8-<4-<4-(1,2-benzisothiazol-3-yl)-1-piperazinyl>butyl>-6-hydroxy-8-azaspiro<4.5>decane-7,9-dione | 128396-57-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 8-<4-<4-(1,2-benzisothiazol-3-yl)-1-piperazinyl>butyl>-6-hydroxy-8-azaspiro<4.5>decane-7,9-dione
• 英文别名: BMY 41047；8-[4-[4-(1,2-benzisothiazol-3 yl)-1-piperazinyl]butyl]-6-hydroxy-8-azaspiro[4.5]decane-7,9-dione；86Mbk442EJ；8-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl]-10-hydroxy-8-azaspiro[4.5]decane-7,9-dione
• CAS: 128396-57-6
• 化学式: C₂₄H₃₂N₄O₃S
• 分子量: 456.609
• InChiKey: JFLFNSMJIVQGSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  8-<4-<4-(1,2-benzisothiazol-3-yl)-1-piperazinyl>butyl>-6-hydroxy-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， 反应 0.5h， 以97%的产率得到8-<4-<4-(1,2-benzisothiazol-3-yl)-1-piperazinyl>butyl>-6-hydroxy-8-azaspiro<4.5>decane-7,9-dione S-oxide
  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
• 作为产物：
  描述：

  替螺酮 在 palladium on activated charcoal 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 为溶剂， -78.0 ℃ 、379.21 kPa 条件下， 反应 7.0h， 生成 8-<4-<4-(1,2-benzisothiazol-3-yl)-1-piperazinyl>butyl>-6-hydroxy-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
• 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.