格鲁米特 | 77-21-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 格鲁米特
• 中文别名: 3-乙基-3-苯基-2,6-哌啶二酮；导眠能
• 英文名称: Glutethimide
• 英文别名: 3-ethyl-3-phenylglutarimide；3-ethyl-3-phenyl-2,6-piperidinedione；3-ethyl-3-phenylpiperidine-2,6-dione；3-phenyl-3-ethylpiperidine-2,6-dione；(rac)-Glutethimid
• CAS: 77-21-4
• 化学式: C₁₃H₁₅NO₂
• 分子量: 217.268
• InChiKey: JMBQKKAJIKAWKF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

肝脏的。格鲁塞米特几乎完全被代谢。

Hepatic. Glutethimide is almost completely metabolized.

来源:DrugBank

代谢

肝脏生物转化。格鲁塞米特几乎完全被代谢。

Hepatic biotransformation. Glutethimide is almost completely metabolized.

来源:Hazardous Substances Data Bank (HSDB)

代谢

格鲁特西咪唑的代谢命运尚未完全阐明，特别是在服用过量药物之后。有相当多的证据表明，治疗剂量的格鲁特西咪唑几乎完全在肝脏通过乙基侧链（左旋异构体）的羟基化代谢，并主要以葡萄糖苷酸形式通过尿液排出。大约2%的剂量被代谢成具有一些催眠活性的戊酸酰胺。... 4-羟基-2-乙基-2-苯基戊酰亚胺是在服用大剂量格鲁特西咪唑的患者血浆和组织（包括大脑）中积累的一种代谢物。在急性格鲁特西咪唑过量服用后，尿液中发现了几种酚类代谢物以及其他尚未确定的代谢物。

The metabolic fate of glutehimide has not been completely elucidated, particularly following toxic doses of the drug. There is considerable evidence that therapeutic doses of glutethimide are almost completely metabolized in the liver by hydroxylation of the ethyl side chain (levorotatory isomer) and excreted in urine chiefly as glucuronides. About 2% of a dose is metabolized to glutaconimide which has some hypnotic activity. ... 4-Hydroxy-2-ethyl-2 phenylglutarimide is a metabolite which accumulates in the plasma and tissues (including the brain) of patients who have ingested large doses of glutethimide. Several phenolic metabolites and others yet to be identified have been found in urine following acute glutethimide overdosage.

来源:Hazardous Substances Data Bank (HSDB)

代谢

尽管格鲁塞米特血药浓度大于10微克/毫升通常与中毒有关，但格鲁塞米特血浆浓度与患者临床过程之间的相关性较差，可能是由于活性代谢物4-羟基-2-乙基-2-苯基戊二酰亚胺的形成和积累。

Although glutethimide blood concentrations greater than 10 ug/mL are generally associated with intoxication, there is a poor correlation between glutethimide plasma concentration and the clinical course of the patient, possibly because of the formation and accumulation of an active metabolite, 4-hyroxy-2-ethyl-2-phenylglutarimide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

格鲁泰米德（Glutethimide）含有一个不对称的碳原子，并且会产生两种光学异构体，这两种异构体的代谢方式各不相同。D-异构体在戊二酰亚胺环处被水解，失去水分，并分解成α-苯基-α-乙基戊二酸亚胺，以非结合代谢物的形式在尿液中的排出量大约占给药剂量的2%。大部分水解的D-异构体与葡萄糖醛酸结合，并以结合代谢物的形式在尿液中的排出量大约占给药剂量的45%。L-异构体在水解时会从α-苯基戊二酰亚胺中释放乙醛。这种代谢物在尿液中的排出量大约占给药剂量的4%。剩余的大部分也会与葡萄糖醛酸结合，并以结合代谢物的形式在尿液中的排出量大约占给药剂量的45%。这两种葡萄糖苷酸都是水溶性的，而不是脂溶性的，并且不再具有镇静作用。

Glutethimide has an asymmetric carbon atom and gives two optical isomers, both of which are metabolized in a different fashion. The D-isomer is hydrolyzed at the glutarimide ring, loses water, and breaks down into alpha-phenyl-alpha-ethylglutaconimide, which is excreted in the urine as a nonconjugated metabolite in approximately 2% of the administered dose. A major portion of the hydrolyzed D-isomer is combined with glucuronic acid and is excreted in the urine in approximately 45% of the administered dose. The L-isomer is hydrolyzed with release of acetaldehyde from a-phenyl glutarimide. This metabolite is isolated in the urine in approximately 4 percent of the administered dose. The remaining major portion is also combined with glucuronic acid and is excreted in the urine in approximately 45 % of the administered dose. Both glucuronides are water soluble but not fat soluble and no longer possess sedative activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别：格鲁塞米特用作催眠剂。格鲁塞米特是无色或白色的无味晶体或粉末。它几乎不溶于水，可溶于乙醇、氯仿和醚。在丙酮和乙酸乙酯中易溶，在甲醇中可溶。稳定性：在pH 5时，化学半衰期在25°C下为28.3年，在pH 8时为1.02个月，分解是由于水解。适应症：格鲁塞米特用作治疗失眠的催眠药，但很少用作镇静剂，最初认为格鲁塞米特几乎无副作用。然而，由于其毒性经验和依赖性，格鲁塞米特在许多国家已被禁用，许多公司已停止生产。 人类暴露：主要风险和靶器官：主要靶器官是中枢神经系统，导致波动深度的昏迷，以及不同程度的低血压。常见抗胆碱能效应。临床效果总结：在较低剂量下，急性中毒可能导致嗜睡、共济失调、肌张力亢进和异常反射。在严重中毒中，可能出现低血压、低体温、休克、昏迷、呼吸抑制和酸中毒。对其他器官的影响通常是由昏迷和休克引起的。禁忌症：格鲁塞米特对卟啉病禁忌。由于其抗毒蕈碱作用，给闭合角青光眼、前列腺增生或尿路梗阻以及某些心律失常患者使用时应极为小心。酒精增强格鲁塞米特的吸收和催眠效果。与巴比妥类药物一样，格鲁塞米特诱导微粒体肝酶，增强香豆素抗凝剂和其他药物的代谢，降低它们的血浆浓度。长期给予格鲁塞米特也可能增强维生素D的代谢。 吸收途径：口服：在六名健康志愿者服用500毫克剂量后，吸收不规则，血浆浓度峰值在一到六小时内出现。然而，在六名受试者中的四名，吸收是双相的。不规则的吸收可能是由于格鲁塞米特在水中的溶解性差。分布途径：口服：在健康受试者口服500毫克格鲁塞米特后，血浆浓度峰值在两到六小时内达到。格鲁塞米特的血浆蛋白结合率约为50%。在服用格鲁塞米特的13名哺乳期母亲中发现了格鲁塞米特浓度。格鲁塞米特高度亲脂，并且迅速在脑和脂肪组织中浓缩。生物半衰期途径：口服：消除半衰期为10到12小时，但在严重中毒时可能增加。在六名健康受试者中，摄入后的初始半衰期为2.7至4.3小时，随后的半衰期范围为5.1至22小时。代谢：格鲁塞米特部分通过羟基化代谢为4-羟基-2-乙基-2-苯基戊二酰亚胺。在小鼠中，这种代谢物的效力似乎是其母体化合物的两倍，并且被认为在过量服用后导致长期昏迷。羟基化代谢物通过尿液主要排出，但也通过胆汁排出。消除途径：口服：格鲁塞米特通过结合失活，代谢物通过尿液排出，只有2%的母体物质通过尿液排出，据报道，剂量中有高达2%的剂量通过粪便排出。 作用方式：毒物动力学药效学：格鲁塞米特直接阻断细胞呼吸中的电子转移。致畸性：从治疗使用中没有致畸的证据。相互作用：格鲁塞米特的效果与苯二氮䓬类药物、巴比妥类药物、可待因和其他中枢神经系统抑制剂的效果是相加的。同时使用抗抑郁药、抗帕金森病药物或其他抗胆碱能药物可能会导致相加的抗胆碱能效果，如尿潴留、青光眼加重或动力性肠梗阻。乙醇增强格鲁塞米特的效果。格鲁塞米特诱导肝代谢一些药物，如双香豆素衍生物，因此同时服用的药物剂量可能需要调整。主要不良影响：常见不良反应如下：恶心、头痛、宿醉、视力模糊、偶尔出现皮疹、血液疾病（巨幼细胞性贫血）。长期使用后也可能发生骨软化性周围神经病和脑损伤。格鲁塞米特是一种滥用药物，可能导致依赖。急性中毒：摄入：摄入是急性中毒可能发生的唯一途径。小剂量轻度中毒导致嗜睡、共济失调、肌张力亢进、异常反射。在严重中毒中，可能出现昏迷、低血压、低体温、休克、呼吸抑制和脑水肿。来自其他器官和系统的症状通常是昏迷和休克的次要表现。慢性中毒：摄入：摄入是人类使用格鲁塞米特的唯一途径。长期使用该药物可能导致周围神经病、低钙血症。格鲁塞米特撤药后急性戒断综合征已有描述。长期摄入高剂量与记忆受损、无法集中注意力、共济失调、震颤、反射

IDENTIFICATION: Glutethimide is used as a hypnotic agent. Glutethimide is colorless or white, odorless crystals or powder. It is practically insoluble in water, soluble in ethanol, chloroform and ether. Freely soluble in acetone and ethyl acetate and soluble in methyl alcohol. Stability: at pH 5 the chemical half life was 28.3 years at 25 °C and 1.02 months at pH 8, the decomposition being due to hydrolysis. Indications: Used as an hypnotic in insomnia but rarely as a sedative, glutethimide was initially believed to be almost free from side effects. However, further experience of its toxicity and because its dependence liability, glutethimide has been banned in many countries and many companies have stopped production. HUMAN EXPOSURE: Main risks and target organs: The main target organ is the central nervous system causing coma with fluctuations in depth, and various degrees of hypotension. Anticholinergic effects often occur. Summary of clinical effects: At lower doses, acute intoxication may cause somnolence, ataxia, tonic muscle spasms and abnormal reflexes. In severe intoxication, hypotension, hypothermia, shock, coma, respiratory depression and acidosis may occur. Effects on other organs are usually secondary to coma and shock. Contraindications: Glutethimide is contraindicated in porphyria. Due to its anti-muscarinic action, it should be given with great care to patients with closed-angle glaucoma, prostatic hypertrophy or urinary tract obstruction, and certain cardiac arrhythmias. Alcohol enhances absorption and the hypnotic effects of glutethimide. Like barbiturates, glutethimide induces microsomal hepatic enzymes and enhances the metabolism of coumarin anticoagulants and other drugs, lowering their plasma concentrations. Chronic administration of glutethimide may also enhance vitamin D metabolism. Absorption by route of exposure: Oral: In six healthy volunteers given a dose of 500 mg, absorption was irregular and peak plasma concentrations occurred over one to six hours. However, in four of the six subjects absorption was biphasic. Erratic absorption may be due to the poor solubility of glutethimide in water. Distribution by route of exposure: Oral: following oral administration of 500 mg of glutethimide to healthy subjects, peak plasma concentrations were achieved within two to six hours. Plasma protein binding of glutethimide was about 50%. Glutethimide concentrations were found in the breast milk of 13 nursing mothers given glutethimide. Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue. Biological half-life by route of exposure: Oral: The elimination half-life is 10 to 12 hours, but may increase in severe poisoning. In six healthy subjects, initial half-lives after ingestion were 2.7 to 4.3 hours and subsequent half-lives ranged from 5.1 to 22 hours. Metabolism: Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2-phenylglutarimide. In the mouse, this appears to be twice as potent as the parent compound in mice and is believed to contribute to prolonged coma following overdosage. Hydroxylated metabolites are conjugated and excreted mainly in the urine but also in bile. Elimination by route of exposure: Oral: glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the feces. Mode of action: Toxicodynamics Pharmacodynamics: Glutethimide directly blocks electron transfer in cellular respiration. Teratogenicity: There is no evidence of teratogenicity from therapeutic use. Interactions: The effects of glutethimide are additive with those of benzodiazepines, barbiturates, codeine and other CNS depressants. Concomitant administration of antidepressants, antiparkinsonian drugs or other anticholinergic agents may cause additive anticholinergic effects such as urinary retention, exacerbation of glaucoma, or adynamic ileus. Ethanol enhances the effects of glutethimide. Glutethimide induces the hepatic metabolism of some drugs, such as dicoumarol derivatives, the dose of drugs taken concomitantly may require adjustment. Main adverse effects: Common adverse effects are as follows: nausea, headache, hangover, blurred vision, occasional skin rashes, blood disorders (megaloblastic anemia). Osteomalacia peripheral neuropathy and cerebral impairment after prolonged use may also occur. Glutethimide is a drug of abuse and may cause dependence. Acute poisoning: Ingestion: Ingestion is the only route by which acute poisoning may occur. Mild intoxication with small doses results in somnolence, ataxia, tonic muscle spasms, abnormal reflexes. In severe intoxication coma, hypotension, hypothermia, shock, respiratory depression and cerebral edema may occur. Signs from other organs and systems are usually secondary to coma and shock. Chronic poisoning: Ingestion: Ingestion is the only route of glutethimide administration in humans. Prolonged use of the drug may cause peripheral neuropathy, hypocalcemia. Acute abstinence syndrome following glutethimide withdrawal has been described. Chronic ingestion of high doses is associated with impaired memory, inability to concentrate, ataxia, tremors, hyporeflexia, slurring of speech and convulsions. Course, prognosis, cause of death: Any acute poisoning without loss of consciousness may be regarded as mild and the patient is not at risk. The occurrence of coma, hypotension, hypothermia, shock, respiratory depression and complications such as pneumonia mean that glutethimide poisoning is potentially serious. However, death is unusual provided intensive care when needed. Cerebral edema may be fatal. Systematic description of clinical effects Cardiovascular: Hypotension, shock and tachycardia have been observed. Unexplained dysrhythmias may be due to the antimuscarinic effects of the drug or low plasma calcium concentrations. Respiratory: Respiratory depression with intermittent apnea and or arrest may occur in very severe cases. Pneumonia due to aspiration and pulmonary oedema have been reported. Neurological: Central Nervous System (CNS): Various degrees of CNS depression may occur, ranging from lethargy to deep coma. Cerebral edema, intracranial hemorrhage, tonic muscle spasms and hyperreflexia may occur. Truncal ataxia has been reported in acute glutethimide intoxication in children. Peripheral nervous system: Peripheral neuropathy and diplopia has been reported following chronic use. Autonomic nervous system: Glutethimide has antimuscarinic/anticholinergic activity, tachycardia, dryness of mouth, mydriasis, irritability, urinary retention and constipation. Skeletal and smooth muscle: Tonic muscle spasm and paralytic ileus (adynamic ileus) may also be observed. Gastrointestinal: Gastrointestinal atony due to parasympatholytic activity may occur. Urinary: Renal: With the exception of possible pre-renal uremia due to severe hypotension, no other renal effects occur. Other: Urinary retention may occur due to the anticholinergic effect of glutethimide. Dermatological: Bullous changes resembling those seen in barbiturate poisoning and erythematous vesicles have been described. Eye, ear, nose, throat: local effects: Mydriasis and papilloedema have been observed. Hematological: Significant methemoglobinemia has been reported rarely. In a further case, megaloblastic anemia, thrombocytopenia and aplastic anemia occurred. Metabolic: Acid-base disturbances: Acid base disturbances may occur secondary to coma or shock. Fluid and electrolyte disturbances: Hypocalcaemia has been described. Others: Hypothermia has been described. Special risks: Glutethimide readily crosses the placenta and may cause neonatal respiratory depression and neonatal withdrawal symptoms. Eight to 12 hours after a maternal dose of glutethimide. It was found in breast milk. ANIMAL/PLANT STUDIES: Parenteral: following intraperitoneal administration of glutethimide in rats, most of drug was found in the brain and spinal cord and other fat-containing tissues after 20 minutes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一系列与格鲁塞特米德（glutethimide）相似的化合物对悬浮的大鼠肾上腺细胞产生的皮质酮（corticosterone）具有浓度依赖性的抑制作用。氨基格鲁塞特米德（aminoglutethimide）的右旋对映体比其左旋对映体更有效地抑制皮质酮的产生。格鲁塞特米德及其代谢物戊酸酰胺（glutaconimide），以及具有抗惊厥活性的同类物，包括4-羟基戊酸酰胺（4-hydroxyglutaconimide）和4-氨基格鲁塞特米德（4-aminoglutethimide），都对大鼠肾上腺细胞产生的皮质酮显示出浓度依赖性的抑制作用。

A series of glutethimide congeners produce concentration-dependent inhibition of corticosterone production by a suspension of isolated rat adrenal cells. The dextro-rotatory antipode of aminoglutethimide is more potent than its levo enantiomer in inhibiting corticosterone production in this system. Glutethimide, its metabolite glutaconimide, and congeners including those with anti-convulsant activity, 4-hydroxyglutaconimide and 4-aminoglutethimide, have all demonstrated concentration-dependent inhibition of corticosterone production by isolated rat adrenal cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

苯巴比妥、司可巴比妥、格鲁米特、水合氯醛和美沙酮对华法林抗凝作用的干扰强度、均匀性和时间过程在16例接受香豆素治疗的病人中进行了系统研究。每个受试者接受个性化的固定日剂量华法林，并作为自己镇静治疗前后对照。在五个长期实验期间，每周四次测量凝血酶原时间。在苯巴比妥、司可巴比妥和格鲁米特给药期间观察到抗凝抑制；在水合氯醛和美沙酮试验期间，凝血酶原测试结果没有显著变化。不应给接受香豆素类药物的病人使用巴比妥类药物和格鲁米特。根据对200份医院病历的调查，这些药物的同时使用正在减少。水合氯醛和美沙酮与口服抗凝剂有药理学的相互作用，但效果在临床上并不显著。因此，可以得出结论，水合氯醛和美沙酮在口服抗凝治疗期间进行凝血酶原测试监测时，可以安全使用，无需额外注意。

The intensity, uniformity and time course of anticoagulant interference by phenobarbital, secobarbital, glutethimide, chloral hydrate and methaqualone were systematically investigated in 16 patients receiving coumarin therapy. Each subject received an individualized fixed daily dose of warfarin and served as his own pre- and postsedative treatment control. Prothrombin times were measured four times weekly during five long-term experiments. Anticoagulant inhibition was observed during the administration of phenobarbital, secobarbital and glutethimide; there was no significant change in prothrombin test results during the trials of chloral hydrate and methaqualone. Barbiturates and glutethimide should not be administered to patients receiving coumarin drugs. The concurrent use of drugs from these groups is decreasing according to a survey of 200 hospital medical records. Chloral hydrate and methaqualone interact pharmacologically with orally administered anticoagulant agents, but the effect is not clinically significant. It is concluded that chloral hydrate and methaqualone may be administered safely without additional caution in prothrombin test monitoring during oral anticoagulant therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

谷司替米德（Glutethimide），与巴比妥类药物相似，可能会诱导肝微粒体酶的增加，导致香豆素类抗凝剂的代谢加快，减少抗凝效果。如果需要给正在接受口服抗凝剂的患者使用催眠药，最好选择不会改变抗凝效果的替代催眠药（例如，苯二氮卓类药物）。对于那些既接受谷司替米德治疗又接受香豆素类抗凝剂治疗的患者，如果停用谷司替米德而没有调整抗凝剂的剂量，则有出血的风险。在接受口服抗凝剂治疗的患者中，不应开始或停止谷司替米德治疗，除非仔细考虑了可能需要调整抗凝剂剂量的情况。

Glutethimide, like barbiturates, may induce hepatic microsomal enzymes resulting in increased metabolism of coumarin anticoagulants and decreased anticoagulant response. If a hypnotic is required in patients receiving oral anticoagulants, it is preferable to use an alternative hypnotic (e.g., a benzodiazepine) which does not alter the anticoagulant response. Patients maintained on both glutethimide and a coumarin anticoagulant have a risk of hemorrhage if glutethimide is discontinued and the dosage of the anticoagulant is not adjusted. Glutethimide therapy should not be initiated or discontinued in patients receiving oral anticoagulants without careful attention to the possible need for adjusting anticoagulant dosage.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

联合给予谷司替米德和三环类抗抑郁药，如阿米替林或丙咪嗪可能会产生加成的抗胆碱能效果。尽管加成的抗胆碱能效果通常是轻微的，但考虑到可能会诱发动力性肠梗阻、尿潴留或急性青光眼，特别是在老年患者中，这一可能性应该被考虑。

Concomitant administration of glutethimide and tricyclic antidepressants such as amitriptyline or imipramine may produce additive anticholinergic effects. Although additive anticholinergic effects are usually minor, the possibility of precipitating adynamic ileus, urinary retention, or acute glaucoma, especially in elderly patients, should be considered.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

变量

Variable

来源:DrugBank

吸收、分配和排泄

• 消除途径

戊巴比妥通过结合作用被灭活，代谢物通过尿液排出，只有2%的原始物质通过尿液排出，据报道，多达2%的剂量可以在粪便中找到。

glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the faeces.

来源:DrugBank

吸收、分配和排泄

Glutethimide appears to be irregularly absorbed from the GI tract. Plasma concentrations of the drug required for sedative or hypnotic effects are not known. In limited studies, oral administration of 500 mg and 1 g single doses of glutethimide produced peak plasma concentrations of 2.9-7.1 ug/mL and 6.2-6.8 ug/mL, respectively, within 1-6 hours. The onset of action of glutethimide is rapid; sleep is usually induced within 30 minutes and lasts 4-8 hours following usual hypnotic doses.

Glutethimide appears to be irregularly absorbed from the GI tract. Plasma concentrations of the drug required for sedative or hypnotic effects are not known. In limited studies, oral administration of 500 mg and 1 g single doses of glutethimide produced peak plasma concentrations of 2.9-7.1 ug/mL and 6.2-6.8 ug/mL, respectively, within 1-6 hours. The onset of action of glutethimide is rapid; sleep is usually induced within 30 minutes and lasts 4-8 hours following usual hypnotic doses.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

一旦被吸收，格鲁塞米特迅速在含有脂肪的器官中集中，例如大脑和脂肪组织，其分布容积大于全身水分。药物从脂肪储存中重新循环，并被输送到肝脏，在那里经历生物转化，这有点让人联想到超短效巴比妥类药物如硫喷妥钠的再分布。

Once absorbed, glutethimide quickly becomes concentrated in organs containing fat such as brain and adipose tissues, with a volume of distribution larger than that of whole body water. The drug recirculates from fat stores and is carried to the liver where it undergoes biotransformation, somewhat reminiscent of redistribution of ultra short acting barbiturates like thiopental.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

分布研究表明，大量的组织中含有格鲁替米特，尤其是在脂肪组织中。此外，格鲁替米特（和/或其代谢物）已在肝脏、肾脏、大脑和胆汁中检测到。格鲁替米特能通过胎盘，少量药物会分布到乳汁中。当给临产前2小时的女性服用1克剂量的格鲁替米特时，母体和新生儿血浆中的格鲁替米特浓度在分娩后立即基本相同。

Distribution studies indicate that there is extensive tissue localization of glutethimide, particularly in adipose tissue. In addition, glutethimide (and/or its metabolites) has been detected in liver, kidneys, brain, and bile. Glutethimide crosses the placenta, and small quantities of the drug are distributed into milk. When 1 g doses of glutethimide were administered to pregnant women 2 hours before delivery, maternal and neonatal plasma concentrations of glutethimide were essentially the same immediately after delivery.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  格鲁米特 在 palladium on activated charcoal 硫酸 、 氢气 、 硝酸 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 氨鲁米特
  参考文献：
  名称：

  芳香酶抑制剂。3-烷基化的3-（4-氨基苯基）哌啶-2,6-二酮对乳腺肿瘤的抑制活性及其合成与评价。

  摘要：

  描述了作为雌激素生物合成抑制剂的3-烷基取代的3-（4-氨基苯基）哌啶-2,6-二酮的合成和生物学评估[H（1），甲基（2），乙基（3），n-丙基（4），异丙基（5），正丁基（6），异丁基（7），仲丁基（8），正戊基（9），异戊基（10），2-甲基丁基（11），仲-戊基（12），正己基（13），正庚基（14）]。与氨基戊二酰亚胺（AG，化合物3）相比，体外化合物4-14对人胎盘芳香酶的抑制作用更强，后者最近已用于治疗激素依赖性乳腺癌。活性最高的化合物10的抑制作用比AG强93倍。除5、7和8外，与AG相比，所有其他化合物对牛肾上腺脱粘酶的抑制作用相似或降低。与母体化合物相比，化合物4和6-12对孕母马血清促性腺激素（PMSG）引发的Sprague-Dawley（SD）大鼠的血浆雌二醇浓度具有更强的抑制作用。化合物4、6-8、10和12抑制睾丸激素刺激的卵巢切除的9,10-二甲基-1,2-苯

  DOI：

  10.1021/jm00158a007
• 作为产物：
  描述：

  3-苯基-3-乙烯基-哌啶-2,6-二酮 在 乙醇 、 铂 作用下， 生成 格鲁米特
  参考文献：
  名称：

  生物学家Abbauversuche III。合成尼古丁酯†

  摘要：

  为了研究“ Doriden”的生物降解，已合成了一些戊二酰亚胺，它们是推测的中间产物。

  DOI：

  10.1002/hlca.19570400217

文献信息

• [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。
• [EN] COMT INHIBITING METHODS AND COMPOSITIONS<br/>[FR] PROCÉDÉS D'INHIBITION DE LA COMT ET COMPOSITIONS ASSOCIÉES
  申请人：LIEBER INST FOR BRAIN DEV

  公开号：WO2016123576A1

  公开（公告）日：2016-08-04

  The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.

  这些发明包括一种抑制受试者中COMT酶的方法，以及式I的化合物或其药用可接受盐，这些化合物在治疗由COMT介导的各种疾病中有用，包括帕金森病和/或精神分裂症。

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