2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid | 1430212-91-1

• 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: 2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid
• 英文别名: 2-[(4-Chlorobenzoyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid；2-[(4-chlorobenzoyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid
• CAS: 1430212-91-1
• 化学式: C₁₅H₁₄ClNO₃S
• 分子量: 323.8
• InChiKey: COVHLQBSXLYIFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  94.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid 在 potassium tert-butylate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 生成 N-[3-[3-(adamantan-1-yl)-1,2,4-oxadiazol-5-yl]-4-ethyl-5-methylthiophen-2-yl]-4-chlorobenzamide
  参考文献：
  名称：

  2-（酰基氨基）噻吩-3-羧酰胺及其类似物的合成，结构性质和药理评价†

  摘要：

  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。

  DOI：

  10.1039/c3ra45546g
• 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 、 lithium hydroxide monohydrate 、 水 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 为溶剂， 反应 24.0h， 生成 2-[((4-chlorophenyl)carbonyl)amino]-4-ethyl-5-methylthiophene-3-carboxylic acid
  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

文献信息

• The GABAB receptor positive allosteric modulator COR659: In vitro metabolism, in vivo pharmacokinetics in rats, synthesis and pharmacological characterization of metabolically protected derivatives
  作者：Francesca Ferlenghi、Paola Maccioni、Claudia Mugnaini、Antonella Brizzi、Federica Fara、Rafaela Mostallino、M Paola Castelli、Giancarlo Colombo、Marco Mor、Federica Vacondio、Federico Corelli

  DOI：10.1016/j.ejps.2020.105544

  日期：2020.12

  vivo. M1, cleavage product of the methyl ester group at C-3, revealed in vitro an unusual mechanism of metabolism by a NADPH-dependent route and, in vivo, it maintained high and persistent levels in plasma, which could represent a potential pharmacokinetic and toxicological issue. In the novel set of COR659 analogues, those bearing branched alkyl substituents on the ester group, showed an improved in vitro

  我们报告了一项对COR659（1）的体外I期代谢研究，COR659是一种2-酰基氨基噻吩衍生物，能够抑制大鼠酒精和巧克力的自我给药，可能是通过对GABA B受体的正变构调节和对大麻素的拮抗作用/反向激动作用CB 1受体。鉴于已将噻吩环C-3处的甲基酯基团鉴定为代谢弱点，我们还报告了化学优化项目，旨在平衡一组3取代COR659类似物在体内和体外的代谢稳定性与代谢稳定性。 高效液相色谱串联和高分辨率质谱用于表征大鼠COR659的体外代谢和体内药代动力学。体外[ 35 S] GTP γ S结合于刺激的GABA测定乙和CB 1点用酒精和巧克力自身给药实验的受体，结合在大鼠中，采用以评估这种新颖的组类似物的药理学特性，使用COR659作为参考化合物。 在肝微粒体温育中发现了COR659的八种代谢物；通过与合成参考标准品比较确定了其中的两个（M1，M2）。M2是噻吩环C-5处甲基的氧化产物，在体外是主
• 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.
• 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。