司可巴比妥 | 76-73-3

• 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: 司可巴比妥
• 中文别名: 5-(1-甲基丁基)-5-(2-丙烯基)-2,4,6(1H,3H,5H)-吡啶三酮
• 英文名称: 5-Allyl-5-(1-methyl-butyl)-barbitursaeure; Secobarbital
• 英文别名: secobarbital；5-pentan-2-yl-5-prop-2-enyl-1,3-diazinane-2,4,6-trione
• CAS: 76-73-3
• 化学式: C₁₂H₁₈N₂O₃
• 分子量: 238.287
• InChiKey: KQPKPCNLIDLUMF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  75.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

Secobarbital通过肝脏代谢，通过1-甲基丁基取代物的倒数第二个氧化反应，形成5-烯丙基-5-(3'-羟基-1'-甲基丁基)巴比妥酸（羟基司可巴比妥），这是主要代谢物。烯丙基取代物的氧化也可能发生，形成5-[2',3'-二羟基丙基-5-(1'-甲基丁基)]巴比妥酸（司可二醇）。这些无活性代谢物以不变形式或作为葡萄糖醛酸苷结合物从尿液中排出。羟基司可巴比妥还可能进一步氧化为酮或羧酸。C 5位的烯丙基取代物可以被移除，尿液中已经发现了少量由此产生的5-(1'-甲基丁基)巴比妥酸代谢物。

Secobarbital is metabolized by the liver via penultimate oxidation of the 1-methylbutyl substituent to form 5-allyl-5(3'-hydroxy-1'-methylbutyl)barbituric acid (hydroxysecobarbital), the major metabolite. Oxidation of the allyl substituent may also occur to form 5-[2',3'-dihydroxypropyl-5-(1'-methylbutyl)]barbituric acid (secodiol). These inactive metabolites are excreted in urine unchanged or as glucuronide conjugates. Hydroxysecobarbital may also be further oxidized to a ketone or a carboxylic acid. The allyl substituent at C 5 may be removed, and small quantities of the resulting 5-(1'-methylbutyl)barbituric acid metabolite have been found in urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠和豚鼠腹腔注射司可巴比妥后，观察到尿液图谱存在差异。大鼠在侧链上羟基化了司可巴比妥，仅产生了少量二醇，这是烯丙基侧链环氧化和水解的产物。这些代谢物在豚鼠体内几乎以相等的量被排出。在大鼠中，这些代谢物的比例在20-100 mg/kg-l的剂量范围内与剂量无关。在豚鼠中，超过50 mg/kg-l的剂量是致命的。

Differences were observed in urine profiles from the rat and guinea pig following ip admin of secobarbital. ... The rat hydroxylated secobarbital on the side-chain and produced only a small amount of the diol, a product of epoxidation and hydrolysis of the allyl side-chain. These metabolites were excreted in almost equal quantities by the guinea pig. The ratio of metabolites was independent of the dose in the range 20-100 mg/kg-l in the rat. Doses over 50 mg/kg-l were lethal in the guinea pig.

来源:Hazardous Substances Data Bank (HSDB)

代谢

allyl侧链和sec-amyl侧链都经过代谢，主要生成seconal二醇和2种对映异构体羟基seconal，在人和狗中；兔中生成羟基seconal和seconal羧酸。

Both the allyl and sec-amyl side-chains undergo metabolism to give mainly seconal diol and 2 diastereoisomers of hydroxyseconal, in man and dog; and hydroxyseconal and seconal carboxylic acid in rabbit.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在狗和人类中，司可巴比妥……被代谢成5-(2,3-二羟基丙基)-5-(1-甲基丁基)巴比妥酸和(±)-5-烯丙基-5-(3-羟基-1-甲基丁基)巴比妥酸……在一些人类的尿液中发现了5-(1-甲基丁基)巴比妥酸，以及在一名自杀者的肝脏提取物中……

In dogs and in man, secobarbital ... is metabolized into 5-(2,3-dihydroxypropyl)-5-(1-methylbutyl)barbituric acid and (+-)5-allyl-5-(3-hydroxy-1-methylbutyl)barbituric acid ... 5-(1-methylbutyl)barbituric acid was found in urine of some human subjects and ... in extracts from the liver of a suicide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

消除途径：巴比妥类药物主要通过肝脏微粒体酶系统代谢，代谢产物通过尿液排出，较少情况下通过粪便排出。

Route of Elimination: 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.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Secobarbital与GABA_A受体的一个与Cl^-离子通道相关联的特定结合位点结合，增加了Cl^-离子通道开启的时间长度。因此，GABA在丘脑中的突触后抑制效应被延长。

Secobarbital binds at a distinct binding site associated with a Cl^- ionopore at the GABA_A 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.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

药物名：异戊巴比妥

Compound:secobarbital

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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

严重程度等级：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

• 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。

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.

来源:DrugBank

吸收、分配和排泄

大约90%的司可巴比妥口服剂量在摄入后2小时内从胃肠道被吸收，血药浓度在2-4小时内达到峰值。几乎所有的药物在直肠给药后都被吸收。

Approximately 90% of an oral dose of secobarbital is absorbed from the GI tract within 2 hours after ingestion, and peak plasma concentrations are reached within 2-4 hours. Virtually all of the drug is absorbed following rectal administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血液中司可巴比妥的浓度在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导致昏迷。超过30微克/毫升的血浆浓度可能具有致命性。

Plasma secobarbital 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 coma. Plasma concentrations in excess of 30 ug/mL are potentially lethal.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当给予催眠剂量的司可巴比妥口服时，通常在15分钟内开始发挥作用。口服或直肠给药后15-30分钟达到完全催眠效果，肌肉注射后7-10分钟，静脉注射后1-3分钟。催眠效果持续时间为口服或直肠给药后1-4小时，静脉注射100-150毫克剂量后约15分钟。

When hypnotic doses of secobarbital are administered orally, the onset of action usually occurs within 15 minutes. Full hypnotic effect of the drug usually occurs 15-30 minutes following oral or rectal administration, 7-10 minutes following im administration, and 1-3 minutes following iv administration. (Rectal and parenteral preparations of the drug are no longer commercially available in the US.) The duration of the hypnotic effect is 1-4 hours following oral or rectal administration of an average dose of secobarbital and about 15 minutes following iv administration of a 100- to 150-mg dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大约30-45%的药物与血浆蛋白结合。

Approximately 30-45% of the drug is bound to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  司可巴比妥 在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 17.0h， 以0.09 g的产率得到戊烯
  参考文献：
  名称：

  Barton; Bojarski, Pharmazie, 1983, vol. 38, # 9, p. 630 - 631

  摘要：

  DOI：
• 作为产物：
  描述：

  苯巴比妥 生成 司可巴比妥
  参考文献：
  名称：

  PATEL, R. M.;JAGODZINSKI, J. J.;BENSON, J. R.;HOMETCHKO, D., LC AND GC, 8,(1990) N1, C. 874, 876-878

  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] 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