cis-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-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,5,8,8a-tetrahydro-2H-phthalazin-1-one
• 英文别名: (4aR,8aS)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
• 化学式: C₁₆H₁₈N₂O₃
• 分子量: 286.331
• InChiKey: MRBFFQVXMIGKST-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 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,5,8,8a-tetrahydro-2H-phthalazin-1-one 在 吡啶 、 4-二甲氨基吡啶 、 氢氧化钾 、 五氯化磷 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 cis-2-[4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-N-[3-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]acetamide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of cis-Tetrahydrophthalazinone/Pyridazinone Hybrids:  A Novel Series of Potent Dual PDE3/PDE4 Inhibitory Agents

  摘要：

  In this study, the synthesis and in vitro and in vivo pharmacological investigations of a new series of phthalazinone/pyridazinone hybrids with both PDE3 and PDE4 inhibitory activities are described. These compounds combine the pharmacophores of recently discovered 4a,5,8,8a-tetrahydro-2H-phthalazin-1-one-type inhibitors of PDE4 and the well-known 2H-pyridazin-3-one-type PDE3 inhibitors such as the tetrahydrobenzimidazoles. Most of the synthesized compounds are pharmacologically spoken PDE3/PDE4 hybrids. All hybrids show potent PDE4 inhibitory activity (pIC(50) = 7.0-8.7), whereas the pIC(50) values for inhibition of PDE3 vary from 5.4 to 7.5. In general, analogues with a 5-methyl-4,5-dihydropyridazinone moiety exhibit the highest PDE3 inhibitory activities. The highest in vivo antiinflammatory activity is displayed by phthalazinones 43 and 44 showing, at a dose of 30 mumol/kg po, 46% inhibition of arachidonic acid (AA) induced mouse ear edema. No correlation was found between the in vitro PDE3 and/or PDE4 inhibitory activity and the in vivo antiinflammatory capacity after oral dosing.

  DOI：

  10.1021/jm030776l
• 作为产物：
  描述：

  cis-1,2,3,6-tetrahydrophthalic 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,5,8,8a-tetrahydro-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

• 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.
• Novel Selective PDE4 Inhibitors. 2. Synthesis and Structure−Activity Relationships of 4-Aryl-Substituted <i>cis</i>-Tetra- and <i>cis</i>-Hexahydrophthalazinones
  作者：Margaretha Van der Mey、Armin Hatzelmann、Gerard P. M. Van Klink、Ivonne J. Van der Laan、Geert J. Sterk、Ulrich Thibaut、Wolf R. Ulrich、Hendrik Timmerman

  DOI：10.1021/jm010838c

  日期：2001.8.1

  A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC(50) = 9.7).