Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate | 173864-46-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate
• 英文别名: ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate；ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H-pyrrole-3-carboxylate；ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate
• CAS: 173864-46-5
• 化学式: C₂₁H₂₁NO₅
• 分子量: 367.401
• InChiKey: GTQMULSWASGYOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate 在 盐酸 、 lithium hydroxide 、 sodium hydroxide 、 正丁基锂 、 双氧水 、 溴甲酚绿 、 三甲基乙酰氯 、 sodium cyanoborohydride 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 1.83h， 生成 阿曲生坦
  参考文献：
  名称：

  2,4-Diarylpyrrolidine-3-carboxylic AcidsPotent ET_A Selective Endothelin Receptor Antagonists. 1. Discovery of A-127722

  摘要：

  We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indan ring in SE 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) pyrrolidine-3-carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-l-induced contraction of the rabbit aorta with a pA(2) = 9.20. The compound has 70% oral bioavailability in rats.

  DOI：

  10.1021/jm9505369
• 作为产物：
  描述：

  5-((E)-2-nitroethenyl)-1,3-benzodioxole 在 Ra-Ni 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 溶剂黄146 、 异丙醇 为溶剂， 生成 Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate
  参考文献：
  名称：

  Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists. 2. Sulfonamide-Based ET_A/ET_B Mixed Antagonists

  摘要：

  When the N,N-dialkylacetamide side chain of the highly ETA-selective endothelin antagonist ABT-627 (1; [2R,3R,4S]-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[[(N,N-dibutylamino)carbonyl]methyl]pyrrolidine-3-carboxylic acid; A-147627) is replaced by N,S-dialkylsulfonamidoethyl, the resultant analogs retain ETA affinity, but exhibit substantial ETB affinity as well. Structure-activity studies reveal that modifications in the length of the two alkyl groups, and in the substitution on the anisyl ring, are important in optimizing this ''balanced'' antagonist profile. In particular the combination of an N-n-propyl group, an S-alkyl chain between four and six carbons in length, and a fluorine atom ortho to the aromatic OCH3 provides compounds with sub-nanomolar affinities for both receptor subtypes, and with ETA/ETB ratios close to 1. A number of these compounds also exhibit oral bioavailabilities (in rats) in the 30-50% range and have substantial plasma half-lives. The balanced receptor-binding profile of these potent and orally bioavailable compounds complements the ETA selectivity observed with 1.

  DOI：

  10.1021/jm970101g

文献信息

• Endothelin antagonists
  申请人：Abbott Laboratories

  公开号：US06162927A1

  公开（公告）日：2000-12-19

  A compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

  公开了一种具有以下化学式（I）的化合物：##STR1##或其药用可接受的盐，以及制备该化合物的方法、中间体，以及一种拮抗内皮素的方法。
• [EN] NOVEL BENZO-1,3-DIOXOLYL- AND BENZOFURANYL SUBSTITUTED PYRROLIDINE DERIVATIVES AS ENDOTHELIN ANTAGONISTS<br/>[FR] DERIVES DE PYRROLIDINE A SUBSTITUTION BENZO-1,3-DIOXOLYL ET BENZOFURANYL SERVANT D'ANTAGONISTES DE L'ENDOTHELINE
  申请人：ABBOTT LABORATORIES

  公开号：WO1997030045A1

  公开（公告）日：1997-08-21

  (EN) A compound of formula (I), or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.(FR) La présente invention concerne un composé représenté par la formule générale (I) ou l'un de ses sels galéniques. L'invention, qui concerne également des procédés convenant à leur préparation, concerne aussi des intermédiaires pour de telles préparations. L'invention concerne enfin un procédé de réalisation d'une fonction antagoniste de l'endothéline.

  该发明涉及一种化合物，其化学式为(I)，或其药学上可接受的盐，以及其制备的过程和中间体，以及一种拮抗内皮素的方法。(翻译后)
• [EN] ENDOTHELIN ANTAGONISTS<br/>[FR] ANTAGONISTES D'ENDOTHELINE
  申请人：ABBOTT LABORATORIES

  公开号：WO1996006095A1

  公开（公告）日：1996-02-29

  (EN) A compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.(FR) Composé de formule (I) ou sel pharmaceutiquement acceptable dudit composé, ainsi que procédés et intermédiaires destinés à la préparation dudit composé, et procédé permettant d'obtenir un effet antagoniste par rapport à l'endothéline.

  揭示了化合物式(I)或其药学上可接受的盐，以及其制备过程中的中间体和制备方法，并且揭示了拮抗内皮素的方法。
• [EN] PYRROLIDINE CARBOXYLIC ACID DERIVATIVES AS ENDOTHELIN ANTAGONISTS<br/>[FR] DERIVES D'ACIDE CARBOXYLIQUE DE PYRROLIDINE COMME ANTAGONISTES D'ENDOTHELINE
  申请人：ABBOTT LABORATORIES

  公开号：WO1998057933A1

  公开（公告）日：1998-12-23

  (EN) A compound of formula (I), or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.(FR) L'invention concerne un composé de la formule (I) ou un sel de ce composé acceptable du point de vue pharmaceutique, ainsi que des procédés et des intermédiaires intervenant dans sa préparation, et une méthode de production d'effets antagonistes d'endothéline.

  该发明涉及一种式（I）的化合物或其药学上可接受的盐，以及其制备过程和中间体，以及拮抗内皮素的方法。
• Treatment of diseases using endothelin antagonists
  申请人：Abbott Laboratories

  公开号：US06380241B1

  公开（公告）日：2002-04-30

  A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

  本发明揭示了化合物(I)的公式或其药学上可接受的盐，以及其制备过程中的中间体和方法，以及拮抗内皮素的方法。