1-chloro-4-(4-methoxybenzyl)phthalazine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-chloro-4-(4-methoxybenzyl)phthalazine
• 英文别名: 1-(4-Methoxybenzyl)-4-chlorophthalazine；1-chloro-4-[(4-methoxyphenyl)methyl]phthalazine
• 化学式: C₁₆H₁₃ClN₂O
• 分子量: 284.745
• InChiKey: DQIMGVZYKGQXRH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-chloro-4-(4-methoxybenzyl)phthalazine 以 甲苯 、 正丁醇 为溶剂， 反应 9.0h， 生成 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(4-(4-methoxybenzyl)phthalazin-1-yl) piperazine-1-carboxamide
  参考文献：
  名称：

  Identification of novel piperazine-tethered phthalazines as selective CDK1 inhibitors endowed with in vitro anticancer activity toward the pancreatic cancer

  摘要：

  Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g, 10a-i and 12a-d) as promising anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines 8g, 10d and 10h displayed potent activity against MDA-PATC53 (IC50 = 0.51, 0.88 and 0.73 μM, respectively) and PL45 (IC50 = 0.74, 1.14 and 1.00 μM, respectively) cell lines. Furthermore, compounds 8g, 10d and 10h exhibited potent and selective inhibitory activity toward CDK1 with IC50 spanning in the range 36.80-44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. Western blotting of CDK1 in MDA-PATC53 cells confirmed the ability of target phthalazines to diminish the CDK1 levels, and cell cycle analyses revealed their ability to arrest the cell cycle at G2/M phase. In conclusion, a panel of potent and selective CDK1 inhibitors were identified which can serve as lead compounds for designing further CDK1 inhibitors.

  DOI：

  10.1016/j.ejmech.2022.114704
• 作为产物：
  描述：

  (3Z)-3-(4-methoxyphenylmethylidene)-2-benzofuran-1(3H)-one 在 N,N-二甲基苯胺 、 sodium hydroxide 、 硫酸肼 、 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 25.0h， 生成 1-chloro-4-(4-methoxybenzyl)phthalazine
  参考文献：
  名称：

  通过扩展其与活性位点之间的疏水性相互作用来提高VEGFR-2抑制剂的结合亲和力：1-取代的4-（4-甲氧基苄基）酞嗪衍生物的设计，合成和生物学评估

  摘要：

  最初合成了一系列 苯并酞菁衍生物4a – j，并测试了其对VEGFR-2的抑制活性，并显示出有希望的活性（IC 50 = 0.636–5.76μM）。分子对接研究指南用于改善4a – j系列的结合亲和力朝向VEGFR-2活性位点。通过增加与衬有Ile888，Leu889，Ile892，Val898，Val899，Leu1019和Ile1044的疏水性侧链的VEGFR-2活性位点的疏水性后口袋的疏水性相互作用，实现了这一改进。疏水相互作用的增强是通过将带有取代苯基部分的苯胺基酞嗪支架通过一个uriedo接头延伸而实现的，这应为该延伸提供足够的灵活性，以使其自身能够深深地容纳在疏水性后袋中。按计划，设计的尿酸-苯胺基酞嗪7a – i的结合亲和力比其苯胺基 酞嗪母体好（IC 50 = 0.083–0.473μM）。特别是化合物7g – i的IC 50分别为0.086、0.083和0.086μM，优于参考药物索拉非尼（IC

  DOI：

  10.1016/j.ejmech.2016.02.029

文献信息

• Aurora kinase modulators and method of use
  申请人：Cee J. Victor

  公开号：US20070185111A1

  公开（公告）日：2007-08-09

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 1 - are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1、A2、C1、C2、D、L1、L2、Z和R1-在此定义，并且具有调节各种蛋白激酶受体酶的能力，从而影响与这些激酶活动相关的各种疾病状态和病况。例如，这些化合物能够调节枢纽激酶，从而影响细胞周期和细胞增殖过程，用于治疗癌症和癌症相关疾病。该发明还包括含有这些化合物的药物组合物，以及治疗与枢纽激酶活性相关的疾病状态的方法。
• Aurora Kinase Modulators and Method of Use
  申请人：CEE Victor J.

  公开号：US20110263530A1

  公开（公告）日：2011-10-27

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7 and R 8 are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中定义了A1、A2、C1、C2、D、L1、L2、Z和R3、R4、R6、R7和R8，这些化合物能够调节极化激酶蛋白活性，从而影响与极化激酶蛋白活性相关的各种疾病状态和情况。例如，这些化合物能够影响细胞周期和细胞增殖的过程，以治疗癌症和与癌症相关的疾病。本发明还包括制备本发明化合物的药物组合物、合成中间体和治疗与极化激酶活性相关疾病的方法。
• AURORA KINASE MODULATORS AND METHOD OF USE
  申请人：Amgen Inc.

  公开号：US20140066430A1

  公开（公告）日：2014-03-06

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7 and R 8 are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1，A2，C1，C2，D，L1，L2，Z和R3，R4，R6，R7和R8在此定义，这些化合物能够调节极化激酶蛋白活性，从而影响与极化激酶蛋白活动相关的各种疾病状态和病情。例如，这些化合物能够影响细胞周期和细胞增殖过程，以治疗癌症和癌症相关疾病。本发明还包括制备本发明化合物的药物组合物、合成中间体和治疗与极化激酶活性相关疾病的方法。
• US7560551B2
  申请人：——

  公开号：US7560551B2

  公开（公告）日：2009-07-14
• US8022221B2
  申请人：——

  公开号：US8022221B2

  公开（公告）日：2011-09-20