N-[3-carbamoyl-5-ethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide

• 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: N-[3-carbamoyl-5-ethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide
• 英文别名: N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide；N-[3-carbamoyl-5-ethyl-1-(pyridin-2-ylmethyl)pyrazol-4-yl]-2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxamide
• 化学式: C₂₆H₃₄N₈O₅S
• 分子量: 570.673
• InChiKey: ZEHWELRKYFJZHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  174
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-[3-carbamoyl-5-ethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide 在 potassium ethoxide 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 120.0 ℃ 、551.59 kPa 条件下， 反应 8.0h， 以83%的产率得到4-{6-Ethoxy-5-[3-ethyl-6,7-dihydro-7-oxo-2-(pyridin-2-ylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-pyridin-3-ylsulfonyl}-1-ethylpiperazine
  参考文献：
  名称：

  Therapeutic agents

  摘要：

  该发明涉及具有以下式（I）的3-乙基-5-［5-（4-乙基哌嗪-1-基磺酰基）-2-（2-甲氧基乙氧基）吡啶-3-基-2-（吡啶-2-基）甲基-2,6-二氢-7H-吡唑并［4,3-d］嘧啶-7-酮的无水对甲苯磺酸盐：制备化合物（I）的方法，含有（I）的药物组合物以及在医学中使用（I）。

  公开号：

  US06350751B1
• 作为产物：
  描述：

  2-乙氧基-5-[(4-乙基-1-哌嗪基)磺酰基]烟酸 在 4-Amino-5-ethyl-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide 、 N,N'-羰基二咪唑 作用下， 以 乙酸乙酯 为溶剂， 反应 18.0h， 以90.7%的产率得到N-[3-carbamoyl-5-ethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide
  参考文献：
  名称：

  Therapeutic agents

  摘要：

  该发明涉及具有以下式（I）的3-乙基-5-［5-（4-乙基哌嗪-1-基磺酰基）-2-（2-甲氧基乙氧基）吡啶-3-基-2-（吡啶-2-基）甲基-2,6-二氢-7H-吡唑并［4,3-d］嘧啶-7-酮的无水对甲苯磺酸盐：制备化合物（I）的方法，含有（I）的药物组合物以及在医学中使用（I）。

  公开号：

  US06350751B1

文献信息

• The Process Development of a Scaleable Route to the PDE5 Inhibitor UK-357,903
  作者：David J. Dale、John Draper、Peter J. Dunn、Michael L. Hughes、Farhat Hussain、Philip C. Levett、Gordon B. Ward、Albert S. Wood

  DOI：10.1021/op0200468

  日期：2002.11.1

  the 2-ethoxyphenyl moiety of sildenafil, necessitating the development of new chemistry. Particular items of note are (i) the new six-step route to the advanced 2-ethoxy-5-(4-ethylpiperazinylsulfonyl)nicotinic acid intermediate and the subsequent telescoping to a two-pot process, (ii) the telescoping of the two steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-et

  概述了开发候选药物 UK-357,903 的可扩展途径的案例历史。尽管与西地那非（伟哥）的结构部分相似，但在 UK-357,903 中引入中心吡啶部分对商业过程产生了重大影响。特别是，UK-357,903 的三重活化 2-烷氧基吡啶基部分比西地那非的 2-乙氧基苯基部分更容易受到亲核攻击，因此需要开发新的化学方法。特别值得注意的项目是 (i) 新的六步法制备先进的 2-乙氧基-5-(4-乙基哌嗪基磺酰基)烟酸中间体以及随后的两锅法，
• Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
  申请人：——

  公开号：US20010039271A1

  公开（公告）日：2001-11-08

  Compounds of the formulae (IA) and (IB): 1 wherein R 1 is C 1 to C 3 alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted by one or more substitutents selected from C 1 to C 4 alkoxy; halo; CN; CF 3 ; OCF 3 or C 1 to C 4 alkyl wherein said C 1 to C 4 alkyl group is optionally substituted by C 1 to C 4 haloalkyl or haloalkoxy either of which is substituted by one or more halo atoms; R 2 is C 1 to C 6 alkyl and R 13 is OR 3 or NR 5 R 6 , or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity are potent and selective inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5) and have utility in the treatment of, inter alia, male erectile dysfunction (MED) and female sexual dysfunction (FSD).

  式(I-A)和(I-B)的化合物：其中，R1是C1到C3烷基，可选地被苯基，Het或选择自哌啶基和吗啉基的N-连接杂环基团取代；其中，所述苯基可选地被一个或多个取代基所取代，所述取代基选择自C1到C4烷氧基，卤素，CN，CF3，O 或C1到C4烷基，其中所述C1到C4烷基可选地被C1到C4卤代烷基或卤代烷氧基所取代，所述卤代烷基或卤代烷氧基中的任意一个被一个或多个卤素原子所取代；R2是C1到C6烷基，R13是OR3或NR5R6，或其药学上或兽医学上可接受的盐，或者是上述任一实体的药学上或兽医学上可接受的溶剂，它们是选择性抑制剂5型环鸟苷酸3′，5′-单磷酸磷酸二酯酶（cGMP PDE5）的有效药物，并且在治疗男性勃起功能障碍（MED）和女性性功能障碍（FSD）等方面具有用途。
• Pyridine-3-carboxylic acid derivatives and their use as intermediates
  申请人：PFIZER INC.

  公开号：EP1371647A2

  公开（公告）日：2003-12-17

  The present invention relates to compounds of the formula (X) which are useful in the synthesis of pyrazolopyrimidinone compounds: wherein: R13 is C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, C1 to C4 alkoxy, benzyloxy, NR5R6, phenyl, furanyl and pyridinyl; C3 to C6 cycloalkyl; 1-(C1 to C4 alkyl)piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; R4 is SO2NR7R8; R5 and R6 are each independently selected from H and C1 to C4 alkyl, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl or morpholinyl group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10 piperazinyl group optionally substituted with one or two C1 to C4 alkyl groups and optionally in the form of its 4-N-oxide; R10 is H; C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with C1 to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 to C6 alkenyl; pyridinyl or pyrimidinyl; or a salt of such compound, or an acid chloride derivative of such compound.

  本发明涉及式（X）化合物，该化合物可用于合成吡唑嘧啶酮化合物： 其中 R13 是任选被一个或两个取代基取代的 C1 至 C4 烷基，这些取代基选自 OH、C1 至 C4 烷氧基、苄氧基、NR5R6、苯基、呋喃基和吡啶基；C3 至 C6 环烷基；1-(C1 至 C4 烷基)哌啶基；四氢呋喃基或四氢吡喃基； R4 是 SO2NR7R8； R5 和 R6 各自独立地选自 H 和 C1 至 C4 烷基，或与它们连接的氮原子一起形成吡咯烷基、哌啶基或吗啉基； R7 和 R8 与它们所连接的氮原子一起形成 4-R10 哌嗪基团，该基团可选择被一个或两个 C1 至 C4 烷基取代，也可选择以其 4-N-oxide 的形式存在； R10 是 H；任选被一个或两个取代基取代的 C1 至 C4 烷基，这些取代基选自 OH、NR5R6、CONR5R6、任选被 C1 至 C4 烷氧基取代的苯基、苯并二噁茂基和苯并二噁烷基；C3 至 C6 烯基；吡啶基或嘧啶基； 或此类化合物的盐，或此类化合物的酸性氯化物衍生物。
• Process for the preparation of pyrazolo [4,3-d] pyrimidin-7-ones-3-pyridylsulphonyl compounds and intermediates thereof
  申请人：Pfizer Limited

  公开号：EP1092720B1

  公开（公告）日：2005-01-12
• Highly potent and selective chiral inhibitors of PDE5: An illustration of Pfeiffer’s rule
  作者：Mark E. Bunnage、John P. Mathias、Anthony Wood、Duncan Miller、Stephen D.A. Street

  DOI：10.1016/j.bmcl.2008.10.037

  日期：2008.12

  A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1). (C) 2008 Elsevier Ltd. All rights reserved.