methyl 2-(4-chlorophenylcarboxamido)−4-ethyl-5-methylthiophene-3-carboxylate | 544450-68-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 2-(4-chlorophenylcarboxamido)−4-ethyl-5-methylthiophene-3-carboxylate
• 英文别名: methyl 2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylate；methyl 2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate；COR659；Methyl 2-(4-chlorobenzamido)-4-ethyl-5-methylthiophene-3-carboxylate；methyl 2-[(4-chlorobenzoyl)amino]-4-ethyl-5-methylthiophene-3-carboxylate
• CAS: 544450-68-2
• 化学式: C₁₆H₁₆ClNO₃S
• 分子量: 337.827
• InChiKey: AAFLALGGEYRGTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  83.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 2-(4-chlorophenylcarboxamido)−4-ethyl-5-methylthiophene-3-carboxylate 在 lithium hydroxide monohydrate 、 水 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 42.0h， 生成 n-propyl 2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylate
  参考文献：
  名称：

  Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABA_B Receptor

  摘要：

  Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABA(B) receptor by potentiating GTP gamma S stimulation induced by GABA at 2.5 and 25 mu M while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.

  DOI：

  10.1021/jm400144w
• 作为产物：
  描述：

  3-戊酮 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成 methyl 2-(4-chlorophenylcarboxamido)−4-ethyl-5-methylthiophene-3-carboxylate
  参考文献：
  名称：

  新型2-（1-金刚烷基羧酰胺基）噻吩衍生物的合成。选择性大麻素2型（CB2）受体激动剂可作为治疗皮肤炎性疾病的潜在药物

  摘要：

  合成了一组基于噻吩骨架的CB2R配体，并在体外分析中进行了评估。在噻吩环的5-位或4-和5-位带有3-羧酸根和2-（金刚烷-1-基）羧酰胺基以及非极性烷基/芳基取代基的化合物8c-i，k，l具有在低纳摩尔浓度下具有高CB2R亲和力，良好的受体选择性和激动性功能活性。在过敏性接触性皮炎的实验模型中对全受体激动剂8g（在受体亲和力和选择性之间取得了最佳平衡）进行了体外测试，结果证明能够以10μM的浓度阻断HaCaT细胞中MCP-2的释放。

  DOI：

  10.1016/j.ejmech.2018.09.070

文献信息

• Synthesis, structural properties, and pharmacological evaluation of 2-(acylamino)thiophene-3-carboxamides and analogues thereof
  作者：Claudia Mugnaini、Valentina Pedani、Daniela Giunta、Barbara Sechi、Maurizio Solinas、Alberto Casti、Maria Paola Castelli、Gianluca Giorgi、Federico Corelli

  DOI：10.1039/c3ra45546g

  日期：——

  previously reported the synthesis and the pharmacological characterization of a family of methyl 2-(acylamino)thiophene-3-carboxylates as GABAB positive allosteric modulators active both in vitro and in vivo. In the present work, we describe the synthesis of new compounds based on the bioisosteric replacement of the ester moiety with amido or heterocyclic groups as well as of thieno[2,3-d]pyrimidine derivatives

  我们之前已经报道了2-（酰基氨基）噻吩-3-羧酸甲酯作为GABA B阳性变构调节剂在体外和体内均具有活性，其合成和药理学表征。在当前的工作中，我们描述了基于酰胺基或杂环基团的酯部分的生物等位取代以及作为其刚性类似物的噻吩并[2,3- d ]嘧啶衍生物的合成，合成新化合物。4 H-噻吩并[2,3- d ] [1,3]恶嗪-4-酮被用作合成中间体，以制备其中一些化合物。恶嗪酮11b，16和17的结构X射线晶体学研究确定了这些化合物的存在，这无疑排除了先前为这些化合物所假定的同分异构的β-内酰胺结构。无论是变构还是正构配体，这些新分子均未在GABA B受体上显示出显着活性。
• Synthesis of novel 2-(1-adamantanylcarboxamido)thiophene derivatives. Selective cannabinoid type 2 (CB2) receptor agonists as potential agents for the treatment of skin inflammatory disease
  作者：Claudia Mugnaini、Alessandro Rabbito、Antonella Brizzi、Nastasja Palombi、Stefania Petrosino、Roberta Verde、Vincenzo Di Marzo、Alessia Ligresti、Federico Corelli

  DOI：10.1016/j.ejmech.2018.09.070

  日期：2019.1

  A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R affinity at low nanomolar concentration, good receptor selectivity, and agonistic

  合成了一组基于噻吩骨架的CB2R配体，并在体外分析中进行了评估。在噻吩环的5-位或4-和5-位带有3-羧酸根和2-（金刚烷-1-基）羧酰胺基以及非极性烷基/芳基取代基的化合物8c-i，k，l具有在低纳摩尔浓度下具有高CB2R亲和力，良好的受体选择性和激动性功能活性。在过敏性接触性皮炎的实验模型中对全受体激动剂8g（在受体亲和力和选择性之间取得了最佳平衡）进行了体外测试，结果证明能够以10μM的浓度阻断HaCaT细胞中MCP-2的释放。
• Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABA_B Receptor
  作者：Claudia Mugnaini、Valentina Pedani、Angelo Casu、Carla Lobina、Alberto Casti、Paola Maccioni、Alessandra Porcu、Daniela Giunta、Stefania Lamponi、Maurizio Solinas、Stefania Dragoni、Massimo Valoti、Giancarlo Colombo、Maria Paola Castelli、Gian Luigi Gessa、Federico Corelli

  DOI：10.1021/jm400144w

  日期：2013.5.9

  Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABA(B) receptor by potentiating GTP gamma S stimulation induced by GABA at 2.5 and 25 mu M while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.