tert-butyl 3-(4-fluorobenzylidene)piperidin-1-carboxylate | 382637-43-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: tert-butyl 3-(4-fluorobenzylidene)piperidin-1-carboxylate
• 英文别名: tert-butyl 3-(4-fluorobenzylidene)piperidine-1-carboxylate；t-butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate；tert-butyl 3-[(4-fluorophenyl)methylidene]piperidine-1-carboxylate
• CAS: 382637-43-6
• 化学式: C₁₇H₂₂FNO₂
• 分子量: 291.366
• InChiKey: YVQDHVVJSQABFM-UHFFFAOYSA-N

物化性质

• 沸点：
  385.9±35.0 °C(Predicted)
• 密度：
  1.135±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(4-fluorobenzylidene)piperidin-1-carboxylate 在 palladium on activated charcoal 盐酸 、 D-扁桃酸 、 氢气 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、379.21 kPa 条件下， 反应 17.0h， 生成 1-(3-Acetyl-4-fluoro-phenyl)-3-{(1R,2S)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-cyclohexyl}-urea
  参考文献：
  名称：

  Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

  摘要：

  Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC50 = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC50 = 41 nM) and its oral bioavailability in mice (20% F) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase 1 clinical trials.

  DOI：

  10.1021/jm049530m
• 作为产物：
  描述：

  1-苄基-3-哌啶酮盐酸盐 在 palladium on activated charcoal 正丁基锂 、 氢气 、 碳酸氢钠 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 水 为溶剂， -78.0 ℃ 、379.21 kPa 条件下， 反应 37.0h， 生成 tert-butyl 3-(4-fluorobenzylidene)piperidin-1-carboxylate
  参考文献：
  名称：

  Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

  摘要：

  Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC50 = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC50 = 41 nM) and its oral bioavailability in mice (20% F) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase 1 clinical trials.

  DOI：

  10.1021/jm049530m

文献信息

• Substituted fused bicyclic amines as modulators of chemokine receptor activity
  申请人：Batt G. Douglas

  公开号：US20050197373A1

  公开（公告）日：2005-09-08

  The present application describes modulators of CCR3 of formula (Ia) and (Ib): or pharmaceutically acceptable salt forms thereof, wherein Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ′, R 6 , a, b, c, d, and u are as defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using said modulators are disclosed.

  本申请描述了公式(Ia)和(Ib)的CCR3调节剂，或其药用盐形式，其中Z、R1、R2、R3、R4、R5、R5'、R6、a、b、c、d和u的定义如本文所述。此外，还公开了利用这些调节剂治疗和预防哮喘和过敏疾病等炎症性疾病，以及类风湿关节炎和动脉粥样硬化等自身免疫病理的方法。
• Efficient Preparation of (3<i>S</i>)-3-(4-Fluorobenzyl)piperidinium Mandelate
  作者：Dean Wacker、George Emmett、Gary Cain、Melissa Estrella、Edd Holler、James Piecara、Andrew Blum、Alfred Mical、Christopher Teleha

  DOI：10.1055/s-2004-834903

  日期：——

  Methods for the preparation of (3S)-3-(4-fluorobenzyl)piperidine (2) and its mandelate salt (9) are described. The first generation synthesis started from 3-benzylpiperidone, and required Boc protection of the nitrogen for efficient separation of the enantiomers using chromatography on a chiral stationary phase. Subsequently, a resolution method using (R)-mandelic acid, produced high %ee salt 9 after

  描述了制备(3S)-3-(4-氟苄基)哌啶(2)及其扁桃酸盐(9)的方法。第一代合成从 3-苄基哌啶酮开始，需要 Boc 保护氮，以便在手性固定相上使用色谱法有效分离对映异构体。随后，使用 (R)-扁桃酸的拆分方法，在重结晶后产生了高 %ee 盐 9，并且无需 Boc 保护。第三代路线，从吡啶-3-甲醛开始，导致外消旋体 2 的流线型合成，并针对生产数百克手性盐进行了优化。
• N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
  申请人：Bristol-Myers Squibb Pharma

  公开号：US06627629B2

  公开（公告）日：2003-09-30

  The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

  本申请描述了CCR3的调节剂，其化学式为(I)或其药学上可以接受的盐形式，对于预防哮喘和其他过敏性疾病有用。
• Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists
  作者：Jeffrey G Varnes、Daniel S Gardner、Joseph B Santella、John V Duncia、Melissa Estrella、Paul S Watson、Cheryl M Clark、Soo S Ko、Patricia Welch、Maryanne Covington、Nicole Stowell、Eric Wadman、Paul Davies、Kimberley Solomon、Robert C Newton、George L Trainor、Carl P Decicco、Dean A Wacker

  DOI：10.1016/j.bmcl.2004.01.059

  日期：2004.4

  The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC50S under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s. (C) 2004 Elsevier Ltd. All rights reserved.
• EP3943488
  申请人：——

  公开号：——

  公开（公告）日：——