Desmethylene-Paroxetine | 159126-30-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: Desmethylene-Paroxetine
• 英文别名: (3S,4R)-3-(3,4-dihydroxyphenoxymethyl)-4-(4-fluorophenyl)-piperidine；paroxetine-catechol；1,2-Benzenediol, 4-(((3S,4R)-4-(4-fluorophenyl)-3-piperidinyl)methoxy)-；4-[[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy]benzene-1,2-diol
• CAS: 159126-30-4
• 化学式: C₁₈H₂₀FNO₃
• 分子量: 317.36
• InChiKey: VJMXXTJAPJRAQL-BBRMVZONSA-N

物化性质

• 熔点：
  104-107?C
• 沸点：
  509.6±50.0 °C(Predicted)
• 密度：
  1.233±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  61.7
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

4-[[(3S,4R)-4-(4-氟苯基)哌啶-3-基]甲氧基]苯-1,2-二醇是帕罗西汀的人类已知代谢物。

4-[[(3S,4R)-4-(4-Fluorophenyl)piperidin-3-yl]methoxy]benzene-1,2-diol is a known human metabolite of Paroxetine.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  帕罗西汀 在 glucose-6-phosphate dehydrogenase 、 CYP₃A₄ 、 D-葡萄糖-6-磷酸 、 nicotinamide adenine dinucleotide phosphate 、 magnesium chloride 作用下， 以 甲醇 为溶剂， 反应 0.17h， 生成 Desmethylene-Paroxetine
  参考文献：
  名称：

  Identification of Cytochrome P450 Isoforms Involved in the Metabolism of Paroxetine and Estimation of Their Importance for Human Paroxetine Metabolism Using a Population-Based Simulator

  摘要：

  我们在这里首次鉴定了代谢帕罗西汀的低亲和力细胞色素 P450 (P450) 同工型，使用 cDNA 表达的人 P450，通过液相色谱-串联质谱法测量底物消耗和帕罗西汀-儿茶酚（产物）形成。 CYP1A2、CYP2C19、CYP2D6、CYP3A4 和 CYP3A5 被鉴定为帕罗西汀儿茶酚形成 P450 异构体，CYP2C19 和 CYP2D6 被鉴定为通过底物耗尽代谢的 P450 异构体。米氏常数 K m 和 V max 通过产物形成和底物消耗来确定。通过对混合和单一供体人肝微粒体进行选择性抑制研究和相对活性因子方法，我们证实了已鉴定的 P450 异构体在 1 和 20 μM 帕罗西汀下参与帕罗西汀-儿茶酚的形成。此外，我们使用基于群体的模拟器 Simcyp 来估计已识别的帕罗西汀代谢 P450 亚型对人类代谢的重要性，并考虑到基于机制的抑制。 Simcyp 还估计了活性肝脏 CYP2D6 和 CYP3A4（未通过基于机制的抑制失活）的量。对于 CYP2D6 的强代谢和弱代谢者，Simcyp 估计的药代动力学特征与已发表的体内研究中报道的一致。考虑到动力学参数、抑制结果、相对活性因子计算和 Simcyp 模拟，CYP2D6（高亲和力）和 CYP3A4（低亲和力）最有可能是人类帕罗西汀代谢的主要贡献者。对于某些个体来说，CYP1A2 可能对帕罗西汀代谢很重要，而 CYP2C19 和 CYP3A5 的重要性可能有限。

  DOI：

  10.1124/dmd.109.030551

文献信息

• Novel benzo[D][1,3]-dioxol derivatives
  申请人：Tung Roger

  公开号：US20070191432A1

  公开（公告）日：2007-08-16

  The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

  本发明涉及一种在苯并二氧杂环环的亚甲基碳上取代氘的化合物1的同位素。本发明的同位素是选择性血清素再摄取抑制剂(SSRI)，与化合物1相比具有独特的生物制药和代谢特性。它们还可以用于准确确定生物液中化合物1的浓度，并确定化合物1及其同位素的代谢模式。本发明还提供了包含这些氘同位素的组合物以及治疗对增加神经元血清素传递敏感的疾病和病症的方法，单独或与其他药物联合使用。
• Novel benzo[d][1,3]-dioxol derivatives
  申请人：Tung Roger

  公开号：US20080287495A1

  公开（公告）日：2008-11-20

  The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

  本发明涉及一种在苯二氧杂环环的亚甲基碳上用氘取代的化合物1的同位素。本发明的同位素选择性地抑制5-羟色胺再摄取，具有与化合物1相比独特的生物制药和代谢特性。它们还可用于准确测定生物液体中化合物1的浓度，并确定化合物1及其同位素的代谢模式。本发明还提供了包含这些氘同位素的组合物和治疗对增加神经元5-羟色胺传递敏感的疾病和病症的方法，单独或与其他药物联合使用。
• DEUTERATED BENZO[D][1,3]-DIOXOL DERIVATIVES
  申请人：Tung Roger

  公开号：US20100222589A1

  公开（公告）日：2010-09-02

  The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

  本发明涉及一种在苯并二氧杂环环的亚甲基碳上用氘取代的化合物1的同位素。本发明的同位素选择性地抑制5-羟色胺再摄取抑制剂（SSRI），并且与化合物1相比具有独特的生物制药和代谢特性。它们还可以用于准确测定生物体液中化合物1的浓度，并确定化合物1及其同位素的代谢模式。本发明还提供了包含这些氘同位素的组合物和治疗对增加神经元5-羟色胺传递敏感的疾病和病症的方法，单独或与其他药物联合使用。
• NOVEL BENZO[d][1,3]-DIOXOL DERIVATIVES
  申请人：Tung Roger D.

  公开号：US20150196544A1

  公开（公告）日：2015-07-16

  The present invention relates to an isotopologue of Compound 1 substituted with deuterium at the methylene carbon of the benzodioxol ring. The isotopologues of this invention selective serotonin reuptake inhibitors (SSRIs) and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions that are responsive to increased neuronal serotonin transmission, alone and in combination with additional agents.

  本发明涉及化合物1的同位素拓扑异构体，在苯并二氧杂环环的亚甲基碳上用氘取代。本发明的同位素拓扑异构体是选择性血清素再摄取抑制剂（SSRI），与化合物1相比具有独特的生物制药和代谢特性。它们还可以用于准确测定生物流体中化合物1的浓度，并确定化合物1及其同位素拓扑异构体的代谢模式。本发明还提供了包含这些氘化同位素拓扑异构体的组合物及其治疗对增加神经元血清素传递响应的疾病和病状的方法，单独使用或与其他药物联合使用。
• Synthesis of the major metabolites of Paroxetine
  作者：Mireia Segura、Lidia Roura、Rafael de la Torre、Jesús Joglar

  DOI：10.1016/s0045-2068(03)00040-3

  日期：2003.6

  Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl) piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route. (C) 2003 Elsevier Science (USA). All rights reserved.