1-(phenylmethyl)-4,4-(2-phenyl-2,4-diaza-4-oxo-cyclopentane)piperidine | 974-42-5

• 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: 1-(phenylmethyl)-4,4-(2-phenyl-2,4-diaza-4-oxo-cyclopentane)piperidine
• 英文别名: 8-benzyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one；8-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]dec-2-en-4-one；1-Oxo-4-phenyl-8-benzyl-2,4,8-triazaspiro(4,5)decen-(2)；1-Phenyl-8-(phenylmethyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one
• CAS: 974-42-5
• 化学式: C₂₀H₂₁N₃O
• 分子量: 319.406
• InChiKey: SWSPODLAWAERSY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  35.9
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(phenylmethyl)-4,4-(2-phenyl-2,4-diaza-4-oxo-cyclopentane)piperidine 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium hydride 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 25.0 ℃ 、310.27 kPa 条件下， 反应 122.5h， 生成 (8-{[(2-甲基-2-丙基)氧基]羰基}-4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸-3-基)乙酸
  参考文献：
  名称：

  Synthesis and Characterization of Pseudopeptide Bradykinin B2 Receptor Antagonists Containing the 1,3,8-Triazaspiro[4.5]decan-4-one Ring System

  摘要：

  A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro(2)-Pro(3)-Gly(4)-Phe(5) section of the peptide bradykinin B2 receptor antagonist [Pro(3), Phe(5)]HOE 140 (D-Arg(0)-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-D-Tic(7)-Oic(8)-Arg(9)) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in, vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.

  DOI：

  10.1021/jm950676i
• 作为产物：
  描述：

  苯胺 在 硫酸 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 36.5h， 生成 1-(phenylmethyl)-4,4-(2-phenyl-2,4-diaza-4-oxo-cyclopentane)piperidine
  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- -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。
• Fluorescent Tools for the Imaging of Dopamine D₂‐Like Receptors**
  作者：Martin Nagl、Denise Mönnich、Niklas Rosier、Hannes Schihada、Alexei Sirbu、Nergis Konar、Irene Reyes‐Resina、Gemma Navarro、Rafael Franco、Peter Kolb、Paolo Annibale、Steffen Pockes

  DOI：10.1002/cbic.202300659

  日期：2024.1.15

  The family of dopamine D₂‐like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D₂‐like receptors. Pharmacological characterization in radioligand binding studies identified UR‐MN212 (20) as a high‐affinity ligand for D₂‐like receptors (pK_i (D_2longR)=8.24, pK_i (D₃R)=8.58, pK_i (D₄R)=7.78) with decent selectivity towards D₁‐like receptors. Compound 20 is a neutral antagonist in a G_o1 activation assay at the D_2longR, D₃R, and D₄R, which is an important feature for studies using whole cells. The neutral antagonist 20, equipped with a 5‐TAMRA dye, displayed rapid association to the D_2longR in binding studies using confocal microscopy demonstrating its suitability for fluorescence microscopy. Furthermore, in molecular brightness studies, the ligand's binding affinity could be determined in a single‐digit nanomolar range that was in good agreement with radioligand binding data. Therefore, the fluorescent compound can be used for quantitative characterization of native D₂‐like receptors in a broad variety of experimental setups.

  摘要多巴胺 D2 样受体家族是治疗各种神经系统疾病（如帕金森病（PD）、成瘾或精神分裂症）的有趣靶点。帕金森病（PD）、成瘾症或精神分裂症。在这项研究中，我们描述了一组新的荧光配体的合成过程，它们是多巴胺 D2 样受体可视化的工具。在放射性配体结合研究中进行的药理学表征发现，UR-MN212（20）是 D2 样受体的高亲和性配体（pKi (D2longR)=8.24, pKi (D3R)=8.58, pKi (D4R)=7.78 ），对 D1 样受体具有良好的选择性。在 D2longR、D3R 和 D4R 的 Go1 激活试验中，化合物 20 是一种中性拮抗剂，这对于使用全细胞进行的研究来说是一个重要特征。中性拮抗剂 20 配有 5-TAMRA 染料，在使用共聚焦显微镜进行的结合研究中显示出与 D2longR 的快速结合，这表明它适用于荧光显微镜。此外，在分子亮度研究中，配体的结合亲和力可在个位数纳摩尔范围内确定，与放射性配体的结合数据十分吻合。因此，该荧光化合物可用于在各种实验装置中对原生 D2 样受体进行定量表征。
• 1,3,8-Triaza-spiro 4,5 decan-4-on derivatives
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0921125A1

  公开（公告）日：1999-06-09

  The present invention relates to compounds of the general formula wherein R1is hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl, lower alkyl-phenyl or (C5-7)-cycloalkyl; R2is hydrogen, lower alkyl, phenyl or lower alkyl-phenyl; R3is hydrogen, lower alkyl, benzyl, lower alkyl-phenyl, lower alkyl-diphenyl, triazinyl, cyanomethyl, lower alkyl-piperidinyl, lower alkyl-naphthyl, (C5-7)-cycloalkyl, lower alkyl-(C5-7)-cycloalkyl, lower alkyl-pyridinyl, lower alkyl-morpholinyl, lower alkyl-dioxolanyl, lower alkyl-oxazolyl or lower alkyl-2-oxo-oxazolidinyl and wherein the ring systems may be substituted by additional lower alkyl, lower alkoxy, trifluoromethyl or phenyl, or -(CH2)nC(O)O-lower alkyl, -(CH2)nC(O)NH2, -(CH2)nC(O)N(lower alkyl)2, -(CH2)nOH or -(CH2)nC(O)NHCH2C6H5; R4is hydrogen, lower alkyl or nitrilo; Ais a ring system, consisting of (a) (C5-15)-cycloalkyl, which may be in addition to R4optionally substituted by lower alkyl, trifluoromethyl, phenyl, (C5-7)-cycloalkyl, spiro-undecan-alkyl or by 2-norbornyl, or is one of the following groups dodecahydro-acenaphthylen-1yl (e), bicyclo[6.2.0]dec-9-yl (f) and bicyclononan-9-yl (g); and wherein R5 and R6are hydrogen, lower alkyl or taken together and with the carbon atoms to which they are attached form a phenyl ring; R7is hydrogen or lower alkyl; the dotted line represents an optional bond and nis 1 to 4; and to pharmaceutically acceptable acid addition salts thereof. Compounds of the present invention are agonists and/or antagonists of the Orphanin FQ (OFQ) receptor. Consequently they will be useful in the treatment of memory and attention deficits, psychiatric, neurological and physiological disorders, especially, but not limited to, amelioration of symptoms of anxiety and stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, epilepsy and convulsions, acute and/or chronic pain conditions, symptoms of addictive drug withdrawal, control of water balance, Na+ excretion, arterial blood pressure disorders and metabolic disorders such as obesity.

  本发明涉及通式如下的化合物 式中 R1是氢、低级烷基、卤素、低级烷氧基、三氟甲基、低级烷基苯基或(C5-7)-环烷基； R2 是氢、低级烷基、苯基或低级烷基苯基； R3是氢、低级烷基、苄基、低级烷基-苯基、低级烷基-二苯基、三嗪基、氰甲基、低级烷基-哌啶基、低级烷基-萘基、（C5-7）-环烷基、低级烷基-（C5-7）-环烷基、低级烷基-吡啶基、低级烷基-吗啉基、低级烷基-二氧戊环基、低级烷基-噁唑基或低级烷基-2-氧代-噁唑烷基，其中环系统可被额外的低级烷基、低级烷氧基、三氟甲基或苯基取代，或被-(CH2)nC(O)O-低级烷基、-( )nC(O)NH2、-( )nC(O)N(低级烷基)2、-( )nOH 或 -( )nC(O)NH C6H5取代； R4 是氢、低级烷基或硝基； A 是一个环状系统，包括 (a) (C5-15)-环烷基，除 R4 外，还可被低级烷基、三氟甲基、苯基、(C5-7)-环 烷基、螺十一烷基或 2-降冰片基取代，或为以下基团之一 十二氢-苊烯-1-基 (e)、双环[6.2.0]癸-9-基 (f) 和双环壬-9-基 (g)； 其中 R5 和 R6 为氢、低级烷基或与它们所连接的碳原子一起形成苯环； R7 为氢或低级烷基； 虚线代表任选键，且 n为 1 至 4； 及其药学上可接受的酸加成盐。 本发明的化合物是孤儿素 FQ（OFQ）受体的激动剂和/或拮抗剂。因此，它们可用于治疗记忆和注意力缺陷、精神、神经和生理疾病，特别是但不限于改善焦虑和应激障碍、抑郁症、创伤、阿尔茨海默病或其他痴呆症引起的记忆丧失、癫痫和抽搐、急性和/或慢性疼痛、成瘾药物戒断症状、控制水平衡、Na+排泄、动脉血压紊乱和代谢紊乱（如肥胖）等症状。
• Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors
  作者：Xiuqi Miao、Lingyun Xing、Ming Guo、Hong Zhang、Sicong Liu、Shiliang Yin、Ping Gong、Dajun Zhang、Xin Zhai

  DOI：10.1016/j.bioorg.2019.103456

  日期：2020.1

  Aiming to develop novel Type -I-1/2 inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22at) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC50 values of 0.06 and 0.23 mu M against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALK(WT) (2.5 nM) and ALK(L1196m )(6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type -I-1/2 inhibitor binding mode.
• Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production of carfentanil, sufentanil, and remifentanil
  作者：Andrew J. Walz、Fu-Lian Hsu

  DOI：10.1016/j.tetlet.2013.11.058

  日期：2014.1

  Two spirodiaza intermediates have been made and employed in the synthesis of 4-anilinopiperidine methyl esters. These intermediates can be utilized in the production of commercial synthetic analgesics carfentanil, sufentanil, and remifentanil. Published by Elsevier Ltd.