8-benzyl-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one | 976-96-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 8-benzyl-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one
• CAS: 976-96-5
• 化学式: C₂₀H₂₂ClN₃O
• 分子量: 355.867
• InChiKey: RGHDGRGJOSPDHW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  8-benzyl-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one 在 10% palladium on carbon 、 氢气 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 生成 1-(4-氯苯基)-1,3,8-三氮螺[4.5]癸烷-4-酮
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Halogenated N-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 Inhibitor

  摘要：

  Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD I and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (> 1700-fold selective), and moderately PLD2-preferring (> 10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date. N-(2-(1-(3-fluorophenyl)-4-oxo-1.3.8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.

  DOI：

  10.1021/jm100814g
• 作为产物：
  描述：

  4-[(4-氯苯基)氨基]-1-(苯基甲基)哌啶-4-甲酰胺 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 18.0h， 生成 8-benzyl-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one
  参考文献：
  名称：

  发现针对F 1 / F O-三磷酸腺苷（ATP）合酶c亚基的新型1,3,8-三氮杂[4.5]癸烷衍生物，用于治疗心肌梗死的再灌注损伤

  摘要：

  近期的心脏病学研究报道了线粒体通透性过渡孔（mPTP）的作用，功能和结构，并表明其打开在继发于再灌注的心肌细胞死亡进程中起关键作用。在本手稿中，我们验证了一种新的药理学方法作为心肌梗塞（MI）治疗中再灌注的辅助手段，并描述了基于a以F 1 / F O的c亚基为靶点的1,3,8-triazaspiro [4.5]癸烷支架-ATP合酶复合物。我们在MI模型中鉴定了三种具有良好mPTP抑制活性和有益作用的潜在化合物，包括全心脏细胞凋亡率降低和再灌注过程中心脏功能的总体改善。所选化合物在细胞和线粒体水平上均未显示脱靶作用。此外，尽管与ATP合酶复合物相互作用，该化合物仍能保持线粒体ATP含量。

  DOI：

  10.1021/acs.jmedchem.8b00278

文献信息

• [EN] 1,3,8-TRIAZASPIRO COMPOUNDS AND THEIR USE AS MEDICAMENTS FOR THE TREATMENT OF REPERFUSION INJURY<br/>[FR] COMPOSÉS 1,3,8-TRIAZASPIRO ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS PERMETTANT LE TRAITEMENT D'UNE LÉSION DE REPERFUSION
  申请人：MARIA CECILIA HOSPITAL S P A

  公开号：WO2020021378A1

  公开（公告）日：2020-01-30

  The present invention relates to a 1,3,8-triazaspiro compound of Formula (I), wherein A is -CH2, -SO2 -, -NH-CO-, -NH-CS- or -CO-; the dashed line represents a single or double bond; R1 is a substituent selected from (C1-C3) alkyl, phenyl, thienyl and cyclohexyl, said substituent being optionally substituted by halogen or (C1 -C3) alkyl; and R2 is a substituent selected from H, (C1-C3) alkyl, (C1-C3) alkoxy, -CF3 and halogen; and wherein, when the dashed line is a double bond, A is -CH2 - and R1 is phenyl, or a pharmaceutically acceptable salt thereof for use in the treatment of reperfusion injury diseases. The 1,3,8-triazaspiro compound of the invention is a selective inhibitor of the C subunit of the F1/Fo-ATP synthase complex and a modulator of the mitochondrial permeability transition pore activity in mammalian cells and tissues, in the treatment of reperfusion injury diseases.

  本发明涉及一种式(I)的1,3,8-三氮杂螺环化合物，其中A为-CH2、-SO2-、-NH-CO-、-NH-CS-或-CO-；虚线代表单键或双键；R1为从(C1-C3)烷基、苯基、噻吩基和环己基中选择的取代基，该取代基可以选择性地被卤素或(C1-C3)烷基取代；R2为从H、(C1-C3)烷基、(C1-C3)烷氧基、-CF3和卤素中选择的取代基；当虚线为双键时，A为-CH2-且R1为苯基，或其在治疗再灌注损伤疾病中的药学上可接受的盐。本发明的1,3,8-三氮杂螺环化合物是F1/Fo-ATP合成酶复合物的C亚基的选择性抑制剂，以及哺乳动物细胞和组织中线粒体通透性转换孔活性的调节剂，在治疗再灌注损伤疾病中。
• 1,3,8-TRIAZASPIRO COMPOUNDS AND THEIR USE AS MEDICAMENTS FOR THE TREATMENT OF REPERFUSION INJURY
  申请人：Maria Cecilia Hospital S.p.A.

  公开号：EP3829579A1

  公开（公告）日：2021-06-09
• Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F₁/F_O-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction
  作者：Giampaolo Morciano、Delia Preti、Gaia Pedriali、Giorgio Aquila、Sonia Missiroli、Anna Fantinati、Natascia Caroccia、Salvatore Pacifico、Massimo Bonora、Anna Talarico、Claudia Morganti、Paola Rizzo、Roberto Ferrari、Mariusz R. Wieckowski、Gianluca Campo、Carlotta Giorgi、Claudio Trapella、Paolo Pinton

  DOI：10.1021/acs.jmedchem.8b00278

  日期：2018.8.23

  function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure–activity relationship

  近期的心脏病学研究报道了线粒体通透性过渡孔（mPTP）的作用，功能和结构，并表明其打开在继发于再灌注的心肌细胞死亡进程中起关键作用。在本手稿中，我们验证了一种新的药理学方法作为心肌梗塞（MI）治疗中再灌注的辅助手段，并描述了基于a以F 1 / F O的c亚基为靶点的1,3,8-triazaspiro [4.5]癸烷支架-ATP合酶复合物。我们在MI模型中鉴定了三种具有良好mPTP抑制活性和有益作用的潜在化合物，包括全心脏细胞凋亡率降低和再灌注过程中心脏功能的总体改善。所选化合物在细胞和线粒体水平上均未显示脱靶作用。此外，尽管与ATP合酶复合物相互作用，该化合物仍能保持线粒体ATP含量。
• Design, Synthesis, and Biological Evaluation of Halogenated <i>N</i>-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 Inhibitor
  作者：Robert R. Lavieri、Sarah A. Scott、Paige E. Selvy、Kwangho Kim、Satyawan Jadhav、Ryan D. Morrison、J. Scott Daniels、H. Alex Brown、Craig W. Lindsley

  DOI：10.1021/jm100814g

  日期：2010.9.23

  Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD I and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (> 1700-fold selective), and moderately PLD2-preferring (> 10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date. N-(2-(1-(3-fluorophenyl)-4-oxo-1.3.8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.