2-((6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-(methyl)amino)-4-(4-fluorophenyl)-thiazole-5-carbonitrile | 1628264-39-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-((6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-(methyl)amino)-4-(4-fluorophenyl)-thiazole-5-carbonitrile
• 英文别名: 2-((6-Bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile；2-[(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile
• CAS: 1628264-39-0
• 化学式: C₂₁H₁₇BrFN₅S
• 分子量: 470.368
• InChiKey: NHKQHDXVPCPCFY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  85.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-((6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-(methyl)amino)-4-(4-fluorophenyl)-thiazole-5-carbonitrile 以82的产率得到tert-butyl 4-[3-[[5-cyano-4-(4-fluorophenyl)thiazol-2-yl]-methyl-amino]-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl]piperazine-1-carboxylate
  参考文献：
  名称：

  NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

  摘要：

  本发明揭示了符合公式I的化合物：其中，R1a，R1b，R2，R4，R5，R6a，R6b，R7，R8，W，X，Cy和下标a如本文所定义。本发明涉及抑制自体脂肪酸酰肌醇磷酸酯酶（NPP2或ENPP2）的化合物，其制备方法，包含它们的制药组合物和使用它们的治疗方法，用于预防和/或治疗涉及纤维化疾病，增生性疾病，炎症性疾病，自身免疫性疾病，呼吸系统疾病，心血管疾病，神经退行性疾病，皮肤疾病和/或异常血管生成相关疾病，通过给予本发明的化合物。

  公开号：

  US20170362227A1
• 作为产物：
  描述：

  2-氨基-3-甲基-5-溴吡啶 在 盐酸 、 T406石油添加剂 、 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 丙酮 、 甲苯 、 mineral oil 为溶剂， 反应 6.5h， 生成 2-((6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-(methyl)amino)-4-(4-fluorophenyl)-thiazole-5-carbonitrile
  参考文献：
  名称：

  [EN] COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
  [FR] COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT DESTINÉS À TRAITER LES TROUBLES INFLAMMATOIRES

  摘要：

  本发明公开了根据式I的化合物：其中R1a、R1b、R2、R4、R5、R6a、R6b、R7、R8、W、X、Cy和下标a如本文所定义。本发明涉及抑制自体脂肪酶（NPP2或ENPP2）的化合物，其制备方法，包含其的药物组合物，以及使用该化合物进行预防和/或治疗涉及纤维化疾病、增生性疾病、炎症性疾病、自身免疫疾病、呼吸系统疾病、心血管疾病、神经退行性疾病、皮肤病和/或与异常血管生成相关疾病的方法。

  公开号：

  WO2014139882A1

文献信息

• 一种ATX抑制剂Ziritaxestat的合成方法
  申请人：沈阳药科大学

  公开号：CN111004235A

  公开（公告）日：2020-04-14

  本发明属于药物化学领域，涉及一种ATX抑制剂Ziritaxestat的合成方法，具体涉及一种基于吡啶并咪唑母核的ATX抑制剂Ziritaxestat的制备方法，还涉及制备该抑制剂的中间体的合成方法。该方法涉及八步反应，首先经环合反应、酯水解、Curtius重排、甲基化、脱苄基保护、再经N‑芳烃化、Buchwald–Hartwig偶联、N‑烷基化得到终产物Ziritaxestat。本发明为Ziritaxestat全新的合成方法，整个反应所需原料廉价易得，避免使用氰化钠及异腈等剧毒试剂，反应条件温和，操作简便易行，适于规模化生产。
• Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
  申请人：Galapagos NV

  公开号：US10125132B2

  公开（公告）日：2018-11-13

  The present invention discloses compounds according to Formula I: Wherein R1a, R1b, R2, R4, R5, R6a, R6b, R7, R8, W, X, Cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

  本发明公开了符合式 I 的化合物： 其中 R1a、R1b、R2、R4、R5、R6a、R6b、R7、R8、W、X、Cy 和下标 a 如本文所定义。 本发明涉及抑制自体表皮生长因子（NPP2 或 ENPP2）的化合物、其生产方法、包含其的药物组合物和使用其的治疗方法，用于通过施用本发明化合物预防和/或治疗涉及纤维化疾病、增殖性疾病、炎症性疾病、自身免疫性疾病、呼吸系统疾病、心血管疾病、神经退行性疾病、皮肤病和/或异常血管生成相关疾病。
• [EN] ATX INHIBITORS, PREPARATION METHOD THEREFOR AND APPLICATIONS THEREOF<br/>[FR] INHIBITEUR D'ATX, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION<br/>[ZH] ATX抑制剂及其制备方法和应用
  申请人：GUANGZHOU HENOVCOM BIOSCIENCE CO LTD

  公开号：WO2019029620A1

  公开（公告）日：2019-02-14

  提供了具有ATX抑制活性的式I化合物以及在制备治疗与ATX相关疾病的药物中的用途。
• Catalyst-Free Cyclization- and Curtius Rearrangement-Induced Functional Group Transformation: An Improved Synthetic Strategy of First-in-Class ATX Inhibitor Ziritaxestat (GLPG-1690)
  作者：Hongrui Lei、Yu Yang、Changtao Li、Fang Jia、Nan Jiang、Ping Gong、Xin Zhai

  DOI：10.1021/acs.oprd.9b00511

  日期：2020.6.19

  A practical and highly efficient protocol for the production of Autotaxin (ATX) inhibitor Ziritaxestat (1) was described. The procedure began with a catalyst-free bicomponent cyclization for the construction of the imidazo[1,2-a]pyridine skeleton 16. Subsequently, a typical Curtius rearrangement of carboxylic acid 17 followed by nucleophilic attacking of 3,5-dichlorobenzyl alcohol 18f led to the carbamate analogue 19f. N-methylated 20 was readily deprotected through HBr/HOAc treatment, which further conveniently took part in an alternative K2CO3-induced N-alkylation reaction with 9 to give 10. 10 coupled directly with piperazine to furnish 13, which ideally circumvent the removal of the Boc group. As a result, the hypertoxic KCN and the hypertoxic and costly isonitrile 3 involved in the tricomponent cyclization were carefully avoided. Ultimately, a novel, scalable, and cost-effective route was favorably developed to afford Ziritaxestat in a 20.4% overall yield.
• Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis
  作者：Nicolas Desroy、Christopher Housseman、Xavier Bock、Agnès Joncour、Natacha Bienvenu、Laëtitia Cherel、Virginie Labeguere、Emilie Rondet、Christophe Peixoto、Jean-Marie Grassot、Olivier Picolet、Denis Annoot、Nicolas Triballeau、Alain Monjardet、Emanuelle Wakselman、Veronique Roncoroni、Sandrine Le Tallec、Roland Blanque、Celine Cottereaux、Nele Vandervoort、Thierry Christophe、Patrick Mollat、Marieke Lamers、Marielle Auberval、Boska Hrvacic、Jovica Ralic、Line Oste、Ellen van der Aar、Reginald Brys、Bertrand Heckmann

  DOI：10.1021/acs.jmedchem.7b00032

  日期：2017.5.11

  Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in once and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.