5-(Benzyloxy)-1-methylindole-3-glyoxyloyl-chloride | 16382-45-9

• 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
• 英文名称: 5-(Benzyloxy)-1-methylindole-3-glyoxyloyl-chloride
• 英文别名: 1-methyl-5-benzyloxy-α-oxo-3-indoleacetyl chloride；2-(1-Methyl-5-phenylmethoxyindol-3-yl)-2-oxoacetyl chloride
• CAS: 16382-45-9
• 化学式: C₁₈H₁₄ClNO₃
• 分子量: 327.767
• InChiKey: JFTZQMYIHZEHMY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  48.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(Benzyloxy)-1-methylindole-3-glyoxyloyl-chloride 在 potassium tert-butylate 、 三溴化硼 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 二氯甲烷 为溶剂， 反应 0.75h， 生成 3-(benzofuran-3-yl)-4-(5-hydroxy-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione
  参考文献：
  名称：

  Structure-Based Design Leads to the Identification of Lithium Mimetics That Block Mania-like Effects in Rodents. Possible New GSK-3β Therapies for Bipolar Disorders

  摘要：

  More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3 beta inhibitors. The best ligand in this series (having a K-i value of 4.6 nM against GSK-3 beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3 beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.

  DOI：

  10.1021/ja068969w
• 作为产物：
  描述：

  5-苄氧基吲哚 在 sodium hydride 作用下， 以 四氢呋喃 、 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 5-(Benzyloxy)-1-methylindole-3-glyoxyloyl-chloride
  参考文献：
  名称：

  Structure-Based Design Leads to the Identification of Lithium Mimetics That Block Mania-like Effects in Rodents. Possible New GSK-3β Therapies for Bipolar Disorders

  摘要：

  More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3 beta inhibitors. The best ligand in this series (having a K-i value of 4.6 nM against GSK-3 beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3 beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.

  DOI：

  10.1021/ja068969w

文献信息

• Alpha-oxoacetamide derivatives
  申请人：SYNTEX (U.S.A.) INC.

  公开号：EP0490263A1

  公开（公告）日：1992-06-17

  α-Oxoacetamides represented by Formula I wherein R¹ is selected from in which: the dashed line denotes an optional bond; X and Y are independently selected from hydrogen, halo, cyano, hydroxy, lower alkoxy, benzyloxy, lower alkyl, nitro, amino, aminocarbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; Z is -O-, -S- or -N(R⁴)-; and R⁴ and R⁵ are independently selected from hydrogen or lower alkyl or (lower cycloalkyl) lower alkyl or are together -(CH₂)n- wherein n is an integer from 3 to 5; R² is selected from in which: p is 0 or 1; q is 1, 2 or 3; and R⁶ is C₁₋₇ alkyl; and R³ is selected from hydrogen or lower alkyl; their pharmaceutically acceptable salts, individual isomers and mixtures of isomers, processes for their preparation, compositions, and methods of use thereof.

  由式 I 代表的 α-氧代乙酰胺 其中 R¹ 选自 其中 虚线表示任选键； X和Y独立地选自氢、卤素、氰基、羟基、低级烷氧基、苄氧基、低级烷基、硝基、氨基、氨基羰基、(低级烷基)氨基、二(低级烷基)氨基和(低级烷酰基)氨基； Z 是-O-、-S-或-N(R⁴)-；以及 R⁴ 和 R⁵ 独立选自氢或低级烷基或（低级环烷基）低级烷基，或共同为-(CH₂)n-，其中 n 为 3 至 5 的整数； R² 选自 其中 p 是 0 或 1 q 是 1、2 或 3；以及 R⁶ 是 C₁₋₇ 烷基；以及 R³ 选自氢或低级烷基； 它们的药学上可接受的盐、单个异构体和异构体混合物、制备工艺、组合物及其使用方法。
• Inhibitors of protein kinase C. 1. 2,3-bisarylmaleimides
  作者：Peter D. Davis、Christopher H. Hill、Geoffrey Lawton、John S. Nixon、Sandra E. Wilkinson、Steven A. Hurst、Elizabeth Keech、Susan E. Turner

  DOI：10.1021/jm00079a024

  日期：1992.1

  The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylznaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11-mu-M). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67-mu-M). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).
• US5192770A
  申请人：——

  公开号：US5192770A

  公开（公告）日：1993-03-09
• Structure-Based Design Leads to the Identification of Lithium Mimetics That Block Mania-like Effects in Rodents. Possible New GSK-3β Therapies for Bipolar Disorders
  作者：Alan P. Kozikowski、Irina N. Gaisina、Hongbin Yuan、Pavel A. Petukhov、Sylvie Y. Blond、Allison Fedolak、Barbara Caldarone、Paul McGonigle

  DOI：10.1021/ja068969w

  日期：2007.7.1

  More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3 beta inhibitors. The best ligand in this series (having a K-i value of 4.6 nM against GSK-3 beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3 beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.