5-ethoxy-2-(4-methoxyphenethyl)-4-methyloxazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-ethoxy-2-(4-methoxyphenethyl)-4-methyloxazole
• 英文别名: 5-Ethoxy-2-[2-(4-methoxyphenyl)ethyl]-4-methyl-1,3-oxazole；5-ethoxy-2-[2-(4-methoxyphenyl)ethyl]-4-methyl-1,3-oxazole
• 化学式: C₁₅H₁₉NO₃
• 分子量: 261.321
• InChiKey: LUWWBMJCIDMYKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.18
• 重原子数：
  19.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  44.49
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  5-ethoxy-2-(4-methoxyphenethyl)-4-methyloxazole 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 1.83h， 生成 ethyl 4-acetyl-5-hydroxy-2-(4-methoxyphenethyl)-6-methylnicotinate
  参考文献：
  名称：

  Design and synthesis of potent and selective P2X3 receptor antagonists derived from PPADS as potential pain modulators

  摘要：

  Pyridoxalphosphate-6-azopheny1-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X(3) receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (-N=N-) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 similar to 700 nM) at the hP2X(3) receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13h-n, dramatically improved the selectivity profiles of hP2X(3) when compared with mP2X(1) and hP2X(7) receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X(3) receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X(3) receptor antagonist with an IC50 of 60 nM at hP2X(3) and marginal antagonistic activities of 10 mu M at mP2X(1) and hP2X(7). Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 mu M 36j displaying 65% inhibition while 20 mu M pregabalin, a clinically available drug, showed only 31% inhibition. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.10.026
• 作为产物：
  描述：

  丙氨酸乙酯 在 四磷十氧化物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 7.0h， 生成 5-ethoxy-2-(4-methoxyphenethyl)-4-methyloxazole
  参考文献：
  名称：

  针对神经性疼痛靶向P2X3受体的有效抗痛觉过敏药物的发现

  摘要：

  P2X3受体的拮抗作用是治疗神经性疼痛的潜在治疗策略之一，因为P2X3受体主要位于小至中等直径的C和Aδ纤维初级传入神经元上，这与疼痛感应系统有关。在这项研究中，设计，合成了5-羟基吡啶衍生物，并通过在hP2X3受体上的两电极电压钳实验评估了它们的体外生物活性。在新型hP2X3受体拮抗剂中，鞘内注射化合物29与pregabalin（钙通道调节剂）具有相似的疗效，并且在评估其对脊髓神经结扎大鼠的抗痛觉过敏作用方面比AF353（P2X3受体拮抗剂）更高。但是，因为化合物29由于低细胞通透性，在神经性疼痛动物模型中腹膜内给药无活性，因此研究了相应的甲酯类似物28（可在体内转化为化合物29）作为前药概念。静脉注射化合物28可产生有效的抗痛觉过敏作用，在脊髓神经结扎和化疗引起的周围神经病变大鼠中，ED 50值分别为2.62和2.93 mg / kg，这表明靶向P2X3受体的新药开发有望成为神经病变的

  DOI：

  10.1021/acschemneuro.6b00401

文献信息

• NOVEL PYRIDINE CARBOXYLIC ACID BASED COMPOUND USED AS A P2X1 AND P2X3 RECEPTOR ANTAGONIST, A PRODUCTION METHOD FOR THE SAME AND A COMPOSITION COMPRISING THE SAME
  申请人：Kim Yong-Chul

  公开号：US20130040997A1

  公开（公告）日：2013-02-14

  Provided are a novel pyridine carboxylic acid based compound used as a P2X 1 and P2X 3 receptor antagonist, a production method for the same and a composition comprising the same. The compound according to the present invention is a powerful antagonist of P2X 1 and P2X 3 receptors, and hence can be used as a drug for treating or preventing diseases involving neurological pain or chronic inflammatory diseases which are diseases caused by P2X 1 and P2X 3 receptor activity.

  提供了一种基于吡啶羧酸的新型化合物，用作P2X1和P2X3受体拮抗剂，以及该化合物的生产方法和包含该化合物的组合物。根据本发明的化合物是P2X1和P2X3受体的强效拮抗剂，因此可用作治疗或预防涉及神经疼痛或慢性炎症疾病的药物，这些疾病是由P2X1和P2X3受体活性引起的疾病。
• NOVEL 5-HYDROXY PYRIDINE-BASED COMPOUND FOR USE AS P2X1 AND P2X3 RECEPTOR ANTAGONIST AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
  申请人：GWANGJU INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US20200131131A1

  公开（公告）日：2020-04-30

  The present invention relates to novel 5-hydroxy pyridine-based compounds useful as P2X1 and P2X3 receptor antagonists and compositions comprising the same. The compounds according to the present invention have an activity of strongly antagonizing P2X1 and P2X3 receptors, and thus can be effectively used as a drug for treating or preventing chronic inflammatory diseases or neuropathic pain diseases caused by P2X1 and P2X3 receptor activity.

  本发明涉及一种新型的以5-羟基吡啶为基础的化合物，其作为P2X1和P2X3受体拮抗剂，并包含该化合物的组合物。根据本发明的化合物具有强烈拮抗P2X1和P2X3受体的活性，因此可有效用作治疗或预防由P2X1和P2X3受体活性引起的慢性炎症性疾病或神经病理性疼痛疾病的药物。
• 5-hydroxy pyridine-based compound for use as P2X1 and P2X3 receptor antagonist and pharmaceutical composition comprising same
  申请人：GWANGJU INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US11319289B2

  公开（公告）日：2022-05-03

  The present invention relates to novel 5-hydroxy pyridine-based compounds useful as P2X1 and P2X3 receptor antagonists and compositions comprising the same. The compounds according to the present invention have an activity of strongly antagonizing P2X1 and P2X3 receptors, and thus can be effectively used as a drug for treating or preventing chronic inflammatory diseases or neuropathic pain diseases caused by P2X1 and P2X3 receptor activity.

  本发明涉及可作为 P2X1 和 P2X3 受体拮抗剂的新型 5-羟基吡啶类化合物以及包含这些化合物的组合物。根据本发明的化合物具有强烈拮抗 P2X1 和 P2X3 受体的活性，因此可以有效地用作治疗或预防由 P2X1 和 P2X3 受体活性引起的慢性炎症性疾病或神经性疼痛疾病的药物。
• US9546139B2
  申请人：——

  公开号：US9546139B2

  公开（公告）日：2017-01-17
• Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors
  作者：Young-Hwan Jung、Yeo Ok Kim、Hai Lin、Joong-Heui Cho、Jin-Hee Park、So-Deok Lee、Jinsu Bae、Koon Mook Kang、Yoon-Gyoon Kim、Ae Nim Pae、Hyojin Ko、Chul-Seung Park、Myung Ha Yoon、Yong-Chul Kim

  DOI：10.1021/acschemneuro.6b00401

  日期：2017.7.19

  vivo, was investigated as a prodrug concept. Intravenous injection of compound 28 resulted in potent antiallodynic effects, with ED50 values of 2.62 and 2.93 mg/kg in spinal nerve ligation and chemotherapy-induced peripheral neuropathy rats, respectively, indicating that new drug development targeting the P2X3 receptor could be promising for neuropathic pain, a disease with high unmet medical needs.

  P2X3受体的拮抗作用是治疗神经性疼痛的潜在治疗策略之一，因为P2X3受体主要位于小至中等直径的C和Aδ纤维初级传入神经元上，这与疼痛感应系统有关。在这项研究中，设计，合成了5-羟基吡啶衍生物，并通过在hP2X3受体上的两电极电压钳实验评估了它们的体外生物活性。在新型hP2X3受体拮抗剂中，鞘内注射化合物29与pregabalin（钙通道调节剂）具有相似的疗效，并且在评估其对脊髓神经结扎大鼠的抗痛觉过敏作用方面比AF353（P2X3受体拮抗剂）更高。但是，因为化合物29由于低细胞通透性，在神经性疼痛动物模型中腹膜内给药无活性，因此研究了相应的甲酯类似物28（可在体内转化为化合物29）作为前药概念。静脉注射化合物28可产生有效的抗痛觉过敏作用，在脊髓神经结扎和化疗引起的周围神经病变大鼠中，ED 50值分别为2.62和2.93 mg / kg，这表明靶向P2X3受体的新药开发有望成为神经病变的