9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one | 322692-77-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one
• 英文别名: 9-amino-2,3,5,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one；9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one；5H-Pyrrolo[2,1-a]isoindol-5-one, 9-amino-1,2,3,9b-tetrahydro-；9-amino-1,2,3,9b-tetrahydropyrrolo[1,2-b]isoindol-5-one
• CAS: 322692-77-3
• 化学式: C₁₁H₁₂N₂O
• 分子量: 188.229
• InChiKey: IXDFDXDYYBLCON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  46.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one 在 锂硼氢 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 为溶剂， 反应 8.0h， 生成 (9bR)-9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one
  参考文献：
  名称：

  Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors:  New de Novo Design Strategy and Library Design

  摘要：

  As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC50 = 0.10 muM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC50 = 0.042 muM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.

  DOI：

  10.1021/jm0103256
• 作为产物：
  描述：

  2-氯-3-硝基苯甲酸 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 4-二甲氨基吡啶 、 氯化亚砜 、 氢气 、 potassium acetate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 异丁酰胺 为溶剂， 反应 30.0h， 生成 9-amino-1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-α]isoindol-5-one
  参考文献：
  名称：

  Novel pyrazinone derivatives

  摘要：

  本发明涉及一种通式(I)的化合物：1[Ar1是芳基，与相邻的吡唑酮环在第5和第6位置融合，等等，X是CO，等等，Y是CH，等等，Z是CH，等等，V是CH，等等，W是-(CH2)n-（n为零至四），R1是H或选择性取代的较低烷基，等等，R2是H，等等，R3和R4相同或不同，分别为H，等等，R5和R6相同或不同，分别为H，羟基，等等]或其药学上可接受的盐或酯；一种含有该化合物作为活性成分的制药组合物，Cdk4和/或Cdk6的抑制剂或抗癌剂；以及其制备方法。

  公开号：

  US20030203907A1

文献信息

• NOVEL PYRAZINONE DERIVATIVES
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP1295878A1

  公开（公告）日：2003-03-26

  The present invention relates to a compound of the general formula (I): [Ar1 is aryl fused to the adjacent pyrazinone ring at the 5th and 6th positions, etc., X is CO, etc., Y is CH, etc., Z is CH, etc., V is CH, etc., Wn is -(CH2)n- (n is zero to four), R1 is H or optionally substituted lower alkyl, etc., R2 is H, etc., R3 and R4 are the same or different and are each H, etc., R5 and R6 are the same or different and are each H, hydroxy, etc.] or a pharmaceutically acceptable salt or ester thereof; a pharmaceutical composition, an inhibitor of Cdk4 and/or Cdk6 or an anti-cancer agent, containing the same as an active ingredient; and a process for preparing them.

  本发明涉及通式(I)的化合物： [Ar1是在第5和第6位与相邻吡嗪酮环融合的芳基等，X是CO等，Y是CH等，Z是CH等，V是CH等，Wn是-(CH2)n-(n为0至4)，R1是H或任选取代的低级烷基等，R2是H等，R3和R4相同或不同且各自是H等、R5和R6相同或不同且各自为H、羟基等]或其药学上可接受的盐或酯；含有相同成分作为活性成分的药物组合物、Cdk4和/或Cdk6抑制剂或抗癌剂；以及制备它们的工艺。
• A Novel Approach for the Development of Selective Cdk4 Inhibitors:  Library Design Based on Locations of Cdk4 Specific Amino Acid Residues
  作者：Teruki Honma、Takashi Yoshizumi、Noriaki Hashimoto、Kyoko Hayashi、Nobuhiko Kawanishi、Kazuhiro Fukasawa、Tohru Takaki、Chinatsu Ikeura、Mari Ikuta、Ikuko Suzuki-Takahashi、Takashi Hayama、Susumu Nishimura、Hajime Morishima

  DOI：10.1021/jm010326y

  日期：2001.12.1

  Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding pattern. To address this issue, we applied the following structure-based approach for designing selective Cdk4 inhibitors: (1) identification of specifically altered amino acid residues around the ATP binding pocket in Cdk4 by comparison of 390 representative kinases, (2) prediction of appropriate positions to introduce substituents in lead compounds based on the locations of the altered amino acid residues and the binding modes of lead compounds, and (3) library design to interact with the altered amino acid residues supported by de novo design programs. Accordingly, Asp99, Thr102, and Gln98 of Cdk4, which are located in the p16 binding region, were selected as first target residues for specific interactions with Cdk4. Subsequently, the 5-position of the pyrazole ring in the pyrazol-3-ylurea class of lead compound (2a) was predicted to be a suitable position to introduce substituents. We then designed a chemical library of pyrazol-3-ylurea substituted with alkylaminomethyl groups based on the output structures of de novo design programs. Thus we identified a highly selective and potent Cdk4 inhibitor, 15b, substituted with a 5-chloroindan-2-ylaminomethyl group. Compound 15b showed higher selectivity on Cdk4 over those on not only Cdk1/2 (780-fold/190-fold) but also many other kinases (> 430-fold) that have been tested thus far. The structural basis for Cdk4 selective inhibition by 15b was analyzed by combining molecular modeling and the X-ray analysis of the Cdk4 mimic Cdk2-inhibitor complex. The results suggest that the hydrogen bond with the carboxyl group of Asp99 and hydrophobic van der Waals contact with the side chains of Thr102 and Gln98 are important. Compound 15b was found to cause cell cycle arrest of the Rb(+) cancer cell line in the G(1) phase, indicating that it is a good biological tool.
• PYRAZINONE DERIVATIVES
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP1295878B1

  公开（公告）日：2004-09-15
• US6914062B2
  申请人：——

  公开号：US6914062B2

  公开（公告）日：2005-07-05
• US7148224B2
  申请人：——

  公开号：US7148224B2

  公开（公告）日：2006-12-12