1-((3-(trifluoromethyl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid | 796883-79-9

• 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-((3-(trifluoromethyl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid
• 英文别名: 1-[[3-(Trifluoromethyl)phenyl]carbamoyl]cyclopropane-1-carboxylic acid
• CAS: 796883-79-9
• 化学式: C₁₂H₁₀F₃NO₃
• 分子量: 273.212
• InChiKey: MCSAKNXMBCYARH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  19
• 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：
  6

反应信息

• 作为反应物：
  描述：

  1-((3-(trifluoromethyl)phenyl)carbamoyl)cyclopropane-1-carboxylic 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 N,N-二甲基甲酰胺 、 1,4-二甲基环己烷 为溶剂， 反应 24.0h， 生成 N-(4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-N'-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarboxamide
  参考文献：
  名称：

  Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2019.07.044
• 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-((3-(trifluoromethyl)phenyl)carbamoyl)cyclopropane-1-carboxylic 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 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。
• Cyclic derivatives as modulators of chemokine receptor activity
  申请人：——

  公开号：US20040235836A1

  公开（公告）日：2004-11-25

  The present application describes modulators of MCP-1 of formula (I): 1 or pharmaceutically acceptable salt forms thereof, useful for the prevention of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.

  本申请描述了MCP-1的调节剂，其化学式为(I)：1或其药学上可接受的盐形式，用于预防类风湿性关节炎、多发性硬化症、动脉粥样硬化和哮喘。
• CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
  申请人：Cherney J. Robert

  公开号：US20080108678A1

  公开（公告）日：2008-05-08

  The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.

  本申请描述了 MCP-1 的调节剂，其化学式为（I）或其药学上可接受的盐形式，可用于预防类风湿性关节炎、多发性硬化症、动脉粥样硬化和哮喘。
• Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate
  作者：Yongtao Li、Qingxiang Guo、Chao Zhang、Zhi Huang、Tianqi Wang、Xin Wang、Xiang Wang、Guangwei Xu、Yanhua Liu、Shengyong Yang、Yan Fan、Rong Xiang

  DOI：10.1016/j.bmcl.2017.06.041

  日期：2017.8

  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.
• EP1620391A4
  申请人：——

  公开号：EP1620391A4

  公开（公告）日：2007-10-31