双炔酰菌胺 | 374726-62-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 双炔酰菌胺
• 中文别名: (RS)-N-2-(4-氯苯基)-N-[2-(3-甲氧基-4-丙炔-2-基氧基苯基)乙基]-2-丙炔-2-基氧基乙酰胺
• 英文名称: mandipropamid
• 英文别名: 2-(4-chlorophenyl)-N-[2-(3-methoxy-4-(2-propynyloxy)phenyl)ethyl]-2-(2-propynyloxy)acetamide；2-(4-chlorophenyl)-N-[2-(3-methoxy-4-prop-2-ynoxyphenyl)ethyl]-2-prop-2-ynoxyacetamide
• CAS: 374726-62-2
• 化学式: C₂₃H₂₂ClNO₄
• 分子量: 411.885
• InChiKey: KWLVWJPJKJMCSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

每组每性别4只大鼠的尿液和粪便混合样本（如下表中的第3、8和9组），接受了单次口服灌胃剂量的[氯苯基-U-14C] NOA446510 300 mg/kg和[甲氧基苯基-U-14C] NOA446510 3 mg/kg及300 mg/kg，对其代谢物/成分进行了评估。此外，每组每性别4只胆管插管大鼠的尿液、粪便和胆汁（第10和11组），接受了单次口服灌胃剂量的[甲氧基苯基-U-14C] NOA446510 3 mg/kg和300 mg/kg，也进行了评估。在报告编号CTL/UR0786/REG/REPT（记录230447）中，3只雄性大鼠的尿液和粪便混合样本在单次口服灌胃3 mg/kg [甲氧基苯基-U-14C] NOA446510后24小时以及连续14次剂量3 mg/kg后24小时，对其代谢物/成分进行了评估。确定了所有主要代谢物/成分，占给药剂量的5%以上（高效液相色谱（HPLC）和质谱（MS））。提出的代谢途径是：失去一个或两个丙炔基团，随后进行葡萄糖醛酸化和O-去甲基化（包括示意图）。两种放射性物种的代谢差异并未表明。在给予高剂量水平（300 mg/kg）的氯苯基和甲氧基苯基放射性形式后，排泄物的代谢轮廓在质量和数量上相似。 单次剂量3 mg/kg [甲氧基苯基-U-14C] NOA446510 雌性大鼠在96小时内通过尿液排出了剂量的46%，通过粪便排出了41%。主要的尿液代谢物（剂量的40%）是NOA458422葡萄糖醛酸苷（NOA458422的O-葡萄糖醛酸苷（2-（4-氯苯基）-N-[2-（4-羟基-3-甲氧基苯基）乙基]-2-丙-2-炔氧基乙酰胺））。在粪便中，NOA446510占剂量的12%，NOA458422占19%。雄性大鼠在96小时内通过尿液排出了剂量的14%，通过粪便排出了72.3%。主要的尿液代谢物（剂量的10%）是SYN534133（CGA 380775的葡萄糖醛酸苷（2-4（氯苯基）-2-羟基-N-[2-（4-羟基-3-甲氧基苯基）乙基]乙酰胺））。在粪便中，NOA458422、原形和NOA458422葡萄糖醛酸苷分别占剂量的29.2%、21.3%和12.9%。 雄性大鼠连续14天每天剂量3 mg/kg [甲氧基苯基-U-14C] NOA446510 排泄物成分轮廓在首次剂量后24小时和14次剂量后相似，并且与上述单次剂量研究的结果一致。 单次剂量300 mg/kg [氯苯基-U-14C] NOA446510 雌性大鼠在96小时内通过尿液排出了剂量的6%，通过粪便排出了81%。NOA458422葡萄糖醛酸苷是主要的尿液代谢物（剂量的3.7%）。NOA446510占雌性大鼠粪便中剂量的75%。雄性大鼠在96小时内通过尿液排出了剂量的2%，通过粪便排出了86%。SYN534133，占剂量的1%，是主要的尿液代谢物。NOA446510占粪便中剂量的79%。 单次剂量300 mg/kg [甲氧基苯基-U-14C] NOA446510 雌性大鼠在96小时内通过尿液排出了剂量的11%，通过粪便排出了82%。尿液和粪便中的主要成分分别是NOA458422葡萄糖醛酸苷（剂量的7%）和NOA446510（剂量的71%）。雄性大鼠在96小时内通过尿液排出了剂量的3%，通过粪便排出了90%。尿液和粪便中的主要成分分别是SYN534133（占剂量的2%）和NOA446510（剂量的73%）。 单次剂量3 mg/kg [甲氧基苯基-U-14C] NOA446510与胆管插管大鼠 在48小时内，雌性大鼠通过尿液排出了剂量的15%，通过胆汁排出了46%，通过粪便排出了22%。尿液和胆汁中的主要成分是NOA458422葡萄糖醛酸苷，分别占剂量的10%和41%。NOA4

Pooled samples of urine and feces from 4 rats per sex per group (Groups 3, 8, and 9 listed in table below) that received a single oral gavage dose of [Chlorophenyl-U-14C] NOA446510 at 300 mg/kg and [methoxyphenyl-U-14C] NOA446510 at 3 and 300 mg/kg were evaluated for metabolites/components. Additionally, urine, feces, and bile from 4 bile duct cannulated rats per sex per group (Groups 10 and 11) that received a single oral gavage dose of [methoxyphenyl-U- 14C] NOA446510 at 3 and 300 mg/kg were evaluated. In Report No. CTL/UR0786/REG/REPT (record 230447), pooled samples of urine and feces from 3 males were evaluated for metabolites/components 24 hours after a single oral gavage dose with 3 mg/kg of [methoxyphenyl-U-14C] NOA446510 and 24 hours after 14 consecutive doses at 3 mg/kg. All major metabolites/components, representing greater than 5% of administered dose were identified (high performance liquid chromatography (HPLC) and mass spectrometry (MS)). The proposed metabolic pathway was described: loss of one or both of the propargyl groups followed by glucuronidation and O-demethylation (a schematic was included). Differences in metabolism of the two radiolabeled species were not indicated. Metabolic profiles of excreta following administration of both the chlorophenyl and methoxyphenyl radiolabeled forms at the high dose level (300 mg/kg) were qualitatively and quantitatively similar. Single Dose of 3 mg/kg [Methoxyphenyl-U-14C] NOA446510 Females excreted 46% of the dose in urine and 41% in feces during 96 hours. The major urinary metabolite (40% of dose) was NOA458422 glucuronide (the O-glucuronide of NOA458422 (2-(4-chloro-phenyl)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]- 2-prop-2-ynyloxy-acetamide)). In feces, NOA446510 was 12% of dose and NOA458422 was 19%. Males excreted 14% of dose in urine and 72.3% in feces during 96 hours. The major urinary metabolite (10% of dose) was SYN534133 (the glucuronide of CGA 380775 (2-4(chlorophenyl)- 2-hudroxy-N-[2-(4-hudroxy-3-methoxy-phenyl)-ethyl]acetamide)). In feces NOA458422, parent, and NOA458422 glucuronide accounted for 29.2%, 21.3%, and 12.9% of dose respectively. 14 Consecutive Daily Doses in Males at 3 mg/kg [Methoxyphenyl-U-14C] NOA446510 Component profiles of excreta were similar between samples taken 24 hours after the first and 14 doses and consistent with results in the single dose study above. Single Dose of 300 mg/kg [Chlorophenyl-U-14C] NOA446510 Females excreted 6% of dose in urine and 81% of dose in feces during 96 hours. NOA458422 glucuronide was the major urinary metabolite (3.7% of dose). NOA446510 accounted for 75% of dose in feces of females. Males excreted 2% of dose in urine and 86% of dose in feces during 96 hours. SYN534133, at 1% of dose, was the major urinary metabolite. NOA446510 accounted for 79% of dose in feces. Single Dose of 300 mg/kg [Methoxyphenyl-U-14C] NOA446510 Females excreted 11% of dose in urine and 82% of dose in feces during 96 hours. NOA458422 glucuronide (7% of dose) and NOA446510 (71% of dose) were the major components in urine and feces respectively. Males had 3% of dose in urine and 90% of dose in feces during 96 hours. SYN534133, accounting for 2% of dose, and NOA446510 (73% of dose) were the major components in urine and feces respectively. Single Dose of 3 mg/kg [Methoxyphenyl-U-14C] NOA446510 with Bile Duct Cannulated Rats During 48 hours, females excreted 15% of dose in urine, 46% of dose in bile, and 22% of dose in feces. The major component in urine and bile was NOA458422 glucuronide at 10% and 41% of dose respectively. NOA446510 was the major component in feces (22.3% of dose). Males excreted 1%, 73%, and 15% of dose in urine, bile, and feces respectively during 48 hours. NOA458422 glucuronide was the major component in urine (0.7% of dose) and bile (62.2% of dose). NOA446510 accounted for 13% of dose in feces. Single Dose of 300 mg/kg [Methoxyphenyl-U- 14C] NOA446510 with Bile Duct Cannulated Rats 28%, 12%, and 37% of administered radioactivity was excreted by females in urine, bile, and feces respectively during 48 hours. NOA458422 glucuronide was the major component in urine (25% of dose) and bile (10% of dose). NOA446510 accounted for 37% of dose in feces. Males excreted 1% of dose in urine, 28% in bile, and 39% in feces during 48 hours. NOA458422 glucuronide was the major component in urine (0.5% of dose) and bile (22.5% of dose). NOA446510 was 38.6% of dose in feces of males.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在口服灌胃研究中，每组每性别27只C57BL/10Jf/Alpk小鼠接受了一次口服剂量的(Methoxyphenyl-U-(14)C) NOA446510/mandipropamid/，剂量为10、50和500 mg/kg。在初步的饮食研究中，每组每性别55只C57BL/10Jf/Alpk小鼠通过饮食接受了(Methoxyphenyl-U-(14)C) NOA446510，剂量为800 ppm，持续2天。在主要的饮食研究中，每组每性别28只C57BL/10Jf/Alpk小鼠通过饮食接受了(Methoxyphenyl-U-(14)C) NOA446510，剂量为300、800、2000和5000 ppm，持续7天。在静脉注射研究中，每组每性别5只C57BL/10Jf/Alpk小鼠接受了一次静脉注射剂量的(Methoxyphenyl-U-(14)C) NOA446510，剂量为10 mg/kg。... 在尿液中，测得五种主要代谢物，占所有样本中放射性活性的90%以上。代谢物4（NOA458422葡萄糖苷酸（NOA458422（2-(4-氯-苯基)-N-(2-(4-羟基-3-甲氧基-苯基)-乙基)-2-丙-2-炔氧基乙酰胺）的O-葡萄糖苷酸）是主要成分，代谢物2（仅提供了一个图表）在所有3个剂量水平上都是第二。尿液中未检测到未改变的NOA446510。在10 mg/kg时，0-24小时粪便样本的代谢概况与尿液概况相似，在雄性中检测到了少量NOA446510，但在雌性中未检测到。在50和500 mg/kg时，粪便中的主要成分是未改变的NOA446510，两种性别都是如此。在血浆中，代谢物4在所有剂量水平上都是两性的主要成分；代谢物2在10和50 mg/kg时是一个非常微小的成分；在500 mg/kg时检测到了少量的未改变的NOA446510。在800 ppm的2天饮食研究中，全血中的Cmax在开始给药后38.5小时（雄性）和41.0小时（雌性）达到。在7天的饮食研究中，与口服灌胃研究一样，放射性活性与血液的血浆部分相关，没有表明性别差异，并且放射性活性与剂量水平成正比（尽管由于缺乏实现的剂量计算，特定的血浆放射性活性浓度数据有限）。尿代谢物概况在质量和数量上与口服灌胃动物相似，并表明与性别、剂量水平和给药次数无关。代谢物4是尿液中的主要成分，在任何样本中均未检测到未改变的NOA446510。粪便样本中在所有样本中都有未改变的NOA446510。代谢物2和4存在于所有血浆样本中，未检测到未改变的NOA446510。在单次静脉注射研究（10 mg/kg）中，大部分放射性标记物也在给药后24小时内排泄。在24小时内，尿液中含有58%（雄性）和72%（雌性）的剂量，粪便中有25%（雄性）和40%（雌性）。从0-24小时和24-48小时后的治疗收集观察到的尿代谢物概况与口服灌胃给药后观察到的相同，没有质的性别差异。丧失丙炔基团和葡萄糖苷酸化被建议作为生物转化的主要途径。

In an oral gavage study, 27 C57BL/10Jf/Alpk mice per sex per group received a single oral dose of (Methoxyphenyl-U-(14)C) NOA446510 /mandipropamid/ at 10, 50, and 500 mg/kg. In a preliminary dietary study, 55 C57BL/10Jf/Alpk mice per sex received (Methoxyphenyl-U-(14)C) NOA446510 in the diet at 800 ppm for 2 days. In the main dietary study, 28 C57BL/10Jf/Alpk mice per sex per group received (Methoxyphenyl-U-(14)C) NOA446510 in the diet at 300, 800, 2000, and 5000 ppm for 7 days. In an intravenous study, 5 C57BL/10Jf/Alpk mice per sex received a single intravenous dose of (Methoxyphenyl-U-(14)C) NOA446510 at 10 mg/kg. ... In urine, five principal metabolites were measured accounting for more than 90% of radioactivity in all samples. Metabolite 4 (NOA458422 glucuronide (the O-glucuronide of NOA458422 (2-(4-chloro-phenyl)-N- (2-(4-hydroxy-3-methoxy-phenyl)-ethyl)-2-prop-2-ynyloxy-acetamide)) was the main component and metabolite 2 (only a diagram was provided) the second, at all 3 dose levels. Unchanged NOA446510 was not present in urine. At 10 mg/kg, the metabolic profile of the 0-24 hour feces sample was similar to the urine profile and a small amount of NOA446510 was detected in males but not females. At 50 and 500 mg/kg, the major component in feces was unchanged NOA446510 in both sexes. In plasma, metabolite 4 was the major component in both sexes at all dose levels; metabolite 2 was a very minor component at 10 and 50 mg/kg; and a small amount of unchanged NOA446510 was detected at 500 mg/kg. In the 2 day dietary study at 800 ppm, Cmax in whole blood was reached at 38.5 hours (males) and 41.0 hours (females) after the start of dosing. In the 7 day dietary study, as with the oral gavage study, radioactivity was associated with the plasma compartment of blood and no sex differences were indicated and radioactivity was proportional to dose level (although specific plasma radioactivity concentration data were limited by lack of achieved dose calculations). Urinary metabolite profiles were qualitatively and quantitatively similar to those for oral gavage animals and were indicated to be independent of sex, dose level, and number of doses. Metabolite 4 was the major urinary component and no unchanged NOA446510 was detected in any samples. Fecal samples had unchanged NOA446510 in all samples. Metabolites 2 and 4 were present in all plasma samples and unchanged NOA446510 was not detected. In the single dose intravenous study (10 mg/kg), the majority of radiolabel was also excreted within 24 hours of dosing. Urine contained 58% (males) and 72% (females) of dose during 24 hours and feces had 25% (males) and 40% (females). Urinary metabolite profiles observed from the 0-24 hour and 24-48 hour post treatment collections were the same as those observed following oral gavage dosing with no qualitative sex differences. Loss of the propargyl groups and glucuronidation was suggested as the principal route of biotransformation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在第1阶段，每组每个性别的大鼠（Wistar系）3只，分别接受100、500和5000 ppm的未标记NOA446510（/mandipropamid/ 96.5%）饮食，连续11天，然后在第12天接受相应水平的放射性标记饮食。此外，在第1阶段，每组每个性别的3只大鼠（组4、5和6）通过口服灌胃连续11天接受未标记的NOA446510，剂量为10、50和500 mg/kg/天，然后在第12天接受相同水平的单次口服(Methoxyphenyl-U-(14)C) NOA446510。在第2阶段，每组每个性别的6只大鼠（组7、8和9）接受连续11天的未标记NOA446510饮食，然后在第12天接受含有(14)C NOA446510的饮食。... 通过尿液和血浆中的高效液相色谱-质谱（HPLC-MS）鉴定代谢物。由于雌性尿液中主要的代谢物NOA458422葡萄糖苷酸（在NOA446510失去一个炔丙基团后通过葡萄糖苷酸化形成）在雄性样本中仅以可忽略的量（如果有的话）存在，这表明雌雄在清除途径和机制上可能存在差异。所有其他雄性和雌性尿液代谢物的比例相似。血浆轮廓对男性和女性是相同的。大多数代谢物是葡萄糖苷酸。请参阅研究报告中代谢物/组分的建议结构、图表、描述、质谱、HPLC色谱图等。SYN 534133（NOA446510失去两个炔丙基团后的葡萄糖苷酸）在雌雄尿液中以相似的浓度存在，是雄性样本中的主要代谢物。NOA458422葡萄糖苷酸是雌雄血浆中的主要代谢物。在第2阶段，48小时内（9.5、31.9和344.0 ug.h.g-1对于雄性，8.0、34.9和328.9 ug.h.g-1对于雌性，在100、500和5000 ppm下分别）血浆浓度与时间暴露曲线下的面积（AUC0-48(ug.h.g-1)）随着饮食剂量的增加而线性增加，对两性的影响相似。

In phase 1, three Alpk:APfSD (Wistar-derived) rats per sex per group (groups 1, 2, and 3) received unlabeled NOA446510 (/mandipropamid/ 96.5%) in the diet at 100, 500, and 5000 ppm for 11 consecutive days followed by radiolabeled diet at the corresponding levels on day 12. Additionally, in phase 1, three rats per sex per group (groups 4, 5, and 6) received unlabeled NOA446510 by oral gavage for 11 consecutive days at 10, 50, and 500 mg/kg/day followed by a single oral dose of (Methoxyphenyl-U-(14)C) NOA446510 on day 12 at the same levels. In phase 2, six rats per sex per group (groups 7, 8, and 9) received unlabeled NOA446510 in the diet for 11 consecutive days followed (14)C NOA446510 containing diets on the 12th day. ... Metabolites were identified (high performance liquid chromatography-mass spectrometry (HPLC-MS)) in urine and plasma. The urinary metabolite profile differed for males and females mainly due to the major metabolite found in female urine NOA458422 glucuronide (formed by glucuronidation of NOA446510 after loss of one of the propargyl groups) which was present in only negligible amounts (if at all) in male samples (may indicate a difference in the route and mechanism of clearance). All other male and female urinary metabolites were present in similar proportions. Plasma profiles were the same for males and females. The majority of metabolites were glucuronides. See study for proposed structures, diagrams, descriptions, mass spectra, HPLC chromatograms, etc. of metabolites/components. SYN 534133 (a glucuronide of NOA446510 after loss of both propargyl groups), present at similar concentrations in urine of both males and females, was the major metabolite in male samples. NOA458422 glucuronide was the major metabolite in both male and female plasma. Phase 2 Area under the plasma concentration vs time exposure curve values (AUC0-48(ug.h.g-1)) increased linearly with dietary dose level similarly for both sexes over 48 hours (9.5, 31.9, and 344.0 ug.h.g-1 for males and 8.0, 34.9, and 328.9 ug.h.g-1 for females at 100, 500, and 5000 ppm respectively).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在第1阶段，每组每性别一只Alderley Park Beagle犬在第一天和第15天分别口服（明胶胶囊）单一剂量的（氯苯基-U-(14)C）NOA446510/mandipropamid/，剂量为100和800 mg/kg。 同样的动物在第5天到第14天也接受了未标记的NOA446510，剂量为100和800 mg/kg/天。 在第2阶段，每组每性别一只犬在第一天接受单一静脉剂量的（14）C NOA446510，剂量为3 mg/kg，并在第15天接受后续单一放射性口服剂量，剂量为3 mg/kg。 在每次放射性剂量给药后，动物被放置在代谢笼中，并在给药后6、12、24、36、48和72小时收集尿液和粪便（在室温下）。 在第1阶段，血液样本（5 mL）在第一天给药后1、2、3、4、6、8、12、24、36、48和72小时收集，在第15天给药后1、2、3、4、5、6、7、8、10、12和24小时收集。 在第2阶段，第一天给药后的血液采样时间为2、5、10、20和30分钟以及1、2、3、4、6、12和24小时，在第15天，血液在给药后1、2、3、4、5、6、7、8、10、12和24小时采样。 第1阶段 在第1阶段，单次口服放射性剂量（明胶胶囊）100 mg/kg后，雄性有7%的剂量，雌性有22%的剂量在72小时内通过尿液排出。 粪便中含雄性95%和雌性63%的剂量，在72小时内。 最大血浆浓度（Cmax），雄性为6.7和雌性为4.6 ug等价物/g，在给药后4和8小时（Tmax）达到。 血浆浓度与时间暴露曲线下的面积值（AUC0-24（h.ug/g））分别为雄性67和雌性51。 未改变的NOA446510在粪便中代表雄性73%和雌性54%的剂量（粪便中还发现了三种其他少量代谢物）。 6小时尿液样本含有5种主要代谢物（未发现未改变的NOA446510）。 雄性和雌性混合血浆含有未改变的NOA446510和5种其他代谢物。 ... 在800 mg/kg单次剂量后，两性的4%放射性剂量通过尿液排出，在72小时内，雄性71%和雌性18%的剂量在粪便中找到。 血浆Cmax浓度为25.0和17.5 ug等价物/g，在给药后6和10小时（Tmax）达到，分别为雄性和雌性。 产生的总暴露/时间（AUC0-24）值分别为雄性98 h.ug/g和雌性152 h.ug/g。 在粪便中，回收剂量的大部分是未改变的NOA446510，雄性67%和雌性12%。 6小时尿液样本中发现了5种主要代谢物（其中4种与100 mg/kg单次剂量相同）。 在0-48小时雄性和雌性血浆池中发现了未改变的NOA446510和3种在100 mg/kg单次剂量样本中发现的代谢物。 在重复（14）C NOA446510剂量100 mg/kg后，雄性和雌性犬分别有6%和5%的剂量通过尿液排出，在72小时内，雄性77%和雌性79%的剂量在粪便中。 Cmax值为6.0和4.3 ug等价物/g，在雄性和雌性给药后4和10小时（Tmax）达到，分别导致（AUC0-24）值为72和48 h.ug/g。 未改变的NOA446510在粪便中是主要成分，雄性59%和雌性70%（还发现了3种少量代谢物）。 6小时尿液样本含有与单次剂量100 mg/kg相同的5种代谢物，另外还有2种，未发现未改变的NOA446510。 雄性和雌性血浆池含有未改变的NOA446510，与单次剂量800 mg/kg样本中发现的3种代谢物相同，以及一种未确定的小种类。 在重复口服800 mg/kg放射性剂量后，雄性和雌性分别有3%和4%的剂量在尿液中，粪便在72小时内含有雄性91%和雌性94%的剂量。 Cmax浓度为49.7和28.6 ug等价物/g，在治疗后6小时（两性的Tmax）达到。 AUC0

In phase 1, one Alderley Park Beagle dog per sex per group received a single oral (gelatin capsule) dose of (Chlorophenyl-U-(14)C) NOA446510 /mandipropamid/ at 100 and 800 mg/kg on days 1 and 15. The same animals also received unlabeled NOA446510 on days 5 through 14 at 100 and 800 mg/kg/day. In phase 2, one dog per sex per group received a single intravenous dose of (14)C NOA446510 at 3 mg/kg on day 1 and a subsequent single radiolabeled oral dose at 3 mg/kg on day 15. Following each radiolabeled dose, animals were placed into metabolism cages and urine and feces were collected (at room temperature) 6, 12, 24, 36, 48, and 72 hours after dosing. In phase 1, blood samples (5 mL) were collected at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours on day 1 after dosing, and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours on day 15. In phase 2, blood sampling times on day 1 were 2, 5, 10, 20, and 30 minutes and 1, 2, 3, 4, 6, 12, and 24 hours post-treatment, and, on day 15, blood was sampled 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after dosing. Phase 1 In phase 1, after a single oral radiolabeled dose (gelatin capsule) at 100 mg/kg, 7% of dose for the male and 22% for the female respectively was excreted in urine over 72 hours. Feces contained 95% (male) and 63% (female) of dose over 72 hours. Maximum plasma concentrations (Cmax), 6.7 and 4.6 ug equivalents/g, were reached 4 and 8 hours after dosing (Tmax) for the male and female respectively. The area under the plasma concentration vs time exposure curve values (AUC0-24 (h.ug/g)) were 67 and 51 for the male and female respectively. Unchanged NOA446510 represented 73% (male) and 54% (female) of dose in feces (three other minor metabolites were found in feces). Six hour urine samples contained 5 major metabolites (no unchanged NOA446510 was found). Male and female pooled plasma contained unchanged NOA446510 and 5 other metabolites. ... After a single dose at 800 mg/kg, 4% of radioactive dose was excreted in urine of both sexes and 71% (male) and 18% (female) of dose was found in feces over 72 hours. Plasma Cmax concentrations were 25.0 and 17.5 ug equivalents/g reached at Tmax times of 6 and 10 hours after treatment for the male and female respectively. The resulting total exposure/time (AUC0-24) values were 98 h.ug/g (male) and 152 h.ug/g (female). In feces, the majority of recovered dose was unchanged NOA446510, 67% (male) and 12% (female). 5 major metabolites (4 were the same as at the100 mg/kg single dose) were found in the 6 hour urine samples (no unchanged NOA446510). Unchanged NOA446510 and 3 of the metabolites found in the 100 mg/kg single dose samples were identified in the 0-48 hour male and female plasma pools. Following the repeat (14)C NOA446510 dose at 100 mg/kg, 6% and 5% of dose was excreted in urine by the male and female dog respectively with 77% (male) and 79% (female) in feces over 72 hours. Cmax values of 6.0 and 4.3 ug equivalents/g were reached 4 and 10 hours after dosing (Tmax) in the male and female respectively, resulting in (AUC0-24) values of 72 and 48 h.ug/g respectively. Unchanged NOA446510 was identified as the major component in feces, 59% (males) and 70% females (3 minor metabolites were also found in feces). 6 hour urine samples contained the same 5 metabolites as the single dose 100 mg/kg plus 2 others and no unchanged NOA446510. The male and female plasma pool contained unchanged NOA446510, the same 3 metabolites found in the single dose 800 mg/kg samples, and an unidentified minor species. After the repeat oral 800 mg/kg radiolabeled dose, 3% (male) and 4% (female) of dose was found in urine, and feces contained 91% (male) and 94% (female) of dose during 72 hours. Cmax concentrations were 49.7 and 28.6 ug equivalents/g at 6 hours after treatment (Tmax for both sexes). AUC0-24 values for total exposure/time were 379 h.ug/g (male) and 410 h.ug/g (female). Unchanged NOA446510 accounted for 52% (male) and 93% (female) of dose in feces. Six hour urine samples contained the same 5 metabolites as the 800 mg/kg single dose group. 0-48 hour plasma samples contained NOA446510 and the same 3 metabolites as in the single dose 800 mg/kg samples (a fourth metabolite was also identified in female plasma). Phase 2 The male dog excreted 24% of dose and the female 31% in urine during 72 hours after the single intravenous radiolabeled 3 mg/kg dose with 45% (male) and 47% (female) of dose in feces. Major urinary metabolites were identified as the same 5 found in the single dose oral 100 mg/kg group samples in phase 1, plus one other. In male 0-24 hour plasma pools, unchanged NOA446510 and 5 of the metabolites identified in the phase one, 100 mg/kg single oral dose samples, plus one other, were detected. After the single radiolabeled oral dose (gelatin capsule) at 3 mg/kg on day 15, urine contained 14% (male) and 21% (female) of dose, and feces contained, 72% (male) and 66% (female) of dose during 72 hours. Major urinary metabolites for each sex were identified as the same 5 detected in the phase 1, single oral 100 mg/kg dose samples (female samples also contained a 6th species). In male and female 0-24 hour plasma pools, 2 of the 3 metabolites found in the phase 1 single oral dose 800 mg/kg samples plus one other were identified (other species were detected but at levels too low to identify). The proposed metabolic pathway was presented: loss of one or both propargyl groups followed by conjugation with glucuronic or sulphuric acid and O-demethylation with no cleavage of the molecule.

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。立即用缓慢流动的水冲洗受污染的眼睛。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。监测肺水肿，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，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（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水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。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、严重肺水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水肿……。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: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

遗传毒性：对女性全人血液的重复培养物进行了实验，在有无大鼠肝脏S9的情况下，分别暴露于NOA446510（/mandipropamid/ 96.5%）的浓度，分别为0（DMSO），0（未处理），10，50，100，250，500，1000，2000，3000和4119 g/mL，持续3小时，这是实验1。在实验2中，重复培养物在有S9的情况下暴露于0（DMSO），1，2.5，5，10，25，50，100和250 ug/mL，持续3小时，并在没有S9混合物的情况下以相同浓度暴露20小时。在处理开始后20小时收获细胞（收获前2小时加入colcemid）。在100 ug/mL及更高浓度下，报告了培养介质中测试材料的沉淀（略显浑浊/不透明）。在第一次试验中，在有无S9混合物的情况下，确定了0，10，50和100 ug/mL的异常中期。在第二次试验中，在没有S9的情况下确定了0，2.5，10和25 g/mL的异常细胞，在有激活的情况下确定了0，5，25和50 ug/mL的异常细胞。每个重复培养物对100个中期进行评分。选择用于染色体分析的处理水平是基于有丝分裂指数（毒性排除了高于所选水平的细胞评分）。与溶剂对照组相比，没有显示出异常细胞的统计学或生物学意义上的显著增加。阳性对照是有效的。

/GENOTOXICITY/ Duplicate cultures of female whole human blood were exposed, in the presence and absence of rat liver S9, to NOA446510 (/mandipropamid/ 96.5%) concentrations of 0 (DMSO), 0 (untreated), 10, 50, 100, 250, 500, 1000, 2000, 3000, and 4119 g/mL for 3 hours in experiment 1. In experiment 2, duplicate cultures were exposed, in the presence of S9 at 0 (DMSO), 1, 2.5, 5, 10, 25, 50, 100, and 250 ug/mL for 3 hours, and, at the same concentrations for 20 hours in the absence of S9 mix. Cells were harvested 20 hours after the start of treatment (colcemid was added 2 hours prior to harvest). Precipitation of test material in culture medium (slightly cloudy/opaque) was reported at 100 ug/mL and higher. In the first assay, aberrant metaphases were determined at 0, 10, 50, and 100 ug/mL in the absence and presence of S9 mix. In the second assay, aberrant cells were determined at 0, 2.5, 10, and 25 g/mL in the absence of S9, and at 0, 5, 25, and 50 ug/mL with activation. 100 metaphases per duplicate culture were scored. Treatment levels chosen for chromosome analysis were selected based on the mitotic index (toxicity precluded scoring cells above the levels chosen). No statistically or biologically significant increases in aberrant cells (compared to solvent controls) were indicated. Positive controls were functional.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/研究类型：豚鼠皮肤致敏；结果：致敏剂。/来自表格/

/LABORATORY ANIMALS: Acute Exposure/ Study type: Skin sensitization guinea pig; Results: Sensitizer. /From table/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

每组3只雄性Alpk:APfSD（Wistar衍生）大鼠，每天接受3毫克/千克的(Methoxyphenyl-U-(14)C) NOA446510 /mandipropamide/，持续多达14天。在连续每天给药3、7、10和14天后24小时内终止3只雄性大鼠，以及在连续14天给药的最后一天后1、4、7、14、21、28和49天终止。分析了肾上腺、大脑、心脏、肾脏、肝脏、肺、胰腺、脾脏、胸腺、甲状腺、睾丸以及血液、血浆、骨骼（股骨）、脂肪（腹部）和肌肉的放射性（LSC）。在首次给药后24小时和连续第14次给药后24小时，从3只雄性大鼠中收集尿液、粪便和笼子洗涤液，并分析其放射性（LSC）。放射性在初始给药后4天内达到稳态，随后在停止给药后迅速下降。在连续14天给药后，平均组织(14)C浓度在肝脏（0.727微克当量/克）和肾脏（0.234微克当量/克）中最高。从肝脏的消除是双相的，终末消除半衰期计算为4.2天，分布半衰期计算为2.3天。在肾脏中，消除半衰期为8.7天。骨骼消除半衰期为12.8天。稳态时所有其他组织的浓度通常较低（0.1微克当量/克或更少），放射性在最后给药后几天内下降到检测限以下。大部分放射性通过粪便排出（1次给药后排出的剂量的79%，连续14次给药后为66%）。尿液在1次给药后含有剂量的2.6%，在连续14次给药后含有7%。

3 male Alpk:APfSD (Wistar-derived) rats per group received (Methoxyphenyl-U-(14)C) NOA446510 /mandipropamide/ at 3 mg/kg/day for up to 14 days. Groups of 3 males were terminated 24 hours after 3, 7, 10, and 14 consecutive daily doses and 1, 4, 7, 14, 21, 28, and 49 days after the last of 14 consecutive daily doses. Adrenals, brain, heart, kidneys, liver, lungs, pancreas, spleen, thymus, thyroid, testes, along with samples of blood, plasma, bone (femur), fat (abdominal), and muscle were analyzed for radioactivity (LSC). Urine, feces, and cage wash were collected from 3 males 24 hours after the first dose and 24 hours after the 14th consecutive dose and analyzed for radioactivity (LSC). Tissue concentrations of radioactivity reached a steady state within 4 days of the initial dose and subsequently declined rapidly after the cessation of dosing. After 14 consecutive daily doses mean tissue (14)C concentrations were highest in liver (0.727 ug equivalents/g) and kidneys (0.234 ug equivalents/g). The elimination from liver was biphasic with terminal elimination half life calculated as 4.2 days and distribution half life calculated as 2.3 days. In kidneys, the elimination half life was 8.7 days. Bone elimination half life was 12.8 days. All other tissue concentrations at steady state were generally low (0.1 ug equivalents/g or less) with radioactivity declining below the limit of detection a few days after the last dose. The majority of radioactivity was excreted in feces (79% of dose after 1 dose and 66% after 14 consecutive doses). Urine contained 2.6% of dose after 1 dose and 7% after 14 consecutive doses.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

每组的每性别1只或4只Wistar衍生的Alpk:APfSD大鼠接受了一次口服灌胃剂量的(氯苯基-U-(14)C) NOA446510 /mandipropamid/或(甲氧基苯基-U-(14)C) NOA446510 /mandipropamid/，剂量为3和300毫克/千克。给药后，从每组每性别1只大鼠（第2、6和7组）收集呼出的二氧化碳，收集在含有2N氢氧化钠溶液的陷阱中，并在8或10小时（雌性）、24、36和48小时收集呼出的代谢物，在活性炭陷阱中。在所有时间点，呼出的二氧化碳和挥发性代谢物中的残留物接近或低于检测限，对于两个(chlorophenyl-U-(14)C) NOA446510和(methoxyphenyl-U-(14)C) NOA446510放射性标记都是如此。在3毫克/千克剂量下，经过48小时，呼出空气中的总放射性在雄性和雌性中均不到剂量的0.1%，对于(chlorophenyl-U-(14)C) NOA446510，在(methoxyphenyl-U-(14)C) NOA446510的两种性别中，不到剂量的0.2%。在活性炭陷阱中没有回收放射性（代谢物）。在300毫克/千克(methoxyphenyl-U-(14)C) NOA446510的48小时后，呼出空气中的放射性占剂量的不到0.2%，在两种性别中，没有在活性炭陷阱中回收放射性。在排泄和组织分布阶段动物的给药后（第3、4、8和9组每性别4只大鼠），在6和10小时收集尿液，在24、48、72、96、120、144和168小时后收集尿液和粪便。168小时内通过尿液和粪便排出的放射性百分比平均值对于(chlorophenyl-U-(14)C) NOA446510和(methoxyphenyl-U-(14)C) NOA446510放射性标记相似。在两个剂量水平上，主要排泄途径是粪便，而在低剂量与300毫克/千克相比，在雌性相比于雄性中，尿液中排泄了更大比例的给药剂量。在300毫克/千克时，粪便排泄在雄性和雌性中分别占平均总量的87%-91%和81%-84%，而尿液排泄在雄性和雌性中分别占平均总量的2.2%-3.3%和6.4%-11.6%。在3毫克/千克时，粪便排泄的平均总量在雄性和雌性中分别为76%-81%和42%-55%，尿液排泄在雄性和雌性中分别占平均总量的14%-15%和29%-47%。治疗后7天，两种放射性标记和两种性别的组织中放射性分布相似。在3毫克/千克时，组织中的放射性占剂量的0.06%-0.17%，残体中的放射性占剂量的0.08%-0.19%。最高的放射性浓度在肝脏（0.033-0.085微克当量/克（0.05%-0.16%的剂量）），肾脏（0.007-0.019微克当量/克（<0.01%的剂量））和甲状腺（<0.010-0.030微克当量/克（<0.01%的剂量））。所有其他组织中的浓度低于0.010微克当量/克。在300毫克/千克/天时，组织中的放射性占剂量的0.02%-0.04%，残体中的放射性占剂量的0.01%-0.11%。最高的放射性浓度也在肝脏（0.81-1.57微克当量/克（0.01%-0.03%的剂量）），肾脏（0.12-0.35微克当量/克（<0.01%的剂量））和甲状腺（<0.17-1.20微克当量/克（<0.01%的剂量））。全血和血浆中的放射性<0.08-0.24微克当量/克和<0.01-0.04微克当量/克。所有其他组织中的浓度低于0.10微克当量/克。在使用胆管插管的大鼠阶段（第10和11组每性别4只大鼠），在10小时（雌性）或12、24和48小时后收集尿液，在24和48小时收集粪便，在1、2、3、4、5、6、7、8、10小时（雌性）或12、24、36和48小时后收集

One or 4 Alpk:APfSD (Wistar-derived) rats per sex per group received a single oral gavage dose of (Chlorophenyl-U-(14)C) NOA446510 /mandipropamid/ or (Methoxyphenyl-U-(14)C) NOA446510 /mandipropamid/ at 3 and 300 mg/kg. Following dosing, exhaled carbon dioxide from 1 per sex per group (groups 2, 6, and 7) was collected in traps containing 2N sodium hydroxide solution and exhaled metabolites were collected in charcoal traps at 8 or 10 (females), 24, 36, and 48 hours. Residues in expired carbon dioxide and volatile metabolites were near or below the limit of detection at all time points for both (chlorophenyl-U-(14)C) NOA446510 and (methoxyphenyl-U-(14)C) NOA446510 radiolabels. At 3 mg/kg after 48 hours, the total radioactivity in expired air amounted to less than 0.1% of dose in males and females for (chlorophenyl-U-(14)C) NOA446510 and less than 0.2% of dose for both sexes for (methoxyphenyl-U-(14)C) NOA446510. No radioactivity (metabolites) was recovered in the charcoal traps. 48 hours after 300 mg/kg of (methoxyphenyl-U-(14)C) NOA446510, radioactivity in expired air amounted to less than 0.2% of dose in both sexes and no radioactivity was recovered in the charcoal traps. Following dosing of the excretion and tissue distribution phase animals (4 rats per sex per group in groups 3, 4, 8, and 9), urine was collected at 6 and 10 hours and urine and feces at 24, 48, 72, 96, 120, 144, and 168 hours post-treatment. The mean total percentages of radioactivity excreted in urine and feces over 168 hours were similar for the (chlorophenyl-U-(14)C) NOA446510 and methoxyphenyl-U-(14)C) NOA446510 radiolabels. The major route of excretion was feces at both dose levels, while a greater proportion of administered dose was excreted in urine at the low dose vs 300 mg/kg and for females compared to males. At 300 mg/kg, fecal excretion accounted for mean totals of 87%-91% in males and 81%-84% in females, while urinary excretion accounted for mean totals of 2.2%-3.3% for males and 6.4%-11.6% for females. At 3 mg/kg, mean totals for fecal excretion were 76%-81% in males and 42%-55% in females, and urinary excretion accounted for mean totals of 14%-15% in males and 29%-47% in females. Tissue distribution of radioactivity was similar for both radiolabels and both sexes seven days after treatment. At 3 mg/kg, radioactivity in tissues accounted for 0.06%-0.17% of dose in total and radioactivity remaining in the carcass was 0.08%-0.19% of dose. Highest radioactive concentrations were in liver (0.033-0.085 ug equivalents/g (0.05%-0.16% of dose)), kidney (0.007-0.019 ug equivalents/g (<0.01% of dose)), and thyroid (<0.010-0.030 ug equivalents/g (<0.01% of dose)). Concentrations in all other tissues were below 0.010 ug equivalents/g. At 300 mg/kg/day, radioactivity in tissues was 0.02%-0.04% of dose in total and radioactivity in residual carcass was 0.01%-0.11% of dose. Highest radioactive concentrations were also in liver (0.81-1.57 ug equivalents/g (0.01%-0.03% of dose)), kidney (0.12-0.35 ug equivalents/g (<0.01% of dose)), and thyroid (<0.17-1.20 ug equivalents/g (<0.01% of dose)). Radioactivity in whole blood and plasma was <0.08-0.24 ug equivalents/g and <0.01-0.04 ug equivalents/g respectively. Concentrations in all other tissues were below 0.10 ug equivalents/g. In the phase using bile duct cannulated rats (4 rats per sex per group in groups 10 and 11), urine was collected at 10 (females) or 12 , 24, and 48 hours after dosing, feces at 24 and 48 hours, and bile at 1, 2, 3, 4, 5, 6, 7, 8, 10 (females) or 12, 24, 36, and 48 hours post-dosing. In bile duct cannulated rats that received (methoxyphenyl-U-(14)C) NOA446510 at 3 mg/kg, the majority of administered dose was eliminated in bile (73% for males and 55% for females) after 48 hours; fecal excretion was 14% and 22% for males and females respectively; and urinary excretion was 1.4% for males and 9.5% for females. At 300 mg/kg, biliary excretion was 28% and 22% for males and females respectively; feces contained 39% (males) and 26% (females); and urine accounted for 0.8% (males) and 19% (females) of dose after 48 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

每组每性别9或15只Alpk:APfSD（Wistar衍生物）大鼠，一次性口服给予（甲氧基苯基-U-(14)C）NOA446510/mandipropamid/，剂量为3和300 mg/kg。在第1阶段，从每组每性别的3只大鼠中（尾部静脉）在3 mg/kg（第1组）和300 mg/kg（第2组）给药后2、4.5、6.5、8-8.5、9.5-10、13、18、24、34、48、72和96小时采集系列血样。结果用于选择第2阶段动物的终止时间。在第2阶段，每组每性别的3只大鼠在3 mg/kg（第3组）和300 mg/kg（第4组）治疗后的8、24、48、72和96小时终止。分析每个动物的血浆和血液、肾上腺、大脑、心脏、肾脏、肝脏、肺、卵巢、胰腺、脾、胸腺、甲状腺、睾丸、子宫、骨骼（股骨）、脂肪（腹部）和肌肉的放射性（LSC）每个时间点。在第1阶段，组平均血放射性浓度峰值时间（Tmax）分别为雄性8.5小时和雌性4.5小时，放射性消除的半衰期（t1/2）分别为雄性18.4小时和雌性20.2小时（3 mg/kg给药后）。在300 mg/kg时，组平均Tmax值为雄性24小时和雌性10小时，而t1/2值分别为雄性32.7小时和雌性24.8小时。在第2阶段，在两个剂量水平上，雌性组织的放射性浓度略低于雄性。肝脏和肾脏组织的残留物是唯一一致高于血浆浓度的测量值（血浆浓度为雄性0.13 ug等价物/g和雌性0.10 ug等价物/g（3 mg/kg），雄性5.12 ug等价物/g和雌性2.65 ug等价物/g（300 mg/kg））（两个性别两个剂量水平）。所有组织的浓度降至在治疗后96小时低或低于检测限的值。最高组平均放射性浓度在肝脏8小时：1.25 ug等价物/g（2.04%的剂量）（雄性）和0.64 ug等价物/g（0.94%的剂量）（雌性）在3 mg/kg，和46.4 ug等价物/g（0.77%的剂量）（雄性）和27.1 ug等价物/g（0.39%的剂量）（雌性）在300 mg/kg。肾脏在8小时的值为雄性0.26 ug等价物/g（0.08%的剂量）和雌性0.25 ug等价物/g（0.08%的剂量）在3 mg/kg，和10.43 ug等价物/g（0.04%的剂量）雄性和6.9 ug等价物/g（0.02%的剂量）雌性在300 mg/kg。肝脏在3 mg/kg的组平均t1/2值为：雄性23.6小时和雌性23.1小时，肾脏分别为雄性22.2小时和雌性21.5小时。在300 mg/kg时，肝脏的组平均t1/2值为雄性19.1小时和雌性17.7小时，肾脏为雄性19.5小时和雌性15.6小时。其他组织的组平均t1/2值通常在18到24小时之间（除了在300 mg/kg雄性中的胸腺（31.5小时）和睾丸（30.0小时））。

Nine or 15 Alpk:APfSD (Wistar-derived) rats per sex per group received a single oral gavage dose of (Methoxyphenyl-U-(14)C) NOA446510 /mandipropamid/ at 3 and 300 mg/kg. In phase 1, serial blood samples were taken (tail veins) from 3 rats per sex per group at 2, 4.5, 6.5, 8-8.5, 9.5-10, 13, 18, 24, 34, 48, 72, and 96 hours after dosing at 3 mg/kg (group 1) and 300 mg/kg (group 2). Results were used to select termination times for phase 2 animals. In phase 2, three rats per sex per group were terminated 8, 24, 48, 72, and 96 hours after treatment at 3 mg/kg (group 3) and 300 mg/kg (group 4). Blood samples (separated into plasma and blood), adrenals, brain, heart, kidneys, liver, lungs, ovaries, pancreas, spleen, thymus, thyroid, testes, uterus, bone (femur), fat (abdominal), and muscle from each animal were analyzed (LSC) for radioactivity at each time point. In phase 1 , group mean peak blood radioactivity concentration times (Tmax) were 8.5 hours for males and 4.5 hours for females and half-lives of elimination of radioactivity (t1/2) were 18.4 hours (males) and 20.2 hours (females) after dosing at 3 mg/kg. At 300 mg/kg, group mean Tmax values were 24 hours (males) and 10 hours (females), while t1/2 values were 32.7 hours for males and 24.8 hours (females ). In phase 2, at both dose levels, tissue concentrations of radioactivity were slightly lower in females compared to males. Liver and kidney tissue residues were the only measurements consistently higher than plasma concentrations (plasma concentrations were 0.13 ug equivalents/g (males) and 0.10 ug equivalents/g (females) at 3 mg/kg and 5.12 ug equivalents/g (males) and 2.65 ug equivalents/g (females) at 300 mg/kg) for both sexes at both dose levels. All tissue concentrations declined to values that were low or below the the limit of detection by 96 hours post-treatment. Highest group mean concentrations of radioactivity were in liver at 8 hours: 1.25 ug equivalents/g (2.04% of dose) (males) and 0.64 ug equivalents/g (0.94% of dose) (females) at 3 mg/kg, and 46.4 ug equivalents/g (0.77% of dose) (males) and 27.1 ug equivalents/g (0.39% of dose) (females) at 300 mg/kg. Values for kidneys at 8 hours were 0.26 ug equivalents/g (0.08% of dose) for males and 0.25 ug equivalents/g (0.08% of dose) for females at 3 mg/kg, and 10.43 ug equivalents/g (0.04% of dose) for males and 6.9 ug equivalents/g (0.02% of dose) for females at 300 mg/kg. Group mean t1/2 values for liver at 3 mg/kg were: 23.6 and 23.1 hours for males and females respectively, and for kidney, were 22.2 and 21.5 hours for males and females respectively. At 300 mg/kg, group mean t1/2 values for liver were 19.1 and 17.7 hours for males and females respectively and, for kidneys, 19.5 hours (males) and 15.6 hours (females). Group mean t1/2 values for other tissues generally ranged from 18 to 24 hours (except for thymus (31.5 hours) and testes (30.0 hours) in males at 300 mg/kg).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在口服灌胃研究中，每组每性别27只C57BL/10Jf/Alpk小鼠接受了一次口服剂量为(Methoxyphenyl-U-(14)C) NOA446510 /mandipropamid/，剂量为10、50和500 mg/kg。在初步的饮食研究中，每组每性别55只C57BL/10Jf/Alpk小鼠通过饮食接受了(Methoxyphenyl-U-(14)C) NOA446510，剂量为800 ppm，持续2天。在主要的饮食研究中，每组每性别28只C57BL/10Jf/Alpk小鼠通过饮食接受了(Methoxyphenyl-U-(14)C) NOA446510，剂量为300、800、2000和5000 ppm，持续7天。在静脉注射研究中，每组每性别5只C57BL/10Jf/Alpk小鼠接受了一次静脉注射剂量为(Methoxyphenyl-U-(14)C) NOA446510，剂量为10 mg/kg。在单次剂量口服灌胃研究中，大部分放射性物质在给药后24小时内被排泄，且无论性别或给药途径和速率均无差异。在10和50 mg/kg剂量下，雄性在两个剂量水平上均通过尿液排出了剂量的29%，并在治疗48小时内通过粪便排出了32%（10 mg/kg）和27%（50 mg/kg）。雌性在相同时间段内通过尿液排出了剂量的29%和47%，通过粪便排出了21%和24%，分别对应10和50 mg/kg。在500 mg/kg剂量下，粪便成为主要的排泄途径，雄性通过粪便排出了剂量的54%，而雌性为40%。尿液中的放射性物质分别占雄性和雌性剂量的16%和11%。血浆药代动力学没有表明性别差异和剂量水平差异。在每一个时间点和剂量水平，全血中测量的放射性物质浓度大约是血浆中测量浓度的一半。在10和50 mg/kg剂量下，吸收是迅速的，给药后30分钟内达到最大血浆浓度（Cmax）（雄性2 ug/mL和雌性3 ug/mL，以及雄性11 ug/mL和雌性16 ug/mL，分别对应10和50 mg/kg）。50 mg/kg剂量下的血浆浓度-时间曲线下面积（AUC，h.ug等价物/mL）大约是10 mg/kg剂量的5倍（雄性88 vs 17，雌性76 vs 17），表明吸收增加是线性的。在500 mg/kg剂量下，吸收阶段较慢，血浆Cmax为40 ug/mL（雄性）和39 ug/mL（雌性），在治疗6小时（雄性）和2小时（雌性）后达到。此外，在500 mg/kg剂量下，AUC值分别为雄性6倍（543 h.ug等价物/mL）和雌性7倍（535 h.ug等价物/mL），与预期的相比，相对于50 mg/kg剂量，分别只有10倍差异。在尿液中，测量到了五种主要代谢物，占所有样本中放射性物质的90%以上。代谢物4（NOA458422葡萄糖苷酸（NOA458422的O-葡萄糖苷酸，2-(4-氯-苯基)-N-(2-(4-羟基-3-甲氧基-苯基)-乙基)-2-丙-2-炔氧基乙酰胺））是主要成分，代谢物2（仅提供了一个图表）在所有3个剂量水平上都是第二成分。未改变的NOA446510在尿液中未出现。在10 mg/kg剂量下，0-24小时粪便样本的代谢轮廓与尿液轮廓相似，且在雄性中检测到了少量的NOA446510，但在雌性中未检测到。在50和500 mg/kg剂量下，粪便中的主要成分是未改变的NOA446510，无论性别。在血浆中，代谢物4在所有剂量水平下均为两性的主要成分；代谢物2在10和50 mg/kg时是一个非常小的成分；在500 mg/kg时检测到了少量未改变的NOA446510。在2天的饮食研究中，800 ppm剂量下，全血中的Cmax在开始给药后38.5小时（雄性）和41.0小时（雌性）达到。在7天的饮食研究中，与口服灌胃研究一样，放射性物质与血液的血浆部分相关联，没有表明性别差异，且放射性物质与剂量水平成比例（尽管由于缺乏实现的剂量计算，具体的血浆放射性物质浓度数据有限）。尿液代谢物轮廓在质量和数量上与口服灌胃动物相似，并表明与性别、剂量水平和给药次数无关。代谢物4是尿液中的主要成分，任何样本中均未检测到未

In an oral gavage study, 27 C57BL/10Jf/Alpk mice per sex per group received a single oral dose of (Methoxyphenyl-U-(14)C) NOA446510 /mandipropamid/ at 10, 50, and 500 mg/kg. In a preliminary dietary study, 55 C57BL/10Jf/Alpk mice per sex received (Methoxyphenyl-U-(14)C) NOA446510 in the diet at 800 ppm for 2 days. In the main dietary study, 28 C57BL/10Jf/Alpk mice per sex per group received (Methoxyphenyl-U-(14)C) NOA446510 in the diet at 300, 800, 2000, and 5000 ppm for 7 days. In an intravenous study, 5 C57BL/10Jf/Alpk mice per sex received a single intravenous dose of (Methoxyphenyl-U-(14)C) NOA446510 at 10 mg/kg. In the single dose oral gavage study, the majority of radioactivity was excreted within the first 24 hours after dosing with no sex differences in either route or rate. At 10 and 50 mg/kg, males excreted 29% of dose in urine at both levels and 32% (10 mg/kg) and 27% (50 mg/kg) in feces during 48 hours after treatment. Females excreted 29% and 47% of dose in urine and 21% and 24% in feces at 10 and 50 mg/kg respectively over the same time period. At 500 mg/kg, feces were the main route of excretion, accounting for 54% of dose in males and 40% in females. Radioactivity in urine represented 16% of dose in males and 11% in females. No sex differences and no dose level differences in the pharmacokinetics of plasma were indicated. At every time point and dose level, the concentration of radioactivity measured in whole blood was approximately half that measured in plasma. At 10 and 50 mg/kg, absorption was rapid with maximum plasma concentrations (Cmax) reached within 30 minutes of dosing (2 ug/mL (males) and 3 ug/mL (females) and 11 ug/mL (males) and 16 ug/mL (females) at 10 and 50 mg/kg respectively). The area under the plasma concentration vs time curve (AUC, h.ug equivalents/mL) at 50 mg/kg was approximately 5 times that at 10 mg/kg (88 vs 17 for males and 76 vs 17 for females), indicating a linear absorption increase. The absorption phase was slower at 500 mg/kg with plasma Cmax of 40 ug/mL (males) and 39 ug/mL (females) reached 6 hours (males) and 2 hours (females) after treatment. Additionally, at 500 mg/kg, AUC values were 6 fold (543 h.ug equivalents/mL) and 7 fold (535 h.ug equivalents/mL) in males and females respectively compared with the expected 10 fold differential vs 50 mg/kg. In urine, five principal metabolites were measured accounting for more than 90% of radioactivity in all samples. Metabolite 4 (NOA458422 glucuronide (the O-glucuronide of NOA458422 (2-(4-chloro-phenyl)-N- (2-(4-hydroxy-3-methoxy-phenyl)-ethyl)-2-prop-2-ynyloxy-acetamide)) was the main component and metabolite 2 (only a diagram was provided) the second, at all 3 dose levels. Unchanged NOA446510 was not present in urine. At 10 mg/kg, the metabolic profile of the 0-24 hour feces sample was similar to the urine profile and a small amount of NOA446510 was detected in males but not females. At 50 and 500 mg/kg, the major component in feces was unchanged NOA446510 in both sexes. In plasma, metabolite 4 was the major component in both sexes at all dose levels; metabolite 2 was a very minor component at 10 and 50 mg/kg; and a small amount of unchanged NOA446510 was detected at 500 mg/kg. In the 2 day dietary study at 800 ppm, Cmax in whole blood was reached at 38.5 hours (males) and 41.0 hours (females) after the start of dosing. In the 7 day dietary study, as with the oral gavage study, radioactivity was associated with the plasma compartment of blood and no sex differences were indicated and radioactivity was proportional to dose level (although specific plasma radioactivity concentration data were limited by lack of achieved dose calculations). Urinary metabolite profiles were qualitatively and quantitatively similar to those for oral gavage animals and were indicated to be independent of sex, dose level, and number of doses. Metabolite 4 was the major urinary component and no unchanged NOA446510 was detected in any samples. Fecal samples had unchanged NOA446510 in all samples. Metabolites 2 and 4 were present in all plasma samples and unchanged NOA446510 was not detected. In the single dose intravenous study (10 mg/kg), the majority of radiolabel was also excreted within 24 hours of dosing. Urine contained 58% (males) and 72% (females) of dose during 24 hours and feces had 25% (males) and 40% (females). Urinary metabolite profiles observed from the 0-24 hour and 24-48 hour post treatment collections were the same as those observed following oral gavage dosing with no qualitative sex differences. Loss of the propargyl groups and glucuronidation was suggested as the principal route of biotransformation.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  双炔酰菌胺 、 苯 、 劳森试剂 以 乙醚 为溶剂， 反应 7.0h， 以2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-thioacetamide is obtained which的产率得到2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-thioacetamide
  参考文献：
  名称：

  N-p-propargyloxyphenethyl-thioacetic acid amides

  摘要：

  本发明涉及一般式（I）的N-丙炔氧基苯乙基硫代乙酸酰胺衍生物，包括其光学异构体和混合物，其中R1为氢、烷基、环烷基或可选取代芳基，R2和R3各自独立地为氢或烷基，R4为烷基、烯基或炔基，R5、R6、R7和R8各自独立地为氢或烷基，R9为氢、可选取代烷基、可选取代烯基或可选取代炔基，R10为可选取代芳基或可选取代杂环芳基，Z为羟基、可选取代芳氧基、可选取代烷氧基、可选取代炔氧基、可选取代芳硫基、可选取代烷硫基、可选取代炔硫基、可选取代烷基亚砜基、可选取代烯基亚砜基、可选取代炔基亚砜基、可选取代烷基磺酰基、可选取代烯基磺酰基、可选取代炔基磺酰基或基团-O-CO-R11，-O-CO-O-R11或-O-CO-CO-O-R11，其中R11为氢、可选取代烷基、可选取代环烷基、可选取代芳基或可选取代杂环芳基。这些化合物具有有用的植物保护性能，可以优势地用于农业实践中，用于控制或预防植物受植物病原微生物，特别是真菌的侵害。

  公开号：

  US07105545B2
• 作为产物：
  描述：

  香草醛 在 lithium aluminium tetrahydride 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 乙二胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 10.25h， 生成 双炔酰菌胺
  参考文献：
  名称：

  Protecting group-free synthesis of the fungicide Mandipropamid

  摘要：

  DOI：

  10.24820/ark.5550190.p012.023
• 作为试剂：
  描述：

  2-(4-chlorophenyl)-N-(4-hydroxy-3-methoxyphenethyl)-2-(prop-2-yn-1-yloxy)acetamide 、 potassium carbonate 、 3-氯丙炔 、 、 、 水 在 四丁基溴化铵 甲苯 、 双炔酰菌胺 、 甲醇 作用下， 以 甲苯 为溶剂， 90.0 ℃ 、266.64 kPa 条件下， 反应 3.5h， 以315 g of 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxyacetamide are obtained with a LC purity of 98%的产率得到双炔酰菌胺
  参考文献：
  名称：

  Process for the synthesis of mandipropamid and derivatives thereof

  摘要：

  一种制备公式（I）化合物的方法，该方法包括：（i）将公式（III）化合物与公式（IV）化合物反应，得到公式（II）化合物，和（ii）将公式（II）化合物与离去基反应，得到公式（I）化合物。

  公开号：

  US08129560B2

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] AZOLINE COMPOUNDS<br/>[FR] COMPOSÉS AZOLINE
  申请人：BASF SE

  公开号：WO2015128358A1

  公开（公告）日：2015-09-03

  The present invention relates to azoline compounds of formula (I) wherein A, B1, B2, B3, G1, G2, X1, R1, R3a, R3b, Rg1 and Rg2 are as defined in the claims and the description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.

  本发明涉及式（I）的噁唑啉化合物，其中A、B1、B2、B3、G1、G2、X1、R1、R3a、R3b、Rg1和Rg2如权利要求和描述中所定义。这些化合物对抗或控制无脊椎动物害虫，特别是节肢动物害虫和线虫方面具有用途。该发明还涉及一种利用这些化合物控制无脊椎动物害虫的方法，以及包括所述化合物的植物繁殖材料、农业和兽医组合物。
• [EN] SUBSTITUTED QUINAZOLINES AS FUNGICIDES<br/>[FR] QUINAZOLINES SUBSTITUÉES, UTILISÉES EN TANT QUE FONGICIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2010136475A1

  公开（公告）日：2010-12-02

  The present invention relates to a compound of formula (I) wherein wherein the substituents have the definitions as defined in claim 1or a salt or a N-oxide thereof, their use and methods for the control and/or prevention of microbial infection, particularly fungal infection, in plants and to processes for the preparation of these compounds.

  本发明涉及一种具有如下式（I）的化合物，其中取代基具有权利要求1中定义的定义，或其盐或N-氧化物，它们的用途以及用于控制和/或预防植物中微生物感染，特别是真菌感染的方法，以及制备这些化合物的方法。
• [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。
• Thieno-pyrimidine compounds having fungicidal activity
  申请人：Brewster Kirkland William

  公开号：US20070093498A1

  公开（公告）日：2007-04-26

  The present invention relates to thieno[2,3-d]-pyrimidine compounds having fungicidal activity.

  本发明涉及具有杀真菌活性的噻吩[2,3-d]-嘧啶化合物。