5-acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide | 393184-83-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide
• 英文别名: 5-acetyl-N-[3-carbamoyl-5-ethyl-1-(1-ethylazetidin-3-yl)pyrazol-4-yl]-2-ethoxypyridine-3-carboxamide
• CAS: 393184-83-3
• 化学式: C₂₁H₂₈N₆O₄
• 分子量: 428.491
• InChiKey: FYHFWEYFFVGKEX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide 在 sodium tetrahydroborate 、 4 A molecular sieve 、 caesium carbonate 作用下， 以 甲醇 为溶剂， 反应 4.0h， 生成 5-[2-butoxy-5-(1-hydroxyethyl)-3-pyridinyl]-3-ethyl-2-(1-ethyl-3-azetidinyl)-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
• 作为产物：
  描述：

  5-ethyl-1-(1-ethyl-3-azetidinyl)-4-nitro-1H-pyrazole-3-carboxamide 在 palladium on activated charcoal 氢气 、 N,N'-羰基二咪唑 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 20.0 ℃ 、413.68 kPa 条件下， 反应 21.5h， 生成 5-acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide
  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

• Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof
  申请人：Pfizer Limited

  公开号：EP1176147A1

  公开（公告）日：2002-01-30

  A process is provided for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of -OR3 and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent (i.e. -OR3 is substituted by the auxiliary base), wherein X is a leaving group and R1 to R4 are as defined.

  提供一种用于制备式（I）化合物的方法，包括在-OR3和氢氧化物捕获剂的存在下，反应式（II）、（III）、（IV）或（V）化合物，或者在辅助碱和氢氧化物捕获剂的存在下反应式（IV）化合物（即-OR3被辅助碱取代），其中X是离去基团，R1至R4如所定义。
• Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof
  申请人：——

  公开号：US20020038024A1

  公开（公告）日：2002-03-28

  A process is provided for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of − OR 3 and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent (i.e. − OR 3 is substituted by the auxiliary base), wherein X is a leaving group and R 1 to R 4 are as defined.

  提供一种制备式(I)化合物的方法，包括在−OR3和羟基捕捉剂的存在下，反应式(II)、(III)、(IV)或(V)的化合物，或在式(IV)化合物的情况下，在辅助碱和羟基捕捉剂的存在下反应(即−OR3被辅助碱取代)，其中X是离去基团，R1到R4如定义。
• Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof
  申请人：Pfizer Inc.

  公开号：US06809200B2

  公开（公告）日：2004-10-26

  A process is provide for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (III), (IV) or (V) wherein the variables are as defined in the specification. The reaction is conducted in the presence of −OR3 and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent.

  本发明提供了一种制备式(I)化合物的方法，包括将式(III)、(IV)或(V)化合物与规范中定义的变量反应。该反应在−OR3和羟基捕捉剂的存在下进行，或者在式(IV)化合物的情况下，在辅助碱和羟基捕捉剂的存在下反应。
• US6809200B2
  申请人：——

  公开号：US6809200B2

  公开（公告）日：2004-10-26