3-[(2,2-dimethyl-1,3-benzodioxol-4-yl)methyl]-3,9-diazaspiro[5.5]undecane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 3-[(2,2-dimethyl-1,3-benzodioxol-4-yl)methyl]-3,9-diazaspiro[5.5]undecane
• 化学式: C₁₉H₂₈N₂O₂
• 分子量: 316.444
• InChiKey: BACZBKZDXRTCKB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  33.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[(2,2-dimethyl-1,3-benzodioxol-4-yl)methyl]-3,9-diazaspiro[5.5]undecane 、 6-氨基嘧啶-4-羧酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 为溶剂， 反应 1.0h， 以17%的产率得到6-({9-[(2,2-dimethyl-1,3-benzodioxol-4-yl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}carbonyl)pyrimidin-4-amine
  参考文献：
  名称：

  WO2007/30061

  摘要：

  公开号：
• 作为产物：
  描述：

  在 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成 3-[(2,2-dimethyl-1,3-benzodioxol-4-yl)methyl]-3,9-diazaspiro[5.5]undecane
  参考文献：
  名称：

  Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites

  摘要：

  The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although Such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.

  DOI：

  10.1021/jm900713y

文献信息

• NOVEL DIAZASPIROALKANES AND THEIR USE FOR TREATMENT OF CCR8 MEDIATED DISEASES
  申请人：Borjesson Lena

  公开号：US20090156575A1

  公开（公告）日：2009-06-18

  The invention provides compounds of general formula wherein A, B, p, w, x, y, and z are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  本发明提供了一般式为的化合物，其中A、B、p、w、x、y和z的定义如规范中所述，以及其制备方法、包含它们的药物组合物和它们在治疗中的应用。
• [EN] NOVEL DIAZASPIROALKANES AND THEIR USE FOR TREATMENT OF CCR8 MEDIATED DISEASES<br/>[FR] NOUVEAUX DIAZASPIROALCANES ET LEUR UTILISATION POUR LE TRAITEMENT DE MALADIES MEDIEES PAR CCR8
  申请人：ASTRAZENECA AB

  公开号：WO2007030061A1

  公开（公告）日：2007-03-15

  [EN] The invention provides compounds of general formula (I) wherein A, B, p, w, x, y, and z are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  [FR] L'invention concerne des composés représentés par la formule générale (I) dans laquelle A, B, p, w, x, y et z sont tels que définis dans le descriptif, des procédés de préparation desdits composés, des compositions pharmaceutiques contenant lesdits composés et leur utilisation à des fins thérapeutiques.
• WO2007/30061
  申请人：——

  公开号：——

  公开（公告）日：——
• Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites
  作者：Igor Shamovsky、Chris de Graaf、Lisa Alderin、Malena Bengtsson、Håkan Bladh、Lena Börjesson、Stephen Connolly、Hazel J. Dyke、Marco van den Heuvel、Henrik Johansson、Bo-Göran Josefsson、Anna Kristoffersson、Tero Linnanen、Annea Lisius、Roope Männikkö、Bo Nordén、Steve Price、Lena Ripa、Didier Rognan、Alexander Rosendahl、Marco Skrinjar、Klaus Urbahns

  DOI：10.1021/jm900713y

  日期：2009.12.10

  The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although Such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.