多西拉敏 | 469-21-6

• 物质功能分类: 原料药 - 抗变态反应药 - 抗组胺药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 多西拉敏
• 中文别名: 抗敏安
• 英文名称: doxylamine
• 英文别名: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine；doxylamine succinate；N,N-dimethyl-2-(1-phenyl-1-pyridin-2-ylethoxy)ethanamine
• CAS: 469-21-6；76210-47-4
• 化学式: C₁₇H₂₂N₂O
• mdl: MFCD00599469
• 分子量: 270.374
• InChiKey: HCFDWZZGGLSKEP-UHFFFAOYSA-N

物化性质

• 熔点：
  25°C
• 沸点：
  bp0.5 137-141°
• 密度：
  1.0023 (rough estimate)
• 溶解度：
  乙腈（微溶）、氯仿（微溶）、甲醇（微溶）
• 物理描述：
  Doxylamine is a clear colorless liquid. (NTP, 1992)
• 颜色/状态：
  LIQ
• 蒸汽压力：
  Slightly volatile
• 折光率：
  INDEX OF REFRACTION: CALCULATED 1.525 (ALPHA), 1.563 (BETA), 1.598 (GAMMA)
• 碰撞截面：
  161.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  1925;1888;1945;1958;1917.7;1907.2;1926.3;1894.2;1888;1915;1920;1906;1968;1925.2

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.352
• 拓扑面积：
  25.4
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

被分离、定量和鉴定的结合型多西拉敏代谢物包括多西拉敏O-葡萄糖苷酸、N-去甲基多西拉敏O-葡萄糖苷酸和N,N-二去甲基多西拉敏O-葡萄糖苷酸。

The conjugated doxylamine metabolites that were isolated, quantitiated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氧化苯海拉明N-氧化物和吡咯拉明N-氧化物作为合成标准和生物源性代谢物通过热喷雾质谱法（TSP/MS）分析，为每个代谢物提供了（M + H）+离子。此外，还报告了环羟基化N-去甲基氧化苯海拉明...的热喷雾质谱法（TSP/MS）和热喷雾质谱/质谱法（TSP/MS/MS）分析。

Analysis of doxylamine N-oxide and pyrilamine N-oxide as synthetic standards and biologically derived metabolites by thermospray mass spectrometry (TSP/MS) provided (M + H) + ions for each metabolite. ... In addition, TSP/MS and TSP/MS/MS analysis of ring-hydroxylated N-desmethyldoxylamine ... is also reported.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏的。半衰期：10小时

Hepatic. Half Life: 10 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

像其他抗组胺药一样，多西拉明通过竞争性抑制H1受体的组胺发挥作用。它还具有显著的镇静和抗胆碱能效果。

Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管已经被广泛使用了几十年，多西拉明并未与肝功能测试异常或临床明显的肝损伤有关联。其安全性可能与它较短的半衰期和有限的使用时长有关。 可能性评分：E（不太可能是临床明显肝损伤的原因）。 关于抗组胺药的安全性和潜在肝毒性的参考资料在抗组胺药概述部分之后给出。 药物类别：抗组胺药

Despite widespread use over many decades, doxylamine has not been linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate its short half-life and limited duration of use. Likelihood score: E (unlikely to be a cause of clinically apparent liver injury). References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines. Drug Class: Antihistamines

来源:LiverTox

毒理性

• 药物性肝损伤

复合物：多西拉明

Compound:doxylamine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

容易通过胃肠吸收。

Readily absorbed via the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

H1受体拮抗剂在儿童体内的消除速度比成人快，而在严重肝病患者体内的消除速度则较慢。/H1受体拮抗剂/

H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. /H1 Receptor Antagonists/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

H1受体拮抗剂从胃肠道吸收良好。口服给药后，2到3小时内达到血浆峰值浓度...。/H1受体拮抗剂/

The H1 antagonists are well absorbed from the gastrointestinal tract. Following oral administration, peak plasma concentrations are achieved in 2 to 3 hours ... . /H1 Receptor Antagonists/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予雄性和雌性Fischer 344大鼠口服(14)C-多西拉明琥珀酸盐（13.3和133毫克/千克剂量）后，确定了多西拉明及其N-去甲基化代谢产物的葡萄糖苷酸产物的消除和代谢轮廓。在13.3毫克/千克剂量下，这些结合多西拉明代谢产物的累积尿和粪便消除分别为雄性和雌性大鼠总回收剂量的44.4 ± 4.2%和47.3 ± 8.1%。在133毫克/千克剂量下，结合多西拉明代谢产物的累积尿和粪便消除分别为雄性和雌性大鼠总回收剂量的55.2 ± 2.6%和47.9 ± 2.5%。被分离、定量和鉴定的结合多西拉明代谢产物包括多西拉明O-葡萄糖苷酸、N-去甲基多西拉明O-葡萄糖苷酸和N,N-二去甲基多西拉明O-葡萄糖苷酸。

Elimination and metabolic profiles of the glucuronide products of doxylamine and its N-demethylated metabolites were determined after the oral admin of (14)C-doxylamine succinate (13.3 and 133 mg/kg doses) to male and female Fischer 344 rats. The cumulative urinary and fecal eliminations of these conjugated doxylamine metaboites at the 13.3 mg/kg dose were 44.4 + or - 4.2% and 47.3 + or - 8.1% of the total recoverd dose for male and female rats, respectively. The cumulative urinary and fecal eliminations of conjugated doxylamine metabolites at the 133 mg/kg dose were 55.2 + or - 2.6% and 47.9 + or - 2.5% of the total recovered dose for male and female rats, respectively. The conjugated doxylamine metabolites that were isolated, quantitiated, and identified are doxylamine O-glucuronide, N-desmethyl-doxylamine O-glucuronide, and N,N-didesmethyldoxylamine O-glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在对成年雌性恒河猴静脉注射0.7和13.3毫克/千克的(14)C-多西拉明琥珀酸盐后，确定了多西拉明及其代谢物的消除。尽管低剂量和高剂量研究中的总放射性回收率相同（90.2%），但高剂量组的多西拉明及其去甲基代谢物（去甲基多西拉明）的血浆消除速率较慢。随着静脉注射多西拉明琥珀酸盐剂量的增加，24小时内尿液中多西拉明代谢物（去甲基和双去甲基多西拉明）的排泄量显著增加，而极性多西拉明代谢物的排泄量显著减少。在给成年雌性恒河猴口服Bendectin（多西拉明琥珀酸盐和盐酸吡哆醇，还含有双环维林盐酸）7、13.3和27毫克/千克后，确定了GC检测到的多西拉明的血浆消除。随着剂量的增加，多西拉明的清除率降低。对口服数据的单室平行一级消除模型和单室平行一级和二级（米氏动力学）消除模型的统计评估拟合表明，包含二级过程的高级模型与观察到的消除数据最为一致。

The elimination of doxylamine and metabolites was determined after iv admin of (14)C-doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly incr and the polar doxylamine metabolites were significantly decr as the iv doxylamine succinate dose was incr. The plasma elimination of GC-detected doxylamine was determined after po admin of Bendectin (doxylamine succinate and pyridoxine hydrochloride) /also contains dicyclomine hydrochloride/ at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose incr, the clearance of doxylamine decr. A statistically evaluated fit of the po data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data. /Doxylamine succinate/

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  多西拉敏 在 (1,5-cyclooctadiene)(methoxy)iridium(I) dimer 、 氘 作用下， 以 四氢呋喃 为溶剂， 55.0 ℃ 、100.0 kPa 条件下， 反应 22.0h， 以83%的产率得到
  参考文献：
  名称：

  药物的多位点氢同位素标记

  摘要：

  摘要放射性标记是药物发现和开发的基础，因为它是临床前 ADME 研究和后期人体临床试验的强制性要求。本文提出了一种通用、有效且易于实施的方法，使用市售且空气稳定的铱预催化剂 [Ir(COD)(OMe)] 来多位点掺入氘和氚原子。2被描述。使用这种方法可以标记大量与药物相关的子结构，包括吡啶、吡嗪、吲哚、咔唑、苯胺、恶唑/噻唑、噻吩以及富电子苯基。各种复杂药物的标记突出了该反应的高官能团耐受性，特别是含有卤素或硫原子和腈基团。多位点氢同位素掺入可以通过原位形成互补的催化活性物质来解释：单金属铱络合物和铱纳米颗粒。

  DOI：

  10.1002/ange.202008519
• 作为产物：
  描述：

  2-(1-phenylethyl)pyridine 在 potassium tert-butylate 、 二甲基亚砜 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 反应 11.0h， 生成 多西拉敏
  参考文献：
  名称：

  Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation–Deuteration of Heterobenzylic Methylenes

  摘要：

  We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.

  DOI：

  10.1021/acs.orglett.0c03108

文献信息

• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• Imidazole and benzimidazole derivatives useful as histamine H3 antagonists
  申请人：Aslanian G. Robert

  公开号：US20060166960A1

  公开（公告）日：2006-07-27

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: n is 2-5; R is R 3 -aryl, R 3 -heteroaryl, R 3 -cycloalkyl, R 3 -heterocycloalkyl, alkyl, haloalkyl, —OR 4 , —SR 4 or —S(O) 1-2 R 5 ; R 1 and R 2 are H or optionally substituted phenyl or optionally substituted and X is —O— or —S—; or R 1 and R 2 , together with the carbon atoms to which they are attached form optionally substituted and X is —O—, —S— or —NR 7 —; Z is and the remaining variables are as defined in the specification; also disclosed are pharmaceutical compositions comprising the compounds of formula I; also disclosed are methods of treating allergy, allergy-induced airway responses, congestion, obesity and metabolic syndrome using the compounds of Formula I, as well as combinations with other drugs useful for treating those diseases.

  揭示了以下公式化合物或其药学上可接受的盐或溶剂，其中：n为2-5；R为R3-芳基，R3-杂环芳基，R3-环烷基，R3-杂环烷基，烷基，卤代烷基，—OR4，—SR4或—S(O)1-2R5；R1和R2为H或可选择地取代的苯基或可选择地取代的，X为—O—或—S—；或R1和R2，连同它们连接的碳原子形成可选择地取代的，X为—O—，—S—或—NR7—；Z为，其余变量如规范中所定义；还揭示了包括公式I化合物的药物组合物；还揭示了使用公式I化合物治疗过敏、过敏引起的气道反应、充血、肥胖和代谢综合征的方法，以及与其他用于治疗这些疾病的药物的组合。
• [EN] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS<br/>[FR] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES UTILISES EN TANT QU'ANTAGONISTES DU RECEPTEUR H3 DE L'HISTAMINE
  申请人：SCHERING CORP

  公开号：WO2003103669A1

  公开（公告）日：2003-12-18

  Disclosed are histamine H3 antagonists of the formula (I) wherein R1 is benzimidazolone derivative, M1 and M2 are optionally substituted carbon or nitrogen, R2 includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula (I). Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula (I) in combination with a H1 receptor antagonist.

  揭示了公式（I）中的组胺H3拮抗剂，其中R1是苯并咪唑酮衍生物，M1和M2是可选择地取代的碳或氮，R2包括可选择地取代的芳基或杂环基，其余变量如规范中所定义。还揭示了包括公式（I）化合物的药物组合物。还揭示了使用公式（I）化合物治疗各种疾病或症状的方法，例如过敏、过敏引起的气道反应和充血（例如，鼻塞）的方法。还揭示了使用公式（I）化合物与H1受体拮抗剂结合治疗各种疾病或症状的方法，例如过敏、过敏引起的气道反应和充血（例如，鼻塞）。
• SUBSTITUTED INDOLES
  申请人：Gant Thomas G.

  公开号：US20090191183A1

  公开（公告）日：2009-07-30

  Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文揭示了Formula I的替代吲哚半胱氨酸白三烯受体调节剂，其制备方法，药物组合物以及使用方法。

表征谱图