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3-碘-N'-(2-甲磺酰基-1,1-二甲基乙烷基-N-{4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-0-甲苯基}邻苯二酰胺 | 272451-65-7

中文名称
3-碘-N'-(2-甲磺酰基-1,1-二甲基乙烷基-N-{4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-0-甲苯基}邻苯二酰胺
中文别名
氟虫双酰胺;垄歌;氟苯虫酰胺
英文名称
flubendiamide
英文别名
3-iodo-N'-(2-mesyl-1,1-dimethylethyl)-N-{4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-o-tolyl}phthalamide;N2-[1,1-dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl) ethyl]phenyl]-1,2-benzenedicarboxamide;1-N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2-methylphenyl]-3-iodo-2-N-(2-methyl-1-methylsulfonylpropan-2-yl)benzene-1,2-dicarboxamide
3-碘-N'-(2-甲磺酰基-1,1-二甲基乙烷基-N-{4-[1,2,2,2-四氟-1-(三氟甲基)乙基]-0-甲苯基}邻苯二酰胺化学式
CAS
272451-65-7
化学式
C23H22F7IN2O4S
mdl
——
分子量
682.398
InChiKey
ZGNITFSDLCMLGI-UHFFFAOYSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

物化性质

  • 熔点:
    218-221 °C
  • 沸点:
    578.6±50.0 °C(Predicted)
  • 密度:
    1.615±0.06 g/cm3(Predicted)
  • 溶解度:
    可溶于DMSO(少许)、甲醇(少许)
  • LogP:
    3.250 (est)
  • 颜色/状态:
    White crystalline powder
  • 蒸汽压力:
    <7.5X10-7 mm Hg at 25 °C
  • 自燃温度:
    435 °C/ 815 °F. /Belt SC Insecticide/
  • 解离常数:
    Does not dissociate

计算性质

  • 辛醇/水分配系数(LogP):
    5.3
  • 重原子数:
    38
  • 可旋转键数:
    7
  • 环数:
    2.0
  • sp3杂化的碳原子比例:
    0.39
  • 拓扑面积:
    101
  • 氢给体数:
    2
  • 氢受体数:
    11

ADMET

代谢
通常情况下,每组4只非禁食的大鼠/性别,每天通过灌胃方式给药14天的氟苯二酰胺(NNI-0001),在邻苯二甲酸环上标记有(14)C,纯化后的放射性纯度为99.2%,在悬浮液中含有2%的羧甲基纤维素和0.4%的Tween 80。本研究评估了包括主要代谢物量化在内的ADME特性。在大鼠最后一次(第14次)给药后9小时、24小时或168小时对其进行处死。...雌性大鼠的代谢标签较少,且比雄性大鼠在长期组织中的标签保留量更大,与其他研究一致。母氟苯二酰胺在雄性和雌性粪便代谢物中分别占82%和91%。剩余粪便标签的相对比例包括苯甲醇代谢物(A-16)(占雄性排泄放射活性的7.2%,雌性的2.2%)、苯甲酸代谢物(A-18)(占雄性排泄放射活性的2.8%,雌性中未检出),其他代谢物未被表征或含量非常小。本研究报告了在脂肪中可量化的大鼠酰亚胺代谢物(A-14)的量。这种代谢物涉及切割酰亚胺氮远处所有组分,但在排泄物中尚未发现可测量的量。
Typically sets of 4 non-fasted rats/sex were gavage-dosed daily for 14 days with Flubendiamide (NNI-0001), (14)C-labeled on the phthalic acid ring, radiochemical purity after purification of 99.2%, in an aqueous suspension of 2% sodium carboxymethylcellulose containing 0.4% Tween 80. This study assessed ADME features including quantification of major metabolites. Rats were sacrificed either 9 hr, 24 hr, or 168 hr after the final (14th) dosing. ... Females showed less metabolized label and greater longterm tissue retention of label than males, consistent with other studies. Parent flubendiamide comprised 82% and 91% of fecal metabolites in males and females, respectively. Relative proportions of remaining fecal label consisted of the benzyl alcohol metabolite (A-16) (7.2% of excreted radioactivity in males, and 2.2% in females), the benzoic acid metabolite (A-18) (2.8% of excreted radioactivity in males and below detection in females), with other metabolites uncharacterized or in very small amounts. This study reported quantifiable amounts of the iodophthalimide metabolite (A-14) of flubendiamide in fat. This metabolite, involving cleavage of all components distal to the phthalamide nitrogen, had not been found in measurable amounts in excreta.
来源:Hazardous Substances Data Bank (HSDB)
代谢
通常,每组4只/性别的禁食大鼠一次通过灌胃给予氟苯二酰胺(NNI-0001),在酞酸环上或(在有限程度上)在苯胺环上标记(14)C,净化后的放射化学含量> 99.5%,在含有0.2% Tween 80的1%羧甲基纤维素悬浮液中。本研究评估了ADME特征,包括用2或200 mg/kg氟苯二酰胺处理后主要代谢物的鉴定。标签在呼出空气中的排泄量没有明显差异。超过90%的给药剂量通过粪便排出,与剂量或性别无关。尽管尿液是一个小途径(< 2%的给药剂量),但雄性在尿液中的标签传递始终高于雌性。高剂量水平导致吸收明显减少。两种标记形式的排泄模式和代谢物色谱图之间没有明显差异,这表明分子的大部分之间几乎没有裂解。血液和血浆的Tmax为6至12小时。标签的组织分布主要在大肠、肝脏和其他高灌注器官以及体脂中。低剂量治疗发现,雄性组织的峰值水平比雌性高几倍。从9小时到24小时,雄性组织的水平降低了约90%,从24小时到168小时又降低了约90%。然而,雌性没有像雄性那样迅速清除组织,因此168小时后雌性的残留组织浓度高于雄性。氟苯二酰胺上可供氧化的主要取代基是苯胺环上的甲基。最常见的产品是那个甲基碳的苄醇(标为A-16)和苯甲酸(标为A-18)。较少的中间物苯甲醛被标为A-17。在代谢轮廓上出现了实质性的性别差异。在2 mg/kg雄性的粪便中,苄醇是主要的代谢物(占给药剂量的31-37%),其次是亲代氟苯二酰胺(占给药剂量的15-30%)和苯甲酸代谢物(占给药剂量的15-16%)。在2 mg/kg雌性的粪便中,66%的给药剂量是氟苯二酰胺,5-6%的给药剂量是苄醇,几乎没有苯甲酸代谢物。没有其他主要代谢物。在200 mg/kg时,两种性别的粪便中主要的标记成分是亲代氟苯二酰胺,这表明吸收是饱和的。雌性大鼠清除放射性的速度非常慢:对比2 mg/kg雄性在9小时和168小时后剂量后肝脏标签含量从5.628%降至0.104%的给药剂量,而雌性在相同的采样时间点为1.623%和1.305%的给药剂量。雌性大鼠对氟苯二酰胺的肝脏代谢能力有限,因此24小时时雌性肝脏中积累了相当数量的亲代氟苯二酰胺(比所有可提取代谢物组合的数量级多)。在雄性中,肝脏中几乎没有发现亲代氟苯二酰胺(不到苯甲醇或苯甲醛代谢物所占剂量的半数)。雄性肝脏中有较小但可测量的两种环结构之间裂解的唯一识别产物(苯胺片段)。
Typically sets of 4 fasted rats/sex were dosed once by gavage with Flubendiamide (NNI-0001), (14)C-labeled on either the phthalic acid ring or (to a limited extent) on the aniline ring, radiochemical content after purification > 99.5%, in an aqueous suspension of 1% sodium carboxymethylcellulose containing 0.2% Tween 80. This study assessed ADME features including identification of major metabolites following treatment with either 2 or 200 mg/kg flubendiamide. There was no significant excretion of label into expired air. Over 90% of administered dose was excreted in feces regardless of dose or sex. Although urine was a minor route (< 2% of administered dose), males consistently passed more label in urine than did females. High dose levels led to markedly reduced absorption. There was no obvious difference in excretion patterns and there were minimal differences in metabolite chromatograms between the two labeled forms, indicating that there was very little cleavage dividing major portions of the molecule. Tmax was 6 to 12 hours for blood and plasma. Tissue distribution of label was preferentially to the g.i. tract, liver and other highly perfused organs, and body fat. Low dose treatments found peak tissue levels in males several-fold higher than females. Tissue levels in males were lower by about 90% from 9 hrs to 24 hrs, and by another 90% from 24 hrs to 168 hrs. Females did not clear tissues as rapidly as males, however, so females had higher residual tissue concentrations at 168 hours than males. The primary substituent available for oxidation on flubendiamide is the methyl group on the aniline ring. The most common products were the benzyl alcohol (designated A-16) and the benzoic acid (designated A-18) of that methyl carbon. The less abundant intermediate benzaldehyde was designated as A-17. Substantial sex differences emerged in metabolic profiles. In the feces, the benzyl alcohol was the dominant metabolite in 2 mg/kg males (31-37% of administered dose), followed by parent flubendiamide (15-30% of administered dose), and the benzoic acid metabolite (15-16% of administered dose). In feces of 2 mg/kg females, 66% of administered dose was flubendiamide, 5-6% of administered dose was benzyl alcohol, and there was very little benzoic acid metabolite. There were no other major metabolites. Parent flubendiamide was the predominant labeled constituent in feces of both sexes at 200 mg/kg, indicating saturable absorption. Female rats were very slow to clear radioactivity: contrast liver label content in 2 mg/kg males dropping from 5.628% to 0.104% of administered dose at 9 hrs and 168 hrs after dosing vs. content in females of 1.623% and 1.305% of administered dose at the same sampling times. Female rats have limited hepatic metabolic capacity for flubendiamide, hence there was appreciable accumulation of parent flubendiamide in the livers of females at 24 hours (an order of magnitude more than all extractable metabolites combined). In males, very little parent flubendiamide was found in liver (less than half of the percent of dose represented by benzyl alcohol or benzaldehyde metabolites). Liver in males had smaller but measurable amounts of the sole identified product of cleavage between the two ring structures of flubendiamide (the aniline fragment).
来源:Hazardous Substances Data Bank (HSDB)
代谢
氟苯尼胺(纯化至99.6%,用于非标记活性成分和邻苯二甲酸环上标记的14C)通过一次灌胃给药(含2%羧甲基纤维素悬浮液,含0.4%吐温80)给予安装了胆管导管的F-344(F344/DuCrj)大鼠。在最终研究中,3只雄性和6只雌性接受了2 mg/kg的剂量。(为了促进代谢物特征的分析,额外的大鼠在16小时间隔内两次给药,每次20 mg/kg活性成分。)……在粪便或胃肠道内容物中观察到的唯一可定量代谢物是苯甲醇代谢物,可能是由于肠道微生物对未被吸收物质的作用。雄性大鼠胆汁中的大部分成分是苯环上甲基基团的氧化产物……。邻苯二甲酰胺氮和磺酰基团之间的甲基基团也有一些氧化(包括研究者指定的A-19、A-20、A-25和A-29的化合物)。最常见的是,苯环上甲基基团的氧化产物并未结合,然而看起来邻苯二甲酰胺氮和磺酰基团之间的甲基基团的氧化在雄性中常常随后发生葡萄糖醛酸结合。两性大鼠都能形成亲本化合物的谷胱甘肽结合物,研究者提出这种结合是在邻苯二甲酸环上。在雌性中,谷胱甘肽结合物(以及结合的下游衍生物)是主要的胆汁代谢物。在胆汁中观察到了一种环状缩醛,尤其是在雄性中。
Flubendiamide (purified to 99.6% purity for non-labeled a.i. and for (14)C-labeled on the phthalic acid ring) was administered once by gavage (aqueous suspension of 2% sodium carboxymethylcellulose containing 0.4% Tween 80) to F-344 (F344/DuCrj) rats provided with biliary cannulae. Three males and 6 females received 2 mg/kg in the definitive study. (Additional rats were dosed twice at 16-hr intervals with 20 mg/kg a.i. to facilitate characterization of metabolites.) ... The only quantifiable metabolite observed in feces or gastrointestinal content was the benzyl alcohol metabolite, possibly resulting from intestinal microbial action of non-absorbed material. Much of the biliary profile in males consisted of oxidation products of the methyl group on the aniline ring ... . There was also some oxidation of the methyl groups between the phthalamide nitrogen and the sulfonyl group (including compounds designated A-19, A-20, A-25, and A-29 by investigators). Most commonly the oxidation products of the methyl group on the aniline ring were not conjugated, however it appears that oxidation of a methyl group between the phthalamide nitrogen and the sulfonyl group frequently was followed by glucuronide conjugation in males. Both sexes were capable of glutathione formation of parent compound, conjugation proposed by investigators to be on the phthalic ring. In females, glutathione conjugates (and downstream derivatives of the conjugation) were the dominant biliary metabolites. A cyclic acetal was observed in bile, particularly in males.
来源:Hazardous Substances Data Bank (HSDB)
代谢
大鼠、狗、小鼠和人类的微体(所有物种中均包括两性)都能够将氟苯二酰胺代谢为A-16,除了雌性大鼠的微体。 (人类微体,而不是大鼠微体,另外还产生了少量的羟基苯甲酸代谢物A-20,然而代谢为A-16似乎是一个有效的整体氟苯二酰胺代谢指标。) 在雄性大鼠微体中测试了对细胞色素P450同型的抗血清,发现抗CYP3A2血清对A-16的产生没有影响,而抗CYP2C11显著抑制了A-16的产生。相比之下,表达大鼠CYP3A2的重组微体产生了A-16,而其他同型包括CYP2C11的重组微体则没有。对人类肝微体活性的抗体的研究发现,抗大鼠CYP3A2和抗人CYP3A4在男性和女性人类肝脏的微体中引起了相似和实质性的抑制(注意到抗大鼠CYP3A2对CYP3A4有强烈的反应性)。在评估A-16产生的5种表达人类肝P450同型的重组微体中,只有CYP3A4产生了可测量的A-16。
Rat, dog, mouse, and human microsomes (from both sexes in all species) were all able to metabolize flubendiamide to A-16, except for microsomes from female rats. (Human microsomes, but not rat microsomes, additionally produced small amounts of hydroxybenzoic acid metabolite, A-20, however metabolism to A-16 appears to be a valid indicator of overall flubendiamide metabolism.) Antisera to CYP isoforms tested in male rat microsomes found that anti-CYP3A2 sera had no effect on A-16 production, whereas anti-CYP2C11 markedly inhibited A-16 production. In contrast, recombinant microsomes expressing rat CYP3A2 produced A-16, whereas other isoforms including CYP2C11 recombinant microsomes did not. Antibody effects on human liver microsome activities found that anti-rat CYP3A2 and anti-human CYP3A4 caused similar and substantial inhibition in microsomes from male or female human liver (it was noted that anti-rat CYP3A2 was strongly reactive toward CYP3A4). Of 5 recombinant microsomes expressing human liver P450 isoforms evaluated for A-16 production, only CYP3A4 yielded measurable A-16.
来源:Hazardous Substances Data Bank (HSDB)
代谢
F-344(F344/DuCrj)大鼠和Crlj: CD1(ICR)小鼠(每种类别、性别和给药期4只)以200 mg/kg/天的剂量经灌胃给予纯度为96.7%的非标记虫酰胺,溶剂为玉米油。治疗持续1、7或14天。动物在最后一次给药后24小时被处死。...测定了血浆、肝脏和脂肪中虫酰胺及其酰亚胺代谢物(A-14)的浓度。在雄性动物中,虫酰胺在这些组织中随时间增加不明显。雌性动物在所有研究组织中都有轻微的积累,到第7天达到稳态。A-14在大鼠两性脂肪中似乎都有积累,到第7天达到稳态。虫酰胺在肝脏和脂肪中的浓度总是高于血浆,且雌性动物中的浓度远高于雄性。第7天,雄性大鼠肝脏和脂肪中的虫酰胺浓度分别为1.3和8.9 mg/kg。雌性大鼠肝脏和脂肪中的浓度为26.7和68.0 mg/kg。第7天,雄性和雌性大鼠肝脏和脂肪中的A-14浓度分别为< 1.0和2.9 mg/kg。第7天,雄性小鼠肝脏和脂肪中的氟虫酰胺浓度为2.3和3.4 mg/kg。相应地,雌性小鼠的浓度为2.4和1.9 mg/kg(即与雌性大鼠显著的积累情况大不相同)。A-14在雄性和雌性小鼠中的水平通常低于定量限。本研究表明,雌性大鼠对虫酰胺的代谢能力有限,并且倾向于代谢大量A-14的情况并不适用于小鼠的任何性别。
F-344 (F344/DuCrj) rats and Crlj: CD1 (ICR) mice (4/species/sex/dosing period) were dosed with 200 mg/kg/day unlabeled flubendiamide, purity 96.7% by gavage in corn oil. Treatments were daily for 1, 7, or 14 days. Animals were sacrificed 24 hr after the final dose. ...Concentrations of flubendiamide and of the iodophthalimide metabolite (A-14) /were determined/ in plasma, liver, and fat. Flubendiamide did not increase in these tissues over time in males. There was a marginal accumulation in females in all studied tissues, reaching steady state by day 7. A-14 appeared to be accumulating in fat in rats of both sexes, reaching steady state by day 7. Flubendiamide was always more concentrated in liver and fat than in plasma, and concentrations were much higher in females than in males. Day 7 concentrations of flubendiamide in liver and fat of male rats at day 7 were 1.3 and 8.9 mg/kg, respectively. Liver and fat concentrations in female rats were 26.7 and 68.0 mg/kg. A-14 concentrations in male and female rats for liver and fat at day 7 were identical at < 1.0 and 2.9 mg/kg, respectively. Flubendiamide concentrations on day 7 in liver and fat of male mice were 2.3 and 3.4 mg/kg, respectively. Corresponding levels in female mice were 2.4 and 1.9 mg/kg (i.e. much unlike the marked accumulation in female rats). A-14 levels were generally below quantification limits in both male and female mice. This study indicates that limited metabolic capacity of female rats toward flubendiamide and tendency to metabolize significant amounts of A-14 do not apply to either sex of mice.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 立即急救:确保已经进行了充分的中和。如果患者停止呼吸,请开始人工呼吸,最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩,按训练操作。如有必要,执行心肺复苏。立即用缓慢流动的冲洗受污染的眼睛。不要催吐。如果患者呕吐,让患者向前倾或将其置于左侧(如果可能的话,头部向下),以保持呼吸道畅通,防止吸入。保持患者安静,维持正常体温。寻求医疗救助。 /毒物A和B/
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 基本治疗:建立专利气道(如有需要,使用口咽或鼻咽气道)。如有必要,进行吸痰。观察呼吸不足的迹象,如有需要,辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺肿,如有必要,进行治疗……。监测休克,如有必要,进行治疗……。预防癫痫发作,如有必要,进行治疗……。对于眼睛污染,立即用冲洗眼睛。在运输过程中,用0.9%的生理盐(NS)持续冲洗每只眼睛……。不要使用催吐剂。对于摄入,如果患者能吞咽、有强烈的干呕反射且不流口,则用温冲洗口腔,并给予5毫升/千克,最多200毫升的进行稀释……。在去污后,用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 高级治疗:对于无意识、严重肺肿或严重呼吸困难的病人,考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺肿……。对于严重的支气管痉挛,考虑给予β激动剂,如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持