3-[2-N-Boc-amino-1-(R)-methylethyl]-5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil | 352303-74-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3-[2-N-Boc-amino-1-(R)-methylethyl]-5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil
• 英文别名: tert-butyl N-[(2R)-2-[5-bromo-3-[(2,6-difluorophenyl)methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]propyl]carbamate
• CAS: 352303-74-3
• 化学式: C₂₀H₂₄BrF₂N₃O₄
• 分子量: 488.329
• InChiKey: UIWWKHBBKWGRKP-LLVKDONJSA-N

物化性质

• 密度：
  1.440±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  79
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[2-N-Boc-amino-1-(R)-methylethyl]-5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil 在 sodium tetrahydroborate 、 四(三苯基膦)钯 、 potassium carbonate 、 三氟乙酸 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 20.0h， 生成 3-[(R)-2-(Cyclopropylmethyl-amino)-1-methyl-ethyl]-1-(2,6-difluoro-benzyl)-5-(3-methoxy-phenyl)-6-methyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Synthesis and Structure–activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor

  摘要：

  A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR Studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K-i=20 nM). (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00619-x
• 作为产物：
  描述：

  (2,6-二氟-苄基)-脲 在 吡啶 、 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 38.0h， 生成 3-[2-N-Boc-amino-1-(R)-methylethyl]-5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists

  摘要：

  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.

  DOI：

  10.1021/jm030472z

文献信息

• Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
  申请人：Zhu Yun-Fei

  公开号：US20070208049A1

  公开（公告）日：2007-09-06

  GnRH receptor antagonists are disclosed that 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: 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.

  本发明揭示了GnRH受体拮抗剂，其在治疗男女性激素相关疾病方面具有用途。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、前药和其药学上可接受的盐。本发明还揭示了含有本发明化合物与药学上可接受的载体组合的组合物，以及与其相关的方法，用于在需要时对抗促性腺激素释放激素。
• US7179815B2
  申请人：——

  公开号：US7179815B2

  公开（公告）日：2007-02-20
• US7462625B2
  申请人：——

  公开号：US7462625B2

  公开（公告）日：2008-12-09
• 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.
• Synthesis and Structure–activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor
  作者：Fabio C. Tucci、Yun-Fei Zhu、Zhiqiang Guo、Timothy D. Gross、Patrick J. Connors、R.Scott Struthers、Greg J. Reinhart、John Saunders、Chen Chen

  DOI：10.1016/s0960-894x(03)00619-x

  日期：2003.10

  A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR Studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K-i=20 nM). (C) 2003 Elsevier Ltd. All rights reserved.