6-benzyl 1-ethyl (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate | 1539277-94-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-benzyl 1-ethyl (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate
• 英文别名: (R)-6-Benzyl 1-ethyl 6-azaspiro[2.5]octane-1,6-dicarboxylate；6-O-benzyl 2-O-ethyl (2R)-6-azaspiro[2.5]octane-2,6-dicarboxylate
• CAS: 1539277-94-5
• 化学式: C₁₈H₂₃NO₄
• 分子量: 317.385
• InChiKey: HPESIWGAJLAFOB-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-benzyl 1-ethyl (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate 在 水 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.08h， 生成 (R)-benzyl 1-(4-isopropylpiperazine-1-carbonyl)-6-azaspiro[2.5]octane-6-carboxylate
  参考文献：
  名称：

  Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition

  摘要：

  A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only sigma 2 (62% at 10 mu M). Compound 6s demonstrated free-plasma exposures above the IC50 (similar to 50x) with a brain-to-plasma ratio of similar to 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H-3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

  DOI：

  10.1021/jm4014828
• 作为产物：
  描述：

  1-Cbz-4-亚甲基哌啶 在 copper(l) cyanide 作用下， 以 二氯甲烷 为溶剂， 反应 100.0h， 生成 6-benzyl 1-ethyl (1R)-6-azaspiro[2.5]octane-1,6-dicarboxylate
  参考文献：
  名称：

  Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition

  摘要：

  A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only sigma 2 (62% at 10 mu M). Compound 6s demonstrated free-plasma exposures above the IC50 (similar to 50x) with a brain-to-plasma ratio of similar to 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H-3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

  DOI：

  10.1021/jm4014828

文献信息

• [EN] SPIROPIPERIDINE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE SPIROPIPÉRIDINE DE RÉCEPTEURS NICOTINIQUES DE L'ACÉTYLCHOLINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2020223136A1

  公开（公告）日：2020-11-05

  The present disclosure relates to compounds of formula (I) that are useful as modulators of 7α nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation.

  本公开涉及式(I)的化合物，这些化合物可用作7α nAChR的调节剂，包含这些化合物的组合物，以及利用这些化合物预防、治疗或改善疾病，特别是中枢神经系统疾病，如阿尔茨海默病、帕金森病和精神分裂症，以及L-多巴引起的运动障碍和炎症。
• [EN] SPIROPIPERIDINE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE SPIROPIPÉRIDINE DES RÉCEPTEURS NICOTINIQUES DE L'ACÉTYLCHOLINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2019212927A1

  公开（公告）日：2019-11-07

  The present disclosure relates to compounds of formula I that are useful as modulators of 7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation (I).

  本公开涉及公式I的化合物，这些化合物可用作7 nAChR的调节剂，包含这些化合物的组合物，以及利用这些化合物预防、治疗或改善疾病，特别是中枢神经系统疾病，如阿尔茨海默病、帕金森病和精神分裂症中的认知障碍，以及L-多巴引起的运动障碍和炎症。
• Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition
  作者：Dean G. Brown、Peter R. Bernstein、Andrew Griffin、Steve Wesolowski、Denis Labrecque、Maxime C. Tremblay、Mark Sylvester、Russell Mauger、Phillip D. Edwards、Scott R. Throner、James J. Folmer、Joseph Cacciola、Clay Scott、Lois A. Lazor、Mehrnaz Pourashraf、Vijayaratnam Santhakumar、William M. Potts、Simon Sydserff、Pascall Giguère、Carine Lévesque、Mohammed Dasser、Thierry Groblewski

  DOI：10.1021/jm4014828

  日期：2014.2.13

  A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only sigma 2 (62% at 10 mu M). Compound 6s demonstrated free-plasma exposures above the IC50 (similar to 50x) with a brain-to-plasma ratio of similar to 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H-3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.