CAS: 2134-36-3; Ethyl 4-Chloro-2-Methylpyrimidine-5-Carboxylate

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2-甲基-6-羟基嘧啶甲酸乙酯置于三氯氧磷体系中,化学反应 2.0H,反应生成4-氯-2-甲基嘧啶-5-甲酸乙酯
参考文献:一系列新的作为肾素抑制剂的n-(哌啶-3-基)嘧啶-5-羧酰胺的结构设计
标题:一系列新的作为肾素抑制剂的n-(哌啶-3-基)嘧啶-5-羧酰胺的结构设计
摘要:天冬氨酰蛋白酶肾素的作用是肾素-血管紧张素-醛固酮系统的限速起始步骤.因此,肾素是血压以及心血管和肾脏疾病的发作和发展的特别有希望的靶标.设计新的嘧啶衍生物5-14是为了增强化合物3的肾素抑制活性,这种化合物是通过我们以前的基于片段的药物设计方法确定的.引入对于在催化位点与两种天冬氨酸相互作用必不可少的碱性胺,并优化s1 / S3结合元素,包括通过leu114诱导拟合的结构改变(leu114由" Leu-In"变为" Leu-Out").基于合理结构的药物设计方法导致了n的发现-(piperidin-3-Yl)pyrimidine-5-Carboxamide 14,比化合物3强65,000倍的有效肾素抑制剂.出人意料的是,化合物14的抑制活性的这种显着增强已经通过仅向化合物3整体添加七个重原子而实现.化合物14在大鼠中显示出优于其他天冬氨酰蛋白酶的优异选择性和中等的口服生物利用度.
Doi:10.1016/j.Bmc.2016.09.030

专利信息

专利号:US-8188113-B2
优先权日:2006-09-14
标 题 :Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
发明人：FLYNN DANIEL L; PETILLO PETER A; KAUFMAN MICHAEL D; PATT WILLIAM C
权利人:FLYNN DANIEL L; PETILLO PETER A; KAUFMAN MICHAEL D; PATT WILLIAM C; DECIPHERA PHARMACEUTICALS INC
摘要:The present invention relates to novel dihydropyridopyrimidinyl, dihydronaphthyridinyl, and related compounds which are kinase inhibitors and modulator useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.