5-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid | 1391029-68-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩哒嗪类
• 英文名称: 5-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid
• 英文别名: 5-Amino-3-(2-chlorophenyl)-4-oxothieno[3,4-d]pyridazine-1-carboxylic acid
• CAS: 1391029-68-7
• 化学式: C₁₃H₈ClN₃O₃S
• 分子量: 321.744
• InChiKey: ZOUKZYRLMPXBCY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid 、 环丙胺 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 以62%的产率得到5-amino-3-(2-chlorophenyl)-N-cyclopropyl-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide
  参考文献：
  名称：

  Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties

  摘要：

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.027
• 作为产物：
  描述：

  邻氯苯胺 在 吗啉 、 盐酸 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 lithium hydroxide monohydrate 、 sodium nitrite 、 4-氨基丁酸 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 22.75h， 生成 5-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylic acid
  参考文献：
  名称：

  Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties

  摘要：

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.027

文献信息

• Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure–activity relationship leads to selection of candidates with desirable in vivo properties
  作者：Carlo Ballatore、Alex Crowe、Francesco Piscitelli、Michael James、Kevin Lou、Gabrielle Rossidivito、Yuemang Yao、John Q. Trojanowski、Virginia M.-Y. Lee、Kurt R. Brunden、Amos B. Smith

  DOI：10.1016/j.bmc.2012.05.027

  日期：2012.7

  Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day. (C) 2012 Elsevier Ltd. All rights reserved.