ethyl 5-isothiocyanato-1-methyl-1H-pyrazole-4-carboxylate | 150892-83-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-isothiocyanato-1-methyl-1H-pyrazole-4-carboxylate
• 英文别名: ethyl 5-isothiocyanato-1-methylpyrazole-4-carboxylate
• CAS: 150892-83-4
• 化学式: C₈H₉N₃O₂S
• 分子量: 211.244
• InChiKey: MTXMYKPCFRHVBQ-UHFFFAOYSA-N

物化性质

• 沸点：
  368.5±27.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  88.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 5-isothiocyanato-1-methyl-1H-pyrazole-4-carboxylate 在 一水合肼 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以26%的产率得到5-[(hydrazinothioxomethyl)amino]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  High affinity and selectivity of [[(arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives for the 5-HT1A receptor.Synthesis and structure–affinity relationships

  摘要：

  In this work we report the affinity of new thienopyrimidinones for 5-HT(1A)Rs and the selectivity versus alpha(1)ARs. The 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-6-ethyl-thieno[2,3-d]pyrimidin-4(3H)-one 27 is the most potent and selective (Ki 0.19 nM, selectivity 115). Compound 31 with the N4 piperazine orthonitrophenyl nucleus instead of the orthomethoxyphenyl also shows a good affinity and selectivity (Ki 1.46 nM, selectivity 84). The results of derivatives 28, 29 and 30 (Ki 3.28, 12.59 and 4.38 nM; selectivity 24, 4 and 5, respectively), which have, respectively, an ethyl, an allyl and an acetylamino group instead of an N3 amino group, indicate the importance of this last group for the interaction with 5-HT1AR. Comparison of the results for the superior homologue 53 (Ki 3.72 nM, selectivity 51) and the inferior homologue 52 (5-HT1A Ki 1 499 nM, alpha(1)A Ki NA) of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6,7-dimethyl-8H-[1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidin-8-one 57 (Ki 23 nM, selectivity 5) shows how important the length of the chain binding the two heterocyclic systems is in the interaction with 5-HT(1A)Rs and alpha(1)ARs. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)00175-6
• 作为产物：
  描述：

  二硫化碳 、 5-氨基-1-甲基吡唑-4-甲酸乙酯 在 sodium hydride 、 碘 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 4.34h， 以73.7%的产率得到ethyl 5-isothiocyanato-1-methyl-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  [EN] SMALL MOLECULE INHIBITORS OF ALDH AND USES THEREOF
  [FR] INHIBITEURS À PETITES MOLÉCULES D'ALDH ET UTILISATIONS ASSOCIÉES

  摘要：

  这项发明属于药物化学领域。特别是，该发明涉及一类具有噻吩嘧啶酮结构的新颖小分子，它们作为ALDH蛋白的抑制剂，以及它们作为治疗癌症和其他疾病的疗法的使用。

  公开号：

  WO2017223086A1

文献信息

• Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy
  作者：Brandt C. Huddle、Edward Grimley、Mikhail Chtcherbinine、Cameron D. Buchman、Cyrus Takahashi、Bikash Debnath、Stacy C. McGonigal、Shuai Mao、Siwei Li、Jeremy Felton、Shu Pan、Bo Wen、Duxin Sun、Nouri Neamati、Ronald J. Buckanovich、Thomas D. Hurley、Scott D. Larsen

  DOI：10.1016/j.ejmech.2020.113060

  日期：2021.2

  There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued

  有强有力的证据表明，抑制一种或多种醛脱氢酶 1A (ALDH1A) 同种型可能对化疗耐药的卵巢癌和其他肿瘤类型有益。虽然之前的许多努力都集中在 ALDH1A1 选择性抑制剂的开发上，但最致命的卵巢癌亚型高级别浆液性 (HGSOC) 表现出 ALDH1A3 的表达升高。在此，我们报告了泛 ALDH1A 抑制剂的持续开发，以评估广谱 ALDH1A 抑制是否是这一关键肿瘤亚型中化疗的有效辅助手段。CM39 支架的优化，在代谢物 ID 和几种新的 ALDH1A1 晶体结构的帮助下，提高了生化效力，改善了 HGSOC 细胞系中的细胞 ALDH 抑制，微粒体稳定性的显着改善，最终产生口服生物可利用的化合物。我们证明了两种化合物68和69能够与耐药细胞系和患者来源的 HGSOC 肿瘤球体中的化学疗法协同作用，表明它们适用于未来的体内概念验证实验。
• Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy
  作者：Brandt C. Huddle、Edward Grimley、Cameron D. Buchman、Mikhail Chtcherbinine、Bikash Debnath、Pooja Mehta、Kun Yang、Cynthia A. Morgan、Siwei Li、Jeremy Felton、Duxin Sun、Geeta Mehta、Nouri Neamati、Ronald J. Buckanovich、Thomas D. Hurley、Scott D. Larsen

  DOI：10.1021/acs.jmedchem.8b00930

  日期：2018.10.11

  Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133(+) putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.
• Guccione, Salvatore; Raffaelli, Andrea; Barretta, Gloria Uccello, Journal of Heterocyclic Chemistry, 1995, vol. 32, # 4, p. 1149 - 1158
  作者：Guccione, Salvatore、Raffaelli, Andrea、Barretta, Gloria Uccello、Scolaro, Luigi Monsu、Pucci, Sergio、Russo, Filippo

  DOI：——

  日期：——
• PYRAZOLOTHIAZOLOPYRIMIDINE DERIVATIVE
  申请人：KYOWA HAKKO KOGYO CO., LTD.

  公开号：EP0573659B1

  公开（公告）日：2000-07-12
• SMALL MOLECULE INHIBITORS OF ALDH AND USES THEREOF
  申请人：The Regents of The University of Michigan

  公开号：EP3471712A1

  公开（公告）日：2019-04-24