2-[5,7-dimethyl-2-(methylamino)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid ethyl ester | 1220645-35-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 2-[5,7-dimethyl-2-(methylamino)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid ethyl ester
• 英文别名: Ethyl 2-[3-(benzenesulfonyl)-5,7-dimethyl-2-(methylamino)pyrazolo[1,5-a]pyrimidin-6-yl]acetate
• CAS: 1220645-35-1
• 化学式: C₁₉H₂₂N₄O₄S
• 分子量: 402.474
• InChiKey: WUJMWZPLNJKCMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-[5,7-dimethyl-2-(methylamino)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid ethyl ester 在 水 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 2-[3-(Benzenesulfonyl)-5,7-dimethyl-2-(methylamino)pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT₆ Receptor (5-HT₆R) Antagonists

  摘要：

  Syntheses, biological evaluation as 5-HT6 receptor (5-HT6R) antagonists, and structure activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.

  DOI：

  10.1021/jm201079g
• 作为产物：
  描述：

  3-乙酰基-4-氧代戊酸乙酯 、 在 溶剂黄146 作用下， 以48%的产率得到2-[5,7-dimethyl-2-(methylamino)-3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidin-6-yl]acetic acid ethyl ester
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT₆ Receptor (5-HT₆R) Antagonists

  摘要：

  Syntheses, biological evaluation as 5-HT6 receptor (5-HT6R) antagonists, and structure activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.

  DOI：

  10.1021/jm201079g

文献信息

• SUBSTITUTED 3-ARYLSULFONYL-PYRAZOLO[1,5-A]PYRIMIDINES, SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS AND METHODS FOR THE PRODUCTION AND USE THEREOF
  申请人：Ivashchenko Andrey Alexandrovich

  公开号：US20110178078A1

  公开（公告）日：2011-07-21

  The invention relates to the novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of the general formula 1, pharmaceutically acceptable salts and/or hydrates thereof, serotonin 5-HT 6 receptor antagonists and pharmaceutical compositions, and also to method for prophylaxis and treatment of various diseases of central nervous system at humans and warm-blooded animals pathogenesis of which is associated with serotonin 5-HT 6 receptors, in particular, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and other neurodegenerative diseases, cognitive disorders and obesity. In the general formula 1: wherein: X═S, SO or NH; R 1 represents hydrogen, optionally substituted C 1 -C 3 alkyl, cycloalkyl, adamantyl, aryl or heterocyclyl; R 2 represents hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, substituted hydroxyl, aryldiazenyl or optionally substituted amino group; R 3 represents hydrogen, optionally substituted C 1 -C 3 alkyl, substituted hydroxyl, pyridyl or optionally substituted amino group, besides, in cases when X═S or X═NH, at least one of R 1 , R 2 or R 3 represent substituted C 1 -C 3 alkyl, cycloalkyl, adamantyl, aryl, heterocyclyl, halogen, substituted hydroxyl, optionally substituted amino group, aryldiazenyl, or at least two of R 1 , R 2 or R 3 represent hydrogen; R 4 represents C 1 -C 3 alkyl; R 5 represents hydrogen, one or two halogens, C 1 -C 3 alkyl or optionally substituted hydroxyl.

  该发明涉及新的取代的3-芳基磺酰基吡唑并[1,5-a]嘧啶，其通式为1，其药学上可接受的盐和/或水合物，血清素5-HT6受体拮抗剂和制药组合物，以及用于预防和治疗与血清素5-HT6受体相关的中枢神经系统各种疾病的方法，特别是阿尔茨海默病、帕金森病、亨廷顿病、精神分裂症和其他神经退行性疾病、认知障碍和肥胖症。在通式1中：其中：X═S、SO或NH；R1代表氢、可选取代的C1-C3烷基、环烷基、金刚烷基、芳基或杂环基；R2代表氢、卤素、可选取代的C1-C3烷基、取代的羟基、芳基重氮基或可选取代的氨基基团；R3代表氢、可选取代的C1-C3烷基、取代的羟基、吡啶基或可选取代的氨基基团，此外，在X═S或X═NH的情况下，至少有R1、R2或R3中的一个代表取代的C1-C3烷基、环烷基、金刚烷基、芳基、杂环基、卤素、取代的羟基、可选取代的氨基基团、芳基重氮基，或者R1、R2或R3中的至少两个代表氢；R4代表C1-C3烷基；R5代表氢、一个或两个卤素、C1-C3烷基或可选取代的羟基。
• [EN] SUBSTITUTED 3-ARYLSULFONYL-PYRAZOLO[1,5-A]PYRIMIDINES, SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS AND METHODS FOR THE PRODUCTION AND USE THEREOF<br/>[FR] 3-ARYLSULFONYL-PYRAZOLO[1,5-A]PYRIMIDINES SUBSTITUÉES, ANTAGONISTES DES RÉCEPTEURS 5-HT6 DE SÉROTONINE, PROCÉDÉS DE FABRICATION ET D'UTILISATION
  申请人：IVASHCHENKO ANDREY ALEXANDROVICH

  公开号：WO2010041983A1

  公开（公告）日：2010-04-15

  Данное изобретение относится к новым замещенным 3-apилcyльфoнил-пиpaзoлo[1,5-a]пиpимидинaм общей формулы 1, их фармацевтически приемлемым солям и/или гидратам, антагонистам серотониновых 5-HT6 рецепторов и фармацевтическим композициям, а также способу лечения и предупреждения развития различных заболеваний центральной нервной системы у людей и теплокровных животных, патогенез которых связан с 5-HT6 рецепторами, в частности, болезни Альцгеймера, болезни Паркинсона, болезни Гантингтона, шизофрении, других нейродегенеративных заболеваний, когнитивных расстройств и ожирения. В общей формуле 1: где: X = S, SO или NH; R1 представляет собой атом водорода, необязательно замещенный С1-С3алкил, циклоалкил, адамантил, арил или гетероциклил; R2 представляет собой атом водорода, атом галогена, необязательно замещенный С1-С3алкил, замещенный гидроксил, арилдиазенил или необязательно замещенную аминогруппу; R3 представляет собой атом водорода, необязательно замещенный С1-С3алкил, замещенный гидроксил, пиридил или необязательно замещенную аминогруппу, причем, в случаях, когда X = S или X = NH, по крайней мере, один из R1, R2 или R3 представляет собой замещенный С1-С3алкил, циклоалкил, адамантил, арил, гетероциклил, атом галогена, замещенный гидроксил, необязательно замещенную аминогруппу, арилдиазенил или, по крайней мере, два из R1, R2 или R3 представляют собой атом водорода; R4 представляет собой С1-С3алкил; R5 представляет собой атом водорода, один или два атома галогена, С1-С3алкил или необязательно замещенный гидроксил.

  This invention relates to new substituted 3-arylcylyl-pyrazolo [1,5-a] pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates, antagonists of serotonin 5-HT6 receptors and pharmaceutical compositions, as well as a method of treating and preventing the development of various central nervous system diseases in humans and warm-blooded animals, the pathogenesis of which is associated with 5-HT6 receptors, in particular Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, other neurodegenerative diseases, cognitive disorders, and obesity. In general formula 1: where: X = S, SO or NH; R1 represents a hydrogen atom, optionally substituted with C1-C3 alkyl, cycloalkyl, adamantyl, aryl or heterocycle; R2 represents a hydrogen atom, a halogen atom, optionally substituted with C1-C3 alkyl, substituted with hydroxyl, aryl diazenyl or optionally substituted amino group; R3 represents a hydrogen atom, optionally substituted with C1-C3 alkyl, substituted with hydroxyl, pyridyl or optionally substituted amino group, wherein in cases where X = S or X = NH, at least one of R1, R2 or R3 represents a substituted C1-C3 alkyl, cycloalkyl, adamantyl, aryl, heterocycle, halogen atom, substituted hydroxyl, optionally substituted amino group, aryl diazenyl or at least two of R1, R2 or R3 represent a hydrogen atom; R4 represents C1-C3 alkyl; R5 represents a hydrogen atom, one or two halogen atoms, C1-C3 alkyl or optionally substituted hydroxyl.
• SUBSTITUTED 3-ARYLSULFONYL-PYRAZOLO[1,5-A]PYRIMIDINES, SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS AND METHODS FOR THE PRODUCTION AND USE THEREOF AND METHODS FOR THE PRODUCTION AND USE THEREOF
  申请人：Alla Chem, LLC.

  公开号：EP3020719B1

  公开（公告）日：2017-09-20
• Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-<i>a</i>]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT₆ Receptor (5-HT₆R) Antagonists
  作者：Alexandre V. Ivachtchenko、Elena S. Golovina、Madina G. Kadieva、Volodymyr M. Kysil、Oleg D. Mitkin、Sergey E. Tkachenko、Ilya M. Okun

  DOI：10.1021/jm201079g

  日期：2011.12.8

  Syntheses, biological evaluation as 5-HT6 receptor (5-HT6R) antagonists, and structure activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.