cis-(+/-)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: cis-(+/-)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one
• 英文别名: cis-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one；cis-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one；(4aR,8aS)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one
• 化学式: C₁₆H₂₀N₂O₃
• 分子量: 288.346
• InChiKey: QKTDYBBFKUXEOZ-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  59.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  cis-(+/-)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成
  参考文献：
  名称：

  Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD

  摘要：

  A novel class of dual pharmacology bronchodilators targeting both beta(2)-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better beta(2)-adrenoceptor agonist activities (pEC(50) = 8.47-9.20) than the reference compound salmeterol (pEC(50) = 8.3) and good inhibitory activity on PDE4B2 (IC50 = 0.235-1.093 mu M). (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.11.058
• 作为产物：
  描述：

  1,2-cis-cyclohexanedicarboxylic anhydride 在 aluminum (III) chloride 、 一水合肼 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 18.0h， 生成 cis-(+/-)-4-(3,4-dimethoxyphenyl)-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  合成和评估苯基吡啶哒嗪酮NPD-001作为有效的锥虫TbrPDEB1磷酸二酯酶抑制剂和体外锥虫杀虫剂的类似物

  摘要：

  锥虫磷酸二酯酶B1和B2（TbrPDEB1和TbrPDEB2）在布鲁氏锥虫的生命周期中起着重要作用，布鲁氏锥虫是人类非洲锥虫病（HAT）的致病性寄生虫，也被称为非洲昏睡病。击倒这两种酶会导致细胞周期停滞，并且对寄生虫具有致命性。最近，我们报道了phenylpyridazinone，NPD-001，具有低纳摩尔IC 50个在两个TbrPDEB1值（IC 50：4 1nM）和TbrPDEB2（IC 50：3 nM）的（。传染病杂志 2012，206（229）。在这项研究中，我们现在报告一系列作为TbrPDEB1抑制剂的苯基哒嗪酮类似物的第一个结构活性关系。还显示了选择的化合物是抗寄生虫的。重要的是，观察到TbrPDEB1 IC 50和EC 50与整个寄生虫之间具有良好的相关性。对TbrPDEB1和人PDE上所选化合物的SAR的初步分析显示出很大的差异，这显示出获得寄生虫选择性PDE抑制剂的潜力

  DOI：

  10.1016/j.bmc.2016.02.032

文献信息

• Novel Selective Phosphodiesterase (PDE4) Inhibitors. 4. Resolution, Absolute Configuration, and PDE4 Inhibitory Activity of <i>cis</i>-Tetra- and <i>cis</i>-Hexahydrophthalazinones
  作者：Margaretha Van der Mey、Hildegard Boss、Dennis Couwenberg、Armin Hatzelmann、Geert J. Sterk、Kees Goubitz、Henk Schenk、Hendrik Timmerman

  DOI：10.1021/jm0110338

  日期：2002.6.1

  8a-tetrahydro-2H-phthalazin-1-ones show potent inhibition of phosphodiesterase (PDE4) activity, while the corresponding trans racemic mixtures exhibit only weak to moderate activity. To determine the absolute configuration and PDE4 inhibitory activity of the individual cis-enantiomers, several optically active phthalazinones have been synthesized. The enantiomers of the various gamma-keto acids, used as starting

  最近，我们报道了4-儿茶酚取代的顺-（+/-）-4a，5,6,7,8,8a-六-和顺-（+/-）-4a，5,8,8a-四氢-2H-酞嗪-1-酮显示出对磷酸二酯酶（PDE4）活性的有效抑制作用，而相应的反式外消旋混合物仅表现出弱至中等的活性。为了确定各个顺式对映异构体的绝对构型和PDE4抑制活性，已合成了几种旋光性邻苯二氮酮。用作起始原料的各种γ-酮酸的对映异构体通过形成非对映异构体盐以经典方式拆分，然后以对映选择性的方式将其分别转化为旋光性酞嗪酮。顺式六氢酞嗪酮（+）-12的（+）-对映体的绝对构型通过X射线晶体学测定。发现在4a和8a位置的碳原子分别具有S-和R-构型。在本系列的六氢和四氢邻苯二氮酮中，观察到了对PDE4抑制的立体选择性。邻苯二氮酮的顺-（+）-对映体显示高抑制活性，而它们的（-）-对映体仅显示弱至中等活性。对于顺式（-）-类似物，所有顺式（+）-邻苯二氮酮都可能具有（4
• PHTHALAZINONE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
  申请人：Kagayama Kohei

  公开号：US20090042879A1

  公开（公告）日：2009-02-12

  The present invention provides a novel compound having an excellent PDE4 inhibitory activity and TNF-α production-suppressing activity, and also provides a preventive and therapeutic agent for atopic dermatitis or the like. The present invention includes a novel phthalazinone derivative of the following general structural formula [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising it as an active ingredient. In the structural formula [1], the partial structure bridging the 6-position and the 7-position represents a single bond or a double bond; R 1 and R 2 are the same or different and each represents alkyl or the like; Y represents phenylene or the like; Z represents alkylene or the like; and R 3 represents a mono- to tri-cyclic saturated or unsaturated cyclic amino group or the like optionally substituted with R 31 and R 32 , wherein R 31 and R 32 represent alkyl or the like.

  本发明提供了一种具有优异的PDE4抑制活性和TNF-α产生抑制活性的新型化合物，同时还提供了预防和治疗特应性皮炎或类似疾病的药物。本发明包括以下一般结构式[1]的新型邻苯二酮衍生物或其药学上可接受的盐，以及包含其作为活性成分的制药组合物。在结构式[1]中，连接6位和7位的部分结构代表单键或双键；R1和R2相同或不同，分别代表烷基或类似物；Y代表苯撑基或类似物；Z代表烷基或类似物；R3代表单环至三环饱和或不饱和环状氨基或类似物，可选地被R31和R32取代，其中R31和R32代表烷基或类似物。
• Phthalazinones
  申请人：Byk Gulden Lomberg Chemische Fabrik GmbH

  公开号：US06103718A1

  公开（公告）日：2000-08-15

  Compounds of formula I wherein R1, R2, R3, R4 and R5 have the means set forth in the description are selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4), which are effective bronchial therapeutics.

  化学式为I的化合物，其中R1、R2、R3、R4和R5的平均值如描述中所述，是选择性环状核苷酸磷酸二酯酶（PDE）抑制剂（特别是类型4），是有效的支气管治疗药物。
• PHTHALAZINONE DERIVATIVE AND PHARMACEUTICAL COMPRISING THE SAME
  申请人：Nippon Shinyaku Co., Ltd.

  公开号：EP1873147A1

  公开（公告）日：2008-01-02

  [Problem] The present invention is to provide a novel compound having an excellent PDE4 inhibitory activity and TNF-α production-suppressing activity, and also to provide a preventive and therapeutical agent for atopic dermatitis or the like. [Means for Solution] The present invention includes a novel phthalazinone derivative of the following general structural formula [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising it as an active ingredient. In the structural formula [1], the following partial structure bridging the 6-position and the 7-position represents a single bond or a double bond: R1 and R2 are the same or different and each represents alkyl or the like, Y represents phenylene or the like, Z represents alkylene or the like, R3 represents a mono- to tri-cyclic saturated or unsaturated cyclic amino group or the like, R31 and R32 represent alkyl or the like.

  [问题]本发明旨在提供一种新型化合物，该化合物具有优异的PDE4抑制活性和TNF-α生成抑制活性，同时提供一种特应性皮炎或类似疾病的预防和治疗剂。 [解决方法]本发明包括以下通式结构式[1]的新型酞嗪酮衍生物或其药学上可接受的盐，以及以其为活性成分的药物组合物。 在结构式[1]中 以下连接 6 位和 7 位的部分结构代表单键或双键： R1和R2相同或不同，各自代表烷基或类似物，Y代表亚苯基或类似物，Z代表亚烷基或类似物，R3代表单环至三环饱和或不饱和环状氨基或类似物，R31和R32代表烷基或类似物。
• Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors
  作者：Kohei Kagayama、Tatsuya Morimoto、Seigo Nagata、Fumitaka Katoh、Xin Zhang、Naoki Inoue、Asami Hashino、Kiyoto Kageyama、Jiro Shikaura、Tomoko Niwa

  DOI：10.1016/j.bmc.2009.08.014

  日期：2009.10

  Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure-activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-alpha production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis. (C) 2009 Elsevier Ltd. All rights reserved.