1-(p-tolylcarbamoyl)cyclopropanecarboxylic acid | 1248667-63-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(p-tolylcarbamoyl)cyclopropanecarboxylic acid
• 英文别名: 1-(p-tolylcarbamoyl)cyclopropane-1-carboxylic acid；1-[(4-Methylphenyl)carbamoyl]cyclopropane-1-carboxylic acid
• CAS: 1248667-63-1
• 化学式: C₁₂H₁₃NO₃
• 分子量: 219.24
• InChiKey: MUDKIRXDRLZLNN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(p-tolylcarbamoyl)cyclopropanecarboxylic acid 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-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)-N-(p-tolyl)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 1-(p-tolylcarbamoyl)cyclopropanecarboxylic acid
  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。
• METHODS OF PREPARING QUINOLINE DERIVATIVES
  申请人：Wilson Jo Ann

  公开号：US20130197230A1

  公开（公告）日：2013-08-01

  Methods of preparing compounds of formula i(1): or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 join together with the nitrogen atom to which they are attached form a 6 membered heterocycloalkyl group; X 1 is H, Br, Cl or F; X 2 is H, Br, Cl or F; s is 2-6; n1 is 1-2; and n2 is 1-2.

  制备式i（1）化合物的方法，或其药学上可接受的盐，其中： R1和R2与它们附着的氮原子结合形成一个6元杂环烷基； X1为H、Br、Cl或F； X2为H、Br、Cl或F； s为2-6； n1为1-2； n2为1-2。
• Processes for Preparing Quinoline Compounds and Pharmaceutical Compositions Containing Such Compounds
  申请人：Wilson Jo Ann

  公开号：US20140200242A1

  公开（公告）日：2014-07-17

  The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X1 is H, Br, CI, or X2 is H, Br, CI, or n1 is 1-2; and n2 is 1-2.

  本发明涉及制备喹啉化合物的方法和含有喹啉化合物的组合物，其中所述喹啉化合物为式I或其药学上可接受的盐，其中：X1为H、Br、CI，或者X2为H、Br、CI，n1为1-2，n2为1-2。
• 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.