5-氨基-1,3-二甲基-2,4-二氧代吡啶并[6,5-d]嘧啶-6-甲腈 | 152708-32-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 中文名称: 5-氨基-1,3-二甲基-2,4-二氧代吡啶并[6,5-d]嘧啶-6-甲腈
• 英文名称: 5-amino-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido<2,3-d>pyrimidine-2,4-dione
• 英文别名: 5-Amino-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidine-2,4-dione；5-amino-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile
• CAS: 152708-32-2
• 化学式: C₁₀H₉N₅O₂
• 分子量: 231.214
• InChiKey: IOBHBQNKZJOMOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-chloro-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido<2,3-d>pyrimidine-2,4-dione 在 氨 作用下， 以 乙醇 为溶剂， 反应 0.5h， 以41%的产率得到5-氨基-1,3-二甲基-2,4-二氧代吡啶并[6,5-d]嘧啶-6-甲腈
  参考文献：
  名称：

  Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists

  摘要：

  Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A(1) and A(2A) receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents. such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyfuracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1.3-dimethyl-5-(2-naphthylmethyl) aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a K-i value of 5 nM at rat and 25 nM at human A, receptors. The compound was more than 60-fold selective versus A(3) and more than 300-fold selective versus A2A receptors. It showed all over 300-fold improvement with respect to the lead compound. In GTP gamma S binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A, receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (K-i = 226 nM) and selective (> 20-fold) A(3) ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A(2A) receptors were identified. Such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dioile 16b (K-i human A(2A) = 81.3 nM, K-i human A(1) = 153 nM, and K-i human A(3) > 10,000 nM). (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.12.008

文献信息

• Heber; Ravens; Schulze, Pharmazie, 1993, vol. 48, # 7, p. 509 - 513
  作者：Heber、Ravens、Schulze

  DOI：——

  日期：——
• Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists
  作者：Jacek Bulicz、Daniela C.G. Bertarelli、Dieter Baumert、Friederike Fülle、Christa E. Müller、Dieter Heber

  DOI：10.1016/j.bmc.2005.12.008

  日期：2006.4

  Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A(1) and A(2A) receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents. such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyfuracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1.3-dimethyl-5-(2-naphthylmethyl) aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a K-i value of 5 nM at rat and 25 nM at human A, receptors. The compound was more than 60-fold selective versus A(3) and more than 300-fold selective versus A2A receptors. It showed all over 300-fold improvement with respect to the lead compound. In GTP gamma S binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A, receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (K-i = 226 nM) and selective (> 20-fold) A(3) ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A(2A) receptors were identified. Such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dioile 16b (K-i human A(2A) = 81.3 nM, K-i human A(1) = 153 nM, and K-i human A(3) > 10,000 nM). (c) 2006 Elsevier Ltd. All rights reserved.