10-amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one | 1245654-44-7

• 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: 10-amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one
• 英文别名: 10-amino-2,3,4,10b-tetrahydro-1H-pyrido[1,2-b]isoindol-6-one
• CAS: 1245654-44-7
• 化学式: C₁₂H₁₄N₂O
• 分子量: 202.256
• InChiKey: ZVUDLLSVKJAHIN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 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：

  10-amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one 在 吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 23.0h， 生成 3-[3-(6-oxo-1,2,3,4,6,10b-hexahydro-pyrido[2,1-a]isoindol-10-yl)ureido]pyrazole-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts

  摘要：

  The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number-of-diverse structures have been reported to inhibit CDKs and GSK-3 beta. in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates: for further development as anticancer agents.

  DOI：

  10.1021/jm3008536
• 作为产物：
  描述：

  4-nitro-2-(3-oxobutyl)isoindoline-1,3-dione 在 盐酸 、 甲醇 、 sodium tetrahydroborate 、 水 、 sodium 、 一水合肼 、 APTS 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 乙醇 、 乙二醇 、 丙酮 、 甲苯 为溶剂， 反应 13.0h， 生成 10-amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one
  参考文献：
  名称：

  DERIVATIVES OF 10-AMINO-1,2,3,4-TETRAHYDROPYRIDO[2,1-A]ISOINDOL-6(10BH)-ONES, METHOD FOR PREPARATION THEREOF AND THERAPEUTIC USES THEREOF

  摘要：

  本发明涉及具有以下一般式（I）的化合物：其中：A代表SO2或CX基团，X代表O或S；R1、R2、R″、R4特别代表H，R特别代表烷基或芳基，以及其药学上可接受的盐，具有一种纯的立体异构体或对映异构体和/或二对映异构体混合物的形式的一般式（I）的化合物，包括消旋混合物。

  公开号：

  US20120095022A1

文献信息

• Synthetic Route to Rare Isoindolones Derivatives
  作者：Killian Oukoloff、Frédéric Buron、Sylvain Routier、Ludovic Jean、Pierre-Yves Renard

  DOI：10.1002/ejoc.201403649

  日期：2015.4

  The isoindolone scaffold is present in many biologically active compounds. Here, we have developed a shorter and more efficient synthesis of tetrahydropyrido[2,1-a]isoindolone. The key step of this approach is a cyclization to form the γ-lactam ring under Shibasaki's conditions. Thus, tetrahydropyrido[2,1-a]isoindolone and superior analogues, namely hexahydroazepino[2,1-a]isoindolone and hexahydroazocino[2

  异吲哚酮支架存在于许多生物活性化合物中。在这里，我们开发了一种更短、更有效的四氢吡啶并 [2,1-a] 异吲哚酮合成方法。这种方法的关键步骤是在柴崎条件下环化形成γ-内酰胺环。因此，四氢吡啶并[2,1-a]异吲哚酮和高级类似物，即六氢氮杂[2,1-a]异吲哚酮和六氢氮杂[2,1-a]异吲哚酮，仅在39、25和19的三个步骤中制备% 的总产率，分别。这种新颖的策略为现有程序提供了更短的替代方案。
• Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3
  作者：Killian Oukoloff、Nicolas Coquelle、Manuela Bartolini、Marina Naldi、Rémy Le Guevel、Stéphane Bach、Béatrice Josselin、Sandrine Ruchaud、Marco Catto、Leonardo Pisani、Nunzio Denora、Rosa Maria Iacobazzi、Israel Silman、Joel L. Sussman、Frédéric Buron、Jacques-Philippe Colletier、Ludovic Jean、Sylvain Routier、Pierre-Yves Renard

  DOI：10.1016/j.ejmech.2018.12.063

  日期：2019.4

  Both cholinesterases (AChE and BChE) and kinases, such as GSK-3 alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3 alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3 alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Ouach, Aziz; Boulahjar, Rajâa; Vala, Christine, European Journal of Medicinal Chemistry, 2016, vol. 115, p. 311 - 325
  作者：Ouach, Aziz、Boulahjar, Rajâa、Vala, Christine、Bourg, Stéphane、Bonnet, Pascal、Guguen-Guillouzo, Christiane、Ravache, Myriam、Le Guevel, Rémy、Lozach, Olivier、Lazar, Saïd、Troin, Yves、Meijer, Laurent、Ruchaud, Sandrine、Akssira, Mohamed、Guillaumet, Gérald、Routier, Sylvain

  DOI：——

  日期：——
• DÉRIVÉS DE 10-AMINO-1,2,3,4-TÉTRAHYDROPYRIDO[2,1-A]ISOINDOL-6(10BH)-ONES, LEUR PROCÉDÉ DE PRÉPARATION ET LEURS UTILISATIONS THÉRAPEUTIQUES
  申请人：Centre National de la Recherche Scientifique (C.N.R.S.)

  公开号：EP2406261B1

  公开（公告）日：2013-01-09
• [EN] 10-AMINO-1,2,3,4-TETRAHYDROPYRIDO[2,1-A]ISOINDOL-6(10BH)-ONE DERIVATIVES, METHOD FOR PREPARING SAME, AND THERAPEUTIC USES THEREOF<br/>[FR] DÉRIVÉS DE 10-AMINO-1,2,3,4-TÉTRAHYDROPYRIDO[2,1-A]ISOINDOL-6(10BH)-ONES, LEUR PROCÉDÉ DE PRÉPARATION ET LEURS UTILISATIONS THÉRAPEUTIQUES
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2010103240A1

  公开（公告）日：2010-09-16

  La présente invention concerne des composés de formule générale (I) suivante dans laquelle : - A représente un groupe SO2 ou CX, X représentant O ou S; - R1, R2, R", R4 représentent notamment H, - R représente notamment un groupe alkyle ou un groupe aryle, ainsi que ses sels pharmaceutiquement acceptables, ledit composé de formule (I) étant sous forme de stéréoisomère pur ou sous forme de mélange d'énantiomères et/ou de diastéréoisomères, y compris de mélanges racémiques.