tert-butyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-yl]-N-ethoxycarbonylcarbamate | 618386-42-8

• 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: tert-butyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-yl]-N-ethoxycarbonylcarbamate
• CAS: 618386-42-8
• 化学式: C₃₄H₄₁FN₂O₆
• 分子量: 592.708
• InChiKey: GJGDLBXDVORODE-KBYIROEVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  95
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-yl]-N-ethoxycarbonylcarbamate 在 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.5h， 生成 ethyl ((1R,3aS,4aS,6R,8aR,9S,9aR)-9-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-3a-hydroxy-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate
  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：

  沃拉帕沙 、 二碳酸二叔丁酯 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 6.0h， 以0.86 g的产率得到tert-butyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-yl]-N-ethoxycarbonylcarbamate
  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：EP1982984A2

  公开（公告）日：2008-10-22

  Heterocyclic-substituted tricyclics of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional single bond; (a) represents an optional double bond; n is 0-2; Q is cycloalkyl, optionally substituted by R13 and R14; each R13 is independently selected from H, (C1-C6)alkyl, (C3-C8)cycloalkyl, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, -(CH2)n6NHSO2NR4R5, and -(CH2)n6C(O)NR28R29 where n6 is 0-4, haloalkyl and halogen; each R14 is independently selected from H, (C1-C6)alkyl, -OH, (C1-C6)alkoxy, R27-aryl (C1-C6)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylallryl, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, -(CH2)n6NHSO2NR4R5, and -(CH2)n6C(O)NR28R29 where n6 is 0-4, halogen and haloalkyl; or R13 and R14 taken together form a spirocyclic or a hetetospirocyclic ring of 3-6 atoms; wherein at least one of R13 or R14 is selected from the group consisting of -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, -(CH2)n6NHSO2NR4R5, and -(CH2)n6C(O)NR28R29 where n6 is 0-4; 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.

  式(I)的杂环取代的三环化合物或其药学上可接受的盐，其中虚线代表任选的单键； (a) 代表任选的双键； n 是 0-2； Q 是环烷基，任选被 R13 和 R14 取代；每个 R13 独立选自 H、(C1-C6)烷基、(C3-C8)环烷基、-(CH2)n6NHC(O)OR16b、-( )n6NHC(O)R16b、-( )n6NHC(O)NR4R5、-( )n6NHSO2R16、-( )n6NHSO2NR4R5 和-( )n6C(O)NR28R29（其中 n6 为 0-4）、卤代烷基和卤素；每个 R14 都独立选自 H、(C1-C6)烷基、-OH、(C1-C6)烷氧基、R27-芳基 (C1-C6)烷基、杂芳基、杂芳烷基、杂环烷基、杂环芳烷基、-( )n6C(O)NR28R29，其中 n6 为 0-4、卤代烷基和卤素-( )n6NHC(O)OR16b、-( )n6NHC(O)R16b、-( )n6NHC(O)NR4R5、-( )n6NHSO2R16、-( )n6NHSO2NR4R5 和-( )n6C(O)NR28R29（其中 n6 为 0-4）、卤素和卤代烷基；或 R13 和 R14 共同形成 3-6 个原子的螺环或七螺环；其中 R13 或 R14 中至少有一个选自以下组成的组-( )n6NHC(O)OR16b、-( )n6NHC(O)R16b、-( )n6NHC(O)NR4R5、-( )n6NHSO2R16、-( )n6NHSO2NR4R5 和-( )n6C(O)NR28R29，其中 n6 为 0-4；Het 是单环或双环任选取代的杂芳基；和 B 是键、亚烷基或任选取代的烯基或亚炔基（其中其余取代基如说明书中所定义），本发明公开了含有这些化合物的药物组合物，以及通过施用所述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、心力衰竭和癌症有关的疾病的方法。还要求与其他心血管药物联合治疗。
• 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