(1H-咪唑-2-基)-N-甲基甲胺 | 473927-72-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: (1H-咪唑-2-基)-N-甲基甲胺
• 中文别名: N-(1H-咪唑基-2-基甲基)-N-甲胺
• 英文名称: 1-(1H-imidazol-2-yl)-N-methylmethanamine
• CAS: 473927-72-9
• 化学式: C₅H₉N₃
• mdl: MFCD07781074
• 分子量: 111.147
• InChiKey: FXNGQGIWLUWGBV-UHFFFAOYSA-N

物化性质

• 沸点：
  294.3±23.0 °C(Predicted)
• 密度：
  1.083±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  8
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  40.7
• 氢给体数：
  2
• 氢受体数：
  2

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933290090

反应信息

• 作为反应物：
  描述：

  (1H-咪唑-2-基)-N-甲基甲胺 在 4-二甲氨基吡啶 、 copper(l) iodide 、 acetoxyhydroxamic acid 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.5h， 生成 benzyl N-[[1-[4-[[2-(3-amino-1,2-benzoxazol-5-yl)-5-(trifluoromethyl)pyrazole-3-carbonyl]amino]-3-fluorophenyl]imidazol-2-yl]methyl]-N-methylcarbamate
  参考文献：
  名称：

  Discovery of 1-(3‘-Aminobenzisoxazol-5‘-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2‘-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor

  摘要：

  Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

  DOI：

  10.1021/jm0497949
• 作为产物：
  描述：

  2-咪唑甲醛 在 sodium borohydrid 、 甲胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 以95%的产率得到(1H-咪唑-2-基)-N-甲基甲胺
  参考文献：
  名称：

  Substituted amino methyl factor Xa inhibitors

  摘要：

  本申请描述了替代氨甲基取代化合物及其衍生物，或其药用盐形式，这些化合物可用作因子Xa的抑制剂。

  公开号：

  US20030212054A1

文献信息

• [EN] SUBSTITUTED PYRIDINES AS INHIBITORS OF DNMT1<br/>[FR] PYRIDINES SUBSTITUÉES EN TANT QU'INHIBITEURS DE DNMT1
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017216726A1

  公开（公告）日：2017-12-21

  The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): (Iar) wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  该发明涉及取代吡啶衍生物。具体而言，该发明涉及符合以下式（Iar）的化合物：（Iar）其中Yar、X1ar、X2ar、R1ar、R2ar、R3ar、R4ar和R5ar如本文所定义；或其药学上可接受的盐或前药。该发明的化合物是DNMT1的选择性抑制剂，可用于治疗癌症、癌前综合征、β血红蛋白病、镰状细胞病、镰状细胞贫血、β地中海贫血以及与DNMT1抑制相关的疾病。因此，该发明进一步涉及包含该发明化合物的药物组合物。该发明还进一步涉及使用该发明化合物或包含该发明化合物的药物组合物抑制DNMT1活性和治疗相关疾病的方法。
• 10.1016/j.ejmech.2024.116511
  作者：La Spada, Gabriella、Miniero, Daniela Valeria、Rullo, Mariagrazia、Cipolloni, Marco、Delre, Pietro、Colliva, Carolina、Colella, Marco、Leonetti, Francesco、Liuzzi, Grazia Maria、Mangiatordi, Giuseppe Felice、Giacchè, Nicola、Pisani, Leonardo

  DOI：10.1016/j.ejmech.2024.116511

  日期：——

  heterocyclic bioisosteres into coumarin derivative , previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by MAO B enzymatic cleft more than AChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from AChE to BChE. In the present work, we

  基于结构的药物设计方法侧重于将苯环杂环生物等排体整合到香豆素衍生物中，香豆素衍生物先前被报道为有效的双重AChE-MAO B抑制剂，目的是改善药物样特征。结构-活性关系强调，MAO B 酶裂比 AChE 对生物电子等排环的耐受性更强。有趣的是，碱性氮上的连接子同源性使得能够选择性地从AChE切换到BChE。在目前的工作中，我们鉴定了基于噻吩的电子等排体和双AChE-MAO B（IC50分别为261和15 nM）和BChE-MAO B（IC50分别为375和20 nM）抑制剂。通过被动扩散（PAMPA-HDM）， 和 都是中等水溶性和膜渗透剂。此外，它们能够抵消 SH-SY5Y 细胞中由 H2O 和 6-OHDA 引起的氧化损伤，并预测在模拟血脑屏障的细胞模型中渗透到中枢神经系统。分子动力学 (MD) 模拟揭示了 AChE 和 BChE 识别过程中的关键差异，这些差异是由 到 的基本链同源性促进的。
• Design, structure–activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors
  作者：Jeffrey G. Varnes、Dean A. Wacker、Irina C. Jacobson、Mimi L. Quan、Christopher D. Ellis、Karen A. Rossi、Ming Y. He、Joseph M. Luettgen、Robert M. Knabb、Steven Bai、Kan He、Patrick Y.S. Lam、Ruth R. Wexler

  DOI：10.1016/j.bmcl.2007.09.091

  日期：2007.12

  A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were pro. led in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban. (c) 2007 Elsevier Ltd. All rights reserved.
• Structure and property based design of factor Xa inhibitors: Biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs
  作者：Robert J. Young、Alan D. Borthwick、David Brown、Cynthia L. Burns-Kurtis、Matthew Campbell、Chuen Chan、Marie Charbaut、Máire A. Convery、Hawa Diallo、Eric Hortense、Wendy R. Irving、Henry A. Kelly、N. Paul King、Savvas Kleanthous、Andrew M. Mason、Anthony J. Pateman、Angela N. Patikis、Ivan L. Pinto、Derek R. Pollard、Stefan Senger、Gita P. Shah、John R. Toomey、Nigel S. Watson、Helen E. Weston、Ping Zhou

  DOI：10.1016/j.bmcl.2007.11.019

  日期：2008.1

  Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
• Potent and selective small molecule inhibitors of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine-phosphorylation-regulated kinases (Dyrk)
  作者：Andrew S. Rosenthal、Cordelle Tanega、Min Shen、Bryan T. Mott、James M. Bougie、Dac-Trung Nguyen、Tom Misteli、Douglas S. Auld、David J. Maloney、Craig J. Thomas

  DOI：10.1016/j.bmcl.2011.02.114

  日期：2011.5

  Continued examination of substituted 6-arylquinazolin-4-amines as Clk4 inhibitors resulted in selective inhibitors of Clk1, Clk4, Dyrk1A and Dyrk1B. Several of the most potent inhibitors were validated as being highly selective within a comprehensive kinome scan. Published by Elsevier Ltd.