methyl 2-amino-4-chloro-5-methylbenzoate | 458533-69-2

• 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: methyl 2-amino-4-chloro-5-methylbenzoate
• CAS: 458533-69-2
• 化学式: C₉H₁₀ClNO₂
• 分子量: 199.637
• InChiKey: QMJVDQIDPQGBCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  52.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 2-amino-4-chloro-5-methylbenzoate 在 吡啶 、 2,6-二甲基吡啶 、 4-二甲氨基吡啶 、 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 硫酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 过氧化苯甲酰 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 59.67h， 生成 CB 300919; 4-[[[7-氯-3,4-二氢-3-甲基-2-[(4-甲基-1-哌嗪基)甲基]-4-氧代-6-喹唑啉基]甲基]-2-丙炔-1-基氨基]-N-(3-吡啶基甲基)苯甲酰胺
  参考文献：
  名称：

  The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

  摘要：

  4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growth-inhibitory activity (W1L2 IC50 = 2.8 +/- 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 muM for 5a at pH 6 and 992 muM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC50 = 0.49 +/- 0.24 nM) and retained its novel biochemical characteristics.

  DOI：

  10.1021/jm011081s
• 作为产物：
  描述：

  2-氨基-4-氯-5-甲基苯甲酸 在 4-二甲氨基吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 9.0h， 生成 methyl 2-amino-4-chloro-5-methylbenzoate
  参考文献：
  名称：

  The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

  摘要：

  4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growth-inhibitory activity (W1L2 IC50 = 2.8 +/- 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 muM for 5a at pH 6 and 992 muM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC50 = 0.49 +/- 0.24 nM) and retained its novel biochemical characteristics.

  DOI：

  10.1021/jm011081s

文献信息

• Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1
  作者：Daniel P. Flaherty、Michael T. Harris、Chad E. Schroeder、Haaris Khan、Elizabeth W. Kahney、Amber L. Hackler、Stephen L. Patrick、Warren S. Weiner、Jeffrey Aubé、Elizabeth R. Sharlow、James C. Morris、Jennifer E. Golden

  DOI：10.1002/cmdc.201700592

  日期：2017.12.7

  molecular‐target‐directed approach involving intervention of hexokinase activity—a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC50=9.1 μm), low mammalian cytotoxicity (IMR90 cells, EC50>25 μm), and no appreciable activity on whole bloodstream‐form (BSF) parasites was optimized to afford a probe with improved TbHK1 potency

  基于动质体的感染是被忽视的疾病，代表着重大的人类健康问题。由于毒性、寄生虫敏感性和患者依从性差，化疗选择受到限制。为此，我们研究了一种分子靶点导向的方法，涉及干预己糖激酶活性（寄生虫代谢中的关键酶）。苯甲酰胺苯甲酸对布氏锥虫己糖激酶 1 (TbHK1，IC 50 =9.1 μm )具有适度的生化抑制作用，对哺乳动物细胞毒性低（IMR90 细胞，EC 50 >25 μm ），并且对全血流形式 (BSF) 无明显活性）寄生虫经过优化，以提供具有改进的 TbHK1 效力的探针，并且显着地提高了针对整个 BSF 寄生虫的效力（TbHK1，IC 50 = 0.28 μ m；BSF，ED 50 = 1.9 μ m）。该系列化合物还抑制了来自大型利什曼原虫(LmHK1)的己糖激酶，尽管其效力低于 TbHK1，这表明糖酵解途径的抑制可能是针对多种致病锥虫原生动物的一个有希望的机会。
• INHIBITORS OF KRAS G12C
  申请人：Araxes Pharma LLC

  公开号：US20150239900A1

  公开（公告）日：2015-08-27

  Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R 1 , R 2a , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

  提供了具有抑制G12C突变KRAS蛋白活性的化合物。这些化合物具有以下结构（I）：或其药学上可接受的盐、互变异构体、前药或立体异构体，其中R1、R2a、R3a、R3b、R4a、R4b、G1、G2、L1、L2、m1、m2、A、B、W、X、Y、Z和E的定义如本文所述。还提供了与制备和使用这些化合物相关的方法，包括含有这些化合物的制药组合物以及用于治疗癌症等疾病的调节G12C突变KRAS蛋白活性的方法。
• [EN] AMINOHETEROCYCLE-SUBSTITUTED TRICYCLIC KRAS INHIBITORS<br/>[FR] INHIBITEURS DE KRAS TRICYCLIQUES SUBSTITUÉS PAR UN AMINOHÉTÉROCYCLE
  申请人：ERASCA INC

  公开号：WO2022265974A1

  公开（公告）日：2022-12-22

  The present embodiments provide compounds of Formula I, pharmaceutical compositions of the compounds, and methods for treating diseases such as cancer.

  本实施例提供了公式I的化合物、该化合物的药物组合物以及用于治疗癌症等疾病的方法。
• SUBSTITUTED QUINAZOLINES AS INHIBITORS OF KRAS G12C
  申请人：Araxes Pharma LLC

  公开号：US20180118757A1

  公开（公告）日：2018-05-03

  Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R 1 , R 2a , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
• US9840516B2
  申请人：——

  公开号：US9840516B2

  公开（公告）日：2017-12-12