(E)-N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl}phenyl)acrylamide lactate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (E)-N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl}phenyl)acrylamide lactate
• 英文别名: panobinostat；LBH589；N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide;2-hydroxypropanoic acid
• 化学式: C₃H₆O₃*C₂₁H₂₃N₃O₂
• 分子量: 439.511
• InChiKey: XVDWNSFFSMWXJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.78
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  135
• 氢给体数：
  6
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1H-2-甲基-3-氨乙基吲哚 在 盐酸羟胺 、 sodium methylate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 (E)-N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl}phenyl)acrylamide lactate
  参考文献：
  名称：

  Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

  摘要：

  A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC I enzyme and COLO 205 cellular IC50), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dos-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

  DOI：

  10.1021/jm2003552

文献信息

• [EN] PROCESS FOR THE PREPARATION OF 2-(E)-N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL) ETHYL]AMINO]METHYL]PHENYL]-2-PROPENAMIDE 2-HYDROXYPROPANOIC ACID (1:1) AND ITS POLYMORPHS THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE L'ACIDE 2- (E)-N-HYDROXY-3-[4- [[ [2- (2-MÉTHYL -1 H-INDOL-3-YL) ÉTHYL] AMINO] MÉTHYL] PHÉNYL]-2-PROPÉNAMIDE 2-HYDROXYPROPANOÏQUE (1 : 1) ET SES POLYMORPHES
  申请人：MSN LABORATORIES PRIVATE LTD R&D CENTER

  公开号：WO2018092151A1

  公开（公告）日：2018-05-24

  The present invention relates to novel amorphous and crystalline forms of 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide and its lactate salt and also its process for the preparation thereof. (1a)

  本发明涉及2-(E)-N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)乙基]氨基]甲基]苯基]-2-丙烯酰胺的新型非晶态和结晶态形式，以及其乳酸盐，以及其制备方法。
• PROCESS FOR MAKING SALTS OF N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE
  申请人：Bajwa Joginder S.

  公开号：US20090187029A1

  公开（公告）日：2009-07-23

  Salts of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide are prepared by various methods.

  通过各种方法制备N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)乙基]氨基]甲基]苯基]-2E-2-丙烯酰胺的盐。
• PROCESS FOR MAKING SALTS OF N-HYDROXY-3-Ý4-ÝÝÝ2-(2-METHYL-1H-INDOL-3-YL)ETHYL¨AMINO¨METHYL¨PHENYL¨-2E-2-PROPENAMIDE
  申请人：NOVARTIS AG

  公开号：EP2032532A2

  公开（公告）日：2009-03-11
• Process for making salts of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide
  申请人：Novartis AG

  公开号：EP2032532B1

  公开（公告）日：2015-04-22
• US7989639B2
  申请人：——

  公开号：US7989639B2

  公开（公告）日：2011-08-02