2-[4-(1,3-dimethyl-2,4-dioxo-5H-pyrrolo[3,2-d]pyrimidin-6-yl)phenoxy]-2-methylpropanoic acid | 875802-31-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 2-[4-(1,3-dimethyl-2,4-dioxo-5H-pyrrolo[3,2-d]pyrimidin-6-yl)phenoxy]-2-methylpropanoic acid
• CAS: 875802-31-6
• 化学式: C₁₈H₁₉N₃O₅
• 分子量: 357.366
• InChiKey: AUMIAEOOLIRGJT-UHFFFAOYSA-N

物化性质

• 熔点：
  >300 °C(Solv: water (7732-18-5); methanol (67-56-1))
• 沸点：
  617.7±65.0 °C(Predicted)
• 密度：
  1.357±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[4-(1,3-dimethyl-2,4-dioxo-5H-pyrrolo[3,2-d]pyrimidin-6-yl)phenoxy]-2-methylpropanoic acid 、 4-N-甲基苄基-n-乙氧甲酰哌啶双盐酸盐 在 polymer-bound morpholine 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以47%的产率得到6-[4-[1-(4,4-diphenylpiperidin-1-yl)-2-methyl-1-oxopropan-2-yl]oxyphenyl]-1,3-dimethyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-dione
  参考文献：
  名称：

  1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor

  摘要：

  A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA2B (K-i = 11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI = 912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI = > 100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI = > 100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at NI larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.01.002
• 作为产物：
  描述：

  2-(4-甲酰基苯氧基)-2-甲基丙酸 在 哌啶 、 甲酸 、 sodium dithionite 作用下， 以 1,4-二氧六环 为溶剂， 生成 2-[4-(1,3-dimethyl-2,4-dioxo-5H-pyrrolo[3,2-d]pyrimidin-6-yl)phenoxy]-2-methylpropanoic acid
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationships of 1-,3-,8-, and 9-Substituted-9-deazaxanthines at the Human A_2B Adenosine Receptor

  摘要：

  Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.

  DOI：

  10.1021/jm0506221

文献信息

• Design, Synthesis, and Structure−Activity Relationships of 1-,3-,8-, and 9-Substituted-9-deazaxanthines at the Human A_2B Adenosine Receptor
  作者：Angelo Carotti、Maria Isabel Cadavid、Nuria B. Centeno、Cristina Esteve、Maria Isabel Loza、Ana Martinez、Rosa Nieto、Enrique Raviña、Ferran Sanz、Victor Segarra、Eddy Sotelo、Angela Stefanachi、Bernat Vidal

  DOI：10.1021/jm0506221

  日期：2006.1.1

  Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.
• 1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor
  作者：Angela Stefanachi、Jose Manuel Brea、Maria Isabel Cadavid、Nuria B. Centeno、Cristina Esteve、Maria Isabel Loza、Ana Martinez、Rosa Nieto、Enrique Raviña、Ferran Sanz

  DOI：10.1016/j.bmc.2008.01.002

  日期：2008.3.15

  A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA2B (K-i = 11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI = 912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI = > 100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI = > 100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at NI larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI. (C) 2008 Elsevier Ltd. All rights reserved.