5-bromo-1-cyclopropanecarbonylazepan-4-one | 1363260-78-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: 5-bromo-1-cyclopropanecarbonylazepan-4-one
• 英文别名: 5-Bromo-1-cyclopropanecarbonyl-azepan-4-one；5-bromo-1-(cyclopropanecarbonyl)azepan-4-one
• CAS: 1363260-78-9
• 化学式: C₁₀H₁₄BrNO₂
• 分子量: 260.131
• InChiKey: XAUATCQEBHTSHP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-bromo-1-cyclopropanecarbonylazepan-4-one 在 亚硝酸特丁酯 、 sodium hydride 、 copper(ll) bromide 作用下， 以 四氢呋喃 、 异丙醇 、 乙腈 、 mineral oil 为溶剂， 反应 2.0h， 生成 cyclopropyl-[2-(1-isopropyl-piperidin-4-yloxy)-4,5,7,8-tetrahydro-thiazolo[5,4-d]azepin-6-yl]-methanone tartrate
  参考文献：
  名称：

  1‐[2‐(1‐Cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4 H ‐thiazolo[5,4‐ c ]pyridin‐5‐yl]propan‐1‐one: a Histamine H ₃ Receptor Inverse Agonist with Efficacy in Animal Models of Cognition

  摘要：

  AbstractA series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1‐[2‐(1‐cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4H‐thiazolo[5,4‐c]pyridin‐5‐yl]propan‐1‐one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)‐α‐methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half‐life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub‐therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.

  DOI：

  10.1002/cmdc.202100583
• 作为产物：
  描述：

  氮杂环庚-4-酮 在 溴 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 生成 5-bromo-1-cyclopropanecarbonylazepan-4-one
  参考文献：
  名称：

  [EN] HETEROCYCLYL COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS
  [FR] COMPOSÉS HÉTÉROCYCLYLE COMME LIGANDS DES RÉCEPTEURS H3 DE L'HISTAMINE

  摘要：

  本发明涉及式(I)的杂环化合物，以及它们的药学上可接受的盐和含有它们的组合物。本发明还涉及一种制备上述新化合物及其药学上可接受的盐的方法。式(I)的化合物在治疗与组胺H3受体相关的各种疾病方面具有用途，例如认知障碍、睡眠障碍、肥胖和疼痛。

  公开号：

  WO2012029070A1

文献信息

• [EN] HETEROCYCLYL COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS<br/>[FR] COMPOSÉS HÉTÉROCYCLYLE COMME LIGANDS DES RÉCEPTEURS H3 DE L'HISTAMINE
  申请人：SUVEN LIFE SCIENCES LTD

  公开号：WO2012029070A1

  公开（公告）日：2012-03-08

  The present invention relates to heterocyclyl compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to Histamine H3 receptors, for example cognitive disorders, sleep disorders, obesity and pain.

  本发明涉及式(I)的杂环化合物，以及它们的药学上可接受的盐和含有它们的组合物。本发明还涉及一种制备上述新化合物及其药学上可接受的盐的方法。式(I)的化合物在治疗与组胺H3受体相关的各种疾病方面具有用途，例如认知障碍、睡眠障碍、肥胖和疼痛。
• HETEROCYCLYL COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS
  申请人：Nirogi Ramakrishna

  公开号：US20140148440A1

  公开（公告）日：2014-05-29

  The present invention relates to heterocyclyl compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to Histamine H 3 receptors, for example cognitive disorders, sleep disorders, obesity and pain.

  本发明涉及式（I）的杂环化合物及其药学上可接受的盐和含有它们的组合物。本发明还涉及上述新型化合物及其药学上可接受的盐的制备方法。式（I）的化合物在治疗与组胺H3受体相关的各种疾病方面具有用途，例如认知障碍、睡眠障碍、肥胖症和疼痛。
• Heterocyclyl compounds as histamine H3 receptor ligands
  申请人：Nirogi Ramakrishna

  公开号：US08912179B2

  公开（公告）日：2014-12-16

  The present invention relates to heterocyclyl compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to Histamine H3 receptors, for example cognitive disorders, sleep disorders, obesity and pain.

  本发明涉及式（I）的杂环化合物及其药学上可接受的盐和含有它们的组合物。本发明还涉及一种制备上述新化合物及其药学上可接受的盐的方法。式（I）的化合物在治疗与组胺H3受体相关的各种疾病方面有用，例如认知障碍、睡眠障碍、肥胖和疼痛。
• US8912179B2
  申请人：——

  公开号：US8912179B2

  公开（公告）日：2014-12-16
• 1‐[2‐(1‐Cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4 <i>H</i> ‐thiazolo[5,4‐ <i>c</i> ]pyridin‐5‐yl]propan‐1‐one: a Histamine H ₃ Receptor Inverse Agonist with Efficacy in Animal Models of Cognition
  作者：Anil Karbhari Shinde、Rajesh Kumar Badange、Veena Reballi、Pramod Kumar Achanta、Kumar Bojja、Sravanthi Manchineella、Nageswara Rao Muddana、Ramkumar Subramanian、Raghava Choudary Palacharla、Vijay Benade、Pradeep Jayarajan、Jagadeesh Babu Thentu、Bujji Babu Lingavarapu、Sivasekhar Yarra、Narendra Kagita、Mallikarjuna Rao Doguparthi、Abdul Rasheed Mohammed、Ramakrishna Nirogi

  DOI：10.1002/cmdc.202100583

  日期：2022.2.4

  AbstractA series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1‐[2‐(1‐cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4H‐thiazolo[5,4‐c]pyridin‐5‐yl]propan‐1‐one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)‐α‐methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half‐life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub‐therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.