Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate | 173864-45-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate
• 英文别名: Ethyl 2-(4-methoxybenzoyl)-3-(3.4-methylenedioxy-phenyl)-4-nitro-butanoate；ethyl 2-(4-methoxybenzoyl)-4-nitromethyl-3-(1,3-benzodioxol-5-yl)butyrate；ethyl 2-(4-methoxybenzoyl)-3-(1,3-benzodioxol-5-yl)-4-nitro-butanoate；ethyl 2-(4-methoxybenzoyl)-4-nitro-3-(1,3-benzodioxol-5-yl)butyrate；ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate
• CAS: 173864-45-4
• 化学式: C₂₁H₂₁NO₈
• 分子量: 415.4
• InChiKey: QPSKREVTKUBJMA-UHFFFAOYSA-N

物化性质

• 沸点：
  603.2±55.0 °C(Predicted)
• 密度：
  1.311±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  117
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate 在 镍 盐酸 、 lithium hydroxide 、 sodium hydroxide 、 正丁基锂 、 氢气 、 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 、 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 25.0 ℃ 、405.3 kPa 条件下， 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：

  对甲氧基苯乙酮 在 sodium hydride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 生成 Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate
  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] CRYSTALLINE FORM OF ATRASENTAN HYDROCHLORIDE<br/>[FR] FORME CRISTALLINE DE L'HYDROCHLORURE D'ATRASENTAN
  申请人：ABBOTT LAB

  公开号：WO2006034085A1

  公开（公告）日：2006-03-30

  Substantially amorphous atrasentan hydrochloride, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

  本文揭示了含有实质上无定形氯化羟氯嗪的组合物，以及使用它治疗疾病和抑制不良生理事件的方法。
• [EN] CRYSTALLINE FORM 1 OF ATRASENTAN HXDROCHLORIDE<br/>[FR] FORME CRISTALLINE 1 DE L'HYDROCHLORURE D'ATRASENTAN
  申请人：ABBOTT LAB

  公开号：WO2006034094A1

  公开（公告）日：2006-03-30

  Atrasentan Hydrochloride Crystalline Form 1, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

  Atrasentan盐酸盐结晶形式1，含有它的组合物以及使用它进行疾病治疗和抑制不良生理事件的方法被披露。
• [EN] CRYSTALLINE FORM 3 OF ATRASENTAN HYDROCHLORIDE<br/>[FR] FORME CRISTALLINE 3 DE L'HYDROCHLORURE D'ATRASENTAN
  申请人：ABBOTT LAB

  公开号：WO2006034234A1

  公开（公告）日：2006-03-30

  Atrasentan Hydrochloride Crystalline Form 3, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed

  Atrasentan盐酸盐结晶型态3，含有它的组合物以及使用它治疗疾病和抑制不良生理事件的方法被披露。
• Development of a Catalytic Enantioselective Conjugate Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes for the Synthesis of Endothelin-A Antagonist <b>ABT-546</b>. Scope, Mechanism, and Further Application to the Synthesis of the Antidepressant Rolipram
  作者：David M. Barnes、Jianguo Ji、Michael G. Fickes、Michael A. Fitzgerald、Steven A. King、Howard E. Morton、Frederick A. Plagge、Margo Preskill、Seble H. Wagaw、Steven J. Wittenberger、Ji Zhang

  DOI：10.1021/ja026788y

  日期：2002.11.1

  The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield

  内皮素-A 拮抗剂 ABT-546 的对映选择性合成是通过发现和开发酮酯与硝基烯烃的高选择性催化不对称共轭加成来完成的。仅使用 4 mol% 双(恶唑啉)-Mg(OTf)(2) 配合物和胺助催化剂，我们在含芳基的立体中心以 88% 的选择性获得了产物硝基酮，并且在 13 mol 的规模范围内以良好的产率获得。描述了配体结构、金属盐和溶剂对反应的影响。对反应特别重要的是水含量。虽然在催化剂生成过程中需要水，但随后必须除去水以最大化立体选择性和反应性。该反应已扩展到其他二羰基底物，并且在硝基烯烃伙伴上可以容忍各种取代模式。该反应还用于合成抗抑郁药咯利普兰。还描述了有关反应机理的研究。