3-amino-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione | 131604-75-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 3-amino-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione
• 英文别名: 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine；3-Amino-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione；3-Amino-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2,4-dioxo-1H-1,5-benzodiazepine；3-amino-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione
• CAS: 131604-75-6
• 化学式: C₁₆H₁₅N₃O₂
• 分子量: 281.314
• InChiKey: IOXFJKIAVCUKQN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-amino-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione 、 异氰酸苯酯 以 二氯甲烷 为溶剂， 以86%的产率得到1-(2,3,4,5-tetrahydro-1-methyl-2,4-dioxo-5-phenyl-1H-benzo[b][1,4]diazepin-3-yl)-3-phenylurea
  参考文献：
  名称：

  Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist

  摘要：

  Seven-transmembrane receptors (7TMRs), also termed G protein-coupled receptors (GPCRs), form the largest class of cell surface membrane receptors, involving several hundred members in the human genome. Nearly 30% of marketed pharmacological agents target 7TMRs. 7TMRs adopt multiple conformations upon agonist binding. Biased agonists, in contrast to non-biased agonists, are believed to stabilize conformations preferentially activating either G-protein- or beta-arrestin-dependent signaling pathways. However, proof that cognate conformations of receptors display structural differences within their binding site where biased agonism initiates, are still lacking. Here, we show that a non-biased agonist, chole-cystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2R(G)) or recruiting beta-arrestin2 (CCK2R(beta)) that are pharmacologically and structurally distinct. Two structurally unrelated antagonists competitively inhibited both pathways. A third ligand (GV150013X) acted as a high affinity competitive antagonist on CCK2R(G) but was nearly inefficient as inhibitor of CCK2R(beta). Several structural elements on both GV150013X and in CCK2R binding cavity, which hinder binding of GV150013X only to the CCK2R(beta) were identified. At last, proximity between two conserved amino acids from transmembrane helices 3 and 7 interacting through sulfur aromatic interaction was shown to be crucial for selective stabilization of the CCK2R(beta) state. These data establish structural evidence for distinct conformations of a 7TMR associated with beta-arrestin-2 recruitment or G-protein coupling and validate relevance of the design of biased ligands able to selectively target each functional conformation of 7TMRs.

  DOI：

  10.1021/ja308784w
• 作为产物：
  描述：

  3-(2-phenylhydrazono)-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione 在 溶剂黄146 、 锌 作用下， 反应 3.0h， 以45%的产率得到3-amino-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione
  参考文献：
  名称：

  Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist

  摘要：

  Seven-transmembrane receptors (7TMRs), also termed G protein-coupled receptors (GPCRs), form the largest class of cell surface membrane receptors, involving several hundred members in the human genome. Nearly 30% of marketed pharmacological agents target 7TMRs. 7TMRs adopt multiple conformations upon agonist binding. Biased agonists, in contrast to non-biased agonists, are believed to stabilize conformations preferentially activating either G-protein- or beta-arrestin-dependent signaling pathways. However, proof that cognate conformations of receptors display structural differences within their binding site where biased agonism initiates, are still lacking. Here, we show that a non-biased agonist, chole-cystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2R(G)) or recruiting beta-arrestin2 (CCK2R(beta)) that are pharmacologically and structurally distinct. Two structurally unrelated antagonists competitively inhibited both pathways. A third ligand (GV150013X) acted as a high affinity competitive antagonist on CCK2R(G) but was nearly inefficient as inhibitor of CCK2R(beta). Several structural elements on both GV150013X and in CCK2R binding cavity, which hinder binding of GV150013X only to the CCK2R(beta) were identified. At last, proximity between two conserved amino acids from transmembrane helices 3 and 7 interacting through sulfur aromatic interaction was shown to be crucial for selective stabilization of the CCK2R(beta) state. These data establish structural evidence for distinct conformations of a 7TMR associated with beta-arrestin-2 recruitment or G-protein coupling and validate relevance of the design of biased ligands able to selectively target each functional conformation of 7TMRs.

  DOI：

  10.1021/ja308784w

文献信息

• Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
  申请人：——

  公开号：US20020045747A1

  公开（公告）日：2002-04-18

  Disclosed are compounds which inhibit &bgr;-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits &bgr;-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

  公开了抑制β-淀粉样肽释放和/或其合成的化合物，因此可用于治疗阿尔茨海默病。还公开了包含抑制β-淀粉样肽释放和/或其合成的化合物的药物组合物，以及使用这些药物组合物预防性和治疗性治疗阿尔茨海默病的方法。
• Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting B-amyloid peptide release and/or its synthesis by use of such compounds
  申请人：——

  公开号：US20020173504A1

  公开（公告）日：2002-11-21

  Disclosed are compounds which inhibit &bgr;-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits &bgr;-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

  本发明涉及抑制&bgr;-淀粉样肽的释放和/或合成的化合物，因此具有治疗阿尔茨海默病的效用。还公开了包含抑制&bgr;-淀粉样肽释放和/或合成的化合物的药物组合物，以及使用这种药物组合物预防和治疗阿尔茨海默病的方法。
• Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting Beta-amyloid peptide release and/or its synthesis by use of such compounds
  申请人：——

  公开号：US20040106598A1

  公开（公告）日：2004-06-03

  Disclosed are compounds which inhibit &bgr;-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions that include a compound which inhibits &bgr;-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

  本发明涉及抑制β-淀粉样肽释放和/或合成的化合物，因此在治疗阿尔茨海默病方面具有用途。还公开了包括抑制β-淀粉样肽释放和/或合成的化合物的药物组合物，以及使用这种药物组合物预防和治疗阿尔茨海默病的方法。
• 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines
  申请人：Uclaf; Roussel

  公开号：US04988692A1

  公开（公告）日：1991-01-29

  A compound in all possible isomeric forms and mixtures thereof of the formula ##STR1## wherein X and X' are individually selected from the group consisting of hydrogen, halogen, cyano, --NO.sub.2, --CF.sub.3 and alkyl and alkoxy of 1 to 8 carbon atoms, R is hydrogen or alkyl of 1 to 8 carbon atoms and Ar is selected from the group consisting of an unsubstituted or substituted aryl of 6 to 14 carbon atoms, an unsubstituted or substituted aromatic heterocyclic or a heterocyclic united with an unsubstituted or substituted aryl having cholecystokinine antagonistic activity.

  一种化合物，具有所有可能的同分异构体和其混合物，其化学式为##STR1##其中X和X'分别选自氢，卤素，氰基，--NO.sub.2，--CF.sub.3和1至8个碳原子的烷基和烷氧基的群组，R为氢或1至8个碳原子的烷基，Ar选自未取代或取代的6至14个碳原子的芳基，未取代或取代的芳香杂环或与具有胆囊收缩素拮抗活性的未取代或取代的芳基结合的杂环。
• 3-phenylureido-1,5-benzodiazepine-diones useful as gastrin or antagonists
  申请人：Glaxo SpA

  公开号：US05641775A1

  公开（公告）日：1997-06-24

  The invention relates to 3-phenylureido-1,5-benzodiazepine-diones of formula (I) ##STR1## and pharmaceutically acceptable salts and solvates thereof, and to their use as gastrin/CCK-B antagonists.

  本发明涉及式(I)的3-苯基脲基-1,5-苯并二氮䓬-二酮，以及其药学上可接受的盐和溶剂化物，并且涉及它们作为胃泌素/CCK-B拮抗剂的用途。