3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-propenyl)benzonitrile | 337519-98-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-propenyl)benzonitrile
• 英文别名: 3-((E)-3-{4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]anilino}propenyl)benzonitrile；3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile；3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl)benzonitrile；tert-butyl 4-[4-[[(E)-3-(3-cyanophenyl)prop-2-enyl]amino]phenoxy]piperidine-1-carboxylate
• CAS: 337519-98-9
• 化学式: C₂₆H₃₁N₃O₃
• 分子量: 433.55
• InChiKey: XKFHSTBFQKDUPR-VMPITWQZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  74.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-propenyl)benzonitrile 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以62%的产率得到3-(3-{4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]anilino}propyl)benzonitrile
  参考文献：
  名称：

  The Discovery of YM-60828: A Potent, Selective and Orally-Bioavailable Factor Xa Inhibitor

  摘要：

  Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure-activity relationship (SAR) of the substituent (R-1) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R-1 showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative 8o (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00418-7
• 作为产物：
  描述：

  4-(4-硝基苯氧基)四氢-1(2H)-吡啶羧酸叔丁酯 在 palladium on activated charcoal 氢气 、 三乙酰氧基硼氢化钠 作用下， 以 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 18.75h， 生成 3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-propenyl)benzonitrile
  参考文献：
  名称：

  The Discovery of YM-60828: A Potent, Selective and Orally-Bioavailable Factor Xa Inhibitor

  摘要：

  Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure-activity relationship (SAR) of the substituent (R-1) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R-1 showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative 8o (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00418-7

文献信息

• Cinnamyl Derivatives: Synthesis and Factor Xa (FXa) Inhibitory Activities
  作者：Tetsuji Noguchi、Naoki Tanaka、Toyoki Nishimata、Riki Goto、Miho Hayakawa、Atsuhiro Sugidachi、Taketoshi Ogawa、Fumitoshi Asai、Koichi Fujimoto

  DOI：10.1248/cpb.56.758

  日期：——

  To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC50 values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).

  为了开发一种强效且可通过口服给药的抗凝剂，合成了一系列含有肉桂基部分的化合物，并检测了它们对因子Xa (FXa)的抑制活性。结果显示，一些肉桂基衍生物具有强效的FXa体外抑制活性。在这些化合物中，含有取代基位于中心苯环3-位的化合物，如(N-4-[1-(乙酰亚胺基)哌啶-4-氧基]-3-氯苯基}-N-[(E)-3-(3-氨基苯基)-2-丙烯基]磺酰胺)乙酸二盐酸盐(45b)和(N-4-[1-(乙酰亚胺基)哌啶-4-氧基]-3-羧酰胺苯基}-N-[(E)-3-(3-氨基苯基)-2-丙烯基]磺酰胺)乙酸二盐酸盐(45j)，表现出强效的FXa抑制活性，其IC50值在体外小于10 nM。这些化合物在体外和体外实验中均显示出强效的抗凝活性。此外，这些化合物没有致命毒性(30 mg/kg，静脉注射)。
• Benzamidine derivatives
  申请人：Sankyo Company, Limited

  公开号：US06555556B1

  公开（公告）日：2003-04-29

  Benzamidine derivatives of formula (I) or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against factor Xa and are useful for treating or preventing blood coagulation disorders: wherein R1 represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group; R2 represents a hydrogen atom, a halogen atom or an alkyl group, R3 represents a hydrogen atom, an optionally substituted alkyl group, an aralkyl group, an optionally substituted alkanoyl group or an optionally substituted alkylsulfonyl group, R4 and R5 are the same as or different from each other and each represent a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group or an optionally substituted carbamoyl group, and R6 represents a substituted pyrrolidine group or substituted piperidine group.

  Benzamidine衍生物的化学式(I)或其药学上可接受的盐对Xa因子表现出优异的抑制活性，并且可用于治疗或预防血液凝固紊乱：其中R1代表氢原子、卤素原子、烷基或羟基；R2代表氢原子、卤素原子或烷基，R3代表氢原子、可选择取代的烷基、芳基烷基、可选择取代的烷酰基或可选择取代的烷基磺酰基，R4和R5彼此相同或不同，各自代表氢原子、卤素原子、可选择取代的烷基、烷氧基、羧基、烷氧羰基或可选择取代的氨基羰基，R6代表取代的吡咯烷基或取代的哌啶基。
• Design and synthesis of aminophenol-Based factor xa inhibitors
  作者：Shung Wu、William J Guilford、Yuo-Ling Chou、Brian D Griedel、Amy Liang、Steve Sakata、Kenneth J Shaw、Lan Trinh、Wei Xu、Zuchun Zhao、Michael M Morrissey

  DOI：10.1016/s0960-894x(02)00142-7

  日期：2002.5

  A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure. (C) 2002 Elsevier Science Ltd. All rights reserved.
• BENZAMIDINE DERIVATIVES
  申请人：Sankyo Company, Limited

  公开号：EP1245564B1

  公开（公告）日：2006-04-05
• US6555556B1
  申请人：——

  公开号：US6555556B1

  公开（公告）日：2003-04-29