N5-(6-氨基己基)-N7-苄基-3-异丙基吡唑并[1,5-a]嘧啶-5,7-二胺 | 1092443-52-1

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 中文名称: N5-(6-氨基己基)-N7-苄基-3-异丙基吡唑并[1,5-a]嘧啶-5,7-二胺
• 中文别名: N5-(6-氨基己基)-3-异丙基-N7-苄基吡唑并[1,5-A]嘧啶-5,7-二胺
• 英文名称: BS-181
• 英文别名: N5-(6-aminohexyl)-N7-benzyl-3-isopropylpyrazolo[1,5-a]-pyrimidine-5,7-diamine；5-N-(6-aminohexyl)-7-N-benzyl-3-propan-2-ylpyrazolo[1,5-a]pyrimidine-5,7-diamine
• CAS: 1092443-52-1
• 化学式: C₂₂H₃₂N₆
• 分子量: 380.536
• InChiKey: DNYBIOICMDTDAP-UHFFFAOYSA-N

物化性质

• 密度：
  1.16
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  80.3
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N5-(6-氨基己基)-N7-苄基-3-异丙基吡唑并[1,5-a]嘧啶-5,7-二胺 在 巯基乙酸 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 N-(18-((7-(benzylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-3,6,9-trioxa-12-azaoctadecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  参考文献：
  名称：

  发现用于靶向三阴性乳腺癌转录调控的强效和选择性 CDK9 降解剂

  摘要：

  由于缺乏有效的靶向治疗，三阴性乳腺癌 (TNBC) 具有高度侵袭性，治疗选择非常有限，因此在临床上仍然具有挑战性。靶向转录相关的细胞周期蛋白依赖性激酶来重塑转录调控在癌症治疗中显示出巨大的希望。在此，我们报告了新系列异双功能分子的合成、优化和评估，这些分子作为高选择性和有效的 CDK9 降解剂，能够有效抑制 TNBC 细胞生长并快速靶向降解 CDK9。此外，最有效的 CDK9 降解剂（化合物45 ）在体外诱导细胞凋亡并抑制 MDA-MB-231 TNBC 模型中的肿瘤生长。此外，RNA-seq、免疫组织化学分析表明，CDK9 降解剂在转录水平下调下游靶标，如MYC，导致 TNBC 细胞凋亡。我们的工作表明，45是一种高效的靶向转录调控 CDK9 降解剂，代表了一种有效的策略和作为 TNBC 新靶向治疗的巨大潜力。

  DOI：

  10.1021/acs.jmedchem.1c01350
• 作为产物：
  描述：

  tert-butyl benzyl(5-((6-((tert-butoxycarbonyl)amino)hexyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 3.0h， 以62%的产率得到N5-(6-氨基己基)-N7-苄基-3-异丙基吡唑并[1,5-a]嘧啶-5,7-二胺
  参考文献：
  名称：

  A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects in Human Tumor Xenografts Following Oral Administration

  摘要：

  Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC50 = 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G(2)/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI(50) = 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

  DOI：

  10.1021/jm100732t

文献信息

• [EN] INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)<br/>[FR] INHIBITEURS DE KINASE CYCLINE-DÉPENDANTE 7 (CDK7)
  申请人：SYROS PHARMACEUTICALS INC

  公开号：WO2015154022A1

  公开（公告）日：2015-10-08

  The present invention provides novel compounds described herein, such as of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

  本发明提供了如下所述的新化合物，例如式（I）的化合物，以及其药学上可接受的盐、溶剂化合物、水合物、互变异构体、立体异构体、同位素标记衍生物和其组合物。还提供了涉及这些化合物或组合物用于治疗或预防增生性疾病（例如癌症（例如白血病、黑色素瘤、多发性骨髓瘤）、良性肿瘤、血管生成、炎症性疾病、自身炎症性疾病和自身免疫性疾病）的方法和试剂盒。使用本发明的化合物或组合物治疗患有增生性疾病的受试者可能抑制细胞周期依赖性激酶7（CDK7）的异常活性，从而诱导细胞凋亡和/或抑制受试者的转录。
• [EN] PHARMACEUTICALLY ACTIVE PYRAZOLO-TRIAZINE DERIVATIVES<br/>[FR] DÉRIVÉS PYRAZOLO-TRIAZINE PHARMACEUTIQUEMENT ACTIFS
  申请人：LEAD DISCOVERY CENTER GMBH

  公开号：WO2013128029A1

  公开（公告）日：2013-09-06

  The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors for a protein kinase.

  本发明涉及吡唑咯[1,5-a][1,3,5]三唑衍生物和/或其药用可接受盐，这些衍生物的用途作为药用活性剂，特别用于预防和/或治疗传染病，包括机会性感染病、免疫性疾病、自身免疫性疾病、心血管疾病、细胞增殖性疾病、炎症、勃起功能障碍和中风，以及含有至少一种所述吡唑咯[1,5-a][1,3,5]三唑衍生物和/或其药用可接受盐的药物组合物。此外，本发明涉及所述吡唑咯[1,5-a][1,3,5]三唑衍生物作为蛋白激酶抑制剂的用途。
• Pyrazolo-triazine derivatives as selective cyclin-dependent kinase inhibitors
  申请人：Lead Discovery Center GmbH

  公开号：EP2634189A1

  公开（公告）日：2013-09-04

  The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors for a protein kinase.

  本发明涉及吡唑并[1,5-a][1,3,5]三嗪衍生物和/或其药用盐，这些衍生物作为药用活性剂的应用，特别是用于预防和/或治疗传染病，包括机会性感染病、免疫性疾病、自身免疫疾病、心血管疾病、细胞增殖性疾病、炎症、勃起功能障碍和中风，以及含有至少一种所述吡唑并[1,5-a][1,3,5]三嗪衍生物和/或其药用盐的药物组合物。此外，本发明涉及所述吡唑并[1,5-a][1,3,5]三嗪衍生物作为蛋白激酶抑制剂的应用。
• Pyrazolo-triazine derivatives as selective cyclin-dependent kinase inhinitors
  申请人：Lead Discovery Center GmbH

  公开号：EP2634190A1

  公开（公告）日：2013-09-04

  The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said pyrazolo[1,5-a][1,3,5]triazine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors for a protein kinase.

  本发明涉及吡唑并[1,5-a][1,3,5]三嗪衍生物和/或其药用可接受盐，以及这些衍生物作为药用活性剂的用途，特别是用于预防和/或治疗传染病，包括机会性疾病、免疫疾病、自身免疫疾病、心血管疾病、细胞增殖性疾病、炎症、勃起功能障碍和中风，以及含有至少一种所述吡唑并[1,5-a][1,3,5]三嗪衍生物和/或其药用可接受盐的药物组合物。此外，本发明涉及将所述吡唑并[1,5-a][1,3,5]三嗪衍生物用作蛋白激酶的抑制剂。
• Process for Preparing 5,7 Diaminopyrazolo [1,5-a] Pyrimidine Compounds
  申请人：Liotta Dennis C.

  公开号：US20120041198A1

  公开（公告）日：2012-02-16

  Processes for the preparation of certain 5,7-diaminopyrazolo[1,5-α]pyrimidine compounds comprising the reaction of a primary or secondary amine and a protected 5-halo-7-aminopyrazolo[1,5-α]pyrimidine compound in solvent system comprising water and one or more organic solvents, optionally in the presence of an exogenous base.

  制备特定5,7-二氨基吡唑并[1,5-α]嘧啶化合物的方法包括在溶剂体系中将一种初级或次级胺和受保护的5-卤代-7-氨基吡唑并[1,5-α]嘧啶化合物反应，所述溶剂体系包括水和一个或多个有机溶剂，可选地在外源碱的存在下。