4-chloroacetyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine | 22178-92-3

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 4-chloroacetyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine
• 英文别名: 2-Chloro-1-(7-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)ethanone
• CAS: 22178-92-3
• 化学式: C₁₁H₁₂ClNO₃
• 分子量: 241.674
• InChiKey: CQFIFCDBWNGEGH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-chloroacetyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine 、 1-Amino-4-[(dimethylsulfamoylamino)methyl]cyclohexane 在 硼烷四氢呋喃络合物 、 potassium carbonate 、 sodium iodide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 N-[[4-[2-(7-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)ethylamino]cyclohexyl]methyl]propane-2-sulfonamide
  参考文献：
  名称：

  N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists

  摘要：

  Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K-i 4 nM vs 1a 27 nM) and microsomal stability (human CLint 2.5 L/min vs 1a 35 L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K-i 9 nM, B/P 520/840 nM 10 mg/kg PO). (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.078
• 作为产物：
  描述：

  氯乙酰氯 、 7-甲氧基-3,4-二氢-2H-苯并[1,4]噁嗪 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 4-chloroacetyl-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine
  参考文献：
  名称：

  N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists

  摘要：

  Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K-i 4 nM vs 1a 27 nM) and microsomal stability (human CLint 2.5 L/min vs 1a 35 L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K-i 9 nM, B/P 520/840 nM 10 mg/kg PO). (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.078