6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H,4H)-quinoxaline-2,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H,4H)-quinoxaline-2,3-dione
• 英文别名: 6,7-Dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydroquinoxaline-2,3-dione
• 化学式: C₁₃H₁₁Cl₂N₅O₂
• 分子量: 340.169
• InChiKey: LEYPOMSTRVKGIO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  88.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  利可替奈 在 盐酸 、 氯化亚砜 、 bis(triphenylphosphine)palladium(II)-chloride 、 四溴化碳 、 氧气 、 臭氧 、 N,N-二甲基甲酰胺 、 三苯基膦 、 lithium chloride 、 tin(ll) chloride 、 sodium nitrite 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 、 氯仿 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 46.75h， 生成 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H,4H)-quinoxaline-2,3-dione
  参考文献：
  名称：

  Structure−Activity Relationships of 1,4-Dihydro-(1H,4H)-quinoxaline-2,3-diones as N-Methyl-d-aspartate (Glycine Site) Receptor Antagonists. 1. Heterocyclic Substituted 5-Alkyl Derivatives

  摘要：

  A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor was measured using the specific radioligand [H-3]- L-689,560, and functional antagonism was demonstrated by inhibition of NMDA-induced depolarizations of rat cortical wedges. The ability to prevent NMDA-induced hyperlocomotion in mice in vivo was measured for selected compounds. Binding affinity increased significantly if the heterocyclic group, e.g. 1,2,3-triazol-1-yl could participate in accepting a hydrogen bond from the receptor. It was difficult to obtain compounds with adequate aqueous solubility and strategies to improve it were investigated. The most potent compound in this series, 6,7-dichloro-5-[1-( 1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-dione (17) (binding IC50 = 2.6 nM; cortical wedge EC50 = 90 nM), inhibited NMDA-induced hyperlocomotion in mice (6/9 protected at 20 mg/kg iv). Pharmacokinetic parameters, including extent of brain penetration, for 11 and 17 are reported.

  DOI：

  10.1021/jm001124p

文献信息

• QUINOXALINEDIONE NMDA RECEPTOR ANTAGONISTS
  申请人：Pfizer Limited

  公开号：EP0781279A1

  公开（公告）日：1997-07-02
• [EN] QUINOXALINEDIONE NMDA RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DU RECEPTEUR NMDA, A BASE DE QUINOXALINEDIONE
  申请人：PFIZER LIMITED

  公开号：WO1996008485A1

  公开（公告）日：1996-03-21

  (EN) Compounds of formula (I) wherein R1 and R2 are each independently F, Cl, Br, CH3, CH2CH3 or CF3; R3 is H, CH3 or CH2CH3; and X is a 5-membered heterocyclic group containing up to four nitrogen atoms, attached via a nitrogen atom, the said group being optionally benzofused and/or substituted by C1-C6 alkyl or (CH2)nNR4R5, wherein n is an integer from 1 to 5 and R4 and R5 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C4 alkyl substituted by phenyl or pyridyl, or R4 and R5 are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, piperazine, N-(C1-C4 alkyl) piperazine, morpholine or azepine group; and their pharmaceutically acceptable salts, are NMDA antagonists of utility in the treatment of acute neurodegenerative disorders, e.g. arising from stroke or traumatic head injury and in chronic neurological disorders, e.g. senile dementia and Alzheimer's disease.(FR) Composés de la formule (I), ainsi que leurs sels acceptables sur le plan pharmacologique, dans laquelle R1 et R2 représentent chacun indépendamment F, Cl, Br, CH3, CH2CH3 ou CF3; R3 représente H, CH3 ou CH2CH3; et X représente un groupe hétérocyclique à 5 chaînons contenant jusqu'à quatre atomes d'azote, ce groupe étant fixé au moyen d'un atome d'azote et étant éventuellement benzo-condensé et/ou substitué par alkyle C1-C6 ou (CH2)nNR4R5, où n est un nombre entier compris entre 1 et 5 et R4 et R5 représentent chacun indépendamment H, alkyle C1-C6, cycloalkyle C3-C6 ou alkyle C1-C4 substitué par phényle ou pyridyle, ou bien R4 et R5 sont liés pour former, ensemble avec l'atome d'azote auquel ils sont fixés, un groupe pyrrolidine, pipéridine, pipérazine, N-(alkyle C1-C4)pipérazine, morpholine ou azépine. Ces composés sont des antagonistes du N-méthyl-D-aspartate (NMDA) utiles dans le traitement de troubles neurodégénératifs aigus consécutifs, par exemple, à une attaque ou à un traumatisme crânien, ainsi que dans les troubles neurologiques chroniques, par exemple la démence sénile ou la maladie d'Alzheimer.
• Structure−Activity Relationships of 1,4-Dihydro-(1H,4H)-quinoxaline-2,3-diones as <i>N</i>-Methyl-<scp>d</scp>-aspartate (Glycine Site) Receptor Antagonists. 1. Heterocyclic Substituted 5-Alkyl Derivatives
  作者：M. Jonathan Fray、David J. Bull、Christopher L. Carr、Elisabeth C. L. Gautier、Charles E. Mowbray、Alan Stobie

  DOI：10.1021/jm001124p

  日期：2001.6.1

  A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor was measured using the specific radioligand [H-3]- L-689,560, and functional antagonism was demonstrated by inhibition of NMDA-induced depolarizations of rat cortical wedges. The ability to prevent NMDA-induced hyperlocomotion in mice in vivo was measured for selected compounds. Binding affinity increased significantly if the heterocyclic group, e.g. 1,2,3-triazol-1-yl could participate in accepting a hydrogen bond from the receptor. It was difficult to obtain compounds with adequate aqueous solubility and strategies to improve it were investigated. The most potent compound in this series, 6,7-dichloro-5-[1-( 1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-dione (17) (binding IC50 = 2.6 nM; cortical wedge EC50 = 90 nM), inhibited NMDA-induced hyperlocomotion in mice (6/9 protected at 20 mg/kg iv). Pharmacokinetic parameters, including extent of brain penetration, for 11 and 17 are reported.