4-(pyridin-2-yl)piperazine-1-carbohydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(pyridin-2-yl)piperazine-1-carbohydrazide
• 英文别名: 4-Pyridin-2-ylpiperazine-1-carbohydrazide
• 化学式: C₁₀H₁₅N₅O
• mdl: MFCD11106043
• 分子量: 221.262
• InChiKey: QTVZKLUELPOKBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  74.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(pyridin-2-yl)piperazine-1-carbohydrazide 在 chloroamine-T 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 0.5h， 生成 2-(4-(pyridin-2-yl)piperazin-1-yl)-5-(p-tolyl)-1,3,4-oxadiazole
  参考文献：
  名称：

  Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease

  摘要：

  The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50 = 0.054 mu M), butyrylcholinesterase (hBChE, IC50 = 0.787 mu M) and beta-secretase-1 (hBACE-1, IC50 = 0.098 mu M). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 mu M). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-A beta aggregation activity in self- and AChE-induced thiofiavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and A beta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111707
• 作为产物：
  描述：

  phenyl 4-(pyridin-2-yl)piperazine-1-carboxylate 在 hydrazine hydrate 作用下， 以 乙醇 为溶剂， 以84%的产率得到4-(pyridin-2-yl)piperazine-1-carbohydrazide
  参考文献：
  名称：

  Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease

  摘要：

  The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50 = 0.054 mu M), butyrylcholinesterase (hBChE, IC50 = 0.787 mu M) and beta-secretase-1 (hBACE-1, IC50 = 0.098 mu M). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 mu M). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-A beta aggregation activity in self- and AChE-induced thiofiavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and A beta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111707

文献信息

• [EN] 1-(2,6-DIAZASPIRO[3.3]HEPTAN-6-YL)-5,6-DIHYDRO-4H-BENZO[F][1,2,4]TRIAZOLO[4,3-A][1,4]DIAZEPINE DERIVATIVES AND RELATED COMPOUNDS AS VASOPRESSIN ANTAGONISTS FOR THE TREATMENT OF NEURO-PSYCHOLOGICAL DISORDERS<br/>[FR] DÉRIVÉS DE 1-(2,6-DIAZASPIRO[3.3]HEPTAN-6-YL)-5,6-DIHYDRO-4H-BENZO[F][1,2,4]TRIAZOLO[4,3-A][1,4]DIAZÉPINE ET COMPOSÉS APPARENTÉS SERVANT D'ANTAGONISTES DE LA VASOPRESSINE POUR LE TRAITEMENT DE TROUBLES NEUROPSYCHOLOGIQUES
  申请人：BLACKTHORN THERAPEUTICS INC

  公开号：WO2020123872A1

  公开（公告）日：2020-06-18

  The present invention relates to l-(2,6-diazaspiro[3.3]heptan-6- yl)-5,6-dihydro-4H-benzo[f][l,2,4]triazolo[4,3-a][l,4]diazepine derivatives and related compounds of Formula (I): wherein A, B, G, R1, Rlb, RiC, R2 and X are as defined herein. The present compounds are vasopressin receptor antagonists (in particular of the Via receptor) for the treatment of neuro- psychological disorders, such as e.g. autism, anxiety, stress-related disorders, depression, schizophrenia or bipolar disorder. The present description discloses the synthesis of exemplary compounds, as well as pharmacological data thereof (e.g. pages 71 to 246; examples 1 to 49; tables 1 to 5). An exemplary compound is e.g. 8-chloro-l-(2-(5-fluoropyridin-2-yl) -2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl-5,6-dihydro-4H-benzo[f] [l,2,4]triazolo[4,3-a][l,4]diazepine (example 1, compound no. 1).

  本发明涉及式(I)的l-(2,6-二氮杂螺[3.3]庚烷-6-基)-5,6-二氢-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷衍生物及相关化合物，其中A、B、G、R1、R1b、R1c、R2和X如本文所定义。本化合物是抗利尿激素受体拮抗剂（特别是Via受体）用于治疗神经心理障碍，例如自闭症、焦虑、与压力有关的障碍、抑郁症、精神分裂症或躁郁症。本说明揭示了示例化合物的合成，以及其药理数据（例如第71至246页；示例1至49；表1至5）。例如化合物为8-氯-l-(2-(5-氟吡啶-2-基)-2,6-二氮杂螺[3.3]庚烷-6-基)-5-甲基-5,6-二氢-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷（示例1，化合物编号1）。
• Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer's disease
  作者：Avanish Tripathi、Priyanka Kumari Choubey、Piyoosh Sharma、Ankit Seth、Prabhash Nath Tripathi、Manish Kumar Tripathi、Santosh Kumar Prajapati、Sairam Krishnamurthy、Sushant Kumar Shrivastava

  DOI：10.1016/j.ejmech.2019.111707

  日期：2019.12

  The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50 = 0.054 mu M), butyrylcholinesterase (hBChE, IC50 = 0.787 mu M) and beta-secretase-1 (hBACE-1, IC50 = 0.098 mu M). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 mu M). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-A beta aggregation activity in self- and AChE-induced thiofiavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and A beta-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies. (C) 2019 Elsevier Masson SAS. All rights reserved.