1-[（4-甲氧基苯基）甲基]-5-（三氟甲氧基）-1H-吲哚-2,3-二酮 | 1160247-92-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 1-[（4-甲氧基苯基）甲基]-5-（三氟甲氧基）-1H-吲哚-2,3-二酮
• 英文名称: VU0238429
• 英文别名: 1-(4-methoxybenzyl)-5-(trifluoromethoxy)indoline-2,3-dione；ML129；1-[(4-methoxyphenyl)methyl]-5-(trifluoromethoxy)indole-2,3-dione
• CAS: 1160247-92-6
• 化学式: C₁₇H₁₂F₃NO₄
• 分子量: 351.282
• InChiKey: CKLGZXFOLMHCMC-UHFFFAOYSA-N

物化性质

• 沸点：
  459.7±55.0 °C(Predicted)
• 密度：
  1.432±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥20mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  7

安全信息

• 危险类别：
  9
• 危险性防范说明：
  P501,P273,P260,P270,P264,P280,P391,P314,P337+P313,P305+P351+P338,P301+P312+P330
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410
• 包装等级：
  III

制备方法与用途

生物活性

VU0238429 (M5 PAM) 是第一个针对 muscarinic acetylcholine receptor subtype 5 (mAChR5/M5) 的阳性变构调节剂，其对 M5 的 EC50 值为 1.16 μM，而对 M1 和 M3 的 EC50 值均大于 30 μM。VU0238429 对于 M2 和 M4 并没有表现出增强剂活性。

靶点

Target	Value
M1 mAChR
M3 mAChR
M5 mAChR (Cell-free assay)	1.16 μM

体外研究

VU0238429 是 muscarinic acetylcholine receptor subtype 5 (mAChR5) 的阳性变构调节剂，其 EC50 值为 1.16 μM，并且对 M1 和 M3 的选择性超过 30 倍，而对 M2 和 M4 没有表现出增强剂活性。

反应信息

• 作为反应物：
  描述：

  1-[（4-甲氧基苯基）甲基]-5-（三氟甲氧基）-1H-吲哚-2,3-二酮 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 、 水 为溶剂， 反应 18.0h， 以81%的产率得到3-(hydroxyimino)-1-(4-methoxybenzyl)-5-(trifluoromethoxy)indolin-2-one
  参考文献：
  名称：

  Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics

  摘要：

  Recent preclinical studies point to muscarinic and GABA(B) receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABA(B) receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABA(B) receptor (GS39783), muscarinic M-4 (VU0152100) and M-5 (VU0238429) receptor, and partial allosteric agonist of M-1 receptor (VU0357017).DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. lialoperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs.All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOl-induced 5EPSC5. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions.Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.

  DOI：

  10.1016/j.bbr.2018.09.019
• 作为产物：
  描述：

  4-甲氧基氯苄 、 5-三氟甲氧基吲哚-2,3-二酮 在 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-[（4-甲氧基苯基）甲基]-5-（三氟甲氧基）-1H-吲哚-2,3-二酮
  参考文献：
  名称：

  通过 α,α-二取代的 N-叔丁亚磺酰基酮亚胺与靛红衍生的酮亚胺的 Mannich 型加成构建无环四元立体中心

  摘要：

  开发了去质子化、高度对映体富集的 α,α-二取代 N-叔丁亚磺酰基酮亚胺与靛红衍生的酮亚胺的 Mannich 反应，以制备带有被两个空间相似基团取代的无环季立体碳的 3-氨基-3-取代羟吲哚。去质子化的出色立体控制能够形成具有立体确定几何形状的金属烯胺中间体，而 C-C 键形成的精确面选择性允许构建具有优异立体选择性的连续四元和四取代立体中心。

  DOI：

  10.1021/acs.orglett.2c00888

文献信息

• Enantioselective Alkynylation of Isatins: A Combination of Metal Catalysis and Organocatalysis
  作者：Dan Jiang、Pei Tang、Qiuyuan Tan、Zhao Yang、Ling He、Min Zhang

  DOI：10.1002/chem.202003118

  日期：2020.12.4

  efficient and catalytic asymmetric alkynylation of isatins has been developed using a bifunctional amidophosphine‐urea/AgBF4 complex as the catalyst. By a combination of metal catalysis and organocatalysis, excellent enantioselectivities (up to 99 % ee) and good yields are achieved. A wide range of both terminal alkynes and isatins are tolerated by this new catalyst system, providing access to structurally

  使用双功能酰胺基膦-尿素/ AgBF 4络合物作为催化剂，已经开发出一种高效的，高效的催化不对称的靛红炔烃。通过金属催化和有机催化的结合，可获得出色的对映选择性（最高99％  ee）和良好的收率。这种新的催化剂体系可耐受各种末端炔烃和异丁烷，可高效获得具有四取代立体异构中心的结构多样的炔丙醇。
• Discovery of the First Highly M5-Preferring Muscarinic Acetylcholine Receptor Ligand, an M5 Positive Allosteric Modulator Derived from a Series of 5-Trifluoromethoxy <i>N</i>-Benzyl Isatins
  作者：Thomas M. Bridges、Joy E. Marlo、Colleen M. Niswender、Carrie K. Jones、Satyawan B. Jadhav、Patrick R. Gentry、Hyekyung C. Plumley、C. David Weaver、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1021/jm900286j

  日期：2009.6.11

  This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca2+ mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC50 of approximately 1.16 mu M at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
• Discovery of ML326: The first sub-micromolar, selective M5 PAM
  作者：Patrick R. Gentry、Thomas M. Bridges、Atin Lamsal、Paige N. Vinson、Emery Smith、Peter Chase、Peter S. Hodder、Julie L. Engers、Colleen M. Niswender、J. Scott Daniels、P. Jeffrey Conn、Michael R. Wood、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2013.03.032

  日期：2013.5

  This Letter describes the further chemical optimization of the M-5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M-5 PAMs (M-5 EC50 >10 mu M) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M-5 PAM, ML326 (VU0467903), (human and rat M-5 EC(50)s of 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M-1-M-4 EC(50)s >30 mu M) and a robust 20-fold leftward shift of the ACh CRC. (C) 2013 Elsevier Ltd. All rights reserved.
• COMPOSITION FOR SUPRESSING SECRETION OF EXTRACELLULAR VESICLES
  申请人：NISSAN CHEMICAL CORPORATION

  公开号：US20220071956A1

  公开（公告）日：2022-03-10

  The invention provides a composition for suppressing secretion of extracellular vesicle, which comprises a compound having a structure of the formula II (wherein, each substituent is as defined in the specification), or a pharmaceutically acceptable salt thereof, or a compound having a structure of the formula I (wherein, each substituent is as defined in the specification), or a metal complex thereof, or a pharmaceutically acceptable salt thereof.
• Construction of Acyclic Quaternary Stereocenters via Mannich-Type Addition of α,α-Disubstituted <i>N</i>-<i>tert</i>-Butanesulfinyl Ketimines to Isatin-Derived Ketimines
  作者：Zheng-Fei Li、Chong-Lin Zhu、Yun Zhang、Yun Yao、Chong-Dao Lu

  DOI：10.1021/acs.orglett.2c00888

  日期：2022.4.22

  deprotonated, highly enantioenriched α,α-disubstituted N-tert-butanesulfinyl ketimines with isatin-derived ketimines was developed to prepare 3-amino-3-substituted oxindoles bearing an acyclic quaternary stereogenic carbon substituted with two sterically similar groups. The excellent stereocontrol of the deprotonation enabled the formation of metalloenamine intermediates with stereodefined geometry, while

  开发了去质子化、高度对映体富集的 α,α-二取代 N-叔丁亚磺酰基酮亚胺与靛红衍生的酮亚胺的 Mannich 反应，以制备带有被两个空间相似基团取代的无环季立体碳的 3-氨基-3-取代羟吲哚。去质子化的出色立体控制能够形成具有立体确定几何形状的金属烯胺中间体，而 C-C 键形成的精确面选择性允许构建具有优异立体选择性的连续四元和四取代立体中心。