6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purine | 327161-46-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purine
• 英文别名: 6-Chloro-8-(3-fluorophenyl)-9-methylpurine
• CAS: 327161-46-6
• 化学式: C₁₂H₈ClFN₄
• 分子量: 262.674
• InChiKey: GVWJXTBLHCSUJU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purine 在 ammonium hydroxide 作用下， 以 乙二醇二甲醚 为溶剂， 反应 8.0h， 生成 8-(3-Fluorophenyl)-9-methylpurin-6-amine
  参考文献：
  名称：

  2-Alkynyl-8-aryl-9-methyladenines as Novel Adenosine Receptor Antagonists:  Their Synthesis and Structure−Activity Relationships toward Hepatic Glucose Production Induced via Agonism of the A_2B Receptor

  摘要：

  Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.

  DOI：

  10.1021/jm990499b
• 作为产物：
  描述：

  6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine 在 copper(l) iodide 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以47%的产率得到6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purine
  参考文献：
  名称：

  2-Alkynyl-8-aryl-9-methyladenines as Novel Adenosine Receptor Antagonists:  Their Synthesis and Structure−Activity Relationships toward Hepatic Glucose Production Induced via Agonism of the A_2B Receptor

  摘要：

  Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.

  DOI：

  10.1021/jm990499b

文献信息

• Novel 8-arylated purines as inhibitors of glycogen synthase kinase
  作者：Nada Ibrahim、Liliane Mouawad、Michel Legraverend

  DOI：10.1016/j.ejmech.2010.04.026

  日期：2010.8

  A series of 8-arylated purine derivatives bearing either an aniline or an alkyl amide at position 6 were found to inhibit glycogen synthase kinase-3, with good selectivity over ten kinases. Molecular modeling studies indicated that the most active compounds (8a and 8e), adopt a planar conformation, close to the shape of AMPPNP in the crystal structure of GSK-3. These compounds are stabilized by hydrophobic contacts between the 8-aromatic group and the protein adenine pocket and by electrostatic contacts. (C) 2010 Elsevier Masson SAS. All rights reserved.
• A New Sandmeyer Iodination of 2-Aminopurines in Non-aqueous Conditions: Combination of Alkali Metal Iodide and Iodine as Iodine Sources
  作者：Naoki Ozeki、Naoyuki Shimomura、andHitoshi Harada

  DOI：10.3987/com-00-9142

  日期：——

  An effective method for iodination using 2-aminopurines in non-aqueous conditions was found. The optimal conditions involved the combination of isopentyl nitrite, cuprous iodide, alkali metal iodide and iodine in ethylene glycol dimethyl ether at 60 degreesC.
• 2-Alkynyl-8-aryl-9-methyladenines as Novel Adenosine Receptor Antagonists:  Their Synthesis and Structure−Activity Relationships toward Hepatic Glucose Production Induced via Agonism of the A_2B Receptor
  作者：Hitoshi Harada、Osamu Asano、Yorihisa Hoshino、Seiji Yoshikawa、Masayuki Matsukura、Yasuhiro Kabasawa、Jun Niijima、Yoshihiko Kotake、Nobuhisa Watanabe、Tsutomu Kawata、Takashi Inoue、Tatsuo Horizoe、Nobuyuki Yasuda、Hiroe Minami、Kaya Nagata、Manabu Murakami、Junsaku Nagaoka、Seiichi Kobayashi、Isao Tanaka、Shinya Abe

  DOI：10.1021/jm990499b

  日期：2001.1.1

  Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.