6-tert-butylisocytosine | 139541-35-8

• 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: 6-tert-butylisocytosine
• 英文别名: 2-amino-6-tert-butylpyrimidin-4(3H)-one；6-t-butyl isocytosine；2-amino-4-tert-butyl-1H-pyrimidin-6-one
• CAS: 139541-35-8
• 化学式: C₈H₁₃N₃O
• 分子量: 167.211
• InChiKey: LTKWJTJJGNNDAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  67.5
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-tert-butylisocytosine 在 盐酸 、 甲酸 、 四乙基氯化铵 、 N,N-二甲基苯胺 、 三乙胺 、 三氯氧磷 作用下， 以 乙醇 、 水 、 乙腈 为溶剂， 反应 18.33h， 生成 4-tert-butyl-6-((R)-3-methylaminopyrrolidin-1-yl)pyrimidin-2-ylamine
  参考文献：
  名称：

  Discovery and SAR of 6-Alkyl-2,4-diaminopyrimidines as Histamine H₄ Receptor Antagonists

  摘要：

  This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.

  DOI：

  10.1021/jm401727m
• 作为产物：
  描述：

  新戊酰基乙酸甲酯 、 碳酸胍 在 水 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6 g), m.p. 285-288° C. (dec.)的产率得到6-tert-butylisocytosine
  参考文献：
  名称：

  Aryl pyrimidine derivatives

  摘要：

  公开的嘧啶衍生物及其药学上可接受的盐和N-氧化物，具有有用的药理学特性，特别是用作选择性5HT.sub.2B-拮抗剂。本发明还涉及制剂和治疗方法。

  公开号：

  US05863924A1

文献信息

• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2010120854A1

  公开（公告）日：2010-10-21

  The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代吲唑衍生物。具体而言，本发明涉及根据公式I的化合物：其中R1-R6和X在此定义。本发明的化合物是PDK1的抑制剂，可用于治疗由组成性激活的ACG激酶（如癌症，特别是白血病、乳腺癌、结肠癌和肺癌）引起的疾病。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步涉及使用本发明化合物或包含本发明化合物的药物组合物来抑制PDK1活性和治疗相关疾病的方法。
• Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV
  作者：Zhiyuan Zhang、Michael B. Wallace、Jun Feng、Jeffrey A. Stafford、Robert J. Skene、Lihong Shi、Bumsup Lee、Kathleen Aertgeerts、Andy Jennings、Rongda Xu、Daniel B. Kassel、Stephen W. Kaldor、Marc Navre、David R. Webb、Stephen L. Gwaltney

  DOI：10.1021/jm101016w

  日期：2011.1.27

  The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

  描述了两类杂环二肽基肽酶IV（DPP-4）抑制剂嘧啶酮和嘧啶二酮的发现。单次口服剂量后，这些有效的，选择性的和非共价的抑制剂可在糖尿病动物模型中持续降低血浆DPP-4活性并降低血糖。选择化合物13a，27b和27j进行开发。
• The Convenient Synthesis of Hydrogen-Bonded Ureidopyrimidinones
  作者：Henk M. Keizer、Rint P. Sijbesma、E. W. Meijer

  DOI：10.1002/ejoc.200300752

  日期：2004.6

  Blocked isocytosine isocyanates are conveniently obtained by the reaction of 1,1′-carbonyldiimidazole (CDI) with isocytosines. The resulting precursors for quadruple hydrogen-bonded structures can be isolated and stored for further use. Reaction with either aliphatic or aromatic amines gives the corresponding mono-, bi-, or trifunctional ureidopyrimidinone derivatives in good to excellent isolated

  封闭的异胞嘧啶异氰酸酯可通过 1,1'-羰基二咪唑 (CDI) 与异胞嘧啶反应方便地获得。产生的四重氢键结构的前体可以被分离和储存以供进一步使用。与脂肪族或芳香族胺反应得到相应的单-、双-或三官能脲基嘧啶酮衍生物，分离产率良好至极好。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
• [EN] MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR<br/>[FR] MODULATEURS DU RÉGULATEUR DE LA CONDUCTANCE TRANSMEMBRANAIRE DE LA MUCOVISCIDOSE
  申请人：VERTEX PHARMA

  公开号：WO2022076627A1

  公开（公告）日：2022-04-14

  This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure:, pharmaceutical compositions containing at least one such modulator, methods of treating CFTR mediated diseases, including cystic fibrosis using such modulators and pharmaceutical compositions, combination therapies and combination pharmaceuticals employing those modulators, and processes and intermediates for making such modulators.

  本公开提供囊性纤维化跨膜传导调节因子（CFTR）的调节剂，其具有以下核心结构：，包含至少一种这样的调节剂的药物组合物，使用这样的调节剂和药物组合物治疗CFTR介导的疾病，包括囊性纤维化的方法，使用这些调节剂的组合疗法和组合药物，以及制造这些调节剂的过程和中间体。
• [EN] ARYL PYRIMIDINE DERIVATIVES<br/>[FR] DERIVES D'ARYL PYRIMIDINE
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：WO1997044326A1

  公开（公告）日：1997-11-27

  (EN) The present invention is directed to pyrimidine derivatives, and pharmaceutically acceptable salts and $i(N)-oxides thereof, which exhibit useful pharmacological properties, in particular use as selective 5HT2B-antagonists, their preparation, pharmaceutical compositions comprising them and their use in the treatment of various diseases, especially migraine. The invention is also directed to formulations and methods for treatment.(FR) Cette invention a trait à des dérivés d'aryl pyrimidine ainsi qu'à leurs sels et à leurs $i(N)-oxydes, acceptables d'un point de vue pharmaceutique. Ces substances, qui font montre d'utiles propriétés pharmacologiques, sont notamment efficaces comme antagonistes sélectifs de 5HT2B. L'invention a également trait à la préparation de ces substances, à des compositions pharmaceutiques les contenant, ainsi qu'à leur utilisation dans le traitement de troubles divers, de la migraine notamment. Elle concerne, de surcroît, des formulations et des méthodes thérapeutiques.

  本发明涉及嘧啶衍生物及其药学上可接受的盐和$i(N)$-氧化物，具有有用的药理学特性，特别是作为选择性5HT2B拮抗剂的用途，其制备，包含它们的制药组合物以及它们在治疗各种疾病，尤其是偏头痛方面的用途。本发明还涉及治疗方法和制剂。