4-fluoro-1-(piperidin-4-yl)-1-H-benzo[d]imidazol-2(3H)-on | 913196-11-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 4-fluoro-1-(piperidin-4-yl)-1-H-benzo[d]imidazol-2(3H)-on
• 英文别名: 4-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one；7-fluoro-3-piperidin-4-yl-1H-benzimidazol-2-one
• CAS: 913196-11-9
• 化学式: C₁₂H₁₄FN₃O
• 分子量: 235.261
• InChiKey: WIFRSJYQMMODEA-UHFFFAOYSA-N

物化性质

• 密度：
  1.289±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  44.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-fluoro-1-(piperidin-4-yl)-1-H-benzo[d]imidazol-2(3H)-on 、 4-(3-bromopropyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 16.0h， 生成 4-{3-[4-(4-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-4H-benzo[1,4]oxazin-3-one
  参考文献：
  名称：

  Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential

  摘要：

  We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D-2 receptor affinity and M-1 receptor agonism. Based on a strategy of controlling log P, we herein describe a hit-to-lead investigation with the aim of retaining the combined D-2/M-1 profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D-2 receptor affinity by this effort; whilst it was feasible to obtain compounds with M-1 receptor agonism, acceptable clearance, and weak hERG inhibition. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.048
• 作为产物：
  描述：

  2,6-二氟硝基苯 在 5%-palladium/activated carbon 盐酸 、 氢气 、 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 乙醚 、 乙醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 70.0 ℃ 、303.99 kPa 条件下， 反应 14.0h， 生成 4-fluoro-1-(piperidin-4-yl)-1-H-benzo[d]imidazol-2(3H)-on
  参考文献：
  名称：

  [EN] NOVEL 1,3-DIHYDRO-BENZOIMIDAZOL-2-ONES AS M1 AGONISTS
  [FR] NOUVEAUX 1,3-DIHYDRO-BENZOIMIDAZOL-2-ONES UTILISÉS EN TANT QU'AGONISTES M1

  摘要：

  本发明涉及本发明的新型MI激动剂化合物。其中，R1和R3分别选自H、氰基、卤素（如F或Cl）、C1-6烷氧基（如甲氧基）或C1-6烷基（如甲基）；R2选自H和卤素（如F或Cl）；Y和Y'分别选自C1-3烷基，或者Y和Y'与它们附着的碳原子一起形成C3-7环烷基；每个C1-3烷基和C3-7环烷基可以选择地用一个或两个取代基Z取代；Z选自氢、C1-3烷基和卤素（如F或Cl）；以及它们在治疗与精神分裂症相关的认知障碍以及治疗其他通过肌动蛋白MI受体介导的疾病中的应用。

  公开号：

  WO2009124883A1

文献信息

• CONSTRAINED COMPOUNDS AS CGRP-RECEPTOR ANTAGONISTS
  申请人：Chaturvedula Prasad V.

  公开号：US20070259851A1

  公开（公告）日：2007-11-08

  The invention encompasses constrained bicyclic and tricyclic CGRP-receptor antagonists, methods for identifying them, pharmaceutical compositions comprising them, and methods for their use in therapy for treatment of migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

  本发明包括受约束的双环和三环CGRP受体拮抗剂，识别它们的方法，包含它们的药物组合物，以及它们在治疗偏头痛和其他头痛、神经源性血管扩张、神经性炎症、热损伤、循环性休克、与更年期相关的潮红、气道炎症性疾病（如哮喘和慢性阻塞性肺病（COPD））中的用途，以及其他可以通过CGRP受体拮抗剂治疗的疾病。
• Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas—The effect of capping the distal basic piperidine nitrogen
  作者：Nicole R. Miller、R. Nathan Daniels、Thomas M. Bridges、Ashley E. Brady、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2008.09.032

  日期：2008.10

  developed through an iterative analog library approach, of analogs of the highly selective M1 allosteric agonist TBPB by deletion of the distal basic piperidine nitrogen by the formation of amides, sulfonamides and ureas. Despite the large change in basicity and topology, M1 selectivity was maintained.

  这封信描述了通过迭代类似物文库方法开发的高度选择性的M1变构激动剂TBPB类似物的进一步合成和SAR，该合成物是通过形成酰胺，磺酰胺和尿素来缺失远端碱性哌啶氮。尽管基本性和拓扑结构发生了很大变化，但仍保持了M1选择性。
• Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties
  作者：Thomas M. Bridges、Ashley E. Brady、J. Phillip Kennedy、R. Nathan Daniels、Nicole R. Miller、Kwango Kim、Micah L. Breininger、Patrick R. Gentry、John T. Brogan、Carrie K. Jones、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2008.09.023

  日期：2008.10

  This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.

  这封信描述了通过高度重复的M1变构激动剂TBPB的类似物通过迭代类似物库方法开发的合成和SAR的首次描述。在轻微的结构变化下，仍保持了mAChR选择性，但是部分M1激动的程度变化很大。
• [EN] NOVEL PIPERIDINYL-1,3-DIHYDRO-BENZOIMIDAZOL-2-ONES AS M1 AGONISTS<br/>[FR] NOUVELLES PIPÉRIDINYL-1,3-DIHYDROBENZOIMIDAZOL-2-ONES COMME AGONISTES DE M1
  申请人：LUNDBECK & CO AS H

  公开号：WO2009124882A1

  公开（公告）日：2009-10-15

  The present invention relates to novel M1 agonistic compounds of the present invention and their use in the treatment of cognitive impairment associated i.a. with schizophrenia and in the treatment of other diseases mediated by the muscarinic M1 receptor.

  本发明涉及本发明的新型M1激动剂化合物及其在治疗与精神分裂症相关的认知障碍以及在治疗由肌动蛋白M1受体介导的其他疾病中的应用。
• [EN] NOVEL 1,3-DIHYDRO-BENZOIMIDAZOL-2-ONES AS M1 AGONISTS<br/>[FR] NOUVEAUX 1,3-DIHYDRO-BENZOIMIDAZOL-2-ONES UTILISÉS EN TANT QU'AGONISTES M1
  申请人：LUNDBECK & CO AS H

  公开号：WO2009124883A1

  公开（公告）日：2009-10-15

  The present invention relates to novel MI agonistic compounds of the present invention. wherein R1 and R3 are idenpendently selected from H, cyano, halogen, such as F or C1, C1-6 alkoxy, such as methoxy, or C1-6 alkyI, such as methyl R2 is selected from H and halogen, such as F or C1; Y and Y' are individually selected from C1-3 alkyl, or Y and Y' together with the carbon atom to which they are attached, form a C3-7 cyctoalkyl group; and wherein each C1-3 alkyl and C3-7 cycloalkyl group may be optionally substituted with one or two substituents Z; Z is selected from hydrogen, C1-3 alkyl and halogen, such as F or C1; and their use in the treatment of cognitive impairment associated 1 a. w ith schizophrenia and in the treatment of other diseases mediated b> the muscarinic MI receptor

  本发明涉及本发明的新型MI激动剂化合物。其中，R1和R3分别选自H、氰基、卤素（如F或Cl）、C1-6烷氧基（如甲氧基）或C1-6烷基（如甲基）；R2选自H和卤素（如F或Cl）；Y和Y'分别选自C1-3烷基，或者Y和Y'与它们附着的碳原子一起形成C3-7环烷基；每个C1-3烷基和C3-7环烷基可以选择地用一个或两个取代基Z取代；Z选自氢、C1-3烷基和卤素（如F或Cl）；以及它们在治疗与精神分裂症相关的认知障碍以及治疗其他通过肌动蛋白MI受体介导的疾病中的应用。