Fenpyroximate was extensively metabolized in rats; 23 metabolites were identified. No parent compound was found in the urine; metabolites found in the excreta represented 0-11% of the administered dose. Multiple pathways have been proposed for the metabolism of fenpyroximate, including oxidation, hydroxylation, demethylation, hydrolysis, and isomerization.
Fenpyroximate is metabolized extensively by hydrolytic cleavage of the oxime ether bond, hydrolysis of the tert-butyl ester, oxidation of the tert-butyl, hydroxylation of the phenoxy ring and 3-methyl, isomerization, N-demethylation, and conjugation, producing a large number of metabolites. The major metabolites identified are (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl) methyleneaminooxymethyl] benzoic acid, (Z)-4-[(1,3-dimethyl-phenoxypyrazol-4yl) methyleneaminooxymethyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl]methyleneaminooxymethyl} benzoic acid, 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid, 4-hydroxymethyl benzoic acid, terephthalic acid, 4-cyano-1-methyl-5-phenoxypyrazole-3-carboxylic acid, (E)-2-{4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl) methyleneaminooxymethyl] benzoyloxy}-2-methylpropanoic acid, (E)-2-{4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid, and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid.
Groups of six male and six female Sprague-Dawley rats with bile-duct cannulae were given a single oral dose of 2 mg/kg (14)C-pyrazole-labeled fenpyroximate. No parent fenpyroximate was found in bile, but metabolites (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (Z)-4-[(1.3-dimethyl-5-phenoxy-pyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid, (E)-2-{4-[(1,3-dimethyl-5-phenoxypyrazol- 4-yl) methyleneaminooxymethyl] benzoyloxy}-2-methylpropanoic acid, 1,3-dimethyl-5-(4-hydroxyphenoxy)pyrazole-4-carbaldehyde, 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid, 3-methyl-5-phenoxypyrazole-4-carbaldehyde, 1,3-dimethyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbonitrile, (E)-1,3-dimethyl-5-phenoxypyrazole-4-carbaldehydeoxime, 3-methyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbaldehyde, and (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid, and conjugates of (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (Z)-4-[(1.3-dimethyl-5-phenoxy-pyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid, (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid, and 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid were found. Total radiolabel represented less than 2% of the dose. The metabolic pathway proposed for fenpyroximate in rats is cleavage of the ester bond, hydroxylation at the phenoxypyrazole group, oxidation at the tert-butyl group, and conjugation with sulfate and glucuronide.
Groups of four male Sprague-Dawley (SLC) rats were treated with a single oral dose of 1.5 mg/kg bw (14)C-pyrazole- or (14)C-benzoyl- labeled fenpyroximate (radioactive purity, > 99%), and urinary and fecal samples were collected for 0-72 hrs. Six urinary and 17 fecal metabolites were identified by thin-layer co-chromatography with authentic samples. ... The major urinary metabolites were 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid (7.3% of the dose), 4-cyano-1-methyl-5-phenoxy-pyrazole-3-carboxylic acid (2.5%), and terephthalic acid (3.8%). The major fecal metabolites were (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxy-methyl] benzoic acid (4.1-11.0% of the dose), (E)-4-{[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoic acid (2.9-4.2%), and (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid (3.5-4.3%); 4-hydroxymethyl benzoic acid (7.5%) was found as a precursor of terephthalic acid and (E)-2-[4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (2.0-9.7%) and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid (3.3-4.5%) as hydroxylated bodies of (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid. The concentrations of the urinary metabolites 1,3-dimethyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbonitrile and 3-methyl-5-(4-hydroxyphenoxy)-pyrazole-4-carbaldehyde and the fecal metabolites tert-butyl(E)-4-[(1,3-dimethyl-5-(4-hydroxyphenoxy)pyrazol-4-yl)methyleneaminooxymethyl] benzoate, (E)-2-[4-[(1,3-dimethyl-5-phenoxy-pyrazol-4-yl)methyleneamniooxy-methyl]benzoyloxy]-2-methyl-propanoic acid, (E)-2-[4-[1,3-dimethyl-5-(4-hydroxyphenoxy) pyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid, and (E)-2-[{4-[3-hydroxymethyl-1-methyl-5-phenoxypyrazol-4-yl] methyleneaminooxymethyl} benzoyloxy]-2-methylpropionic acid were increased by enzymatic hydrolysis of the excreta with beta-glucuronidase or sulfatase.
In the present study, least 3 rats/sex/dose/time interval combination were treated with a single oral dose of (Pyrazole-(14)C) Fenpyroximate (NNI-850, purity: 99.6%), prior to collection of urine, feces, organic volatiles, and carbon dioxide. The preliminary study found no detectable carbon dioxide, and organic volatiles were either non-detectable or below quantifiable levels. ... Single oral doses were low (2 mg/kg) or high (400 mg/kg). Sacrifice time intervals after radiolabeled Fenpyroximate treatment were 12, 24, and 168 hr for low dose groups, and 12, 24, 96, 120, and 168 hr for high dose groups. Repeat dose groups received 2 mg/kg/day unlabeled Fenpyroximate for 14 days, followed by a single treatment with labeled Fenpyroximate at 2 mg/kg. This group was maintained for 168 hr before sacrifice. All 168-hr groups consisted of 5/sex, and these were used for excretion samples at intervals throughout that period. Metabolite identification was performed by comparisons of 2-dimensional TLC mobilities of excreta extracts with mobilities of a series of proposed metabolites in two sets of solvent systems (i.e. standard chromatograms by visualization under UV light were compared to autoradiograms of fecal or urinary extracts). ... A single 2 mg/kg dose found about 8% of fecal metabolites as parent compound, about 13% presumed to be the ester hydrolysis product, with other characterized metabolites accounting for about 5% or less of fecal radioactivity. Uncharacterized metabolites which remained at the origin of the 0-24 hr TLC plates of 2 mg/kg groups constituted 47-50% of fecal label, compared to 2-4% in 400 mg/kg groups, suggesting that most of the dose was absorbed and metabolized following low dose administration. ... The major identified urinary metabolite was evidently 1,3-dimethyl-5-phenoxypyrazol- 4-carboxylic acid. This compound, designated M-8, was substantially conjugated as a glucuronide. ...
/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D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（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/
/SURVEILLANCE/ The results of medical surveillance of workers manufacturing a 5% formulation of fenpyroximate were reported. Ocular and dermal irritation were seen in July and November 1990 and March 1991. The concentrations of fenpyroximate in the air at eight to nine sites in the working place were 0.117 mg/cu m in January 1991, 0.012 mg/cu m in April 1991, 0.005 mg/cu m in November 1991, and 0.004 mg/cu m in January 1993; however, the actual exposure of the workers to fenpyroximate was not determined.
/GENOTOXICITY/ Fenpyroximate (NNI-850, purity: 97.3%) was tested for the formation of chromosomal aberrations with human lymphocytes in culture. Whole blood was obtained from a male volunteer, placed into culture with phytohemagglutinin for 48 hrs, then exposed to fenpyroximate at concentrations of 0 (acetone), 1.25, 5 or 20 ug/mL, for 2 hrs with and without activation with rat liver S-9. Following the two hrs, cells were washed, resuspended in complete medium, and the test solutions added at the original concentrations for an additional 22 hrs of exposure without S9 activation. Colcemid was added for the last 3 hrs of the incubation. There were triplicate cultures per group. Negative control was untreated, positive controls were chlorambucil for minus S9 and cyclophosphamide with activation. A single trial was conducted. Mitotic indices were determined by counting approximately 1000 lymphocytes per culture. For chromosomal aberrations, 100 cells per culture were scored. Results were reported as percent cells with aberrations including and excluding gaps. The mitotic indices for the treated groups were lower than the vehicle and negative controls. Excluding gaps, there was no indication of a treatment-induced increase in chromosomal aberrations under the study conditions.
Fenpyroximate was relatively well absorbed by rats after oral administration. Absorbed fenpyroximate was excreted predominantly via the biliary route, with lesser amounts in urine. The residual levels in organs and tissues after 168 hr were low. There was no evidence of bioaccumulation.
Groups of four male Sprague-Dawley CD rats received single dermal applications of 14C-pyrazole-fenpyroximate suspended in water at doses of 0.1, 1.0, or 5.2 mg in 1 mL on a 10 sq cm area of skin for 0.5, 1, 2, 4, 10, or 24 hr and were sacrificed at the end of the exposure period, The concentration of radiolabel in blood was very low after all applications. Excretion in urine was slight but increased with duration of exposure; after 24 hr of exposure, 0.7-0.9% of the applied dose had been excreted. Radiolabel was found in feces after 10 and 24 hr of treatment, and fecal excretion was 1.4% at a dose of 1 mg, 0.5% at 10 mg, and 0.2% at 52 mg. These results suggest that fenpyroximate is barely absorbed from the skin and is excreted via the biliary-faecal and urinary routes.
Groups of six male and six female Sprague-Dawley rats with bile duct cannulae were given a single oral dose of 2 mg/kg of (14)C-pyrazole- or (14)C-benzyl-fenpyroximate. Within 48 hr after treatment with pyrazole-labelled fenpyroximate, 47% (females) to 55% (males) of the radiolabel had been excreted in the bile, 5%, (males) to 10% (females) in urine, and 17% (females) to 28% (males) in feces. Total excretion 48 hr after treatment was about 88% for males and 73% for females. The Tmax, Cmax, and half-lives of the radiolabel in the blood of cannulated rats were similar to those of rats with no cannulae. Within 48 hr after oral administration of benzyl-labelled fenpyroximate, 47% (females) to 51% (males) of the radiolabel had been excreted in the bile, 6% (males) to 8% (females) in urine, and 28% (females) to 40% (males) in feces.
Groups of six male and six female Sprague-Dawley (Crl;CD)rats were given single doses by gavage of 2 or 400 mg/kg bw of (3-(14)C)-pyrazole-(radiochemical purity, 96.4-99.9%) or (U-(14)C)-benzyl-fenpyroximate (radiochemical purity, 99.2-99.5%) suspended in 1% aqueous Tween 80. Blood was collected from the tail vein of five rats per group at various times up to 168 hrs after dosing. In rats given 2 mg/kg bw, the concentration of radiolabel in blood peaked within 1 hr after dosing and reached a plateau, which was sustained for about 18 hrs... In the group given 400 mg/kg bw, absorption was delayed, and radiolabel was not detectable in blood within the first 12 hrs after dosing. A nearly maximal level was achieved 12-24 hrs after dosing; the plateau was sustained for 80-100 hrs ...
Identification of antitumor activity of pyrazole oxime ethers
摘要：
A series of pyrazole oxime ether derivatives were prepared and examined as cytotoxic agents. In particular, 5-phenoxypyrazole was comparable to doxorubicin, while exhibiting very potent cytotoxicity against XF 498 and HCT15. (c) 2005 Elsevier Ltd. All rights reserved.
[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.
Novel thienylpyridylcarboxamides of the formula (I)
The present application is also directed to a plurality of processes for preparing these compounds and their use for controlling unwanted microorganisms, and also novel intermediates and their preparation.
