benzyl {(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate | 1266230-12-9

• 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: benzyl {(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate
• 英文别名: Benzyl{(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate；benzyl N-[(1S)-2-[(3S,8aR)-3-[[(4R)-3,4-dihydro-2H-chromen-4-yl]carbamoyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-1-(4,4-difluorocyclohexyl)-2-oxoethyl]carbamate
• CAS: 1266230-12-9
• 化学式: C₃₃H₄₀F₂N₄O₅
• 分子量: 610.701
• InChiKey: XZKRCFUDOITUBW-ZLMHUZRLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  100
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  benzyl {(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate 在 palladium-carbon 氢气 作用下， 以 甲醇 、 四氢呋喃 为溶剂， 25.0 ℃ 、40.53 MPa 条件下， 反应 4.0h， 以to give the title compound (1.13 g) as a colorless oil的产率得到(3S,8aR)-2-[(2S)-2-amino-2-(4,4-difluorocyclohexyl)acetyl]-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]octahydropyrrolo[1,2-a]pyrazine-3-carboxamide
  参考文献：
  名称：

  Heterocyclic Compound

  摘要：

  本发明提供了一种化合物，其表示为式中的每个符号如规范中所定义，或其盐。本发明的化合物表现出强烈的IAP拮抗活性。

  公开号：

  US20110034469A1
• 作为产物：
  描述：

  D-焦谷氨酸 在 盐酸 、 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 70.0h， 生成 benzyl {(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate
  参考文献：
  名称：

  Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic

  摘要：

  To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo-[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to X1AP and to cIAPI was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over X1AP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

  DOI：

  10.1021/jm301674z

文献信息

• Heterocyclic Compound
  申请人：HASHIMOTO Kentaro

  公开号：US20110034469A1

  公开（公告）日：2011-02-10

  The present invention provides a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof. The compound of the present invention shows a strong IAP antagonistic activity.

  本发明提供了一种由下式表示的化合物 其中，每个符号如说明书中所定义，或其盐。本发明的化合物表现出强烈的IAP拮抗活性。
• Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-<i>a</i>]pyrazine Scaffold as a Novel Proline Mimetic
  作者：Kentaro Hashimoto、Bunnai Saito、Naoki Miyamoto、Yuya Oguro、Daisuke Tomita、Zenyu Shiokawa、Moriteru Asano、Hiroyuki Kakei、Naohiro Taya、Masanori Kawasaki、Hiroyuki Sumi、Masato Yabuki、Kenichi Iwai、Sei Yoshida、Mie Yoshimatsu、Kazunobu Aoyama、Yohei Kosugi、Takashi Kojima、Nao Morishita、Douglas R. Dougan、Gyorgy P. Snell、Shinichi Imamura、Tomoyasu Ishikawa

  DOI：10.1021/jm301674z

  日期：2013.2.14

  To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo-[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to X1AP and to cIAPI was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over X1AP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).