9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione

• 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)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione
• 英文别名: 9-(6-aminopyridin-3-yl)-1-[3-(trifluoromethyl)phenyl]pyrimido[5,4-c][1,5]naphthyridine-2,4-dione
• 化学式: C₂₂H₁₃F₃N₆O₂
• 分子量: 450.379
• InChiKey: OIOOKLQHEDGJOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  33
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione 在 potassium carbonate 、 三氟乙酸 、 potassium iodide 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 生成 (9-(6-aminopyridin-3-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyrimidino[5,4-c][1,5]naphthyridine-3(4H)-yl)methyldihydrophosphate
  参考文献：
  名称：

  Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite

  摘要：

  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.

  DOI：

  10.2147/ott.s142492
• 作为产物：
  描述：

  ethyl 6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate 在 四(三苯基膦)钯 、 氯化亚砜 、 ammonium cerium (IV) nitrate 、 水 、 potassium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 乙腈 为溶剂， 反应 168.0h， 生成 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione
  参考文献：
  名称：

  PI3K AND/OR MTOR INHIBITOR

  摘要：

  本发明涉及一种具有式（I）的化合物，或其药学上可接受的盐、立体异构体或溶剂化合物，其中R1、R2、R3、R4、X、Y、A和B如规范中所定义。本发明还涉及一种制备这些化合物的方法，含有这些化合物的药物组合物，以及利用这些化合物制造用于治疗和/或预防增殖性疾病的药物的用途。

  公开号：

  US20150239885A1

文献信息

• PI3K and/or mTOR inhibitor
  申请人：XUANZHU PHARMA CO., LTD.

  公开号：US09365572B2

  公开（公告）日：2016-06-14

  The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, a stereoisomer or a solvate thereof, wherein R1, R2, R3, R4, X, Y, A and B are as defined in the specification. The present invention further relates to a method for preparing these compounds, a pharmaceutical composition containing these compounds, and a use of these compounds in manufacture of a medicament for treating and/or preventing proliferative diseases.

  本发明涉及式（I）的化合物，或其药学上可接受的盐、立体异构体或溶剂化物，其中R1、R2、R3、R4、X、Y、A和B如规范中所定义。本发明还涉及制备这些化合物的方法，含有这些化合物的制药组合物，以及使用这些化合物制造治疗和/或预防增殖性疾病的药物的用途。
• [EN] PI3K AND/OR MTOR INHIBITOR<br/>[FR] INHIBITEUR DE PI3K ET/OU DE MTOR
  申请人：XUANZHU PHARMA CO LTD

  公开号：WO2014040373A1

  公开（公告）日：2014-03-20

  提供一类通式（I）化合物、其药学上可接受的盐、立体异构体和溶剂化物，以及其制备方法和含有通式（I）化合物的药物组合物。还提供这些化合物制备治疗和/或预防增殖性疾病的药物中的应用。
• [EN] PI3K AND/OR mTOR INHIBITOR PRODRUG<br/>[FR] PROMÉDICAMENT INHIBITEUR DE PI3K ET/OU MTOR
  申请人：XUANZHU PHARMA CO LTD

  公开号：WO2014154026A1

  公开（公告）日：2014-10-02

  提供一种通式（I）所示的化合物、其药学上可接受的盐和立体异构体，以及含有通式（I）化合物的药物组合物。还提供这些化合物、其药学上可接受的盐和立体异构体在制备治疗和/或预防增殖性疾病的药物中的用途。
• US9365572B2
  申请人：——

  公开号：US9365572B2

  公开（公告）日：2016-06-14
• PI3K AND/OR MTOR INHIBITOR
  申请人：Xuanzhu Pharma Co., Ltd.

  公开号：EP2896622B1

  公开（公告）日：2017-05-03