3-amino-5-methylsulfanyl-4-phenylsulfonyl-2H-pyrazole | 64824-79-9

• 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: 3-amino-5-methylsulfanyl-4-phenylsulfonyl-2H-pyrazole
• 英文别名: 3-(methylthio)-4-(phenylsulfonyl)-1H-pyrazol-5-amine；4-(phenylsulfonyl)-5-(methylthio)-2H-pyrazol-3-ylamine；4-benzenesulfonyl-5-methylsulfanyl-1(2)H-pyrazol-3-ylamine；4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine；5-amino-3-methylthio-4-phenylsulfonyl-1H-pyrazole；4-(benzenesulfonyl)-3-methylsulfanyl-1H-pyrazol-5-amine
• CAS: 64824-79-9
• 化学式: C₁₀H₁₁N₃O₂S₂
• 分子量: 269.348
• InChiKey: GKLYGEGLNUHNLL-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：
  123
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-amino-5-methylsulfanyl-4-phenylsulfonyl-2H-pyrazole 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-methylthio-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：

  3-(dimethylamino)-3-(methylthio)-2-(phenylsulfonyl)acrylonitrile 在 一水合肼 作用下， 以 异丙醇 为溶剂， 反应 3.0h， 以33%的产率得到N3,N3-dimethyl-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

• Pyrazolopyrimidine and pyrazolines and process for preparation thereof
  申请人：Hoffman-La Roche Inc.

  公开号：US06194410B1

  公开（公告）日：2001-02-27

  The present invention is concerned with pyrazolopyrimidines and pyrazolotriazines of the general formula and their pharmaceutically acceptable salts. Surprisingly, these compounds evidence selective affinity to 5HT-6 receptors. They are accordingly suitable for use in the treatment and prevention of central nervous disorders such as, for example, psychoses, schizophrenia, manic depressions, depressions, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.

  本发明涉及一般式的吡唑吡嘧啶和吡唑三嗪，以及它们的药用盐。令人惊讶的是，这些化合物表现出对5HT-6受体的选择性亲和力。因此，它们适用于治疗和预防中枢神经系统疾病，例如精神病、精神分裂症、躁郁症、抑郁症、神经系统疾病、记忆障碍、帕金森病、肌萎缩侧索硬化、阿尔茨海默病和亨廷顿舞蹈症。
• 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
• 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) 3-SULFONYL-PYRAZOLO[1,5-A] PYRIMIDINES / ANTAGONISTS OF SEROTONIN 5-HT6 RECEPTORS, METHODS FOR THE PRODUCTION AND THE USE THEREOF
  申请人：Ivashcenko Andrey Alexandrovich

  公开号：US20100331347A1

  公开（公告）日：2010-12-30

  The present invention relates to novel substituted 3-(arylsulfonyl)pyrazolo[1,5-a]pyrimidines of general formula 1 pharmaceutically acceptable salts and/or hydrates, to novel serotonin 5-HT 6 receptor antagonists, to novel drug substances, pharmaceutical compositions, medicaments and methods for their preparation and use for treatment and prophylaxis of pathological states and diseases of CNS, pathogenesis of which is associated with disturbance of serotonin 5-HT 6 receptor activation. In compounds of general formula 1 Ar represents optionally substituted aryl or heterocyclyl; R 1 , R 2 and R 3 independently of each other represent hydrogen, C 1 -C 3 alkyl or phenyl; R 4 represents hydrogen, optionally substituted C 1 -C 5 alkyl, substituted hydroxyl group or substituted sulfanyl group.

  本发明涉及新型的取代的3-(芳基磺酰基)吡唑并[1,5-a]嘧啶通式1的药学上可接受的盐和/或水合物，新型的血清素5-HT6受体拮抗剂，新型的药物物质、制药组合物、药物和其制备和使用的方法，用于治疗和预防与血清素5-HT6受体激活紊乱相关的中枢神经系统的病理状态和疾病的发病机制。在通式1中，Ar代表可选取代的芳基或杂环基；R1、R2和R3分别代表氢、C1-C3烷基或苯基；R4代表氢、可选取代的C1-C5烷基、取代的羟基基团或取代的磺酰基基团。
• Synthesis of cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines and their evaluation as 5-HT6 receptor antagonists
  作者：Alexandre V. Ivachtchenko、Dmitri E. Dmitriev、Elena S. Golovina、Elena S. Dubrovskaya、Madina G. Kadieva、Angela G. Koryakova、Volodymyr M. Kysil、Oleg D. Mitkin、Sergey E. Tkachenko、Ilya M. Okun、Anton A. Vorobiov

  DOI：10.1016/j.bmcl.2010.02.046

  日期：2010.4

  Synthesis and biological evaluation of 1 ('angular') and 2 ('linear') cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT6 receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (K-i < 1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT6 receptor antagonists pharmacophore model. (C) 2010 Elsevier Ltd. All rights reserved.