2-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate | 630103-53-6

• 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-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate
• 英文别名: 2-amino-6-chloropurin-9-ylmethyl 2,2-dimethylpropionate；2-amino-6-chloropurin-9-ylmethyl-2,2-dimethylpropionate；(2-amino-6-chloro-9H-purine-9-yl)methyl pivalate；2-amino-6-chloro-9-(pivaloyloxymethyl)-purine；(2-amino-6-chloropurin-9-yl)methyl 2,2-dimethylpropanoate
• CAS: 630103-53-6
• 化学式: C₁₁H₁₄ClN₅O₂
• 分子量: 283.717
• InChiKey: OZDLKRCROJTAEG-UHFFFAOYSA-N

物化性质

• 沸点：
  490.6±55.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  95.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate 在 sodium hydroxide 、 亚硝酸特丁酯 、 二碘甲烷 作用下， 以 异丙醇 、 乙腈 为溶剂， 反应 74.5h， 生成 2-碘-6-氯嘌呤
  参考文献：
  名称：

  2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation:  Enhanced Potency as P2Y₁ Receptor Antagonists

  摘要：

  Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1), receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1), receptor and by using the radiolabeled antagonist [H-3](2)-chloro-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N-6-methyl-2-iodo analogue 12, which displayed a K-i value in competition for binding of [H-3]5 of 0.79 nM and a K-B value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1), receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(l-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1), receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.

  DOI：

  10.1021/jm030127+
• 作为产物：
  描述：

  特戊酸氯甲酯 、 2-氨基-6-氯嘌呤 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 以80%的产率得到2-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate
  参考文献：
  名称：

  嘌呤-2-基和嘌呤-6-基-氨基葡萄糖醇的合成（作为C-核苷ATP模拟物）和作为FGFR3抑制剂的生物学评估

  摘要：

  已经使用一种有效且通用的合成途径合成了两个新系列的C-核苷ATP模拟物。使用嘌呤作为中心支架，将这些化合物设计为FGFR3抑制剂。为了研究任何可能的结合方式，两个取代基，即多羟基化的核糖模拟物和亲脂性部分，在嘌呤环的2或6位连接。所有化合物都能够在浓度为50μM的情况下抑制FGFR3激酶活性。出乎意料的是，发现最好的抑制剂是位置2上带有碘原子的合成中间体13之一。对接研究证实了其在ATP结合位点的位置，并揭示了关键相互作用之间的卤素键。

  DOI：

  10.1016/j.ejmech.2011.01.048

文献信息

• [EN] PURINE DERIVATIVES AS A3 AND A1 ADENOSINE RECEPTOR AGONISTS<br/>[FR] DERIVES DE PURINE COMME AGONISTES DU RECEPTEUR D'ADENOSINE A3 ET A1
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006031505A1

  公开（公告）日：2006-03-23

  Disclosed are (N)-methanocarba adenine nucleosides of the formula: [Formula] as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A1 and A3 adenosine receptors for use in cardioprotection.

  揭示了一种公式为[N-甲烷卡巴腺嘌呤核苷]的高效A3腺苷受体激动剂，包括这种核苷的制药组合物，以及这些核苷的使用方法，其中R1-R6如规范中所定义。这些核苷被考虑用于治疗多种疾病，例如炎症、心肌缺血、中风、哮喘、糖尿病和心律失常。该发明还提供了既是A1受体又是A3受体激动剂的化合物，用于心脏保护。
• Design, Synthesis and Preliminary Biological Evaluation of Purine-2,6-diamine Derivatives as Cyclin-dependent Kinase (CDK) Inhibitors
  作者：Junhua Wang、Quande Wang、Liangren Zhang、Hao Fang

  DOI：10.1002/cjoc.201300420

  日期：2013.9

  Novel purine‐2,6‐diamine derivatives were designed and synthesized as cyclin‐dependent kinase (CDK) inhibitors. According to the preliminary biological evaluation, most of the compounds show good inhibitory activities in CDK1 enzyme assay and potent antiproliferative activities in some tumor cell lines. Especially, compound 11a (IC50=0.35 µmol/L for CDK1/cyclin B and IC50=0.023 µmol/L for CDK2/cyclin

  设计并合成了新型嘌呤-2,6-二胺衍生物，作为细胞周期蛋白依赖性激酶（CDK）抑制剂。根据初步的生物学评估，大多数化合物在CDK1酶分析中显示出良好的抑制活性，并且在某些肿瘤细胞系中显示出强大的抗增殖活性。尤其是，化合物11a（CDK1 /细胞周期蛋白B的IC 50 = 0.35 µmol / L，CDK2 /细胞周期蛋白A的IC 50 = 0.023 µmol / L）与Roscovitine（IC 50 = 2.54（CDK1 /细胞周期蛋白B和CD 50 /细胞周期蛋白A的IC 50 = 0.092 µmol / L）。
• Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-α-threofuranosyl ring systems: interactions with P2Y receptors
  作者：Michihiro Ohno、Stefano Costanzi、Hak Sung Kim、Veerle Kempeneers、Karen Vastmans、Piet Herdewijn、Savitri Maddileti、Zhan-Guo Gao、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1016/j.bmc.2004.07.067

  日期：2004.11

  5'-bisphosphate antagonists of the P2Y(1) receptor has been successfully substituted with a rigid methanocarba ring system, leading to the conclusion that the North (N) ring conformation is preferred in receptor binding. Similarly, at P2Y(2) and P2Y(4) receptors, nucleotides constrained in the (N) conformation interact equipotently with the corresponding ribosides. We now have synthesized and examined

  P2Y（1）受体的腺嘌呤核苷酸3'，5'-二磷酸拮抗剂的核糖部分已成功地被刚性的甲烷甲环系统取代，从而得出结论，在受体结合中优选North（N）环构象。类似地，在P2Y（2）和P2Y（4）受体上，受约束于（N）构象的核苷酸与相应的核苷等位相互作用。我们现在已经合成并检查了被两个新的环系统取代的P2Y受体配体核苷酸类似物：（1）含氧杂双环[2.2.1]庚烷环系统的（N）锁碳环（cLNA）衍生物和（2）l- α-苏呋喃糖基衍生物。我们还比较了这些核苷酸与已知的含脱水己糖醇的P2Y（1）受体拮抗剂MRS2283的效力和优选构象。cLNA双磷酸酯衍生物MRS2584 21在与人P2Y（1）受体结合时显示22.5 nM的K（i）值，并与强效P2Y（1）受体激动剂2-甲硫基ADP（30 nM ），IC（50）为650 nM。亲本cLNA核苷仅弱绑定到腺苷受体（A（3））。因此，该环系统提供了一些P2Y
• Purine Derivatives as A3 and A1 Adenosine Receptor Agonists
  申请人：Jacobson A. Kenneth

  公开号：US20070232626A1

  公开（公告）日：2007-10-04

  Disclosed are (N)-methanocarba adenine nucleosides of the formula: [Formula] as highly potent A 3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R 1 -R 6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A 1 and A 3 adenosine receptors for use in cardioprotection.

  本发明公开了一种(N)-甲烷卡巴腺嘌呤核苷，其化学式为：[Formula]，作为高效的A3腺苷受体激动剂，包括这种核苷的制药组合物和使用这些核苷的方法，其中R1-R6如规范中所定义。这些核苷可用于治疗多种疾病，例如炎症，心脏缺血，中风，哮喘，糖尿病和心律失常。本发明还提供了既是A1受体激动剂又是A3受体激动剂的化合物，用于心脏保护。
• Purine derivatives as A3 and A1 adenosine receptor agonists
  申请人：The United States of America as represented by the Department of Health and Human Services

  公开号：US07825126B2

  公开（公告）日：2010-11-02

  Disclosed are (N)-methanocarba adenine nucleosides of the formula: as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A1 and A3 adenosine receptors for use in cardioprotection.

  本发明涉及一种公式为(N)-methanocarba腺嘌呤核苷的化合物，其具有高效的A3腺苷受体激动剂作用，包括这些核苷的制药组合物和使用这些核苷的方法，其中R1-R6如规范所定义。这些核苷可用于治疗多种疾病，例如炎症、心脏缺血、中风、哮喘、糖尿病和心律失常。本发明还提供了既是A1受体又是A3受体激动剂的化合物，用于心脏保护。