(4R)-8-bromo-1'-{[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4R)-8-bromo-1'-{[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate
• 英文别名: [(4R)-8-bromo-1'-[[4-(trifluoromethoxy)phenyl]carbamoyl]spiro[3,4-dihydrochromene-2,4'-piperidine]-4-yl] (2S)-3-(1H-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoate
• 化学式: C₄₀H₃₆BrF₃N₄O₇
• 分子量: 821.648
• InChiKey: PYGJOUURGKMIEI-SZAHLOSFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.2
• 重原子数：
  55
• 可旋转键数：
  11
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (4R)-8-bromo-1'-{[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate 在 lithium hydroxide monohydrate 、 水 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 1.0h， 以71%的产率得到(4R)-(-)-8-bromo-4-hydroxy-N-[4-(trifluoromethoxy)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
• 作为产物：
  描述：

  1-(3-溴-2-羟基苯基)乙酮 在 四氢吡咯 、 盐酸 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 乙酸乙酯 为溶剂， 反应 45.0h， 生成 (4R)-8-bromo-1'-{[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate
  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

• 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.