2,4-Diamino-5-(4-methylphenoxy)quinazoline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2,4-Diamino-5-(4-methylphenoxy)quinazoline
• 英文别名: 5-(4-methylphenoxy)quinazoline-2,4-diamine
• 化学式: C₁₅H₁₄N₄O
• 分子量: 266.302
• InChiKey: BYDBBHVBHPKCHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氟-6-(4-甲基苯氧基)苯甲腈 、 碳酸胍 以 N,N-二甲基乙酰胺 为溶剂， 反应 10.0h， 生成 2,4-Diamino-5-(4-methylphenoxy)quinazoline
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel 2,4-Diaminoquinazoline Derivatives as SMN2 Promoter Activators for the Potential Treatment of Spinal Muscular Atrophy

  摘要：

  Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound Ila possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound Ila up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type I SMA patient fibroblasts, compound Ila induced Smn in a dose-dependent manner when analyzed by immuno-blotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.

  DOI：

  10.1021/jm061475p

文献信息

• Methods of modulating serine/threonine protein kinase function with quinazoline-based compounds
  申请人：——

  公开号：US20010014679A1

  公开（公告）日：2001-08-16

  The present invention is directed in part towards methods of modulating the function of serine/threonine protein kinases with quinazoline-based compounds. The methods incorporate cells that express a serine/threonine protein kinase, such as RAF. In addition, the invention describes methods of preventing and treating serine/threonine protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to quinazoline compounds and pharmaceutical compositions comprising these compounds.

  本发明部分涉及使用基于喹唑啉的化合物调节丝氨酸/苏氨酸蛋白激酶功能的方法。该方法包括表达丝氨酸/苏氨酸蛋白激酶（例如RAF）的细胞。此外，本发明还描述了使用本发明所确定的化合物预防和治疗有关丝氨酸/苏氨酸蛋白激酶的异常情况的方法。此外，本发明还涉及喹唑啉化合物和包含这些化合物的制药组合物。
• METHODS OF MODULATING SERINE/THREONINE PROTEIN KINASE FUNCTION WITH QUINAZOLINE-BASED COMPOUNDS
  申请人：Sugen, Inc.

  公开号：EP0981519A1

  公开（公告）日：2000-03-01
• US6204267B1
  申请人：——

  公开号：US6204267B1

  公开（公告）日：2001-03-20
• US6911446B2
  申请人：——

  公开号：US6911446B2

  公开（公告）日：2005-06-28
• US7465738B2
  申请人：——

  公开号：US7465738B2

  公开（公告）日：2008-12-16