alpha-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇 | 105565-56-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: alpha-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇
• 中文别名: 苯甲腈,2-[(4-羟基-1-哌啶基)甲基]-
• 英文名称: 4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-(4-fluorophenyl)butanol
• 英文别名: BMS-181100；BMY 14802；α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol monohydrochloride；α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride；(+/-)-α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol；1-[4-(4-fluorophenyl)-4-hydroxybutyl]-4-(5-fluoropyrimidin-2-yl)-piperazine；alpha-(4-Fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol；1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]butan-1-ol
• CAS: 105565-56-8
• 化学式: C₁₈H₂₂F₂N₄O
• 分子量: 348.396
• InChiKey: ZXUYYZPJUGQHLQ-UHFFFAOYSA-N

物化性质

• 沸点：
  520.8±60.0 °C(Predicted)
• 密度：
  1.256±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  52.5
• 氢给体数：
  1
• 氢受体数：
  7

制备方法与用途

BMY 14802是一种σ1R拮抗剂，同时也是5-HT1A和肾上腺素能α-1受体的激动剂。研究显示，BMY 14802能够通过下调AIM的表达来抑制帕金森病模型大鼠的异常非自主运动(AIM)。

反应信息

• 作为反应物：
  描述：

  alpha-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇 在 三氯硅烷 、 三乙胺 作用下， 以 甲苯 、 苯 为溶剂， 反应 216.0h， 生成 (+)-BMY 14802
  参考文献：
  名称：

  Synthesis and biological characterization of .alpha.-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogs as potential atypical antipsychotic agents

  摘要：

  A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[H-3]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

  DOI：

  10.1021/jm00102a002
• 作为产物：
  描述：

  BMY 14786 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 生成 alpha-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇
  参考文献：
  名称：

  Synthesis and biological characterization of .alpha.-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogs as potential atypical antipsychotic agents

  摘要：

  A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[H-3]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

  DOI：

  10.1021/jm00102a002

文献信息

• Agents for treatment of brain ischemia
  申请人：Bristol-Myers Squibb Co.

  公开号：US04994460A1

  公开（公告）日：1991-02-19

  A series of 5-halopyrimidin-2-ylpiperazinylalkyl derivatives having useful anti-ischemic properties for treatment and prevention of dirorders resulting from brain and/or spinal cord anoxia.

  一系列具有有用的抗缺血特性的5-卤代嘧啶-2-基哌嗪基烷基衍生物，用于治疗和预防由脑部和/或脊髓缺氧引起的疾病。
• Sigma ligands for use in the prevention and/or treatment of postoperative pain
  申请人：Laboratorios del. Dr. Esteve, S.A.

  公开号：EP2353598A1

  公开（公告）日：2011-08-10

  The invention refers to the use of a sigma ligand, particularly a sigma ligand of formulae (I), (II) or (III) to prevent and/or treat acute and chronic pain developed as a consequence of surgery, especially superficial and/or deep pain secondary to surgical tissue injury, and peripheral neuropathic pain, neuralgia, allodynia, causalgia, hyperalgesia, hyperesthesia, hyperpathia, neuritis or neuropathy secondary to surgical procedure.

  本发明涉及使用sigma配体，特别是公式（I），（II）或（III）的sigma配体，以预防和/或治疗由手术引起的急性和慢性疼痛，特别是手术组织损伤引起的表浅和/或深层疼痛，以及周围神经病理性疼痛，神经痛，触痛，烧伤性痛，痛觉过敏，疼痛过敏，神经炎或手术过程引起的神经病变。
• NEUROGENESIS BY MUSCARINIC RECEPTOR MODULATION
  申请人：Barlow Carrolee

  公开号：US20070049576A1

  公开（公告）日：2007-03-01

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  该即时披露描述了通过刺激或增加神经发生来治疗中枢神经系统和外周神经系统的疾病和病症的方法。该披露包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经生成剂结合以刺激或激活新神经细胞的形成。
• Use of 4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-(4-fluorophenyl)-butanol in pharmaceutical compositions for the treatment of ischemia in brain
  申请人：Bristol-Myers Squibb Company

  公开号：EP0410114A3

  公开（公告）日：1992-01-02

  The invention relates to the use of BMY 14802 or a pharmaceutically acceptable acid addition salt and/or hydrate thereof for preparing a pharmaceutical composition for protecting brain cells from ischemia and for treating ischemic and degenerative brain disorders.

  本发明涉及 BMY 14802 或其药学上可接受的酸加成盐和/或水合物用于制备保护脑细胞免受缺血和治疗缺血性和退行性脑疾病的药物组合物。
• Neurogenesis by muscarinic receptor modulation with sabcomelin
  申请人：Braincells, Inc.

  公开号：EP2258359A2

  公开（公告）日：2010-12-08

  The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on muscarinic receptor modulation, such as via inhibition of acetylcholine esterase (AChE) activity, alone or in combination with another neurogenic agent to stimulate or activate the formation of new nerve cells.

  本公开描述了通过刺激或增加神经发生来治疗中枢和周围神经系统疾病和病症的方法。本公开包括基于毒蕈碱受体调节的组合物和方法，例如通过抑制乙酰胆碱酯酶（AChE）活性，单独或与另一种神经发生剂联合使用，以刺激或激活新神经细胞的形成。