tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-{(2S)-2-[(3-hydroxyadamantan-1-yl)carbamoyl]-3-methylbutyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | 1436430-33-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-{(2S)-2-[(3-hydroxyadamantan-1-yl)carbamoyl]-3-methylbutyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 1436430-33-9
• 化学式: C₃₉H₅₉ClN₄O₆
• 分子量: 715.374
• InChiKey: FXBSSWHMNYSVPN-IFWFZFNFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.37
• 重原子数：
  50.0
• 可旋转键数：
  8.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  111.65
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-{(2S)-2-[(3-hydroxyadamantan-1-yl)carbamoyl]-3-methylbutyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 、 富马酸 在 盐酸 、 甲醇 作用下， 以 甲醇 为溶剂， 反应 12.08h， 以60%的产率得到(2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-N-(3-hydroxyadamantan-1-yl)-2-isopropylhexanamide fumarate
  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：

  (S)-3-(3-甲基丁酰基)-4-苄基-2-恶唑烷酮 在 盐酸 、 N,N-二甲基丙烯基脲 、 Oxone 、 sodium azide 、 Shi's ketone 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 水 、 氢气 、 双氧水 、 四丁基硫酸氢铵 、 sodium hexamethyldisilazane 、 4-甲基苯磺酸吡啶 、 edetate disodium 、 potassium carbonate 、 caesium carbonate 、 苯硫酚 、 三乙胺 、 三苯基膦 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 148.67h， 生成 tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-{(2S)-2-[(3-hydroxyadamantan-1-yl)carbamoyl]-3-methylbutyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
  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