Darexaban glucuronide | 432029-12-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: Darexaban glucuronide
• 英文别名: 3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl β-D-glucopyranosiduronic acid；(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[3-[(4-methoxybenzoyl)amino]-2-[[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino]phenoxy]oxane-2-carboxylic acid
• CAS: 432029-12-4
• 化学式: C₃₃H₃₈N₄O₁₀
• 分子量: 650.686
• InChiKey: IOUMBCGOXOKZAE-CLIYFGAVSA-N

物化性质

• 沸点：
  778.9±60.0 °C(Predicted)
• 密度：
  1.436±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  47
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  190
• 氢给体数：
  6
• 氢受体数：
  12

制备方法与用途

Darexaban葡萄糖醛酸是人体口服Darexaban后血浆中的主要成分。Darexaban（YM150）是一种直接针对因子Xa的抑制剂。

反应信息

• 作为产物：
  描述：

  2-氨基-3-硝基苯酚 在 吡啶 、 palladium 10% on activated carbon 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 甲醇 、 氯仿 、 乙腈 为溶剂， 5.0~70.0 ℃ 、101.33 kPa 条件下， 反应 118.0h， 生成 Darexaban glucuronide
  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

• SUBSTITUTED BENZENE DERIVATIVES OR SALTS THEREOF
  申请人：Ishihara Tsukasa

  公开号：US20090137498A1

  公开（公告）日：2009-05-28

  There are provided compounds having an anticoagulant action on the basis of inhibition of activated blood coagulation factor X and being useful as anticoagulants or preventive/therapeutic agents for diseases induced by thrombosis or embolism. Effective ingredients are the compounds such as 4′-bromo-2′-[(5-chloro-2-pyridyl)carbamoyl]-6′-β-D-galactopyranosyloxy-1-isopropylpiperidine-4-carboxanilide, 2′-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-4′-bromo-6′-[(5-chloro-2-pyridyl)carbamoyl]-1-isopropylpiperidine-4-carboxanilide, etc. or salts thereof.

  提供了一些化合物，基于抑制活化的血液凝血因子X，具有抗凝作用，并可用作抗凝剂或预防/治疗由血栓形成或栓塞引起的疾病的药物。有效成分是化合物，例如4'-溴-2'-[(5-氯-2-吡啶基)氨基甲酰基]-6'-β-D-半乳糖苷氧基-1-异丙基哌啶-4-羧酰胺，2'-(2-乙酰氨基-2-脱氧-β-D-葡萄糖苷氧基)-4'-溴-6'-[(5-氯-2-吡啶基)氨基甲酰基]-1-异丙基哌啶-4-羧酰胺等或其盐。
• US7504417B2
  申请人：——

  公开号：US7504417B2

  公开（公告）日：2009-03-17
• US7786106B2
  申请人：——

  公开号：US7786106B2

  公开（公告）日：2010-08-31
• Discovery of <i>N</i>-[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
  作者：Fukushi Hirayama、Hiroyuki Koshio、Tsukasa Ishihara、Shunichiro Hachiya、Keizo Sugasawa、Yuji Koga、Norio Seki、Ryouta Shiraki、Takeshi Shigenaga、Yoshiyuki Iwatsuki、Yumiko Moritani、Kenichi Mori、Takeshi Kadokura、Tomihisa Kawasaki、Yuzo Matsumoto、Shuichi Sakamoto、Shin-ichi Tsukamoto

  DOI：10.1021/jm200868m

  日期：2011.12.8

  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.