(2S)-2-((叔丁氧基)羰基氨基)-4-甲基-N-((3S)-四氢-2-氧代-3-呋喃基)戊酰胺 | 202815-09-6

• 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
• 中文名称: (2S)-2-((叔丁氧基)羰基氨基)-4-甲基-N-((3S)-四氢-2-氧代-3-呋喃基)戊酰胺
• 英文名称: (2S)-2-((tert-butoxy)carbonylamino)-4-methyl-N-((3S)-tetrahydro-2-oxo-3-furanyl)pentanamide
• 英文别名: tert-butyl N-[(2S)-4-methyl-1-oxo-1-[[(3S)-2-oxooxolan-3-yl]amino]pentan-2-yl]carbamate
• CAS: 202815-09-6
• 化学式: C₁₅H₂₆N₂O₅
• 分子量: 314.382
• InChiKey: DXXAMNHZMZEASF-QWRGUYRKSA-N

物化性质

• 沸点：
  537.9±50.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S)-2-((叔丁氧基)羰基氨基)-4-甲基-N-((3S)-四氢-2-氧代-3-呋喃基)戊酰胺 在 盐酸 、 三乙胺 作用下， 以 乙酸乙酯 为溶剂， 反应 21.0h， 生成 (2S)-4-methyl-2-((((3-methylphenyl)amino)thioxomethyl)amino)-N-((3S)-tetrahydro-2-oxo-3-furanyl)pentanamide
  参考文献：
  名称：

  Exploration of Orally Available Calpain Inhibitors 2:  Peptidyl Hemiacetal Derivatives

  摘要：

  We previously reported a potent calpain inhibitor 1 ( SJA6017, N-( 4-fluorophenyl)-L-valyl-L-leucinal), which displayed relatively low oral bioavailability ( BA). Replacing the metabolically labile aldehyde moiety of 1 with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 ( SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.

  DOI：

  10.1021/jm060157n
• 作为产物：
  描述：

  Boc-L-亮氨酸N-羟基琥珀酰亚胺脂 、 高丝氨酸内酯氢溴酸盐 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以99%的产率得到(2S)-2-((叔丁氧基)羰基氨基)-4-甲基-N-((3S)-四氢-2-氧代-3-呋喃基)戊酰胺
  参考文献：
  名称：

  Exploration of cornea permeable calpain inhibitors as anticataract agents

  摘要：

  To explore cornea permeable calpain inhibitors, four compounds displaying different characteristics were designed and synthesized based on the known potent calpain inhibitor, peptidyl aldehyde SJA6017. Two approaches were adopted; an improvement in the physicochemical properties, and conversion of the active aldehyde. The water-soluble peptidyl aldehyde 1 containing a pyridine ring at the P3 site showed a modest inhibition against calpains and an improvement of corneal permeability in comparison with SJA6017. Replacement of the aldehyde of SJA6017 by an alpha-ketoamide provided compound 2 that was approximately equipotent with SJA6017, but it was extremely water-in soluble. However, compound 3, in which the aldehyde was converted into a cyclic hemiacetal, proved to be a less potent calpain inhibitor than SJA6017, but demonstrated excellent transcorneal permeability. Further modification generating the cyclic hermacetal 4 containing a thiourea linker between the P3 and P2 sites exhibited potent inhibitory activities, high cornea permeability and excellent efficacy in the rat lens culture cataract model. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00612-0

文献信息

• Cyclic hemiacetal derivative and use thereof
  申请人：Nakamura Masayuki

  公开号：US20050119499A1

  公开（公告）日：2005-06-02

  A compound represented by the following formula (I) wherein R 1 is a lower alkyl group, R 2 is a hydrogen, a halogen, a cyano group, a lower alkyl group or a lower alkoxy group, and n is 0 or 1, which has a calpain inhibitory activity, is provided.

  下式(I)代表的化合物 其中 R 1 是低级烷基，R 2 是氢、卤素、氰基、低级烷基或低级烷氧基，n 是 0 或 1，该化合物具有钙蛋白酶抑制活性。
• CYCLIC HEMIACETAL DERIVATIVE AND USE THEREOF
  申请人：Senju Pharmaceutical Co., Ltd.

  公开号：EP1489076B1

  公开（公告）日：2008-08-13
• US7202274B2
  申请人：——

  公开号：US7202274B2

  公开（公告）日：2007-04-10
• Exploration of Orally Available Calpain Inhibitors 2:  Peptidyl Hemiacetal Derivatives
  作者：Yoshihisa Shirasaki、Masayuki Nakamura、Masazumi Yamaguchi、Hiroyuki Miyashita、Osamu Sakai、Jun Inoue

  DOI：10.1021/jm060157n

  日期：2006.6.1

  We previously reported a potent calpain inhibitor 1 ( SJA6017, N-( 4-fluorophenyl)-L-valyl-L-leucinal), which displayed relatively low oral bioavailability ( BA). Replacing the metabolically labile aldehyde moiety of 1 with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 ( SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.
• Exploration of cornea permeable calpain inhibitors as anticataract agents
  作者：Masayuki Nakamura、Masazumi Yamaguchi、Osamu Sakai、Jun Inoue

  DOI：10.1016/s0968-0896(02)00612-0

  日期：2003.4

  To explore cornea permeable calpain inhibitors, four compounds displaying different characteristics were designed and synthesized based on the known potent calpain inhibitor, peptidyl aldehyde SJA6017. Two approaches were adopted; an improvement in the physicochemical properties, and conversion of the active aldehyde. The water-soluble peptidyl aldehyde 1 containing a pyridine ring at the P3 site showed a modest inhibition against calpains and an improvement of corneal permeability in comparison with SJA6017. Replacement of the aldehyde of SJA6017 by an alpha-ketoamide provided compound 2 that was approximately equipotent with SJA6017, but it was extremely water-in soluble. However, compound 3, in which the aldehyde was converted into a cyclic hemiacetal, proved to be a less potent calpain inhibitor than SJA6017, but demonstrated excellent transcorneal permeability. Further modification generating the cyclic hermacetal 4 containing a thiourea linker between the P3 and P2 sites exhibited potent inhibitory activities, high cornea permeability and excellent efficacy in the rat lens culture cataract model. (C) 2003 Elsevier Science Ltd. All rights reserved.