1-(1-cyclohexylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one | 1190838-47-1

• 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: 1-(1-cyclohexylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
• 英文别名: 1-(1-cyclohexyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one；3-(1-cyclohexylpiperidin-4-yl)-1H-benzimidazol-2-one
• CAS: 1190838-47-1
• 化学式: C₁₈H₂₅N₃O
• 分子量: 299.416
• InChiKey: VSWSLQBTTUYKSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  环己酮 、 4-（2-酮酸-1-苯并咪唑）哌啶 在 Na(OAc)3BH 、 溶剂黄146 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 16.0h， 以44%的产率得到1-(1-cyclohexylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
  参考文献：
  名称：

  新型N取代苯并咪唑酮类化合物，具有强效，选择性，中枢神经系统渗透性和口服活性M1 mAChR激动剂。

  摘要：

  对公司化合物集合的虚拟筛选产生了作为亚型选择性毒蕈碱M1受体激动剂的化合物1。中央哌啶环的N-封端基团的初步优化导致化合物2和3的效力和选择性大大提高。随后优化苯并咪唑酮部分的苯环上的取代基导致发现新型毒蕈碱M1受体激动剂4和5，它们具有出色的效能，一般和亚型选择性以及药代动力学（PK）特性，包括良好的中枢神经系统（CNS）渗透性和口服生物利用度。化合物5在认知增强的动物模型中显示出强大的体内活性。高效能，出色的选择性，

  DOI：

  10.1021/ml100105x

文献信息

• Novel <i>N</i>-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M₁ mAChR Agonists
  作者：Brian Budzik、Vincenzo Garzya、Dongchuan Shi、Graham Walker、Marie Woolley-Roberts、Joanne Pardoe、Adam Lucas、Ben Tehan、Ralph A. Rivero、Christopher J. Langmead、Jeannette Watson、Zining Wu、Ian T. Forbes、Jian Jin

  DOI：10.1021/ml100105x

  日期：2010.9.9

  compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency

  对公司化合物集合的虚拟筛选产生了作为亚型选择性毒蕈碱M1受体激动剂的化合物1。中央哌啶环的N-封端基团的初步优化导致化合物2和3的效力和选择性大大提高。随后优化苯并咪唑酮部分的苯环上的取代基导致发现新型毒蕈碱M1受体激动剂4和5，它们具有出色的效能，一般和亚型选择性以及药代动力学（PK）特性，包括良好的中枢神经系统（CNS）渗透性和口服生物利用度。化合物5在认知增强的动物模型中显示出强大的体内活性。高效能，出色的选择性，
• [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。
• [EN] 1- (1-CYCLOHEXYL-4-PIPERIDINYL) -1, 3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE DERIVATIVES WHICH HAVE ACTIVITY ON THE M1 RECEPTOR AND THEIR USE IN MEDICINE<br/>[FR] DÉRIVÉS DE 1- (1-CYCLOHEXYL-4-PIPÉRIDINYL) -1, 3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE PRÉSENTANT UNE ACTIVITÉ SUR LE RÉCEPTEUR M1 ET LEUR UTILISATION EN MÉDECINE
  申请人：GLAXO GROUP LTD

  公开号：WO2008119713A1

  公开（公告）日：2008-10-09

  [EN] Compounds of formula (I) or a salt thereof are provided, wherein X₁, X₂, X₃, R⁶, Q and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders and cognitive impairments are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.
  [FR] L'invention concerne des composés représentés par la formule (I), ou un sel de ces derniers. Dans ladite formule, X₁, X₂, X₃, R⁶, Q et R sont tels que définis dans la description. L'invention concerne également des utilisations des composés en tant que médicaments ainsi que dans la fabrication de médicaments destinés au traitement de troubles psychotiques et de troubles cognitifs. L'invention concerne en outre des compositions pharmaceutiques comprenant lesdits composés.
• [EN] 1- (1-CYCLOHEXYL-4-PIPERIDINYL) -1, 3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE DERIVATIVES WHICH HAVE ACTIVITY ON THE M1 RECEPTOR AND THEIR USE IN MEDICINE<br/>[FR] DÉRIVÉS DE 1-(1-CYCLOHEXYL-4-PIPERIDINYL)-1,3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE QUI ONT UNE ACTIVITÉ SUR LE RÉCEPTEUR M1 ET LEUR UTILISATION EN MÉDECINE
  申请人：GLAXO GROUP LTD

  公开号：WO2008119719A1

  公开（公告）日：2008-10-09

  [EN] Compounds of formula (I) or a salt thereof are provided, wherein R⁴, R⁵, R⁶, Q, R¹ and R² are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders and cognitive impairments are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.
  [FR] L'invention concerne des composés de formule (I) ou un sel de ceux-ci, formule dans laquelle R⁴, R⁵, R⁶, Q, R¹ et R² sont tels que définis dans le descriptif. L'invention concerne également les utilisations de ces composés comme médicaments, et dans la fabrication de médicaments visant à traiter des troubles psychotiques et des déficiences cognitives. L'invention concerne également des compositions pharmaceutiques comprenant ces composés.
• Reverse Engineering of the Selective Agonist TBPB Unveils Both Orthosteric and Allosteric Modes of Action at the M₁ Muscarinic Acetylcholine Receptor
  作者：Peter Keov、Celine Valant、Shane M. Devine、J. Robert Lane、Peter J. Scammells、Patrick M. Sexton、Arthur Christopoulos

  DOI：10.1124/mol.113.087320

  日期：2013.9

  Recent interest in the M1 muscarinic acetylcholine (ACh) receptor (mAChR) has led to the discovery of various selective agonists for the receptor. The novel selective agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1 H- benzo[ d ]imidazol-2(3 H )-1 (TBPB) displays unprecedented functional selectivity at the M1 mAChR. This functional selectivity has been described to stem from sole interaction with an allosteric site, although the evidence for such a mechanism is equivocal. To delineate TBPB’s mechanism of action, several truncated variants of TBPB were synthesized and characterized. Binding experiments with [3H] N -methylscopolamine at the M1, M2, M3, and M4 mAChRs revealed radioligand displacement in a manner consistent with a competitive binding mode at the orthosteric site by TBPB and fragment derivatives. Cell-based functional assays of fragment derivatives of TBPB identified both agonistic and antagonistic moieties, one of which, 1-(1-cyclohexylpiperidin-4-yl)-1 H -benzo[ d ]imidazol-2(3 H )-1 (VCP794), lost agonistic selectivity for the M1 mAChR. Further interaction experiments between TBPB or its antagonist fragments with ACh also indicated a mechanism consistent with competitive binding at mAChRs. However, interaction with an allosteric site by an antagonist fragment of TBPB was demonstrated via its ability to retard radioligand dissociation. To reconcile this dual orthosteric/allosteric pharmacological behavior, we propose that TBPB is a bitopic ligand, interacting with both the orthosteric site and an allosteric site, at the M1 mAChR. This mechanism may also be the case for other selective agonists for mAChRs, and should be taken into consideration in the profiling and classification of new novel selective agonists for this receptor family.

  最近对M1毒蕈碱乙酰胆碱（ACh）受体（mAChR）的关注，导致发现了该受体的多种选择性激动剂。新型选择性激动剂1-(1′-(2-甲基苄基)-1,4′-联哌啶-4-基)-1 H-苯并[d]咪唑-2(3 H )-1 (TBPB)在M1 mAChR上表现出前所未有的功能选择性。这种功能选择性被认为源于与变构位点的唯一相互作用，尽管这种机制的证据并不明确。为了描述TBPB的作用机制，我们合成并表征了TBPB的几个截短变体。在M1、M2、M3和M4 mAChR上与[3H] N-甲基东莨菪碱的结合实验表明，放射性配体的置换方式与TBPB和片段衍生物在正构位点的竞争性结合模式一致。TBPB片段衍生物的细胞功能测定确定了激动剂和拮抗剂部分，其中一种1-(1-环己基哌啶-4-基)-1 H-苯并[d]咪唑-2(3 H )-1 (VCP794)失去了对M1 mAChR的激动剂选择性。TBPB或其拮抗剂片段与ACh的