卡博替尼杂质47 | 113136-79-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 卡博替尼杂质47
• 英文名称: 1-((4-chlorophenyl)carbamoyl)cyclopropanecarboxylic acid
• 英文别名: 1-((4-chlorophenyl)carbamoyl)cyclopropane-1-carboxylic acid；1-[(4-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid
• CAS: 113136-79-1
• 化学式: C₁₁H₁₀ClNO₃
• 分子量: 239.658
• InChiKey: MLZWLPGHVWZLJO-UHFFFAOYSA-N

物化性质

• 沸点：
  502.8±35.0 °C(Predicted)
• 密度：
  1.551±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	methyl 1-[(4-chlorophenyl)carbamoyl]cyclopropane-1-carboxylate	1373611-16-5	C12H12ClNO3	253.685

反应信息

• 作为反应物：
  描述：

  卡博替尼杂质47 在 palladium diacetate 、 1-羟基苯并三唑 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 N-(4-chlorophenyl)-N-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)cyclopropane-1,1-dicarboxamide
  参考文献：
  名称：

  Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

  摘要：

  A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 = 12 nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.06.041
• 作为产物：
  描述：

  1,1-环丙基二羧酸 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 卡博替尼杂质47
  参考文献：
  名称：

  Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

  摘要：

  Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 mu M. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

  DOI：

  10.1021/ml500066m

文献信息

• Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors
  作者：Yanmei Zhao、Jiankang Zhang、Rangxiao Zhuang、Ruoyu He、Jianjun Xi、Xuwang Pan、Yidan Shao、Jinming Pan、Jingjing Sun、Zhaobin Cai、Shourong Liu、Weiwei Huang、Xiaoqing Lv

  DOI：10.1016/j.bmc.2017.04.003

  日期：2017.6

  In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also

  在这项研究中，设计，合成和生物学评估了一系列新颖的吡啶和含嘧啶的衍生物的c-Met抑制活性。在生物学评估中，一半的目标化合物表现出中等至有效的c-Met抑制活性。其中，值得注意的是，化合物13d不仅显示出最强的c-Met抑制能力，而且显示出出色的抗增殖活性（针对EBC-1细胞系的IC50 = 127nM）以及可接受的激酶选择性谱。此外，蛋白质印迹分析表明13d以剂量依赖的方式抑制了EBC-1细胞中的c-Met磷酸化，并在0.1mM时被完全消除。所有这些实验结果表明，13d可以作为抗癌药物开发的有前途的先导化合物。
• Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2
  作者：Dengshuai Wei、Haoru Fan、Kun Zheng、Xuemei Qin、Leifu Yang、Yajuan Yang、Ye Duan、Qiang Zhang、Chengchu Zeng、Liming Hu

  DOI：10.1016/j.bioorg.2019.04.010

  日期：2019.7

  4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft

  c-Met和VEGFR-2都是癌症治疗的重要靶标。为了开发可逆的和非共价的c-Met和VEGFR-2双重抑制剂，设计并合成了一系列[1,4]二恶英[2,3-f]喹唑啉衍生物。酶分析表明，大多数目标化合物对c-Met和VEGFR-2均具有抑制作用，IC50值在纳摩尔范围内，尤其是化合物7m和7k。基于进一步的体外细胞增殖测定，化合物7k在体内对肝细胞癌（MHCC97H细胞）异种移植小鼠模型具有明显的抗肿瘤活性。我们将化合物7m与c-Met和VEGFR-2激酶对接，并解释了这些类似物的SAR。所有结果表明目标化合物是c-Met和VEGFR-2激酶的双重抑制剂，在癌症治疗中具有广阔的发展前景。
• 一种用作VEGFR抑制剂的抗肿瘤化合物及其用途
  申请人：南京科默生物医药有限公司

  公开号：CN114957136A

  公开（公告）日：2022-08-30

  本发明公开了一种具有VEGFR抑制活性的化合物或其药学上可接受的盐、含有该类化合物作为活性物质的药物组合物、制备方法及应用，所述的化合物结构通式如式（I）所示，其中R1和R2如本发明中所定义。本发明所述的含有该类化合物药物作为治疗剂中，可用于治疗恶性肿瘤、肾病、免疫系统疾病或者循环系统疾病。特别是在恶性肿瘤治疗领域中，初步药物活性研究表明，本发明所述的化合物与阳性对照物效果相当甚至更优，药代动力学实验表明本发明所述的化合物具有更加显著的药代吸收效果。
• Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss
  作者：Sarwat Chowdhury、Kelly N. Owens、R. Jason Herr、Qin Jiang、Xinchao Chen、Graham Johnson、Vincent E. Groppi、David W. Raible、Edwin W Rubel、Julian A. Simon

  DOI：10.1021/acs.jmedchem.7b00932

  日期：2018.1.11

  Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a ureathiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 mu M with protection against 200 mu M neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structureactivity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.
• Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis
  作者：Zhi Huang、Borui Zhao、Zhongxiang Qin、Yongtao Li、Tianqi Wang、Wei Zhou、Jianyu Zheng、Shengyong Yang、Yi Shi、Yan Fan、Rong Xiang

  DOI：10.1016/j.ejmech.2019.07.044

  日期：2019.11

  Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study. (C) 2019 Elsevier Masson SAS. All rights reserved.