7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide | 790254-64-7

• 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: 7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide
• 英文别名: 3-Ethyl-9-methyl-10,10-dioxo-10lambda6-thia-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxylic acid；3-ethyl-9-methyl-10,10-dioxo-10λ6-thia-1,9-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7-tetraene-6-carboxylic acid
• CAS: 790254-64-7
• 化学式: C₁₄H₁₆N₂O₄S
• 分子量: 308.358
• InChiKey: QUHVKKMNTBBFFN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  88
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide 、 肼基甲酸叔丁酯 在 N-羟基-7-氮杂苯并三氮唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 tert-butyl 2-[(7-ethyl-1-methyl-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-9-yl)carbonyl]hydrazinecarboxylate
  参考文献：
  名称：

  WO2007/19078

  摘要：

  公开号：
• 作为产物：
  描述：

  methyl 7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate 2,2-dioxide 在 sodium hydroxide 、 乙醇 、 水 、 盐酸 作用下， 反应 14.0h， 以57%的产率得到7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide
  参考文献：
  名称：

  [EN] TRICYCLIC INDOLE DERIVATIVES FOR USE IN THE TREATMENT OF ALZHEIMER'S DISEASE
  [FR] DERIVES INDOLIQUES TRICYCLIQUES POUR LE TRAITEMENT DE LA MALADIE D'ALZHEIMER

  摘要：

  本发明涉及具有Asp2（β-分泌酶、BACE1或Memapsin-2）抑制活性的新型酮化合物（I）的公式，其制备方法，包含它们的组合物以及它们在治疗由高β-淀粉样蛋白水平或β-淀粉样蛋白沉积特征的疾病，尤其是阿尔茨海默病中的用途。

  公开号：

  WO2006040148A1

文献信息

• [EN] TRICYCLIC INDOLE DERIVATIVES FOR USE IN THE TREATMENT OF ALZHEIMER'S DISEASE<br/>[FR] DERIVES INDOLIQUES TRICYCLIQUES POUR LE TRAITEMENT DE LA MALADIE D'ALZHEIMER
  申请人：GLAXO GROUP LTD

  公开号：WO2006040148A1

  公开（公告）日：2006-04-20

  The present invention relates to novel ketone compounds of formula (I) having Asp2 (β-secretase, BACE1 or Memapsin-2) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated β- amyloid levels or β-amyloid deposits, particularly Alzheimer's disease.

  本发明涉及具有Asp2（β-分泌酶、BACE1或Memapsin-2）抑制活性的新型酮化合物（I）的公式，其制备方法，包含它们的组合物以及它们在治疗由高β-淀粉样蛋白水平或β-淀粉样蛋白沉积特征的疾病，尤其是阿尔茨海默病中的用途。
• Tricyclic Beta-Secretase Inhibitors for the Treatment of Alzheimer's Disease
  申请人：Nantermet Philippe G.

  公开号：US20090170830A1

  公开（公告）日：2009-07-02

  The present invention is directed to tricyclic compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

  本发明涉及公式（I）的三环化合物，其为β-分泌酶酶的抑制剂，可用于治疗β-分泌酶酶参与的疾病，如阿尔茨海默病。本发明还涉及包含这些化合物的制药组合物以及在β-分泌酶酶参与的这种疾病的治疗中使用这些化合物和组合物。
• Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure
  作者：Arun K. Ghosh、Kalapala Venkateswara Rao、Navnath D. Yadav、David D. Anderson、Navnath Gavande、Xiangping Huang、Simon Terzyan、Jordan Tang

  DOI：10.1021/jm3008823

  日期：2012.11.8

  The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective beta-secretase inhibitors are described. The inhibitors are designed specifically to interact with S-1' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K-i = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
• [EN] TRICYCLIC BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE<br/>[FR] INHIBITEURS DE LA BETA-SECRETASE TRICYCLIQUE POUR TRAITER LA MALADIE D'ALZHEIMER
  申请人：MERCK & CO INC

  公开号：WO2007019078A2

  公开（公告）日：2007-02-15

  [EN] The present invention is directed to tricyclic compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.
  [FR] L'invention concerne des composés tricycliques représentés par la formule (I), qui sont des inhibiteurs de l'enzyme bêta-sécrétase tricyclique utiles dans le traitement de maladies dans lesquelles cette enzyme intervient, telles que la maladie d'Alzheimer. L'invention concerne aussi des compositions pharmaceutiques comprenant ces composés, et l'utilisation de ces composés et compositions pour traiter des maladies dans lesquelles intervient la bêta-sécrétase.
• Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability
  作者：Nicolas Charrier、Brian Clarke、Leanne Cutler、Emmanuel Demont、Colin Dingwall、Rachel Dunsdon、Philip East、Julie Hawkins、Colin Howes、Ishrut Hussain、Phil Jeffrey、Graham Maile、Rosalie Matico、Julie Mosley、Alan Naylor、Alistair O’Brien、Sally Redshaw、Paul Rowland、Virginie Soleil、Kathrine J. Smith、Sharon Sweitzer、Pam Theobald、David Vesey、Daryl S. Walter、Gareth Wayne

  DOI：10.1021/jm800138h

  日期：2008.6.1

  BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.