6-chloro-1-(2-chlorophenyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one | 1351413-67-6

• 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-1-(2-chlorophenyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one
• CAS: 1351413-67-6
• 化学式: C₁₁H₆Cl₂N₄O
• 分子量: 281.101
• InChiKey: NUIWAGQUYVBVKG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  59.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-amino-N-(4-propan-2-yloxyphenyl)propanamide 、 6-chloro-1-(2-chlorophenyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one 在 三乙胺 、 异丙醇 作用下， 反应 6.0h， 以47%的产率得到2-((1-(2-chlorophenyl)-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(4-isopropoxyphenyl)propanamide
  参考文献：
  名称：

  Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design

  摘要：

  A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 mu M, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

  DOI：

  10.1021/jm301189c
• 作为产物：
  描述：

  4,6-Dichloro-1-(2-chlorophenyl)pyrazolo[3,4-D]pyrimidine 在 potassium hydroxide 作用下， 生成 6-chloro-1-(2-chlorophenyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one
  参考文献：
  名称：

  Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design

  摘要：

  A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 mu M, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

  DOI：

  10.1021/jm301189c

文献信息

• N-SUBSTITUTED PYRAZOLO [3,4-D] PYRIMIDINE KETONE COMPOUND, AND PREPARATION PROCESS AND USE THEREOF
  申请人：SUN YAT-SEN UNIVERSITY

  公开号：US20150218168A1

  公开（公告）日：2015-08-06

  Disclosed are an N-substituted pyrazolo[3,4-d]pyrimidine ketone compound of formula (I), and a preparation process and use thereof as a phosphodiesterase IX (PDEIX) inhibitor: wherein R′ is selected from isopropyl, cyclopentyl, cyclohexyl, isobutyl, and o-chlorophenyl; when R″═CH 3 , R represents benzyl; and when R″═H, R is selected from 3-methylpyridine, 1-phenylethyl, 1-(4-chlorophenyl)ethyl, D- or L-configured CHCH 3 CONHR′″, D- or L-configured CH 2 CONHR′″, D- or L-configured CH 2 CH 2 CONHR′″; wherein R 1 is selected from hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and R 2 is selected from hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy, and wherein R′″ is p-methoxyphenyl.

  本发明公开了一种式为(I)的N-取代吡唑并[3,4-d]嘧啶酮化合物，以及其作为磷酸二酯酶IX（PDEIX）抑制剂的制备方法和用途： 其中， 当R″ = CH3时，R代表苄基； 当R″ = H时，R选自3-甲基吡啶，1-苯乙基，1-(4-氯苯基)乙基，D-或L-构型的CH CONHR′″，D-或L-构型的CH2CONHR′″，D-或L-构型的CH2CH2CONHR′″； 其中R′选自异丙基，环戊基，环己基，异丁基和o-氯苯基； 其中R1选自氢，氯，甲氧基，甲基，三氟甲基，二甲氧基，甲亚氧基和二氯，R2选自氢，甲氧基，乙氧基，异丙氧基，甲基，二甲氧基和2-甲基-4-甲氧基，其中R′″为对甲氧基苯基。
• Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent
  作者：Yong-xian Shao、Manna Huang、Wenjun Cui、Ling-Jun Feng、Yinuo Wu、Yinghong Cai、Zhe Li、Xinhai Zhu、Peiqing Liu、Yiqian Wan、Hengming Ke、Hai-Bin Luo

  DOI：10.1021/jm500836h

  日期：2014.12.26

  Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimers disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.
• US9617269B2
  申请人：——

  公开号：US9617269B2

  公开（公告）日：2017-04-11