(5-Bromo-9H-thioxanthen-2-yl)-carbamic acid tert-butyl ester | 845936-88-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻喃类
• 英文名称: (5-Bromo-9H-thioxanthen-2-yl)-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-(5-bromo-9H-thioxanthen-2-yl)carbamate
• CAS: 845936-88-1
• 化学式: C₁₈H₁₈BrNO₂S
• 分子量: 392.316
• InChiKey: KVTCAAWYDJUCJC-UHFFFAOYSA-N

物化性质

• 沸点：
  444.0±45.0 °C(Predicted)
• 密度：
  1.448±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (5-Bromo-9H-thioxanthen-2-yl)-carbamic acid tert-butyl ester 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 二甲胺 、 三乙胺 、 三氟乙酸 、 联硼酸频那醇酯 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 57.0h， 生成 N-(5-(6-morpholino-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)-2-(pyrrolidin-1-yl)acetamide
  参考文献：
  名称：

  Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington’s Disease Models

  摘要：

  Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

  DOI：

  10.1021/acs.jmedchem.8b01819
• 作为产物：
  描述：

  2-溴-5-硝基苯甲酸 在 甲烷磺酸 、 potassium hydroxide 、 锌 作用下， 以 水 、 溶剂黄146 为溶剂， 反应 70.5h， 生成 (5-Bromo-9H-thioxanthen-2-yl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington’s Disease Models

  摘要：

  Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

  DOI：

  10.1021/acs.jmedchem.8b01819

文献信息

• [EN] AMINOPYRONES AND THEIR USE AS ATM INHIBITORS<br/>[FR] AMINOPYRONES ET LEUR UTILISATION EN TANT QU'INHIBITEURS D'ATM
  申请人：KUDOS PHARM LTD

  公开号：WO2005016919A1

  公开（公告）日：2005-02-24

  Compounds of formula (I) wherein R1 and R2 together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring, X is S, NR’’ or CH2, R and R’ are hydrogen or specified substituents, and R’’ is a specified substituent, are useful as inhibitors of the kinase ATM (ataxia-telangiectasia mutated), particularly in the treatment of cancer and retroviral mediated diseases.

  具有式（I）的化合物，其中R1和R2与它们连接的氮原子一起形成一个可选择取代的杂环环，X为S、NR’’或CH2，R和R’为氢或指定的取代基，R’’为一个指定的取代基，可用作激酶ATM（共济失调-毛细血管扩张性疾病突变）的抑制剂，特别是在癌症和逆转录病原体介导的疾病的治疗中。
• ATM INHIBITOR
  申请人：Smith Cameron Murray Graeme

  公开号：US20070049588A1

  公开（公告）日：2007-03-01

  A compound of formula (I): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, and their use in treating diseases ameliorated by the inhibition of ATM.

  公式(I)的化合物及其异构体、盐、溶剂合物、化学保护形式和前药，以及它们在治疗通过抑制ATM改善的疾病中的用途。
• ATM inhibitors
  申请人：Smith Cameron Murray Graeme

  公开号：US20050054657A1

  公开（公告）日：2005-03-10

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R 1 and R 2 together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and R N1 is selected from hydrogen, an optionally substituted C 1-7 alkyl group, an optionally substituted C 3-20 heterocyclyl group, an optionally substituted C 5-20 aryl group, an acyl group, an ester group and an amido group, and its use as a pharmaceutical.

  化合物I的化学式为：以及其异构体、盐、溶剂合物、化学保护形式和前药，其中：R1和R2与它们所连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子; RN1选自氢、可选取代的C1-7烷基、可选取代的C3-20杂环基、可选取代的C5-20芳基、酰基、酯基和酰胺基，并且其用作制药。
• ATM INHIBITORS
  申请人：Smith Graeme Cameron Murray

  公开号：US20090043091A1

  公开（公告）日：2009-02-12

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R 1 and R 2 together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and R N1 is selected from hydrogen, an optionally substituted C 1-7 alkyl group, an optionally substituted C 3-20 heterocyclyl group, an optionally substituted C 5-20 aryl group, an acyl group, an ester group and an amido group, and its use as a pharmaceutical.

  化合物I的化学式为：其异构体，盐，溶剂合物，化学保护形式和前药，其中：R1和R2与它们附着的氮原子一起形成一个可选取代的杂环，该杂环具有4到8个环原子；RN1选自氢，可选取代的C1-7烷基，可选取代的C3-20杂环基，可选取代的C5-20芳基，酰基，酯基和酰胺基，并用作制药用途。
• AMINOPYRONES AND THEIR USE AS ATM INHIBITORS
  申请人：Kudos Pharmaceuticals Limited

  公开号：EP1654257A1

  公开（公告）日：2006-05-10