1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-1-ol | 1032758-24-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-1-ol
• 英文别名: 1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol；1-(2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl)ethanol
• CAS: 1032758-24-9
• 化学式: C₁₂H₁₄ClN₃O₂S
• 分子量: 299.781
• InChiKey: DEYFURBTEDJPSS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  86.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-1-ol 在 manganese(IV) oxide 、 四(三苯基膦)钯 、 potassium acetate 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 72.33h， 生成 5-(6-(1,1-difluoroethyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine
  参考文献：
  名称：

  The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α

  摘要：

  Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3K alpha has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.

  DOI：

  10.1021/jm300867c
• 作为产物：
  描述：

  1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 生成 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethan-1-ol
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors

  摘要：

  Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.

  DOI：

  10.1021/acs.jmedchem.7b00357

文献信息

• Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer
  作者：Daniel P. Sutherlin、Deepak Sampath、Megan Berry、Georgette Castanedo、Zhigang Chang、Irina Chuckowree、Jenna Dotson、Adrian Folkes、Lori Friedman、Richard Goldsmith、Tim Heffron、Leslie Lee、John Lesnick、Cristina Lewis、Simon Mathieu、Jim Nonomiya、Alan Olivero、Jodie Pang、Wei Wei Prior、Laurent Salphati、Steve Sideris、Qingping Tian、Vickie Tsui、Nan Chi Wan、Shumei Wang、Christian Wiesmann、Susan Wong、Bing-Yan Zhu

  DOI：10.1021/jm901284w

  日期：2010.2.11

  an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3Kγ−ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative

  已经证明PI3K / AKT / mTOR途径在癌症中起重要作用。以化合物1和2（GDC-0941）为模板开始，发现（噻吩并嘧啶-2-基）氨基嘧啶是PI3K或PI3K和mTOR的有效抑制剂。从1和2的PI3Kγ-配体共晶体结构获得的结构信息用于设计抑制剂，该抑制剂相对于1可以保持PI3K的效力，但可以改善代谢稳定性和口服生物利用度。在优化的5个分子中添加一个甲基会产生21个，这大大降低了mTOR的效价。铅化合物5（GNE-493）和21（GNE-490）具有良好的药代动力学（PK）参数，具有很高的选择性，在体内表现出途径标记的敲低作用，并且在PI3K途径失控的异种移植模型中有效。在PI3Kα突变的MCF7.1异种移植模型中对这两种化合物进行了比较，发现当标准化进行暴露时具有同等效力。
• Phosphoinositide 3-kinase inhibitor compounds and methods of use
  申请人：Folkes Adrian

  公开号：US20080039459A1

  公开（公告）日：2008-02-14

  Compounds of Formulas Ia and Ib, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式Ia和Ib的化合物，包括立体异构体，几何异构体，互变异构体，溶剂化物，代谢物和其药学上可接受的盐，可用于抑制脂质激酶包括PI3K，并用于治疗由脂质激酶介导的癌症等疾病。公开了使用公式Ia和Ib的化合物用于哺乳动物细胞中的体外，体内和原位诊断，预防或治疗此类疾病或相关病理条件的方法。
• PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
  申请人：Bayliss Tracy

  公开号：US20080242665A1

  公开（公告）日：2008-10-02

  Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R 3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  化学式Ia-d的化合物，其中X为S或O，mor为吗啡啶基团，R3为单环杂芳基团，包括立体异构体、几何异构体、互变异构体、溶剂化物、代谢物和药学上可接受的盐，可用于调节脂质激酶包括PI3K的活性，并用于治疗由脂质激酶介导的癌症等疾病。本文公开了使用化合物Ia-d的方法，用于哺乳动物细胞中体外、体内诊断、预防或治疗这种疾病或相关病理条件。
• WO2007/127183
  申请人：——

  公开号：——

  公开（公告）日：——
• PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
  申请人：Genentech, Inc.

  公开号：EP2046799A1

  公开（公告）日：2009-04-15