78755-81-4

• 常用中文名：氟吗西尼
• 常用英文名：Flumazenil
• CAS号：78755-81-4
• 分子式：C₁₅H₁₄FN₃O₃
• 分子量：303.288
• 相关类别： 原料药 专科用药 解毒药
• 发布时间：2018-07-26 18:54:32
• 更新时间：2024-01-02 19:52:23
• Flumazenil 是一种有竞争性的 GABAA receptor 拮抗剂,用于治疗苯二氮类药物过量问题。

名称

• 中文名: 氟马西尼
• 英文名: flumazenil
• 中文别名: 氟吗西尼; 氟马泽尼
• 英文别名: Romazicon; Lanexat; Anexate; Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate; Ro-15-1788; Ro 15-1788; YM-684; Ro 1722; Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate; 4H-Imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-, ethyl ester; Mazicon; Flumazenil; FMZ; Flumazepil; 8-Fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester; Ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate; 4H-Imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylic acid, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-, ethyl ester; MFCD00242764

物化性质

• 密度: 1.4±0.1 g/cm3
• 沸点: 528.0±50.0 °C at 760 mmHg
• 熔点: 201-203°C
• 分子式: C₁₅H₁₄FN₃O₃
• 分子量: 303.288
• 闪点: 273.1±30.1 °C
• 精确质量: 303.101929
• PSA: 64.43000
• LogP: 0.67
• 外观性状: solid | white
• 蒸汽压: 0.0±1.4 mmHg at 25°C
• 折射率: 1.634
• 储存条件: 2-8°C
• 水溶解性: 128 mg/L
• 分子结构:

  1、 摩尔折射率：77.58

  2、 摩尔体积（cm³/mol）：217.0

  3、 等张比容（90.2K）：572.7

  4、 表面张力（dyne/cm）：48.4

  5、 极化率（10-24cm3）：30.75

• 计算化学:

  1.疏水参数计算参考值（XlogP）:无

  2.氢键供体数量:0

  3.氢键受体数量:5

  4.可旋转化学键数量:3

  5.互变异构体数量:无

  6.拓扑分子极性表面积64.4

  7.重原子数量:22

  8.表面电荷:0

  9.复杂度:461

  10.同位素原子数量:0

  11.确定原子立构中心数量:0

  12.不确定原子立构中心数量:0

  13.确定化学键立构中心数量:0

  14.不确定化学键立构中心数量:0

  15.共价键单元数量:1

• 更多:

  1.性状：在酒精中结晶。

  2.熔点（℃）：20l～203。

生物活性

• 描述: Flumazenil 是一种有竞争性的 GABAA receptor 拮抗剂,用于治疗苯二氮类药物过量问题。
• 相关类别:
  信号通路 >> 跨膜转运 >> GABA受体
  信号通路 >> 神经信号通路 >> GABA受体
  研究领域 >> 神经疾病
• 体内研究: 氟马西尼与中枢苯二氮卓受体相互作用,以拮抗或逆转苯二氮卓类激动剂和反向激动剂的行为,神经和电生理作用。氟马西尼在肝性脑病中有一定的益处,但在进行精心设计的临床试验之前,必须将肝性脑病视为氟马西尼的研究指征。氟马西尼已经被证明可以逆转单独使用苯二氮卓类药物或苯二氮卓类药物与其他药物联合使用引起的镇静作用,但是当怀疑使用环状抗抑郁药时,不应该使用它[1]。氟马西尼(1 mg/kg)在升高的迷宫和光/暗试验中测试的BALB/c小鼠中诱导强烈的抗焦虑作用[2]。氟马西尼(10 mg/kg)可有效预防大鼠中allopregnanolone的减少[3]。氟马西尼(5-20mg/kg)拮抗地西泮的抗惊厥和不良反应,但不影响小鼠的GYKI 52466。氟马西尼在MES模型中略微降低了NBQX的抗惊厥活性,但在PTZ试验中没有[4]。氟马西尼(3.0 mg/kg)可阻止慢性乙醇治疗的退出,从而减少开放臂时间和开放臂进入百分比[5]。
• 动物实验: 在实验测试前20分钟腹腔注射氟马西尼，体积为10mL / kg体重。用树脂玻璃覆盖的两个聚氯乙烯盒（20×20×14cm）通过不透明的塑料通道（5×7×10cm）连接。其中一个盒子变暗了。 100瓦的台灯在另一个箱子上方40厘米处的灯光提供了唯一的室内照明。选择该光水平（300勒克斯）是为了避免在对照动物的点亮盒中（时间焦虑行为的测量）中及时检测到应变差异。实际上，在先前的实验中，BALB / c小鼠仅在高光条件下与C57BL / 6不同。受试者在1400至1700小时之间的5分钟内进行单独测试。将小鼠放在点亮的盒子中以开始测试。在隧道中的第一个条目之后记录在点亮的框中花费的时间以及从暗盒到点亮的盒子的过渡的数量。
• 参考文献:

  [1]. Hoffman EJ, et al. Flumazenil: a benzodiazepine antagonist. Clin Pharm. 1993 Sep;12(9):641-56; quiz 699-701.

  [2]. Belzung C, et al. Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice. Psychopharmacology (Berl). 2000 Jan;148(1):24-32.

  [3]. Fernandez-Guasti A, et al. Flumazenil blocks the anxiolytic action of allopregnanolone. Eur J Pharmacol. 1995 Jul 25;281(1):113-5.

  [4]. Loscher W, et al. Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. Br J Pharmacol. 1994 Dec;113(4):1349-57.

  [5]. Moy SS, et al. Flumazenil blockade of anxiety following ethanol withdrawal in rats. Psychopharmacology (Berl). 1997 Jun;131(4):354-60.

毒性和生态

毒理学数据: 急性毒性LD50小鼠，大鼠(mg/kg)：4000，1360腹腔注射；4300，6000口服。 CHEMICAL IDENTIFICATION RTECS NUMBER : NI2922170 CHEMICAL NAME : 4H-Imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylic acid, 8-fluoro-5,6-dihydro-5-methyl-6- oxo-, ethyl ester CAS REGISTRY NUMBER : 78755-81-4 LAST UPDATED : 199612 DATA ITEMS CITED : 15 MOLECULAR FORMULA : C15-H14-F-N3-O3 MOLECULAR WEIGHT : 303.32 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Human - man DOSE/DURATION : 5700 ng/kg/C TOXIC EFFECTS : Cardiac - cardiomyopathy including infarction Cardiac - arrhythmias (including changes in conduction) Cardiac - change in rate REFERENCE : BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- Volume(issue)/page/year: 304,1415,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Human - woman DOSE/DURATION : 2 mg/kg/2D-I TOXIC EFFECTS : Behavioral - hallucinations, distorted perceptions Behavioral - excitement Behavioral - aggression REFERENCE : LANCAO Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- Volume(issue)/page/year: 339,488,1992 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Human - woman DOSE/DURATION : 4 ug/kg TOXIC EFFECTS : Behavioral - convulsions or effect on seizure threshold Cardiac - EKG changes not diagnostic of specified effects Cardiac - pulse rate increase, without fall in BP REFERENCE : PECAE5 Pediatric Emergency Care. (Williams & Wilkins, 428 E. Preston St., Baltimore, MD 21202) V.1- 1985- Volume(issue)/page/year: 11,186,1995 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 4200 mg/kg TOXIC EFFECTS : Behavioral - somnolence (general depressed activity) Behavioral - tremor Behavioral - rigidity (including catalepsy) REFERENCE : JTCEEM Journal de Toxicologie Clinique et Experimentale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.5- 1985- Volume(issue)/page/year: 7,223,1987 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 1360 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : DRFUD4 Drugs of the Future. (J.R. Prous, S.A., Apartado de Correos 540, 08080 Barcelona, Spain) V.1- 1975/76- Volume(issue)/page/year: 7,402,1982 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 85 mg/kg TOXIC EFFECTS : Behavioral - convulsions or effect on seizure threshold Behavioral - rigidity (including catalepsy) REFERENCE : JTCEEM Journal de Toxicologie Clinique et Experimentale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.5- 1985- Volume(issue)/page/year: 7,223,1987 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 1300 mg/kg TOXIC EFFECTS : Behavioral - somnolence (general depressed activity) Behavioral - tremor Behavioral - rigidity (including catalepsy) REFERENCE : JTCEEM Journal de Toxicologie Clinique et Experimentale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.5- 1985- Volume(issue)/page/year: 7,223,1987 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intraperitoneal SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 4 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : DRFUD4 Drugs of the Future. (J.R. Prous, S.A., Apartado de Correos 540, 08080 Barcelona, Spain) V.1- 1975/76- Volume(issue)/page/year: 7,402,1982 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Subcutaneous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >1 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 23,201,1992 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 143 mg/kg TOXIC EFFECTS : Behavioral - convulsions or effect on seizure threshold Behavioral - rigidity (including catalepsy) REFERENCE : JTCEEM Journal de Toxicologie Clinique et Experimentale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.5- 1985- Volume(issue)/page/year: 7,223,1987 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Mammal - dog DOSE/DURATION : >640 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 23,201,1992 TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : >30 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value REFERENCE : IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 23,201,1992 TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rabbit DOSE/DURATION : 2 gm/kg TOXIC EFFECTS : Behavioral - somnolence (general depressed activity) Behavioral - tremor Behavioral - rigidity (including catalepsy) REFERENCE : JTCEEM Journal de Toxicologie Clinique et Experimentale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.5- 1985- Volume(issue)/page/year: 7,223,1987 ** REPRODUCTIVE DATA ** TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 21 mg/kg SEX/DURATION : female 14-20 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Newborn - behavioral REFERENCE : PNPPD7 Progress in Neuro-Psychopharmacology and Biological Psychiatry. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.6- 1982- Volume(issue)/page/year: 17,151,1993 TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 220 mg/kg SEX/DURATION : female 11-21 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Newborn - behavioral REFERENCE : GEPHDP General Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.6- 1975- Volume(issue)/page/year: 22,43,1991

安全

• 个人防护装备: Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter
• 危害码 (欧洲): Xi
• 风险声明 (欧洲): R36/37/38:Irritating to eyes, respiratory system and skin .
• 安全声明 (欧洲): S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice . S27:Take off immediately all contaminated clothing . S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
• 危险品运输编码: NONH for all modes of transport
• WGK德国: 2
• RTECS号: NI2922170
• 海关编码: 2933990090

合成路线

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制备

方法1：5-氟靛红在冰醋酸和浓硫酸中，用30%过氧化氢氧化，得黄色固体的6-氟靛红酸酐，收率82%。然后和肌氨酸(即N-甲基甘氨酸)在二甲亚砜中，于100℃反应，得化合物(Ⅰ)，收率80%。再在氯仿中，N，N-二甲基苯胺存在下，和三氯氧磷回流。氯化所得化合物(Ⅱ)经处理后，在二甲基甲酰胺中，叔丁醇钠存在下，和氰基醋酸乙酯反应，得氟马西尼，收率40%，熔点200～203℃。
方法2：4-氟-2-(N-羧基氨基)苯甲酸和N-甲基甘氨酸环合，生成化合物(Ⅲ)，再和2-氰基乙酸乙酯环合，得到氟马西尼。

海关

海关编码	2933990090
中文概述	2933990090. 其他仅含氮杂原子的杂环化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0%
申报要素	品名, 成分含量, 用途, 乌洛托品请注明外观, 6－己内酰胺请注明外观, 签约日期
Summary	2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%