戊巴比妥 | 76-74-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 戊巴比妥
• 中文别名: 5-乙基-5-(1-甲基丁基)巴比妥酸；5-乙基-5-(1-甲基丁基)-2,4,6-(1H,3H,5H)-嘧啶三酮
• 英文名称: pentobarbital
• 英文别名: 5-ethyl-5-(1-methylbutyl)barbituric acid；5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione
• CAS: 76-74-4
• 化学式: C₁₁H₁₈N₂O₃
• 分子量: 226.276
• InChiKey: WEXRUCMBJFQVBZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.727
• 拓扑面积：
  75.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

由肝微粒体酶系统

by hepatic microsomal enzyme system

来源:DrugBank

代谢

戊巴比妥主要通过肝脏代谢，主要是通过1-甲基丁基侧链的倒数第二个碳原子的氧化，形成二级醇，即5-乙基-5-(3'-羟基-1'-甲基丁基)巴比妥酸（羟基戊巴比妥），这是一种无活性的代谢物。大约40-50%的口服催眠剂量戊巴比妥以羟基戊巴比妥的形式通过尿液排出。戊巴比妥的1-甲基丁基侧链也可以被氧化形成戊巴比妥羧酸，尿液中已经发现了这种代谢物的小量存在。

Pentobarbital is metabolized by the liver chiefly by penultimate oxidation of the 1-methylbutyl substituent to a secondary alcohol, 5-ethyl-5-(3'-hydroxy-1'-methylbutyl) barbituric acid (hydroxypentobarbital) which is an inactive metabolite. Approximately 40-50% of an oral hypnotic dose of pentobarbital is excreted in urine as hydroxypentobarbital. The 1-methylbutyl substituent of pentobarbital can also be oxidized to form pentobarbital carboxylic acid, and small quantities of this metabolite have been found in urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏对大多数短效巴比妥类药物（90%-99%）进行生物转化。短效化合物（例如戊巴比妥和司可巴比妥）被氧化成更具极性和不活性的化合物（如醇、酮、酚或羧酸）。/巴比妥类药物/

The liver biotransforms most ... short acting barbiturates (90%-99%). Short-acting compounds /eg, pentobarbital & secobarbital/ are oxidized to more polar & inactive compounds (alcohols, ketones, phenol, or carboxylic acid). /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

代谢

戊巴比妥在丁基侧链中含有一个不对称的碳原子。主要的代谢途径是通过（ω-1）-氧化生成5-乙基-5-(3'-羟基-1'-甲基丁基)巴比妥酸。这个过程创造了一个新的手性中心，从而产生4种可能的非对映异构体代谢物。

Pentobarbital contains an asymmetric carbon atom in butyl side chain. Main route of metabolism is (omega-1)-oxidation to yield 5-ethyl-5-(3'-hydroxy-1'-methylbutyl)barbituric acid. This process creates a new center of asymmetry, thus giving rise to 4 possible diastereoisomeric metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

由肝脏代谢，通过1-甲基丁基取代物的氧化转化为5-乙基-5-(3-羟基-1-甲基丁基)巴比妥酸（羟基戊巴比妥）和戊巴比妥羧酸。尿液中还发现了醇的葡萄糖苷酸结合物和进一步未识别的氧化产物。

Metabolized by liver by ... oxidation of 1-methylbutyl substituent to ... 5-ethyl-5-(3-hydroxy-1-methylbutyl)barbituric acid (hydroxypentobarbital) /and/ pentobarbital carboxylic acid ... Glucuronide conjugates of alcohols /and further unidentified oxidation products also found in urine of /humans/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

戊巴比妥与GABAA受体上与Cl-离子通道相关的一个独特结合位点结合，增加了Cl-离子通道开放的时间长度。因此，GABA在丘脑中的突触后抑制效应被延长。所有这些效应都与GABA敏感神经元钙离子电导（gCa）的显著降低有关。巴比妥类药物作用的净结果是急性增强抑制性GABA能神经递质的活性。巴比妥类药物还通过强烈（尽管不太明确）且直接抑制兴奋性AMPA型谷氨酸受体发挥作用，导致谷氨酸能神经传递的深刻抑制。

Pentobarbital binds at a distinct binding site associated with a Cl- ionopore at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. All of these effects are associated with marked decreases in GABA-sensitive neuronal calcium conductance (gCa). The net result of barbiturate action is acute potentiation of inhibitory GABAergic tone. Barbiturates also act through potent (if less well characterized) and direct inhibition of excitatory AMPA-type glutamate receptors, resulting in a profound suppression of glutamatergic neurotransmission.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

戊巴比妥

Compound:pentobarbital

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

巴比妥类药物在口服、直肠或非肠道给药后以不同程度被吸收。

Barbiturates are absorbed in varying degrees following oral, rectal, or parenteral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

巴比妥类药物主要通过肝脏的微粒体酶系统进行代谢，代谢产物通过尿液排出，较少情况下通过粪便排出。大约25%到50%的阿普巴比妥或苯巴比妥剂量以原形在尿液中排出，而其他巴比妥类药物以原形在尿液中排出的量可以忽略不计。

Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine, and less commonly, in the feces. Approximately 25 to 50 percent of a dose of aprobarbital or phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible.

来源:DrugBank

吸收、分配和排泄

几乎所有的戊巴比妥口服或直肠给药剂量都会从胃肠道被吸收。口服戊巴比妥后，血浆中的峰值浓度通常在30-60分钟内达到。

Nearly all of an oral or rectal dose of pentobarbital is absorbed from the GI tract. Following oral administration of pentobarbital, peak plasma concentrations are usually reached in 30-60 minutes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当通过口服或直肠给药时，戊巴比妥的起效时间在15-60分钟内。静脉注射后1分钟内起效，肌肉注射后10-25分钟内起效。与司可巴比妥一样，戊巴比妥口服或直肠给药后的催眠作用持续时间大约为1-4小时，静脉注射后大约15分钟。

When pentobarbital is administered orally or rectally, the onset of action occurs within 15-60 minutes. The onset of action is within 1 minute following iv administration and within 10-25 minutes following im administration. Like secobarbital, pentobarbital probably has a duration of hypnotic effect of 1-4 hours following oral or rectal administration and about 15 minutes following iv administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血浆中戊巴比妥的浓度在1-5微克/毫升通常会产生镇静效果，而5-15微克/毫升的浓度会在大多数患者中产生睡眠；然而，超过10微克/毫升的血浆浓度可能会产生深度昏迷，而超过30微克/毫升的浓度则可能致命。

Plasma pentobarbital concentrations of 1-5 ug/mL generally produce sedation, and plasma concentrations of 5-15 ug/mL produce sleep in most patients; however, plasma concentrations of greater than 10 ug/mL may produce deep coma, and those in excess of 30 mcg/mL are potentially lethal.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  戊巴比妥 在 sodium methylate 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 1.5h， 以97.96%的产率得到nembutal
  参考文献：
  名称：

  5-乙基-5-(1-甲基丁基)巴比妥酸钠的制备方 法

  摘要：

  本发明属于药物制备领域，具体涉及一种制备用于镇静、催眠、麻醉前给药及抗惊厥药物5‑乙基‑5‑(1‑甲基丁基)巴比妥酸钠的制备方法,采用5‑乙基‑5‑(1‑甲基丁基)丙二酰脲化合物为原料,该工艺包括两个步骤：A、5‑乙基‑5‑(1‑甲基丁基)丙二酰脲在丙酮溶液中与甲醇钠的甲醇溶液作用制得5‑乙基‑5‑(1‑甲基丁基)巴比妥酸钠的湿品；B、将上述得到的5‑乙基‑5‑(1‑甲基丁基)巴比妥酸钠的湿品经真空干燥得5‑乙基‑5‑(1‑甲基丁基)巴比妥酸钠的成品。该工艺稳定，操作简单、生产周期短，产品质量好，纯度高，收率高，生产成本低，能耗低，母液回收循环利用，三废少，适合工业化生产。

  公开号：

  CN106986834B
• 作为产物：
  描述：

  2-ethyl-2-cyano-3-methyl-hex-3-enoic acid ethyl ester 在 palladium on activated charcoal 、 乙醇 、 sodium isopropylate 、 尿素 作用下， 生成 戊巴比妥
  参考文献：
  名称：

  Cope; Hancock, Journal of the American Chemical Society, 1939, vol. 61, p. 776,779

  摘要：

  DOI：

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] ALPHA-KETOAMIDE DERIVATIVE, AND PRODUCTION METHOD AND USE THEREOF<br/>[FR] DERIVE D'ALPHA-CETOAMIDE, SON PROCEDE DE PRODUCTION ET D'UTILISATION
  申请人：SENJU PHARMA CO

  公开号：WO2005056519A1

  公开（公告）日：2005-06-23

  The present invention provides a compound represented by the formula (I): (INSERT CHEMICAL FORMULA) (wherein R1 is a lower alkyl substituted by a lower alkoxy or a heterocyclic group, or a heterocyclic group; R2 is a lower alkyl optionally substituted by a phenyl; and R3 is a lower alkyl optionally substituted by a halogen, a lower alkoxy or a phenyl, or a fused polycyclic hydrocarbon group), which is well absorbed orally, exhibits durability of good blood level and has potent calpain inhibitory activity.

  本发明提供了一种化合物，其化学式表示为（I）：（插入化学式）（其中R1是由低烷基取代的低烷氧基或杂环基，或者是杂环基；R2是可选择地由苯基取代的低烷基；R3是可选择地由卤素、低烷氧基或苯基取代的低烷基，或者是融合的多环碳氢基），该化合物在口服后被很好地吸收，表现出良好的血液水平持久性，并具有强大的钙蛋白酶抑制活性。
• Dual Pharmacophores - PDE4-Muscarinic Antagonistics
  申请人：Callahan James Francis

  公开号：US20090203657A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.

  本发明涉及具有式（I）的新化合物及其药用盐，药物组合物及其用作对PDE4和肌胆碱受体（mAChRs）具有抑制活性的双色素，因此可用于治疗呼吸道疾病。
• [EN] DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS<br/>[FR] PHARMACOPHORES DUALS, ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES ET INHIBITEURS DE L'ACTIVITÉ PDE4
  申请人：GLAXO GROUP LTD

  公开号：WO2009100169A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.

  本发明涉及式(I) - (VI)的新化合物，以及其药学上可接受的盐、药物组合物及其在治疗中的应用，例如作为磷酸二酯酶IV (PDE4)的抑制剂和肌碱乙酰胆碱受体 (mAChRs)的拮抗剂，用于治疗和/或预防呼吸道疾病，包括炎症性和/或过敏性疾病，如慢性阻塞性肺病（COPD）、哮喘、鼻炎（例如过敏性鼻炎）、特应性皮炎或银屑病。

表征谱图