4-benzyl-3-ethoxy-5-methyl-1H-pyrazole | 1116655-96-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-benzyl-3-ethoxy-5-methyl-1H-pyrazole
• CAS: 1116655-96-9
• 化学式: C₁₃H₁₆N₂O
• 分子量: 216.283
• InChiKey: ORVBQCQRMOKROM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  37.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-benzyl-3-ethoxy-5-methyl-1H-pyrazole 在 三溴化硼 、 potassium carbonate 、 caesium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 98.0h， 生成 2-(4-benzyl-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine
  参考文献：
  名称：

  Original 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine Derivatives as Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

  摘要：

  From a research program aimed at the design of new chemical entities followed by extensive screening on various models of infectious diseases, an original series of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidines endowed with notable antiviral properties were found. Using a whole cell measles virus replication assay, we describe here some aspects of the iterative process that, from 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyrimidine, led to 2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine and a 4000-fold improvement of antiviral activity with a subnanomolar level of inhibition. Moreover, recent precedents in the literature describing antiviral derivatives acting at the level of the de novo pyrimidine biosynthetic pathway led us to determine that the mode of action of this series is based on the inhibition of the cellular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this pathway. Biochemical studies with recombinant human DHODH led us to measure IC50 as low as 13 nM for the best example of this original series when using 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone (coenzyme Q(1)) as a surrogate for coenzyme Q(10), the cofactor of this enzyme.

  DOI：

  10.1021/jm501446r
• 作为产物：
  描述：

  2-苄基乙酰乙酸乙酯 在 盐酸肼 作用下， 以 乙醇 为溶剂， 反应 8.0h， 以55%的产率得到4-benzyl-3-ethoxy-5-methyl-1H-pyrazole
  参考文献：
  名称：

  An Improved Preparation of 3-Alkoxypyrazoles

  摘要：

  烷基乙酰乙酸酯与肼之间的缩合反应构成了著名的Knorr合成方法，生成吡唑-3/5-酮。然而，近期报告描述了一种替代反应路径，使用肼盐得到的3/5-烷氧基吡唑产量较低。目前尚未报告用于选择性合成3-烷氧基吡唑的一般方法，因此我们集中研究这一副反应，试图将其转化为主要转化反应。根据起始材料的不同，获得了多种3-烷氧基吡唑（甲氧基、乙氧基、苄氧基、异丙氧基、烯丙氧基），产率高达56%。

  DOI：

  10.1055/s-0028-1083186

文献信息

• Alkoxypyrazoles and the process for their preparation
  申请人：Institut Pasteur

  公开号：EP2151433A1

  公开（公告）日：2010-02-10

  The present invention relates to a alkoxypyrazoles preparation process, and new alkoxypyrazole compounds.

  本发明涉及一种烷氧基吡唑的制备方法，以及新的烷氧基吡唑化合物。
• Pyrazole derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors
  申请人：INSTITUT PASTEUR

  公开号：EP2929883A1

  公开（公告）日：2015-10-14

  The present invention relates to compounds of formula (I) for their use in the treatment and/or prevention of auto-immune or auto-immune related diseases, cancer, viral infections, and central nervous system diseases and disorders, by inhibiting human dehydroorate dehydrogenase (DHODH): Wherein R1, R2, R3, R4 and Ar are as defined in claim 1.

  本发明涉及式（I）化合物，通过抑制人脱氢脱氢酶（DHODH），用于治疗和/或预防自身免疫或自身免疫相关疾病、癌症、病毒感染以及中枢神经系统疾病和失调： 其中 R1、R2、R3、R4 和 Ar 如权利要求 1 所定义。
• WO2015/155680
  申请人：——

  公开号：——

  公开（公告）日：——
• Original 2-(3-Alkoxy-1<i>H</i>-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)
  作者：Marianne Lucas-Hourani、Hélène Munier-Lehmann、Farah El Mazouni、Nicholas A. Malmquist、Jane Harpon、Eloi P. Coutant、Sandrine Guillou、Olivier Helynck、Anne Noel、Artur Scherf、Margaret A. Phillips、Frédéric Tangy、Pierre-Olivier Vidalain、Yves L. Janin

  DOI：10.1021/acs.jmedchem.5b00606

  日期：2015.7.23

  Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in out previous report, the structure activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its Use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other Series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
• N-arylation of 3-alkoxypyrazoles, the case of the pyridines
  作者：Sandrine Guillou、Frédéric J. Bonhomme、Di Betina Chahine、Olivier Nesme、Yves L. Janin

  DOI：10.1016/j.tet.2010.02.032

  日期：2010.4

  In the course of a research program focused on the preparation of libraries of new chemical entities derived from 3-alkoxypyrazoles, we studied their N-pyridylation using 2, 3 or 4-bromopyridines This was achieved using Cristau and Taillefer copper-catalyzed arylation method and mostly led to the 3-alkoxy-1H-pyrazol-1-yl pyridine isomer along with lesser amount of the alternative 5-alkoxy-1H-pyrazol-1-yl pyridine The structures of these isomers were often established via their chemical tansformations and sometimes recourse to unambiguous synthetic routes for comparison purposes The alternative use of 2-fluoropyridine-based arylation was also investigated and lifted some of the limitations encountered in the course of this study (C) 2010 Elsevier Ltd All rights reserved