3-{4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl}propenoic acid methyl ester

• 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: 3-{4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl}propenoic acid methyl ester
• 英文别名: methyl 3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enoate
• 化学式: C₂₂H₂₄N₂O₂
• 分子量: 348.445
• InChiKey: RPLQUEPXYREGMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  乳酸 、 3-{4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl}propenoic acid methyl ester 在 盐酸羟胺 、 sodium methylate 作用下， 以 甲醇 、 水 为溶剂， 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
• 作为产物：
  描述：

  3-(2-溴乙基)-2-甲基-1H-吲哚 在 potassium phtalimide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 3-{4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl}propenoic acid methyl ester
  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

• Deacetylase inhibitors
  申请人：——

  公开号：US20030018062A1

  公开（公告）日：2003-01-23

  The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

  本发明提供了羟肟酸酯化合物，这些化合物是脱乙酰酶抑制剂。这些化合物适用于具有抗增殖特性的药物组合物。
• PROCESS FOR MAKING N-HYDROXY-3-[4-[[[2-(2-METHYL-1H-INDOL-3-YL)ETHYL]AMINO]METHYL]PHENYL]-2E-2-PROPENAMIDE AND STARTING MATERIALS THEREFOR
  申请人：Acemoglu Murat

  公开号：US20090306405A1

  公开（公告）日：2009-12-10

  N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and starting materials therefor are prepared by new synthetic methods.

  N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)乙基]氨基]甲基]苯基]-2E-2-丙烯酰胺及其起始原料是通过新的合成方法制备的。
• [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。
• [EN] CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION<br/>[FR] COMBINAISON D'INHIBITEUR DE CYCLOOXIGENASE-2 /INHIBITEUR D'HISTONE DESACETYLASE
  申请人：NOVARTIS AG

  公开号：WO2003039599A1

  公开（公告）日：2003-05-15

  The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor ('COX-2 inhibitor') and (b) a histone deacetylase inhibitor ('HDAI') for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g.polyps)and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.

  本发明涉及一种组合物，包括（a）环氧合酶-2抑制剂（“COX-2抑制剂”）和（b）组蛋白去乙酰化酶抑制剂（“HDAI”），用于同时、并行、分离或顺序使用，特别是用于治疗哺乳动物，尤其是人类的癌前结肠病变或结肠癌或其他恶性肿瘤。本发明还涉及包含这种组合物的制药组合物，以及使用这种组合物治疗癌前结肠病变（例如息肉）和结肠癌以及其他恶性肿瘤的方法，特别是在哺乳动物，尤其是人类中使用。本发明还涉及包含这种组合物的商业包装或产品。
• Rapid method for screening compounds for in vivo activity
  申请人：——

  公开号：US20040067540A1

  公开（公告）日：2004-04-08

  The present invention provides a rapid method for screening potentially pharmaceutically useful compounds for activity in vivo. The method has the steps of growing a target cell into which a reporter gene was introduced in a biocompatible, semipermeable encapsulation device; implanting the semi-permeable encapsulation device into a subject; administering a potentially pharmaceutically active compound to said subject; removing said encapsulation device from said subject after in vivo exposure to the potentially pharmaceutically active compound and evaluating said target cell for reaction to said potentially paharmaceutically active compound by measuring the expression of said reporter gene.

  本发明提供了一种快速筛选潜在药用化合物在体内活性的方法。该方法包括以下步骤：将报告基因引入到一个靶细胞中，并将该细胞生长于一种生物相容的半透性封装装置中；将该半透性封装装置植入到一个受试者体内；向该受试者施用一种潜在药用活性化合物；在该潜在药用活性化合物在体内暴露后，将该封装装置从该受试者体内移除，并通过测量该报告基因的表达来评估该靶细胞对该潜在药用活性化合物的反应。