2-amino-3-nitrophenyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate hydrochloride | 365462-75-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 缩酚酸和缩酚酸环醚类
• 英文名称: 2-amino-3-nitrophenyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate hydrochloride
• 英文别名: (2-Amino-3-nitrophenyl) 4-(4-methyl-1,4-diazepan-1-yl)benzoate;hydrochloride
• CAS: 365462-75-5
• 化学式: C₁₉H₂₂N₄O₄*ClH
• 分子量: 406.869
• InChiKey: KHTXPRKFISNDNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.96
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-amino-3-nitrophenyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate hydrochloride 在 吡啶 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 甲醇 、 乙腈 为溶剂， 20.0~70.0 ℃ 、101.33 kPa 条件下， 反应 92.0h， 生成 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
  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：

  4-(4-methyl-1,4-diazepan-1-yl)benzoyl chloride hydrochloride 、 2-氨基-3-硝基苯酚 在 吡啶 、 碳酸氢钠 作用下， 以 乙腈 、 氯仿 、 水 为溶剂， 反应 21.0h， 以21.4 g的产率得到2-amino-3-nitrophenyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate 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

文献信息

• Diazepane derivatives or salts thereof
  申请人：——

  公开号：US20030195193A1

  公开（公告）日：2003-10-16

  To provide a compound which has an anticoagulation action based upon inhibition of activated blood coagulation factor X and is useful as an anticoagulant or an agent for prevention and treatment of diseases caused by thrombus or embolus. A diazepan derivative such as 4-[(3-carbamimidoylphenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoic acid and 3-hydroxy-4′methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide or a salt thereof is an effective ingredient.

  提供一种基于抑制活化的血液凝血因子X而具有抗凝作用的化合物，可用作抗凝剂或预防和治疗由血栓或栓塞引起的疾病的药物。4-[(3-羧基胍基苯基氨基)甲基]-3-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯甲酰氨基]苯甲酸和3-羟基-4′-甲氧基-2-{[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯甲酰]氨基}苯甲酰胺或其盐是有效成分。
• Diazepan derivatives or salts thereof
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：US20040068109A1

  公开（公告）日：2004-04-08

  To provide a compound which has an anticoagulation action based upon inhibition of activated blood coagulation factor X and is useful as an anticoagulant or an agent for prevention and treatment of diseases caused by thrombus or embolus. A diazepan derivative such as 4-[(3-carbamimidoylphenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoic acid and 3-hydroxy-4′-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide or a salt thereof is an effective ingredient.

  提供一种化合物，其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和治疗由血栓或栓子引起的疾病的药物。一种苯二氮平衍生物，例如4-[(3-氨基甲酰苯基)氨基甲基]-3-[(4-甲基-1,4-二氮平-1-基)苯甲酰氨基]苯甲酸和3-羟基-4'-甲氧基-2-[4-(4-甲基-1,4-二氮平-1-基)苯甲酰]氨基}苯甲酰苯胺或其盐是有效成分。
• DIAZEPANE DERIVATIVES OR SALTS THEREOF
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP1273575A1

  公开（公告）日：2003-01-08

  To provide a compound which has an anticoagulation action based upon inhibition of activated blood coagulation factor X and is useful as an anticoagulant or an agent for prevention and treatment of diseases caused by thrombus or embolus. A diazepan derivative such as 4-[(3-carbamimidoylphenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoic acid and 3-hydroxy-4'-methoxy-2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide or a salt thereof is an effective ingredient.

  提供一种化合物，它具有基于抑制活化的血液凝固因子 X 的抗凝作用，可用作抗凝剂或预防和治疗由血栓或栓子引起的疾病的药物。一种二氮杂卓衍生物，如 4-[(3-氨基甲酰基苯基氨基)甲基]-3-[4-(4-甲基-1,4-二氮杂卓-1-基)苯甲酰基氨基]苯甲酸和 3-羟基-4'-甲氧基-2-[4-(4-甲基-1,4-二氮杂卓-1-基)苯甲酰基]氨基}苯甲酰苯胺或其盐是一种有效成分。
• Diazepan derivatives useful as factor X inhibitor
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP1415990A1

  公开（公告）日：2004-05-06

  To provide a compound which has an anticoagulation action based upon inhibition of activated blood coagulation factor X and is useful as an anticoagulant or an agent for prevention and treatment of diseases caused by thrombus or embolus. A diazepan derivative such as 4-[(3-carbamimidoylphenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoic acid and 3-hydroxy-4'-methoxy-2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide or a salt thereof is an effective ingredient.

  提供一种化合物，它具有基于抑制活化的血液凝固因子 X 的抗凝作用，可用作抗凝剂或预防和治疗由血栓或栓子引起的疾病的药物。一种二氮杂卓衍生物，如 4-[(3-氨基甲酰基苯基氨基)甲基]-3-[4-(4-甲基-1,4-二氮杂卓-1-基)苯甲酰基氨基]苯甲酸和 3-羟基-4'-甲氧基-2-[4-(4-甲基-1,4-二氮杂卓-1-基)苯甲酰基]氨基}苯甲酰苯胺或其盐是一种有效成分。
• US6642224B1
  申请人：——

  公开号：US6642224B1

  公开（公告）日：2003-11-04