1-(2,6-二氟苄基)-6-甲基-2,4(1H,3H)-嘧啶二酮 | 352303-65-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 1-(2,6-二氟苄基)-6-甲基-2,4(1H,3H)-嘧啶二酮
• 中文别名: 1-[(2,6-二氟苯基)甲基]-6-甲基-嘧啶-2,4-二酮
• 英文名称: N-1-(2,6-difluorobenzyl)-6-methyluracil
• 英文别名: 1-(2,6-difluorobenzyl)-6-methyluracil；1-(2,6-Difluorobenzyl)-6-methyl-uracil；1-[(2,6-Difluorophenyl)methyl]-6-methyl-pyrimidine-2,4-dione；1-[(2,6-difluorophenyl)methyl]-6-methylpyrimidine-2,4-dione
• CAS: 352303-65-2
• 化学式: C₁₂H₁₀F₂N₂O₂
• 分子量: 252.22
• InChiKey: QNKAHAJVXBOISU-UHFFFAOYSA-N

物化性质

• 密度：
  1.366±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2933599090

反应信息

• 作为反应物：
  描述：

  1-(2,6-二氟苄基)-6-甲基-2,4(1H,3H)-嘧啶二酮 在 溴 、 溶剂黄146 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 13.0h， 生成 2-甲基-2-丙基{(1R)-2-[5-溴-3-(2,6-二氟苄基)-4-甲基-2,6-二氧代-3,6-二氢-1(2H)-嘧啶基]-1-苯基乙基}氨基甲酸酯
  参考文献：
  名称：

  尿嘧啶衍生的人GnRH受体拮抗剂的合成与构效关系：（R）-3- [2-（2-氨基）苯乙基] -1-（2,6-二氟苄基）-6-甲基尿嘧啶，含有取代的噻吩或噻唑在C-5。

  摘要：

  描述了一系列在C-5处含有取代的噻吩或噻唑的（R）-3- [2-（2-氨基）苯乙基] -1-（2，6-二氟苄基）-6-甲基尿嘧啶的合成。尿嘧啶C-5周围的SAR导致发现最佳受体结合需要2-噻吩基或（2-苯基）噻唑-4-基。该系列中最好的化合物对人GnRH受体的结合亲和力为2 nM（K（i））。还描述了一种新颖且方便的N-1-（2,6-二氟苄基）-6-甲基尿嘧啶的制备方法。

  DOI：

  10.1016/j.bmcl.2004.07.022
• 作为产物：
  描述：

  (2,6-二氟-苄基)-脲 在 吡啶 、 溶剂黄146 作用下， 反应 25.0h， 生成 1-(2,6-二氟苄基)-6-甲基-2,4(1H,3H)-嘧啶二酮
  参考文献：
  名称：

  作为有效的GnRH受体拮抗剂的1-芳基甲基-3-（2-氨基丙基）-5-芳基-6-甲基尿嘧啶的合成及其构效关系。

  摘要：

  讨论了新型的合成和SAR研究作为人类GnRH受体拮抗剂的6-甲基尿嘧啶。在尿嘧啶的N 3的β-位引入一个小的甲基取代基可使GnRH结合力提高5至10倍。该系列中最好的化合物对人GnRH受体的结合亲和力为5 nM（K（i））。

  DOI：

  10.1016/s0960-894x(03)00620-6

文献信息

• Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
  申请人：Neurocrine Biosciences, Inc.

  公开号：US20020132820A1

  公开（公告）日：2002-09-19

  GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: 1 wherein A, Q, R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

  GnRH受体拮抗剂被披露，可用于治疗男性和女性的各种与性激素相关的疾病。本发明的化合物具有以下结构：其中A、Q、R1、R2、R3a、R3b、R4、R5、R6和n的定义如本文所述，包括立体异构体、前药和其药用可接受盐。还披露了含有本发明化合物与药用可接受载体结合的组合物，以及与使用这些组合物拮抗需要的受试者中的促性腺激素释放激素相关的方法。
• Discovery of Sodium <i>R</i>-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor
  作者：Chen Chen、Dongpei Wu、Zhiqiang Guo、Qiu Xie、Greg J. Reinhart、Ajay Madan、Jenny Wen、Takung Chen、Charles Q. Huang、Mi Chen、Yongsheng Chen、Fabio C. Tucci、Martin Rowbottom、Joseph Pontillo、Yun-Fei Zhu、Warren Wade、John Saunders、Haig Bozigian、R. Scott Struthers

  DOI：10.1021/jm8006454

  日期：2008.12.11

  The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
• Synthesis and Structure−Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists
  作者：Zhiqiang Guo、Yun-Fei Zhu、Timothy D. Gross、Fabio C. Tucci、Yinghong Gao、Manisha Moorjani、Patrick J. Connors,、Martin W. Rowbottom、Yongsheng Chen、R. Scott Struthers、Qiu Xie、John Saunders、Greg Reinhart、Ta Kung Chen、Anne L. Killam Bonneville、Chen

  DOI：10.1021/jm030472z

  日期：2004.2.1

  Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-alpha]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-alpha]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.
• 5-Aryluracils as potent GnRH antagonists—Characterization of atropisomers
  作者：Liren Zhao、Zhiqiang Guo、Yongsheng Chen、Tao Hu、Dongpei Wu、Yun-Fei Zhu、Martin Rowbottom、Timothy D. Gross、Fabio C. Tucci、R. Scott Struthers、Qiu Xie、Chen Chen

  DOI：10.1016/j.bmcl.2008.04.029

  日期：2008.6

  Optimization of a series of uracils bearing a 2-fluoro-or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II. (C) 2008 Elsevier Ltd. All rights reserved.
• GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
  申请人：NEUROCRINE BIOSCIENCES, INC.

  公开号：EP1255738B1

  公开（公告）日：2012-03-07