(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 | 900180-04-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (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
• CAS: 900180-04-3
• 化学式: C₁₆H₂₀O₆
• 分子量: 308.331
• InChiKey: ARJSBMNGADVTBW-WECGXBHGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 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,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 、 四(三苯基膦)钯 盐酸 、 正丁基锂 、 氯化亚砜 、 氢气 、 三正丁基氢锡 作用下， 以 四氢呋喃 、 正己烷 、 乙酸乙酯 、 丙酮 、 甲苯 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 反应 53.17h， 生成 (3R,3aS,4S,4aR,8aR,9aR)-octahydro-3-methyl-4-[(E)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]naphtho[2,3-c]furan-1,7(3H,4H)-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：

  benzyl (1'R,3'aS,8'aS,9'S,9'aR)-1'-methyl-3'-oxospiro[1,3-dioxolane-2,6'-1,3a,5,7,8,8a,9,9a-octahydrobenzo[f][2]benzofuran]-9'-carboxylate 在 palladium on activated charcoal 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 2.0h， 生成 (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
  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

• EXO-SELECTIVE SYNTHESIS OF HIMBACINE ANALOGS
  申请人：Thiruvengadam Tiruvettipuram K.

  公开号：US20120142914A1

  公开（公告）日：2012-06-07

  This application discloses a novel process for the synthesis of himbacine analogs, as well as the compounds produced thereby. The synthesis proceeds by alternative routes including the cyclic ketal amide route, the chiral carbamate amide route, and the chiral carbamate ester route. The compounds produced thereby are useful as thrombin receptor antagonists. The chemistry disclosed herein is exemplified in the following synthesis sequence:

  这个应用程序披露了一种合成Himbacine类似物的新工艺，以及由此产生的化合物。合成可以通过替代路线进行，包括环状酮缩酰胺路线、手性氨基甲酸酯路线和手性氨基甲酸酰路线。由此产生的化合物可用作凝血酶受体拮抗剂。本文披露的化学在以下合成序列中得到了示范：
• US7541471B2
  申请人：——

  公开号：US7541471B2

  公开（公告）日：2009-06-02
• US8273790B2
  申请人：——

  公开号：US8273790B2

  公开（公告）日：2012-09-25