9-(6-aminopyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 9-(6-aminopyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-one
• 英文别名: 9-(6-aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-4H-pyrimido[5,4-c][1,5]naphthyridin-2-one
• 化学式: C₂₃H₁₇F₃N₆O
• 分子量: 450.423
• InChiKey: HZGZOVZQRGKICN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  33
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  88.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-溴-5-硝基吡啶 在 盐酸 、 manganese(IV) oxide 、 sodium tetrahydroborate 、 四(三苯基膦)钯 、 铁粉 、 碳酸氢钠 、 sodium carbonate 、 potassium carbonate 、 三乙胺 、 三氯氧磷 作用下， 以 二苯醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基苯胺 、 甲苯 、 叔丁醇 为溶剂， 反应 78.75h， 生成 9-(6-aminopyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-one
  参考文献：
  名称：

  THREE-RING PI3K AND/OR MTOR INHIBITOR

  摘要：

  公开号：

  EP2781520B1

文献信息

• [EN] THREE-RING PI3K AND/OR MTOR INHIBITOR<br/>[FR] INHIBITEUR TRICYCLIQUE DE PI3K ET/OU MTOR
  申请人：XUANZHU PHARMA CO LTD

  公开号：WO2013071698A1

  公开（公告）日：2013-05-23

  本申请涉及通式（I）所示的化合物、其药学上可接受的盐、酯、溶剂化物或它们的立体异构体，这些化合物的制备方法，含有这些化合物的药物组合物，这些化合物在制备治疗和/或预防增殖性疾病的药物中的应用，以及使用这些化合物治疗或预防增殖性疾病的方法。式中R1、R2、R3、R4、R5、R6、X、A和B如说明书中所定义。
• Developing a novel dual PI3K&amp;ndash;mTOR inhibitor from the prodrug of a metabolite
  作者：Yan Zhou、Genyan Zhang、Feng Wang、Jin Wang、Yanwei Ding、Xinyu Li、Chongtie Shi、Jiakui Li、Chengkon Shih、Song You

  DOI：10.2147/ott.s142492

  日期：——

  This study presents a process of developing a novel PI3K-mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future.
• US9284315B2
  申请人：——

  公开号：US9284315B2

  公开（公告）日：2016-03-15