(1'R,3'aR,4'aR,8'aR,9'S,9'aS)-decahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid | 226916-27-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并呋喃类
• 英文名称: (1'R,3'aR,4'aR,8'aR,9'S,9'aS)-decahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid
• 英文别名: (1R,3aR,4aR,8aR,9S,9aR)-1-Methyl-3-Oxodecahydro-3H-Spiro[Naphtho[2,3-c]Furan-6,2'-[1,3]Dioxolane]-9-；(1'R,3'aR,4'aR,8'aR,9'S,9'aR)-1'-methyl-3'-oxospiro[1,3-dioxolane-2,6'-1,3a,4,4a,5,7,8,8a,9,9a-decahydrobenzo[f][2]benzofuran]-9'-carboxylic acid
• CAS: 226916-27-4
• 化学式: C₁₆H₂₂O₆
• 分子量: 310.347
• InChiKey: ARRAXCRPHLPBNL-GRRRKWKPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  82.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1'R,3'aR,4'aR,8'aR,9'S,9'aS)-decahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid 在 四(三苯基膦)钯 正丁基锂 、 氯化亚砜 、 三正丁基氢锡 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 反应 21.17h， 生成 (1'R,3'aR,4'aR,8'aR,9'S,9'aS)-decahydro-1'-methyl-9'-[(E)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-spiro[1,3-dioxolane-26'(3'H)-naphtho[2,3-c]furan]-3'-one
  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：

  (1'R,3'aR,8'aS,9'S,9'aS)-1'-methyl-3'-oxospiro[1,3-dioxolane-2,6'-1,3a,5,7,8,8a,9,9a-octahydrobenzo[f][2]benzofuran]-9'-carboxylic acid 在 platinum(IV) oxide 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 16.0h， 生成 (1'R,3'aR,4'aR,8'aR,9'S,9'aS)-decahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid
  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

• WO2006/76564
  申请人：——

  公开号：——

  公开（公告）日：——
• SYNTHESIS OF HIMBACINE ANALOGS
  申请人：Schering Corporation

  公开号：EP1853592B1

  公开（公告）日：2011-03-02
• US7541471B2
  申请人：——

  公开号：US7541471B2

  公开（公告）日：2009-06-02
• US7626045B2
  申请人：——

  公开号：US7626045B2

  公开（公告）日：2009-12-01
• 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.