4-苯甲酰基-1-甲基-1H-吡咯-2-甲醛 | 128843-58-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 4-苯甲酰基-1-甲基-1H-吡咯-2-甲醛
• 英文名称: 4-benzoyl-1-methyl-1H-pyrrole-2-carboxaldehyde
• 英文别名: 4-benzoyl-1-methyl-1H-pyrrole-2-carbaldehyde；4-benzoyl-1-methylpyrrole-2-carbaldehyde
• CAS: 128843-58-3
• 化学式: C₁₃H₁₁NO₂
• mdl: MFCD00172168
• 分子量: 213.236
• InChiKey: WDCINSJQPIINCX-UHFFFAOYSA-N

物化性质

• 熔点：
  112-114°C
• 沸点：
  388.7±27.0 °C(Predicted)
• 密度：
  1.12±0.1 g/cm3(Predicted)
• 溶解度：
  30.7 [ug/mL]

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.076
• 拓扑面积：
  39.1
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  4-苯甲酰基-1-甲基-1H-吡咯-2-甲醛 在 氢氧化钾 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 生成 3-(4-苯甲酰基-1-甲基-1H-2-吡咯)丙烯酸
  参考文献：
  名称：

  3-（4-芳酰基-1H-吡咯-2-基）-N-羟基-2-丙烯酰胺，一类新型的合成组蛋白脱乙酰基酶抑制剂。

  摘要：

  新型的3-（4-芳酰基-2-吡咯基）-N-羟基-2-丙烯酰胺被公开为新型的组蛋白脱乙酰基酶（HDAC）抑制剂。基于三维结构的药物设计和对组蛋白脱乙酰基酶样蛋白（HDLP）催化核心的构象分析表明化合物7a-h的合成和生物学评估。实验性pK（i）值与新衍生物的VALIDATE预测pK（i）值非常吻合。所有化合物7a-h在微摩尔范围内均显示出HDAC抑制活性，其中7e是最有效的衍生物（IC（50）= 1.9 microM）。芳酰基部分中的4'取代基对抑制活性的影响并不明显，因为所有化合物7a-g的IC（50）值在1.9和3.9 microM之间。除此以外，

  DOI：

  10.1021/jm015515v
• 作为产物：
  描述：

  N-甲基吡咯 在 三氯化铝 、 草酰氯 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 3.25h， 生成 4-苯甲酰基-1-甲基-1H-吡咯-2-甲醛
  参考文献：
  名称：

  3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-alkylamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 1. Design, Synthesis, Biological Evaluation, and Binding Mode Studies Performed through Three Different Docking Procedures

  摘要：

  Recently we reported a novel series of hydroxamates, called 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides (APHAs), acting as HDAC inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072). Among them, 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide 1 was chosen as lead compound, and its binding mode into the modeled HDAC1 catalytic core together with its histone hyperacetylation, antiproliferative, and cytodifferentiating properties in cell-based assays were investigated (Mai, A.; et al. J. Med. Chem. 2002, 45, 1778-1784). Here we report the results of some chemical manipulations performed on (i) the aroyl portion at the C-4-pyrrole position, (ii) the N-1-pyrrole substituent, and (iii) the hydroxamate moiety of 1 to determine structure-activity relationships and to improve enzyme inhibitory activity of APHAs. In the 1 structure, pyrrole N-1-substitution with groups larger than methyl gave a reduction in HDAC inhibiting activity, and replacement of hydroxamate function with various non-hydroxamate, metal ion-complexing groups yielded poorly active or totally inactive compounds. On the contrary, proper substitution at the C-4-position favorably affected enzyme inhibiting potency, leading to 8 (IC50 = 0.1 muM) and 9 (IC50 = 1.0 muM) which were 38- and 3.8-fold more potent than 1 in in vitro anti-HD2 assay. Against mouse HDAC1, 8 showed an IC50 = 0.5 muM (IC50 of 1 = 4.9 muM), and also in cell-based assay, 8 was endowed with higher histone hyperacetylating activity than 1, although it was less potent than TSA and SAHA. Such enhancement of inhibitory activity can be explained by the higher flexibility of the pyrrole C-4-substituent of 8 which accounts for a considerably better fitting into the HDAC1 pocket and a more favorable enthalpy ligand receptor energy compared to 1. The enhanced fit allows a closer positioning of 8 hydroxamate moiety to the zinc ion. These findings were supported by extensive docking studies (SAD, DOCK, and Autodock) performed on both APHAs and reference drugs (TSA and SAHA).

  DOI：

  10.1021/jm021070e

文献信息

• 3-(4-Aroyl-1-methyl-1<i>H</i>-2-pyrrolyl)-<i>N</i>-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 2. Effect of Pyrrole-C₂ and/or -C₄ Substitutions on Biological Activity
  作者：Antonello Mai、Silvio Massa、Ilaria Cerbara、Sergio Valente、Rino Ragno、Patrizia Bottoni、Roberto Scatena、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm030990+

  日期：2004.2.1

  pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f)

  先前的SAR研究（第1部分：Mai，A .；等人，J。Med。Chem。2003，46，512-524）在3-（- 4-苯甲酰基-1-甲基-1H-吡咯-2-基）-N-羟基-2-丙烯酰胺（1a）突出显示了其4-苯基乙酰基（1b）和4-肉桂酰基（1c）类似物是抑制玉米的更有效化合物体外HD2活性。在本文中，我们研究了化学取代对1a-c的吡咯-C2乙烯链进行的化学取代对抗HD2活性的影响，这些链被亚甲基，乙烯，取代的乙烯和1,3-丁二烯链（化合物2）。生物学结果清楚地表明，未取代的乙烯链是获得最高HDAC抑制活性的最佳结构基序，唯一的例外是引入了1，3-丁二烯基部分变成1a化学结构（IC50（2f）= 0.77 microM; IC50（1a）= 3.8 microM）。化合物3的IC50值（制备为1b的同系物）显示，吡咯C-（4）位置的苯和羰基之间的APHA模板很好地接受了2至5个亚甲基的烃间
• 3-(4-Aroyl-1<i>H</i>-pyrrol-2-yl)-<i>N</i>-hydroxy-2-propenamides, a New Class of Synthetic Histone Deacetylase Inhibitors
  作者：Silvio Massa、Antonello Mai、Gianluca Sbardella、Monica Esposito、Rino Ragno、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm015515v

  日期：2001.6.1

  class of histone deacetylase (HDAC) inhibitors. Three-dimensional structure-based drug design and conformational analyses into the histone deacetylase-like protein (HDLP) catalytic core suggested the synthesis and biological evaluation of compounds 7a-h. Experimental pK(i) values are in good agreement with VALIDATE predicted pK(i) values of new derivatives. All compounds 7a-h show HDAC inhibitory activity

  新型的3-（4-芳酰基-2-吡咯基）-N-羟基-2-丙烯酰胺被公开为新型的组蛋白脱乙酰基酶（HDAC）抑制剂。基于三维结构的药物设计和对组蛋白脱乙酰基酶样蛋白（HDLP）催化核心的构象分析表明化合物7a-h的合成和生物学评估。实验性pK（i）值与新衍生物的VALIDATE预测pK（i）值非常吻合。所有化合物7a-h在微摩尔范围内均显示出HDAC抑制活性，其中7e是最有效的衍生物（IC（50）= 1.9 microM）。芳酰基部分中的4'取代基对抑制活性的影响并不明显，因为所有化合物7a-g的IC（50）值在1.9和3.9 microM之间。除此以外，
• Pyridin-2-one compounds useful as inhibitors of thrombin
  申请人：Bayrakdarian Malken

  公开号：US20070161643A1

  公开（公告）日：2007-07-12

  There is provided a compound of formula I wherein the dashed line, R 1 , R 2 , R 3a , R 3b , A, D, E, G and L have meanings given in the description, which compounds are useful as, or are useful as prodrugs of, competitive inhibitors of trypsin-like proteases, such as thrombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is beneficial (e.g. conditions, such as thrombo-embolisms, where inhibition of thrombin is required or desired, and/or conditions where anticoagulant therapy is indicated).

  提供了一种I式化合物，其中虚线，R1，R2，R3a，R3b，A，D，E，G和L的含义在说明书中给出，这些化合物可用作竞争性蛋白酶抑制剂，例如凝血酶，或可用作其前药，因此特别适用于治疗需要抑制凝血酶的情况（例如需要或期望抑制凝血酶的血栓栓塞等疾病，以及需要抗凝治疗的情况）。
• [DE] ACYLPYRROLALKANSÄUREN UND INDOL-2-ALKANSÄUREN SOWIE IHRE DERIVATE ALS HEMMSTOFFE DER PHOSPHOLIPASE A2<br/>[EN] ACYLPYRROLE-ALKANOIC ACIDS AND INDOLE-2-ALKANOIC ACIDS PLUS THEIR DERIVATIVES FOR USE AS INHIBITORS OF PHOSPHOLIPASE A2<br/>[FR] ACIDES ACYLPYRROLE-ALCANOIQUES ET INDOLE-2-ALCANOIQUES ET LEURS DERIVES UTILISES COMME INHIBITEURS DE LA PHOSPHOLIPASE A2
  申请人：MERCKLE GMBH CHEM.-PHARM. FABRIK

  公开号：WO1995013266A1

  公开（公告）日：1995-05-18

  (DE) Die Erfindung betrifft neue Acylpyrrolalkansäure-Derivate und Indol-2-alkansäure-Derivate der allgemeinen Formel (I) sowie deren Salze und Ester und deren pharmazeutische Verwendung. Die erfindungsgemäßen Verbindungen sind potente Hemmstoffe der Phospholipase A2 und daher brauchbar zur Prävention und/oder zur Behandlung von Erkrankungen, die durch eine erhöhte Aktivität der Phospholipase A2 verursacht bzw. mitverursacht werden, wie Entzündungen, Schmerz, Fieber, Allergien, Asthma, Psoriasis und Endotoxinschock.(EN) The invention concerns novel acylpyrrole-alkanoic acid derivatives and indole-2-alkanoic acid derivatives of general formula (I), plus their salts and esters, and the pharmaceutical use of such compounds. The compounds described are potent inhibitors of phospholipase A2 and thus usable in the prevention and/or treatment of ailments caused or aggravated by increased activity of phospholipase A2, such as inflammation, pain, fever, allergies, asthma, psoriasis and endotoxin shock.(FR) L'invention concerne de nouveaux dérivés de l'acide acylpyrrole-alcanoïque et de l'acide indole-2-alcanoïque, de formule générale (I), ainsi que leurs sels et esters et leur utilisation pharmaceutique. Les composés selon l'invention sont de puissants inhibiteurs de la phospholipase A2 et sont donc utilisables pour la prévention et/ou le traitement d'affections provoquées ou aggravées par une activité accrue de la phospholipase A2, telles que inflammations, douleurs, fièvre, allergies, asthme, psoriasis et choc endotoxinique.

  这项发明涉及新的酸尿嘧啶衍生物和stoff-2-酸尿嘧啶衍生物，其通用化学式为(I)，以及它们的盐和酯，同时涉及前述化合物的药用用途。根据本发明描述的化合物是强力抑制磷脂酶A₂的，因此可应用于通过增强磷脂酶A₂活性而导致或加重的病症预防和/or治疗，如炎症、疼痛、发烧、过敏、哮喘、皮疹和端otoxine-Tonburst。
• Lehr, Matthias, Journal of Medicinal Chemistry, 1997, vol. 40, # 21, p. 3381 - 3392
  作者：Lehr, Matthias

  DOI：——

  日期：——