N-[3-氟-5-(3-吡啶)苯基]-2,3-二氢-5-甲氧基-6-(三氟甲基)-1H-吲哚-1-羧酰胺 | 181629-93-6

• 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: N-[3-氟-5-(3-吡啶)苯基]-2,3-二氢-5-甲氧基-6-(三氟甲基)-1H-吲哚-1-羧酰胺
• 英文名称: SB 228357
• 英文别名: N-[3-fluoro-5-(3-pyrindyl)phenyl]-2,3-dihydro-5-methoxy-6-(trifluoromethyl)-1H-indole-1-carboxamide；1-[3-fluoro-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline；N-(3-(3-Pyridinyl)-5-fluorophenyl)-5-methoxy-6-(trifluoromethyl)indoline-1-carboxamide；N-(3-fluoro-5-pyridin-3-ylphenyl)-5-methoxy-6-(trifluoromethyl)-2,3-dihydroindole-1-carboxamide
• CAS: 181629-93-6
• 化学式: C₂₂H₁₇F₄N₃O₂
• mdl: MFCD00950378
• 分子量: 431.389
• InChiKey: RRJLJKRFFRZRAF-UHFFFAOYSA-N

物化性质

• 沸点：
  625.4±55.0 °C(Predicted)
• 密度：
  1.398±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：~8 mg/mL，可溶

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.181
• 拓扑面积：
  54.5
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• WGK Germany：
  3
• 安全说明：
  S22,S24/25

制备方法与用途

生物活性

SB228357 是一种选择性的、有效的具有口服活性的 5-HT2C/2B 受体拮抗剂，其对 5-HT2A、5-HT2B 和 5-HT2C 的 pKi 值分别为 6.9、8.0 和 9.0。SB228357 具有抗抑郁和抗焦虑作用。

靶点

受体	pKi
5-HT2A受体	6.9
5-HT2C受体	9.0
5-HT2B受体	8.0

体内研究

SB228357 (0-10 mg/kg，口服给药，持续 90 分钟，雄性 Sprague Dawley 大鼠) 处理显著逆转了 Haloperidol 引起的猫滞反应。

实验数据

实验项目	雄性 Sprague Dawley 大鼠 (200-250 g) 注射 Haloperidol
剂量	0 mg/kg, 0.32 mg/kg, 1 mg/kg, 3.2 mg/kg, 10 mg/kg
给药方式	口服给药，持续 90 分钟
结果	显著逆转 Haloperidol 引起的猫滞反应。

反应信息

• 作为产物：
  描述：

  1-氟-3-碘-5-硝基苯 在 盐酸 、 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 、 tin(ll) chloride 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.0h， 生成 N-[3-氟-5-(3-吡啶)苯基]-2,3-二氢-5-甲氧基-6-(三氟甲基)-1H-吲哚-1-羧酰胺
  参考文献：
  名称：

  Biarylcarbamoylindolines Are Novel and Selective 5-HT_2C Receptor Inverse Agonists:  Identification of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a Potential Antidepressant/Anxiolytic Agent

  摘要：

  The evolution, synthesis, and biological activity of a novel series of 5-HT2C receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT2C affinity and selectivity over 5-HT2A receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT2B receptor. Compounds from this series are inverse agonists at the human cloned 5-HT2C receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

  DOI：

  10.1021/jm990388c

文献信息

• [EN] INDOLE DERIVATIVES AS 5-HT RECEPTOR ANTAGONIST<br/>[FR] DERIVES D'INDOLE UTILISES COMME ANTAGONISTE DU RECEPTEUR DE 5-HT
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1996023783A1

  公开（公告）日：1996-08-08

  (EN) The invention relates to heterocyclic compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders such as anxiety.(FR) L'invention concerne des composés hétérocycliques présentant une activité pharmacologique, leurs procédés de préparation, des compositions les contenant ainsi que leur utilisation dans le traitement de troubles du système nerveux central tels que l'anxiété.

  该发明涉及具有药理活性的杂环化合物，其制备过程，包含它们的组成物以及它们在治疗中枢神经系统障碍，如焦虑症方面的应用。
• Indole derivatives as 5-HT receptor antagonist
  申请人：SmithKline Beecham p.l.c.

  公开号：US20030105139A1

  公开（公告）日：2003-06-05

  The invention relates to heterocyclic compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders such as anxiety.

  本发明涉及具有药理活性的杂环化合物，其制备过程，含有它们的组合物以及它们在治疗中枢神经系统疾病如焦虑症方面的应用。
• A Divergent SAR Study Allows Optimization of a Potent 5-HT_2c Inhibitor to a Promising Antimalarial Scaffold
  作者：Félix Calderón、Jaume Vidal-Mas、Jeremy Burrows、Juan Carlos de la Rosa、María Belén Jiménez-Díaz、Teresa Mulet、Sara Prats、Jorge Solana、Michael Witty、Francisco Javier Gamo、Esther Fernández

  DOI：10.1021/ml300008j

  日期：2012.5.10

  From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.
• A Simple Method for the Synthesis of Unsymmetrical Ureas
  作者：J. Kitteringham、M. R. Shipton、M. Voyle

  DOI：10.1080/00397910008087243

  日期：2000.6

  A simple one pot procedure for the synthesis of N,N'-unsymmetrical ureas using phenyl chloroformate in THF is described.
• INDOLE DERIVATIVES AS 5-HT RECEPTOR ANTAGONIST
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0808312A1

  公开（公告）日：1997-11-26