6-(3-chloro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion | 1360118-40-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion
• 英文别名: Ddtpa；3-[4-(3-chloro-4-propan-2-yloxyanilino)-3-[(4-methylphenyl)methyl]-2,6-dioxo-1,3,5-triazin-1-yl]propanoic acid
• CAS: 1360118-40-6
• 化学式: C₂₃H₂₅ClN₄O₅
• 分子量: 472.928
• InChiKey: KRHNDEFYSFIWAD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-(4-氯苄基)-2-硫脲 在 偶氮二甲酸二异丙酯 、 溶剂黄146 、 三苯基膦 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 叔丁醇 为溶剂， 反应 24.0h， 生成 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion
  参考文献：
  名称：

  二氧三嗪衍生物作为一类新的 P2X3 受体拮抗剂：先导和初步 SAR 研究的确定

  摘要：

  P2X 3受体是一种 ATP 门控离子通道，主要位于外周感觉神经元。目前，正在使用 P2X 3受体拮抗剂治疗慢性疼痛或咳嗽进行多项临床试验。为了鉴定 P2X 3先导化合物，我们重新检查了 HTS 评估化合物并选择了二氧代三嗪衍生物，从中我们鉴定了一种命中化合物。由于命中先导 SAR，我们获得了对 P2X 3受体具有中等抑制作用的先导化合物1 (IC 50 , 128 nM)。这种先导化合物的效力和 PK 曲线的进一步改进最终导致了选定的化合物74（P2X 3 IC50 , 16.1 nM；P2X 2/3 IC 50 , 2931 nM)，在神经性疼痛的大鼠坐骨神经部分结扎模型 (ED 50 , 3.1 mg/kg) 中显示出对口服给药的异常性疼痛有很强的镇痛作用。

  DOI：

  10.1016/j.bmcl.2021.127833

文献信息

• TRIAZINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION HAVING AN ANALGESIC ACTIVITY COMPRISING THE SAME
  申请人：Kai Hiroyuki

  公开号：US20130172317A1

  公开（公告）日：2013-07-04

  The present invention provides novel compounds having a P2X 3 and/or P2X 2/3 receptor antagonistic effect. A pharmaceutical composition having an analgesic effect or an improving effect of urination disorder comprising a compound of the formula (I): wherein R h and R j are taken together to form a bond; R a and R b and/or R d and R e are taken together to form oxo or the like; R c is hydrogen, substituted or unsubstituted alkyl or the like; R f is —(CR 4a R 4b ) n —R 2 ; R 4a and R 4b are hydrogen, substituted or unsubstituted alkyl or the like; R 2 is substituted or unsubstituted cycloalkyl or the like; n is an integer of 1 to 4; —R g is —X—R 3 ; —X— is —O—, —S— or the like; R 3 is substituted or unsubstituted cycloalkyl or the like, or its pharmaceutically acceptable salt or a solvate thereof.

  本发明提供了具有P2X3和/或P2X2/3受体拮抗作用的新型化合物。一种具有镇痛作用或改善排尿障碍作用的药物组合物，包括式（I）的化合物：其中Rh和Rj结合形成键；Ra和Rb和/或Rd和Re结合形成氧化物或类似物；Rc是氢、取代或未取代的烷基或类似物；Rf是-(CR4aR4b)n-R2；R4a和R4b是氢、取代或未取代的烷基或类似物；R2是取代或未取代的环烷基或类似物；n是1到4的整数；-R是-X-R3；-X-是-O-、-S-或类似物；R3是取代或未取代的环烷基或类似物，或其药学上可接受的盐或其溶剂化物。
• Druggable site near the upper vestibule determines the high affinity and P2X3 homotrimer selectivity of sivopixant/S‐600918 and its analogue DDTPA
  作者：Dong‐Ping Wang、Meng Zhang、Ming Li、Xiao‐Na Yang、Changzhu Li、Peng Cao、Michael X. Zhu、Yun Tian、Ye Yu、Yun‐Tao Lei

  DOI：10.1111/bph.16273

  日期：2024.4

  The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF‐219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S‐600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3‐(4‐([3‐chloro‐4‐isopropoxyphenyl]amino)‐3‐(4‐methylbenzyl)‐2,6‐dioxo‐3,6‐dihydro‐1,3,5‐triazin‐1(2H)‐yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear.

  To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole‐cell recording.

  The high affinity and selectivity of sivopixant/DDTPA for hP2X3 receptors was determined by the tri‐symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant/DDTPA as the hP2X3 homotrimer.

  From the receptor‐ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough‐suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors.

  背景和目的P2X3受体是一种三聚离子型嘌呤能受体，已成为难治性慢性咳嗽（RCC）的潜在治疗靶点。然而，已上市的唯一一种 P2X3 受体拮抗剂 gefapixant/AF-219 可能会通过调节人类 P2X2/3（hP2X2/3）异三聚体而导致味觉障碍。因此，在 RCC 药物开发中，对 hP2X3 同源三聚体具有强亲和力而对 hP2X2/3 异源三聚体具有弱亲和力的化合物大有可为。Sivopixant/S-600918 就是这样一种分子，它是临床 II 期 RCC 候选药物，与 gefapixant 相比，可降低味觉障碍的发生率。Sivopixant 及其类似物（3-(4-([3-氯-4-异丙氧基苯基]氨基)-3-(4-甲基苄基)-2,6-二氧代-3,6-二氢-1,3,5-三嗪-1(2H)-基)丙酸 (DDTPA)）与 hP2X2/3 杂三聚体相比，对 hP2X3 同源三聚体具有高亲和力和高选择性。实验方法为了分析该候选药物与其他 P2X3 受体抑制剂的区别机制，我们结合使用了嵌合体构建、位点共价占据、元动力学、诱变和全细胞记录等方法。主要结果西维潘坦/DDTPA 对 hP2X3 受体的高亲和力和高选择性是由位于上前庭附近的三对称位点决定的。只需将 hP2X2 上体结构域内的四个氨基酸替换为 hP2X3 的氨基酸，就能使 hP2X2/3 异源三聚体与 hP2X3 同源三聚体一样，对西维必沙/滴滴涕表现出相似的表观亲和力。结论与启示从受体-配体识别的角度，我们阐明了新型 RCC 临床候选药物镇咳特性和减少副作用的分子基础，为发现特异性靶向 P2X3 受体的新型药物提供了一种前景广阔的方法。
• TRIAZINE DERIVATIVE AND PHARMACEUTICAL COMPOUND THAT CONTAINS SAME AND EXHIBITS ANALGESIC ACTIVITY
  申请人：Shionogi & Co., Ltd.

  公开号：EP2604595A1

  公开（公告）日：2013-06-19

  The present invention provides novel compounds having a P2X3 and/or P2X2/3 receptor antagonistic effect. A pharmaceutical composition having an analgesic effect or an improving effect of urination disorder comprising a compound of the formula (I): wherein Rh and Rj are taken together to form a bond; Ra and Rb and/or Rd and Re are taken together to form oxo or the like; Rc is hydrogen, substituted or unsubstituted alkyl or the like; Rf is -(CR4aR4b)n-R2; R4a and R4b are hydrogen, substituted or unsubstituted alkyl or the like; R2 is substituted or unsubstituted cycloalkyl or the like; n is an integer of 1 to 4; -Rg is -X-R3; -X- is -O-, -S- or the like; R3 is substituted or unsubstituted cycloalkyl or the like, or its pharmaceutically acceptable salt or a solvate thereof.

  本发明提供了具有 P2X3 和/或 P2X2/3 受体拮抗作用的新型化合物。 一种具有镇痛效果或改善排尿障碍效果的药物组合物，由式（I）化合物组成： 其中 Rh 和 Rj 共同形成键；Ra 和 Rb 和/或 Rd 和 Re 共同形成氧代或类似物；Rc 是氢、取代或未取代的烷基或类似物； Rf是-(CR4aR4b)n-R2；R4a和R4b是氢、取代或未取代的烷基或类似物；R2是取代或未取代的环烷基或类似物；n是1至4的整数；-Rg是-X-R3；-X-是-O-、-S-或类似物；R3是取代或未取代的环烷基或类似物、 或其药学上可接受的盐或其溶液。
• EP2604595
  申请人：——

  公开号：——

  公开（公告）日：——
• EP2604595B1
  申请人：——

  公开号：EP2604595B1

  公开（公告）日：2016-03-16