4-Dimethylamino-2-methylthio-5-pyrimidincarbonsaeure-ethylester | 15400-44-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-Dimethylamino-2-methylthio-5-pyrimidincarbonsaeure-ethylester
• 英文别名: 4-dimethylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester；4-Dimethylamino-2-methylmercapto-pyrimidincarbonsaeure-(5)-ethylester；Ethyl 4-(dimethylamino)-2-methylsulfanylpyrimidine-5-carboxylate
• CAS: 15400-44-9
• 化学式: C₁₀H₁₅N₃O₂S
• mdl: MFCD00476789
• 分子量: 241.314
• InChiKey: SWFRATAVGJNRKK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  80.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-Dimethylamino-2-methylthio-5-pyrimidincarbonsaeure-ethylester 在 tin(II) chloride dihdyrate 、 水 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.0h， 生成 2-(3-amino-4-methylphenylamino)-4-(dimethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)pyrimidine-5-carboxamide
  参考文献：
  名称：

  Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  摘要：

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

  DOI：

  10.1021/acs.jmedchem.5b01618
• 作为产物：
  描述：

  4-氯-2-甲硫基嘧啶-5-羧酸乙酯 以 二氯甲烷 、 苯 为溶剂， 反应 4.5h， 生成 4-Dimethylamino-2-methylthio-5-pyrimidincarbonsaeure-ethylester
  参考文献：
  名称：

  Hermann, Klaus; Simchen, Gerhard, Liebigs Annalen der Chemie, 1981, # 2, p. 333 - 341

  摘要：

  DOI：

文献信息

• Discovery of 2-((3-Amino-4-methylphenyl)amino)-<i>N</i>-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
  作者：Xiaofei Liang、Xiaochuan Liu、Beilei Wang、Fengming Zou、Aoli Wang、Shuang Qi、Cheng Chen、Zheng Zhao、Wenchao Wang、Ziping Qi、Fengchao Lv、Zhenquan Hu、Li Wang、Shanchun Zhang、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.5b01618

  日期：2016.3.10

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.
• Hermann, Klaus; Simchen, Gerhard, Liebigs Annalen der Chemie, 1981, # 2, p. 333 - 341
  作者：Hermann, Klaus、Simchen, Gerhard

  DOI：——

  日期：——