N-[4-(4-ethylmorpholin-2-yl)-2-methylphenyl]-4-(propan-2-yl)benzenesulfonamide | 1010382-72-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: N-[4-(4-ethylmorpholin-2-yl)-2-methylphenyl]-4-(propan-2-yl)benzenesulfonamide
• 英文别名: N-(4-(4-ethylmorpholin-2-yl)-2-methylphenyl)-4-isopropylbenzenesulfonamide；Benzenesulfonamide, N-(4-(4-ethyl-2-morpholinyl)-2-methylphenyl)-4-(1-methylethyl)-；N-[4-(4-ethylmorpholin-2-yl)-2-methylphenyl]-4-propan-2-ylbenzenesulfonamide
• CAS: 1010382-72-5
• 化学式: C₂₂H₃₀N₂O₃S
• 分子量: 402.558
• InChiKey: SVIVAENOUMHBBT-UHFFFAOYSA-N

物化性质

• 沸点：
  523.8±60.0 °C(Predicted)
• 密度：
  1.164±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  67
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[4-(4-ethylmorpholin-2-yl)-2-methylphenyl]-4-(propan-2-yl)benzenesulfonamide 在 Chiralpak AD column 作用下， 以 乙醇 、 正庚烷 为溶剂， 以7.7 g的产率得到(-)-N-{4-[(2S)-4-ethylmorpholin-2-yl]-2-methylphenyl}-4-(propan-2-yl)benzenesulfonamide
  参考文献：
  名称：

  Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

  摘要：

  Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor(D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PE-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (>= 4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K-i = 3.1 nM), good subtype selectivity over D2R (D2 K-i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-depeodentlye attenuated opioid self-administration and opioid drug-seeking, behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further,. traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3e has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.

  DOI：

  10.1021/acschemneuro.6b00297
• 作为产物：
  描述：

  3-甲基-4-硝基苯甲酰氯 在 吡啶 、 三乙基硅烷 、 氢溴酸 、 氢气 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 乙腈 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 113.5h， 生成 N-[4-(4-ethylmorpholin-2-yl)-2-methylphenyl]-4-(propan-2-yl)benzenesulfonamide
  参考文献：
  名称：

  Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

  摘要：

  Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor(D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PE-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (>= 4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K-i = 3.1 nM), good subtype selectivity over D2R (D2 K-i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-depeodentlye attenuated opioid self-administration and opioid drug-seeking, behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further,. traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3e has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.

  DOI：

  10.1021/acschemneuro.6b00297

文献信息

• [EN] MORPHOLINE D3 DOPAMINE ANTAGONISTS<br/>[FR] ANTAGONISTES À BASE DE MORPHOLINE DE LA DOPAMINE D3
  申请人：PFIZER PROD INC

  公开号：WO2008026046A1

  公开（公告）日：2008-03-06

  [EN] The present invention relates to compounds of the formula (I) wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in the specification, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use as modulators of the dopamine D3 receptor, particularly as psychotherapeutic agents.
  [FR] La présente invention concerne des composés de formule (I) dans laquelle R¹, R², R³, R⁴, R⁵ et R⁶ sont tels que définis dans la description, des intermédiaires pour leur préparation, des compositions pharmaceutiques les contenant et leur application médicale en tant que modulateurs du récepteur de la dopamine D3, notamment en tant qu'agents psychothérapeutiques.
• Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects
  作者：Travis T. Wager、Thomas Chappie、David Horton、Ramalakshmi Y. Chandrasekaran、Brian Samas、Elizabeth R. Dunn-Sims、Cathleen Hsu、Nawshaba Nawreen、Michelle A. Vanase-Frawley、Rebecca E. O’Connor、Christopher J. Schmidt、Keith Dlugolenski、Nancy C. Stratman、Mark J. Majchrzak、Bethany L. Kormos、David P. Nguyen、Aarti Sawant-Basak、Andy N. Mead

  DOI：10.1021/acschemneuro.6b00297

  日期：2017.1.18

  Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor(D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PE-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (>= 4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K-i = 3.1 nM), good subtype selectivity over D2R (D2 K-i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-depeodentlye attenuated opioid self-administration and opioid drug-seeking, behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further,. traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3e has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.