5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester | 1345962-85-7

• 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: 5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester
• 英文别名: Dimethyl 5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methylpyridine-3,4-dicarboxylate；dimethyl 5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methylpyridine-3,4-dicarboxylate
• CAS: 1345962-85-7
• 化学式: C₂₀H₂₁NO₇
• 分子量: 387.389
• InChiKey: ROXJQGCWMBTXLE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester 在 水 、 potassium hydroxide 作用下， 反应 6.0h， 以54%的产率得到2-[2-(4-carboxyphenyl)ethyl]-5-hydroxy-6-methylpyridine-3,4-dicarboxylic acid
  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：

  3-(4-甲氧基羰基苯基)丙酸 在 盐酸 、 四磷十氧化物 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 21.0h， 生成 5-hydroxy-2-[2-(4-methoxycarbonylphenyl)ethyl]-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester
  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

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。
• US9546139B2
  申请人：——

  公开号：US9546139B2

  公开（公告）日：2017-01-17