5-(8-chloro-4-methyl-1-oxophthalazin-2(1H)-yl)picolinic acid | 1338224-16-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 5-(8-chloro-4-methyl-1-oxophthalazin-2(1H)-yl)picolinic acid
• 英文别名: 5-(8-Chloro-4-methyl-1-oxophthalazin-2-yl)pyridine-2-carboxylic acid
• CAS: 1338224-16-0
• 化学式: C₁₅H₁₀ClN₃O₃
• 分子量: 315.716
• InChiKey: KJGMVTFISOPXCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  82.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine 、 5-(8-chloro-4-methyl-1-oxophthalazin-2(1H)-yl)picolinic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以68%的产率得到(R)-5-(8-chloro-4-methyl-1-oxophthalazin-2(1H)-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)picolinamide
  参考文献：
  名称：

  Discovery of Potent, Orally Bioavailable Phthalazinone Bradykinin B1 Receptor Antagonists

  摘要：

  The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.

  DOI：

  10.1021/jm200808v
• 作为产物：
  描述：

  5-氨基-2-吡啶羧酸 在 盐酸 、 氯化亚砜 、 硫酸 、 水 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 68.05h， 生成 5-(8-chloro-4-methyl-1-oxophthalazin-2(1H)-yl)picolinic acid
  参考文献：
  名称：

  Discovery of Potent, Orally Bioavailable Phthalazinone Bradykinin B1 Receptor Antagonists

  摘要：

  The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.

  DOI：

  10.1021/jm200808v