ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)acrylate | 168109-91-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)acrylate
• 英文别名: tert-butyl (3S)-3-[4-[1-(5-cyano-1-benzofuran-2-yl)-3-ethoxy-3-oxoprop-1-en-2-yl]phenoxy]pyrrolidine-1-carboxylate
• CAS: 168109-91-9
• 化学式: C₂₉H₃₀N₂O₆
• 分子量: 502.567
• InChiKey: VEYNWBDFWPHTLE-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)acrylate 在 盐酸 、 palladium(II) oxide 、 barium sulfate 、 氨 、 氢气 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 20.0~25.0 ℃ 、101.33 kPa 条件下， 反应 42.0h， 生成 ethyl 3-(5-amidino-2-benzofuranyl)-2-<4-<(3S)-3-pyrrolidinyloxy>phenyl>propanoate dihydrochloride
  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
• 作为产物：
  描述：

  2-(4-羟苯基)-2-氧代乙酸乙酯 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 1.75h， 生成 ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)acrylate
  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

• Aromatic amidine derivatives and salts thereof
  申请人：Daiichi Pharmaceutical Co., Ltd.

  公开号：US05620991A1

  公开（公告）日：1997-04-15

  An anticoagulant agent which comprises, as an active ingredient, an aromatic amidine derivative represented by the following general formula (1) or a salt thereof: ##STR1## wherein the group represented by ##STR2## is a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl; X is a single bond, an oxygen atom, a sulfur atom or a carbonyl group; and Y is a saturated or unsaturated 5- or 6-membered heterocyclic moiety or cyclic hydrocarbon moiety optionally having a substituent group, an amino group optionally having a substituent group or an aminoalkyl group optionally having a substituent group. The inventive compound has a high anticoagulant capacity based on its excellent FXa inhibition activity.

  一种抗凝剂，其包括以下通式（1）所表示的芳香族酰胺衍生物或其盐作为活性成分：##STR1## 其中，由##STR2##所表示的基团是从吲哚基，苯并呋喃基，苯并噻吩基，苯并咪唑基，苯并噁唑基，苯并噻唑基，萘基，四氢萘基和吲烷基中选择的基团；X是一个单键，一个氧原子，一个硫原子或一个羰基；Y是一个饱和或不饱和的5-或6-环杂环基团或环烃基团，可选地具有取代基，一个氨基可选地具有取代基或一个氨基烷基可选地具有取代基。这种创新化合物具有基于其优异的FXa抑制活性的高抗凝能力。
• 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).