(4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexyl)methanamine

• 分子结构分类: 有机化合物 - 有机卤素化合物 - 卤代烷
• 英文名称: (4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexyl)methanamine
• 英文别名: [4,4-Difluoro-1-[4-(1-methyltriazol-4-yl)sulfonylpiperazin-1-yl]cyclohexyl]methanamine
• 化学式: C₁₄H₂₄F₂N₆O₂S
• 分子量: 378.446
• InChiKey: WRBKXPVMTWZAMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexyl)methanamine 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 16.5h， 生成 2-chloro-N-((4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluorobenzamide hydrochloride
  参考文献：
  名称：

  Synthesis and Biological Evaluation ofN-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

  摘要：

  We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

  DOI：

  10.1021/acs.jmedchem.6b00914
• 作为产物：
  描述：

  4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexanecarbonitrile 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以87%的产率得到(4,4-difluoro-1-(4-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)piperazin-1-yl)cyclohexyl)methanamine
  参考文献：
  名称：

  Synthesis and Biological Evaluation ofN-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

  摘要：

  We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

  DOI：

  10.1021/acs.jmedchem.6b00914

文献信息

• GLYCINE TRANSPORTER-1 INHIBITORS, METHODS OF MAKING THEM, AND USES THEREOF
  申请人：CIOFFI Christopher L.

  公开号：US20110312931A1

  公开（公告）日：2011-12-22

  The compounds of the present invention are represented by the following formula (I): wherein the substituents R 1 , R 2 , R 3 , R 4 , (R 5 ) m , R 6 , A, X, and Y are as defined herein. The compounds are useful in methods of treating a disorder which is created by or is dependent upon inhibiting GlyT-1.

  本发明的化合物由以下公式（I）表示：其中，取代基R1、R2、R3、R4、（R5）m、R6、A、X和Y的定义如本文所述。这些化合物可用于治疗由抑制GlyT-1引起或依赖于GlyT-1抑制的疾病的方法。
• US9045445B2
  申请人：——

  公开号：US9045445B2

  公开（公告）日：2015-06-02
• [EN] GLYCINE TRANSPORTER-1 INHIBITORS, METHODS OF MAKING THEM, AND USES THEREOF<br/>[FR] INHIBITEURS DU TRANSPORTEUR 1 DE LA GLYCINE, PROCÉDÉS DE FABRICATION ASSOCIÉS, ET UTILISATIONS ASSOCIÉES
  申请人：ALBANY MOLECULAR RES INC

  公开号：WO2011153359A1

  公开（公告）日：2011-12-08

  The compounds of the present invention are represented by the following formula (I): wherein the substituents R1, R2, R3, R4, (R5)m, R6, A, X, and Y are as defined herein. The compounds are useful in methods of treating a disorder which is created by or is dependent upon inhibiting GlyT-1.
• Synthesis and Biological Evaluation of<i>N</i>-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1
  作者：Christopher L. Cioffi、Shuang Liu、Mark A. Wolf、Peter R. Guzzo、Kashinath Sadalapure、Visweswaran Parthasarathy、David T. J. Loong、Jun-Ho Maeng、Edmund Carulli、Xiao Fang、Kalesh Karunakaran、Lakshman Matta、Sok Hui Choo、Shailijia Panduga、Ronald N. Buckle、Randall N. Davis、Samuel A. Sakwa、Priya Gupta、Bruce J. Sargent、Nicholas A. Moore、Michele M. Luche、Grant J. Carr、Yuri L. Khmelnitsky、Jiffry Ismail、Mark Chung、Mei Bai、Wei Yee Leong、Nidhi Sachdev、Srividya Swaminathan、Andrew J. Mhyre

  DOI：10.1021/acs.jmedchem.6b00914

  日期：2016.9.22

  We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).