6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline | 178619-90-4

• 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-2,3-dimethoxy-5-iodoquinoxaline
• 英文别名: 6,7-dichloro-5-iodo-2,3-dimethoxyquinoxaline
• CAS: 178619-90-4
• 化学式: C₁₀H₇Cl₂IN₂O₂
• 分子量: 384.988
• InChiKey: JLFLGSYJXFGJPO-UHFFFAOYSA-N

物化性质

• 沸点：
  402.4±40.0 °C(Predicted)
• 密度：
  1.887±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  44.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline 在 bis(triphenylphosphine)palladium(II)-chloride 、 四溴化碳 、 氧气 、 臭氧 、 三苯基膦 、 lithium chloride 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.5h， 生成 6,7-Dichloro-5-(1-imidazol-1-ylpropyl)-2,3-dimethoxyquinoxaline
  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
• 作为产物：
  描述：

  2,3,6,7-tetrachloro-5-nitro-quinoxaline 在 盐酸 、 tin(ll) chloride 、 sodium nitrite 作用下， 以 甲醇 、 乙酸乙酯 、 丙酮 为溶剂， 反应 7.25h， 生成 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline
  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 Inc.

  公开号：US05783572A1

  公开（公告）日：1998-07-21

  Compounds of formula (I): ##STR1## and their pharmaceutically acceptable salts, wherein R.sup.1 and R.sub.2 are each independently Cl, Br, CH.sub.3, CH.sub.2 CH.sub.3 or CF.sub.3 ; R.sup.3 is H, CH.sub.3 or CH.sub.2 CH.sub.3 ; and X is a 5-membered heterocyclic group containing up to four nitrogen atoms, attached via a nitrogen atom, the said group being optionally substituted by C.sub.1 -C.sub.6 alkyl or (CH.sub.2).sub.n NR.sup.4 R.sup.5, wherein n is an integer from 1 to 5 and R.sup.4 and R.sup.5 are each independently H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.1 -C.sub.4 alkyl substituted by phenyl or pyridyl, or R.sup.4 and R.sup.5 are linked to form, together with the nitrogen atom to which attached, a pyrrolidine, piperidine, piperazine, N-(C.sub.1 -C.sub.4 alkyl) piperazine, morpholine or azepine group, or, when X is triazolyl, said group may optionally be benzofused, are NMDA antagonists of value 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.

  式(I)的化合物及其药学上可接受的盐，其中R.sup.1和R.sub.2各自独立地为Cl、Br、CH.sub.3、CH.sub.2 CH.sub.3或CF.sub.3；R.sup.3为H、CH.sub.3或CH.sub.2 CH.sub.3；X为通过氮原子连接的含有最多四个氮原子的5-成员杂环基团，该基团可选地被C.sub.1-C.sub.6烷基或(CH.sub.2).sub.nNR.sup.4R.sup.5取代，其中n是从1到5的整数，R.sup.4和R.sup.5各自独立地为H、C.sub.1-C.sub.6烷基、C.sub.3-C.sub.6环烷基或被苯基或吡啶基取代的C.sub.1-C.sub.4烷基，或者R.sup.4和R.sup.5连接在一起，与连接的氮原子一起形成吡咯烷、哌嗪、哌嗪二氮杂环、N-(C.sub.1-C.sub.4烷基)哌嗪、吗啉或氮杂庚烷基团，或者当X为三唑基时，该基团可选地被苯并，是NMDA拮抗剂，对于急性神经退行性疾病的治疗具有价值，例如由中风或创伤性头部损伤引起的疾病，以及慢性神经系统疾病，例如老年性痴呆和阿尔茨海默病。
• Quinoxalinediones
  申请人：Pfizer Inc

  公开号：US06376490B1

  公开（公告）日：2002-04-23

  The invention provides compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon or nitrogen atom said group being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, C3-C7 cycloalkyloxy, —COOH, C1-C4 alkoxycarbonyl, —CONR3R4, —NR3R4, —S(O)p(C1-C4 alkyl), —SO2NR3R4, aryl, aryloxy, aryl(C1-C4)alkoxy, and het, said C1-C4alkyl being optionally substituted by C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, halo(C1C4)alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkyl (C1-C4) alkoxy, —COOH, C1-C4 alkoxycarbonyl, —CONR3R4, —NR3R4,—S(O)p(C1-C4 alkyl), —SO2(aryl), —SO2NR3R4 morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or het, and said C2-C4 alkenyl being optionally substituted by aryl; and R1 and R2 are each independently selected from H, fluoro, chloro, bromo, C1-C4 alkyl and halo(C1-C4)alkyl. The compounds are useful as NDMA receptor antagonists for treating acute neurodegenerative and chronic neurological disorders.

  本发明提供了化合物(I)或其药学上可接受的盐，其中R是一个5元环杂芳基基团，包含3或4个氮杂原子，该基团通过一个环碳或环氮原子与喹哌啉二酮环相连，该基团可以选择苯并和选择性取代，在苯并部分中，每个独立选择自C1-C4烷基，C2-C4烯基，C3-C7环烷基，卤素，羟基，C1-C4烷氧基，C3-C7环烷氧基，-COOH，C1-C4烷氧羰基，-CONR3R4，-NR3R4，-S（O）p（C1-C4烷基），-SO2NR3R4，芳基，芳基氧基，芳基（C1-C4）烷氧基和杂环中的1或2个取代基，所述C1-C4烷基可以选择性地被C3-C7环烷基，卤素，羟基，C1-C4烷氧基，卤素（C1C4）烷氧基，C3-C7环烷氧基，C3-C7环烷基（C1-C4）烷氧基，-COOH，C1-C4烷氧羰基，-CONR3R4，-NR3R4，-S（O）p（C1-C4烷基），-SO2（芳基），-SO2NR3R4，吗啉基，芳基，芳基氧基，芳基（C1-C4）烷氧基或杂环取代，所述C2-C4烯基可以选择性地被芳基取代；R1和R2各自独立选择自H，氟，氯，溴，C1-C4烷基和卤素（C1-C4）烷基。这些化合物可用作NDMA受体拮抗剂，用于治疗急性神经退行性和慢性神经疾病。
• QUINOXALINEDIONE NMDA RECEPTOR ANTAGONISTS
  申请人：Pfizer Limited

  公开号：EP0781279A1

  公开（公告）日：1997-07-02
• QUINOXALINEDIONES
  申请人：Pfizer Research and Development Company, N.V./S.A.

  公开号：EP0885212A1

  公开（公告）日：1998-12-23
• US5783572A
  申请人：——

  公开号：US5783572A

  公开（公告）日：1998-07-21