Metabolism involved cleavage of the ether bond, with formation of the 4-hydroxyquinazoline and carboxylic acid derivatives. Other biotransformations included oxidation of one of the methyl groups on the alkyl side chain to produce either an alcohol, which was further metabolised by hydroxylation of the O-ether alkyl moiety, or a carboxylic acid, which was further metabolised by hydroxylation of the 2-position of the quinazoline ring.
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. ... In the urine, the primary metabolite was AN-1 (4-(2-hydroxy-1,1-dimethylethyl) phenylacetic acid) (24-29% of total urinary radioactivity) plus numerous minor metabolites. This metabolite was characterized by the absence of protons associated with the quinazoline portion of the molecule, indicating cleavage of the ether bridge. No significant differences between the sexes or dose groups were observed. Four primary metabolites and numerous minor metabolites were found in the feces. The parent compound, fenazaquin, represented 1.2-4.2% of the recovered radioactivity in the single or multiple low-dose groups and 11.5-20.6% of the recovered activity in single high-dose rats. Metabolite F1 (4.6-9.4% of the administered dose) had the phenyl and quinazoline rings and both sets of methylene protons intact, as well as the addition of a single oxygen atom to the phenyl-t-butyl portion of the parent molecule. Metabolite F-1A, a minor metabolite contributing 0.6-2.6% of the radioactivity, was characterized by intact phenyl and quinazoline rings and hydroxylation of the ethoxy bridge. Metabolite F-2 was the primary fecal metabolite identified (16.3-22.8% of the recovered radioactivity) and was similar to metabolite F1, but with the addition of two oxygen atoms and the loss of two hydrogen atoms to form a carboxylic acid on one of the methyl alky groups attached to the phenyl ring. Metabolite F3 contributed 6.5-12.6% of the recovered radioactivity and contained both the phenyl and quinazoline ring systems; however, the quinazoline ring had been hydroxylated and one of the methyl alkyl groups of the phenyl ring had been carboxylated. While the fecal metabolites were likely produced by the liver, it is not possible to exclude metabolism by intestinal microflora. These studies show that radiolabeled fenazaquin is rapidly metabolized and eliminated from male and female rats following treatment with either single or multiple low doses or following a single high dose of the compound. However, there is no information on biliary excretion or fecal/urinary elimination following iv administration.
/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/
/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5%葡萄糖水（D5W）/SRP: "保持开放"，最低流速/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸钠林格氏液。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……。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/
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 90-day oral toxicity study, XDE-436 (/fenazaquin/ 98.1% ai) was administered to 4 Beagle dogs/sex/dose in diet at dose levels of 0, 1, 5, or 15 mg/kg bw/day at constant dosing. All percentages presented are changes from controls. No toxicological effects on organ weight, clinical chemistry, clinical signs, hematology, gross and histopathology were related to the dietary exposure of fenazaquin to beagle dogs. At 15 mg/kg/day dose, significant reductions in body weight of males (6 to 12%) and females (4 to 11%) were reported. At the high dose, overall body weight gain decreased in males (76%) and females (73%); mean food consumption was reduced in males (6 to 24%) and females (10 to 27%). Food efficiency values were also significantly decreased in high dose groups, males (72%) and females (67%). ... The toxicologically significant body weight changes correspond to the decrease in food consumption reported for the high dose group, which appears to be due only in part to a reduction in palatability of the diet. Based on the toxicological findings associated with fenazaquin 90-day dietary exposure to beagle dogs, the NOAEL is established at 5 mg/kg/day and the LOAEL is established at 15 mg/kg/day based on reductions of body weight, body weight gain, food consumption and food efficiency.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 90-day oral toxicity study EL-436 (/fenazaquin/ purity 98%) was administered to 15 Syrian golden hamster [Lak:LVG(SYR)]/sex/dose by gavage at doses of 0, 5, 25, 75, or 150 mg/kg/day for males and 0, 5, 25, 50, or 100 mg/kg/day for females. Control animals received 5 mL/kg of the vehicle (10% aqueous acacia solution). There were no treatment related mortalities or clinical signs and no difference between the controls and the fenazaquin treated groups in urinalysis. Food consumption data from the first 10- weeks of the study were considered unreliable due to excessive spillage. There were slight dose-related increases (22-69%) in liver microsomal p-nitroanisole-o-demethylase enzyme activity in all animals that received fenazaquin at > or = 25 mg/kg/day but no changes were seen in hepatic peroxisomal beta-oxidation activity (fatty acyl CoA oxidase). Small changes occurred in some hematology parameters (< or = 6% decrease) among treated hamsters but, the changes were within the normal ranges of biological variation and were not considered toxicologically meaningful. The greatest effect of treatment was on body weight. At termination, the body weight in males decreased (p<0.01) 16 and 23% relative to the controls in the 75 and 150 mg/kg/day groups. Similarly, body weight in females decreased (p<0.01) 19 and 28% relative to the controls in the 50 and 100 mg/kg/day groups, respectively. The body weight gains from the same treated groups were also substantially reduced 54 and 74% less than the controls in males and 39 and 61% less than the controls in females, respectively. Because of growth retardation, the absolute organ weights of kidney, heart, and spleen were decreased in animals at dose levels > or = 50 mg/kg/day. The large decrease in absolute (42-49%) and relative weights (27-36%) of testes and prostate are considered treatment-related in males administered 75 and 150 mg/kg/day fenazaquin. These findings are corroborated by histopathology findings of increased testicular hypospermatogenesis (0/15, 1/15, 2/15/, 5/15/ and 8/15 in control through the high dose groups, respectively, moderate to severe at the top two doses). Under the conditions of the study, the LOAEL for fenazaquin in male hamsters is 75 mg/kg/day based on decreased body weight, reduced testes and prostate weights, and testicular hypospermatogenesis. The LOAEL is 50 mg/kg/day in females based on decreased body weight. The NOAEL for EL-436 is 25 mg/kg/day for both males and females.
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. Overall recovery of the radiolabel was excellent (89.5-107.7% of the administered dose). Within 48 hours of treatment, approximately 75% of the radiolabel was recovered in the excreta, and by 72 hours after treatment, >84% was recovered. No sex-related differences in elimination were noted. Approximately 20% of the radiolabel was recovered in the urine with the remainder in the feces. Less than 1.6% of the radiolabel was recovered in the residual carcass or tissues and essentially no significant amount of radiolabel was recovered in the expired air. There are no available excretion studies following bile cannulation or intravenous (i.v.) administration to determine test material bioavailability (gastrointestinal absorption). Therefore, while the nearly 20% of the administered dose was absorbed before it was excreted in urine, it is not clear if any or all of the remaining dose (nearly 80%) that was found in feces was actually absorbed prior to its fecal elimination.
Insecticidal Quinazoline Derivatives with (Trifluoromethyl)diazirinyl and Azido Substituents as NADH:Ubiquinone Oxidoreductase Inhibitors and Candidate Photoaffinity Probes
摘要：
Two candidate photoaffinity probes are designed from 4-substituted quinazolines known to be potent insecticides/acaricides and NADH:ubiquinone oxidoreductase inhibitors acting at or near the rotenone site. 4-(11-Azidoundecyl-2-amino)quinazoline, based on the undecylamino analog SAN 548A as a prototype, was synthesized in 18% overall yield from ethyl 10-undecenoate by oxidation of the terminal double bond, reductive amination, coupling to 4-chloroquinazoline, and functional group manipulation of the terminal ethyl ester to an alcohol, a mesylate and finally nucleophilic displacement with azide ions. 4-(4-(3-(Trifluoromethyl)3H-diazirin-3-yl)phenethoxy)quinazoline [the (trifluoromethyl)diazirinyl analog of fenazaquin insecticide/acaricide] was prepared from 4-bromophenethyl alcohol in 31% overall yield by first introducing the trifluoromethylketone moiety followed by its conversion to the (trifluoromethyl)diazirine and finally coupling to 8-chloroquinazoline as above. Both candidate photoaffinity probes have the inhibitory potency of rotenone (IC50 Of 3-4 nM in each case). The azidoundecylamino compound has inadequate photoreactivity whereas that of the (trifluoromethyl)diazirinyl analog is ideal at 350 nm. Radiosynthesis of the latter photoaffinity ligand included introduction of the diazirinyl moiety as the carbene precursor, oxidation of (trifluoromethyl)diazirinylphenethyl alcohol to the corresponding acid with Jones' reagent, and reduction of the phenacetyl chloride intermediate with sodium borotritide to incorporate tritium.
[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.
[EN] BICYCLYL-SUBSTITUTED ISOTHIAZOLINE COMPOUNDS<br/>[FR] COMPOSÉS ISOTHIAZOLINE SUBSTITUÉS PAR UN BICYCLYLE
申请人：BASF SE
公开号：WO2014206910A1
公开（公告）日：2014-12-31
The present invention relates to bicyclyl-substituted isothiazoline compounds of formula (I) wherein the variables are as defined in the claims and 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.
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.
