2,6-dichloro-7-isopropyl-7H-purine | 953018-13-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 2,6-dichloro-7-isopropyl-7H-purine
• 英文别名: 2,6-dichloro-7-propan-2-ylpurine
• CAS: 953018-13-8
• 化学式: C₈H₈Cl₂N₄
• 分子量: 231.084
• InChiKey: BMKLSAIGMUTOQX-UHFFFAOYSA-N

物化性质

• 熔点：
  151-153 °C
• 沸点：
  290.6±50.0 °C(Predicted)
• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,6-dichloro-7-isopropyl-7H-purine 、 5-(1,1-二甲基乙基)-2-甲基苯胺 在 N,N-二异丙基乙胺 作用下， 以 乙醇 为溶剂， 生成 N-(5-(tert-butyl)-2-methylphenyl)-2-chloro-7-isopropyl-7H-purin-6-amine
  参考文献：
  名称：

  Purine derivatives as potent γ-secretase modulators

  摘要：

  The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces A beta 42 in an APP-YAC transgenic mouse model. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.02.008
• 作为产物：
  描述：

  2,6-二氯嘌呤 在 sodium hydride 、 二异丁基氢化铝 、 三乙胺 、 三氟乙酸 作用下， 以 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 4.0h， 生成 2,6-dichloro-7-isopropyl-7H-purine
  参考文献：
  名称：

  Selective Synthesis of 7-Substituted Purines via 7,8-Dihydropurines

  摘要：

  A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N-9-tritylated and then transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N-7-alkylation followed by N-9-trityl deprotection with trifluoroacetic acid was accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55-88% overall isolated yields.

  DOI：

  10.1021/ol1025525

文献信息

• PURINE DERIVATIVES
  申请人：PFIZER INC.

  公开号：US20150141402A1

  公开（公告）日：2015-05-21

  The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

  本发明涉及式(I)的化合物或其药用盐，其中Q、G、环A、环B、R1、R2、R3、R4、R5、R5a、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和m在此定义。这些新颖的嘌呤衍生物在治疗哺乳动物中的异常细胞生长，如癌症方面具有用途。另外，还涉及含有这些化合物的药物组合物，以及在治疗哺乳动物中的异常细胞生长方面使用这些化合物和组合物的方法。
• Synthesis and Pharmacophore Modelling of 2,6,9-Trisubstituted Purine Derivatives and Their Potential Role as Apoptosis-Inducing Agents in Cancer Cell Lines
  作者：Jeannette Calderón-Arancibia、Christian Espinosa-Bustos、Álvaro Cañete-Molina、Ricardo Tapia、Mario Faúndez、Maria Torres、Adam Aguirre、Margot Paulino、Cristian Salas

  DOI：10.3390/molecules20046808

  日期：——

  A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds.

  合成并研究了一系列2,6,9-三取代嘌呤衍生物，以探讨其作为抗肿瘤剂的潜在作用。通过三步合成程序获得了十二个化合物，其中微波辐射在一个关键步骤中发挥了重要作用。所有化合物都进行了体外评估，以确定其对细胞毒性的潜在影响，使用MTT法和流式细胞术分析四种癌细胞系和Vero细胞。与已知的有效抗癌药物依托泊苷相比，十二个化合物中有三个在四种癌细胞系中显示出良好的选择性，具有潜在的应用前景。初步的流式细胞术数据显示，上述化合物能诱导这些细胞的凋亡。每种癌细胞系的活性主要结构要求通过初步药效团模型进行了表征，该模型确定了芳香中心、氢受体/供体中心和疏水区域。这些特征与所测试化合物的细胞毒性活性一致。
• Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity
  作者：Michal Rouchal、Jana Rudolfová、Vladimír Kryštof、Veronika Vojáčková、Richard Čmelík、Robert Vícha

  DOI：10.3390/ijms222312675

  日期：——

  adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin

  细胞周期蛋白依赖性激酶 (CDK) 在细胞分裂周期中发挥重要作用。CDKs 的合成抑制剂基于 2,6,9-三取代嘌呤，被开发为潜在的抗癌药物；然而，它们在水中的溶解度很低。在这项研究中，我们证明了通过适当取代金刚烷部分可以改善基于嘌呤的抑制剂的药物化学性质。我们制备了十种新的具有金刚烷骨架的嘌呤衍生物，这些骨架使用可变几何形状和极性的亚苯基间隔物连接在 6 位。我们证明了金刚烷骨架不会影响生物活性，并且一些新的嘌呤对 CDK2/细胞周期蛋白 E 的抑制活性甚至高于母体化合物。这些发现得到了对接研究的支持，这表明结合口袋内的金刚烷支架参与了非极性相互作用的复杂稳定。此外，我们证明了 β-环糊精 (CD) 增加了药物在水中的溶解度，尽管这是以降低生化和细胞效应为代价的。最有可能的是，靶标参与所必需的药物浓度通过与 β-CD 复合物内的竞争性药物结合而降低。
• Discovery of <i>N</i>-((3<i>R</i>,4<i>R</i>)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1<i>H</i>-pyrazol-4-yl)amino)-9-methyl-9<i>H</i>-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
  作者：Simon Planken、Douglas C. Behenna、Sajiv K. Nair、Theodore O. Johnson、Asako Nagata、Chau Almaden、Simon Bailey、T. Eric Ballard、Louise Bernier、Hengmiao Cheng、Sujin Cho-Schultz、Deepak Dalvie、Judith G. Deal、Dac M. Dinh、Martin P. Edwards、Rose Ann Ferre、Ketan S. Gajiwala、Michelle Hemkens、Robert S. Kania、John C. Kath、Jean Matthews、Brion W. Murray、Sherry Niessen、Suvi T. M. Orr、Mason Pairish、Neal W. Sach、Hong Shen、Manli Shi、James Solowiej、Khanh Tran、Elaine Tseng、Paolo Vicini、Yuli Wang、Scott L. Weinrich、Ru Zhou、Michael Zientek、Longqing Liu、Yiqin Luo、Shuibo Xin、Chengyi Zhang、Jennifer Lafontaine

  DOI：10.1021/acs.jmedchem.6b01894

  日期：2017.4.13

  Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.(1) Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
• 2,6-SUBSTITUTED PURINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：Pfizer Inc.

  公开号：EP3071570B1

  公开（公告）日：2018-06-20