5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one | 335077-81-1

• 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-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
• 英文别名: 5-(2-butoxy-5-iodopyridin-3-yl)-3-ethyl-2-(2-morpholin-4-ylethyl)-6H-pyrazolo[4,3-d]pyrimidin-7-one
• CAS: 335077-81-1
• 化学式: C₂₂H₂₉IN₆O₃
• 分子量: 552.415
• InChiKey: QZKBQGKELRAWEN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  93.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 在 bis-triphenylphosphine-palladium(II) chloride 、 potassium fluoride 、 copper(l) iodide 、 硫酸 、 mercury(II) sulfate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 8.0h， 生成 5-(2-butoxy-5-acetylpyridin-3-yl)-3-ethyl-2-[2-(morpholin-4-yl)ethyl]-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：

  2-n-butoxy-5-iodopyridine-3-carboxylic acid 在 吡啶 、 草酰氯 、 双(三甲基硅烷基)氨基钾 、 caesium carbonate 、 N,N-二甲基甲酰胺 、 正丁醇 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 56.0h， 生成 5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-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

• [EN] 5-(2-SUBSTITUTED-5-HETEROCYCLYLSULPHONYLPYRID-3-YL)-DIHYDROPYRAZOLO[4,3-D]PYRIMIDIN-7-ONES AS PHOSPHODIESTERASE INHIBITORS<br/>[FR] PYRIMIDINE-7-ONES 5-(2-SUBSTITUTEES-5-HETEROCYCLYLSULPHONYLPYRIDE-3-YL)-DIHYDROPYRAZOLO[4,3-D] SERVANT D'INHIBITEURS DE LA PHOSPHODIESTERASE
  申请人：PFIZER LTD

  公开号：WO2001027112A1

  公开（公告）日：2001-04-19

  There is provided compounds of formula (I) wherein R?1, R2, R3, R4¿ and X have meanings given in the description, which are useful in the curative and prophylactic treatment of a medical condition for which inhibition of a cyclic guanosine 3',5'-monophosphate phosphodiesterase (e.g. cGMP PDE5) is desired.

  提供了式（I）的化合物，其中R?1，R2，R3，R4¿和X具有在说明中给出的含义，这些化合物在治疗和预防需要抑制环磷酸鸟苷3'，5'-单磷酸磷酸二酯酶（例如cGMP PDE5）的医疗状况中是有用的。
• 5-(2-SUBSTITUTED-5-HETEROCYCLYLSULPHONYLPYRID-3-YL)-DIHYDROPYRAZOLO[4,3-D]PYRIMIDIN-7-ONES AS PHOSPHODIESTERASE INHIBITORS
  申请人：Pfizer Limited

  公开号：EP1222190A1

  公开（公告）日：2002-07-17
• US6756373B1
  申请人：——

  公开号：US6756373B1

  公开（公告）日：2004-06-29
• 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.