3-(4-fluoro-2-hydroxyphenylamino)-6H-dibenzo[b,e]oxepine-11-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: 3-(4-fluoro-2-hydroxyphenylamino)-6H-dibenzo[b,e]oxepine-11-one
• 英文别名: 3-(2,4-difluoro-phenylamino)-6,11-dihydrodibenzo[b,e]oxepin-11-one；3-(2,4-Difluoro-phenylamino)-6H-dibenzo[b,e]oxepin-11-one；3-(2,4-difluoroanilino)-6H-benzo[c][1]benzoxepin-11-one
• 化学式: C₂₀H₁₃F₂NO₂
• 分子量: 337.326
• InChiKey: JELAHDQPMBHMAI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(4-fluoro-2-hydroxyphenylamino)-6H-dibenzo[b,e]oxepine-11-one 在 baculovirus cDNA-expressed isoenzymes (Supersomes) of CYP₂B₆ with P₄₅₀ reductase 作用下， 生成 3-((2-fluoro-4-hydroxyphenyl)amino)dibenzo[b,e]oxepin-11(6H)-one
  参考文献：
  名称：

  Metabolism of a novel skepinone l-like p38 mitogen-activated protein kinase inhibitor

  摘要：

  p38 丝裂原激活蛋白激酶 (MAPK) 是细胞因子诱导的信号转导事件中的关键介质，并响应各种细胞外刺激（例如应激因子、紫外线和炎症细胞因子）而被激活。因此，p38 MAP 激酶在肿瘤发生、免疫紊乱和炎症过程等疾病状态中发挥着不可或缺的作用。最近，一类新型高选择性 p38α 抑制剂被描述和表征为体内研究的工具和探针。当前研究的目的是 3-((2,4-二氟苯基)氨基)二苯并[b,e]oxepin-11(6H)-one（一种有效的 p38α MAP 激酶抑制剂）的临床前表征。在大鼠和人肝微粒体孵育中，所检测的化合物通过 CYP2B6 介导的第 1 相代谢完全失活（考虑到分离的 p38α 酶的抑制效力）。发现 2,4-二氟苯基残基对位的脱卤和随后的羟基化是主要的转化。在两个物种中均检测到不同数量的代谢物。在连续反应中，第一相代谢物与葡萄糖醛酸结合，形成第二相代谢。相关同工酶被鉴定为 UGT1A3、UGT1A9 和 UGT1A10。在此反应中，UGT1A10 是转化的主要驱动力。与第一相代谢物类似，在两个受检物种中也发现了不同量的缀合物。

  DOI：

  10.1039/c4md00106k
• 作为产物：
  描述：

  3-氟苯酚 在 sodium hydride 作用下， 以 环丁砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.5h， 生成 3-(4-fluoro-2-hydroxyphenylamino)-6H-dibenzo[b,e]oxepine-11-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Phenylamino-Substituted 6,11-Dihydro-dibenzo[b,e]oxepin-11-ones and Dibenzo[a,d]cycloheptan-5-ones:  Novel p38 MAP Kinase Inhibitors

  摘要：

  The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.

  DOI：

  10.1021/jm061072p

文献信息

• Dibenzocycloheptane compounds and pharmaceuticals containing these compounds
  申请人：Laufer Stefan

  公开号：US20090105327A1

  公开（公告）日：2009-04-23

  The present invention relates to compounds of the formula I in which R1, R2, R3, R4, X and Y have the meanings indicated in the description. These compounds have immunomodulating effects, as well as an inhibiting or regulating effect on the release of IL-1β and/or TNF-α. They can therefore be used for the treatment of diseases associated with a disturbance of the immune system.

  本发明涉及式I的化合物，其中R1、R2、R3、R4、X和Y具有描述中所示的含义。这些化合物具有免疫调节作用，以及对IL-1β和/或TNF-α的释放具有抑制或调节作用。因此，它们可用于治疗与免疫系统紊乱相关的疾病。
• DIBENZOCYCLOHEPTANVERBINDUNGEN UND PHARMAZEUTISCHE MITTEL, WELCHE DIESE VERBINDUNGEN ENTHALTEN
  申请人：MERCKLE GMBH

  公开号：EP1881968A2

  公开（公告）日：2008-01-30
• [DE] DIBENZOCYCLOHEPTANVERBINDUNGEN UND PHARMAZEUTISCHE MITTEL, WELCHE DIESE VERBINDUNGEN ENTHALTEN<br/>[EN] DIBENZOCYCLOHEPTANE COMPOUNDS AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS<br/>[FR] DIBENZOCYCLOHEPTANES ET AGENTS PHARMACEUTIQUES CONTENANT CES COMPOSES
  申请人：MERCKLE GMBH

  公开号：WO2006120010A2

  公开（公告）日：2006-11-16

  [EN] The present invention relates to compounds of formula (I), in which R1, R2, R3, R4, X and Y have the meanings indicated in the description. These compounds have immuno-modulating effects, as well as an inhibiting or regulating effect on the release of IL-1ß and/or TNF-a. They can therefore be used for the treatment of diseases associated with a disturbance of the immune system.
  [FR] La présente invention concerne des composés de formule (I), dans laquelle R1, R2, R3, R4, X et Y ont les significations indiquées dans la description. Ces composés possèdent une action immunomodulatrice et un effet d'inhibition ou de régulation de la libération de IL-1ß et/ou TNF-a. Ils peuvent donc être utilisés pour traiter des maladies liées à un trouble du système immunitaire.
  [DE] Die vorliegende Erfindung betrifft Verbindungen der Formel (I), worin R1, R2, R3, R4, X und Y die in der Beschreibung angegebenen Bedeutungen besitzen. Die Verbindungen besitzen immunmodulierende und die Freisetzung von IL-1ß und/oder TNF-a inhibierende bzw. regulierende Wirkung. Sie sind daher zur Behandlung von Erkrankungen brauchbar, die im Zusammenhang mit einer Störung des Immunsystems stehen.
  [EN] Dibenzocycloheptane compounds (I) and their salt and solvate and its salts, are new. Dibenzocycloheptane compounds of formula (I) and their salt and solvate and its salts, are new. Either X, Y1 : CH2, O, S, SO, SO2 or NR5; or X-Y1- : -(CH2)2- or -CH=CH-; R1 : H or 1-6C alkyl; R2 : H, halo or 1-4C alkyl-C?=C- (optionally substituted with amino group); R3 : -NH2, phenyl compound of formula (a) or (b), cyclohexane compound of formula (c), -NH-1-6C alkylene-NH2 or halo; either R4 : H, halo or 1-6C alkyl; or CR3R4 : phenyl ring, 5-6 membered aromatic or non-aromatic heterocyclic ring with heteroatom such as N (where the heterocyclic ring is substituted with one or two 1-6C alkyl group or is condensed with a cyclohexyl group); R5, R6 : H or 1-6C alkyl; R7 : H, NH2, mono-1-6C alkyl amino, di-1-6C alkylamino, 1-6C alkyl-CONH-, 1-6C alkyl-NHCONH-, 1-6C alkyl-O-CO-NH-, 1-6C alkyl, 1-6C alkoxy, NO2 or halo; R8 : H, NH2, mono-1-6C alkylamino, di-1-6C alkylamino, 1-6C alkoxy or halo; and R9 : H or NH2. [Image] [Image] - ACTIVITY : Immunosuppressive; Cytostatic; Antiarthritic; Antirheumatic; Litholytic; Antibacterial; Osteopathic; Neuroprotective; Anti-HIV; Virucide; Antidiabetic; Antiinflammatory; Vasotropic; Endocrine-Gen.; Antipsoriatic; Antiarteriosclerotic; Immunomodulator; Nootropic; Cerebroprotective; Antiulcer; Gastrointestinal-Gen.; Cardiovascular-Gen.; Cardiant; Respiratory-Gen.; Hepatotropic; CNS-Gen.; Dermatological. - MECHANISM OF ACTION : Interleukin-1beta inhibitor; Tumor necrosis factor-alpha inhibitor; Interleukin-1beta regulator; Tumor necrosis factor-alpha regulator. The ability of (I) to inhibit interleukin-1beta was tested using biological assays. The results showed that (I) exhibited an IC50 value of 1.8 mu M.
• Design, Synthesis, and Biological Evaluation of Phenylamino-Substituted 6,11-Dihydro-dibenzo[<i>b</i>,<i>e</i>]oxepin-11-ones and Dibenzo[<i>a</i>,<i>d</i>]cycloheptan-5-ones:  Novel p38 MAP Kinase Inhibitors
  作者：Stefan A. Laufer、Gabriele M. Ahrens、Solveigh C. Karcher、Jörg S. Hering、Raimund Niess

  DOI：10.1021/jm061072p

  日期：2006.12.1

  The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.
• Metabolism of a novel skepinone l-like p38 mitogen-activated protein kinase inhibitor
  作者：K. Storch、M. Gehringer、B. Baur、S. A. Laufer

  DOI：10.1039/c4md00106k

  日期：——

  The p38 mitogen-activated protein kinase (MAPK) is a key mediator in cytokine-induced signaling events and is activated in response to a variety of extracellular stimuli such as stress factors, UV-light and inflammatory cytokines. Therefore, the p38 MAP kinase plays an integral role in disease states including oncogenesis, immune disorders and inflammatory processes. Recently a novel class of highly selective p38α inhibitors was described and characterized as tools and probes for in vivo studies. The objective of the current study was the preclinical characterization of 3-((2,4-difluorophenyl)amino)dibenzo[b,e]oxepin-11(6H)-one, a potent p38α MAP kinase inhibitor. In rat and human hepatic microsomal incubations, the examined compound is completely inactivated (concerning the inhibitory potency of the isolated p38α enzyme) by a CYP2B6 mediated phase 1 metabolism. The dehalogenation and subsequent hydroxylation in the para position of the 2,4-difluorophenyl residue was found to be the predominant transformation. The metabolite was detected in different quantities in both species. In a consecutive reaction the phase 1 metabolite conjugates with glucuronic acid in terms of a phase 2 metabolism. The responsible isoenzymes were identified to be UGT1A3, UGT1A9 and UGT1A10. In this reaction UGT1A10 is the predominant driver of the conversion. Similar to the phase 1 metabolite, the conjugate could also be found in different amounts in both examined species.

  p38 丝裂原激活蛋白激酶 (MAPK) 是细胞因子诱导的信号转导事件中的关键介质，并响应各种细胞外刺激（例如应激因子、紫外线和炎症细胞因子）而被激活。因此，p38 MAP 激酶在肿瘤发生、免疫紊乱和炎症过程等疾病状态中发挥着不可或缺的作用。最近，一类新型高选择性 p38α 抑制剂被描述和表征为体内研究的工具和探针。当前研究的目的是 3-((2,4-二氟苯基)氨基)二苯并[b,e]oxepin-11(6H)-one（一种有效的 p38α MAP 激酶抑制剂）的临床前表征。在大鼠和人肝微粒体孵育中，所检测的化合物通过 CYP2B6 介导的第 1 相代谢完全失活（考虑到分离的 p38α 酶的抑制效力）。发现 2,4-二氟苯基残基对位的脱卤和随后的羟基化是主要的转化。在两个物种中均检测到不同数量的代谢物。在连续反应中，第一相代谢物与葡萄糖醛酸结合，形成第二相代谢。相关同工酶被鉴定为 UGT1A3、UGT1A9 和 UGT1A10。在此反应中，UGT1A10 是转化的主要驱动力。与第一相代谢物类似，在两个受检物种中也发现了不同量的缀合物。