5-(5-acetyl-2-propoxypyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-2H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one | 335077-60-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-(5-acetyl-2-propoxypyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-2H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one
• 英文别名: 5-(5-acetyl-2-propoxypyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-6H-pyrazolo[4,3-d]pyrimidin-7-one
• CAS: 335077-60-6
• 化学式: C₂₁H₂₆N₆O₃
• 分子量: 410.476
• InChiKey: CXFRDANOUSHETD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-(5-acetyl-2-propoxypyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-2H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one 、 正丁醇 在 4 A molecular sieve 、 caesium carbonate 作用下， 以33%的产率得到5-(2-butoxy-5-acetylpyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-2H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one
  参考文献：
  名称：

  A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

  摘要：

  Sildenafil ( 5-[ 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one), a potent and selective phosphodiesterase type 5 ( PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C-max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-( 1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one ( 2) was selected for progression into the clinic.

  DOI：

  10.1021/jm060113e
• 作为产物：
  描述：

  5-(5-Acetyl-2-propoxy-3-pyridinyl)-2-(3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 、 聚合甲醛 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 0.75h， 以56%的产率得到5-(5-acetyl-2-propoxypyridin-3-yl)-3-ethyl-2-(1-methylazetidin-3-yl)-2H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one
  参考文献：
  名称：

  A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

  摘要：

  Sildenafil ( 5-[ 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one), a potent and selective phosphodiesterase type 5 ( PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C-max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-( 1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one ( 2) was selected for progression into the clinic.

  DOI：

  10.1021/jm060113e

文献信息

• Inhibitors of Phosphodiesterase Type 5A for Treating or Preventing Muscle Disease or the Symptoms Thereof in a Patient
  申请人：Campbell Kevin P.

  公开号：US20110160219A1

  公开（公告）日：2011-06-30

  Disclosed are pharmaceutical compositions and methods for treating or preventing muscle diseases or the symptoms thereof. The compositions typically include and the methods typically utilize phosphodiesterase type 5A inhibitors.
• US6756373B1
  申请人：——

  公开号：US6756373B1

  公开（公告）日：2004-06-29
• US9387210B2
  申请人：——

  公开号：US9387210B2

  公开（公告）日：2016-07-12
• US9943518B2
  申请人：——

  公开号：US9943518B2

  公开（公告）日：2018-04-17
• A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability
  作者：Charlotte M. N. Allerton、Christopher G. Barber、Kevin C. Beaumont、David G. Brown、Susan M. Cole、David Ellis、Charlotte A. L. Lane、Graham N. Maw、Natalie M. Mount、David J. Rawson、Colin M. Robinson、Stephen D. A. Street、Nicholas W. Summerhill

  DOI：10.1021/jm060113e

  日期：2006.6.1

  Sildenafil ( 5-[ 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one), a potent and selective phosphodiesterase type 5 ( PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C-max of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-( 1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[ 4,3-d] pyrimidin-7-one ( 2) was selected for progression into the clinic.