7-氯-1-乙基-6-氟-1,4-二氢-4-羰基喹啉-3-羧酸 | 77-26-9

• 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: 7-氯-1-乙基-6-氟-1,4-二氢-4-羰基喹啉-3-羧酸
• 中文别名: 异丁烯丙巴比妥；丙烯异丁比妥；烯丙基巴比妥酸；异丁巴比妥；烯丙基丙二酰脲；5-异丁基-5-烯丙基巴比妥酸；布他比妥；布它比托；5-异丁基-5-烯丙基巴比妥酸；烯丙基巴比妥
• 英文名称: 5-allyl-5-isobutyl-pyrimidine-2,4,6-trione
• 英文别名: 5-(2-methylpropyl)-5-(2-propenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione；butalbital；Itobarbital；5-(2-methylpropyl)-5-prop-2-enyl-1,3-diazinane-2,4,6-trione
• CAS: 77-26-9
• 化学式: C₁₁H₁₆N₂O₃
• 分子量: 224.26
• InChiKey: UZVHFVZFNXBMQJ-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  1. 在常温常压下保持稳定。 2. 要避免与氧化物接触。 3. 口服有毒，大量使用时应穿戴适当的防护装备。

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  75.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

布他比妥预计将经历近乎完全的肝脏代谢。它主要经历C5氧化，形成5-异丁基-5-(2,3-二羟基丙基)巴比妥酸，这是主要的代谢物。布他比妥还可能经历ω-羟基化，形成5-烯丙基-5-(3-羟基-2-甲基-1-丙基)巴比妥酸。

Butalbital is expected to undergo nearly complete hepatic metabolism. It primarily undergoes C5 oxidation to form 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid, which is the major metabolite. Butalbital may also undergo omega-hydroxylation to form 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid.

来源:DrugBank

代谢

尿液排泄产物包括母药（约占总剂量的3.6%）、5-异丁基-5-(2,3-二羟基丙基)巴比妥酸（约占总剂量的24%）、5-烯丙基-5-(3-羟基-2-甲基-1-丙基)巴比妥酸（约占总剂量的4.8%）、巴比妥酸环水解产生尿素排出的产物（约占总剂量的14%）以及未识别的物质。在尿液排出的物质中，有32%是结合物。

Urinary excretion products include parent drug (about 3.6% of the dose), 5-isobutyl-5-(2, 3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated.

来源:Hazardous Substances Data Bank (HSDB)

代谢

丁巴比妥（5-烯丙基-5-异丁基巴比妥酸），在2位标记有14C，被给予狗。剂量的92%的放射性在尿液中排出。药物及其三个主要尿液代谢物在狗的尿液中得到鉴定。主要代谢物是5-异丁基-5-(2,3-二羟基丙基)巴比妥酸，占剂量的50.2%。较少量的未改变药物（占剂量的2.6%）和尿素（占剂量的8.6%）也存在。通过ω-羟基化形成的5-烯丙基-5-(3-羟基-2-甲基-1-丙基)巴比妥酸，占剂量的10.1%；1,3-二乙基衍生物的旋光度为[alpha]D20 = +10.5。五个次要的和未识别的代谢物占额外10.7%的剂量。总共有82.2%的剂量得到了解释。

Butalbital, 5-allyl-5-isobutylbarbituric acid, labeled in the 2-position with 14C, was administered to dogs. Ninety-two percent of the radioactivity of the dose was excreted in the urine. The drug and three major urinary metabolites were identified in the urinary excretion of the dog. The major metabolite was 5-isobutyl-5-(2,3-dihydroxypropyl)barbituric acid, which accounted for 50.2% of the dose. Smaller amounts of the unchanged drug (2.6% of the dose) and urea (8.6% of the dose) were present. 5-Allyl-5-(3-hydroxy-2-methyl-1-propyl)barbituric acid, formed by omega-hydroxylation, accounted for 10.1% of the dose; the optical rotation of the 1,3-diethyl derivative was [alpha]D20 = +10.5. Five minor and unidentified metabolities accounted for an additional 10.7% of the dose. A total of 82.2% of the dose was accounted for.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：布他比妥在母乳中出现曾导致一名婴儿出现喂养困难和呕吐。在哺乳新生儿或早产儿时，应优先选择其他药物。如果使用布他比妥，需监测婴儿是否出现镇静、喂养困难和体重增长不良。 ◉ 对哺乳婴儿的影响：一名新生儿母亲为了治疗脊髓头痛，每6小时服用一次含有对乙酰氨基酚325毫克、布他比妥50毫克和咖啡因40毫克的产品，持续24小时，最后一次服药是在去急诊室的前一天。她7天大的婴儿有1到2天的喂养困难、倦怠和呕吐的历史。婴儿表现出嗜睡、倦怠和反射减弱。尿液定性检测布他比妥呈阳性，且入院15小时后尿液中咖啡因浓度为1毫克/升。婴儿的症状在24小时内得到缓解。这些症状很可能是由于布他比妥引起的。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Butalbital in breastmilk has caused poor feeding and vomiting in one infant. Other agents are preferred, especially while nursing a newborn or preterm infant. If butalbital is used, monitor the infant for sedation, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants:The mother of a newborn took a product containing acetaminophen 325 mg, butalbital 50 mg, and caffeine 40 mg every 6 hours for 24 hours for a spinal headache, with the last dose a day prior to presentation at the emergency department. Her 7-day-old infant had a history of 1 to 2 days of poor feeding, lethargy and vomiting. The infant was somnolent, lethargic, and demonstrating diminished reflexes. The urine was qualitatively positive for barbiturate and had also had 1 mg/L of caffeine 15 hours after hospital admission. The infant's symptoms resolved within 24 hours. The symptoms were probably caused by butalbital. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

巴比妥类药物的中枢神经系统（CNS）作用可能被单胺氧化酶（MAO）抑制剂增强。

The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一位44岁的女性因抑郁症加重被送往精神科病房。她的抗抑郁药——丙米嗪的血药浓度在正常范围内，与过去的浓度一致。她的病史中值得注意的是她患有慢性头痛，为此她在入院时被开了一种含有布他比妥的处方药。患者的抑郁症很快得到了控制，但两周后又复发了。丙米嗪的浓度下降了大约50%。丙米嗪在肝脏中通过细胞色素P-450（CYP 1A2）系统代谢，而巴比妥类药物已知是这种酶亚型的诱导剂。

A 44-year-old woman was admitted to the psychiatric unit for exacerbation of her depressive disorder. Blood concentrations of her antidepressant, imipramine, were within normal range and consistent with past concentrations. Her medical history was significant for a chronic headache disorder for which she was given a prescription containing butalbital on admission. The patient's depressive disorder was quickly controlled but relapsed 2 weeks later. Concentrations of imipramine showed a decrease of approximately 50%. Imipramine is metabolized in the liver by the cytochrome P-450 (CYP 1A2) system, and barbiturates are known inducers of this enzyme subset.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支援措施。如有必要，保护气道并辅助通气。如果出现昏迷、体温过低和低血压，则进行治疗。/巴比妥类药物/

Emergency and supportive measures. Protect the airway and assist ventilation if necessary. Treat coma, hypothermia, and hypotension if they occur. /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

解毒。如果条件适当，口服活性炭。在小到中等摄入量后，如果能及时给予活性炭，则不需要洗胃。/巴比妥类药物/

Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

丁丙诺啡（Butalbital）能够被胃肠道快速且容易地吸收。达到血浆峰浓度的时间大约为2小时。丁丙诺啡的典型血药浓度峰值在2.1毫克/升，并在24小时后下降到1.5毫克/升。血浆浓度在10到20微克/毫升时与毒性相关；而浓度在25到30微克/毫升时曾出现昏迷和死亡的情况。

Butalbital gets readily and rapidly absorbed from the gastrointestinal tract. The time to reach the peak plasma concentrations is reported to be approximately 2 hours. Typical blood concentrations of butalbital peaked at 2.1 mg/L and declined to 1.5 mg/L at 24 hr. Plasma concentrations of 10 to 20 μg/mL have been associated with toxicity; coma and fatalities have occurred with concentrations of 25 to 30 μg/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

布他比妥主要通过肾脏消除，给药总量的59%至88%以未改变的母药或代谢物的形式从肾脏排出。尿液排泄产物包括母药（约占总剂量的3.6%）、5-异丁基-5-(2,3-二羟基丙基)巴比妥酸（约占总剂量的24%）、5-烯丙基-5-(3-羟基-2-甲基-1-丙基)巴比妥酸（约占总剂量的4.8%）、巴比妥酸环水解并排泄尿素的产品（约占总剂量的14%），以及未识别的物质。在尿液中排出的物质中，有32%是结合物。24小时内消除不完全，且药物在频繁给药时会累积。

Butalbital predominantly undergoes renal elimination with 59 to 88% of the total dose administered being excreted from the kidneys as unchanged parent drug or metabolites. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8%), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated. Elimination is not complete within 24 hours, and the drug accumulates with frequent administration.

来源:DrugBank

吸收、分配和排泄

• 分布容积

布他比妥的分布容积据报道大约为0.8升/千克。布他比妥预计会分布到身体的大多数组织中，包括乳腺和胎盘。血浆与血液的浓度比值几乎为1，这表明布他比妥在血浆和血细胞之间没有优先分布。

The volume of distribution of butalbital is reported to be approximately 0.8 L/kg. Butalbital is expected to distribute to most of the tissues in the body, including the mamillary glands and placenta. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells.

来源:DrugBank

吸收、分配和排泄

• 清除

关于布他比妥的清除数据有限。

There is limited data on the clearance of butalbital.

来源:DrugBank

吸收、分配和排泄

巴特拉比妥从胃肠道吸收良好，预计会分布到体内大多数组织中。一般来说，巴比妥类药物可能会出现在母乳中，并且容易穿过胎盘屏障。它们与血浆和组织蛋白的结合程度各不相同，且结合程度随着脂溶性的增加而直接增加。

Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法

1. 通过有机合成制备。
2. 用作镇静剂。

用途简介 用途

1. 用于有机合成。
2. 作为镇静剂使用。

反应信息

• 作为反应物：
  描述：

  7-氯-1-乙基-6-氟-1,4-二氢-4-羰基喹啉-3-羧酸 在 potassium permanganate 、 magnesium chloride 作用下， 以 丙酮 为溶剂， 反应 3.0h， 以47%的产率得到2-[5-(2-Methylpropyl)-2,4,6-trioxo-1,3-diazinan-5-yl]acetic acid
  参考文献：
  名称：

  大鼠中伯碳原子和叔碳原子的β-羟基化之间的竞争。

  摘要：

  为了研究空间位阻对两种β-羟基化之间竞争的影响，在嘧啶三酮核上带有一个化合物，该化合物同时具有在β位（异丁基）上带有叔碳原子的支链侧链和一个线性侧链（乙基）组），并选择对大鼠给药。收集并提取尿液和粪便。分离并鉴定了羟基代谢物及其衍生物。直链的β-羟基化比支链的β-羟基化更重要。立体位阻在该区域选择性中起决定性作用。

  DOI：

  10.1016/s0223-5234(00)00110-0
• 作为产物：
  描述：

  烯丙基异丁基丙二酸二乙酯 在 sodium ethanolate 、 尿素 作用下， 生成 7-氯-1-乙基-6-氟-1,4-二氢-4-羰基喹啉-3-羧酸
  参考文献：
  名称：

  CH135161

  摘要：

  公开号：

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