1,4,6,7-tetrachlorophthalazine | 98436-35-2

• 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: 1,4,6,7-tetrachlorophthalazine
• CAS: 98436-35-2
• 化学式: C₈H₂Cl₄N₂
• 分子量: 267.929
• InChiKey: PEEUMZRLMXYRAW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1,4,6,7-tetrachlorophthalazine 在 N-甲基吡咯烷酮 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 异丙醇 为溶剂， 反应 10.5h， 生成 1-[6,7-Dichloro-4-(3-chloro-4-methoxy-benzylamino)-phthalazin-1-yl]-piperidin-4-ol
  参考文献：
  名称：

  4-(3-Chloro-4-methoxybenzyl)aminophthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

  摘要：

  We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2 alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 mu g/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

  DOI：

  10.1021/jm9905054
• 作为产物：
  描述：

  4,5-二氯邻苯二甲酸酐 在 盐酸 、 hydrazine hydrate 、 三氯氧磷 作用下， 以 喹啉 为溶剂， 反应 27.0h， 生成 1,4,6,7-tetrachlorophthalazine
  参考文献：
  名称：

  N-氯化诱导的1,4-二甲氧基酞嗪的氧化环收缩

  摘要：

  描述了很少探索的富电子的1,2-二嗪的氧化环收缩。用亲电子氯化试剂（TCICA）处理后，1,4-二甲氧基邻苯二甲azine嗪会经历N-氯化诱导的环收缩，并伴有一个氮原子的损失。用一系列的1，4-二甲氧基邻苯二甲醛衍生物检查了这种异常反应性的范围。另外，基于分离的反应中间体和DFT计算，提出了经由双环物质进行的机理。

  DOI：

  10.1016/j.tetlet.2020.152048

文献信息

• N-Chlorination-induced, oxidative ring contraction of 1,4-dimethoxyphthalazines
  作者：Jeong Kyun Im、ByeongDo Yang、Ilju Jeong、Jun-Ho Choi、Won-jin Chung

  DOI：10.1016/j.tetlet.2020.152048

  日期：2020.6

  A rarely explored oxidative ring contraction of electron-rich 1,2-diazine is described. Upon treatment with an electrophilic chlorinating reagent (TCICA), 1,4-dimethoxyphthalazines undergo an N-chlorination-induced ring contraction that is accompanied by the loss of one nitrogen atom. The scope of this unusual reactivity was examined with a range of 1,4-dimethoxyphthalazine derivatives. In addition

  描述了很少探索的富电子的1,2-二嗪的氧化环收缩。用亲电子氯化试剂（TCICA）处理后，1,4-二甲氧基邻苯二甲azine嗪会经历N-氯化诱导的环收缩，并伴有一个氮原子的损失。用一系列的1，4-二甲氧基邻苯二甲醛衍生物检查了这种异常反应性的范围。另外，基于分离的反应中间体和DFT计算，提出了经由双环物质进行的机理。
• KRAS G12C INHIBITORS AND METHODS OF USING THE SAME
  申请人：AMGEN INC.

  公开号：US20180177767A1

  公开（公告）日：2018-06-28

  Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

  本文提供了KRAS G12C抑制剂，其组成，以及使用方法。这些抑制剂对治疗多种疾病有用，包括胰腺癌、结直肠癌和肺癌。
• Condensed pyridazinyl guanidines, their production and use
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0825187A1

  公开（公告）日：1998-02-25

  Pyridazinyl guanidines of the formula: wherein ring A is a benzene ring or a nitrogen-containing 6-membered aromatic ring, each of which may be substituted; and R1 is an aromatic ring group which may be substituted, or a salt thereof, which have activity for inhibiting Na-H exchange and are useful as a prophylactic/therapeutic agent for ischemic cardiovascular diseases such as myocardial infarction and arrythmia.

  吡啶并嗪基胍类化合物，其通式为：其中环A为苯环或含氮的6元芳香环，每个环均可被取代；R1为可被取代的芳香环基团，或其盐，具有抑制Na-H交换的活性，可作为预防/治疗缺血性心血管疾病如心肌梗死和心律失常的药物。
• Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors
  作者：Brian A. Lanman、Jennifer R. Allen、John G. Allen、Albert K. Amegadzie、Kate S. Ashton、Shon K. Booker、Jian Jeffrey Chen、Ning Chen、Michael J. Frohn、Guy Goodman、David J. Kopecky、Longbin Liu、Patricia Lopez、Jonathan D. Low、Vu Ma、Ana E. Minatti、Thomas T. Nguyen、Nobuko Nishimura、Alexander J. Pickrell、Anthony B. Reed、Youngsook Shin、Aaron C. Siegmund、Nuria A. Tamayo、Christopher M. Tegley、Mary C. Walton、Hui-Ling Wang、Ryan P. Wurz、May Xue、Kevin C. Yang、Pragathi Achanta、Michael D. Bartberger、Jude Canon、L. Steven Hollis、John D. McCarter、Christopher Mohr、Karen Rex、Anne Y. Saiki、Tisha San Miguel、Laurie P. Volak、Kevin H. Wang、Douglas A. Whittington、Stephan G. Zech、J. Russell Lipford、Victor J. Cee

  DOI：10.1021/acs.jmedchem.9b01180

  日期：2020.1.9

  in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design

  KRASG12C已成为治疗实体瘤的有希望的靶标。靶向突变半胱氨酸12残基的共价抑制剂已显示出可以通过这个长期的“不可吸收的”靶标破坏信号传导。然而，尚未确定临床上可行的抑制剂。在这里，我们报告了开发利用我们在KRASG12C中鉴定出的隐窝（H95 / Y96 / Q99）的努力，以鉴定适合临床开发的抑制剂。描述了基于结构的设计努力，该努力导致鉴定了新颖的喹唑啉酮支架，以及克服了围绕轴向手性联芳基键旋转受限而引起的构型稳定性问题的优化努力。对产生的潜在生物进行生物制药优化，最终鉴定出了AMG 510，这是一种高效，选择性强，
• [EN] SUBSTITUTED PHTHALAZINES<br/>[FR] PHTALAZINES SUBSTITUÉES
  申请人：ABBVIE INC

  公开号：WO2016123796A1

  公开（公告）日：2016-08-11

  Provided are compounds of formula (I), Wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined in the specification, and pharmaceutically acceptable salts thereof, which are useful as agents in the treatment of diseases and conditions mediated and modulated by SUV402H1. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

  提供的是式(I)的化合物，其中R1、R2、R3、R4、R5和R6如规范中定义，并且其药用盐，这些化合物可用作治疗由SUV402H1介导和调节的疾病和症状的药物。还提供了由一个或多个式(I)化合物组成的药物组合物。