(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro-4-methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide | 1369766-47-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro-4-methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide
• 英文别名: (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluoro-4-methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide；(1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluoro-4-methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
• CAS: 1369766-47-1
• 化学式: C₂₃H₂₂F₂N₄O₃
• 分子量: 440.449
• InChiKey: PKCHWHMQABQDIP-GAJHUEQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  86.2
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (1S,2R)-1-[3-fluoro-4-(methoxymethoxy)phenyl]cyclopropane-1,2-dimethanol 在 盐酸 、 草酰氯 、 偶氮二甲酸二异丙酯 、 lipase acrylic resin from Candida antarctica 、 caesium carbonate 、 二甲基亚砜 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 55.0h， 生成 (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro-4-methoxyphenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor

  摘要：

  Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyri- din-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [C-11]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX(2)Rs). In vivo PET study of [C-11]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.

  DOI：

  10.1021/jm400772t

文献信息

• CYCLOPROPANE COMPOUND
  申请人：Terauchi Taro

  公开号：US20120095031A1

  公开（公告）日：2012-04-19

  A cyclopropane compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof has orexin receptor antagonism, and therefore has a potencial of usefulness for the treatment of sleep disorder for which orexin receptor antagonism is effective, for example, insomnia: wherein Q represents —CH— or a nitrogen atom, R 1a and R 1b each independently represent a C 1-6 alkyl group and the like, R 1c represents a hydrogen atom and the like, R 2a , R 2b , R 2c and R 2d each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group and the like, R 3a , R 3b and R 3c each independently represent a hydrogen atom, a halogen atom and the like, and R 3d represents a hydrogen atom and the like.

  一种环丙烷化合物，其化学式如下（A），或其药学上可接受的盐具有促进俄雷昔康受体拮抗作用，因此具有治疗俄雷昔康受体拮抗有效的睡眠障碍的潜力，例如失眠：其中Q代表—CH—或氮原子，R1a和R1b分别独立表示C1-6烷基基团等，R1c表示氢原子等，R2a，R2b，R2c和R2d分别独立表示氢原子，卤素原子，C1-6烷基基团等，R3a，R3b和R3c分别独立表示氢原子，卤素原子等，R3d表示氢原子等。
• Cyclopropane compound
  申请人：Eisai R&D Management Co., Ltd.

  公开号：US08268848B2

  公开（公告）日：2012-09-18

  A cyclopropane compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof has orexin receptor antagonism, and therefore has a potencial of usefulness for the treatment of sleep disorder for which orexin receptor antagonism is effective, for example, insomnia: wherein Q represents —CH— or a nitrogen atom, R1a and R1b each independently represent a C1-6 alkyl group and the like, R1c represents a hydrogen atom and the like, R2a, R2b, R2c and R2d each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group and the like, R3a, R3b and R3c each independently represent a hydrogen atom, a halogen atom and the like, and R3d represents a hydrogen atom and the like.

  下列化学式（A）所代表的环丙烷化合物或其药学上可接受的盐具有促进睡眠受体拮抗作用，因此在治疗对促进睡眠受体拮抗有效的睡眠障碍，例如失眠方面具有潜在的用处：其中Q代表—CH—或氮原子，R1a和R1b各自独立代表C1-6烷基等，R1c代表氢原子等，R2a，R2b，R2c和R2d各自独立代表氢原子、卤素原子、C1-6烷基等，R3a，R3b和R3c各自独立代表氢原子、卤素原子等，R3d代表氢原子等。
• US8268848B2
  申请人：——

  公开号：US8268848B2

  公开（公告）日：2012-09-18
• Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor
  作者：Norihito Oi、Michiyuki Suzuki、Taro Terauchi、Masaki Tokunaga、Yosuke Nakatani、Noboru Yamamoto、Toshimitsu Fukumura、Ming-Rong Zhang、Tetsuya Suhara、Makoto Higuchi

  DOI：10.1021/jm400772t

  日期：2013.8.22

  Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyri- din-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [C-11]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX(2)Rs). In vivo PET study of [C-11]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers.