(R)-2-(1-(3-(but-2-yn-1-yl)-5-(4-methoxybenzyl)-4-oxo-3,4,5,7,8,9-hexahydropyrimido[2,1-b]purin-2-yl)piperidin-3-yl)isoindoline-1,3-dione | 1381795-32-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (R)-2-(1-(3-(but-2-yn-1-yl)-5-(4-methoxybenzyl)-4-oxo-3,4,5,7,8,9-hexahydropyrimido[2,1-b]purin-2-yl)piperidin-3-yl)isoindoline-1,3-dione
• 英文别名: 2-[(3R)-1-[3-but-2-ynyl-5-[(4-methoxyphenyl)methyl]-4-oxo-8,9-dihydro-7H-pyrimido[2,1-b]purin-2-yl]piperidin-3-yl]isoindole-1,3-dione
• CAS: 1381795-32-9
• 化学式: C₃₃H₃₃N₇O₄
• 分子量: 591.67
• InChiKey: FKDNFFAGSPWDFW-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  44
• 可旋转键数：
  6
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-2-(1-(3-(but-2-yn-1-yl)-5-(4-methoxybenzyl)-4-oxo-3,4,5,7,8,9-hexahydropyrimido[2,1-b]purin-2-yl)piperidin-3-yl)isoindoline-1,3-dione 在 sodium hydride 、 一水合肼 、 三氟乙酸 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 14.5h， 生成 (R)-2-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-6-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrimido[2,1-b]purin-4(3H)-one
  参考文献：
  名称：

  Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

  摘要：

  Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.09.007
• 作为产物：
  描述：

  2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine 在 N-溴代丁二酰亚胺(NBS) 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 potassium iodide 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.0h， 生成 (R)-2-(1-(3-(but-2-yn-1-yl)-5-(4-methoxybenzyl)-4-oxo-3,4,5,7,8,9-hexahydropyrimido[2,1-b]purin-2-yl)piperidin-3-yl)isoindoline-1,3-dione
  参考文献：
  名称：

  Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

  摘要：

  Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.09.007

文献信息

• [EN] TRICYCLIC HETEROCYCLES USEFUL AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS<br/>[FR] HÉTÉROCYCLES TRICYCLIQUES UTILES COMME INHIBITEURS DE LA DIPEPTIDYL PEPTIDASE IV
  申请人：SCHERING CORP

  公开号：WO2012078448A1

  公开（公告）日：2012-06-14

  The present invention is directed to novel tricyclic heterocycles of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. I

  本发明涉及具有结构式I的新型三环杂环化合物，这些化合物是二肽基肽酶-IV酶的抑制剂，对治疗或预防二肽基肽酶-IV酶参与的疾病具有用处，如糖尿病，特别是2型糖尿病。该发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗二肽基肽酶-IV酶参与的疾病中的使用。
• TRICYCLIC HETEROCYCLES USEFUL AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS
  申请人：Burnett Duane A.

  公开号：US20130261140A1

  公开（公告）日：2013-10-03

  The present invention is directed to novel tricyclic heterocycles of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. I

  本发明涉及结构式I的新型三环杂环，其是二肽基肽酶-IV酶的抑制剂，可用于治疗或预防二肽基肽酶-IV酶参与的疾病，如糖尿病，尤其是2型糖尿病。本发明还涉及包含这些化合物的制药组合物以及在预防或治疗二肽基肽酶-IV酶参与的这些疾病中使用这些化合物和组合物的用途。
• Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors
  作者：Dmitri A. Pissarnitski、Zhiqiang Zhao、David Cole、Wen-Lian Wu、Martin Domalski、John W. Clader、Giovanna Scapin、Johannes Voigt、Aileen Soriano、Theresa Kelly、Mary Ann Powles、Zuliang Yao、Duane A. Burnett

  DOI：10.1016/j.bmc.2016.09.007

  日期：2016.11

  Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test. (C) 2016 Elsevier Ltd. All rights reserved.