5-(乙氧基甲基)-7-氟-N-(2-氟苯基)-3-氧代-1,2-二氢吡啶并[1,2-a]苯并咪唑-4-甲酰胺 | 205701-85-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并吡啶类
• 中文名称: 5-(乙氧基甲基)-7-氟-N-(2-氟苯基)-3-氧代-1,2-二氢吡啶并[1,2-a]苯并咪唑-4-甲酰胺
• 英文名称: RWJ 51204
• 英文别名: 5-(ethoxymethyl)-7-fluoro-N-(2-fluorophenyl)-1,2,3,5-tetrahydro-3-oxopyrido[1,2-a]benzimidazole-4-carboxamide；5-ethoxymethyl-7-fluoro-4-[N-(2-fluorophenyl)carboxamido]-1,2-dihydro-3-oxopyrido[1,2-a]benzimidazole；Pyrido[1,2-A]benzimidazole-4-carboxamide, 5-(ethoxymethyl)-7-fluoro-N-(2-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-；5-(ethoxymethyl)-7-fluoro-N-(2-fluorophenyl)-3-oxo-1,2-dihydropyrido[1,2-a]benzimidazole-4-carboxamide
• CAS: 205701-85-5
• 化学式: C₂₁H₁₉F₂N₃O₃
• 分子量: 399.397
• InChiKey: VQOQDABVGWLROX-UHFFFAOYSA-N

物化性质

• 沸点：
  533.0±50.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  61.9
• 氢给体数：
  1
• 氢受体数：
  7

制备方法与用途

生物活性

RWJ-51204 是 GABA(A) 受体的部分激动剂，Ki 值为 0.2-2 nM。

靶点

Ki: 0.2-2 nM (GABA(A))

体外研究

RWJ-51204 在大脑皮层、小脑或延髓脊髓中与受体结合的 Ki 值范围为 0.2 至 0.6 nM。

体内研究

RWJ-51204 口服后在抗焦虑效果测试中有活性。在口服给药时，RWJ-51204 以剂量相关的方式拮抗戊四氮诱导的阵挛性惊厥（ED50 = 0.04 mg/kg）。此外，在猴冲突实验中，RWJ-51204 的 ED50 约为 0.5 mg/kg 口服。RWJ-51204 剂量为 30 mg/kg 时显著影响大鼠的转棒测试表现（ED50 = 0.12 mg/kg），所有口服给药 30 mg/kg 的大鼠均表现出镇静、肌肉张力降低以及转棒测试表现受损。

反应信息

• 作为产物：
  描述：

  4-氟-2-硝基苯胺 在 盐酸 、 palladium on activated charcoal 、 氢气 、 sodium ethanolate 、 苄基三甲基氢氧化铵 、 sodium hydride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 5-(乙氧基甲基)-7-氟-N-(2-氟苯基)-3-氧代-1,2-二氢吡啶并[1,2-a]苯并咪唑-4-甲酰胺
  参考文献：
  名称：

  Process Research for the Synthesis of RWJ-51204, A Novel Anxiolytic Agent

  摘要：

  RWJ-51204, the lead compound in our pyrido [1,2-a] benzimidazole (PBI) series, was shown to exhibit anxiolytic efficacy in animal models at doses which did not cause central nervous system side effects commonly observed with other anxiolytic agents. To prepare supplies of drug substance for early toxicological and clinical studies, we needed to develop a safe and scaleable synthesis, Our main focus was to improve the last two steps of the process which involved formation of the penultimate carboxamide intermediate followed by alkylation using potentially toxic chloromethyl ethyl ether. Due to safety issues concerning storage and handling of this reagent during the large scale synthesis, we investigated alternate routes to minimize potential exposure risks. The process research carried out for the final steps that led to the safe and cost-effective multi-kilogram synthesis of RWJ-51204 is described herein.

  DOI：

  10.1021/op990182l

文献信息

• S-heteroatom containing alkyl
  申请人：Ortho Pharmaceutical Corporation

  公开号：US05817668A1

  公开（公告）日：1998-10-06

  A compound of the general formula 1; ##STR1## is disclosed as useful in treating disorders of the central nervous system. Pharmaceutical compositions and methods of treatment are also disclosed.

  公式为1；##STR1## 的化合物被披露为有用的治疗中枢神经系统疾病。还披露了药物组成和治疗方法。
• Potential Anxiolytic Agents. Part 4: Novel Orally-Active N5-Substituted Pyrido[1,2-a]benzimidazoles with High GABA-A Receptor Affinity
  作者：Alfonzo D Jordan、Anil H Vaidya、Daniel I Rosenthal、Barry Dubinsky、Cheryl P Kordik、Pauline J Sanfilippo、Wu-Nan Wu、Allen B Reitz

  DOI：10.1016/s0960-894x(02)00463-8

  日期：2002.9

  A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N-5-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC50 of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Org. Process Res. Dev. 1999, 3, 260-265
  作者：

  DOI：——

  日期：——
• POSITIVE ALLOSTERIC MODULATORS OF THE GABA-A RECEPTOR IN THE TREATMENT OF AUTISM
  申请人：UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

  公开号：US20150313913A1

  公开（公告）日：2015-11-05

  Provided herein are methods and formulations for treating an Autism Spectrum Disorder using low doses of an agent that enhances signaling through the GABA receptor.
• Process Research for the Synthesis of RWJ-51204, A Novel Anxiolytic Agent
  作者：Judith H. Cohen、Cynthia A. Maryanoff、Stephen M. Stefanick、Kirk L. Sorgi、Frank J. Villani

  DOI：10.1021/op990182l

  日期：1999.7.1

  RWJ-51204, the lead compound in our pyrido [1,2-a] benzimidazole (PBI) series, was shown to exhibit anxiolytic efficacy in animal models at doses which did not cause central nervous system side effects commonly observed with other anxiolytic agents. To prepare supplies of drug substance for early toxicological and clinical studies, we needed to develop a safe and scaleable synthesis, Our main focus was to improve the last two steps of the process which involved formation of the penultimate carboxamide intermediate followed by alkylation using potentially toxic chloromethyl ethyl ether. Due to safety issues concerning storage and handling of this reagent during the large scale synthesis, we investigated alternate routes to minimize potential exposure risks. The process research carried out for the final steps that led to the safe and cost-effective multi-kilogram synthesis of RWJ-51204 is described herein.