异戊巴比妥 | 57-43-2

• 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: 异戊巴比妥
• 中文别名: 5-乙基-5-(3-甲基丁基)巴比妥酸；5-異戊-5-乙巴比妥酸；5-乙基-5-(3-甲基丁基)-2,4,6-(1H,3H,5H)-嘧啶三酮；阿米妥
• 英文名称: amobarbital
• 英文别名: amylobarbitone；5-ethyl-5-isopentyl-barbituric acid；5-ethyl-5-isopentylbarbiturate；5-ethyl-5-isopentylmalonylurea；amylobarbital；5-ethyl-5-(3-methylbutyl)-1,3-diazinane-2,4,6-trione
• CAS: 57-43-2
• 化学式: C₁₁H₁₈N₂O₃
• 分子量: 226.276
• InChiKey: VIROVYVQCGLCII-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：

  在低温干燥条件下保持稳定

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：
  0.73
• 拓扑面积：
  75.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

戊巴比妥通过肝脏代谢，通过3-甲基丁基基团的次末端氧化形成三级醇，羟基戊巴比妥，这是一种无活性的代谢物。口服催眠剂量的大约40-50%的戊巴比妥以羟基戊巴比妥及其葡萄糖醛酸苷形式从尿液中排出。不到1%的口服催眠剂量的药物未改变地从尿液中排出。粪便或尿液中排出的羟基戊巴比妥的苷结合物和/或尚未确定的进一步氧化产物可能占剩余剂量的部分。

Amobarbital is metabolized by the liver via penultimate oxidation of the 3-methylbutyl substituent to form a tertiary alcohol, hydroxyamobarbital, which is an inactive metabolite. About 40-50% of an oral hypnotic dose of amobarbital is excreted in urine as hydroxyamobarbital and its glucuronide conjugates. Less than 1% of an oral hypnotic dose of the drug is excreted in urine unchanged. Conjugates of hydroxyamobarbital excreted in feces or urine and/or further oxidation products not yet identified may account for the remainder of the dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给两个健康受试者静脉注射放射性标记的戊巴比妥后...发现少于50%的剂量被识别为3'-羟基戊巴比妥。第二种主要代谢物被识别为N-羟基戊巴比妥，并发现其占剂量的高达30%。

Following admin of radioactively labelled amylobarbitone to two healthy subjects ... less than 50% of the dose was identified as 3'-hydroxyamylobarbitone. A second main metabolite was identified as N-hydroxyamylobarbitone and was found to account for up to 30% of the dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

尿液中戊巴比妥代谢物相对比例的高度变异，而血浆半衰期的观察并未显示出这种变异性。通过研究分布后相的单个尿样，可以获得给定人的代谢物模式的可靠估计。在分布后相的尿样中测量了两种代谢物。这两种代谢物是3'-羟基戊巴比妥，作为侧链羟基化的产物，以及N-beta-d-吡喃葡萄糖基戊巴比妥，一种葡萄糖苷结合物。

Relative proportion of amobarbital metabolites in urine is highly variable and observations of plasma half-life give no indication of this variability. A valid estimate of a given person's metabolite pattern can be obtained by studying single urine specimen in postdistributive phase. Two metabolites were measured in urine specimen in the postdistributive phase. The 2 metabolites were 3'-hydroxyamobarbital as product of side chain hydroxylation and N-beta-d-glycopyranosyl amobarbital, a glucose conjugate.

来源:Hazardous Substances Data Bank (HSDB)

代谢

N-羟基丁巴比妥合成，并研究了其作为尿代谢物在13名服用200毫克戊巴比妥钠的受试者中的出现。结果表明，在戊巴比妥钠的代谢中，自由N-羟基丁巴比妥的排泄并不显著。/戊巴比妥钠/

N-Hydroxyamylobarbitone was synthesized and its occurrence as a urinary metabolite was studied in 13 subjects taking 200 mg sodium amobarbital. It was concluded that the excretion of free N-hydroxyamylobarbitone is not significant in the metabolism of amobarbital sodium. /Amobarbital sodium/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

戊巴比妥（像所有的巴比妥类药物一样）通过绑定到GABAA受体的alpha或beta亚单位来发挥作用。这些结合位点与GABA本身以及苯二氮卓类药物的结合位点是不同的。和苯二氮卓类药物一样，巴比妥类药物增强了GABA在这个受体上的效果。这种GABAA受体结合降低了输入电阻，抑制了爆发和持续性放电，特别是在腹侧基底和层内神经元中，同时增加了单个氯离子通道的爆发持续时间和平均电导；这增加了抑制性突触后电流的振幅和衰减时间。除了这种GABA能效应外，巴比妥类药物还阻断了AMPA受体，这是谷氨酸受体的一种亚型。谷氨酸是哺乳动物中枢神经系统的主要兴奋性神经递质。戊巴比妥似乎还能结合神经元的尼古丁型乙酰胆碱受体。

Amobarbital (like all barbiturates) works by binding to the GABAA receptor at either the alpha or the beta sub unit. These are binding sites that are distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. This GABAA receptor binding decreases input resistance, depresses burst and tonic firing, especially in ventrobasal and intralaminar neurons, while at the same time increasing burst duration and mean conductance at individual chloride channels; this increases both the amplitude and decay time of inhibitory postsynaptic currents. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Amobarbital also appears to bind neuronal nicotinic acetylcholine receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 相互作用

为了确定人类生长激素（生长激素）对人体代谢的影响，对6名生长激素缺乏的儿童每周三次给予单一口服剂量的戊巴比妥钠3-5毫克。戊巴比妥钠的半衰期从13.89小时增加到22.75小时，分布容积保持不变，清除率下降。结果表明，生长激素通过影响肝微粒体药物氧化系统，减慢戊巴比妥钠的代谢。/戊巴比妥钠/

To determine the effect of human growth hormone (somatropin) on human metabolism, 6 somatropin deficient children were given single oral doses of amobarbital sodium 3-5 mg 3 times/wk. The half-life of amobarbital sodium rose from 13.89 to 22.75 hr, vol of distribution was unchanged, and clearance fell. Results indicate that somatropin slows the metabolism of amobarbital sodium, probably through an effect on hepatic microsomal drug oxidizing system. /Amobarbital sodium/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用双硫仑和巴比妥类药物可能会导致巴比妥类药物的代谢受到抑制，增加巴比妥类药物中毒效应的发生率。/巴比妥类药物/

Concurrent administration of disulfiram with barbiturates may result in inhibition of metabolism of the barbiturates and an increased incidence of barbiturate toxic effects. /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与巴比妥类药物同时使用可能会导致代谢增加，由于诱导肝微粒体酶活性，这会导致卡马西平或琥珀酰亚胺抗惊厥药的血清浓度降低和消除半衰期缩短。建议监测血清浓度作为指导剂量的依据，特别是在向现有方案中添加或从中撤除卡马西平或琥珀酰亚胺抗惊厥药时。/巴比妥类药物/

Concurrent use with barbiturates may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of carbamazepine or succinimide anticonvulsants because of induction of hepatic microsomal enzyme activity. Monitoring of serum concentrations as a guide to dosage is recommended, especially when carbamazepine or a succinimide anticonvulsant is added to or withdrawn from an existing regimen. /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服或直肠给药后，作用的开始时间从10-30分钟不等，对于戊巴比妥来说...。静脉注射戊巴比妥钠盐后，作用的开始时间几乎立即显现，对于戊巴比妥来说...。

Following oral or rectal admin, the onset of action varies from 10-30 min for ... amobarbital ... Following iv admin of the sodium salts of ... amobarbital, the onset of action ranges from almost immediately for pentobarbital ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大约40%到60%的阿米洛巴比妥与血浆蛋白结合。

About 40 to 60% of amylobarbitone is bound to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予两名健康受试者放射性标记的戊巴比妥后，6天内尿液中有79%至92%被回收，而粪便中仅有4%至5%。未改变的药物在尿液和粪便中几乎不存在。

Following admin of radioactively labelled amylobarbitone to 2 healthy subjects 79 to 92% was recovered in urine in 6 days and only 4 to 5% in the feces. Unchanged drug was practically absent from both urine and feces.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从30个尸检对象收集的液体和组织样本中检测了戊巴比妥（戊巴比妥）、异戊巴比妥（丁巴比妥）、戊巴比妥（戊巴比妥）、葵巴比妥（司可巴比妥）及其相应的羟基代谢物。当摄入一种巴比妥类药物时，观察到药物在液体和组织中的分布与其脂溶性呈反比关系。在大多数情况下，肝脏含有最高的巴比妥浓度，其余情况则是脾脏。胆汁中的浓度通常超过相应肝脏中的浓度。四种镇静巴比妥的代谢物在大多数受试者的液体和组织中的含量通常低于母药，但尿液中常常含有更高的代谢物浓度，有时甚至超过肝脏中母药的浓度。同时使用两种或多种巴比妥类药物似乎并不影响个别药物的分布和代谢。

Fluid & tissue specimens collected from 30 subjects at autopsy were assayed for amylobarbitone (amobarbital), butobarbitone (butethal), pentobarbitone (pentobarbital), quinalbarbitone (secobarbital) and the corresponding hydroxylated metabolites by GLC. Where one barbiturate was ingested, an inverse relationship between lipid solubility of the drug and the distribution in fluids and tissues was observed. In most cases the liver, and in the remainder the spleen, contained the highest concn of barbiturate. Bile concn were often in excess of those in the corresponding liver. The metabolites of the 4 sedative barbiturates were usually present in lower amounts than the parent drugs in the fluids and tissues of most subjects, but urine often contained much higher concn of metabolites, sometimes exceeding that of the parent drug in the liver. Admin of 2 or more barbiturates together did not appear to affect the distribution and metabolism of the individual drugs.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

根据文档内容，以下是关于药物的用途和制备过程的关键信息：

用途：

1. 中效催眠药：主要用于治疗短暂或中度失眠。
2. 镇静作用：帮助患者放松，减轻焦虑感。
3. 催眠作用：能迅速诱导睡眠状态。
4. 抗惊厥作用：有助于控制轻度到中度的癫痫发作。

用药注意事项：

• 由于药物在肝脏内被代谢，因此其药效短暂。
• 长期使用可能会导致耐受性和依赖性。
• 肝肾功能严重受损者应避免使用或在医生指导下减量使用。

制备过程简述：

1. 制备 α-乙基 -α-异戊基丙二酸二乙酯：首先合成该中间体，具体步骤未详述但包含酯化反应。
2. 环合反应：
   • 将上述中间体与尿素在 75-80℃条件下进行加热回流 0.5小时。
   • 随后回收乙醇并使用活性炭脱色处理。
   • 盐酸酸化后过滤得到最终产品。

总结：

该药物主要用于短期或中度失眠症的治疗，并具有一定的镇静和抗惊厥作用。由于其快速起效但药效短暂的特点，需谨慎使用，特别是对于肝肾功能不全患者以及长期使用者需要密切关注可能产生的耐受性及依赖性问题。

请注意，上述信息是基于提供的文本内容进行总结概括，在实际应用中应参考完整的药物说明书或专业医学文献以获取最准确的信息。

反应信息

• 作为反应物：
  描述：

  异戊巴比妥 在 氨 作用下， 生成 2-乙基-5-甲基己酰胺
  参考文献：
  名称：

  Hydrolysis of 5,5-Disubstituted Barbituric Acids

  摘要：

  DOI：

  10.1021/jo01060a048
• 作为产物：
  描述：

  5-乙基-2,3-二氢-5-(3-甲基丁基)-2-硫代-4,6(1H,5H)-嘧啶二酮 在 chromium(VI) oxide 、 溶剂黄146 作用下， 以63%的产率得到异戊巴比妥
  参考文献：
  名称：

  Competition between two metabolic pathways: oxidation and desulfuration in the thiobarbiturate series

  摘要：

  In order to study the competition between hepatic hydroxylation and desulfuration in the thiobarbiturate series, two compounds bearing a branched side chain with a tertiary carbon atom in position omega-1 were administered to rats over about one week, Urine and faeces were collected and extracted. The metabolites isolated were identified. It was shown that desulfuration was not the major metabolic pathway, and that, when it took place, it remained a minor process and was accompanied by gamma-hydroxylation into a tertiary alcohol.

  DOI：

  10.1016/0223-5234(96)88296-1

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] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。

表征谱图