5-[1-(toluene-3-sulfonyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine

• 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-[1-(toluene-3-sulfonyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine
• 英文别名: 5-[[1-(3-methylphenyl)sulfonylpiperidin-4-yl]methoxy]quinazoline-2,4-diamine
• 化学式: C₂₁H₂₅N₅O₃S
• 分子量: 427.527
• InChiKey: SWULWYQIEVFRET-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine 、 间甲苯磺酰氯 在 3-(morpholino)propylpolystyrene sulfonamide 、 tris(2-aminoethyl)aminomethyl polystyrene 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 62.0h， 以83%的产率得到5-[1-(toluene-3-sulfonyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine
  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

• 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY
  申请人：Singh Jasbir

  公开号：US20090042900A1

  公开（公告）日：2009-02-12

  2,4-Diaminoquinazolines of formula (I) are provided herein and are useful for treating spinal muscular atrophy (SMA).

  本文提供了式(I)的2,4-二氨基喹唑啉，并且对于治疗脊髓肌萎缩症（SMA）有用。
• 2,4-diaminoquinazolines for spinal muscular atrophy
  申请人：Families of Spinal Muscular Atrophy

  公开号：US07985755B2

  公开（公告）日：2011-07-26

  2,4-Diaminoquinazolines of formula (I) are provided herein and are useful for treating spinal muscular atrophy (SMA).

  本文提供了式(I)的2,4-二氨基喹唑啉，并且可用于治疗脊髓性肌肉萎缩症（SMA）。
• 2,4-Diaminoquinazolines for the treatment of spinal muscular atrophy
  申请人：Families of Spinal Muscular Atrophy

  公开号：EP2615086A1

  公开（公告）日：2013-07-17

  2,4-Diaminoquinazolines of formula (I) are provided herein and are useful for treating spinal muscular atrophy (SMA).

  本文提供了式 (I) 的 2,4-二氨基喹唑啉类，可用于治疗脊髓性肌萎缩症 (SMA)。
• US7985755B2
  申请人：——

  公开号：US7985755B2

  公开（公告）日：2011-07-26
• [EN] 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY<br/>[FR] 2,4-DIAMINOQUINAZOLINES CONTRE L'AMYOTROPHIE SPINALE
  申请人：DECODE CHEMISTRY INC

  公开号：WO2008016973A1

  公开（公告）日：2008-02-07

  [EN] 2,4-Diaminoquinazolines of formula (I) are provided herein and are useful for treating spinal muscular atrophy (SMA).
  [FR] La présente invention a pour objet des 2,4-diaminoquinazolines de formule (I) qui peuvent être employées dans le traitement de l'amyotrophie spinale (SMA).