2-{[1-(3-methylbenzyl)piperidin-4-yl]methyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide | 1262417-46-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 2-{[1-(3-methylbenzyl)piperidin-4-yl]methyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide
• 英文别名: 2-[[1-[(3-methylphenyl)methyl]piperidin-4-yl]methyl]-3-oxo-1H-isoindole-4-carboxamide
• CAS: 1262417-46-8
• 化学式: C₂₃H₂₇N₃O₂
• 分子量: 377.486
• InChiKey: CJNLSQVARWMQSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  [1-(3-methylbenzyl)piperidin-4-ylmethyl]amine 在 盐酸 、 1-羟基-1H-苯并三唑铵盐 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 2-{[1-(3-methylbenzyl)piperidin-4-yl]methyl}-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide
  参考文献：
  名称：

  Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy

  摘要：

  The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-4,4-difluorocyclohexyl)piperidin-4-yl] -6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

  DOI：

  10.1021/acs.jmedchem.5b00680

文献信息

• 3-OXO-2,3-DIHYDRO-1H-ISOINDOLE-4-CARBOXAMIDES AS PARP INHIBITORS
  申请人：Papeo Gianluca Mariano Enrico

  公开号：US20120245142A1

  公开（公告）日：2012-09-27

  There are provided substituted 3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide derivatives (I) which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP-1 with respect to poly (ADP-ribose) polymerase PARP-2. The compounds of this invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating, diseases utilizing pharmaceutical compositions comprising these compounds.

  本发明提供了替代的3-氧代-2,3-二氢-1H-异吲哚-4-羧酰胺衍生物（I），其能够选择性地抑制PARP-1相对于PARP-2的活性。因此，本发明的化合物可用于治疗癌症、心血管疾病、中枢神经系统损伤和不同形式的炎症等疾病。本发明还提供了制备这些化合物的方法、包含这些化合物的制药组合物以及利用包含这些化合物的制药组合物治疗疾病的方法。
• [EN] 3-OXO-2, 3-DIHYDRO-1H-ISOINDOLE-4-CARBOXAMIDES AS PARP INHIBITORS<br/>[FR] 3-OXO-2,3-DIHYDRO-1H-ISOINDOLE-4-CARBOXAMIDES EN TANT QU'INHIBITEURS DE PARP
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2011006794A9

  公开（公告）日：2011-05-05
• 3-OXO-2, 3-DIHYDRO-1H-ISOINDOLE-4-CARBOXAMIDES AS PARP INHIBITORS
  申请人：Nerviano Medical Sciences S.r.l.

  公开号：EP2454236A1

  公开（公告）日：2012-05-23
• US8877944B2
  申请人：——

  公开号：US8877944B2

  公开（公告）日：2014-11-04
• Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1<i>H</i>-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy
  作者：Gianluca Papeo、Helena Posteri、Daniela Borghi、Alina A. Busel、Francesco Caprera、Elena Casale、Marina Ciomei、Alessandra Cirla、Emiliana Corti、Matteo D’Anello、Marina Fasolini、Barbara Forte、Arturo Galvani、Antonella Isacchi、Alexander Khvat、Mikhail Y. Krasavin、Rosita Lupi、Paolo Orsini、Rita Perego、Enrico Pesenti、Daniele Pezzetta、Sonia Rainoldi、Federico Riccardi-Sirtori、Alessandra Scolaro、Francesco Sola、Fabio Zuccotto、Eduard R. Felder、Daniele Donati、Alessia Montagnoli

  DOI：10.1021/acs.jmedchem.5b00680

  日期：2015.9.10

  The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-4,4-difluorocyclohexyl)piperidin-4-yl] -6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.