3-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)acrylic acid methyl ester | 934618-58-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 3-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)acrylic acid methyl ester
• 英文别名: methyl (E)-3-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)prop-2-enoate
• CAS: 934618-58-3
• 化学式: C₁₂H₁₆O₄
• 分子量: 224.257
• InChiKey: XJHDCKZRYUETOW-AATRIKPKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)acrylic acid methyl ester 在 palladium on activated charcoal 、 四(三苯基膦)钯 盐酸 、 sodium hydroxide 、 正丁基锂 、 氯化亚砜 、 氢气 、 三正丁基氢锡 、 4-吡咯烷基吡啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 、 丙酮 、 甲苯 、 xylene 为溶剂， 215.0 ℃ 、101.33 kPa 条件下， 生成 (1R,3aR,4aS,8aS,9S,9aS)-1-methyl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-1,3a,4,4a,6,7,8,8a,9,9a-decahydrobenzo[f][2]benzofuran-3,5-dione
  参考文献：
  名称：

  Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

  摘要：

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

  DOI：

  10.1021/jm061043e
• 作为产物：
  描述：

  6-溴-1,4-二氧杂螺[4.5]癸-6-烯 、 丙烯酸甲酯（MA） 在 bis-triphenylphosphine-palladium(II) chloride 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以48%的产率得到3-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)acrylic acid methyl ester
  参考文献：
  名称：

  Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

  摘要：

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

  DOI：

  10.1021/jm061043e

文献信息

• Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist
  作者：Martin C. Clasby、Samuel Chackalamannil、Michael Czarniecki、Dario Doller、Keith Eagen、William Greenlee、Grace Kao、Yan Lin、Hsingan Tsai、Yan Xia、Ho-Sam Ahn、Jacqueline Agans-Fantuzzi、George Boykow、Madhu Chintala、Carolyn Foster、April Smith-Torhan、Kevin Alton、Matthew Bryant、Yunsheng Hsieh、Janice Lau、Jairam Palamanda

  DOI：10.1021/jm061043e

  日期：2007.1.1

  The metabolism of our prototypical thrombin receptor antagonist 1, K-i = 2.7 nM, was studied and three major metabolites (2,4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K-i = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.