4-(4-fluorophenyl)amino-5-phenyl-pyrrolo[2,3-d]pyrimidine | 186393-47-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 4-(4-fluorophenyl)amino-5-phenyl-pyrrolo[2,3-d]pyrimidine
• 英文别名: 5-phenyl-4-N-(4-fluorophenyl)aminopyrrolo(2,3-d)pyrimidine；4-N-(4-fluorophenyl)amino-5-phenylpyrrolo[2,3-d]pyrimidine；N-(4-fluorophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• CAS: 186393-47-5
• 化学式: C₁₈H₁₃FN₄
• 分子量: 304.326
• InChiKey: PARBAJYAFDEHHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  53.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-fluorophenyl)amino-5-phenyl-pyrrolo[2,3-d]pyrimidine 在 氢氧化钾 作用下， 以 甲苯 为溶剂， 反应 45.0h， 生成 GP-3269
  参考文献：
  名称：

  Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues

  摘要：

  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.

  DOI：

  10.1021/jm0000259
• 作为产物：
  描述：

  2-氨基-3-氰基-4-苯基吡咯 在 对甲苯磺酸 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.25h， 生成 4-(4-fluorophenyl)amino-5-phenyl-pyrrolo[2,3-d]pyrimidine
  参考文献：
  名称：

  Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues

  摘要：

  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.

  DOI：

  10.1021/jm0000259

文献信息

• Adenosine Kinase Inhibitors. 5. Synthesis, Enzyme Inhibition, and Analgesic Activity of Diaryl-<i>erythro</i>-furanosyltubercidin Analogues
  作者：Serge H. Boyer、Bheemarao G. Ugarkar、Joel Solbach、Joseph Kopcho、Michael C. Matelich、Kristin Ollis、Jorge E. Gomez-Galeno、Rohan Mendonca、Megumi Tsuchiya、Atsushi Nagahisa、Masami Nakane、James B. Wiesner、Mark D. Erion

  DOI：10.1021/jm0503650

  日期：2005.10.1

  lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model. Described herein are the synthesis, enzyme inhibition structure-activity relationships (SARs) of erythro-furanosyltubercidin analogues, and SARs of analgesic activity of various

  腺苷是一种内源性神经调节剂，当在中枢和周围神经系统中产生时，具有抗惊厥，抗炎和镇痛作用。然而，剂量限制的心血管副作用困扰着使用腺苷受体激动剂的努力。作为替代方案，我们探索了腺苷激酶抑制剂（AKIs）作为潜在的抗癫痫药的用途，并证明了在没有明显的心血管副作用的情况下腺苷受体介导的治疗作用。这些活性与以部位和事件特异性方式抑制AK导致的细胞外腺苷浓度升高有关。几种基于结核菌素的AKI，包括核糖和呋喃呋喃糖基结核病类似物，以及新近发现的赤呋喃呋喃糖基结核病类似物，旨在预防5' 在大鼠福尔马林爪模型中测试了-O-磷酸化作用和相关的毒性。在此描述的是赤型-呋喃糖基tubercidin类似物的合成，酶抑制结构-活性关系（SAR），以及各种类型的AKI的镇痛活性。还报道了AKI铅19d（GP3966）的表征，这是一种口服生物利用化合物（狗中F％= 60％），具有广谱镇痛活性（ED50 <或= 4 mg /
• C-4' modified adenosine kinase inhibitors
  申请人：Metabasis Therapeutics, Inc.

  公开号：US05763596A1

  公开（公告）日：1998-06-09

  This invention relates to adenosine kinase inhibitors and to nucleoside analogs, C-4' modified pyrrolo\x9b2,3-d!pyrimidine and pyrazolo\x9b3,4-d!pyrimidine nucleoside analogs having activity as adenosine kinase inhibitors. The invention relates to nucleoside analogs of this kind, having zero substitutions or two substitutions at the C-4' position of the furanose (sugar) moiety. The invention also relates to the preparation and use of these adenosine kinase inhibitors in the treatment of cardiovascular, and cerebrovascular diseases, inflammation and other diseases which can be regulated by increasing the local concentration of adenosine.

  这项发明涉及腺苷激酶抑制剂和核苷类似物，即C-4'修饰的吡咯[2,3-d]嘧啶和吡唑[3,4-d]嘧啶核苷类似物，具有作为腺苷激酶抑制剂的活性。该发明涉及这种类型的核苷类似物，在呋喃糖（糖）基团的C-4'位置具有零个或两个取代基。该发明还涉及这些腺苷激酶抑制剂的制备和用途，用于治疗心血管和脑血管疾病、炎症以及其他可以通过增加腺苷局部浓度来调节的疾病。
• Adenosine Kinase Inhibitors. 3. Synthesis, SAR, and Antiinflammatory Activity of a Series of <scp>l</scp>-Lyxofuranosyl Nucleosides
  作者：Bheemarao G. Ugarkar、Angelo J. Castellino、Jay S. DaRe、Michele Ramirez-Weinhouse、Joseph J. Kopcho、Sanna Rosengren、Mark D. Erion

  DOI：10.1021/jm030230z

  日期：2003.10.1

  Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, L-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical. orientation of the CH2OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-L-lyxofuranosyl. nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC50 = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propylxanthine (DMPX) is also described.
• Process for the synthesis of nucleoside analogs
  申请人：Pfizer Products Inc.

  公开号：EP1052264B1

  公开（公告）日：2005-03-23
• ORALLY ACTIVE ADENOSINE KINASE INHIBITORS
  申请人：GENSIA, INC.

  公开号：EP0832092A1

  公开（公告）日：1998-04-01