4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine | 1202885-72-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine
• 英文别名: 2-Chloro-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
• CAS: 1202885-72-0
• 化学式: C₁₀H₁₁ClN₄O
• 分子量: 238.677
• InChiKey: ZDAFERBEWASSAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  54
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine 在 sodium hydride 、 一水合肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer

  摘要：

  In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with the in vivo HCT116(DPD) cells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01%-75.87%. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into alpha-fluoro-beta-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs.Significance: This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.

  DOI：

  10.1016/j.phrs.2020.104717
• 作为产物：
  描述：

  吗啉 、 2,4-二氯-7H吡咯[2,3-D]嘧啶 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 10.0h， 以75.4%的产率得到4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine
  参考文献：
  名称：

  新型CHK1抑制剂2,6-二取代-9H-嘌呤，2,4-二取代-噻吩并[3,2- d ]嘧啶和-7H-吡咯并[2,3- d ]嘧啶类似物的合成及生物学评价

  摘要：

  Checkpoint激酶1（CHK1）抑制剂可增强脱氧核糖核酸（DNA）破坏剂在治疗癌症中的有效性。一系列新的2,6-二取代的9H-嘌呤（3a - p，5a和5b），2,4-二取代的噻吩并[3,2- d ]嘧啶（8a - c）和2,4-取代的-设计并合成了7H-吡咯并[2,3- d ]嘧啶（11a - c）类似物作为有效的CHK1抑制剂。化合物（3a，3d，3f和3j - 1）具有9H-嘌呤核的化合物显示出对CHK1的更强抑制作用。最有效的化合物（3l）对HT29和Hek293细胞系也表现出较低的抗增殖作用。另外，3l对吉西他滨对HT29细胞的抗增殖活性显示出强大的增强作用（7倍）。细胞周期测定的结果表明3l可以显着影响吉西他滨处理的HT29细胞的细胞周期分布并诱导显着的S期积累。3l的激酶选择性谱显示出对其他激酶的可接受的选择性。这些结果使3l成为CHK1抑制剂的有效先导化合物有待进一步研究。

  DOI：

  10.1016/j.ejmech.2018.03.075

文献信息

• (2-ARYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)MORPHOLINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
  申请人：Chen Zecheng

  公开号：US20100003250A1

  公开（公告）日：2010-01-07

  The invention relates to 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine compounds of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.

  这项发明涉及Formula I的2-芳基-7H-吡咯并[2,3-d]嘧啶-4-基)吗啉化合物或其药用可接受的盐，其中组分变量如本文所定义，包括这些化合物的组合物，以及制备和使用这些化合物的方法。
• [EN] (2-ARYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)MORPHOLINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES<br/>[FR] COMPOSÉS (2-ARYL-7H-PYRROLO[2,3-D]PYRIMIDINE-4-YL)MORPHOLINE, LEUR UTILISATION EN TANT QU'INHIBITEURS DE LA MTOR KINASE ET DE LA PI3 KINASE, ET LEURS SYNTHÈSES
  申请人：WYETH CORP

  公开号：WO2010002954A1

  公开（公告）日：2010-01-07

  The invention relates to 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine compounds of the Formula (I): or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.

  本发明涉及公式（I）的2-芳基-7H-吡咯[2,3-d]嘧啶-4-基)吗啡啶化合物或其药学上可接受的盐，其中组成变量如本文所定义，包括该化合物的组合物以及制备和使用该化合物的方法。
• Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors
  作者：Miao Zhan、Yufang Deng、Lifeng Zhao、Guoyi Yan、Fangying Wang、Ye Tian、Lanxi Zhang、Hongxia Jiang、Yuanwei Chen

  DOI：10.1021/acs.jmedchem.7b00357

  日期：2017.5.11

  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.
• Synthesis and SAR of Novel 4-Morpholinopyrrolopyrimidine Derivatives as Potent Phosphatidylinositol 3-Kinase Inhibitors
  作者：Zecheng Chen、Aranapakam M. Venkatesan、Christoph M. Dehnhardt、Semiramis Ayral-Kaloustian、Natasja Brooijmans、Robert Mallon、Larry Feldberg、Irwin Hollander、Judy Lucas、Ker Yu、Fangming Kong、Tarek S. Mansour

  DOI：10.1021/jm901783v

  日期：2010.4.22

  Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110 alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3K alpha and mTOR, leading to the discovery of PI3K alpha selective inhibitors (e.g., 9) and dual PI3K alpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3K alpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
• S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer
  作者：Yu-Hang Zhang、Dong-Dong Luo、Sheng-Biao Wan、Xian-Jun Qu

  DOI：10.1016/j.phrs.2020.104717

  日期：2020.5

  In this study, S1PR2 was reckoned as a brand-new GPCR target for designing inhibitors to reverse 5-FU resistance. Herein a series of pyrrolidine pyrazoles as the S1PR2 inhibitors were designed, synthesized and evaluated for their activities of anti-FU-resistance. Among them, the most promising compound JTE-013, exhibited excellent inhibition on DPD expression and potent anti-FU-resistance activity in various human cancer cell lines, along with the in vivo HCT116(DPD) cells xenograft model, in which the inhibition rate of 5-FU was greatly increased from 13.01%-75.87%. The underlying mechanism was uncovered that JTE-013 demonstrated an anti-FU-resistance activity by blocking S1PR2 internalization to the endoplasmic reticulum (ER), which inhibited the degradation of 5-FU into alpha-fluoro-beta-alanine (FBAL) by downregulating tumoral DPD expression. Overall, JTE-013 could serve as the lead compound for the discovery of new anti-FU-resistance drugs.Significance: This study provides novel insights that S1PR2 inhibitors could sensitize 5-FU therapy in colorectal cancer.