4-chloro-5-iodo-7-(5-deoxy-2,3-O-isopropylidene-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine | 186394-15-0

• 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-chloro-5-iodo-7-(5-deoxy-2,3-O-isopropylidene-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine
• 英文别名: 7-[(3aR,4R,6R,6aR)-2,2,6-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloro-5-iodopyrrolo[2,3-d]pyrimidine
• CAS: 186394-15-0
• 化学式: C₁₄H₁₅ClIN₃O₃
• 分子量: 435.649
• InChiKey: UFTOVWJZUIASNJ-ZRFIDHNTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  58.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-chloro-5-iodo-7-(5-deoxy-2,3-O-isopropylidene-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 在 70percent aq. TFA 作用下， 反应 0.33h， 以65%的产率得到2-(4-Chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-methyl-tetrahydro-furan-3,4-diol
  参考文献：
  名称：

  腺苷激酶抑制剂。1. 5-碘代结核菌素类似物的合成，酶抑制和抗癫痫活性。

  摘要：

  腺苷受体激动剂产生多种治疗上有用的药理学。然而，迄今为止，由于剂量限制的副作用，它们未能成功进行临床开发。腺苷激酶抑制剂（AKIs）代表了另一种策略，因为AKIs可以以更多位点和事件特异性的方式提高局部腺苷水平，从而以更大的治疗窗口引发所需的药理作用。从5-碘代小球蛋白（IC50 = 0.026 microM）和5'-氨基-5'-脱氧腺苷（IC50 = 0.17 microM）作为分离的人AK的主要抑制剂开始，各种吡咯并[2,3-d]嘧啶核苷类似物通过使用钠盐介导的糖基化方法将5-取代的4-取代的4-氯吡咯并[2,3-d]嘧啶碱基与核糖类似物偶联来设计和制备。5'-氨基-5' 发现5-溴和5-碘结核菌素的β-脱氧类似物是迄今为止报道的最有效的AKI（IC50S <0.001 microM）。在大鼠最大电击（MES）诱发的癫痫发作试验中，几种有效的AKIs表现出抗惊厥活性。

  DOI：

  10.1021/jm000024g
• 作为产物：
  描述：

  5-deoxy-2,3-O-isopropylidene-D-ribofuranose 在 四氯化碳 、 sodium hydride 作用下， 以 四氢呋喃 、 六甲基磷酰三胺 、 乙腈 为溶剂， 反应 16.75h， 生成 4-chloro-5-iodo-7-(5-deoxy-2,3-O-isopropylidene-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine
  参考文献：
  名称：

  Design, Synthesis and Anticonvulsant Activity of the Potent Adenosine Kinase Inhibitor GP3269

  摘要：

  The pyrrolopyrimidine nucleoside GP3269 (12) was shown to be a potent and selective inhibitor of human adenosine kinase (IC50 = 11 nM) and to exhibit anticonvulsant activity in rats after oral administration. Synthesis of GP3269 was accomplished in 4 steps from 4-chloro-5-iodopyrrolopyrimidine (9) and the protected 5-deoxy-1-alpha-chlororibose (8) using a base-catalyzed nucleoside coupling reaction and the Suzuki reaction to replace the 5-iodo substituent with phenyl.

  DOI：

  10.1080/07328319708006124

文献信息

• Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues
  作者：Bheemarao G. Ugarkar、Angelo J. Castellino、Jay M. DaRe、Joseph J. Kopcho、James B. Wiesner、Juergen M. Schanzer、Mark D. Erion

  DOI：10.1021/jm0000259

  日期：2000.7.1

  In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy-5-iodotubercidin (1c) (IC50 = 0.0006 mu M), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylanlino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-suylamino-5-arylpyrrolo[2,3-d]pyrimdine bases were constructed and then glycosylated with appropriately protected alpha-ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED(50)s less than or equal to 2.0 mg/kg, ip, and showed relatively mild side effects.
• WATER-SOLUBLE ADENOSINE KINASE INHIBITORS
  申请人：Metabasis Therapeutics, Inc.

  公开号：EP0836613B1

  公开（公告）日：2005-05-25