认知功能的一般损失。发病率随年龄而增加,从而使得所有超过85岁的个体中预计有25-50%患有一定程度的痴呆。对阿尔茨海默病的诊断显示,剩余预期寿命与正常成人相比减半。
阿尔茨海默病的临床体征为进行性认知衰退、进行日常生活活动的能力降低及神经精神症状或行为变化。在该疾病的后期,肌肉组织与运动性的衰退可导致不能自己进食,且最终导致患者卧床不起。语言变得非常混乱,且之后完全丧失。患者甚至不能独立完成简单的任务并且需要持续监护。住院护理费用占该疾病费用的近70%。因此,非常需要可增强认知功能并延迟住院的疗法。
已有若干个研究显示阿尔茨海默病伴随皮质及海马中的烟碱受体降低。已报导烟碱注射或烟碱皮肤贴剂可显著改善阿尔茨海默病患者的注意力、记忆及学习。尽管在阿尔茨海默病病程期间烟碱受体仍继续损失,但α7神经元与更丰富的α4受体相比相对较少。最近,已显示在长达8周期间给药时,给予选择性烟碱α7激动剂可增强阿尔茨海默病患者的认知功能。此临床数据与临床前数据一致,该临床前数据显示α7激动剂及部分激动剂可改善正常及老年动物的学习及记忆功能并逆转东莨菪碱诱导的记忆缺陷。因此,本发明化合物可用于治疗及预防阿尔茨海默病。已显示淀粉样肽Aβ42可结合α7烟碱受体(Wang等人,J.Biol.Chem.,2000,275:5626-5632;J.Neurochem.2000,75:1155-1161)。此缔合(association)可促进Aβ42的聚集(认为其在Aβ42的毒性效应中具有重要作用),且也可引发经α7烟碱受体的信号传导失调。缺失α7受体基因可在阿尔茨海默病小鼠模型中改善认知缺陷及突触病状(Dziewczapolski等人,J.Neuroscience,2009,第8805-8815页)。本发明化合物可破坏Aβ42与α7受体的相互作用。用α7激动剂及部分激动剂治疗可代表对阿尔茨海默病进行疾病修饰的方法。α7受体也可在诸如阿尔茨海默病等神经变性病症中介导炎症过程(Conejero-Goldberg等人,Neurosci.and Biobehav.Rev.,2008,32,第693-706页)。本发明α7激动剂及部分激动剂可用于在诸如阿尔茨海默病等神经变性疾病及病症中降低炎症。
已显示α7受体可参与降低迷走神经炎症。另外,α7受体在RA及OA患者的滑膜细胞中表达,且已显示α7激动剂可抑制在类风湿性关节中出现的促炎症级联(Waldberger等人,Arthritis and Rheumatism,第58卷,第3439-3449页)。因此,本发明化合物可用于治疗炎性病症,例如类风湿性关节炎及骨关节炎。
含有α7亚单元的烟碱受体存于已知参与胃肠过敏症的粘膜肥大细胞上(Kageyama-Yahara等人,Biochem and Biophys.Research Commun.,2008,第377卷,第321-325页)。α7激动剂GTS-21抑制粘膜肥大细胞的抗原诱导去粒,从而表明α7激动剂可用于治疗过敏性肠病,诸如溃疡性结肠炎。
在近期报导(Marrero等人,JPET Fast Forward,2009年9月28日,DOI:10.1124/jpet.109.154633)中,显示α7激动剂可在II型糖尿病小鼠模型(瘦蛋白受体缺陷型db/db小鼠)中降低体重增长及食物摄取并降低甘油三酯、葡萄糖、糖基化血红蛋白及TNFa的血浆含量增加。本发明α7激动剂及部分激动剂可用于治疗糖尿病。
以下参考文献提供烟碱受体系统及α7受体及配体的概述:Picciotto及Zoli,J.Neurobio.(2002)53:641-655;Brening等人,Ann.Reports in Med.Chem.(2005)40:3-16;Dani及Bertrand,Ann.Rev.Pharm.Tox.(2007)47:699-729;Olincy及Stevens,Biochem.Pharmacol.(2007)74:1192-1201;Broad等人,Drugs Future (2007)32(2):161-70;de Jonge及Ulloa,Brit.J.Pharmacol.(2007)151:915-929;Romanelli等人,ChemMed Chem (2007)2(6):746-767;Lightfoot等人,Progress in Medicinal Chemistry(2008),第46卷,第131-171页;Concotta等人,Current Opinion in Investigational Drugs(2008),第9卷,第47-56页;Leiser等人,Pharmacol.and Therapeutics(2009),doi:10:1016/j.pharmthera.2009.03.009)。
烟碱α7受体的配体已被披露。参见:美国专利7,863,291及US20100099684。
本发明提供技术优势,例如,化合物具有新颖性且为烟碱α7受体的配体的前药且可用于治疗各种中枢神经系统病症,特别是情感障碍及神经变性病症。另外,所述化合物在(例如)以下中的一个或多个方面提供医药应用的优势:其作用机制、结合、抑制效能、靶标选择性、可溶性、安全分布或生物利用度。
发明内容
本发明涵盖式I的化合物,包括药用盐,及使用所述化合物的组合物及治疗方法。所述化合物可用于治疗各种中枢神经系统病症。
本发明一方面为式I的化合物,或其立体异构体或其药用盐,
其中:
m为0或1;
n为1或2;
R1选自:异噁唑基、吡唑基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、三唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、喹唑啉基、二氮杂萘基、吲唑基、吲哚基、2-吲哚酮基、苯并异噁唑基、苯并异噻唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、呋喃并吡啶基、噻吩并吡啶基、噻吩并嘧啶基、异噻唑并吡啶基、噻唑并吡啶基、噻唑并吡啶酮基、噻唑并吡嗪基、噻唑并嘧啶基、三唑并吡啶基、三唑并吡嗪基、吡咯并三嗪基、5,6-二氢苯并[h]喹唑啉基、5H-苯并吡喃并[4,3-d]嘧啶基、6,7-二氢-5H-环戊二烯并[d]嘧啶基、5,6,7,8-四氢喹唑啉基、7,8-二氢喹唑啉-5(6H)-酮基、四氢苯并噻唑基、咪唑并噻唑基、噁唑并吡啶基、三唑并哒嗪基、三唑并嘧啶基、咪唑并哒嗪基、咪唑并吡嗪基、咪唑并吡啶基、吡咯并吡嗪基、苯并三唑基、吡咯并嘧啶基、嘌呤基、吡咯并吡啶基及苯并三嗪基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、硝基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、吡唑基、咪唑基、吡咯基、噁二唑基、噻唑基、三唑基、吡嗪基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中咪唑基、吡啶基、苯基、吡咯基、噁二唑基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基、苄基、吡啶基甲基及NR2R3;
R2为氢、苯基、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
R3为氢、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
或者R2及R3与它们所连接的氮原子一起为氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、N-(C1-4烷基)哌嗪基、吗啉基或者高哌啶基。
本发明另一方面为式I的化合物或其药用盐
其中:
m为0或1;
n为1或2;
R1选自:异噁唑基、吡唑基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、三唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、喹唑啉基、二氮杂萘基、吲唑基、吲哚基、2-吲哚酮基、苯并异噁唑基、苯并异噻唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、呋喃并吡啶基、噻吩并吡啶基、噻吩并嘧啶基、异噻唑并吡啶基、噻唑并吡啶基、噻唑并吡啶酮基、噻唑并吡嗪基、噻唑并嘧啶基、三唑并吡啶基、三唑并吡嗪基、吡咯并三嗪基、5,6-二氢苯并[h]喹唑啉基、5H-苯并吡喃并[4,3-d]嘧啶基、6,7-二氢-5H-环戊二烯并[d]嘧啶基、5,6,7,8-四氢喹唑啉基、7,8-二氢喹唑啉-5(6H)-酮基及四氢苯并噻唑基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、硝基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、三唑基、吡嗪基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中咪唑基、吡啶基、苯基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基及NR2R3;
R2为氢、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
R3为氢、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
或者R2及R3与它们所连接的氮原子一起为氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、N-(C1-4烷基)哌嗪基、吗啉基或者高哌啶基。
本发明另一方面为式I的立体异构体,其具有式Ia。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:二甲基异噁唑基、(甲基)(苯基)异噁唑基、甲基吡唑基、二甲基吡唑基、噻吩基吡唑基、甲氧基苯基吡唑基、噻唑基、溴噻唑基、氰基噻唑基、甲基噻唑基、二甲基噻唑基、(甲基)(苯基)噻唑基、异丙基噻唑基、丁基噻唑基、苄基噻唑基、甲氧基苯基甲基噻唑基、苯基噻唑基、氯苯基噻唑基、甲氧基苯基噻唑基、(甲氧基苯基)(甲基)噻唑基、吡啶基噻唑基、(苯基)(甲基)咪唑基、甲基噁二唑基、乙基噁二唑基、甲基噻二唑基、氟苯基噻二唑基、呋喃基噻二唑基、(二甲基氨甲酰基)(甲基)噻唑基、(吡咯烷基CO)噻唑基、苯基三唑基、吡啶基、溴吡啶基、氯吡啶基、(氯)(氟)吡啶基、(氯)(甲基)吡啶基、二氯吡啶基、氟吡啶基、氰基吡啶基、(氰基)(甲基)吡啶基、(氰基)(二甲基)吡啶基、甲氧基吡啶基、(甲基吡咯烷基)吡啶基、苯基吡啶基、甲氧基吡啶基吡啶基、哒嗪基、溴哒嗪基、氯哒嗪基、甲基哒嗪基、甲氧基哒嗪基、甲基硫基哒嗪基、吡咯烷基哒嗪基、吡咯烷酮基哒嗪基、苯基哒嗪基、吡啶基哒嗪基、甲氧基吡啶基哒嗪基、嘧啶基、(溴)(异丙基)嘧啶基、(溴)(二甲基)嘧啶基、(溴)(环丙基)嘧啶基、(溴)(甲氧基)嘧啶基、(溴)(苯基)嘧啶基、(溴)(吡啶基)嘧啶基、氯嘧啶基、(氯)(二甲基)嘧啶基、(甲基)(甲氧基)嘧啶基、甲基嘧啶基、乙基嘧啶基、(甲基)(苯基)嘧啶基、二甲基嘧啶基、丁基嘧啶基、异丙基嘧啶基、环丙基嘧啶基、甲氧基嘧啶基、二甲氧基嘧啶基、异丙氧基嘧啶基、环戊氧基嘧啶基、二氟甲氧基嘧啶基、三氟乙氧基嘧啶基、苯氧基嘧啶基、甲基硫基嘧啶基、苯基嘧啶基、氯苯基嘧啶基、甲基苯基嘧啶基、甲氧基苯基嘧啶基、(苯基)(三唑基)嘧啶基、吡啶基嘧啶基、甲氧基吡啶基嘧啶基、甲氧基嘧啶基嘧啶基、萘基嘧啶基、吡嗪基、溴吡嗪基、(溴)(甲氧基)吡嗪基、氯吡嗪基、甲基吡嗪基、二甲基吡嗪基、丁基吡嗪基、氰基吡嗪基、甲氧基吡嗪基、异丙氧基吡嗪基、三氟甲基吡嗪基及苯基吡嗪基及二甲基三嗪基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:二甲基吡啶并异噁唑基、苯并噁唑基、氯苯并噁唑基、氟苯基苯并噁唑基、乙基苯基苯并噁唑基、二甲基氨基苯基苯并噁唑基、吡啶基苯并噁唑基、苯并噻唑基、乙酰氨基苯并噻唑基、溴苯并噻唑基、氯苯并噻唑基、(氯)(甲基)苯并噻唑基、(氯)(甲氧基)苯并噻唑基、氟苯并噻唑基、二氟苯并噻唑基、氰基苯并噻唑基、甲基苯并噻唑基、二甲基苯并噻唑基、(甲基)(甲氧基)苯并噻唑基、乙基苯并噻唑基、三氟甲基苯并噻唑基、羟基苯并噻唑基、甲氧基苯并噻唑基、乙氧基苯并噻唑基、异丙氧基苯并噻唑基、三氟甲氧基苯并噻唑基、二氟甲氧基苯并噻唑基、二甲氧基苯并噻唑基、吗啉基苯并噻唑基、(吡咯烷基CO)苯并噻唑基、甲基磺酰基苯并噻唑基、氯噻唑并吡啶基、二甲基噻唑并吡啶基、苄基氧基噻唑并吡啶基、二氟甲氧基噻唑并吡啶基、苯并三唑基、吲哚酮基、吲唑基、溴吲唑基、氯吲唑基、氟吲唑基、(甲基)(甲氧基)吲唑基、甲氧基吲唑基、三氟甲基吲唑基、三氟甲氧基吲唑基、二氟甲氧基吲唑基、苯并咪唑基、氟苯并咪唑基、甲基苯并咪唑基、(甲基)(甲氧基)苯并咪唑基、甲氧基苯并咪唑基、四氢苯并噻唑基、呋喃并吡啶基、二甲基呋喃并嘧啶基、噻吩并嘧啶基、异丙基噻吩并嘧啶基、二甲基噻吩并嘧啶基、氯三唑并吡啶基、甲基三唑并吡啶基、三氟甲基三唑并吡啶基、甲氧基三唑并吡啶基、三唑并吡嗪基、溴吡咯并三嗪基、二甲基氨基噻唑并嘧啶基、噻唑并吡嗪基、溴噻唑并吡嗪基、甲氧基噻唑并吡嗪基、甲基硫基噻唑并吡嗪基、甲氧基噻唑并嘧啶基、(甲基)(甲氧基)噻唑并嘧啶基、喹啉基、溴喹啉基、氟喹啉基、甲基喹啉基、(甲基)(甲氧基)喹啉基、异喹啉基、溴异喹啉基、二氯异喹啉基、甲基异喹啉基、二甲基异喹啉基、喹喔啉基、氯喹喔啉基、甲基喹喔啉基、甲氧基喹喔啉基、喹唑啉基、溴喹唑啉基、二氮杂萘基、5,6-二氢苯并[h]喹唑啉基、5H-苯并吡喃并[4,3-d]嘧啶基、6,7-二氢-5H-环戊二烯并[d]嘧啶基、5,6,7,8-四氢喹唑啉基及7,8-二氢喹唑啉-5(6H)-酮基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:苯基噻唑基、(氯)(甲基)吡啶基、(溴)(苯基)嘧啶基、甲氧基嘧啶基、二氟甲氧基嘧啶基、二氟乙氧基嘧啶基、环戊氧基嘧啶基、(甲基苯基)嘧啶基、(甲氧基苯基)嘧啶基、溴吡嗪基、氯吡嗪基、甲基硫基吡嗪基、甲氧基苯并噻唑基、乙氧基苯并噻唑基、二氟甲氧基苯并噻唑基、噻唑并吡啶酮基、三氟甲基吲唑基、苯并咪唑基、异喹啉基及喹唑啉基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:溴吡啶基、二氯吡啶基、甲氧基吡啶基、(吡啶基)吡啶基、(苯基)嘧啶基、(甲氧基吡啶基)嘧啶基、(吡唑基)嘧啶基、氯吡嗪基、(溴)(氯)吡嗪基及氯苯并噻唑基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、苯并噻唑基、噻唑并吡啶基、吲唑基、苯并咪唑基、异喹啉基及喹唑啉基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、三唑基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中吡啶基、苯基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基及NR2R3。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:吡啶基、嘧啶基、吡嗪基、噻唑并吡啶基及异喹啉基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、三唑基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中吡啶基、苯基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基及NR2R3。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:吡啶基及异喹啉基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、三唑基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中吡啶基、苯基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基及NR2R3。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:噻唑基、吡啶基、吡嗪基、嘧啶基、异喹啉基或喹喔啉基,且经0-2个独立选自下述的取代基取代:卤素;烷基;烷氧基;环烷氧基;吡唑基;咪唑基;经0-2个卤素、烷基或烷氧基取代基取代的吡啶基;及经0-2个卤素、烷基或烷氧基取代基取代的苯基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:(苯基)噻唑基、(氟)(溴)吡啶基、(氯)(甲基)吡啶基、氯吡嗪基、(氟吡啶基)吡啶基、(溴)(苯基)嘧啶基、(环戊氧基)嘧啶基、(咪唑基)嘧啶基、((甲基)苯基)嘧啶基、异喹啉基、氟异喹啉基或喹喔啉基。
本发明另一方面为式I或Ia的化合物或其药用盐,其中R1选自:溴吡啶基、二氯吡啶基、(吡啶基)吡啶基、(吡唑基)嘧啶基、甲氧基嘧啶基、(甲氧基吡啶基)嘧啶基、(苯基)嘧啶基或溴氯吡嗪基。
本发明另一方面为式I的化合物或其药用盐,其中R1选自:噻唑基、噻二唑基、异噁唑基、噁唑基、吡唑基、咪唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、喹啉基、异喹啉基、喹喔啉基、吲唑基、吲哚基、2-吲哚酮基、苯并噻唑基、苯并咪唑基、苯并噁唑基、苯并(d)异噻唑基、苯并异噁唑基、异噻唑并-[5,4-b]吡啶基、(1,2,4)-三唑并[1,5-a]吡啶基、噻唑并[5,4-b]吡啶基及四氢苯并噻唑基,其中每个基团任选经1或2个选自下述的取代基取代:C1-4烷基、C1-4烷氧基、卤素、羟基、氰基、三氟甲基、二氟甲基、氟甲基、三氟甲氧基、二氟甲氧基、C1-4烷基磺酰基、呋喃基、吗啉代、亚甲二氧基、吡啶基、C1-4烷基苯基、卤代苯基、二甲基氨基苯基、C1-4烷基氨甲酰基、-CONR2R3,其中R2和R3各自独立为氢、C1-4烷基、羟基C1-4烷基、氨基C1-4烷基或者R2及R3与它们所连接的氮原子一起为C3-6环烷基;苯基、取代的苯基、苯基甲基、取代的苯基甲基,其中所述取代的苯基和取代的苯基甲基经独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、三氟甲基及三氟甲氧基。
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
本发明另一方面为以下结构的式I的化合物:
对于式I或Ia的化合物,可变取代基(包括R1、R2及R3)的任一实例的范围的使用可与可变取代基的任一其它实例的范围无关。因此,本发明包括不同方面的组合。
除非另有说明,否则所述术语具有以下含义。“烷基”意指由1至4个碳组成的直链或支链烷基。“烯基”意指由2至4个碳组成且具有至少一个双键的直链或支链烷基。“炔基”意指由2至4个碳组成且具有至少一个三键的直链或支链烷基。“环烷基”意指由3至7个碳组成的单环环系。“卤代烷基”及“卤代烷氧基”包括由单卤素至全卤素的所有卤化异构体。具有烃部分(例如烷氧基)的术语包括该烃部分的直链及支链异构体。括号及多重括号内的术语意在向本领域技术人员阐明键合关系。例如,诸如((R)烷基)的术语意指进一步经取代基R取代的烷基取代基。
除非另有说明,否则上述取代基可连接在任何适合的连接点上。然而,应理解,本发明所涵盖的化合物是本领域技术人员所了解的化学稳定的那些化合物。另外,本公开所涵盖的化合物是在用作药物时适当稳定的那些化合物。
本发明包括化合物的所有药用盐形式。药用盐为抗衡离子对化合物的生理活性或毒性无显著影响且因此可用作药理学等价物的盐。所述盐可根据常用有机技术采用商购得到的试剂来制备。某些阴离子盐形式包括乙酸盐、醋硬脂酸盐、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡萄糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、扑酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐及昔萘酸盐(xinofoate)。某些阳离子盐形式包括铵盐、铝盐、苄星(benzathine)盐、铋盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、锂盐、镁盐、葡甲胺盐、4-苯基环己胺盐、哌嗪盐、钾盐、钠盐、丁三醇胺(tromethamine)盐及锌盐。
某些本发明化合物以立体异构体形式存在。本发明包括化合物的所有立体异构体形式,包括对映异构体及非对映异构体。制备及分离立体异构体的方法为本领域已知。
本发明包括化合物的所有互变异构体形式。互变异构体对的一个实例如下显示。
本发明意在包括出现在本发明化合物中的原子的所有同位素。同位素包括那些具有相同原子序数但不同质量数的原子。作为一般实例但不作为限制,氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记的化合物大体上可通过对本领域的技术人员已知的常用技术或者通过类似于本申请所述的方法使用适当的同位素标记的试剂代替另作使用的非标记的试剂来制备。所述化合物可具有多种潜在的用途,例如作为确定生物活性的标准和试剂。在稳定同位素的情况下,所述化合物可具有有利地修饰生物学、药理学或者药动学性质的潜力。
合成方法
本发明的化合物可通过本领域中已知的方法(包括下面描述的那些且包括本领域范围内的变化形式)来制备。某些试剂和中间体在本领域已知。其它试剂和中间体可通过在本领域已知的方法使用易于得到的物质来制备。用于描述化合物合成的变化形式(例如标号的“R”取代基)仅意在示例说明如何制备化合物且不意在与在权利要求中或者在说明书的其它部分中使用的变化形式混淆。下述方法用于示例说明的目的而不用于限制本发明的范围。
某些化合物可使用本部分中所述的反应及技术来制备。各反应在适于所用试剂及材料且适于所实施转化的溶剂中进行。有机合成领域的技术人员应理解,分子各部分上存在的官能团必须与所提出的试剂及反应相容。本领域技术人员可容易地了解对与反应条件相容的取代基的所述限制且随后必须使用替代方法。
在方案中使用的缩写通常按照在本领域使用的惯例。在说明书和实施例中使用的化学缩写如下定义:“NaHMDS”表示二(三甲基甲硅烷基)氨基钠;"DMF"表示N,N-二甲基甲酰胺;“MeOH”表示甲醇;“NBS”表示N-溴代琥珀酰亚胺;“Ar”表示芳基;"TFA"表示三氟乙酸;“LAH”表示氢化铝锂;“BOC”、“DMSO”表示二甲基亚砜;“h”表示小时;“rt”表示室温或者保留时间(上下文将指明);“min”表示分钟;"EtOAc"表示乙酸乙酯;"THF"表示四氢呋喃;“EDTA”表示乙二胺四乙酸;“Et2O”表示乙醚;"DMAP"表示4-二甲基氨基吡啶;“DCE”表示1,2-二氯乙烷;“ACN”表示乙腈;“DME”表示1,2-二甲氧基乙烷;“HOBt”表示1-羟基苯并三唑水合物;“DIEA”表示二异丙基乙胺,“Nf”表示CF3(CF2)3SO2-;且“TMOF”表示原甲酸三甲酯。
如本申请使用的缩写如下定义:“1x”用于一次、“2x”用于两次、“3x”用于三次、"°C"用于摄氏度、“eq”用于当量(equivalent或者equivalents)、“g”用于克(gram或者grams)、“mg”用于毫克(milligram或者milligrams)、“L”用于升(liter或者liters)、“mL”用于毫升(milliliter或者milliliters)、“μL”用于微升(microliter或者microliters)、“N”用于常量、“M”用于摩尔浓度、“mmol”用于毫摩尔(millimole或者millimoles)、“min”用于分钟(minute或者minutes)、“h”用于小时(hour或者hours)、“rt”用于室温、“RT”用于保留时间、“atm”用于气氛、“psi”用于磅每平方英寸、“conc.”用于浓的、“sat”或者“sat’d”用于饱和的、“MW”用于分子量、“mp”用于熔点、“ee”用于对映体过量、“MS”或者“Mass Spec”用于质谱法、“ESI”用于电喷射离子化质谱法、“HR”用于高分辨率、“HRMS”用于高分辨率质谱法、“LCMS”用于液相色谱质谱法、“HPLC”用于高效液相色谱法、“RP HPLC”用于反相HPLC、“TLC”或者“tlc”用于薄层色谱法、“NMR”用于核磁共振光谱法、“1H”用于质子、“δ”用于delta、“s”用于单峰、“d”用于二重峰、“t”用于三重峰、“q”用于四重峰、“m”用于多重峰、“br”用于宽峰、“Hz”用于赫兹以及“α”、“β”、“R”、“S”、“E”和“Z”为本领域技术人员熟知的立体化学命名。
1H-NMR光谱在Bruker 500、400或300MHz仪器上记录,且化学位移以相对于四甲基甲硅烷(δ=0.0)的百万分之一(ppm)(δ)进行报告。所有蒸发均在减压进行。除非另有说明,LC/MS分析在Shimadzu仪器上进行,其采用流速为4mL/分钟、梯度为0.1% TFA的甲醇/水溶液[3分钟内0-100%,运行时间为4分钟]和设置为220nm的UV检测器的Phenomenex-Luna 4.6×50mm S 10反相柱,或采用流速为5mL/分钟、梯度为10mM乙酸铵的乙腈/水溶液[3分钟内5-95%,运行时间为4分钟]和设置为220nm的UV检测器(负离子质谱)的Gemini C184.6×50mm 5u反相柱。除非另有说明,纯化可以通过梯度为含0.1%三氟乙酸(TFA)的甲醇-水溶液的制备性C-18柱进行,并使用Shimadzu高效液相制备性色谱系统,其采用流速为40mL/分钟的XTERRA 30×100mm S5柱,且梯度为12分钟。
某些本发明化合物可通过使用适合的氧化剂例如3-氯过氧苯甲酸将烟碱α7配体的游离碱氧化成N-氧化物来制备:
也可使用氧化剂“Oxone”(过硫酸氢钾)。
实施例1
(S)-2-(异喹啉-3-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将(R)-N-(异喹啉-3-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(771mg,2.5mmol)(指定化合物A)和3-氯过氧苯甲酸(518mg,3.00mmol)在THF(12.5mL)中的溶液室温搅拌3.5小时。浓缩反应混合物,在160g硅胶柱上经快速色谱法(用5至15%[9:1MeOH/NH4OH]/EtOAc)纯化粗产物。将纯化的馏分混合,浓缩并干燥。将残余物溶于5mL水,并在Waters OasisHLB 35cc(6g)LP萃取柱上用500mL水洗脱,随后用MeOH洗脱,洗脱得到纯产物(S)-2-(异喹啉-3-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(指定化合物B)(695mg,86%产率)。1H NMR(400MHz,MeOD)δppm 8.96(1H,s),7.87(1H,d,J=8.31Hz),7.67(1H,d,J=8.56Hz),7.55(1H,ddd,J=8.25,6.99,1.13Hz),7.47(1H,s),7.37(1H,td,J=7.55,1.01Hz),3.92(1H,d,J=10.83Hz),3.78(1H,d,J=10.83Hz),3.58-3.72(2H,m),3.37-3.47(3H,m),3.19-3.30(1H,m),2.38(1H,td,J=6.67,3.53Hz),2.18(1H,宽单峰),1.93-2.10(3H,m)。LCMS:RT=0.55分钟,MH+=325.2[Waters Acquity SDS:2至98%B,1分钟梯度;保持98%B,0.5分钟;流速0.8mL/分钟;溶剂A:100%H2O/0.05%TFA;溶剂B:100%ACN/0.05%TFA]。
实施例2
(S)-2-(喹喔啉-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将(R)-N-(喹喔啉-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(190mg,0.614mmol)和3-氯过氧苯甲酸(165mg,0.737mmol)在4mL THF中的溶液室温搅拌2小时。浓缩反应混合物,在40g硅胶柱上经快速色谱法(用1至30%[9:1MeOH/NH4OH]/EtOAc)纯化粗产物。将纯化的馏分混合,浓缩,再溶于CHCl3,并通过0.45u的滤器过滤,得到(S)-2-(喹喔啉-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(192mg,96%产率)。1H NMR(400MHz,氯仿-d)δppm 9.89(1H,宽单峰),8.58(1H,s),7.93(1H,dd,J=8.31,1.26Hz),7.70(1H,dd,J=8.31,1.01Hz),7.60(1H,ddd,J=8.25,6.99,1.38Hz),7.50(1H,ddd,J=8.25,6.99,1.38Hz),4.01(1H,d,J=10.07Hz),3.84(1H,d,J=9.82Hz),3.78-3.83(1H,m),3.64(1H,dd,J=14.35,2.27Hz),3.26-3.58(4H,m),2.50-2.65(1H,m),2.27(1H,宽单峰),2.06-2.19(1H,m,J=14.26,10.42,4.15,4.15Hz),1.88-2.03(2H,m)。LCMS:RT=0.72分钟,MH+=326.1[Waters Acquity SDS:2至98%B,1分钟梯度;保持98%B,0.5分钟;流速0.8mL/分钟;溶剂A:100%H2O/0.05%TFA;溶剂B:100% ACN/0.05%TFA]。LCMS:RT=1.15分钟,MH-=324.2,MH+=326.2[Phenomenex LUNA C18 3m(2.0X30mm);0至100%B,2分钟梯度;流速1mL/分钟;溶剂A:5% MeOH:95%水:10mM NH4OAc;溶剂B:95% MeOH:5%水:10mM NH4OAc;220nM]。
实施例3
(R)-2-(异喹啉-3-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
使用与实施例1类似的方法,(S)-N-(异喹啉-3-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(108mg,0.350mmol)和3-氯过氧苯甲酸(72.5mg,0.420mmol)得到(R)-2-(异喹啉-3-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(95mg,83%产率)。1H NMR(500MHz,MeOD)δppm 9.04(1H,s),7.97(1H,d,J=8.24Hz),7.76(1H,d,J=8.24Hz),7.61-7.67(1H,m),7.44-7.49(2H,m),4.03(1H,d,J=10.99Hz),3.87(1H,d,J=10.99Hz),3.65-3.77(2H,m),3.44-3.53(3H,m),3.27-3.31(1H,m),2.43-2.55(1H,m),2.32(1H,宽单峰),2.04-2.22(3H,m)。LCMS:RT=0.54分钟,MH+=325.2[Waters Acquity SDS:2至98%B,1分钟梯度;保持98%B,0.5分钟;流速0.8mL/分钟;溶剂A:100%H2O/0.05%TFA;溶剂B:100%ACN/0.05% TFA]。
实施例4
(S)-2-(5-间甲苯基嘧啶-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将mCPBA(0.074g,0.332mmol)加入到(R)-N-(5-间甲苯基嘧啶-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.116g,0.332mmol)在THF(10ml)中的混悬液中。将混合物室温搅拌18小时,浓缩,经硅胶色谱(5-25%9:1甲醇:氢氧化铵-乙酸乙酯)纯化,得到(S)-2-(5-间甲苯基嘧啶-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.067g,0.176mmol,53%),其为灰白色固体。1H NMR(400MHz,MeOD)δppm 8.79(2H,s),7.27-7.49(3H,m),7.20(1H,d,J=7.55Hz),4.03(1H,d,J=10.32Hz),3.88(1H,d,J=10.58Hz),3.59-3.77(2H,m),3.38-3.52(3H,m),3.21-3.28(1H,m),2.40-2.52(1H,m),2.28-2.35(1H,m),1.96-2.21(3H,m)。LC/MS RT=1.71;[M+H]+=366.34。
实施例5
(S)-2-(6-(环戊基氧基)嘧啶-4-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将mCPBA(0.114g,0.510mmol)加入到(R)-N-(6-(环戊基氧基)嘧啶-4-基)-4H-1'-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]-2-胺(0.175g,0.510mmol)在THF(15ml)中的溶液中。将混合物室温搅拌18小时,浓缩。残余物经硅胶色谱(5-25%9:1甲醇:氢氧化铵-乙酸乙酯)纯化,得到(S)-2-(6-(环戊基氧基)嘧啶-4-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.076g,0.207mmol,41%),其为灰白色固体。1H NMR(400MHz,MeOD)δppm 8.38(1H,s),6.34(1H,宽单峰),5.18-5.37(1H,m),4.01(1H,d,J=11.08Hz),3.85(1H,d,J=10.83Hz),3.58-3.75(2H,m),3.34-3.53(3H,m),3.20-3.27(1H,m),2.32-2.46(1H,m),2.23-2.31(1H,m),1.98-2.19(3H,m),1.93-1.99(2H,m),1.68-1.84(4H,m),1.55-1.70(2H,m)。LC/MSRT=1.61;[M+H]+=360.39。
实施例6
(S)-2-(5-溴-4-苯基嘧啶-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将mCPBA(0.060g,0.266mmol)加入到(R)-N-(5-溴-4-苯基嘧啶-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.1g,0.241mmol)在THF(10ml)中的混悬液中。将混合物室温搅拌18小时,浓缩,经硅胶色谱(5-25%9:1甲醇:氢氧化铵-乙酸乙酯)纯化,得到(S)-2-(5-溴-4-苯基嘧啶-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.066g,0.149mmol,62%),其为灰白色固体。1H NMR(400MHz,MeOD)δppm 8.72(1H,s),7.74(2H,dd,J=6.92,2.64Hz),7.39-7.53(3H,m),4.01(1H,d,J=10.58Hz),3.85(1H,d,J=10.32Hz),3.61-3.74(2H,m),3.37-3.50(3H,m),3.19-3.26(1H,m),2.37-2.51(1H,m),2.26-2.33(1H,m),1.95-2.20(3H,m)。LC/MS RT=1.78;[M+2]+=432.19。
实施例7
(S)-2-(5-氯-4-甲基吡啶-2-基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]1’-氧化物
向(R)-N-(5-氯-4-甲基吡啶-2-基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]-2-胺(0.04g,0.13mmol)在THF(10mL)中的溶液中,加入m-CPBA(0.025g,0.14mmol)。将反应混合物室温搅拌2小时,然后浓缩至粗粉。产物经色谱(Biotage:85%CHCl3,14%MeOH,1%NH4OH)纯化,得到(S)-2-(5-氯-4-甲基吡啶-2-基氨基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]1’-氧化物(0.019g,0.06mmol,44%产率),其为白色粉末1H NMR(500MHz,MeOD)δppm 8.18(s,1H),6.75–7.09(m,1H),4.00(d,J=10.4Hz,1H),3.84(d,J=10.4Hz,1H),3.61-3.78(m,2H),3.41-3.54(m,3H),3.23-3.38(m,3H),2.45(宽单峰,1H),2.25-2.38(m,4H),1.88-2.22(m,1H)。MS(LC/MS)R.T.=0.91;[M+H]+=323.11。
实施例8
(S)-2-(5-氯吡嗪-2-基氨基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]1’-氧化物
将3-氯过氧苯甲酸(104mg,0.466mmol)在室温加入到(R)-N-(5-氯吡嗪-2-基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]-2-胺(114mg,0.388mmol)在THF(3mL)中的溶液中,搅拌2小时。浓缩混合物,在40g硅胶柱上经快速色谱法(用10至30%[9:1MeOH/NH4OH]/EtOAc)纯化粗产物,纯化30分钟。将纯化的馏分混合,浓缩并干燥。将残余物溶于95:5的EtOAC/MeOH,通过0.22微米滤器,浓缩并高真空干燥,得到(S)-2-(5-氯吡嗪-2-基氨基)-4H-1’-氮杂螺[噁唑-5,3’-二环[2.2.2]辛烷]1’-氧化物(113mg,94%产率)。
1H NMR(400MHz,MeOD)ppm 8.25(1H,d,J=1.51Hz),8.00(1H,宽单峰),4.00(1H,d,J=10.58Hz),3.85(1H,d,J=10.58Hz),3.60–3.76(2H,m),3.35–3.52(3H,m),3.21–3.27(1H,m),2.34–2.52(1H,m),2.26–2.36(1H,m),2.00–2.21(3H,m)
1H NMR(400MHz,乙腈-d3)δppm 8.74(1H,宽单峰),8.18(1H,d,J=1.51Hz),8.01(1H,宽单峰),3.89(1H,d,J=10.32Hz),3.72(1H,d,J=10.32Hz),3.50(2H,q,J=14.52Hz),3.20–3.32(3H,m),3.03–3.15(1H,m),2.21–2.33(1H,m),2.18(1H,宽单峰),1.95–2.05(2H,m)
LCMS:RT=0.76分钟,MH+=310.0
[Waters Acquity:2至98%B,1分钟梯度;保持98%B,0.5分钟;流速0.8mL/分钟;溶剂A:100%H2O/0.05%TFA;溶剂B:100%ACN/0.05%TFA。]
HPLC:RT=4.67分钟,纯度=100%
[XTERRA S3.5C18(4.6×150mm):5至100%B,15分钟梯度;流速1mL/分钟;溶剂A:10mM NH4OAc,pH6.8,在水/ACN(95/5)中;溶剂B:10mM NH4OAc,pH6.8,在水/ACN(5/95)中;220/254nM。]
HPLC:RT=7.26分钟,纯度=99.6%
[Gemini S5C18(4.6×150mm):5至100%B,15分钟梯度,保持100%B 3分钟;流速1mL/分钟;溶剂A:10mM碳酸氢铵。pH 9.5,在水/MeOH(95:5)中;溶剂B:10mM碳酸氢铵。pH 9.5,在水/MeOH(5:95)中;220/254nM]。
实施例9
(S)-2-(6-(1H-咪唑-1-基)嘧啶-4-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将(R)-N-(6-(1H-咪唑-1-基)嘧啶-4-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(52.9mg,0.163mmol)和3-氯过氧苯甲酸(33.7mg,0.195mmol)在2mL THF中的溶液室温搅拌24小时。浓缩反应混合物,在40g硅胶柱上经快速色谱法(用20至40%[9:1MeOH/NH4OH]/EtOAc)纯化粗产物,纯化40分钟。将纯化的馏分混合,浓缩并干燥。将残余物溶于CDCl3,通过0.4μ的滤器过滤,浓缩,高真空干燥,得到(S)-2-(6-(1H-咪唑-1-基)嘧啶-4-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(53mg,95%产率)。
1H NMR(400MHz,MeOD)δppm 8.69(1H,s),8.60(1H,d,J=1.01Hz),7.91(1H,t,J=1.39Hz),7.15(1H,d,J=0.76Hz),6.99(1H,宽单峰),4.07(1H,d,J=10.58Hz),3.92(1H,d,J=10.58Hz),3.61-3.79(2H,m),3.36-3.53(3H,m),3.21-3.26(1H,m),2.30-2.48(2H,m),1.97-2.22(3H,m)
LCMS:RT=1.23分钟,MH-=340.2,MH+=342.1
[Phenomenex LUNA C183μ(2.0×30mm);0至100%B,2分钟梯度;流速1mL/分钟;溶剂A:5% MeOH:95%水:10mM NH4OAc;溶剂B:95%MeOH:5%水:10mMNH4OAc;220nM]
HPLC
RT=5.48分钟,纯度=99.7%,柱:XbridgeC18 3.5um,3.0×150mm
RT=6.74分钟,纯度=98.9%,柱:Xbridge Phenyl 3.5um,3.0×150mm
方法:
10-100%B,15分钟,0.5ml/分钟;220/254nM
溶剂对=10mM碳酸氢铵(pH=9.5)/水/甲醇
溶剂A=10mM碳酸氢铵(pH 9.5)/95%水/5%甲醇
溶剂B=10mM碳酸氢铵(pH=9.5)/5%水/95%甲醇
实施例10
(S)-2-(5-苯基噻唑-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
将(R)-N-(5-苯基噻唑-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.101g,0.297mmol)溶于THF(15mL),并用m-CPBA(0.061g,0.356mmol)室温处理30分钟。真空浓缩反应混合物,得到粗产物。粗产物经反相HPLC纯化,得到纯化的馏分。真空浓缩所述馏分,在真空烘箱中干燥18小时,得到(S)-2-(5-苯基噻唑-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.03g,0.082mmol,27.8%产率),其为白色粉末。1H NMR(500MHz,DMSO-d6)ppm 7.86-8.12(m,1H),7.64(宽单峰,2H),7.44(s,3H),4.13-4.31(m,3H),3.97-4.07(m,1H),3.90(d,J=10.7Hz,4H),3.54-3.74(m,1H),2.28-2.42(m,1H),1.95-2.24(m,3H)。LC/MS:保留时间1.04(M+1=357.1)。
实施例11
(S)-2-(6-氟-3,4′-联吡啶-2′-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1’-氧化物
用m-CPBA(0.059g,0.342mmol)处理(R)-N-(6-氟-3,4'-联吡啶-2'-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.11g,0.311mmol)在THF(10mL)中的溶液,室温搅拌2小时。TLC显示反应完全,产物经色谱(Biotage:5-20%的8:2MeOH:NH4OH在CHCl3中)纯化,合并纯化的馏分,得到(S)-2-(6-氟-3,4'-联吡啶-2'-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.05g,0.134mmol,43.1%产率),其为黄色粉末。1H NMR(500MHz,DMSO-d6)δppm 9.11(宽单峰,1H),8.64(宽单峰,1H),8.21-8.43(m,2H),7.04-7.44(m,3H),3.77(d,J=10.1Hz,2H),2.98-3.65(m,6H),2.18(宽单峰,2H),1.74-2.01(m,3H)。LC/MS:保留时间0.78(M+1=370.2)。
实施例12
(S)-2-(1-氟异喹啉-3-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
向(R)-N-(1-氟异喹啉-3-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.063g,0.193mmol)在CHCl3(15mL)中的溶液中,室温加入m-CPBA(0.034g,0.195mmol)。将反应混合物室温搅拌3小时。TLC显示较低的点并且未显示起始物质。混合物经色谱(Biotage:15-20%的9:1MeOH:NH4OH在CHCl3中;~1.1L)纯化,得到纯化的馏分。合并所述馏分,除去溶剂,得到(S)-2-(1-氟异喹啉-3-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.050g,0.146mmol,76%产率),其为白色粉末。1H NMR(500MHz,DMSO-d6)δppm 8.12-8.42(m,1H),8.01(d,J=8.2Hz,1H),7.86(宽单峰,1H),7.73(宽单峰,1H),7.43-7.60(m,1H),6.93-7.35(m,1H),3.69-4.05(m,1H),3.58(宽单峰,1H),3.00-3.33(m,6H),2.19(宽单峰,2H),1.94(d,J=10.1Hz,3H)。LC/MS:保留时间1.78(M+1=343.1)。
实施例13
(S)-2-(5-溴-6-氟吡啶-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
向(R)-N-(5-溴-6-氟吡啶-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(0.064g,0.180mmol)在CHCl3(15mL)中的溶液中,室温加入m-CPBA(0.032g,0.186mmol)。将反应混合物室温搅拌3小时。TLC显示较低的点并且未显示起始物质。混合物经色谱(Biotage:15-20%的9:1MeOH:NH4OH在CHCl3中;~1.1L)纯化,得到纯化的馏分。合并所述馏分,除去溶剂,得到(S)-2-(5-溴-6-氟吡啶-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(0.045g,0.119mmol,65.9%产率),其为黄色粉末。1H NMR(500MHz,DMSO-d6)δppm 8.31-8.76(m,1H),8.00(宽单峰,1H),6.46-6.96(m,1H),3.73(d,J=11.0Hz,2H),3.56(宽单峰,1H),3.37(宽单峰,3H),2.98-3.27(m,2H),2.11(宽单峰,2H),1.73-2.00(m,3H)。LC/MS:保留时间1.59(M+1=372.95)。
实施例14
(S)-2-(5-甲基噁唑并[5,4-b]吡啶-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
在室温将(3'R,4'S)-N-(5-甲基噁唑并[5,4-b]吡啶-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(40mg,0.13mmol)、间氯过氧苯甲酸(34mg,0.15mmol)以及THF(640μL)装入到10ml小瓶中。将得到的溶液室温搅拌1.5小时。然后减压除去挥发物,并用甲醇稀释粗反应物质,并经硅胶柱色谱(0-30%甲醇(包含10%氢氧化铵)在氯仿中)纯化,得到(S)-2-(5-甲基噁唑并[5,4-b]吡啶-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(35mg,0.10mmol,78%产率),其为无色油状物。1H NMR(400MHz,MeOD)δppm7.69-7.74(1H,m),7.14-7.19(1H,m),4.07-4.13(1H,m),3.92-3.98(1H,m),3.70-3.80(2H,m),3.42-3.54(3H,m),3.23-3.30(1H,m),2.55(3H,s),2.35-2.51(2H,m),2.00-2.25(3H,m)。MS(LC/MS)R.T.=1.32,[M+H]+=330.49。
实施例15
(S)-2-(6-甲基苯并[d]噁唑-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
在室温将(3'R,4'S)-N-(6-甲基苯并[d]噁唑-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(75mg,0.24mmol)、间氯过氧苯甲酸(65mg,0.29mmol)以及THF(1.2mL)装入到10ml小瓶中。将得到的溶液室温搅拌1.5小时。减压除去挥发物,并用甲醇稀释粗反应物质,并经硅胶柱色谱(0-30%甲醇(包含10%氢氧化铵)在氯仿中)纯化,得到(S)-2-(6-甲基苯并[d]噁唑-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(76mg,0.23mmol,96%产率),其为无色油状物。1H NMR(400MHz,MeOD)δppm 7.31-7.35(1H,m),7.20-7.23(1H,m),7.03-7.08(1H,m),4.06-4.11(1H,m),3.91-3.96(1H,m),3.71-3.81(2H,m),3.44-3.55(3H,m),3.25-3.31(1H,m),2.35-2.51(5H,m),2.00-2.24(3H,m)。MS(LC/MS)R.T.=1.42,[M+H]+=329.09。
实施例16
(S)-2-(5-甲氧基噁唑并[5,4-b]吡啶-2-基氨基)-4H-1′-氮杂螺[噁唑-5,3′-二环[2.2.2]辛烷]1′-氧化物
在室温将(3'R,4'S)-N-(5-甲氧基噁唑并[5,4-b]吡啶-2-基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]-2-胺(75mg,0.23mmol)、间氯过氧苯甲酸(61mg,0.27mmol)以及THF(1.1mL)装入到10ml小瓶中。将得到的溶液室温搅拌1.5小时。减压除去挥发物,并用甲醇稀释粗反应物质,并经硅胶柱色谱(0-30%甲醇(包含10%氢氧化铵)在氯仿中)纯化,得到(S)-2-(5-甲氧基噁唑并[5,4-b]吡啶-2-基氨基)-4H-1'-氮杂螺[噁唑-5,3'-二环[2.2.2]辛烷]1'-氧化物(33mg,0.095mmol,42%产率),其为白色固体。1H NMR(400MHz,DMSO-d6)δppm9.07(1H,宽单峰),7.78(1H,d,J=8.3Hz),6.74(1H,d,J=8.5Hz),3.82-3.96(5H,m),3.69(1H,dd,J=14.2,1.9Hz),3.48(1H,d,J=14.1Hz),3.07-3.40(4H,m),2.10-2.30(2H,m),1.88-2.06(3H,m)。MS(LC/MS)R.T.=1.28,[M+H]+=346.09。
生物学测试
以下部分详细介绍了以液相色谱-串联质谱法(LC/MS/MS)为基础的生物分析方法,其在犬和大鼠中进行的研究中用于支持体内生物样本(脑、血浆、尿液)的分析。
标准曲线的制备。用于定义生物分析方法的动态范围的标准曲线和质量控制(QC)样本在各自的生物基质中进行制备,并按照与测试样本相同的方式进行加工,除非另有说明。
样本制备:血液、血浆、血清、尿液。血浆和血液样本按下述方法制备。如果需要稀释,则将样本的等分试样在各自的基质中进行稀释。对于尿液样本的分析,首先将等分部分在空白血浆中进行稀释,然后按如下所述进行处理。
手动或在Packard MultiPROBE自动化液体处理器中进行样本制备。内标物(IS)溶液(1000nM(S,E)-5-溴-N-(1'-氮杂螺[噁唑烷-5,3'-二环[2.2.2]辛烷]-2-亚基)吡嗪-2-胺)在乙腈中制备。将两百微升的IS溶液加入到Strata蛋白沉淀过滤板(Phenomenex,Torrance,CA)的每个孔中。将生物样本(60μL)加入到过滤板中。将过滤板连接在标准96孔板的顶部,整个单元以1100rpm离心2分钟。收集96孔板中的上清液。将五微升的每个样本注入到LC/MS/MS系统中用于分析。
仪器。所用的UHPLC系统为与CTC分析HTS PAL自动进样器(LeapTechnologies,Carrboro,NC)偶联的Agilent 1200系列(Agilent Technologies,Wilmington,DE),其配备冷却塔使得样本在分析期间在10℃保持。所用分析柱在60℃为Waters Acquity HSS T3(2.1×50mm,1.8um颗粒)。流动相由0.1%甲酸的水溶液(A)和0.1%甲酸的乙腈溶液(B)组成,以0.6mL/分钟的流速输送。分析梯度条件列于下表。
表I.化合物A和化合物B的LC/MS/MS分析的流动相梯度
时间(分钟) | %A | %B | 流速(mL/分钟) |
0.0 | 100 | 0 | 0.6 |
0.1 | 100 | 0 | 0.6 |
1.8 | 50 | 50 | 0.6 |
1.9 | 50 | 50 | 0.6 |
2.0 | 5 | 95 | 0.6 |
2.1 | 5 | 95 | 0.6 |
2.2 | 100 | 0 | 0.6 |
2.3 | 100 | 0 | 0.6 |
化合物A、化合物B和内标物的保留时间分别发生在1.26、1.29和1.26分钟。总的分析时间为2.3分钟。
UHPLC与配备有电喷雾离子化接口的API4000 QTrap LC/MS/MS系统(应用生物系统/MDS Sciex,Foster City,CA)对接,在正离子化模式下进行操作。源温度为500℃。每种分析物的检测通过选择反应监测来实现。代表化合物A、化合物B和IS的前体(M+H)+类型的离子在四极杆1中选取,与氮气碰撞解离产生特定的产物离子,随后被四极杆3监测。监测转换和质谱仪的设定总结于下表中。
表II.用于LC/MS/MS样本分析的监测转换和质谱仪设定
标准曲线范围。除非另有说明,化合物A和化合物B分别在标准曲线范围为0.6至1,250nM和4.8至5,000nM中进行分析。标准曲线用浓度倒数的平方(1/x2)加权的线性回归进行拟合。标准品采用一式两份进行分析。质量控制样本在浓度水平位于标准曲线范围内的空白生物基质中进行制备。来自多个不同基质的多于80%的QCs,其预测浓度均在标称值的20%范围内,证实测定性能是可接受的。
化合物A和化合物B的LC/MS定量分析
以下部分详细介绍了以液相色谱-质谱法(LC/MS)为基础的生物分析方法,其用于支持来自肝细胞的体外样本分析和反应表型研究。
仪器。使用具有光谱检测的HPLC分离对化合物A进行定量测定。HPLC系统由Shimadzu LC-10ADvp泵和与Waters XBridge C185微米(2.1×50mm)HPLC柱连接的Shimadzu SIL-10ADvp自动进样器组成。流动相A由含0.1%甲酸的水溶液组成,而流动相B由含0.1%甲酸的乙腈溶液组成。色谱法测定在烘箱温度为45℃、流速为0.3mL/分钟的条件下进行。所用的HPLC梯度总结在以下的表中。
表III.化合物A和化合物B的LC/MS分析的流动相梯度
时间(分钟) | %A | %B | 流速(mL/分钟) |
0.0 | 95 | 5 | 0.3 |
1.0 | 95 | 5 | 0.3 |
3.2 | 0 | 100 | 0.3 |
3.3 | 0 | 100 | 0.3 |
4.2 | 0 | 100 | 0.3 |
时间(分钟) | %A | %B | 流速(mL/分钟) |
4.3 | 95 | 5 | 0.3 |
5.0 | 95 | 5 | 0.3 |
化合物A、化合物B和IS的保留时间分别发生在2.85、2.87和2.85分钟。总的分析时间为5.8分钟。
HPLC系统与配备有电喷雾源的Waters Micromass LCQ质谱仪对接。采用正离子电喷雾电离检测化合物A的[M+H]+离子(m/z 309)。采用正离子电喷雾电离检测化合物B的[M+H]+离子(m/z 325)。源模块温度为130℃,去溶剂化温度为350℃,毛细管电压为3kV,化合物A的锥孔电压(cone voltage)为29V,化合物B的锥孔电压为39V。使用350L/h的超高纯度的氮气作为去溶剂化气体。测量化合物A的m/z 309产物离子的峰面积相对于IS的峰面积。分析结果表示为峰面积比,即峰面积(化合物A)/峰面积(IS)。
化合物B向化合物A的体内转化
大鼠体内N-氧化物化合物B向化合物A的转化。化合物B向化合物A的转化在雄性Sprague-Dawley大鼠(260-280g)中进行评价。动物(每组N=3)通过留置十二指肠内插管(IDC)以十二指肠内输注(10mg/kg在10分钟内)的方式接受化合物B,并通过门静脉内收集。连续的血样在给药前和给药后0.17、0.25、0.5、0.75、1、2、4、6、8和24小时获得。在4℃离心(1500-2000×g)获得血浆样本,并储存于-20℃直至分析。
大鼠内的所有转化研究在十二指肠及门静脉内含有留置套管的动物中进行。研究被设计用来在还原化合物B时隔离胃肠道的作用。表IV总结了大鼠十二指肠内输注化合物B后,化合物B和化合物A在门静脉中的暴露。十二指肠内输注化合物B后,来自门静脉的样本中的化合物A的浓度增加(AUC化合物A/AUC化合物B=3.6),证实N-氧化物在体内向母体药物还原。
表IV.
时间(小时) | 化合物A(uM) | 化合物B(uM) |
0.167 | 0.003 | 0.601 |
0.25 | 0.007 | 0.758 |
0.5 | 0.112 | 0.177 |
0.75 | 0.207 | 0.090 |
1 | 0.448 | 0.069 |
时间(小时) | 化合物A(uM) | 化合物B(uM) |
2 | 0.75 | 0.052 |
4 | 0.455 | 0.018 |
6 | 0.434 | <LLQ |
8 | 0.125 | <LLQ |
24 | 0.006 | <LLQ |
“LLQ”=“定量下限”
表V中总结了大鼠单次给药后化合物B的PK参数以及化合物A的出现。
表V
犬内N-氧化物化合物B向化合物A的转化。在雄性小猎犬中,采用交叉设计的研究对化合物B向化合物A的转化进行评估。三只动物(5至8kg)通过头静脉的静脉内输注(1mg/kg,超过5分钟)和通过口腔灌饲(5mg/kg)接受化合物B,治疗期间有1周的间歇期(washout)。给药前和给药后(仅0.083,0.17IV)0.25、0.5、0.75、1、2、4、6、8和24小时,从隐静脉收集连续的血样(~0.3ml),随后在4℃(1500-2000×g)离心得到血浆。样本储存于-20℃直至LC/MS/MS分析。
表VI总结了犬单次给药后化合物B的PK参数和化合物A的出现。IV或PO给药后,观察化合物B向化合物A的转化;然而,这在口服给药后更加广泛。PO给予化合物B(10mg/kg)后,化合物A的血浆AUC为0.7μM·h。这表示PO单独给予化合物A后,观察到约40%的化合物A的口服AUC(1.74μM·h)。IV给予化合物B后,化合物A的血浆AUC仅为0.03μM·h。这表示IV给予化合物A后,仅观察到3%的化合物A的AUC。这些结果表明,化合物B向化合物A的转化在体内发生。
表VI.
因此证实,在两个物种中给予前药(化合物B)可导致活性配体(化合物A)的出现。
对本领域技术人员明显的是本发明不限于前面示例说明的实施例,且其可具体化为其它特别的形式而不偏离其本质属性。因此理想的是将实施例考虑为如示例说明的所有的方面且不是限制的,将参考文献附于权利要求中而不是前面的实施例中,且因此将所有的在权利要求的等价物的意义和范围内的改变包含在此发明中。
Claims (14)
1.式I的化合物或其立体异构体或其药用盐,
其中:
m为0或1;
n为1或2;
R1选自:异噁唑基、吡唑基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、三唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、喹唑啉基、二氮杂萘基、吲唑基、吲哚基、2-吲哚酮基、苯并异噁唑基、苯并异噻唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、呋喃并吡啶基、噻吩并吡啶基、噻吩并嘧啶基、异噻唑并吡啶基、噻唑并吡啶基、噻唑并吡啶酮基、噻唑并吡嗪基、噻唑并嘧啶基、三唑并吡啶基、三唑并吡嗪基、吡咯并三嗪基、5,6-二氢苯并[h]喹唑啉基、5H-苯并吡喃并[4,3-d]嘧啶基、6,7-二氢-5H-环戊二烯并[d]嘧啶基、5,6,7,8-四氢喹唑啉基、7,8-二氢喹唑啉-5(6H)-酮基、四氢苯并噻唑基、咪唑并噻唑基、噁唑并吡啶基、三唑并哒嗪基、三唑并嘧啶基、咪唑并哒嗪基、咪唑并吡嗪基、咪唑并吡啶基、吡咯并吡嗪基、苯并三唑基、吡咯并嘧啶基、嘌呤基、吡咯并吡啶基及苯并三嗪基,且R1经0-3个独立选自下述的取代基取代:C1-4烷基、C3-7环烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-7环烷氧基、C1-4烷基硫基、苯氧基、苄基氧基、卤素、羟基、氰基、硝基、C1-4烷基磺酰基、NR2R3、吡咯烷酮基、亚甲二氧基、呋喃基、噻吩基、吡唑基、咪唑基、吡咯基、噁二唑基、噻唑基、三唑基、吡嗪基、嘧啶基、萘基、C1-4烷基氨甲酰基、CONR2R3、吡啶基、苯基及苄基,且其中咪唑基、吡啶基、苯基、吡咯基、噁二唑基及苄基经0-2个独立选自下述的取代基取代:卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、苯基、苄基、吡啶基甲基及NR2R3;
R2为氢、苯基、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
R3为氢、C1-4烷基、羟基C1-4烷基或氨基C1-4烷基;
或者R2及R3与它们所连接的氮原子一起为氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、N-(C1-4烷基)哌嗪基、吗啉基或者高哌啶基。
4.权利要求3的化合物或者其药用盐,其中R1为噻唑基、吡啶基、吡嗪基、嘧啶基、异喹啉基或喹喔啉基,且经0-2个选自下述的取代基取代:卤素;烷基;烷氧基;环烷氧基;吡唑基;咪唑基;经0-2个卤素、烷基或烷氧基取代基取代的吡啶基;及经0-2个卤素、烷基或烷氧基取代基取代的苯基。
5.权利要求4的化合物或其药用盐,其中R1为(苯基)噻唑基、(氟)(溴)吡啶基、(氯)(甲基)吡啶基、氯吡嗪基、(氟吡啶基)吡啶基、(溴)(苯基)嘧啶基、(环戊氧基)嘧啶基、(咪唑基)嘧啶基、((甲基)苯基)嘧啶基、异喹啉基、氟异喹啉基或喹喔啉基。
6.权利要求4的化合物或其药用盐,其中R1为溴吡啶基、二氯吡啶基、(吡啶基)吡啶基、(吡唑基)嘧啶基、甲氧基嘧啶基、(甲氧基吡啶基)嘧啶基、(苯基)嘧啶基或溴氯吡嗪基。
11.药物组合物,其包含治疗有效量的权利要求1的化合物或其药用盐及药用载体。
12.治疗精神分裂症、阿尔茨海默病、认知障碍、类风湿性关节炎、骨关节炎、溃疡性结肠炎、克罗恩病或糖尿病的方法,包括给予患者治疗有效量的权利要求1的化合物。
13.权利要求12的方法,涉及精神分裂症。
14.权利要求12的方法,涉及阿尔茨海默病。
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EP2563796A1 (en) | 2013-03-06 |
EP2563796B1 (en) | 2015-03-18 |
US20120108596A1 (en) | 2012-05-03 |
JP2013525457A (ja) | 2013-06-20 |
US8481555B2 (en) | 2013-07-09 |
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