(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride | 150611-80-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride
• 英文别名: DX 9065a；(2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydrochloride
• CAS: 150611-80-6
• 化学式: C₂₆H₂₈N₄O₃*ClH
• 分子量: 480.994
• InChiKey: MQAQKHCMPMBWIS-UKOKCHKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.41
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  124
• 氢给体数：
  5
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride 以 水 为溶剂， 反应 72.0h， 生成 7-(2-{4-[1-(1-Imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-ethyl)-naphthalene-2-carboxamidine
  参考文献：
  名称：

  新型Xa因子抑制剂DX-9065a在水溶液中的光脱羧作用。

  摘要：

  （2S）-2- [4-[[（（3S）-1-乙酰亚胺基-3-吡咯烷基]氧基]苯基] -3-（7-ami基-2-萘基）丙酸盐酸盐五水合物（DX-在25°C下于各种pH值（1.1-8.0）的水溶液中研究了9065a）（一种新的Xa因子抑制剂）。DX-9065a的光降解以相当好的方式遵循了人造阳光下明显的一级动力学。DX-9065a在中性溶液中的光降解速率高于酸性溶液。log k-pH谱表明，DX-9065a的光降解速率与羧基的解离有关，表明主要的光不稳定物质是羧酸盐形式。进一步的动力学研究表明，DX-9065a的羧酸盐形式经过定量脱羧生成D41-1077，在照射时，光脱羧产物，而DX-9065a的羧酸形式不进行任何光脱羧。此外，讨论了动力学和光降解途径的光脱羧机理。

  DOI：

  10.1248/cpb.46.131
• 作为产物：
  描述：

  7-(溴甲基)萘-2-甲腈 在 盐酸 、 palladium(II) oxide 、 barium sulfate 、 氨 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 xylene 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 403.5h， 生成 (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride
  参考文献：
  名称：

  Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors

  摘要：

  Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxyl phenyl]propanoic acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[(3S)-1- acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4, DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 mu M, doubled plasma recalcification time (PRCT) at 0.5 mu M, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 mu M).

  DOI：

  10.1021/jm00034a018

文献信息

• PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：EP0953359A1

  公开（公告）日：1999-11-03

  The present invention is directed to a pharmaceutical composition for oral administration, comprising a basic drug, a lipophilic substance, and/or a cyclodextrin. The composition exhibits improved peroral absorption of a basic drug which is difficult to be absorbed by oral administration.

  本发明涉及一种口服药物组合物，其中包括一种碱性药物、一种亲脂性物质和/或一种环糊精。 该组合物改善了难以通过口服吸收的碱性药物的口腔吸收。
• Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors
  作者：Takayasu Nagahara、Yukio Yokoyama、Kazue Inamura、Shin-ichi Katakura、Satoshi Komoriya、Hitoshi Yamaguchi、Tsuyoshi Hara、Masahiro Iwamoto

  DOI：10.1021/jm00034a018

  日期：1994.4

  Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxyl phenyl]propanoic acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[(3S)-1- acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4, DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 mu M, doubled plasma recalcification time (PRCT) at 0.5 mu M, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 mu M).
• Photodecarboxylation of DX-9065a, a New Factor Xa Inhibitor, in Aqueous Solution.
  作者：Yukinori KAWAI、Kyuichi MATSUBAYASHI

  DOI：10.1248/cpb.46.131

  日期：——

  The photodegradation reaction of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3- (7-amidino-2-naphthyl) propanoic acid hydrochloride pentahydrate (DX-9065a), a new factor Xa inhibitor, was investigated in aqueous solution at various pH values (1.1-8.0) at 25 degrees C. The photodegradation of DX-9065a followed apparent first-order kinetics under artificial sunlight in a fairly good manner

  （2S）-2- [4-[[（（3S）-1-乙酰亚胺基-3-吡咯烷基]氧基]苯基] -3-（7-ami基-2-萘基）丙酸盐酸盐五水合物（DX-在25°C下于各种pH值（1.1-8.0）的水溶液中研究了9065a）（一种新的Xa因子抑制剂）。DX-9065a的光降解以相当好的方式遵循了人造阳光下明显的一级动力学。DX-9065a在中性溶液中的光降解速率高于酸性溶液。log k-pH谱表明，DX-9065a的光降解速率与羧基的解离有关，表明主要的光不稳定物质是羧酸盐形式。进一步的动力学研究表明，DX-9065a的羧酸盐形式经过定量脱羧生成D41-1077，在照射时，光脱羧产物，而DX-9065a的羧酸形式不进行任何光脱羧。此外，讨论了动力学和光降解途径的光脱羧机理。