4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one | 1000049-87-5

• 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: 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one
• 英文别名: 4-[(2S)-2-amino-2-[(2S,4S)-5-oxo-4-propan-2-yloxolan-2-yl]ethyl]-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one
• CAS: 1000049-87-5
• 化学式: C₂₁H₂₉ClFN₃O₃
• 分子量: 425.931
• InChiKey: BUFGFXSZDHNILU-ZVZYQTTQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  75.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one 在 2-羟基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 生成 {(1S,2S,4S)-4-butylcarbamoyl-1-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxy-5-methylhexyl}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：

  (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 、 氢气 、 双氧水 、 四丁基硫酸氢铵 、 sodium hexamethyldisilazane 、 edetate disodium 、 potassium carbonate 、 caesium carbonate 、 苯硫酚 、 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 、 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 117.42h， 生成 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-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：US08158790B2

  公开（公告）日：2012-04-17

  The present invention provides an excellent antihypertensive medicament. The medicament of the present invention comprises a compound having the general formula (I) and the like: [wherein R1: H, substitutable alkyl, substitutable alkenyl, substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; R2: H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R3, R4; H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R5, R6: H, substitutable alkyl, substitutable cycloalkyl, substitutable alkoxy or the like; R7, R8: H, substitutable alkyl, substitutable cycloalkyl or the like; X: the formula (II) or the like; A: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; Y: a single bond, substitutable alkylene, substitutable alkenylene, —(CH2)a—X1—(CH2)b—(X1: the formula —NH—, —O— or the like; a, b: 0-5) or the like; B: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like].

  本发明提供了一种优秀的降压药物。该药物包括具有通式（I）等的化合物：[其中R1：氢，可取代烷基，可取代烯基，可取代环烃基，可取代杂环基或类似物；R2：氢，可取代烷基，可取代烯基，可取代环烷基或类似物；R3、R4：氢，可取代烷基，可取代烯基，可取代环烷基或类似物；R5、R6：氢，可取代烷基，可取代环烷基，可取代烷氧基或类似物；R7、R8：氢，可取代烷基，可取代环烷基或类似物；X：式（II）或类似物；A：可取代环烃基，可取代杂环基或类似物；Y：单键，可取代亚烷基，可取代烯亚烷基，—（CH2）a—X1—（CH2）b—（X1：式—NH—、—O—或类似物；a、b：0-5）或类似物；B：可取代环烃基，可取代杂环基或类似物]。
• CYCLIC AMINE COMPOUND
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP2036896B1

  公开（公告）日：2012-03-14
• 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.