3-(benzyloxy)-4-fluorobenzonitrile | 1351862-19-5

• 物质功能分类: 有机原料 - 有机氟化合物 - 氟苯腈系列
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3-(benzyloxy)-4-fluorobenzonitrile
• 英文别名: 4-fluoro-3-phenylmethoxybenzonitrile
• CAS: 1351862-19-5
• 化学式: C₁₄H₁₀FNO
• 分子量: 227.238
• InChiKey: GINIXKDPEJSSCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  33
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(benzyloxy)-4-fluorobenzonitrile 在 ammonium hydroxide 、 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 氢气 、 sodium hydride 、 potassium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 0.17h， 生成 3-[2-(2,4-Dioxopyrimidin-1-yl)ethoxy]-4-[3-[3-(oxan-2-yloxy)propoxy]phenoxy]benzonitrile
  参考文献：
  名称：

  Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

  摘要：

  A 5-mu M docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (PEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.

  DOI：

  10.1021/jm201134m
• 作为产物：
  描述：

  4-氟-3-甲氧基苯腈 在 potassium carbonate 、 lithium chloride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(benzyloxy)-4-fluorobenzonitrile
  参考文献：
  名称：

  Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

  摘要：

  A 5-mu M docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (PEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.

  DOI：

  10.1021/jm201134m

文献信息

• [EN] TRIAZOLE DERIVATIVES AS TANKYRASE INHIBITORS<br/>[FR] DÉRIVÉS DE TRIAZOLE UTILISÉS EN TANT QU'INHIBITEURS DE TANKYRASE
  申请人：OSLO UNIV HOSPITAL HF

  公开号：WO2018118868A1

  公开（公告）日：2018-06-28

  The present invention relates to compounds of formula (I'), tautomers, stereoisomers, and pharmaceutically acceptable salts thereof, to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy (I') (wherein: Z represents an optionally substituted, 5- or 6-membered unsaturated heterocyclic group comprising at least one nitrogen atom; L represents a 4-, 5- or 6-membered cycloalkyl group, preferably a cyclobutyl group; each R1 independently represents F, CI, Br, I, C1-3 alkyl, C1-3 haloalkyl (e.g. -CF3), -CN, -OH or -NO2, preferably F, CI, Br or 1, e.g. CI or F; each R2independently represents F, CI, Br, I, C1-3 alkyl, -CN, -OH or -NO2, preferably F, CI, Br, I or -CN, e.g. F or -CN; X represents -NR3- or -0-; R3 represents H or a C1-3 alkyl group (e.g. methyl); n is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g 1; and m is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g. 0 or 1). These compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the WNT pathway and increased presence of nuclear β-catenin. For example, these may be used in preventing and/or retarding proliferation of tumor cells and metastasis, for example carcinomas such as colon carcinomas.

  本发明涉及式(I')的化合物，其互变异构体、立体异构体和药学上可接受的盐，以及其制备方法、含有这种化合物的药物配方以及它们在治疗中的用途(I')（其中：Z代表一个可选择取代的、含有至少一个氮原子的5-或6-成员不饱和杂环基团；L代表一个4-、5-或6-成员的环烷基基团，优选为环丁基基团；每个R1独立地代表F、Cl、Br、I、C1-3烷基、C1-3卤代烷基（例如-CF3）、-CN、-OH或-NO2，优选为F、Cl、Br或I，例如Cl或F；每个R2独立地代表F、Cl、Br、I、C1-3烷基、-CN、-OH或- ，优选为F、Cl、Br、I或-CN，例如F或-CN；X代表-NR3-或-0-；R3代表H或一个C1-3烷基基团（例如甲基）；n是一个从0到5的整数，优选为0到3，更优选为0、1或2，例如1；m是一个从0到5的整数，优选为0到3，更优选为0、1或2，例如0或1）。这些化合物在治疗和/或预防受WNT途径信号过度激活和核β-连环蛋白增加影响的疾病或病症方面具有特殊用途。例如，它们可用于预防和/或延缓肿瘤细胞和转移的增殖，例如结肠癌等癌症。
• Identification of a Dual Autophagy and REV-ERB Inhibitor with <i>in Vivo</i> Anticancer Efficacy
  作者：Martina Palomba、Donatella Vecchio、Giulia Allavena、Vito Capaccio、Claudia De Mei、Rita Scarpelli、Benedetto Grimaldi

  DOI：10.1021/acs.jmedchem.3c01432

  日期：2024.1.11

  autophagy process appears as a promising target for anticancer interventions. Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are the only FDA-approved autophagy flux inhibitors. Although diverse anticancer clinical trials are providing encouraging results, several limitations associated with the need of high dosage and long-term administration of these autophagy inhibitors are also emerging

  自噬过程似乎是抗癌干预的一个有希望的目标。氯喹 (CQ) 及其衍生物羟氯喹 (HCQ) 是 FDA 唯一批准的自噬通量抑制剂。尽管各种抗癌临床试验提供了令人鼓舞的结果，但也出现了与这些自噬抑制剂需要高剂量和长期给药相关的一些限制。我们发现，抑制 REV-ERB（一种调节昼夜节律和代谢的核受体）可增强 CQ 介导的癌细胞死亡，并鉴定出一类自噬和 REV-ERB 双重抑制剂，对多种肿瘤细胞显示出体外抗癌活性高于CQ。在此，我们描述了我们的先导优化策略，该策略导致化合物24被鉴定为双重自噬和 REV-ERB 抑制剂，显示出在阻断自噬方面的改进效力、增强的对癌细胞的毒性、最佳的药物样特性以及在小鼠中的功效作为单一抗癌剂的黑色素瘤异种移植模型。
• ARYL OR HETEROARYL DERIVATIVE
  申请人：Teijin Pharma Limited

  公开号：EP4137481A1

  公开（公告）日：2023-02-22

  A compound indicated by formula (I) or a pharmacologically acceptable salt thereof is provided as a compound that can be a therapeutic or prophylactic drug for TRPC6-related diseases, such as nephrotic syndrome, membranous nephropathy, acute renal failure, septicemia, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, and muscular dystrophy. (In the formula, Ar1, Ar2, X1-X3, R1, R3, R7, R8, L1, and L2 are as defined in the specifications.)

  本发明提供了一种根据式(I)指示的化合物，或其药理上可接受的盐，所述化合物可用于作为治疗或预防TRPC6相关疾病的药物，例如肾病综合征、膜性肾病、急性肾功能衰竭、败血症、慢性肾功能衰竭、糖尿病肾病、肺动脉高压、急性肺损伤、心力衰竭、恶性肿瘤和肌营养不良。 (在式(I)中，Ar1、Ar2、X1-X3、R1、R3、R7、R8、L1和L2的定义如说明书中所定义。)
• [EN] CATECHOL DIETHERS AS POTENT ANTI-HIV AGENTS<br/>[FR] DIÉTHERS DE CATÉCHOL COMME AGENTS ANTI-HIV PUISSANTS
  申请人：UNIV YALE

  公开号：WO2013056003A3

  公开（公告）日：2013-06-20
• Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor
  作者：Jo Waaler、Ruben G. G. Leenders、Sven T. Sowa、Shoshy Alam Brinch、Max Lycke、Piotr Nieczypor、Sjoerd Aertssen、Sudarshan Murthy、Albert Galera-Prat、Eddy Damen、Anita Wegert、Marc Nazaré、Lari Lehtiö、Stefan Krauss

  DOI：10.1021/acs.jmedchem.0c00208

  日期：2020.7.9

  Tankyrases 1 and 2 are central biotargets in the WNT/beta-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/beta-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.