2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester | 204325-47-3

• 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: 2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester
• 英文别名: ethyl 2-<4-<<(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl>oxy>phenyl>-3-(7-cyano-2-naphthyl)propanoate；ethyl 2-(4-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}phenyl)-3-(7-cyano-2-naphthyl)propanoate；ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(7-cyano-2-naphthyl)propionate；ethyl 2-(4-{[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-3-(7-cyano-2-naphthyl)propanoate；tert-butyl (3S)-3-[4-[3-(7-cyanonaphthalen-2-yl)-1-ethoxy-1-oxopropan-2-yl]phenoxy]pyrrolidine-1-carboxylate
• CAS: 204325-47-3
• 化学式: C₃₁H₃₄N₂O₅
• 分子量: 514.621
• InChiKey: NMJRXFTUIGIPII-MBMZGMDYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  88.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester 在 盐酸 、 乙醇 、 氨 作用下， 以 乙醇 为溶剂， 反应 48.0h， 以56%的产率得到ethyl 3-(7-amidino-2-naphthyl)-2-{4-[(3S)-pyrrolidin-3-yloxy]phenyl}propanoate
  参考文献：
  名称：

  Design, synthesis and biological activity of amidinobicyclic compounds (derivatives of DX-9065a) as factor Xa inhibitors: SAR study of S1 and aryl binding sites

  摘要：

  Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2,)-2-[4-[[(3S)-l-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called SI) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.02.032
• 作为产物：
  描述：

  2-[4-[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenylacetic acid ethyl ester 以 N-甲基乙酰胺 为溶剂， 以91%的产率得到2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester
  参考文献：
  名称：

  Process for preparing 2-phenyl-3-naphthylpropionic acid derivatives

  摘要：

  一种制备以下反应方案中的通用化合物（5）和（6）或其盐的方法，其中R1代表氮原子的保护基团；R2代表甲磺酰基团或对甲苯磺酰基团；R3代表氢原子、芳基烷基或具有1至6个碳原子的烷基；X代表卤素原子。上述方法可用作制备日本专利申请公开（公开号208946/1993）中描述的抗凝血芳香胺衍生物中间体的工业过程。

  公开号：

  US06252088B1

文献信息

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

  公开号：US05576343A1

  公开（公告）日：1996-11-19

  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，其包括作为活性成分的芳香胺基衍生物，其由以下一般式（1）或其盐所表示：##STR1## 其中由##STR2##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，四氢萘基和吲哚基中选择的基团；X是单键，氧原子，硫原子或羰基；Y是饱和或不饱和的5-或6-成员杂环基团或环烃基团，可选地具有取代基团，可选地具有取代基团的氨基团或可选地具有取代基团的氨基烷基团。这种创新化合物具有基于其出色的FXa抑制活性的高抗凝能力。
• PROCESS FOR PREPARING 2-PHENYL-3-NAPHTHYLPROPIONIC ACID DERIVATIVES
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：EP0936215A1

  公开（公告）日：1999-08-18

  A process for preparing a compound represented by general formulae (5) and (6) in the following reaction scheme or salts thereof, wherein R1 represents a protective groupfor a nitrogen atom; R2 represents a methanesulfonyl group or p-toluenesulfonyl group; R3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X represents a halogen atom. The above process is useful as an industrial process for preparing intermediates of anticoagulant aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 208946/1993.

  一种制备下述反应方案中通式(5)和(6)所代表的化合物或其盐的工艺，其中 R1 代表氮原子的保护基团；R2 代表甲磺酰基或对甲苯磺酰基；R3 代表氢原子、芳烷基或具有 1 至 6 个碳原子的烷基；以及 X 代表卤素原子。 上述工艺可作为制备日本专利申请公开（kokai）第 208946/1993 号所述抗凝剂芳香族脒衍生物中间体的工业工艺。
• 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).
• Nagahara Takayasu, Yokoyama Yukio, Inamura Kazue, Katakura Shin-ichi, Kom+, J. Med. Chem, 37 (1994) N 8, S 1200-1207
  作者：Nagahara Takayasu, Yokoyama Yukio, Inamura Kazue, Katakura Shin-ichi, Kom+

  DOI：——

  日期：——
• US5576343A
  申请人：——

  公开号：US5576343A

  公开（公告）日：1996-11-19