硫利达嗪N-氧化物 | 103827-30-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 中文名称: 硫利达嗪N-氧化物
• 中文别名: 苯甲酸,4-(6-硝基-3-吡啶基)-
• 英文名称: N-Oxide thioridazine
• 英文别名: Thioridazine N-oxide；10-[2-(1-methyl-1-oxidopiperidin-1-ium-2-yl)ethyl]-2-methylsulfanylphenothiazine
• CAS: 103827-30-1
• 化学式: C₂₁H₂₆N₂OS₂
• 分子量: 386.582
• InChiKey: IDYOECPECKJFRF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  71.9
• 氢给体数：
  0
• 氢受体数：
  4

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  硫利达嗪	thioridazine	50-52-2	C21H26N2S2	370.583

反应信息

• 作为产物：
  描述：

  硫利达嗪 生成 硫利达嗪N-氧化物
  参考文献：
  名称：

  Metabolism of thioridazine by microsomal monooxygenases: relative roles of P450 and flavin-containing monooxygenase

  摘要：

  1. The metabolism of thioridazine by the flavin-containing monooxygenase (FMO) of mouse liver and several P450 isozymes was examined using microsomes, purified FMO, and expressed P450 isozymes. Metabolites were identified by hplc.2. Thermal inactivation and antibodies to NADPH P450 reductase were used to selectively inactivate FMO and P450 respectively. Inactivation of FMO by heat-treatment reduced the formation of thioridazine-N-oxide and northioridazine, whereas inactivation of P450 resulted in decreased amounts of thioridazine-2-sulphoxide, northioridazine, and thioridazine-5-sulphoxide.3. Liver microsomes from mouse induced with phenobarbital, 3-methylcholanthrene, or acetone were compared with control microsomes. Phenobarbital induction resulted in increased formation of all metabolites except thioridazine-N-oxide, while retaining a general metabolic profile similar to that achieved with control microsomes. Neither 3-methylcholanthrene nor acetone induction had any effect on the in vitro metabolism of thioridazine.4. FMO purified from mouse liver produced thioridazine-N-oxide as the major metabolite.5. Preliminary experiments with commercially prepared microsomes made from cells expressing recombinant human liver P450 2D6 and 3A4 suggested that thioridazine is metabolized by 2D6 but not 3A4.

  DOI：

  10.3109/00498259509061859

文献信息

• [EN] N-OXIDE-CONTAINING PHARMACEUTICAL COMPOUNDS<br/>[FR] COMPOSÉS PHARMACEUTIQUES CONTENANT UN N-OXYDE
  申请人：SENTINEL ONCOLOGY LTD

  公开号：WO2008139152A1

  公开（公告）日：2008-11-20

  [EN] The invention provides a method of preparing a therapeutically active compound having reduced hERG activity, which method comprises: (a) selecting a non-N-oxide drug compound containing a basic tertiary amino group, wherein said non-N-oxide compound is known to have or is suspected of having a therapeutically unacceptable level of hERG inhibitory activity; (b) testing the non-N-oxide drug compound for hERG inhibitory activity; (c) reacting the non-N-oxide drug compound with an oxidising agent to form an N- oxide drug compound having an N-oxide at the basic tertiary amino group; (d) testing the N-oxide drug compound for hERG inhibitory activity; (e) testing the N-oxide drug compound for therapeutically useful activity; (f) comparing the hERG inhibitory activity of the N-oxide drug compound and non- N-oxide drug compound; and (g) when the N-oxide drug compound has therapeutically useful activity and has hERG activity which is at least ten fold less than the hERG inhibitory activity of the non-N-oxide drug compound, formulating the N-oxide drug compound for use in medicine. Also provided by the invention are novel compounds prepared by the aforementioned method and the use of the novel compounds in medicine.
  [FR] L'invention porte sur un procédé de préparation d'un composé thérapeutiquement actif ayant une activité hERG réduite. Ce procédé comprend les opérations consistant à : (a) sélectionner un composé médicament non N-oxyde contenant un groupe amino tertiaire basique, ledit composé non N-oxyde étant connu pour avoir ou étant soupçonné avoir un niveau thérapeutiquement inacceptable d'activité inhibitrice de hERG ; (b) tester le composé médicament non N-oxyde pour l'activité inhibitrice de hERG ; (c) amener à réagir le composé médicament non N-oxyde avec un agent oxydant pour former un composé médicament N-oxyde ayant un N-oxyde au niveau du groupe amino tertiaire basique ; (d) tester le composé médicament N-oxyde pour l'activité inhibitrice de hERG ; (e) tester le composé médicament N-oxyde pour une activité thérapeutiquement utile ; (f) comparer l'activité inhibitrice de hERG du composé médicament N-oxyde et du composé médicament non N-oxyde ; et (g) lorsque le composé médicament N-oxyde a une activité thérapeutiquement utile et a une activité hERG qui est au moins dix fois inférieure à celle de l'activité inhibitrice de hERG du composé médicament non N-oxyde, formuler le composé médicament N-oxyde pour une utilisation en médecine. L'invention porte également sur de nouveaux composés préparés par le procédé mentionné ci-dessus et sur l'utilisation des nouveaux composés en médecine.
• Metabolism of thioridazine by microsomal monooxygenases: relative roles of P450 and flavin-containing monooxygenase
  作者：B. L. Blake、R. L. Rose、R. B. Mailman、P. E. Levi、E. Hodgson

  DOI：10.3109/00498259509061859

  日期：1995.1

  1. The metabolism of thioridazine by the flavin-containing monooxygenase (FMO) of mouse liver and several P450 isozymes was examined using microsomes, purified FMO, and expressed P450 isozymes. Metabolites were identified by hplc.2. Thermal inactivation and antibodies to NADPH P450 reductase were used to selectively inactivate FMO and P450 respectively. Inactivation of FMO by heat-treatment reduced the formation of thioridazine-N-oxide and northioridazine, whereas inactivation of P450 resulted in decreased amounts of thioridazine-2-sulphoxide, northioridazine, and thioridazine-5-sulphoxide.3. Liver microsomes from mouse induced with phenobarbital, 3-methylcholanthrene, or acetone were compared with control microsomes. Phenobarbital induction resulted in increased formation of all metabolites except thioridazine-N-oxide, while retaining a general metabolic profile similar to that achieved with control microsomes. Neither 3-methylcholanthrene nor acetone induction had any effect on the in vitro metabolism of thioridazine.4. FMO purified from mouse liver produced thioridazine-N-oxide as the major metabolite.5. Preliminary experiments with commercially prepared microsomes made from cells expressing recombinant human liver P450 2D6 and 3A4 suggested that thioridazine is metabolized by 2D6 but not 3A4.