N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine | 375853-73-9

• 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: N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine
• 英文别名: tert-butyl N-[[3-[1-(3-ethynylbenzoyl)piperidin-4-yl]phenyl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
• CAS: 375853-73-9
• 化学式: C₃₁H₃₈N₂O₅
• 分子量: 518.653
• InChiKey: OOSLJWVJVHVDPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 [3-[4-[3-[4-[3-(Aminomethyl)phenyl]piperidine-1-carbonyl]phenyl]buta-1,3-diynyl]phenyl]-[4-[3-(aminomethyl)phenyl]piperidin-1-yl]methanone
  参考文献：
  名称：

  Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?

  摘要：

  The tetrameric folding of beta-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for beta-tryptase. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.01.021
• 作为产物：
  描述：

  3-溴苄溴 在 palladium on activated charcoal (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 氢气 、 potassium acetate 、 sodium hydride 、 potassium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 生成 N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine
  参考文献：
  名称：

  Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of βII tryptase

  摘要：

  Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.

  DOI：

  10.1016/j.bmc.2005.02.014

文献信息

• Chemical compounds
  申请人：——

  公开号：US20030187020A1

  公开（公告）日：2003-10-02

  Provided herein are novel and useful compounds having a tryptase inhibition activity, pharmaceutical compositions comprising such compounds, and methods treating subjects suffering from a condition, disease, or disorder that can be ameliorated by the administration of an inhibitor of tryptase, e.g., asthma and inflammatory diseases, to name only a few.

  本文提供了具有胰蛋白酶抑制活性的新颖和有用化合物，包括含有这些化合物的药物组合物，以及治疗患有可以通过给予胰蛋白酶抑制剂（例如哮喘和炎症性疾病等）而得到改善的疾病、疾病或紊乱的方法。
• [EN] ARYLMETHYLAMINE DERIVATIVES FOR USE AS TRYPTASE INHIBITORS<br/>[FR] DERIVES D'ARYLMETHYLAMINE UTILISES COMME INHIBITEURS DE LA TRYPTASE
  申请人：AVENTIS PHARM PROD INC

  公开号：WO2001090101A1

  公开（公告）日：2001-11-29

  Provided herein are compounds of formula (I) wherein R1-4, n and Ar are as defined in claim 1, and their pharmaceutical compositions. These compounds are tryptase inhibitors and may be used in the treatment of e.g. asthma and inflammatory diseases.

  本发明提供了式(I)的化合物，其中R1-4、n和Ar如权利要求1所定义，以及它们的药物组成物。这些化合物是胰蛋白酶抑制剂，可用于治疗哮喘和炎症性疾病等疾病。
• ARYLMETHYLAMINE DERIVATIVES FOR USE AS TRYPTASE INHIBITORS
  申请人：Aventis Pharmaceuticals Inc.

  公开号：EP1296972B1

  公开（公告）日：2009-12-23
• US6977263B2
  申请人：——

  公开号：US6977263B2

  公开（公告）日：2005-12-20
• Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of βII tryptase
  作者：Julian Levell、Peter Astles、Paul Eastwood、Jennifer Cairns、Olivier Houille、Suzanne Aldous、Gregory Merriman、Brian Whiteley、James Pribish、Mark Czekaj、Guyan Liang、Sebastien Maignan、Jean-Pierre Guilloteau、Alain Dupuy、Jane Davidson、Trevor Harrison、Andrew Morley、Simon Watson、Garry Fenton、Clive McCarthy、Joseph Romano、Rose Mathew、Darren Engers、Michael Gardyan、Keith Sides、Jennifer Kwong、Joseph Tsay、Sam Rebello、Liduo Shen、Jie Wang、Yongyi Luo、Odessa Giardino、Heng-Keang Lim、Keith Smith、Henry Pauls

  DOI：10.1016/j.bmc.2005.02.014

  日期：2005.4

  Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.