(4R)-2,2-dimethyl-7-fluorochroman-4-amine D-(-)-tartaric acid | 1221445-06-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (4R)-2,2-dimethyl-7-fluorochroman-4-amine D-(-)-tartaric acid
• 英文别名: (R)-7-fluoro-2,2-dimethylchroman-4-ammonium (2S,3S)-2,3-dihydroxysuccinate；(2S,3S)-2,3-dihydroxybutanedioic acid;(4R)-7-fluoro-2,2-dimethyl-3,4-dihydrochromen-4-amine
• CAS: 1221445-06-2
• 化学式: C₄H₆O₆*C₁₁H₁₄FNO
• 分子量: 345.325
• InChiKey: VXOJDFFBWLNFEE-VXLLBCKSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.26
• 重原子数：
  24.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  150.31
• 氢给体数：
  5.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (4R)-2,2-dimethyl-7-fluorochroman-4-amine D-(-)-tartaric acid 在 盐酸 、 正丁基锂 、 potassium tert-butylate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 水 为溶剂， 反应 6.33h， 生成 (4R)-8-chloro-7-fluoro-2,2-dimethylchroman-4-amine
  参考文献：
  名称：

  TRPV1 Antagonists

  摘要：

  披露于此的是公式（I）的化合物： 或其药用可接受的盐，其中X 1 ，L，R x ，R y ，R z ，A，m，n，p，q，s，以及位置a和b如说明书所述定义。还披露了包含此类化合物的组合物以及使用此类化合物和组合物治疗状况和失调的方法。

  公开号：

  US20130158067A1

文献信息

• Discovery of 4-[(2<i>R</i>,4<i>R</i>)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2<i>H</i>-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for the Treatment of Cystic Fibrosis
  作者：Xueqing Wang、Bo Liu、Xenia Searle、Clinton Yeung、Andrew Bogdan、Stephen Greszler、Ashvani Singh、Yihong Fan、Andrew M Swensen、Timothy Vortherms、Corina Balut、Ying Jia、Kelly Desino、Wenqing Gao、Hong Yong、Chris Tse、Philip Kym

  DOI：10.1021/acs.jmedchem.7b01339

  日期：2018.2.22

  Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structureactivity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele.
• Discovery of (<i>R</i>)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy
  作者：Eric A. Voight、Arthur R. Gomtsyan、Jerome F. Daanen、Richard J. Perner、Robert G. Schmidt、Erol K. Bayburt、Stanley DiDomenico、Heath A. McDonald、Pamela S. Puttfarcken、Jun Chen、Torben R. Neelands、Bruce R. Bianchi、Ping Han、Regina M. Reilly、Pamela H. Franklin、Jason A. Segreti、Richard A. Nelson、Zhi Su、Andrew J. King、James S. Polakowski、Scott J. Baker、Donna M. Gauvin、LaGeisha R. Lewis、Joseph P. Mikusa、Shailen K. Joshi、Connie R. Faltynek、Philip R. Kym、Michael E. Kort

  DOI：10.1021/jm500916t

  日期：2014.9.11

  The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.