N(3)-methyl-4-(phenylsulfonyl)-1H-pyrazole-3,5-diamine | 1161177-06-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N(3)-methyl-4-(phenylsulfonyl)-1H-pyrazole-3,5-diamine
• 英文别名: N~3~-methyl-4-(phenylsulfonyl)-1H-pyrazole-3,5-diamine；4-(benzenesulfonyl)-3-N-methyl-1H-pyrazole-3,5-diamine
• CAS: 1161177-06-5
• 化学式: C₁₀H₁₂N₄O₂S
• 分子量: 252.297
• InChiKey: YXVOUPHTWMCEDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N(3)-methyl-4-(phenylsulfonyl)-1H-pyrazole-3,5-diamine 在 三溴化硼 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 12.5h， 生成 (7-methyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-7-yl)-methanol
  参考文献：
  名称：

  Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists

  摘要：

  Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT6 receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K-i = 190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K-i = 240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K-i = 270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K-i = 280 pM) are the most potent antagonists of the 5-HT6 receptors. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.12.055
• 作为产物：
  描述：

  2-phenylsulfonyl-3-methylamino-3-methylsulfanylacrylonitrile 在 一水合肼 作用下， 以 异丙醇 为溶剂， 反应 3.0h， 以90%的产率得到N(3)-methyl-4-(phenylsulfonyl)-1H-pyrazole-3,5-diamine
  参考文献：
  名称：

  (3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT₆ Receptor

  摘要：

  5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.

  DOI：

  10.1021/jm100350r

文献信息

• Antagonists of 5-HT6 receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines—Synthesis and ‘structure–activity’ relationship
  作者：Alexandre V. Ivachtchenko、Elena S. Golovina、Madina G. Kadieva、Volodymyr M. Kysil、Oleg D. Mitkin、Anton A. Vorobiev、Ilya Okun

  DOI：10.1016/j.bmcl.2012.05.036

  日期：2012.7

  Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT6

  一系列新的3-（苯基磺酰基）吡唑并[1,5- a ]吡啶并[3,4- e ]嘧啶（角三环）和3-（苯基磺酰基）的结构不受限制和分子内氢键限制的衍生物的合成及生物学评价描述了吡唑并[1，5- a ]吡啶基[4，3- d ]嘧啶（线性三环）。结构上受限制的衍生物是5-HT 6受体的强效和选择性阻滞剂，三环核的角形或线性形状之间几乎没有差异，角形物质的效力稍强。3-（苯基磺酰基）吡唑并[1,5- a ]吡啶基[3,4- e ]嘧啶的角代表5，可以被认为是用于进一步开发更有利的候选，因为它显示只有弱5-HT 2B阻断活性（IC 50  = 6.16μM与IC相比，50  = 1.8 nM的对5-HT 6个受体）和非常低的hERG钾通道阻断效能（IC 50  = 54.2μM）。线性类似物11较不受欢迎，因为它在高达10μM的浓度下未显示与5-HT 2B受体的结合，但具有相当高的阻断hERG通道的能力（IC
• 2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: New series of highly potent and specific serotonin 5-HT6 receptor antagonists
  作者：Alexandre V. Ivachtchenko、Elena S. Golovina、Madina G. Kadieva、Angela G. Koryakova、Oleg D. Mitkin、Sergey E. Tkachenko、Volodymyr M. Kysil、Ilya Okun

  DOI：10.1016/j.ejmech.2011.01.038

  日期：2011.4

  Syntheses, biological evaluation, and structure activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (K-i varied from 260 pM to 2.96 mu M), no significant correlation of 5-HT6R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (K-i = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT6 receptor. (C) 2011 Elsevier Masson SAS. All rights reserved.
• Bioorg. Med. Chem. Lett. 2012, 22, 4273-4280
  作者：

  DOI：——

  日期：——
• J. Med. Chem. 2011, 54, 8161-8173
  作者：

  DOI：——

  日期：——
• (3-Phenylsulfonylcycloalkano[<i>e</i> and <i>d</i>]pyrazolo[1,5-<i>a</i>]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT₆ Receptor
  作者：Alexandre V. Ivachtchenko、Dmitri E. Dmitriev、Elena S. Golovina、Madina G. Kadieva、Angela G. Koryakova、Volodymyr M. Kysil、Oleg D. Mitkin、Ilya M. Okun、Sergey E. Tkachenko、Anton A. Vorobiev

  DOI：10.1021/jm100350r

  日期：2010.7.22

  5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.