8-chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxamide | 1245737-91-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 8-chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxamide
• 英文别名: 8-chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamide；8-chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]spiro[3,4-dihydrochromene-2,4'-piperidine]-1'-carboxamide
• CAS: 1245737-91-0
• 化学式: C₂₁H₁₉ClF₄N₂O₂
• 分子量: 442.841
• InChiKey: JZJAURYLWHJLDY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  30
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(3-chloro-5-fluoro-2-hydroxyphenyl)ethanone 在 四氢吡咯 、 三乙基硅烷 、 sodium tetrahydroborate 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 乙醇 、 二甲基亚砜 为溶剂， 反应 45.0h， 生成 8-chloro-6-fluoro-N-[4-(trifluoromethyl)phenyl]-3,4-dihydrospiro[chromene-2,4'-piperidine]-1'-carboxamide
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists

  摘要：

  A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.08.031

文献信息

• [EN] SPIROCYCLIC PIPERIDINE DERIVATIVES AS TRPM 8 MODULATORS<br/>[FR] DÉRIVÉS DE PIPÉRIDINE SPIROCYCLIQUES EN TANT QUE MODULATEURS DE TRPM8
  申请人：GLENMARK PHARMACEUTICALS SA

  公开号：WO2010103381A1

  公开（公告）日：2010-09-16

  The present invention provides Transient Receptor Potential subfamily M, member 8 (TRPM8) modulators of formula (I). In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPM8. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPM8.

  本发明提供了公式（I）的瞬时受体电位亚家族M，成员8（TRPM8）调节剂。特别地，本文所描述的化合物对于治疗或预防TRPM8调节的疾病，状况和/或紊乱非常有用。本文还提供了制备所述化合物的过程，用于其合成的中间体，其制药组合物以及用于治疗或预防由TRPM8调节的疾病，状况和/或紊乱的方法。
• Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists
  作者：Sachin S. Chaudhari、Ashok B. Kadam、Neelima Khairatkar-Joshi、Indranil Mukhopadhyay、Pallavi V. Karnik、Anupindi Raghuram、Shobha S. Rao、Thamil Selvan Vaiyapuri、Dinesh P. Wale、Vikram M. Bhosale、Girish S. Gudi、Ramchandra R. Sangana、Abraham Thomas

  DOI：10.1016/j.bmc.2013.08.031

  日期：2013.11

  A novel series of N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain. (C) 2013 Elsevier Ltd. All rights reserved.