化工社化工社 化学情報印刷レポート · 研究参考用
フェルバメート
ジカルバミド酸2-フェニルトリメチレン · ビスカルバミド酸2-フェニル-1,3-プロパンジイル · フェルバトール · フェルバマート · 2-フェニル-1,3-プロパンジオールジカルバマート · フェルバメート · フェルバメート 溶液 · 3-(カルバモイルオキシ)-2-フェニルプロピル カルバマート
識別子と物理属性
| CAS No. | 25451-15-4 |
|---|---|
| 分子式 | C11H14N2O4 |
| 平均分子量 | 238.24 g/mol |
| 単同位体質量 | 238.09535693 g/mol |
| SMILES | NC(=O)OCC(COC(N)=O)c1ccccc1 |
| InChIKey | WKGXYQFOCVYPAC-UHFFFAOYSA-N |
| PubChem CID | 3331 |
| ChEMBL | CHEMBL1094 |
| ChEBI | CHEBI:4995 |
| EC No. | 247-001-4 |
| DTXSID | DTXSID9023041 |
| 現地名 | フェルバメート |
化学・物理的性質
| XLogP | 0.6 |
|---|---|
| 極性表面積 | 105 |
| 水素結合供与体数 | 2 |
| 水素結合受容体数 | 4 |
| 回転可能結合数 | 7 |
| 重原子数 | 17 |
| 形式電荷 | 0 |
| 複雑度 | 246 |
| LogP（分配係数） | 0.3 |
| 臭い | Odorless |
| Color/Form | White powder |
| 溶解度 | Slightly soluble in waterSparingly soluble in water, methanol, ethanol, acetone and chloroformfreely soluble in DSMO, 1-methyl-2-pyrrolidinone and DMF.7.42e-01 g/Lアルコール：可溶 |
| Decomposition | When heated to decomposition it emits toxic vapors of /nitrogen oxides/. |
| 融点 | 151.5151-153 °C151.5 °C148-1500C |
| Physical Description | Solid |
| Kovats Retention Index | 2157 |
| Collision Cross Section | 159.6 Ų [M+Na]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: TOXCASTSource Identifier: DTXSID9023041] |
| 沸点 | 511.9±50.0 °C(Predicted) |
| 密度 | 1.275±0.06 g/cm3(Predicted) |
| 引火点 | 9℃ |
| 貯蔵条件 | Keep in dark place,Inert atmosphere,Room temperature |
| pKa（酸解離定数） | 12.99±0.50(Predicted) |
| 外観・状態 | 個体 |
| 色 | 白い |
| BCS Class | 2 |
| 主な用途 | 医薬品（低分子化合物） |
| InChI | InChI=1S/C11H14N2O4/c12-10(14)16-6-9(7-17-11(13)15)8-4-2-1-3-5-8/h1-5,9H,6-7H2,(H2,12,14)(H2,13,15) |
| InChIKey | WKGXYQFOCVYPAC-UHFFFAOYSA-N |
| SMILES | C(OC(=O)N)C(C1=CC=CC=C1)COC(=O)N |
| CAS データベース | 25451-15-4(CAS DataBase Reference) |
| NISTの化学物質情報 | Felbamate(25451-15-4) |
化学的特性
White Powder. Solubility in water 0.33 mg/mL, in ethanol 5.0 mg/mL, and in DMF 333.4 mg/mL.
安全性と法規制
| GHS 分類 | This chemical does not meet GHS hazard criteria for 2.2% (1 of 45) of reports.DangerH317 (95.6%): May cause an allergic skin reaction [Warning Sensitization, Skin]H334 (95.6%): May cause allergy or asthma symptoms or breathing difficulties if inhaled [Danger Sensitization, respiratory]P233, P260, P261, P271, P272, P280, P284, P302+P352, P304+P340, P321, P333+P317, P342+P316, P362+P364, P403, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 45 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Reported as not meeting GHS hazard criteria per 1 of 45 reports by companies.There are 2 notifications provided by 44 of 45 reports by companies with hazard statement code(s).Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| Hazard Classes and Categories | Skin Sens. 1 (95.6%)Resp. Sens. 1 (95.6%) |
| 保管条件 | Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer. |
| 処分方法 | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Treatment | General supportive measures should be employed if overdosage occurs. It is not known if felbamate is dialyzable. (L1712) |
| 相互作用 | Enzyme induction by phenytoin may lead to decreased felbamate plasma concentrations during concurrent useincreased felbamate plasma concentrations may occur when phenytoin dosage is reduced or phenytoin is discontinuedsince both felbamate and phenytoin are hydroxylated by the cytochrome P-450 system, possible competitive inhibition of phenytoin metabolism may result in phenytoin plasma concentrations being increased by 20 to 40%, leading to increased adverse effects... plasma concentrations of phenytoin should be monitored ...Felbamate may increase phenobarbital plasma concentrations, leading to increased adverse effectsphenobarbital dosage should be reduced by 20 to 33% when felbamate therapy is initiated, and plasma phenobarbital concentrations should be monitored ...Felbamate may increase plasma concentrations of N-desmethylmethsuximide, an active metabolite of methsuximide, leading to increased adverse effectsmethsuximide dosage should be reduced by 20 to 33% when felbamate therapy is initiated ...Enzyme induction by carbamazepine may lead to decreased felbamate plasma concentrationsincreased felbamate plasma concentrations may occur when carbamazepine dosage is reduced or carbamazepine is discontinuedconcurrent use may also decrease carbamazepine plasma concentrations by about 20 to 30% and may increase the plasma concentrations of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, by about 60%, leading to an increase in adverse effectscarbamazepine dosage should be reduced by 20 to 33% when felbamate therapy is initiated, and plasma concentrations of carbamazepine should be monitored...For more Interactions (Complete) data for 2-PHENYL-1,3-PROPANEDIOL DICARBAMATE (7 total), please visit the HSDB record page. |
| 健康影響 | May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. |
| Hepatotoxicity | Prospective studies suggest that chronic felbamate therapy is not accompanied by significant elevations in serum aminotransferase levels. Nevertheless, clinically apparent hepatotoxicity from felbamate is well described, although uncommon, estimated to occur in 1 in 18,500 to 25,000 exposures, often with severe outcome. The onset of injury is 1 to 6 months after starting therapy and the pattern of enzyme elevations is typically hepatocellular. More than a dozen instances of acute liver failure and death were attributed to felbamate before severe restrictions were placed upon its use. Felbamate has not been associated with anticonvulsant hypersensitivity syndrome and is a potential alternative for persons who have developed that syndrome from other anticonvulsants.Likelihood score: B (highly likely cause of clinically apparent liver injury). |
| 有害作用 | Initial studies showed that felbamate carried relatively little systemic toxicity and less CNS depression when compared to the older generation antiseizure medications (ASMs). Common adverse effects include drowsiness, insomnia, anorexia, nausea, dizziness, and headache. Anorexia and other adverse effects are more likely to occur with higher serum levels.A rapid titration schedule can increase the risk of neurologic adverse effects. Decreasing the titration rate may reduce this risk. Somnolence is more likely to occur in the first 4 weeks of treatment and decreases with continued therapy.Drug-Drug InteractionsFelbamate has several drug interactions with commonly used ASMs. Enzyme-inducing antiepileptic medications, such as carbamazepine and phenytoin, can increase the clearance of felbamate. Gabapentin and valproic acid will decrease the clearance of felbamate. Lastly, felbamate can increase levels of phenytoin, phenobarbital, and valproic acid and reduce levels of carbamazepine. |
| 暴露経路 | Oral. >90% |
| Milk Concentrations | Felbamate is distributed into breast milk. |
| 毒性の概要 | Signs and Symptoms of Acute OverdoseFelbamate overdose may cause central nervous system depression, altered mental status, ataxia, vomiting, and crystalluria, which may lead to acute kidney injury (AKI). Crystals may be visible on urinalysis and primarily contain unchanged felbamate and its metabolites. A 20-year-old woman presented with altered mental status, extensive crystalluria, unilateral hydronephrosis, and AKI after intentionally ingesting felbamate with sodium valproate. In another case, a 3-year-old child developed vomiting, ataxia, hematuria, and needle-like urinary crystals after accidental overdose of felbamate.Management of OverdoseThere is no antidote for felbamate. The initial management includes stabilization of airway, breathing, and circulation. Endotracheal intubation may be required in patients with markedly altered mental status. Supportive treatment with intravenous fluids enhances renal clearance of felbamate, especially when crystalluria or AKI is present. Urine microscopy and renal ultrasound may help identify nephrotoxic effects. In both reported cases, crystalluria and AKI resolved following parenteral hydration, and both patients made a complete recovery.The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. <i>In vitro</i> receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding. |
| Human Toxicity Excerpts | /HUMAN EXPOSURE STUDIES/ ... The single and multiple dose pharmacokinetics of felbamate were examined in an open-label two-dose level parallel group study in 24 elderly (66 to 78-year-old) and 11 young (18 to 45-year-old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120 hr after administration of single 600 mg or 1200 mg doses, and after multiple doses of 600 mg or 1200 mg administered every 12 hr. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events. Single dose felbamate pharmacokinetic parameters differed between young and elderly subjectscompared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1 mL min(-1)90% CI -11.4 to -0.9P = 0.02) and a trend towards a greater half-life (18.6 vs 21.0 hr90% CI -0.6 to 5.4P = 0.11). Mean AUC and C(max) values were also higher in elderly subjects. No gender differences were noted for weight-adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. .../SIGNS AND SYMPTOMS/ /After/ ingestion of 12,000 mg felbamate in a 12-hour period the only adverse experiences reported were mild gastric distress and a resting heart rate of 100 beats per min. No serious adverse reactions have been reported./CASE REPORTS/ At least 21 reported cases (20 of which occurred in the US) of aplastic anemia have developed in association with felbamate therapy. The rate of aplastic anemia cases currently reported with the drug appears to be at least 40-100 times higher than the expected rate of 2-5 cases per million untreated individuals per year. However, because the onset of felbamate-induced aplastic anemia typically is delayed for weeks to months after initiation of the drug and a substantial fraction of patients had felbamate therapy withdrawn for other reasons prior to this period, the absolute rate of this anemia associated with felbamate probably is higher than the currently reported rate of 1 case per 5000 patients per year. Based on this probability, the manufacturer estimates that the actual risk of aplastic anemia associated with felbamate therapy may be as high as 1 case per 2000 patients (500 cases per million patients) per year or more among those who remain on the drug for longer than a few weeks. While postmarketing surveillance usually captures only a fraction of incident cases, the syndrome is still relatively rare, and no cases were observed during premarket testing in which more than 1600 patients received felbamate therapy. All reports of aplastic anemia associated with felbamate therapy to date have occurred in patients receiving the drug for at least 5 weeks./CASE REPORTS/ Of the 21 patients who developed aplastic anemia while receiving felbamate therapy, 5 (all from the US) have died. While current experience and data are too limited to estimate reliably the fatality rate associated with felbamate-induced aplastic anemia, the estimated case fatality rate for untreated individuals with aplastic anemia from any cause ranges from 20-30%. However, historical fatality rates as high as 70% have been reported for aplastic anemia, and the risk of death secondary to this anemia generally varies with severity and etiology. Although most reported cases have been in white females, risk factors for the development of aplastic anemia in patients receiving felbamate therapy have not been identified. Whether age (range for cases to date: 12-68 years old), gender, or race of the patient, duration of exposure to the drug, dosage, or concomitant use of other anticonvulsant agents or drugs affects the incidence of aplastic anemia in patients receiving felbamate remains to be established. Therefore, the manufacturer recommends that felbamate therapy be discontinued in any patient receiving the drug and alternative therapy initiated as necessary, unless in the clinician's judgment continued felbamate therapy outweighs the risk for aplastic anemia.For more Human Toxicity Excerpts (Complete) data for 2-PHENYL-1,3-PROPANEDIOL DICARBAMATE (16 total), please visit the HSDB record page. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)FelbamatevMost-DILI-concern7Box warningDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ Felbamate, 2-phenyl-1,3-propanediol dicarbamate, is a novel anticonvulsant that is effective against both chemically and electrically induced seizures in laboratory animals. Acute ... studies were conducted in mice, rats, and dogs to establish a preclinical safety profile for this drug. Clinical signs following single intraperitoneal doses included hypoactivity, tremors, decreased muscle tone, ataxia, prostration, and labored breathing. Death was observed after intraperitoneal but not oral administration. .../LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Studies to determine the carcinogenic potential of felbamate were performed in mice and rats. Mice received felbamate orally in dosages of 300, 600, and 1200 mg/kg daily for 92 weeks, while male rats received the drug orally in dosages of 30, 100, and 300 mg/kg and female rats received 10, 30, and 100 mg/kg daily for 104 weeks. The maximum dosages used in these studies produced steady-state plasma felbamate concentrations that were equal to or less than the steady-state plasma concentrations in patients with epilepsy receiving 3600 mg of the drug daily. There was an increase in hepatic cell adenomas in male and female mice receiving the high dosages as well as in female rats receiving the high dosages. Hepatic hypertrophy also was increased in a dose-related manner in mice, principally in males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from hepatic enzyme induction has not been evaluated. There also was an increase in benign interstitial cell tumors of the testes in male rats receiving high dosages of felbamate./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats revealed no evidence of impaired fertility in males or females receiving oral felbamate dosages of up to 13.9 times the human total daily dosage of 3600 mg on a mg/kg basis (up to 3 times the human total daily dose on a mg/sq m basis)./GENOTOXICITY/ No evidence of mutagenicity was demonstrated by felbamate in the Ames Salmonella microbial mutagen test, the CHO/HGPRT mammalian cell forward gene mutation assay, the sister chromatid exchange assay in CHO cells, or bone marrow cytogenetics assay. |
| 水環境危害等級（WGK） | 2 |
| RTECS 番号 | TZ1070000 |
| 輸送番号（UN） | UN1230 - class 3 - PG 2 - Methanol |
| 毒性 | LD50 i.p. in mice: 4000 mg/kg (Ludwig et al.) |
| 税関コード | 2924296000 |
| 貯蔵分類 | 11 - Combustible Solids |
| 有害物質データ | 25451-15-4(Hazardous Substances Data) |
用途
説明
Felbamate, characterized by its low toxicity and wide margin of safety, is efficacious in treating refractory patients with generalized tonic-clonic and complex partial seizures as monotherapy and adjunctive therapy.It has also been demonstrated to have a neuroprotective effect in cerebral ischemia and hypoxia. It has been suggested that the mechanism of its anticonvulsant activity is possibly through an interaction with the strychnineinsensitive receptor site on the NMDA receptor complex.