フルマゼニル
アネキサート · アネキセート · フルマゼピル · フルマゼニル · 5-メチル-6-オキソ-8-フルオロ-5,6-ジヒドロ-4H-イミダゾ[1,5-a][1,4]ベンゾジアゼピン-3-カルボン酸エチル · 8-フルオロ-5,6-ジヒドロ-5-メチル-6-オキソ-4H-イミダゾ[1,5-a][1,4]ベンゾジアゼピン-3-カルボン酸エチル · フルメナジル · フルマゼニル (JAN)
識別子と物理属性
| CAS No. | 78755-81-4 |
|---|---|
| 分子式 | C15H14FN3O3 |
| 平均分子量 | 303.29 g/mol |
| 単同位体質量 | 303.10191953 g/mol |
| SMILES | CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2 |
| InChIKey | OFBIFZUFASYYRE-UHFFFAOYSA-N |
| PubChem CID | 3373 |
| ChEMBL | CHEMBL407 |
| ChEBI | CHEBI:5103 |
| EC No. | 616-650-9 |
| DTXSID | DTXSID2023064 |
| 現地名 | フルマゼニル |
化学・物理的性質
| XLogP | 1 |
|---|---|
| 極性表面積 | 64.4 |
| 水素結合供与体数 | 0 |
| 水素結合受容体数 | 5 |
| 回転可能結合数 | 3 |
| 重原子数 | 22 |
| 形式電荷 | 0 |
| 複雑度 | 461 |
| 医薬品 | Pharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Various |
| LogP（分配係数） | 1.91.26 |
| 溶解度 | 1.04e+00 g/LDMSOに25mMで可溶128mg/L |
| Human Drugs | Breast FeedingLactationMilk, HumanAntidotesGABA ModulatorsBenzodiazepinesFDA approved drugs -> Active ingredient |
| 融点 | 201-203 °C201 - 203 °C201-203°C |
| Physical Description | Solid |
| Collision Cross Section | 164.31 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]165.6 Ų [M+H]+ [CCS Type: TW165.8 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)] |
| 沸点 | 528.0±50.0 °C(Predicted) |
| 密度 | 1.39±0.1 g/cm3(Predicted) |
| 貯蔵条件 | Sealed in dry,2-8°C |
| 外観・状態 | 個体 |
| pKa（酸解離定数） | 0.86±0.20(Predicted) |
| 色 | 白い |
| Merck | 14,4135 |
| 安定性 | 購入日から2年間安定です。この DMSO 溶液は、-20°C で 3 か月間保存できます。 |
| 主な用途 | 医薬品（低分子化合物） |
| InChI | InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3 |
| InChIKey | OFBIFZUFASYYRE-UHFFFAOYSA-N |
| SMILES | N12C=NC(C(OCC)=O)=C1CN(C)C(=O)C1=CC(F)=CC=C12 |
| CAS データベース | 78755-81-4(CAS DataBase Reference) |
| NISTの化学物質情報 | Flumazenil(78755-81-4) |
化学的特性
Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions.
安全性と法規制
| GHS 分類 | This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.WarningH302 (80%): Harmful if swallowed [Warning Acute toxicity, oral]P261, P264, P270, P271, P301+P317, P304+P340, P317, P330, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 5 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Hazard Classes and Categories | Acute Tox. 4 (80%) |
| 有害作用 | Serious Adverse Events |
| 毒性の概要 | Flumazenil has some associations with the precipitation of seizures in patients with benzodiazepine dependency with a history of seizures. However, flumazenil overdose is extremely rare. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)FlumazenilvNo-DILI-concernNo matchDOI:10.1016/j.drudis.2016.02.015 |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| 水環境危害等級（WGK） | 2 |
| RTECS 番号 | NI2922170 |
| 毒性 | LD50 in mice, rats (mg/kg): 4000, 1360 i.p.4300, 6000 orally (Hunkeler) |
| 税関コード | 2933997500 |
| 危険文句（R） | 36/37/38 |
| 危険表示 | Xi |
| 安全措置（S） | 26-27-36/37/39 |
| 貯蔵分類 | 11 - Combustible Solids |
用途
用途
フルマゼニル(Flumazenil)はベンゾジアゼピン系薬剤の拮抗薬。 フルマゼニルはイミダゾベンゾジアゼピン系物質であり、非定型ベンゾジアゼピン受容体リガンドに分類される。人体においては殆ど鎮静効果を持たず、ベンゾジアゼピン系薬剤による鎮静や呼吸抑制の解除を目的に用いられる。急性のベンゾジアゼピン中毒患者の治療の他、内視鏡治療や検査、日帰り処置等の終了後に速やかにベンゾジアゼピン系鎮静剤の作用を解除する用途で良く使用される。臓器毒性や組織刺激性もなく安全性の高い薬剤とされる。
説明
Flumazenil is a benzodiazepine antagonist useful as a fast-acting antidote in the treatment of benzodiazepine intoxication, and in reversing the central sedative effects of benzodiazepines during anesthesia.
使用
Flumazenil is an imidazodiazepine which selectively blocks the central effects of classic benzodiazepines. It is used as benzodiazepine antagonist sedation reversal drug.
製法・合成法
製造方法
The Synthesis of FlumazenilStarting with 4-fluoroaniline (15) the isatin 17 is synthesized via the Sandmeyer synthesis; isatin is then oxidized with peracetic acid to the isatoic anhydride 18. Reaction with sarcosine in DMF leads to the benzodiazepine-2,5-dione 19. This is converted to the iminochloride by reaction with POCI3 . In the key step the imidazoester is built up by reaction with deprotonated ethyl isocyanoacetate [8]. Since ethyl isocyanoacetate is not very stable, an alternative synthesis based on the synthesis of midazolam was developed for large scale-production. Tnthis synthesis diethylmalonate is used. The diester 21 is then transformed to the monoester 22 hy deethoxycarbonylation. Nitrosation and catalytic reduction lead to the amino compound 23. The final carbon atom is introduced by reaction with the orthoester.