8-phenylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine | 1122023-25-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 8-phenylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine
• 英文别名: 12-Phenyl-8-thia-3,5,10-triazatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaen-6-amine；12-phenyl-8-thia-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-amine
• CAS: 1122023-25-9
• 化学式: C₁₅H₁₀N₄S
• 分子量: 278.337
• InChiKey: KOEWWBBSRQMABA-UHFFFAOYSA-N

物化性质

• 沸点：
  557.3±45.0 °C(predicted)
• 密度：
  1.431±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  92.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-溴-2-氯烟腈 在 四(三苯基膦)钯 、 sodium carbonate 、 formamide 、 potassium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 8-phenylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine
  参考文献：
  名称：

  5-溴苯并[2,3- b ]吡啶的铃木交叉偶联，用于方便地合成8-芳基吡啶[3'，2'：4,5]噻吩并[3,2 - d ]嘧啶-4-胺

  摘要：

  铃木交叉偶联反应首次用于在新型吡啶并[3'，2'：4,5]噻吩并[3,2 - d ]嘧啶-4-的吡啶环的8位引入芳族基团胺类。这种可靠，简单的方法可能会扩展到各种硼酸中，以允许制备这些化合物的更大的文库，以期进一步研究结构-活性关系。

  DOI：

  10.1016/j.tetlet.2012.12.077

文献信息

• [EN] PYRIDO [3',2' :4,5] THIENO [3, 2-D] PYRIMIDIN- 4 - YLAMINE DERIVATIVES AND THEIR THERAPEUTICAL USE<br/>[FR] DÉRIVÉS DE PYRIDO[3',2':4,5]THIÉNO[3,2-D]PYRIMIDIN-4-YLAMINE ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：BAELL JONATHAN BAYLDON

  公开号：WO2012131297A1

  公开（公告）日：2012-10-04

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain fused triaryl amine compounds of the following formula (for convenience, collectively referred to herein as "FTA compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension).

  本发明一般涉及治疗化合物领域，更具体地涉及以下公式的某些融合三芳基胺化合物（为方便起见，统称为“FTA化合物”），该化合物等等可以抑制LIM激酶（LIMK）活性。本发明还涉及包含这些化合物的药物组合物，以及利用这些化合物和组合物在体内和体外抑制LIMK活性，以及治疗由LIMK介导，通过抑制LIMK活性得到改善等疾病和症状的用途，包括增生性疾病，如癌症（如乳腺癌、前列腺癌、黑色素瘤、胶质瘤等），以及血管扩张（包括高血压、心绞痛、脑血管痉挛和蛛网膜下腔出血后缺血等）、神经退行性疾病、动脉硬化、纤维化和炎症性疾病（如克罗恩病和慢性阻塞性肺病（COPD）），以及青光眼（又称眼高压）等。
• Suzuki cross-coupling of 5-bromothieno[2,3-b]pyridines for the convenient synthesis of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines
  作者：Yvonnick Loidreau、Vincent Levacher、Thierry Besson

  DOI：10.1016/j.tetlet.2012.12.077

  日期：2013.2

  For the first time, Suzuki cross-coupling reactions were used for introducing an aromatic group in position 8 of the pyridine ring of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines. This reliable and simple method may be extended to various boronic acids for allowing preparation of a larger library of these compounds in the hope of further structure–activity relationship investigations.

  铃木交叉偶联反应首次用于在新型吡啶并[3'，2'：4,5]噻吩并[3,2 - d ]嘧啶-4-的吡啶环的8位引入芳族基团胺类。这种可靠，简单的方法可能会扩展到各种硼酸中，以允许制备这些化合物的更大的文库，以期进一步研究结构-活性关系。
• Synthesis and evaluation of pyrido-thieno-pyrimidines as potent and selective Cdc7 kinase inhibitors
  作者：Chunlin Zhao、Christian Tovar、Xuefeng Yin、Qui Xu、Ivan T. Todorov、Lyubomir T. Vassilev、Li Chen

  DOI：10.1016/j.bmcl.2008.11.093

  日期：2009.1

  Cdc7 kinase plays a critical role in the regulation of DNA replication in eukaryotic cells and has been proposed as a target for cancer therapy. We have identified a class of Cdc7/Dbf4 inhibitors with a pyrido-thieno-pyrimidine core structure. Synthesis of a focused pyrido-thieno-pyrimidine library yielded potent and selective Cdc7 inhibitors with antiproliferative activity against cancer cells in vitro. Their synthesis and SAR data are presented herein. (C) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and molecular modelling studies of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors
  作者：Yvonnick Loidreau、Emmanuel Deau、Pascal Marchand、Marie-Renée Nourrisson、Cédric Logé、Gaël Coadou、Nadège Loaëc、Laurent Meijer、Thierry Besson

  DOI：10.1016/j.ejmech.2014.12.038

  日期：2015.3

  This paper reports the design and synthesis of a novel series of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N'-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1 delta/epsilon, GSK3 alpha/beta, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyppyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1 delta/epsilon and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl) pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1 delta/epsilon and CLK1 showed that functionalization at position 7 of pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1 delta/epsilon P-loop and thus a complete loss of inhibitory activity. (C) 2014 Elsevier Masson SAS. All rights reserved.