3-(3-联苯基-1,2,3,4-四氢萘基-1-基)-4-羟基-2H-1-苯并吡喃-2-酮 | 56073-07-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: 3-(3-联苯基-1,2,3,4-四氢萘基-1-基)-4-羟基-2H-1-苯并吡喃-2-酮
• 中文别名: 联苯杀鼠萘；鼠得克
• 英文名称: difenacoum
• 英文别名: 3-(3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl)-4-hydroxycoumarin；4-hydroxy-3-[3-(4-phenylphenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]chromen-2-one
• CAS: 56073-07-5
• 化学式: C₃₁H₂₄O₃
• 分子量: 444.53
• InChiKey: FVQITOLOYMWVFU-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：

  可燃；燃烧会产生刺激性烟雾。

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

Bromadiolone, brodifacoum 和 coumatetralyl 也同样在大鼠体内发现了未改变的父母化合物，而对于difenacoum来说，代谢物占主导地位。difenacoum 反式异构体的代谢和消除速度比顺式异构体更快。

Bromadiolone, brodifacoum and coumatetralyl were also found in rats as unchanged parent compounds, whereas in the case of difenacoum metabolites predominated. The metabolism and elimination of the difenacoum trans isomer was more rapid than for the cis isomer.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维生素K1（Konakion）/磷酸氢钠/在抗凝血（凝血酶原复合物活性<30%）的新西兰白兔中的药理反应是通过测量外周血浆中的凝血酶原复合物活性（P.C.A.）来确定的。在预先用...迪芬纳库姆（0.85 mg/kg或8.5 mg/kg）处理的动物中，P.C.A.在给予维生素K1（0.5 mg/kg）后4小时达到最大值，并以下降速率表明完全抑制了凝血因子合成。...迪芬纳库姆的作用持续时间比华法林长得多。...迪芬纳库姆/是/...比华法林在体内更能持续有效地拮抗维生素K1。...

The pharmacological response to vitamin K1 (Konakion) /phytonadione/ in anticoagulated (prothrombin complex activity <30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with ... difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a max 4 hr after admin of vitamin K1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. ... The duration of action of ... difenacoum was much longer than that of warfarin. ... Difenacoum /is a/ ... more potent and persistent antagonist of vitamin K1 than warfarin in vivo. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

以下药物可能会增加对香豆素或香豆素衍生物的反应：酒精（急性中毒）、别嘌醇、氨基水杨酸、胺碘酮、雄激素类固醇、水合氯醛、氯霉素、西咪替丁、吉非贝齐、复方新诺明、达那唑、碘赛罗宁钠、二氮嗪、二氟尼柳、双硫仑、红霉素、依他尼酸、苯丙酸钙、胰高血糖素、布洛芬、吲哚美辛、流感病毒疫苗、异烟肼、美洛昔康、甲芬那酸、甲巯咪唑、甲硝唑、咪康唑、萘啶酸、新霉素（口服）、己酮可可碱、保泰松、丙氧酚、丙硫氧嘧啶、奎尼丁、奎宁、水杨酸盐、链激酶、磺吡酮、磺胺类药物、舒林酸、四环素、噻嗪类利尿剂、甲状腺药物、三环类抗抑郁药、尿激酶、维生素E。/香豆素和香豆素衍生物/

The following drugs ... may increase ... response to coumarin or indandione derivatives: alcohol (acute intoxication), allopurinol, aminosalicylic acid, amiodarone, anabolic steroids, chloral hydrate, chloramphenicol, cimetidine, clofibrate, co-trimoxazole, danazol, dextrothyroxine sodium, diazoxide, diflunisal, disulfiram, erythromycin, ethacrynic acid, fenoprofen calcium, glucagon, ibuprofen, indomethacin, influenza virus vaccine, isoniazid, meclofenamate, mefenamic acid, methylthiouracil, metronidazole, miconazole, nalidixic acid, neomycin (oral), pentoxifylline, phenylbutazone, propoxyphene, propylthiouracil, quinidine, quinine, salicylates, streptokinase, sulfinpyrazone, sulfonamides, sulindac, tetracyclines, thiazides, thyroid drugs, tricyclic antidepressants, urokinase, vitamin E. /Coumarin and indandione derivatives/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

以下是可能会降低香豆素或香豆素衍生物类药物效果的药物：酒精（慢性酒精中毒）、巴比妥类药物、卡马西平、皮质类固醇、促皮质激素、乙氯戊醇、氯喹咪唑、灰黄霉素、巯嘌呤、美沙酮、含有雌激素的口服避孕药、利福平、螺内酯、维生素K。/香豆素和香豆素衍生物/

The following drugs ... may ... decrease ... response to coumarin or indandione derivatives: alcohol (chronic alcoholism), barbiturates, carbamazepine, corticosteroids, corticotropin, ethchlorvynol, glutethimide, griseofulvin, mercaptopurine, methaqualone, oral contraceptives containing estrogen, rifampin, spironolactone, vitamin K. /Coumarin and indandione derivatives/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一系列抗凝血杀鼠剂与主要土壤有机成分——腐殖酸（HA）的绑定常数（K）是通过前沿分析法定量的。绑定常数的顺序与之前论文中获得的顺序相同，即：溴鼠隆>溴敌隆>双酚钠>氯鼠酮>双香豆素，这确认了前沿分析法在确定绑定常数方面的有效性。此外，首次可以确定与HA未结合的杀鼠剂浓度。通过这种方法，研究人员清楚地展示了HA酸能保护人类肝癌细胞系HepG2免受所有测试杀鼠剂的细胞毒性，并且杀鼠剂的毒性直接与介质中自由杀鼠剂部分（即与HA未结合的杀鼠剂）相关。

The binding constants (K) of a series of anticoagulant rodenticides with the main soil organic component, humic acid (HA), were determined using frontal analysis approach. The order of the binding constants was identical as the one obtained in a previous paper, i.e. bromadiolone>brodifacoum>difenacoum>chlorophacinone>diphacinone, confirming the power of this frontal analysis approach for the determination of binding constants. Moreover, and for the first time, the concentration of unbound rodenticide to HAs could be determined. Thanks this approach, /researchers/ could clearly demonstrate that HA acid protected the human hepatoma cell line HepG2 against the cytotoxicity of all the rodenticides tested and that the toxicity of rodenticides was directly linked to the free rodenticide fraction in the medium (i.e. unbound rodenticide to HA).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

人类暴露于第二代和香豆素类抗凝剂会产生与抗凝效果一致的症状（例如，血肿、呕血、血尿、容易瘀伤）。对于暴露情况的处理，特别是大量和反复暴露的情况，可能需要维生素K1治疗并监测凝血酶原时间，持续数月。

Human exposure to second-generation and indandione anticoagulants produces symptoms consistent with anticoagulation effects (e.g., hematomas, hematemesis, hematuria, easy bruisability). Treatment of cases of exposure, particularly of substantial and repeated exposure, may require vitamin K1 therapy and monitoring of prothrombin times for periods of many months.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在单次口服14C-二苯甲酮剂量为1.2 mg/kg体重后，24小时内在大鼠肝脏中发现了最高的放射性浓度（剂量的41.5%）。从肝脏中的消除是双相的。在第一个快速阶段，放射性消除的半衰期是3天，对于较慢的阶段是118天。肾脏中也出现了类似的双相消除。在胰腺中，浓度下降比任何其他组织都要慢（182天）。在给药后24小时内，肝脏中的主要成分是母化合物（42%）。

After a single oral (14)C-difenacoum dose of 1.2 mg/kg bw, the highest concn of radioactivity (41.5% of the dose) was found in the rat liver 24 hr after dosing. The elimination from the liver was biphasic. The half-life of elimination of the radioactivity during the first rapid phase was 3 days, and for the slower phase was 118 days. A similar biphasic elimination was also apparent in the kidney. In the pancreas the concn declined more slowly than in any of the other tissues (182 days). The parent compound was the major component in the liver 24 hr after dosing (42%).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在我们的第一次实验中，双炔酚（0.5毫克/千克）在给药后9天内杀死了50%的雄性小鼠，而在这项研究中没有雌性小鼠死亡。在第二组实验中，测定了双炔酚对雄性和雌性大鼠的抗凝作用。在静息状态下，雄性和雌性大鼠的凝血酶原复合物活性（PCA）没有显著差异。在双炔酚给药后（0.4毫克/千克，腹腔注射）的前24小时内，两种性别的PCA都呈单指数下降。然而，在双炔酚给药后6、12和24小时，雄性大鼠的PCA显著（P<0.05）低于雌性大鼠。PCA在随后的48小时内开始恢复，在这段时间内，雌性大鼠的恢复情况有很大的变异性。双炔酚在雄性和雌性大鼠中的作用起始差异似乎不是由于雌性大鼠药物消除速率更快，因为给药后24小时双炔酚的血浆浓度在两种性别中是相同的。还研究了大鼠肝脏中维生素K1的浓度。对照组大鼠中维生素K1水平为35.1 +/- 18.6 ng/(克肝脏)（雄性）和29.4 +/- 5.4 ng/(克肝脏)（雌性），但在双炔酚给药后24小时，所有大鼠的维生素K1水平都非常低或检测不到。

... In our first experiment difenacoum (0.5 mg/kg) killed 50% of male mice within 9 days of its admin, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 hr after admin of difenacoum (0.4 mg/kg ip), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 hr after difenacoum, the PCA in male rats was significantly (P<0.05) lower than in female rats. PCA began to recover over the subsequent 48 hr in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concns of difenacoum 24 hr after its admin were the same in both sexes. The concn of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 +/- 18.6 ng/(g liver) (male), and 29.4 +/- 5.4 ng/(g liver) (females) in control rats, but 24 hr after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

三十二只雄性大鼠通过口服灌胃方式给予1.2毫克/千克的(14)C-标记-二苯甲酰亚砜（香豆素部分的苯环）（比活性：1961兆贝克勒尔/毫摩尔；放射化学纯度：93.1%，顺式：反式比例：44:56）。每个时间点有三只动物在给药后1、4和8天以及2、4、8、12和26周被安乐死。通过心脏穿刺收集血液，并取出肝脏、肾脏、胰腺、唾液腺和一部分腹部脂肪进行放射性分析。测量每个血样的凝血酶原时间和kaolin- cephalin时间。肝脏是隔离放射性标记的主要组织。给药后24小时，从器官中回收了41%的给药剂量。即使在给药后6个月，仍有3%的给药剂量存在于肝脏中。注意到双相消除过程，快速相的半衰期为3天，慢相的半衰期为118天。活性成分的顺式异构体在肝脏中停留时间更长。到14天时，反式形式已不再可检测。肝脏中还隔离了其他代谢物，但在研究中未进行化学鉴定。...

Thirty two male rats were dosed orally by gavage with 1.2 mg/kg of (14)C-labeled-Difenacoum (phenyl-ring of coumarin moiety) (specific activity: 1961 Mbq/mmole; radiochemical purity: 93.1%, cis:trans ratio: 44:56). Three animals per time point were euthanized at 1, 4 and 8 days and 2, 4, 8, 12 and 26 weeks after dosing. Blood was collected by cardiac puncture and the liver, kidneys, pancrease, salivary glands and a sample of abdominal fat were removed for radioanalysis. The prothrombin time and kaolin- cephalin time were measured for each blood sample. The liver was the primary tissue in which the radiolabel was isolated. Forty one percent of the administered dose was recovered from the organ 24 hours after dosing. Even 6 months after dosing, 3% of the administered dose was still present in the liver. A biphasic elimination process was noted with a half-life for the rapid phase being 3 days and a half-life of the slow phase of 118 days. The cis isomer of the active ingredient demonstrated a longer residence time in the liver. By 14 days, the trans form was no longer detectable. Other metabolites were also isolated in the liver, but were not chemically identified in the study. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

脂肪中的浓度相对较低。difencoum具有很强的亲脂性，但由于对组织中的特定结合位点具有高亲和力，因此对组织分布的影响并不显著。

The concentration in fat was relatively low. Difenacoum is highly lipophilic, but that does not significantly affect tissue distribution due to a high affinity for specific binding sites in tissues.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  4-羟基香豆素 、 3-(4-联苯基)-1,2,3,4-四氢-1-萘酚 在 对甲苯磺酸 作用下， 以 甲醇 、 甲苯 为溶剂， 生成 3-(3-联苯基-1,2,3,4-四氢萘基-1-基)-4-羟基-2H-1-苯并吡喃-2-酮
  参考文献：
  名称：

  PROCESS FOR THE PREPARATION OF SUBSTITUTED 4-HYDROXYCOUMARINS

  摘要：

  公开号：

  EP0681577B1

文献信息

• [EN] MICROBIOCIDAL OXADIAZOLE DERIVATIVES<br/>[FR] DÉRIVÉS D'OXADIAZOLE MICROBIOCIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2017157962A1

  公开（公告）日：2017-09-21

  Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially fungicides.

  式(I)的化合物，其中取代基如权利要求1所定义，作为杀虫剂特别是杀菌剂有用。
• [EN] INSECTICIDAL TRIAZINONE DERIVATIVES<br/>[FR] DÉRIVÉS DE TRIAZINONE INSECTICIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2013079350A1

  公开（公告）日：2013-06-06

  Compounds of the formula (I) or (I'), wherein the substituents are as defined in claim 1, are useful as pesticides.

  式(I)或(I')的化合物，其中取代基如权利要求1所定义的那样，可用作杀虫剂。
• Novel insecticides
  申请人：Syngenta Participations AG

  公开号：EP2540718A1

  公开（公告）日：2013-01-02

  Compounds of formula I wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts and all stereoisomers and tautomeric forms of the compounds of formula I can be used as insecticides and can be prepared in a manner known per se.

  式I的化合物 其中取代基如权利要求1所定义，并且式I化合物的农药可接受盐以及所有立体异构体和互变异构形式可用作杀虫剂，并且可以按照已知的方法制备。
• Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
  申请人：Dow AgroSciences LLC

  公开号：US20180279612A1

  公开（公告）日：2018-10-04

  This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (“Formula One”).

  这份披露涉及具有对节肢动物门、软体动物门和线虫门害虫具有杀虫效用的分子领域，用于生产此类分子的过程，用于此类过程的中间体，含有此类分子的杀虫组合物，以及使用此类杀虫组合物对抗此类害虫的过程。这些杀虫组合物可以用作螨虫剂、杀虫剂、螨虫剂、软体动物杀虫剂和线虫杀虫剂。本文件披露了具有以下式（“式一”）的分子。
• [EN] MOLECULES HAVING PESTICIDAL UTILITY, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES, RELATED THERETO<br/>[FR] MOLÉCULES PRÉSENTANT UNE UTILITÉ EN TANT QUE PESTICIDE, ET LEURS INTERMÉDIAIRES, COMPOSITIONS ET PROCÉDÉS
  申请人：DOW AGROSCIENCES LLC

  公开号：WO2017040194A1

  公开（公告）日：2017-03-09

  This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions aga inst such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula ("Formula One").

  这份披露涉及具有对节肢动物门、软体动物门和线虫门害虫有用的分子领域，用于生产这种分子的过程，用于这种过程的中间体，含有这种分子的杀虫剂组合物，以及使用这种杀虫剂组合物对抗这些害虫的过程。这些杀虫剂组合物可以用作螨虫剂、杀虫剂、螨虫剂、软体动物杀虫剂和线虫杀虫剂。本文件披露了具有以下化学式（“化学式一”）的分子。