5-(3-chlorophenoxy)-2,4-diamino quinazoline | 1009734-17-1

• 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: 5-(3-chlorophenoxy)-2,4-diamino quinazoline
• 英文别名: 5-(3-Chlorophenoxy)quinazoline-2,4-diamine
• CAS: 1009734-17-1
• 化学式: C₁₄H₁₁ClN₄O
• 分子量: 286.721
• InChiKey: VXHZDNWEKYXBEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 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-(3-chlorophenoxy)-6-fluorobenzonitrile 、 碳酸胍 以 N,N-二甲基乙酰胺 为溶剂， 反应 10.0h， 以46%的产率得到5-(3-chlorophenoxy)-2,4-diamino 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

• USE OF A QUINAZOLINE COMPOUND IN PREPARING A MEDICAMENT AGAINST FLAVIVIRIDAE VIRUS
  申请人：Zuo Jianping

  公开号：US20130261139A1

  公开（公告）日：2013-10-03

  Disclosed is a use of a quinazoline compound of Formula I having 2,4-diaminoquinazoline as a parent nucleus in preparation of a medicament for treating diseases caused by flaviviridae infection, especially a use in combating Hepatitis C virus infection and Dengue fever virus infection.

  本发明揭示了一种使用式I的喹唑啉化合物，其中2,4-二氨基喹唑啉作为母核，用于制备治疗由黄病毒科感染引起的疾病的药物，特别是用于对抗丙型肝炎病毒感染和登革热病毒感染的用途。
• USE OF QUINAZOLINE COMPOUND IN PREPARATION OF ANTI-FLAVIVIRUS DRUG
  申请人：Shanghai Institute Materia Medica, Chinese Academy Of Sciences

  公开号：EP2649999A1

  公开（公告）日：2013-10-16

  Disclosed is a use of a quinazoline compound of Formula I having 2,4-diaminoquinazoline as a parent nucleus in preparation of a medicament for treating diseases caused by flaviviridae infection, especially a use in combating Hepatitis C virus infection and Dengue fever virus infection.

  本发明公开了以 2,4-二氨基喹唑啉为母核的式 I 喹唑啉化合物在制备治疗由黄病毒感染引起的疾病的药物中的用途，特别是在防治丙型肝炎病毒感染和登革热病毒感染中的用途。
• US9133138B2
  申请人：——

  公开号：US9133138B2

  公开（公告）日：2015-09-15
• Synthesis and Biological Evaluation of Novel 2,4-Diaminoquinazoline Derivatives as <i>SMN2</i> Promoter Activators for the Potential Treatment of Spinal Muscular Atrophy
  作者：John Thurmond、Matthew E. R. Butchbach、Marty Palomo、Brian Pease、Munagala Rao、Louis Bedell、Monica Keyvan、Grace Pai、Rama Mishra、Magnus Haraldsson、Thorkell Andresson、Gisli Bragason、Margret Thosteinsdottir、Jon Mar Bjornsson、Daniel D. Coovert、Arthur H. M. Burghes、Mark E. Gurney、Jasbir Singh

  DOI：10.1021/jm061475p

  日期：2008.2.1

  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.