1,4,5,6-四氢环戊并吡唑-3-酰肼 | 299166-55-5

• 物质功能分类: 医药中间体 - 杂环化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1,4,5,6-四氢环戊并吡唑-3-酰肼
• 中文别名: 1,4,5,6-四氢环戊并[c]吡唑-3-甲酰肼；1,4,5,6-四氢环戊并[c]吡唑-3-碳酰肼
• 英文名称: 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbohydrazide
• 英文别名: 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbohydrazide
• CAS: 299166-55-5
• 化学式: C₇H₁₀N₄O
• mdl: MFCD00611174
• 分子量: 166.183
• InChiKey: SVCCSHLJCQVHGW-UHFFFAOYSA-N

物化性质

• 密度：
  1.413

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.428
• 拓扑面积：
  83.8
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933990090

制备方法与用途

应用

1,4,5,6-四氢环戊并吡唑-3-酰肼是一种医药中间体，可通过以下步骤制备：首先由环戊酮和草酸二乙酯作为起始物料制备1,4,5,6-四氢环戊并吡唑-3-甲酸乙酯；再与水合肼反应得到目标产物。

制备

在搅拌条件下，将23.8g（0.283mol）环戊酮和42g（0.288mol、1.02eq）草酸二乙酯加入500mL三口瓶中，并加入110mL乙醇。随后，在21~23℃下，滴加含有24.2g (0.288mol, 1.02eq)乙醇钾和115mL乙醇的混合液。滴加完毕后，室温下加入28mL浓盐酸并将pH调至1。保持温度不超过40℃，搅拌反应20分钟后冷却至室温，随后缓慢滴加21.8g (0.37mol, 1.3eq) 85%的水合肼，滴加过程中伴有白色烟雾生成。继续搅拌反应1.5小时，并通过薄层色谱监控反应进度直至原料完全消耗。向反应瓶中加入100mL纯水蒸干后得到明黄色稠状物，冷却至室温并分次加入150mL 5%的碳酸氢钠溶液。室温下搅拌10分钟后抽滤产物，并用冷水洗涤。65℃下烘干后得到黄色固体1,4,5,6-四氢环戊并吡唑-3-甲酸乙酯，总收率为74.7%。

接着，在回流条件下将1,4,5,6-四氢环戊并吡唑-3-酰肼（970mg，5mmol）和肼（1.34g，35mmol）溶于10mL乙醇中并加热一天。此阶段结束后，蒸发掉乙醇，通过过滤收集沉淀物，并用乙酸乙酯和水进行洗涤以得到最终产物。

反应信息

• 作为反应物：
  描述：

  1,4,5,6-四氢环戊并吡唑-3-酰肼 在 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 19.5h， 生成 6-(pyridin-4-yl)-3-(2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
  参考文献：
  名称：

  新型STAT3途径抑制剂-含吡唑的1,2,4-三唑-[3,4- b ]噻二嗪的优化

  摘要：

  在1,2-，3,4-三唑并[3,4- b ]噻二嗪支架上的结构-活性关系研究在针对选择性STAT3途径抑制剂的HTS运动中确定，确定吡唑基和噻二嗪上的特定芳基取代是必要的活动。通过在噻二嗪上引入α-甲基来实现效力和代谢稳定性的改善。优化的化合物表现出抗增殖活性，磷酸化的STAT3水平降低以及对STAT3目标基因的影响。这些化合物代表了针对STAT3途径的进一步药物发现努力的起点。

  DOI：

  10.1016/j.bmcl.2016.06.017
• 作为产物：
  描述：

  2-氧代-2-(2-氧代环戊基)乙酸乙酯 在 一水合肼 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 36.0h， 生成 1,4,5,6-四氢环戊并吡唑-3-酰肼
  参考文献：
  名称：

  Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors

  摘要：

  Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP‐4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP‐4 inhibitors, featuring the pyrazole‐3‐carbohydrazone scaffold, have been discovered using an integrated approach of structure‐based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low‐to‐mid‐micromolar inhibitory level compounds (1–5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k–l, and 7a–e) were found to show inhibitory effects against DPP‐4. Molecular docking models give rational explanation about structure–activity relationships. Based on eight DPP‐4 inhibitors (1–5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP‐4 inhibitors design.

  DOI：

  10.1111/j.1747-0285.2012.01365.x

文献信息

• Suprafenacine, an Indazole-Hydrazide Agent, Targets Cancer Cells Through Microtubule Destabilization
  作者：Bo-Hwa Choi、Souvik Chattopadhaya、Le Nguyen Thanh、Lin Feng、Quoc Toan Nguyen、Chuan Bian Lim、Amaravadhi Harikishore、Ravi Prakash Reddy Nanga、Nagakumar Bharatham、Yan Zhao、Xuewei Liu、Ho Sup Yoon

  DOI：10.1371/journal.pone.0110955

  日期：——

  Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule - 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK - mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.

  微管是抗癌疗法中经过充分验证的目标。然而，微管结合剂（TBA）的临床开发一直受到毒性和化疗抗性问题的阻碍，因此有必要寻找新的TBA。在此，我们报告了一种新型细胞通透性、微管不稳定性分子的鉴定——4,5,6,7-四氢-1H-吲唑-3-羧酸[1-甲苯基-甲-(E)-亚基]-酰肼（命名为Suprafenacine，SRF）。SRF是通过对注释化学库的计算机筛选鉴定的，它被证明在秋水仙素结合位点与微管结合并抑制聚合。这导致G2/M细胞周期阻滞和通过线粒体介导的凋亡途径的细胞死亡。细胞死亡之前是线粒体膜电位的丧失，JNK介导的Bcl-2和Bad的磷酸化，以及caspase-3的激活。有趣的是，SRF被发现能选择性抑制癌细胞增殖，并通过其绕过多药耐药转运蛋白P-糖蛋白的能力对耐药癌细胞有效。总的来说，我们的结果表明SRF具有作为抗癌化疗药物的潜力，并为开发改进的抗癌药物提供了另一种支架结构。
• 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-B][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
  申请人：UNIVERSITY OF PITTSBURGH—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

  公开号：US10618914B2

  公开（公告）日：2020-04-14

  Compounds that selectivity inhibit the STAT3 pathway and not the STAT1 pathway and exhibit anti-proliferative activity are disclosed. Also disclosed are methods of treatment of cancers that are characterized by overexpression of STAT3, which are safer that other therapies.

  本研究公开了选择性抑制 STAT3 通路而非 STAT1 通路并具有抗增殖活性的化合物。还公开了治疗以 STAT3 过表达为特征的癌症的方法，这些方法比其他疗法更安全。
• Heteroaryl-substituted triazoles as APJ receptor agonists
  申请人：AMGEN INC.

  公开号：US11046680B1

  公开（公告）日：2021-06-29

  Compounds of Formula (I) and Formula (II), pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: where the definitions of the variables are provided herein.

  式（I）和式（II）化合物、其药学上可接受的盐、前述任何化合物的立体异构体或其混合物是 APJ 受体的激动剂，可用于治疗心血管疾病和其他疾病。式 I 和式 II 的化合物具有如下结构： 其中变量的定义在本文中提供。
• 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
  申请人：UNIVERSITY OF PITTSBURGH—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

  公开号：US11111253B2

  公开（公告）日：2021-09-07

  Compounds that selectivity inhibit the STAT3 pathway and not the STAT1 pathway and exhibit anti-proliferative activity are disclosed. Also disclosed are methods of treatment of cancers that are characterized by overexpression of STAT3, which are safer that other therapies.

  本研究公开了选择性抑制 STAT3 通路而非 STAT1 通路并具有抗增殖活性的化合物。还公开了治疗以 STAT3 过表达为特征的癌症的方法，这些方法比其他疗法更安全。
• HETEROARYL-SUBSTITUTED TRIAZOLES AS APJ RECEPTOR AGONISTS
  申请人：Amgen Inc.

  公开号：EP3541805B1

  公开（公告）日：2020-10-14