2-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)ethanoic acid methyl ester | 913687-69-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)ethanoic acid methyl ester
• 英文别名: methyl (3,4-dihydro-4-oxo-1,5-benzothiazepin-5(2H)-yl)acetate；methyl (4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl)acetate；methyl 2-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)acetate
• CAS: 913687-69-1
• 化学式: C₁₂H₁₃NO₃S
• mdl: MFCD25949532
• 分子量: 251.306
• InChiKey: BSCWBBAGTANDLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  71.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)ethanoic acid methyl ester 在 sodium hydroxide 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 间氯过氧苯甲酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成
  参考文献：
  名称：

  合理设计，发现和合成一系列新颖的有效生长激素促分泌素。

  摘要：

  在这里报道的获得新化学实体作为生长激素促分泌素（GHS）的联合实验和计算成果中，使用了一个已知具有GHS活性的小型肽和非肽数据库来生成和评估该活性的3D药效团。该药效团是通过我们实验室开发的系统有效的程序“ DistComp”获得的。然后，将识别出的3D药效团用于搜索3D数据库，以探索可能是新型GHS的化学结构。选择了其中一些用于合成和评估其从大鼠垂体细胞释放生长激素（GH）的能力。在测试的化合物中，发现具有苯并噻唑啉骨架的化合物具有微摩尔活性。为了促进线索优化，第二个程序 开发了一种依赖于位点的片段QSAR程序。该程序计算已知药效团中“片段”或化学成分的化学和物理性质的库，并确定这些性质中的哪些对观察到的活性很重要。3D药效团的结合使用和位点依赖性片段QSAR分析的结果导致发现和合成了一系列新的有效GHS，其中许多具有纳摩尔体外活性。

  DOI：

  10.1021/jm010207i
• 作为产物：
  描述：

  2-氨基苯硫醇 在 四丁基溴化铵 、 potassium hydroxide 作用下， 以 四氢呋喃 为溶剂， 生成 2-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)ethanoic acid methyl ester
  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

• Isolation and Characterization of Atropisomers of Seven-Membered-Ring Benzolactams
  作者：Hidetsugu Tabata、Naoya Wada、Yuko Takada、Tetsuta Oshitari、Hideyo Takahashi、Hideaki Natsugari

  DOI：10.1021/jo2008725

  日期：2011.6.17

  The atropisomeric properties of seven-membered-ring benzolactams (7a-c and 8a) [1,5-benzodiazepin-2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2-one (c)] were examined. The atropisomers were isolated as the diastereomers with an (S)-phenethylamide moiety, which were characterized by X-ray crystallography, and the barriers to their interconversion were clarified.
• Rational Design, Discovery, and Synthesis of a Novel Series of Potent Growth Hormone Secretagogues
  作者：Ping Huang、Gilda H. Loew、Hidenori Funamizu、Mitsuo Mimura、Nobuo Ishiyama、Mitsuo Hayashida、Tadashi Okuno、Osafumi Shimada、Akihiko Okuyama、Satoru Ikegami、Jun Nakano、Kiyoshi Inoguchi

  DOI：10.1021/jm010207i

  日期：2001.11.1

  In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The

  在这里报道的获得新化学实体作为生长激素促分泌素（GHS）的联合实验和计算成果中，使用了一个已知具有GHS活性的小型肽和非肽数据库来生成和评估该活性的3D药效团。该药效团是通过我们实验室开发的系统有效的程序“ DistComp”获得的。然后，将识别出的3D药效团用于搜索3D数据库，以探索可能是新型GHS的化学结构。选择了其中一些用于合成和评估其从大鼠垂体细胞释放生长激素（GH）的能力。在测试的化合物中，发现具有苯并噻唑啉骨架的化合物具有微摩尔活性。为了促进线索优化，第二个程序 开发了一种依赖于位点的片段QSAR程序。该程序计算已知药效团中“片段”或化学成分的化学和物理性质的库，并确定这些性质中的哪些对观察到的活性很重要。3D药效团的结合使用和位点依赖性片段QSAR分析的结果导致发现和合成了一系列新的有效GHS，其中许多具有纳摩尔体外活性。
• N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists
  作者：Lingyun Wu、Kai Lu、Mahesh Desai、Mathivanan Packiarajan、Amita Joshi、Mohammad R. Marzabadi、Vrej Jubian、Kim Andersen、Gamini Chandrasena、Noel J. Boyle、Mary W. Walker

  DOI：10.1016/j.bmcl.2011.06.078

  日期：2011.9

  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.