2-溴-1-(6-氟-3-吡啶基)乙酮 | 84331-15-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 2-溴-1-(6-氟-3-吡啶基)乙酮
• 英文名称: 2-bromo-1-(6-fluoropyridin-3-yl)ethan-1-one
• 英文别名: 5-bromo-acetyl-2-fluoropyridine；2-bromo-1-(6-fluoropyridin-3-yl)ethanone；2-Bromo-1-(6-fluoro-3-pyridinyl)ethanone
• CAS: 84331-15-7
• 化学式: C₇H₅BrFNO
• 分子量: 218.025
• InChiKey: LJKBMOJQJMPXQW-UHFFFAOYSA-N

物化性质

• 密度：
  1.656

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  11
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  30
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-溴-1-(6-氟-3-吡啶基)乙酮 生成 6-Fluoro-α-{[(1,1-dimethyl-3-phenylpropyl)amino]-methyl}-3-pyridinemethanol
  参考文献：
  名称：

  ATKINSON, JOSEPH G.;BALDWIN, JOHN J.;MCCLURE, DAVID E.

  摘要：

  DOI：
• 作为产物：
  描述：

  1-(6-氟吡啶)-2-乙酮 生成 2-溴-1-(6-氟-3-吡啶基)乙酮
  参考文献：
  名称：

  ATKINSON, JOSEPH G.;BALDWIN, JOHN J.;MCCLURE, DAVID E.

  摘要：

  DOI：

文献信息

• Aralkylaminoethanol heterocyclic compounds
  申请人：——

  公开号：US04816457A1

  公开（公告）日：1989-03-28

  Heterocyclic aminoethanols of the formula: Het--CHOH--CH.sub.2 --NH-aralkyl where Het is a 6-10 membered N-heterocycle are disclosed. The compounds are useful as pharmaceuticals.

  公开了公式为：Het--CHOH--CH.sub.2 --NH-aralkyl的杂环氨基乙醇，其中Het是6-10成员N-杂环。这些化合物可用作药物。
• Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils
  作者：Bright C. Uzuegbunam、Junhao Li、Wojciech Paslawski、Wolfgang Weber、Per Svenningsson、Hans Ågren、Behrooz Hooshyar Yousefi

  DOI：10.3389/fnagi.2022.830704

  日期：——

  The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[¹⁸F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [¹⁸F]d₂, 6-(4′-(3-[¹⁸F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [¹⁸F]d₄, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[¹⁸F]fluoropyridin-3-yl)-2,2′-bithiazole [¹⁸F]d₆, and 6-(4′-(6-[¹⁸F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [¹⁸F]d₈ were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d₂, d₄, d₆, and d₈ showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (S_NAr) reaction ([¹⁸F]d₂ and [¹⁸F]d₄) or typical S_NAr reaction ([¹⁸F]d₆ and [¹⁸F]d₈) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [¹⁸F]d₂ and [¹⁸F]d₄ showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [¹⁸F]d₆ and [¹⁸F]d₈ showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [¹⁸F]d₆ and [¹⁸F]d₈ were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [¹⁸F]d₈ seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

  α-突触核蛋白（α-syn）在人类大脑中的聚集是所有α-突触核蛋白病变的共同现象。目前还无法使用特定靶向放射性示踪剂在活体大脑中非侵入性地检测这些聚集。我们最近发现，在二芳基双噻唑（DABTA）基础示踪剂的结构中包含亚甲二氧基基团可以提高与α-syn的结合亲和力和选择性。随后，我们采用补充的in silico建模和机器学习（ML）来预测配体结合的表面位点和结构-性质关系。基于这一观察，我们开发了一系列小型DABTA库，其中4-（苯并[d][1,3]二氧杂环-5-基）-4'-（3-[¹⁸F]氟-4-甲氧基苯基）-2,2'-双噻唑[¹⁸F]d₂，6-（4'-（3-[¹⁸F]氟-4-甲氧基苯基）-[2,2'-双噻唑]-4-基）-[1,3]二氧杂杂环[4,5-b]吡啶[¹⁸F]d₄，4-（苯并[d][1,3]二氧杂环-5-基）-4'-（6-[¹⁸F]氟吡啶-3-基）-2,2'-双噻唑[¹⁸F]d₆和6-（4'-（6-[¹⁸F]氟吡啶-3-基）-[2,2'-双噻唑]-4-基）-[1,3]二氧杂杂环[4,5-b]吡啶[¹⁸F]d₈基于它们对α-syn的高结合亲和力而被选择并进一步评估。使用上述示踪剂的非放射性版本进行结合测定实验表明，这些配体对α-syn具有很高的结合亲和力：分别为1.22、0.66、1.21和0.10 nM，并且对β-淀粉样斑块（Aβ）和微管蛋白tau聚集物具有极高的选择性（>200倍选择性）。为获得这些示踪剂，它们的前体物通过创新的铑介导的（S_NAr）反应（[¹⁸F]d₂和[¹⁸F]d₄）或典型的S_NAr反应（[¹⁸F]d₆和[¹⁸F]d₈）进行放射性标记，并具有中等到高的放射化学收率（13% - 40%）和高的摩尔活性>60 GBq/μmol。在健康小鼠中进行的示踪剂生物分布实验表明，[¹⁸F]d₂和[¹⁸F]d₄显示出亚优的脑药代动力学：分别为5分钟后的1.58和4.63%ID/g，以及60分钟后的1.93和3.86%ID/g。然而，[¹⁸F]d₆和[¹⁸F]d₈显示出改善的脑药代动力学：分别为5分钟后的5.79和5.13%ID/g，60分钟后的1.75和1.07%ID/g，以及120分钟后的1.04和0.58%ID/g。[¹⁸F]d₆和[¹⁸F]d₈的脑摄取动力学在动态PET研究中得到确认。这两种示踪剂在健康小鼠中的初始in vivo稳定性实验中也没有脑放射代谢物。基于其结合性能和in vivo稳定性，[¹⁸F]d₈似乎非常有前途，因此鼓励进一步验证其作为α-syn活体内可视化示踪剂在临床前和临床设置中的有用性。此外，in silico和ML预测值与配体的实验结合亲和力相关。
• NOVEL PEPTIDE INHIBITORS OF HEPATITIS C VIRUS REPLICATION
  申请人：SEIWERT SCOTT

  公开号：US20090297476A1

  公开（公告）日：2009-12-03

  The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments provide compounds of the general Formula II, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

  本实施例提供通式I的化合物，以及包含该主体化合物的组合物，包括药物组合物。本实施例提供通式II的化合物，以及包含该主体化合物的组合物，包括药物组合物。本实施例进一步提供治疗方法，包括治疗丙型肝炎病毒感染的方法和治疗肝纤维化的方法，通常涉及向需要的个体施用有效量的主体化合物或组合物。
• In Silico and In Vitro Study towards the Rational Design of 4,4′-Disarylbisthiazoles as a Selective α-Synucleinopathy Biomarker
  作者：Bright C. Uzuegbunam、Junhao Li、Wojciech Paslawski、Wolfgang Weber、Per Svenningsson、Hans Ågren、Behrooz Hooshyar Yousefi

  DOI：10.3390/ijms242216445

  日期：——

  The α-synucleinopathies are a group of neurodegenerative diseases characterized by the deposition of α-synuclein aggregates (α-syn) in the brain. Currently, there is no suitable tracer to enable a definitive early diagnosis of these diseases. We reported candidates based on 4,4′-disarylbisthiazole (DABTA) scaffold with a high affinity towards α-syn and excellent selectivity over Aβ and tau fibrils. Based on prior in silico studies, a focused library of 23 halogen-containing and O-methylated DABTAs was prepared. The DABTAs were synthesized via a modified two-step Hantzsch thiazole synthesis, characterized, and used in competitive binding assays against [3H]PiB and [3H]DCVJ. The DABTAs were obtained with an overall chemical yield of 15–71%, and showed a calculated lipophilicity of 2.5–5.7. The ligands demonstrated an excellent affinity to α-syn with both [3H]PiB and [3H]DCVJ: Ki 0.1–4.9 nM and up to 20–3900-fold selectivity over Aβ and tau fibrils. It could be concluded that in silico simulation is useful for the rational design of a new generation of DABTAs. Further investigation of the leads in the next step is encouraged: radiolabeling of the ligands with radioisotopes such as fluorine-18 or carbon-11 for in vivo, ex vivo, and translational research and for further in vitro experiments on human-derived protein aggregates.

  α-突触核蛋白病是一组以α-突触核蛋白聚集体（α-syn）在大脑中沉积为特征的神经退行性疾病。目前，还没有合适的示踪剂能对这些疾病进行明确的早期诊断。我们报告了基于 4,4′-二芳基双噻唑（DABTA）支架的候选药物，它们对 α-syn 具有高亲和力，对 Aβ 和 tau 纤维具有出色的选择性。根据之前的硅学研究，我们制备了一个由 23 种含卤素和 O-甲基化的 DABTAs 组成的重点库。这些 DABTAs 是通过改进的两步 Hantzsch 噻唑合成法合成的，经过表征并用于与 [3H]PiB 和 [3H]DCVJ 的竞争性结合试验。DABTAs 的总化学收率为 15-71%，计算得出的亲油性为 2.5-5.7。这些配体与 [3H]PiB 和 [3H]DCVJ 对 α-syn 均表现出极佳的亲和力：Ki 0.1-4.9 nM，对 Aβ 和 tau 纤维的选择性高达 20-3900 倍。由此可以得出结论，硅学模拟有助于新一代 DABTAs 的合理设计。我们鼓励在下一步对这些线索进行进一步研究：用放射性同位素（如氟-18 或碳-11）对配体进行放射性标记，用于体内、体外和转化研究，以及对源自人类的蛋白质聚集体进行进一步的体外实验。
• WO2008/141227
  申请人：——

  公开号：——

  公开（公告）日：——