2-(phenylmethyl)-2,3-dihydro-1H-isoindole-4-carbonitrile | 1165876-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-(phenylmethyl)-2,3-dihydro-1H-isoindole-4-carbonitrile
• 英文别名: 2-phenylmethyl-2,3-dihydro-1H-isoindole-4-carbonitrile；2-benzyl-1,3-dihydroisoindole-4-carbonitrile
• CAS: 1165876-15-2
• 化学式: C₁₆H₁₄N₂
• 分子量: 234.301
• InChiKey: HGJMVLUHCAUDEN-UHFFFAOYSA-N

物化性质

• 沸点：
  370.1±42.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(phenylmethyl)-2,3-dihydro-1H-isoindole-4-carbonitrile 在 1-氯乙基氯甲酸酯 、 盐酸羟胺 、 碳酸氢钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 氯苯 为溶剂， 反应 15.25h， 生成 1,1-dimethylethyl 4-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindole-2-carboxylate
  参考文献：
  名称：

  Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

  摘要：

  The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P(1) receptors, while a variety of side effects have been ascribed to its S1P(3) receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P(1) receptor agonism. Here we describe a study of the tolerance of the S1P(1) and S1P(3) receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P(1) receptor agonists with good selectivity vs S1P(3) receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.

  DOI：

  10.1021/jm5010336
• 作为产物：
  描述：

  2,3-二甲基苯腈 在 N-溴代丁二酰亚胺(NBS) 、 sodium carbonate 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 乙腈 为溶剂， 反应 22.75h， 生成 2-(phenylmethyl)-2,3-dihydro-1H-isoindole-4-carbonitrile
  参考文献：
  名称：

  Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

  摘要：

  The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P(1) receptors, while a variety of side effects have been ascribed to its S1P(3) receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P(1) receptor agonism. Here we describe a study of the tolerance of the S1P(1) and S1P(3) receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P(1) receptor agonists with good selectivity vs S1P(3) receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.

  DOI：

  10.1021/jm5010336

文献信息

• [EN] OXADIAZOLE DERIVATIVES FOR USE AS S1P1 AGONISTS IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS<br/>[FR] DÉRIVÉS D'OXADIAZOLE DESTINÉS À ÊTRE UTILISÉS EN TANT QU'AGONISTES DE S1P1 DANS LE TRAITEMENT DE TROUBLES AUTO-IMMUNS ET INFLAMMATOIRES
  申请人：GLAXO GROUP LTD

  公开号：WO2009080729A1

  公开（公告）日：2009-07-02

  The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有药理活性的新型噁唑烷衍生物，其制备过程，含有它们的制药组合物以及它们在治疗各种疾病中的应用。
• OXADIAZOLE DERIVATIVES FOR USE AS S1P1 AGONISTS IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS
  申请人：Heer Jag Paul

  公开号：US20100261767A1

  公开（公告）日：2010-10-14

  The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有药理活性的新型噁唑烷衍生物、其制备方法、含有它们的制药组合物以及它们在治疗各种疾病中的应用。
• Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles
  作者：John Skidmore、Jag Heer、Christopher N. Johnson、David Norton、Sally Redshaw、Jennifer Sweeting、David Hurst、Andrew Cridland、David Vesey、Ian Wall、Mahmood Ahmed、Dean Rivers、James Myatt、Gerard Giblin、Karen Philpott、Umesh Kumar、Alexander Stevens、Rino A. Bit、Andrea Haynes、Simon Taylor、Robert Watson、Jason Witherington、Emmanuel Demont、Tom D. Heightman

  DOI：10.1021/jm5010336

  日期：2014.12.26

  The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P(1) receptors, while a variety of side effects have been ascribed to its S1P(3) receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P(1) receptor agonism. Here we describe a study of the tolerance of the S1P(1) and S1P(3) receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P(1) receptor agonists with good selectivity vs S1P(3) receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.