(3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-yl]piperidine-1-carboxylic acid tert-butyl ester | 1613721-60-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-yl]piperidine-1-carboxylic acid tert-butyl ester
• 英文别名: (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid tert-butyl ester；tert-butyl (3R,4R)-3-methyl-4-[(1R)-1-methyl-2-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydro-1H-[1,2,4]triazino[3,4-c][1,4]benzoxazin-9-yl]piperidine-1-carboxylate
• CAS: 1613721-60-0
• 化学式: C₂₈H₄₁BN₄O₆
• 分子量: 540.468
• InChiKey: JXKGPFXIBMMNCS-RCCFBDPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.38
• 重原子数：
  39
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-yl]piperidine-1-carboxylic acid tert-butyl ester 在 盐酸 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 水 、 乙酸乙酯 为溶剂， 反应 1.0h， 生成 (R)-7-(2,6-difluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one
  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：

  3-甲基-4-氧代哌啶-1-羧酸叔丁酯 在 potassium phosphate 、 四(三苯基膦)钯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 palladium 10% on activated carbon 、 氢气 、 potassium acetate 、 tetra-N-butylammonium tribromide 、 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， -78.0~90.0 ℃ 、101.33 kPa 条件下， 反应 23.0h， 生成 (3R,4R)-3-methyl-4-[(R)-4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-yl]piperidine-1-carboxylic acid tert-butyl ester
  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

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.

  该发明提供了公式(I)的化合物，其药学上可接受的盐，前药，生物活性代谢物，立体异构体和同分异构体，其中变量在此定义。该发明的化合物可用于治疗免疫和肿瘤病症。
• 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。
• Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis
  作者：Dawn M. George、Eric C. Breinlinger、Maria A. Argiriadi、Yang Zhang、Jianfei Wang、Pratima Bansal-Pakala、David B. Duignan、Prisca Honore、QingYu Lang、Scott Mittelstadt、Lian Rundell、Annette Schwartz、Jiakang Sun、Jeremy J. Edmunds

  DOI：10.1021/jm5013006

  日期：2015.1.8

  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.