(3R)-N-[6-(1H-咪唑-1-基)-4-嘧啶基]螺[1-氮杂双环[2.2.2]辛烷-3,5-'(4'H)-噁唑]-2'-胺 | 1221973-93-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 中文名称: (3R)-N-[6-(1H-咪唑-1-基)-4-嘧啶基]螺[1-氮杂双环[2.2.2]辛烷-3,5-'(4'H)-噁唑]-2'-胺
• 英文名称: (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine
• 英文别名: (R)-N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine；BMS-933043；(3R)-N-(6-imidazol-1-ylpyrimidin-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-4H-1,3-oxazole]-2'-amine
• CAS: 1221973-93-8
• 化学式: C₁₆H₁₉N₇O
• 分子量: 325.373
• InChiKey: RLXBHTUZCPORKT-INIZCTEOSA-N

物化性质

• 沸点：
  539.3±60.0 °C(Predicted)
• 密度：
  1.59±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  80.5
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

BMS-933043是一种新型、高选择性的α7nAChR部分激动剂，对大鼠和人α7受体的结合Ki分别为3.3纳摩尔和8.1纳摩尔；它对其他nAChR亚型的选择性超过100倍，对5-HT3A受体的选择性则超过300倍。

在认知障碍的临床前模型中，BMS-933043表现出体内活性，尤其是在鼠标新物体识别测试中。此外，在精神分裂症1期试验中已停止使用。

反应信息

• 作为反应物：
  描述：

  (3R)-N-[6-(1H-咪唑-1-基)-4-嘧啶基]螺[1-氮杂双环[2.2.2]辛烷-3,5-'(4'H)-噁唑]-2'-胺 在 间氯过氧苯甲酸 作用下， 以 四氢呋喃 为溶剂， 反应 0.25h， 以24%的产率得到(2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine 4-oxide
  参考文献：
  名称：

  BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

  摘要：

  The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that a? neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent alpha 7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

  DOI：

  10.1021/acsmedchemlett.7b00032
• 作为产物：
  描述：

  (3-((benzyloxycarbonylamino)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate 在 盐酸 、 二氧化碳 、 caesium carbonate 作用下， 以 四氢呋喃 、 水 、 丙酮 、 乙腈 为溶剂， 反应 0.53h， 生成 (3R)-N-[6-(1H-咪唑-1-基)-4-嘧啶基]螺[1-氮杂双环[2.2.2]辛烷-3,5-'(4'H)-噁唑]-2'-胺
  参考文献：
  名称：

  BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

  摘要：

  The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that a? neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent alpha 7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

  DOI：

  10.1021/acsmedchemlett.7b00032

文献信息

• [EN] QUINUCLIDINE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS<br/>[FR] COMPOSÉ DE QUINUCLIDINE COMME LIGANDS DU RÉCEPTEUR NICOTINIQUE ALPHA-7 DE L'ACÉTYLCHOLINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2011053292A1

  公开（公告）日：2011-05-05

  The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic 7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  该披露提供了公式I的化合物，包括它们的盐，以及使用这些化合物的组合物和方法。这些化合物是烟碱7受体的配体，可能对治疗中枢神经系统的各种紊乱，特别是情感和神经退行性疾病有用。
• [EN] AZA-BICYCLIC AMINE N-OXIDE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGAND PRO-DRUGS<br/>[FR] COMPOSÉS N-OXYDE D'AMINE AZA-BICYLIQUE EN TANT QUE PROMÉDICAMENTS DE LIGANDS DE RÉCEPTEURS NICOTINIQUES D'ACÉTYLCHOLINE ALPHA-7
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2011137313A1

  公开（公告）日：2011-11-03

  The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are prodrugs for ligands, agonists, and partial agonists for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  该披露通常涉及到公式I的化合物，包括它们的盐，以及使用这些化合物的组合物和方法。这些化合物是尼古丁α7受体的配体、激动剂和部分激动剂的前体药物，可能对中枢神经系统的各种障碍，特别是情感和神经退行性障碍的治疗有用。
• Quinuclidine Compounds as Alpha-7 Nicotinic Acetylcholine Receptor Ligands
  申请人：Cook, II James H.

  公开号：US20100099684A1

  公开（公告）日：2010-04-22

  The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  本公开提供公式I的化合物，包括其盐，以及使用这些化合物的组合物和方法。这些化合物是尼古丁α7受体的配体，可能对中枢神经系统的各种疾病，特别是情感和神经退行性疾病的治疗有用。
• Aza-Bicyclic Amine N-Oxide Compounds as Alpha-7 Nicotinic Acetylcholine Receptor Ligand Pro-Drugs
  申请人：Lentz Kimberley A.

  公开号：US20120108596A1

  公开（公告）日：2012-05-03

  The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are prodrugs for ligands, agonists, and partial agonists for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  本公开涉及式I的化合物，包括其盐，以及使用该化合物的组合物和方法。这些化合物是尼古丁α7受体的配体、激动剂和部分激动剂的前药，可用于治疗中枢神经系统的各种疾病，特别是情感和神经退行性疾病。
• Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands
  申请人：Bristol-Myers Squibb Company

  公开号：US08309577B2

  公开（公告）日：2012-11-13

  The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  本披露提供了I式化合物及其盐，以及使用这些化合物的组合物和方法。这些化合物是尼古丁α7受体的配体，可用于治疗各种中枢神经系统疾病，特别是情感和神经退行性疾病。