2,2-Dimethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine | 40359-00-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: 2,2-Dimethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
• 英文别名: 2,2-dimethyl-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine；2,2-dimethyl-4,5-dihydro-3H-1,5-benzothiazepine
• CAS: 40359-00-0
• 化学式: C₁₁H₁₅NS
• 分子量: 193.313
• InChiKey: VAKMHNZNNZZXLN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2,2-Dimethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 在 四丁基溴化铵 、 水 、 间氯过氧苯甲酸 、 potassium hydroxide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 2-(2,2-dimethyl-1,1-dioxido-3,4-dihydrobenzo[b][1,4]thiazepin-5(2H)-yl)acetic acid
  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：

  3,3-二甲基丙烯酸甲酯 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 生成 2,2-Dimethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
  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

文献信息

• Spectroscopic and mass spectral investigation of some dihydro- and tetrahydro-1,5-benzodiazepines and thiazepines
  作者：P.W.W. Hunter、G.A. Webb

  DOI：10.1016/s0040-4020(01)93621-x

  日期：1972.1