10'-nitro-3',4',6',10'b-tetrahydro-1'H-spiro[1,3-dioxolane-2,2'-pyrido[2,1-a]isoindole]-6'-one | 1245654-38-9

• 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'-nitro-3',4',6',10'b-tetrahydro-1'H-spiro[1,3-dioxolane-2,2'-pyrido[2,1-a]isoindole]-6'-one
• 英文别名: 10'-nitro-3',4'-dihydro-1'H-spiro[[1,3]dioxolane-2,2'-pyrido[2,1-a]isoindol]-6'(10b'H)-one；10-nitrospiro[1,3,4,10b-tetrahydropyrido[1,2-b]isoindole-2,2'-1,3-dioxolane]-6-one
• CAS: 1245654-38-9
• 化学式: C₁₄H₁₄N₂O₅
• 分子量: 290.276
• InChiKey: KJTZQWBKCQKVFB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  21
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  84.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  10'-nitro-3',4',6',10'b-tetrahydro-1'H-spiro[1,3-dioxolane-2,2'-pyrido[2,1-a]isoindole]-6'-one 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 sodium 、 一水合肼 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 丙酮 、 二乙二醇 为溶剂， 反应 25.0h， 生成 1-(6-oxo-2,3,4,10b-tetrahydro-1H-pyrido[2,1-a]isoindol-10-yl)-3-(4-oxo-1H-quinolin-2-yl)urea
  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 甲醇 、 sodium tetrahydroborate 、 APTS 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 6.0h， 生成 10'-nitro-3',4',6',10'b-tetrahydro-1'H-spiro[1,3-dioxolane-2,2'-pyrido[2,1-a]isoindole]-6'-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

• DERIVATIVES OF 10-AMINO-1,2,3,4-TETRAHYDROPYRIDO[2,1-A]ISOINDOL-6(10BH)-ONES, METHOD FOR PREPARATION THEREOF AND THERAPEUTIC USES THEREOF
  申请人：Routier Sylvain Cesar Leonce

  公开号：US20120095022A1

  公开（公告）日：2012-04-19

  The present invention relates to compounds having the following general formula (I): wherein: A represents a SO 2 or CX group, X representing O or S; R 1 , R 2 , R″, R 4 represent in particular H, R represents in particular an alkyl group or an aryl group, as well as to the pharmaceutically acceptable salts thereof, the compound of formula (I) taking the form of a pure stereoisomer or an enantiomer and/or diastereoisomer mixture, including racemic mixtures.

  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。
• Advances in tetrahydropyrido[1,2- a ]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors
  作者：Rajâa Boulahjar、Aziz Ouach、Stéphane Bourg、Pascal Bonnet、Olivier Lozach、Laurent Meijer、Christiane Guguen-Guillouzo、Rémy Le Guevel、Saïd Lazar、Mohamed Akssira、Yves Troin、Gérald Guillaumet、Sylvain Routier

  DOI：10.1016/j.ejmech.2015.06.046

  日期：2015.8

  An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine iso-indolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSM as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro Kinase activities and the best effects were obtained with lung and colon cell lines. (C) 2015 Elsevier Masson SAS. All rights reserved.
• 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.
• Novel Tetrahydropyrido[1,2-<i>a</i>]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts
  作者：Rajâa Boulahjar、Aziz Ouach、Chiurato Matteo、Stephane Bourg、Myriam Ravache、Rémy le Guével、Séverine Marionneau、Thibauld Oullier、Olivier Lozach、Laurent Meijer、Christiane Guguen-Guillouzo、Saïd Lazar、Mohamed Akssira、Yves Troin、Gérald Guillaumet、Sylvain Routier

  DOI：10.1021/jm3008536

  日期：2012.11.26

  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.