CN104703981A - 作为cns活性药剂的苯并咪唑类化合物 - Google Patents
作为cns活性药剂的苯并咪唑类化合物 Download PDFInfo
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- CN104703981A CN104703981A CN201380050747.1A CN201380050747A CN104703981A CN 104703981 A CN104703981 A CN 104703981A CN 201380050747 A CN201380050747 A CN 201380050747A CN 104703981 A CN104703981 A CN 104703981A
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- Prior art keywords
- phenyl
- benzoglyoxaline
- pyrazole
- fluoro
- chloro
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Abstract
本发明涉及以下通式的化合物,其中R1是氢,低级烷基,卤素或被卤素取代的低级烷基;R2是氢或卤素;X1是N或CH;X2是N或CH;前提条件是X1或X2中仅一个是N;X3是C(R)或N;并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;或涉及其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。所述化合物可以用于治疗精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用。
Description
本发明涉及以下通式的化合物
其中
R1 是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2 是氢或卤素;
X1 是N或CH;
X2 是N或CH;
前提条件是X1或X2中仅一个是N;
X3 是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或涉及其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
现在已经显示,本发明的化合物刺激从神经干细胞(NSCs)的神经发生。神经发生在发育过程中和成人脑中发生。概念上,该神经发生过程可以分为四个步骤:(i)NSCs的增殖;(ii)NSC的神经元命运决定;(iii)新的神经元的存活和成熟;和(iv)新神经元功能性整合入神经元网络。
成人神经发生是整个生命中成人脑中发生的发育过程,借此,新的功能神经元从成人神经干细胞产生。在生理条件下组成型成人神经发生主要发生在两个“神经源性的”脑区域,1)海马齿状回中的亚颗粒区(SGZ),在那里产生新的齿状颗粒细胞,2)侧脑室的亚脑室区(SVZ),在那里新的神经元产生并且随后通过嘴侧迁移流(RMS)迁移至嗅球,从而成为中间神经元。
广泛的证据提示,海马的成人神经发生在认知和情绪状态中发挥重要作用,尽管精确的功能仍然难以得到。已经争论,相对小量的新生颗粒神经元可以影响整个脑功能,因为它们使齿状回内的很多中间神经元受神经支配,其每个抑制数百个成熟颗粒细胞,导致神经发生依赖性的反馈抑制。与低激发阈值联合,所述新生神经元针对环境中非常细微的变化引发响应。该过程中的失调可以在行为上表明与精神疾病相关的模式分离上的短缺。例如,成人海马的神经发生与认知和情感能力相关,例如,体育锻炼,暴露于丰富的外界环境和典型的抗抑郁药并发地促进成人海马神经发生和认知和/或情绪状态,同时慢性应激(chronic stress),抑郁症,睡眠剥夺和衰老减少成人神经发生并且与负面的认知与和/或情绪状态相关(Neuron 70,2011年5月26日,pp 582-588和pp 687-702;WO2008/046072)。有趣地是,抗抑郁药促进海马成人神经发生并且其对某些行为的影响需要刺激神经发生。通常相信,在其它成人CNS区域中的神经发生在正常生理条件下是非常有限的,但在损伤诸如中风(stroke),和中枢和外周脑损伤之后可以被诱导。
因此,据信,成人神经发生的刺激代表了用于正常衰老和尤其是用于多种神经变性疾病和神经精神疾病的神经再生治疗靶点,所述神经变性疾病和神经精神疾病包括精神分裂症(schizophrenia),强迫型人格障碍(obsessive-compulsive personality disorder),重度抑郁症(major depression),双相型障碍(bipolar disorders),焦虑症(anxiety disorders),癫痫(epilepsy),视网膜变性(retinal degeneration),外伤性脑损伤(traumatic brain injury),脊髓损伤(spinal cord injury),创伤后精神紧张性障碍(post-traumatic stressdisorder),惊恐性障碍(panic disorder),帕金森病(Parkinson's disease),痴呆(dementia),阿尔茨海默病(Alzheimer’s disease),轻度认知损害(mildcognitive impairment),化疗引起的认知功能障碍(chemotherapy-inducedcognitive dysfunction)(″化疗后大脑(chemobrain)″),唐氏综合征(Downsyndrome),自闭症谱系障碍(autism spectrum disorders),听力损失(hearingloss)(Neuroscience,167(2010)1216-1226;Nature Medicine,第11卷,第3期,(2005),271-276)耳鸣(tinnitus),脊髓小脑性共济失调(spinocerebellarataxia),肌萎缩侧索硬化(amyotrophic lateral sclerosis),多发性硬化(multiple sclerosis),亨廷顿病(Huntington’s disease),中风(stroke),和由放射治疗(radiation therapy),慢性应激(chronic stress),或神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用导致的失调(US2012/0022096)。
因此,化学刺激成人神经发生提供新的再生手段和机会,以开发用于治疗神经系统疾病和神经精神障碍的新药。
因此,本发明的目的是鉴定调节神经发生的化合物。已经发现,式I的化合物在该领域有活性并且它们可以因此用于治疗精神分裂症(schizophrenia),强迫型人格障碍(obsessive-compulsive personalitydisorder),重度抑郁症(major depression),双相型障碍(bipolar disorders),焦虑症(anxiety disorders),正常衰老,癫痫(epilepsy),视网膜变性(retinaldegeneration),外伤性脑损伤(traumatic brain injury),脊髓损伤(spinal cordinjury),创伤后精神紧张性障碍(post-traumatic stress disorder),惊恐性障碍(panic disorder),帕金森病(Parkinson’s disease),痴呆(dementia),阿尔茨海默病(Alzheimer’s disease),轻度认知损害(mild cognitive impairment),化疗引起的认知功能障碍(chemotherapy-induced cognitive dysfunction)(″chemobrain″),唐氏综合征(Down syndrome),自闭症谱系障碍(autismspectrum disorders),听力损失(hearing loss),耳鸣(tinnitus),脊髓小脑性共济失调(spinocerebellar ataxia),肌萎缩侧索硬化(amyotrophic lateralsclerosis),多发性硬化(multiple sclerosis),亨廷顿病(Huntington’s disease),中风(stroke),和由放射治疗(radiation therapy),慢性应激(chronic stress),或神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用导致的失调。
式I的化合物的最优选的适应症是阿尔茨海默病(Alzheimer’s disease),抑郁症(depression),焦虑症(anxiety disorders)和中风(stroke)。
本发明涉及式I的化合物和其药用盐(在这适用于对映异构体或非对映异构体的混合物或其对映异构体或非对映异构体纯的形式的情况下),涉及作为药学活性物质的这些化合物,涉及它们的生产方法,以及涉及治疗或预防疾病的用途,所述疾病涉及神经发生,精神分裂症(schizophrenia),强迫型人格障碍(obsessive-compulsive personalitydisorder),重度抑郁症(major depression),双相型障碍(bipolar disorders),焦虑症(anxiety disorders),正常衰老,癫痫(epilepsy),视网膜变性(retinaldegeneration),外伤性脑损伤(traumatic brain injury),脊髓损伤(spinal cordinjury),创伤后精神紧张性障碍(post-traumatic stress disorder),帕金森病(Parkinson's disease),痴呆(dementia),阿尔茨海默病(Alzheimer’s disease),轻度认知损害(mild cognitive impairment),化疗引起的认知功能障碍(chemotherapy-induced cognitive dysfunction),唐氏综合征(Downsyndrome),自闭症谱系障碍(autism spectrum disorders),听力损失(hearingloss),耳鸣(tinnitus),脊髓小脑性共济失调(spinocerebellar ataxia),肌萎缩侧索硬化(amyotrophic lateral sclerosis),多发性硬化(multiple sclerosis),亨廷顿病(Huntington’s disease),中风(stroke),放射治疗(radiation therapy),慢性应激(chronic stress),神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用,并且涉及含有式I化合物的药物组合物。
不论讨论的术语单独或组合出现,以下用于本说明书的通用术语的定义都适用。
如本文中使用的,术语“低级烷基”表示包括具有1-4个碳原子的直链或支链碳链的饱和的,即脂族烃基团。“烷基”的实例是甲基,乙基,正丙基,和异丙基。
术语“低级烷氧基”表示基团-O-R’,其中R’是上文定义的低级烷基。
术语“被卤素取代的低级烷基”表示上文定义的低级烷基基团并且其中至少一个氢原子被卤素替代。
术语“卤素”表示氯,溴,氟或碘。
术语″药用盐″或“药用酸加成盐”包括无机和有机酸盐,诸如盐酸,硝酸,硫酸,磷酸,柠檬酸,甲酸,富马酸,马来酸,乙酸,琥珀酸,酒石酸,甲磺酸,对苯甲磺酸盐等。
本发明的一个实施方案是式IA的化合物
其中
R1 是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2 是氢或卤素;
X3 是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体,例如
1-对-甲苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-苯基-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-苯基-1H-苯并咪唑
1-苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-(2-苯基-2H-吡唑-3-基)-1-对-甲苯基-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-对-甲苯基-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-氟-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(2,4-二氟-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-iH-苯并咪唑。
本发明的一个进一步实施方案是式IA-1的化合物
其中
R1 是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2 是氢或卤素;
R 是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体,例如
1-对-甲苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-苯基-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-苯基-1H-苯并咪唑
1-苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-(2-苯基-2H-吡唑-3-基)-1-对-甲苯基-iH-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-对-甲苯基-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-氟-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(2,4-二氟-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑。
本发明的一个进一步实施方案是式IA-2的化合物
其中
R1 是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2 是氢或卤素;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体,例如
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑。
本发明的一个进一步实施方案是式IB的化合物
其中
R1 是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2 是氢或卤素;
X3 是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体,例如
1-(4-氟-苯基)-6-(3-苯基-3H-咪唑-4-基)-1H-苯并咪唑
6-[3-(4-氯-苯基)-3H-咪唑-4-基]-1-(4-氟-苯基)-1H-苯并咪唑,或
1-(4-氟-苯基)-6-[3-(4-氟-苯基)-3H-咪唑-4-基]-1H-苯并咪唑。
可以通过本领域已知的方法,例如通过下文描述的方法制备本发明的式I的化合物和其药用盐,所述方法包括
使式1的化合物
与式2的化合物
反应产生式I的化合物
并且,如果需要,将获得的化合物转变为药用酸加成盐。
本发明式I的化合物的制备可以以顺序或会聚的合成途径进行。本发明化合物的合成显示在以下方案1中。进行所述反应和纯化产生的产物的技术对于本领域技术人员已知。除非有相反说明,以下方法描述中使用的取代基和标记具有上文中给出的意义。
更详细地,可以通过下文给出的方法,通过实施例中给出的方法或通过类似方法制造式I的化合物。各个反应步骤的适当反应条件是本领域技术人员已知的。反应顺序不限于方案1中显示的顺序,然而,依赖于起始材料和其相应反应性,反应步骤的顺序可以随意改变。起始材料是可商购的或可以通过与下文给出的方法类似的方法,通过说明书引用的参考文献中或实施例中描述的方法,或通过本领域已知的方法制备。
方案1
式IA的化合物可以通过钯催化的溴-苯并咪唑2和硼酸1的偶联反应制备(方案I)。
硼酸1可商购或可以在-78℃通过用正丁基锂和硼酸三异丙酯处理而从相应的苯基-咪唑6制备。如果不可商购,则苯基-咪唑6可以从相应的苯基-肼5制备。
溴-苯并咪唑2可以通过如下方式制备:将4-溴-2-氟-硝基苯7与相应的苯胺8反应,接着还原硝基基团,产生1,2-二氨基-苯衍生物9,其随后通过用原甲酸三甲酯和甲酸处理而转化成苯并咪唑2。
方案2
相关的式IB的咪唑衍生物可以容易地通过钯催化的溴-苯并咪唑3与可商购的苯基-咪唑4的偶联反应而制备(方案2)。
化合物的分离和纯化
如果需要,本文中描述的化合物和中间体的分离和纯化可以通过任意合适的分离或纯化方法进行,所述方法诸如,例如,过滤,萃取,结晶,柱层析,薄层层析,厚层层析,制备型低或高压液相色谱或这些方法的组合。可以通过参考下文的制备和实施例获得适当的分离和离析方法的具体说明。然而,当然可以使用其它相当的分离或离析方法。可以使用手性HPLC分离式I的手性化合物的外消旋混合物。
式I的化合物的盐
式I的化合物是碱性的并且可以被转变为相应酸加成盐。通过用至少化学计量的量的适当酸诸如盐酸,氢溴酸,硫酸,硝酸,磷酸等,和有机酸诸如乙酸,丙酸,乙醇酸,丙酮酸,草酸,苹果酸,丙二酸,琥珀酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸等处理实现转变。典型地,将游离碱溶解在惰性有机溶剂诸如二乙醚,乙酸乙酯,氯仿,乙醇或甲醇等中,并且将酸加入类似的溶剂中。将温度维持在0℃和50℃之间。产生的盐自发沉淀或可以用较小极性的溶剂带出溶液。
式I的碱性化合物的酸加成盐可以通过用至少化学计量当量的适当碱诸如氢氧化钠或氢氧化钾,碳酸钾,碳酸氢钠,氨水等处理转变为相应的游离碱。
式I的化合物和其药用加成盐具有有益的药学性质。具体地,已经发现本发明的化合物具有作为神经源性剂的活性。
根据下文给出的测试研究所述化合物。
神经发生测定
神经干细胞增殖测定
小分子的神经源性性质基于通过之前描述的双重smad抑制衍生的人胚胎干细胞衍生的神经干细胞(NSCs)的增殖而确定(Chambers,S.M.,等人,Highly efficient neural conversion of human ES and iPS cells by dualinhibition of SMAD signaling,Nature biotechnology,2009.27(3):p.275-80.)
4天的孵育期之后通过基于ATP水平的细胞增加(Promega:)测量化合物响应。
将NSCs解冻并扩充3代。在第14天,将NSCs以38μl培养基体积中21’000个细胞/cm2的细胞密度接种入Polyornithin/Laminin包被的384孔板中。
细胞接种后4小时,以2μl的体积添加化合物溶液。将化合物的储液(水,5%DMSO)稀释以获得剂量响应(11个点,稀释因子是2),范围从8μM至8nM。运行对照以不断确定细胞的神经源性性质:
阴性(中性)对照是细胞培养基(最终DMSO浓度:0.25%).
阳性对照是:
1.细胞培养基+100ng/ml FGF2(最终DMSO浓度:0.1%)
2.细胞培养基+20ng/ml EGF(最终DMSO浓度:0.1%)
3.细胞培养基+100ng/ml Wnt3a(最终DMSO浓度:0.1%)
在37℃,5%CO2孵育4天之后,定量每孔的ATP量。ATP浓度与细胞数量成比例。通过使用Promega 试剂盒定量ATP。试剂含有细胞溶解缓冲液,热稳定荧光素酶(UltraGloTM重组荧光素酶),镁和荧光素。荧光素与ATP反应产生氧化荧光素,AMP和光。发光信号与ATP含量成比例。
对于各个测定板,通过采用16个阴性对照孔的平均确定阴性(中性)对照值。对于各个化合物,将神经源性化合物响应计算为(化合物/阴性对照)*100。
对于各个测试化合物,确定来自剂量响应曲线的EC150值。EC150是达到对照(100%)的150%活性的化合物浓度。
优选的化合物显示在<2.8μM的范围内的EC150(μM),如下表所示。
实施例和EC
150
数据表
中间体
中间体A:1-(4-氟苯基)-1H-吡唑-5-基硼酸
在氮气氛下在-78℃,向可商购的1-(4-氟苯基)-1H-吡唑[CAS No81329-32-0](1.6g,9.87mmol)在THF(39.5ml)中的搅拌溶液中逐滴添加正丁基锂(1.6N,在己烷中,6.47ml,10.4mmol)。在使混合物在-78℃搅拌1h后,在-78℃添加硼酸三异丙酯(7.65g,9.35ml,39.5mmol)。使混合物在-78℃搅拌1h,逐渐温热至室温,并用1M HCl溶液将混合物的pH调节至5。蒸发该混合物并将剩余的水层用乙酸乙酯(2x 30ml)萃取。合并的有机层用盐水(30ml)洗涤,用MgSO4干燥并蒸发。粗产物通过硅胶柱色谱(二氯甲烷/MeOH)和研磨(二乙醚/己烷)纯化,得到标题化合物,为白色固体(479mg,24%),MS(ISN)m/z=205.0[(M-H)-],mp 115℃。
中间体B:1-(对甲苯基)-1H-吡唑-5-基硼酸
该标题化合物,灰白色固体(629mg,37%),MS(ISN)m/z=201.2[(M-H)-],mp 111℃,根据中间体A的通用方法从可商购的1-(对甲苯基)-1H-吡唑[CAS No.20518-17-6](1.35g,8.53mmol)和硼酸三异丙酯制备。
中间体C:1-(4-(三氟甲基)-苯基)-1H-吡唑-5-基硼酸
该标题化合物,浅褐色固体(2.26g,62%),MS(ISN)m/z=255.5[(M-H)-],mp 306℃,根据中间体A的通用方法从可商购的1-(4-(三氟甲基)-苯基)-1H-吡唑[CAS No.207797-05-5](3g,14.1mmol)和硼酸三异丙酯制备。
中间体D:1-(4-氯苯基)-1H-吡唑-5-基硼酸
该标题化合物,浅褐色固体(400mg,17%),MS(ISN)m/z=221.2[(M-H)-],根据中间体A的通用方法从可商购的1-(4-氯苯基)-1H-吡唑[CASNo.25419-86-7](1.87g,10.5mmol)和硼酸三异丙酯制备。
中间体E:6-溴-1-苯基-1H-苯并[d]咪唑
步骤A
向可商购的4-溴-2-氟-1-硝基苯(1g,4.47mmol)和碳酸钾(680mg,4.92mmol)在DMSO(17.9ml)中的搅拌混合物中添加苯胺(419mg,410μl,4.47mmol)并使反应混合物在室温搅拌65h。将反应混合物倒入水(100ml)中并乙酸乙酯(2x 70ml)萃取。合并的有机层用水(1x 50ml)洗涤,干燥(MgSO4)并蒸发。粗产物(橙色固体,1.32g)通过硅胶上的快速色谱[庚烷/乙酸乙酯(0-10%)]纯化,得到橙色固体(1.06g,3.62mmol),随后将其溶解在甲醇(50.0ml)中。向搅拌溶液中,在室温添加盐酸(37%,50ml)和氯化锡(II)二水合物(4.9g,21.7mmol),之后使反应混合物在80℃搅拌1h。将反应混合物蒸发,添加冰和3N氢氧化钠溶液(50ml),并且混合物用乙酸乙酯(2x100ml)萃取。合并的有机层用盐水(50ml)洗涤,干燥(MgSO4)并蒸发。粗产物(0.94g)通过硅胶上的快速色谱(庚烷/乙酸乙酯4∶1)纯化,得到4-溴-N2-苯基-苯-1,2-二胺,为浅褐色固体(429mg,36%),MS(ISN)m/z=261.0[(M-H)-],mp 103℃。
步骤B
向4-溴-N2-苯基-苯-1,2-二胺(步骤A)(420mg,1.6mmol)和原甲酸三甲酯(4.8g,5ml,45.2mmol)的搅拌混合物中,在室温添加甲酸(1.2g,1ml,26.1mmol),之后使反应混合物在回流条件下搅拌2h。将反应混合物冷却至室温,蒸发并用乙酸乙酯(2x 40ml)萃取。合并的有机层用饱和碳酸氢钠溶液(20ml)和盐水(20ml)洗涤,干燥(MgSO4)并蒸发。粗产物(400mg)通过硅胶上的快速色谱(庚烷/乙酸乙酯3∶2)纯化,得到标题化合物,为灰白色固体(358mg,82%),MS(ISP)m/z=275.0[(M+H)+]。
中间体F:6-溴-1-对-甲苯基-1H-苯并[d]咪唑
步骤A
4-溴-N2-对-甲苯基-苯-1,2-二胺,橙色油状物(0.95g,76%),MS(ISN)m/z=275.1[(M-H)-],根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(1g,4.47mmol)和对-甲苯胺(484mg,4.47mmol)制备。
步骤B
该标题化合物,浅褐色油状物(854mg,88%),MS(ISP)m/z=289.0[(M+H)+],根据中间体E的通用方法(步骤B)从4-溴-N2-对-甲苯基-苯-1,2-二胺(步骤A)(0.94g,3.39mmol)制备。
中间体G:6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-氟-苯基)-苯-1,2-二胺,褐色油状物(0.83g,33%),MS(ISN)m/z=281.1[(M-H)-],根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(2g,8.94mmol)和4-氟-苯胺(1.02g,8.94mmol)制备。
步骤B
该标题化合物,灰白色固体(751mg,88%),MS(ISP)m/z=293.0[(M+H)+],mp 111.5℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(4-氟-苯基)-苯-1,2-二胺(步骤A)(0.82g,2.92mmol)制备。
中间体H:6-溴-1-(4-氯-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-氯-苯基)-苯-1,2-二胺,浅褐色油状物(0.9g,41%),MS(ISP)m/z=299.3[(M+H)+],根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(1.5g,6.71mmol)和4-氯-苯胺(0.97g,7.38mmol)制备。
步骤B
该标题化合物,浅褐色固体(492mg,53%),MS(ISP)m/z=309.3[(M+H)+],mp 131℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(4-氯-苯基)-苯-1,2-二胺(步骤A)(0.9g,3.02mmol)制备。
中间体I:6-溴-1-(4-三氟甲基-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-三氟甲基-苯基)-苯-1,2-二胺,浅褐色固体(0.46g,21%),MS(ISP)m/z=331.3[(M+H)+],mp 84℃,根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(1.5g,6.71mmol)和4-三氟甲基-苯胺(1.23g,7.38mmol)制备。
步骤B
该标题化合物,浅褐色固体(461mg,97%),MS(ISP)m/z=341.3[(M+H)+],mp 84.5℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(4-三氟甲基-苯基)-苯-1,2-二胺(步骤A)(0.46g,1.39mmol)制备。
中间体K:6-溴-1-(2,4-二氟-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(2,4-二氟-苯基)-苯-1,2-二胺,褐色固体(1.98g,73%),MS(ISP)m/z=299.3[(M+H)+],mp 77℃,根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(2g,9.09mmol)和2,4-二氟-苯胺(2.35g,18.2mmol)制备。
步骤B
该标题化合物,浅褐色固体(2.0g,98%),MS(ISP)m/z=309.3[(M+H)+],mp 84℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(2,4-二氟-苯基)-苯-1,2-二胺(步骤A)(1.98g,6.62mmol)制备。
中间体L:6-溴-1-吡啶-4-基-1H-苯并咪唑
步骤A
4-溴-N2-吡啶-4-基-苯-1,2-二胺,白色固体(0.31g,30%),MS(ISP)m/z=266.3[(M+H)+],mp 137.5℃,根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(0.865g,3.93mmol)和4-氨基-吡啶(0.37g,3.93mmol)制备。
步骤B
该标题化合物,白色固体(207mg,67%),MS(ISP)m/z=274.3[(M+H)+],mp 132℃,根据中间体E的通用方法(步骤B)从4-溴-N2-吡啶-4-基-苯-1,2-二胺(步骤A)(0.3g,1.14mmol)制备。
中间体M:6-溴-1-(4-氯-2-氟-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-氯-2-氟-苯基)-苯-1,2-二胺,浅褐色油状物(1.4g,49%),MS(ISP)m/z=317.3[(M+H)+],根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(2g,9.09mmol)和4-氯-2-氟-苯胺(2.65g,18.2mm01)制备。
步骤B
该标题化合物,灰白色固体(1.33g,92%),MS(ISP)m/z=327.3[(M+H)+],mp 154℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(4-氯-2-氟-苯基)-苯-1,2-二胺(步骤A)(1.4g,4.44mmol)制备。
中间体N:6-溴-1-(4-甲氧基-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-甲氧基-苯基)-苯-1,2-二胺,深红色固体(2.48g,93%),MS(ISP)m/z=293.4[(M+H)+],mp 96℃,根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(2.0g,9.09mmol)和4-甲氧基-苯胺(2.24g,18.2mmol)制备。
步骤B
该标题化合物,浅粉红色固体(2.3g,90%),MS(ISP)m/z=305.4[(M+H)+],mp 122℃,根据中间体E的通用方法(步骤B)从4-溴-N2-(4-甲氧基-苯基)-苯-1,2-二胺(步骤A)(2.47g,8.43mmol)制备。
中间体O:6-溴-1-(4-甲磺酰基-苯基)-1H-苯并[d]咪唑
步骤A
4-溴-N2-(4-甲磺酰基-苯基)-苯-1,2-二胺,浅褐色固体(186mg,10%),MS(ISN)m/z=339.5[(M-H)-],mp 179℃,根据中间体E的通用方法(步骤A)从可商购的4-溴-2-氟-1-硝基苯(1.21g,5.49mmol)和4-甲磺酰基-苯胺(0.94g,5.49mmol)制备。
步骤B
该标题化合物,灰白色泡沫(147mg,79%),MS(ISP)m/z=353.3[(M+H)+],根据中间体E的通用方法(步骤B)从4-溴-N2-(4-甲磺酰基-苯基)-苯-1,2-二胺(步骤A)(0.18g,0.53mmol)制备。
实施例1
1-对-甲苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
向6-溴-1-对-甲苯基-1H-苯并[d]咪唑(中间体F)(100mg,348μmol)和1-对-甲苯基-1H-吡唑-5-基硼酸(中间体B)(91.5mg,453μmol)在1,2-二甲氧基乙烷(3ml)中的混合物中添加2M碳酸钠溶液(696μl,1.39mmol),并在超声浴中将反应混合物用氩气吹洗10min。向该搅拌混合物中,在室温添加四(三苯基膦)钯(0)(80.5mg,69.6μmol),并使反应混合物在回流条件下搅拌15h。将反应混合物冷却至室温,倒入水(20ml)中并用乙酸乙酯(2x20ml)萃取。合并的有机层用盐水(1x 20ml)洗涤,干燥(MgSO4)并蒸发。粗物料(200mg)通过硅胶上的快速色谱(庚烷/乙酸乙酯1∶1)和从二乙醚/庚烷研磨纯化,得到标题化合物,为灰白色固体(55mg,43%),MS(ISP)m/z=365.2[(M+H)+],mp 165℃。
实施例2
1-苯基-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
该标题化合物,灰白色固体(36mg,29%),MS(ISP)m/z=337.3[(M+H)+],mp 194℃,根据实施例1的通用方法从6-溴-1-苯基-1H-苯并[d]咪唑(中间体E)(100ng,366μmol)和可商购的1-苯基-1H-吡唑-5-基硼酸[CAS No.1238702-56-1](89.5mg,476μmol)制备。
实施例3
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-苯基-1H-苯并咪唑
该标题化合物,灰白色固体(39mg,30%),MS(ISP)m/z=355.2[(M+H)+],mp 201℃,根据实施例1的通用方法从6-溴-1-苯基-1H-苯并[d]咪唑(中间体E)(100mg,366μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(98.0mg,476μmol)制备。
实施例4
1-苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
该标题化合物,灰白色泡沫(36mg,28%),MS(ISP)m/z=351.3[(M+H)+],根据实施例1的通用方法从6-溴-1-苯基-1H-苯并[d]咪唑(中间体E)(100mg,366μmol)和1-对-甲苯基-1H-吡唑-5-基硼酸(中间体B)(96.2mg,476μmol)制备。
实施例5
6-(2-苯基-2H-吡唑-3-基)-1-对-甲苯基-1H-苯并咪唑
该标题化合物,灰白色固体(27mg,22%),MS(ISP)m/z=351.3[(M+H)+],mp 146℃,根据实施例1的通用方法从6-溴-1-对-甲苯基-1H-苯并[d]咪唑(中间体F)(100mg,348μmol)和可商购的1-苯基-1H-吡唑-5-基硼酸[CAS No.1238702-56-1](85.1mg,453μmol)制备。
实施例6
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-对-甲苯基-1H-苯并咪唑
该标题化合物,灰白色固体(22mg,17%),MS(ISP)m/z=369.2[(M+H)+],mp 149℃,根据实施例1的通用方法从6-溴-1-对-甲苯基-1H-苯并[d]咪唑(中间体F)(100mg,348μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(93.3mg,453μmol)制备。
实施例7
1-(4-氟-苯基)-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
该标题化合物,浅褐色固体(26mg,21%),MS(ISP)m/z=355.2[(M+H)+],mp 194℃,根据实施例1的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(100mg,344μmol)和可商购的1-苯基-1H-吡唑-5-基硼酸[CAS No.]238702-56-1](83.9mg,447μmol)制备。
实施例8
1-(4-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,白色固体(40mg,31%),MS(ISP)m/z=373.1[(M+H)+],mp 173℃,根据实施例1的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(100mg,344μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(92.0mg,447μmol)制备。
实施例9
1-(4-氟-苯基)-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
该标题化合物,浅褐色泡沫(78mg,61%),MS(ISP)m/z=369.2[(M+H)+],根据实施例1的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(100mg,344μmol)和1-对-甲苯基-1H-吡唑-5-基硼酸(中间体B)(90.2mg,447μmol)制备。
实施例10
1-(4-氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,黄色固体(45mg,31%),MS(ISP)m/z=423.5[(M+H)+],mp 167℃,根据实施例1的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(100mg,344μmol)和1-(4-三氟甲基-苯基)-1H-吡唑-5-基硼酸(中间体C)(96.7mg,378μmol)制备。
实施例11
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-氟-苯基)-1H-苯并咪唑
该标题化合物,灰白色固体(28mg,21%),MS(ISP)m/z=389.4[(M+H)+],mp 180℃,根据实施例1的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(100mg,344μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(84.0mg,378μmol)制备。
实施例12
1-(4-氯-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,浅褐色固体(56mg,39%),MS(ISP)m/z=439.4[(M+H)+],mp 198℃,根据实施例1的通用方法从6-溴-1-(4-氯-苯基)-1H-苯并[d]咪唑(中间体H)(100mg,325μmol)和1-(4-三氟甲基-苯基)-1H-吡唑-5-基硼酸(中间体C)(91.6mg,358μmol)制备。
实施例13
1-(4-氯-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,浅褐色固体(29mg,22%),MS(ISP)m/z=405.4[(M+H)+],mp 182℃,根据实施例1的通用方法从6-溴-1-(4-氯-苯基)-1H-苯并[d]咪唑(中间体H)(100mg,325μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(79.6mg,358μmol)制备。
实施例14
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
该标题化合物,浅褐色固体(37mg,29%),MS(ISP)m/z=439.4[(M+H)+],mp 196℃,根据实施例1的通用方法从6-溴-1-(4-三氟甲基-苯基)-1H-苯并[d]咪唑(中间体I)(100mg,293μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(71.7mg,322μmol)制备。
实施例15
1-(2,4-二氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,灰白色固体(48mg,34%),MS(ISP)m/z=441.4[(M+H)+],mp 129℃,根据实施例1的通用方法从6-溴-1-(2,4-二氟-苯基)-1H-苯并[d]咪唑(中间体K)(100mg,324μmol)和1-(4-三氟甲基-苯基)-1H-吡唑-5-基硼酸(中间体C)(91.1mg,356μmol)制备。
实施例16
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(2,4-二氟-苯基)-1H-苯并咪唑
该标题化合物,灰白色固体(29mg,22%),MS(ISP)m/z=407.4[(M+H)+],mp 133℃,根据实施例1的通用方法从6-溴-1-(2,4-二氟-苯基)-1H-苯并[d]咪唑(中间体K)(100mg,324μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(79.2mg,356μmol)制备。
实施例17
1-(2,4-二氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,浅褐色固体(69mg,55%),MS(ISP)m/z=391.5[(M+H)+],mp 152℃,根据实施例1的通用方法从6-溴-1-(2,4-二氟-苯基)-1H-苯并[d]咪唑(中间体K)(100mg,324μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(79.9mg,388μmol)制备。
实施例18
6-12-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
该标题化合物,浅褐色固体(67mg,54%),MS(ISP)m/z=423.3[(M+H)+],mp 204℃,根据实施例1的通用方法从6-溴-1-(4-三氟甲基-苯基)-1H-苯并[d]咪唑(中间体I)(100mg,293μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(72.5mg,352μmol)制备。
实施例19
1-(4-氯-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,灰白色固体(44mg,35%),MS(ISP)m/z=389.4[(M+H)+],mp 173℃,根据实施例1的通用方法从6-溴-1-(4-氯-苯基)-1H-苯并[d]咪唑(中间体H)(100mg,325μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(80.3mg,390μmol)制备。
实施例20
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
该标题化合物,灰白色固体(62mg,48%),MS(ISP)m/z=356.4[(M+H)+],mp 199℃,根据实施例1的通用方法从6-溴-1-吡啶-4-基-1H-苯并咪唑(中间体L)(100mg,365μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(90.2mg,438μmol)制备。
实施例21
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
该标题化合物,白色固体(50mg,37%),MS(ISP)m/z=372.4[(M+H)+],mp 203℃,根据实施例1的通用方法从6-溴-1-吡啶-4-基-1H-苯并咪唑(中间体L)(100mg,365μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(97.4mg,438μmol)制备。
实施例22
1-(4-氯-2-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,白色固体(46mg,37%),MS(ISP)m/z=407.5[(M+H)+],mp 153℃,根据实施例1的通用方法从6-溴-1-(4-氯-2-氟-苯基)-1H-苯并[d]咪唑(中间体M)(100mg,307μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(76.0mg,369μmol)制备。
实施例23
1-(4-氯-2-氟-苯基)-6-12-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
该标题化合物,白色固体(23mg,18%),MS(ISP)m/z=423.4[(M+H)+],mp 158℃,根据实施例1的通用方法从6-溴-1-(4-氯-2-氟-苯基)-1H-苯并[d]咪唑(中间体M)(100mg,307μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(82.1mg,369μmol)制备。
实施例24
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
该标题化合物,灰白色固体(34mg,27%),MS(ISP)m/z=385.5[(M+H)+],mp 143℃,根据实施例1的通用方法从6-溴-1-(4-甲氧基-苯基)-1H-苯并[d]咪唑(中间体N)(100mg,330μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(81.6mg,396μmol)制备。
实施例25
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
该标题化合物,灰白色固体(16mg,12%),MS(ISP)m/z=401.5[(M+H)+],mp 163℃,根据实施例1的通用方法从6-溴-1-(4-甲氧基-苯基)-1H-苯并[d]咪唑(中间体N)(100mg,330μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(88.1mg,396μmol)制备。
实施例26
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑
该标题化合物,白色固体(12mg,14%),MS(ISP)m/z=433.4[(M+H)+],mp 247℃,根据实施例1的通用方法从6-溴-1-(4-甲磺酰基-苯基)-1H-苯并[d]咪唑(中间体O)(70mg,199μmol)和1-(4-氟-苯基)-1H-吡唑-5-基硼酸(中间体A)(49.2mg,239μmol)制备。
实施例27
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑
该标题化合物,白色固体(13mg,15%),MS(ISP)m/z=449.4[(M+H)+],mp 280℃,根据实施例1的通用方法从6-溴-1-(4-甲磺酰基-苯基)-1H-苯并[d]咪唑(中间体O)(70mg,199μmol)和1-(4-氯-苯基)-1H-吡唑-5-基硼酸(中间体D)(53.2mg,239μmol)制备。
实施例28
1-(4-氟-苯基)-6-(3-苯基-3H-咪唑-4-基)-1H-苯并咪唑
向火焰干燥的反应烧瓶中添加可商购的1-苯基-1H-咪唑(50.5mg,0.35mmol)、乙酸钯(II)(7.86mg,35.0μmol)、氟化铯(106mg,0.7mmol)、三苯胂(21.4mg,70.0μmol)和6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(204mg,0.7mmol)。将反应烧瓶抽真空,并用氩气回填,并将此过程重复两次。之后在室温通过注射器在氩气流下连续添加DMF(1.75ml)。使所得混合物在氩气氛下在140℃搅拌48h。之后将反应混合物冷却至室温,倒入水(20ml)中,用乙酸乙酯(2x 30ml)萃取并用盐水(20ml)洗涤。将合并的有机层干燥(MgSO4)并蒸发。粗产物通过在硅胶上的快速色谱[二氯甲烷/MeOH(0-3%)]和从二氯甲烷/己烷结晶进行纯化,得到标题化合物,为灰白色固体(23mg,19%),MS(ISP)m/z=355.1[(M+H)+],mp 216℃。
实施例29
6-[3-(4-氯-苯基)-3H-咪唑-4-基]-1-(4-氟-苯基)-1H-苯并咪唑
该标题化合物,灰白色固体(20mg,15%),MS(ISP)m/z=389.5[(M+H)+],mp 254℃,根据实施例28的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(204mg,0.7mmol)和可商购的1-(4-氯-苯基)-1H-咪唑(62.5mg,0.35mmol)制备。
实施例30
1-(4-氟-苯基)-6-[3-(4-氟-苯基)-3H-咪唑-4-基]-1H-苯并咪唑
该标题化合物,浅褐色固体(26mg,20%),MS(ISP)m/z=373.5[(M+H)+],mp 247℃,根据实施例28的通用方法从6-溴-1-(4-氟-苯基)-1H-苯并[d]咪唑(中间体G)(204mg,0.7mmol)和可商购的1-(4-氟-苯基)-1H-咪唑(56.8mg,0.35mmol)制备。
Claims (19)
1.式I的化合物
其中
R1是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2是氢或卤素;
X1是N或CH;
X2是N或CH;
前提条件是X1或X2中仅一个是N;
X3是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
2.根据权利要求1的式IA的化合物,
其中
R1是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2是氢或卤素;
X3是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
3.根据权利要求1或2中任一项的式IA的化合物,其中所述化合物是
1-对-甲苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-苯基-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-苯基-1H-苯并咪唑
1-苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-(2-苯基-2H-吡唑-3-基)-1-对-甲苯基-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-对-甲苯基-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-氟-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(2,4-二氟-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑。
4.根据权利要求1-3中任一项的式IA-1的化合物
其中
R1是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2是氢或卤素;
R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基,
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
5.根据权利要求1-4中任一项的式IA-1的化合物,其中所述化合物是
1-对-甲苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-苯基-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-苯基-1H-苯并咪唑
1-苯基-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
6-(2-苯基-2H-吡唑-3-基)-1-对-甲苯基-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-对-甲苯基-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氟-苯基)-6-(2-对-甲苯基-2H-吡唑-3-基)-1H-苯并咪唑
1-(4-氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-氟-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-三氟甲基-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(2,4-二氟-苯基)-1H-苯并咪唑
1-(2,4-二氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-三氟甲基-苯基)-1H-苯并咪唑
1-(4-氯-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
1-(4-氯-2-氟-苯基)-6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲氧基-苯基)-1H-苯并咪唑
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-(4-甲磺酰基-苯基)-1H-苯并咪唑。
6.根据权利要求1-3中任一项的式IA-2的化合物
其中
R1是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2是氢或卤素;
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
7.根据权利要求1-3和6中任一项的式IA-2的化合物,其中所述化合物是
6-[2-(4-氟-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑,或
6-[2-(4-氯-苯基)-2H-吡唑-3-基]-1-吡啶-4-基-1H-苯并咪唑。
8.根据权利要求1的式IB的化合物
其中
R1是氢,低级烷基,卤素或被卤素取代的低级烷基;
R2是氢或卤素;
X3是C(R)或N;
并且R是氢,低级烷基,卤素,被卤素取代的低级烷基,低级烷氧基或SO2-低级烷基,
或其药用酸加成盐,外消旋混合物或其相应的对映异构体和/或光学异构体。
9.根据权利要求1或8中任一项的化合物,所述化合物是
1-(4-氟-苯基)-6-(3-苯基-3H-咪唑-4-基)-1H-苯并咪唑
6-[3-(4-氯-苯基)-3H-咪唑-4-基]-1-(4-氟-苯基)-1H-苯并咪唑,或
1-(4-氟-苯基)-6-[3-(4-氟-苯基)-3H-咪唑-4-基]-1H-苯并咪唑。
10.一种制造权利要求1至9中任一项所限定的式I的化合物的方法,所述方法包括:
使式1的化合物
与式2的化合物
反应生成式I的化合物
并且,如果需要,将获得的化合物转变为药用酸加成盐。
11.由根据权利要求10的方法制造的根据权利要求1至9中任一项所述的化合物。
12.药物组合物,所述药物组合物包含根据权利要求1至9中任一项所述的化合物和药用载体和/或辅料。
13.药物组合物,所述药物组合物包含根据权利要求1至9中任一项所述的化合物和药用载体和/或辅料,所述药物组合物用于治疗精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用。
14.根据权利要求1至9中任一项所述的化合物,所述化合物用作治疗活性物质。
15.根据权利要求1至9中任一项所述的化合物,所述化合物在以下疾病的治疗中用作治疗活性物质:精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用。
16.根据权利要求1至9中任一项所述的化合物用于制备药物的用途,所述药物用于治疗性和/或预防性治疗精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用。
17.一种用于治疗或预防以下疾病的方法:精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用,所述方法包括施用有效量的如权利要求1至9中任一项所限定的化合物。
18.根据权利要求1至9中任一项所述的化合物用于治疗或预防以下疾病的用途:精神分裂症,强迫型人格障碍,重度抑郁症,双相型障碍,焦虑症,正常衰老,癫痫,视网膜变性,外伤性脑损伤,脊髓损伤,创伤后精神紧张性障碍,惊恐性障碍,帕金森病,痴呆,阿尔茨海默病,轻度认知损害,化疗引起的认知功能障碍,唐氏综合征,自闭症谱系障碍,听力损失,耳鸣,脊髓小脑性共济失调,肌萎缩侧索硬化,多发性硬化,亨廷顿病,中风,放射治疗,慢性应激,神经活性药物诸如酒精、阿片制剂、甲基苯丙胺、苯环利定和可卡因的滥用。
19.如上所述的发明。
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US11352328B2 (en) | 2016-07-12 | 2022-06-07 | Arisan Therapeutics Inc. | Heterocyclic compounds for the treatment of arenavirus |
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US11951092B2 (en) | 2017-06-02 | 2024-04-09 | Fujifilm Toyama Chemical Co., Ltd. | Agent for preventing or treating brain atrophy |
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