甲基8-氨基-2,3-二氢-1,4-苯并二氧杂环己烷-5-羧酸酯 | 158504-37-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 甲基8-氨基-2,3-二氢-1,4-苯并二氧杂环己烷-5-羧酸酯
• 英文名称: methyl 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate
• 英文别名: methyl 5-amino-2,3-dihydro-1,4-benzodioxine-8-carboxylate
• CAS: 158504-37-1
• 化学式: C₁₀H₁₁NO₄
• 分子量: 209.202
• InChiKey: YYDFBLDAFWLMSG-UHFFFAOYSA-N

物化性质

• 沸点：
  397.2±42.0 °C(Predicted)
• 密度：
  1.319±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  70.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  甲基8-氨基-2,3-二氢-1,4-苯并二氧杂环己烷-5-羧酸酯 在 N-氯代丁二酰亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以85%的产率得到methyl 8-amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylate
  参考文献：
  名称：

  Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699

  摘要：

  Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [F-18] MNI-698 and [F-18] MNI-699 were consistent with the known densities of 5-HT4 in brain. [F-18] MNI-698 and [F-18] MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.097
• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二氧-5-甲醛 在 palladium on activated charcoal 、 氨基磺酸 、 氢气 、 溴 、 硝酸 、 乙酸酐 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， -55.0~90.0 ℃ 、413.7 kPa 条件下， 反应 58.83h， 生成 甲基8-氨基-2,3-二氢-1,4-苯并二氧杂环己烷-5-羧酸酯
  参考文献：
  名称：

  [EN] TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
  [FR] COMPOSÉS TRICYCLIQUES À TITRE D'INHIBITEURS DE LA MPGES-1

  摘要：

  本公开涉及式(I)的化合物及其药学上可接受的盐，作为m PGES-1抑制剂。这些化合物是微粒体前列腺素E合成酶-1（m PGES-1）酶的抑制剂，因此在治疗来自多种疾病或状况的疼痛和/或炎症方面非常有用，如哮喘、骨关节炎、风湿性关节炎、急性或慢性疼痛和神经退行性疾病。

  公开号：

  WO2013153535A1

文献信息

• [EN] 4-(AMINOMETHYL)-PIPERIDINE BENZAMIDES AS 5HT4-ANTAGONISTS<br/>[FR] 4-(AMINOMETHYL)-PIPERIDINE BENZAMIDES SERVANT D'ANTAGONISTES DE 5HT4
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005000838A1

  公开（公告）日：2005-01-06

  The present invention is concerned with novel compounds of formula (I) having 5HT4-antagonistic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.

  本发明涉及具有5HT4拮抗性质的式(I)的新化合物。该发明还涉及制备这种新化合物的方法，包括将该新化合物作为药物的药物组合物以及该化合物的药用用途。
• [EN] MDM2 DEGRADERS AND USES THEREOF<br/>[FR] AGENTS DE DÉGRADATION DE MDM2 ET LEURS UTILISATIONS
  申请人：KYMERA THERAPEUTICS INC

  公开号：WO2021188948A1

  公开（公告）日：2021-09-23

  The present invention relates to compounds and methods useful for the modulation of mouse double minute 2 homolog ("MDM2") protein via ubiquitination and/or degradation by compounds according to the present invention.

  本发明涉及化合物和方法，通过本发明的化合物对小鼠双分子2同源蛋白（"MDM2"）蛋白进行泛素化和/或降解的调节。
• Rapid Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide Promoted by Solid Inorganic-Bases in DMF
  作者：Lisheng Cai、Rong Xu、Xuelei Guo、Victor W. Pike

  DOI：10.1002/ejoc.201101499

  日期：2012.3

  substrates with no-carrier-added [11C]methyl iodide in DMF at room temperature to give 11C-methylated products in useful radiochemical yields. In particular, we discovered that some primary arylamines in Li3N-DMF were converted into their formanilides, and that these were readily N-methylated with [11C]methyl iodide, preceding easy basic hydrolysis to the desired [11C]N-methyl secondary arylamines. Use

  11[C] 甲基碘是使用碳 11（t1/2 = 20.4 分钟）标记放射性示踪剂的最广泛使用的试剂，用于正电子发射断层扫描的分子成像。然而，一些用于标记的底物，尤其是伯芳胺和吡咯，对 [11C] 甲基碘反应缓慢。我们发现不溶性无机碱，尤其是 Li3N 或 Li2O，可有效促进此类底物与未添加载体的 [11C] 碘甲烷在室温下在 DMF 中的快速反应，从而得到有用的 11C 甲基化产物。放射化学产率。特别是，我们发现 -DMF 中的一些伯芳胺转化为它们的甲酰苯胺，并且它们很容易被 [11C] 甲基碘 N-甲基化，然后容易碱性水解成所需的 [11C]N-甲基仲芳胺。固体碱的使用允许在芳氨基上进行选择性反应，并且在某些情况下还避免了不希望的副反应，例如酯基水解。事实证明，超声波装置可用于远程和持续搅拌放射性异质反应混合物，但不会产生“超声波特异性”化学效应。
• Tricyclic heterocyclic compounds as 5-HT.sub.4 receptor antagonists
  申请人：SmithKline Beecham plc

  公开号：US05705509A1

  公开（公告）日：1998-01-06

  Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X.sub.1 --(CH.sub.2).sub.x --X.sub.2 and the aromatic carbon atoms to which they are attached form 5-7 membered ring wherein X.sub.1 is O or S; X.sub.2 is O, S, NR.sub.5 or NR.sub.6 CO wherein R.sub.5 is hydrogen or C.sub.1-6 alkyl; or one of X.sub.1 and X.sub.2 is O, S or CH.sub.2 and the other is CH.sub.2 ; x is 1, 2 or 3; R.sub.1 and R.sub.2 together are Q--CH.sub.2 --CH.sub.2, Q--CH.dbd.CH, or Q--CH.dbd.N where Q is linked either to the R.sub.1 or the R.sub.2 substitution position and Q is O, S or NR.sub.t wherein R.sub.t is hydrogen or C.sub.1-6 alkyl; R.sub.3 is hydrogen halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino; R.sub.4.sup.1 and R.sub.4.sup.2 are independently hydrogen or C.sub.1-6 alkyl; Y is O or NH; Z is of sub-formula (a), (b) or (c) and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders. ##STR1##

  化合物的式子（I）或其药学上可接受的盐，其中X.sub.1--(CH.sub.2).sub.x--X.sub.2和它们所连接的芳香碳原子形成5-7元环，其中X.sub.1是O或S；X.sub.2是O，S，NR.sub.5或NR.sub.6 CO，其中R.sub.5是氢或C.sub.1-6烷基；或者X.sub.1和X.sub.2中的一个是O，S或CH.sub.2，另一个是CH.sub.2；x为1、2或3；R.sub.1和R.sub.2在一起是Q--CH.sub.2--CH.sub.2，Q--CH.dbd.CH或Q--CH.dbd.N，其中Q链接到R.sub.1或R.sub.2取代位置之一，Q为O，S或NR.sub.t，其中R.sub.t为氢或C.sub.1-6烷基；R.sub.3为氢卤素，C.sub.1-6烷基，C.sub.1-6烷氧基或氨基；R.sub.4.sup.1和R.sub.4.sup.2分别为氢或C.sub.1-6烷基；Y为O或NH；Z为亚式（a）、（b）或（c）的亚基，并用作治疗胃肠道疾病、心血管疾病和中枢神经系统疾病的药物。
• Discovery of 2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitor
  作者：Nagarajan Muthukaman、Sanjay Deshmukh、Neelam Sarode、Shital Tondlekar、Macchindra Tambe、Dnyandeo Pisal、Mahamadhanif Shaikh、Vidya G. Kattige、Srinivasa Honnegowda、Vikas Karande、Abhay Kulkarni、Satyawan B. Jadhav、Mahamad Yunnus A. Mahat、Girish S. Gudi、Neelima Khairatkar-Joshi、Laxmikant A. Gharat

  DOI：10.1016/j.bmcl.2016.10.079

  日期：2016.12

  The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d (24(2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)pheny1)-1-methy1-7,8-dihydro-1H- [1,4]dioxino[2',3':3,4]benzo[1,2-dlimidazole-5-carboxamide) exhibited excellent mPGES-1 enzyme (IC50: 8 nM), cell (A549 IC50: 16.24 nM) and human whole blood potency (IC50: 249.9 nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79 nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7 mg/kg, respectively. (C) 2016 Elsevier Ltd. All rights reserved.