8-(3,4-epoxybutyl)-8-azaspiro<4.5>decane-7,9-dione | 131779-64-1

• 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: 8-(3,4-epoxybutyl)-8-azaspiro<4.5>decane-7,9-dione
• 英文别名: 8-(3,4-Epoxybutyl)-8-azaspiro[4.5]decane-7,9-dione；8-[2-(oxiran-2-yl)ethyl]-8-azaspiro[4.5]decane-7,9-dione
• CAS: 131779-64-1
• 化学式: C₁₃H₁₉NO₃
• 分子量: 237.299
• InChiKey: CFUBKFWKZKRJQA-UHFFFAOYSA-N

物化性质

• 沸点：
  409.1±18.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  49.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2-嘧啶基)哌嗪 、 8-(3,4-epoxybutyl)-8-azaspiro<4.5>decane-7,9-dione 在 lithium perchlorate 作用下， 以 乙腈 为溶剂， 生成 8-[3-Hydroxy-4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione
  参考文献：
  名称：

  The design and preparation of metabolically protected new arylpiperazine 5-HT1A ligands

  摘要：

  New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT1A affinity and potential sites of metabolism by human cytochrome P450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT1A affinity and CYP3A4 stability are described. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.01.045
• 作为产物：
  描述：

  8-(3-butenyl)-8-azaspiro<4.5>decane-7,9-dione 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 以75%的产率得到8-(3,4-epoxybutyl)-8-azaspiro<4.5>decane-7,9-dione
  参考文献：
  名称：

  Synthesis and biological activity of the putative metabolites of the atypical antipsychotic agent tiospirone

  摘要：

  Putative oxidative metabolites of the lead antipsychotic agent tiospirone (1) were synthesized to assist in the identification of the authentic metabolic products found in human urine samples. Thus far, six authentic metabolites have been correlated to the synthetic species. 4a The putative metabolites were further examined in vitro to assess their central nervous system therapeutic potential. SAR analysis of these derivatives indicates that hydroxyl substitution, particularly in the azaspirodecanedione region of the molecule, diminishes the dopamine D-2 affinity of the species without significantly altering the serotonin type-1A and type-2 interactions. In addition, an increase in alpha-1-adrenergic affinity appears to be linked to the attenuation of effects at the dopamine receptors. The biological profile of the 6-hydroxytiospirone metabolite 42 was exemplary in these respects and the in vivo actions of this compound suggest potent antipsychotic potential with a minimal liability for extrapyramidal side effects (EPS). While compound 42 has been unambiguously characterized as an actual human metabolite of tiospirone, the role of 42 in the observed antipsychotic activity of the parent drug, if any, has not yet been determined.

  DOI：

  10.1021/jm00115a024

文献信息

• Metabolites and prodrug formulations of
  申请人：Bristol-Myers Company

  公开号：US04956368A1

  公开（公告）日：1990-09-11

  Various metabolites and prodrug formulations of 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]deca ne-7,9-dione which are particularly useful in the treatment of psychotic disorders, especially derivatives thereof which have been oxygenated at specified sites about the original structure, rearranged compounds, and prodrug formulations of these species. One particularly desired group of compounds have the general Formula I where ##STR1## R.sup.1 is hydrogen, hydroxyl, alkoxy, acyloxy and oxo; R.sup.2 is hydrogen, methyl, hydroxyl, alkoxy, and acyloxy; R.sup.3 is hydrogen, hydroxyl, and methoxy: R.sup.4 is hydrogen, methyl and oxo; and X is S, SO, and SO.sub.2.

  8-[4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基]-8-氮杂螺[4.5]癸烷-7,9-二酮的各种代谢产物和前药制剂，特别适用于治疗精神疾病，特别是在原始结构的指定位置被氧化的衍生物，重排的化合物以及这些物种的前药制剂。一组特别理想的化合物具有通式I，其中##STR1## R.sup.1是氢、羟基、烷氧基、酰氧基和羰基；R.sup.2是氢、甲基、羟基、烷氧基和酰氧基；R.sup.3是氢、羟基和甲氧基；R.sup.4是氢、甲基和羰基；X是S、SO和SO
• US4956368A
  申请人：——

  公开号：US4956368A

  公开（公告）日：1990-09-11
• The design and preparation of metabolically protected new arylpiperazine 5-HT1A ligands
  作者：Manish Tandon、Mary-Margaret O'Donnell、Alex Porte、David Vensel、Donglai Yang、Rocio Palma、Alan Beresford、Mark A. Ashwell

  DOI：10.1016/j.bmcl.2004.01.045

  日期：2004.4

  New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT1A affinity and potential sites of metabolism by human cytochrome P450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT1A affinity and CYP3A4 stability are described. (C) 2004 Elsevier Ltd. All rights reserved.
• Synthesis and biological activity of the putative metabolites of the atypical antipsychotic agent tiospirone
  作者：Joseph A. Cipollina、Edward H. Ruediger、James S. New、Mary E. Wire、Timothy A. Shepherd、David W. Smith、Joseph P. Yevich

  DOI：10.1021/jm00115a024

  日期：1991.11

  Putative oxidative metabolites of the lead antipsychotic agent tiospirone (1) were synthesized to assist in the identification of the authentic metabolic products found in human urine samples. Thus far, six authentic metabolites have been correlated to the synthetic species. 4a The putative metabolites were further examined in vitro to assess their central nervous system therapeutic potential. SAR analysis of these derivatives indicates that hydroxyl substitution, particularly in the azaspirodecanedione region of the molecule, diminishes the dopamine D-2 affinity of the species without significantly altering the serotonin type-1A and type-2 interactions. In addition, an increase in alpha-1-adrenergic affinity appears to be linked to the attenuation of effects at the dopamine receptors. The biological profile of the 6-hydroxytiospirone metabolite 42 was exemplary in these respects and the in vivo actions of this compound suggest potent antipsychotic potential with a minimal liability for extrapyramidal side effects (EPS). While compound 42 has been unambiguously characterized as an actual human metabolite of tiospirone, the role of 42 in the observed antipsychotic activity of the parent drug, if any, has not yet been determined.