(1'R,3'aR,8'aS,9'S,9'aR)-1',3'a,5',7',8',8'a,9',9'a-octahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid phenylmethyl ester | 226916-25-2

• 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,8'aS,9'S,9'aR)-1',3'a,5',7',8',8'a,9',9'a-octahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid phenylmethyl ester
• 英文别名: benzyl (1'R,3'aR,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
• CAS: 226916-25-2
• 化学式: C₂₃H₂₆O₆
• 分子量: 398.456
• InChiKey: XCSIWISENMJVQK-CBFGRJNTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 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'aR)-1',3'a,5',7',8',8'a,9',9'a-octahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid phenylmethyl ester 在 platinum(IV) oxide 、 palladium on activated charcoal 、 四(三苯基膦)钯 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 、 甲苯 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 反应 38.17h， 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：

  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 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以13 g的产率得到(1'R,3'aR,8'aS,9'S,9'aR)-1',3'a,5',7',8',8'a,9',9'a-octahydro-1'-methyl-3'-oxo-spiro[1,3-dioxolane-2,6'(3'H)-naphtho[2,3-c]furan]-9'-carboxylic acid phenylmethyl 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

• THROMBIN RECEPTOR ANTAGONISTS
  申请人：Chackalamannil Samuel

  公开号：US20070179187A1

  公开（公告）日：2007-08-02

  Heterocyclic-substituted tricyclics of the formula or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional single bond; represents an optional double bond, n is 0-2; Q is cycloalkyl, optionally substituted by R 13 and R 14 ; R 13 and R 14 are independently selected from (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —OH, (C 1 -C 6 )alkoxy, R 27 -aryl(C 1 -C 6 )alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen and haloalkyl; or R 13 and R 14 together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms, Het is a mono- or bi-cyclic optionally substituted heteroaryl group; and B is a bond, alkylene, or optionally substituted alkenylene or alkynylene, wherein the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.

  公式为Heterocyclic-substituted tricyclics或其药学上可接受的盐，其中：虚线代表可选的单键；代表可选的双键，n为0-2；Q为环烷基，可选地由R13和R14取代；R13和R14独立地选择自（C1-C6）烷基，（C3-C8）环烷基，—OH，（C1-C6）烷氧基，R27-芳基（C1-C6）烷基，杂芳基，杂芳基烷基，杂环基，杂环基烷基，卤素和卤基；或R13和R14一起形成3-6个原子的螺环或杂螺环；Het是一个单环或双环的可选取代杂芳基基团；B为键，烷基，或可选取代的烯烃基或炔基，其中其余取代基如规范中所定义。还公开了含有这些化合物的制药组合物以及通过给予这些化合物治疗与血栓形成、动脉粥样硬化、再狭窄、高血压、心绞痛、心律失常、心力衰竭和癌症相关的疾病的方法。还声称与其他心血管药物的联合治疗。
• Tricyclic thrombin receptor antagonists
  申请人：Schering Corporation

  公开号：EP1860106A1

  公开（公告）日：2007-11-28

  Claimed is a process for the manufacture of compounds of the following general formula (II): wherein Rx represent a group selected from COOCH2CH3, SO2CH3, CONHCH3, and COCH3, comprising the step of reacting the compound of the following formula (α-13) with a compound of the general formula Rx-X, wherein X represents a leaving group and wherein Rx is as defined above. Also claimed is a process for the manufacture of pharmaceutical compositions comprising compounds of the following formula (II) or pharmaceutically acceptable salts or solvates thereof.

  所要求的是一种制造下列通式(II)化合物的工艺： 其中 Rx 代表选自 COOCH2CH3、SO2CH3、CONHCH3 和 COCH3 的基团、 包括使下式（α-13）化合物反应的步骤 与通式 Rx-X 的化合物反应，其中 X 代表离去基团，Rx 如上所定义。 还要求一种制造药物组合物的工艺，该组合物包含下式(Ⅱ)化合物或其药学上可接受的盐或溶液。
• TRICYCLIC THROMBIN RECEPTOR ANTAGONISTS
  申请人：Schering Corporation

  公开号：EP1495018B1

  公开（公告）日：2007-11-14
• US7304078B2
  申请人：——

  公开号：US7304078B2

  公开（公告）日：2007-12-04
• US7713999B2
  申请人：——

  公开号：US7713999B2

  公开（公告）日：2010-05-11