N-[2-(2-hydroxyethoxy)-6-[(4-methoxybenzoyl)amino]phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide | 719994-87-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[2-(2-hydroxyethoxy)-6-[(4-methoxybenzoyl)amino]phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide
• CAS: 719994-87-3
• 化学式: C₂₉H₃₄N₄O₅
• 分子量: 518.613
• InChiKey: VGWZNBYCFHUGJL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[2-(2-hydroxyethoxy)-6-[(4-methoxybenzoyl)amino]phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 以107 mg的产率得到N-[3-(2-hydroxyethoxy)-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl]-4-methoxybenzamide hydrochloride
  参考文献：
  名称：

  Discovery of N-[2-Hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor

  摘要：

  Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound la that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of la without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 141 is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

  DOI：

  10.1021/jm200868m
• 作为产物：
  描述：

  N-[2-羟基-6-(4-甲氧基苯甲酰氨基)苯基]-4-(4-甲基-1,4-二氮杂庚烷-1-基)苯甲酰胺 在 盐酸 、 甲醇 、 sodium tetrahydroborate 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 20.0~100.0 ℃ 、293.86 kPa 条件下， 反应 26.0h， 生成 N-[2-(2-hydroxyethoxy)-6-[(4-methoxybenzoyl)amino]phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide
  参考文献：
  名称：

  Discovery of N-[2-Hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor

  摘要：

  Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound la that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of la without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 141 is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

  DOI：

  10.1021/jm200868m

文献信息

• US7307074B2
  申请人：——

  公开号：US7307074B2

  公开（公告）日：2007-12-11
• USRE43481E1
  申请人：——

  公开号：USRE43481E1

  公开（公告）日：2012-06-19