(1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)dodecahydronaphtho[2,3-c]furan-6-carboxylic acid | 618386-52-0

• 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: (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)dodecahydronaphtho[2,3-c]furan-6-carboxylic acid
• 英文别名: (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-carboxylic acid
• CAS: 618386-52-0
• 化学式: C₂₈H₂₈F₃NO₄
• 分子量: 499.53
• InChiKey: ICPVGUVJWIBHSM-AKEUPDIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  76.5
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-氨基吡啶 、 (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)dodecahydronaphtho[2,3-c]furan-6-carboxylic acid 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-N-pyridin-4-yl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-carboxamide
  参考文献：
  名称：

  Himbacine-Derived Thrombin Receptor Antagonists: C₇-Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

  摘要：

  We have synthesized several C-7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K-i = 5 nM). We have also synthesized a C-9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K-i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.

  DOI：

  10.1021/ml400452v
• 作为产物：
  描述：

  (3R,3aS,4S,4aR,8aR,9aR)-7-(methoxymethylene)-3-methyl-4-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)decahydronaphtho[2,3-c]furan-1(3H)-one 在 盐酸 、 sodium dihydrogen phosphate 、 双氧水 、 sodium chloride 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 5.25h， 生成 (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-((E)-2-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)vinyl)dodecahydronaphtho[2,3-c]furan-6-carboxylic acid
  参考文献：
  名称：

  Himbacine-Derived Thrombin Receptor Antagonists: C₇-Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

  摘要：

  We have synthesized several C-7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K-i = 5 nM). We have also synthesized a C-9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K-i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.

  DOI：

  10.1021/ml400452v

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。
• 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
• Himbacine-Derived Thrombin Receptor Antagonists: C₇-Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar
  作者：Mariappan V. Chelliah、Samuel Chackalamannil、Yan Xia、William J. Greenlee、Ho-Sam Ahn、Stan Kurowski、George Boykow、Yunsheng Hsieh、Madhu Chintala

  DOI：10.1021/ml400452v

  日期：2014.2.13

  We have synthesized several C-7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K-i = 5 nM). We have also synthesized a C-9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K-i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.