(3R,5S)-3-ethyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridin-2-yl}dihydrofuran-2(3H)-one | 1000052-72-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3R,5S)-3-ethyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridin-2-yl}dihydrofuran-2(3H)-one
• 英文别名: (3R,5S)-3-ethyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]tetrahydrofuran-2-one；(3R,5S)-3-ethyl-5-[(2S)-1-(2-nitrophenyl)sulfonylaziridin-2-yl]oxolan-2-one
• CAS: 1000052-72-1
• 化学式: C₁₄H₁₆N₂O₆S
• 分子量: 340.357
• InChiKey: XOTFESRWAPTRDI-MBNMGENJSA-N

物化性质

• 沸点：
  563.9±60.0 °C(Predicted)
• 密度：
  1.474±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  118
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,5S)-3-ethyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridin-2-yl}dihydrofuran-2(3H)-one 在 2-羟基吡啶 、 caesium carbonate 、 苯硫酚 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 20.5h， 生成 {(1S,2S,4R)-4-(2,2-dimethylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester
  参考文献：
  名称：

  Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

  摘要：

  With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.022
• 作为产物：
  描述：

  (3R,5S)-5-[(1R)-2-(benzyloxy)-1-hydroxyethyl]-3-ethyldihydrofuran-2(3H)-one 在 盐酸 、 N,N-二甲基丙烯基脲 、 sodium azide 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 83.17h， 生成 (3R,5S)-3-ethyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridin-2-yl}dihydrofuran-2(3H)-one
  参考文献：
  名称：

  Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

  摘要：

  With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.022

文献信息

• CYCLIC AMINE COMPOUND
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP2036896B1

  公开（公告）日：2012-03-14
• Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor
  作者：Yuji Nakamura、Teppei Fujimoto、Yasuyuki Ogawa、Chie Sugita、Shojiro Miyazaki、Kazuhiko Tamaki、Mizuki Takahashi、Yumi Matsui、Takahiro Nagayama、Kenichi Manabe、Makoto Mizuno、Noriko Masubuchi、Katsuyoshi Chiba、Takahide Nishi

  DOI：10.1021/ml300168e

  日期：2012.9.13

  A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
• US8158790B2
  申请人：——

  公开号：US8158790B2

  公开（公告）日：2012-04-17
• Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor
  作者：Yuji Nakamura、Teppei Fujimoto、Yasuyuki Ogawa、Hidenori Namiki、Sayaka Suzuki、Masayoshi Asano、Chie Sugita、Akiyoshi Mochizuki、Shojiro Miyazaki、Kazuhiko Tamaki、Yoko Nagai、Shin-ichi Inoue、Takahiro Nagayama、Mikio Kato、Katsuyoshi Chiba、Kiyoshi Takasuna、Takahide Nishi

  DOI：10.1016/j.bmc.2013.03.022

  日期：2013.6

  With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. (C) 2013 Elsevier Ltd. All rights reserved.