(R)-4-methyl-6-(3-methylazetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one trifluoroacetic acid | 1613717-27-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: (R)-4-methyl-6-(3-methylazetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one trifluoroacetic acid
• 英文别名: (R)-1-methyl-9-((3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid；(1R)-1-methyl-9-[(3-methylazetidin-3-yl)amino]-8-(trifluoromethyl)-3,5-dihydro-1H-[1,2,4]triazino[3,4-c][1,4]benzoxazin-2-one;2,2,2-trifluoroacetic acid
• CAS: 1613717-27-3
• 化学式: C₂HF₃O₂*C₁₆H₁₈F₃N₅O₂
• 分子量: 483.37
• InChiKey: MVAWKOQMNONEDT-DDWIOCJRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.14
• 重原子数：
  33
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  115
• 氢给体数：
  4
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 (R)-4-methyl-6-(3-methylazetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one trifluoroacetic acid 在 溶剂黄146 、 sodium cyanoborohydride 作用下， 以 甲醇 为溶剂， 反应 5.5h， 以12%的产率得到(R)-4-methyl-6-[methyl-(1,3-dimethylazetidin-3-yl)-amino]-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one trifluoroacetic acid
  参考文献：
  名称：

  Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis

  摘要：

  We previously demonstrated that selective inhibition of protein kinase C theta (PKC theta) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKC theta inhibition alone is insufficient for complete efficacy in this rodent arthritis model.

  DOI：

  10.1021/jm5013006
• 作为产物：
  描述：

  6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanylethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one 在 四丁基氟化铵 、 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 27.0h， 生成 (R)-4-methyl-6-(3-methylazetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triazaphenanthren-3-one trifluoroacetic acid
  参考文献：
  名称：

  TRIAZINONE COMPOUNDS

  摘要：

  本发明提供了一种公式(I)的化合物，其中变量如本文所述定义。所述化合物的药用盐、前药、生物活性代谢物、立体异构体和同分异构体。本发明的化合物可用于治疗免疫学和肿瘤学疾病。

  公开号：

  US20140206663A1

文献信息

• TRIAZINONE COMPOUNDS
  申请人：Wang Jianfei

  公开号：US20140206663A1

  公开（公告）日：2014-07-24

  The invention provides a compound of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

  本发明提供了一种公式(I)的化合物，其中变量如本文所述定义。所述化合物的药用盐、前药、生物活性代谢物、立体异构体和同分异构体。本发明的化合物可用于治疗免疫学和肿瘤学疾病。
• Substituted 2,10-dihydro-9-oxa-1,2,4A-triazaphenanthren-3-ones and uses thereof
  申请人：George Dawn M.

  公开号：US09115151B2

  公开（公告）日：2015-08-25

  The invention provides a compound of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

  本发明提供了公式（I）的化合物，其包括药物可接受的盐、前药、生物活性代谢物、立体异构体和同分异构体，其中所述变量在此定义。本发明的化合物可用于治疗免疫和肿瘤疾病。
• US9115151B2
  申请人：——

  公开号：US9115151B2

  公开（公告）日：2015-08-25
• [EN] TRIAZINONE COMPOUNDS<br/>[FR] COMPOSÉS TRIAZINONES
  申请人：ABBVIE INC

  公开号：WO2014089904A1

  公开（公告）日：2014-06-19

  The invention provides a compound of Formula (I), pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.
• Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit
  作者：Dawn M. George、Eric C. Breinlinger、Michael Friedman、Yang Zhang、Jianfei Wang、Maria Argiriadi、Pratima Bansal-Pakala、Martine Barth、David B. Duignan、Prisca Honore、QingYu Lang、Scott Mittelstadt、Dominique Potin、Lian Rundell、Jeremy J. Edmunds

  DOI：10.1021/jm500669m

  日期：2015.1.8

  Protein kinase C theta (PKC theta) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKC theta inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.