Following a single oral administration of (phenyl-U-(14)C)-fluopicolide, up to 33 different radioactive fractions were observed in the urine from male rats, and up to 42 fractions were found in female rat urine. Very few of these metabolites exceeded 1% of the dose. The highest single fraction was found in female rat urine and represented 1.534% of the dose. This was a thiomethyl derivative that was also conjugated with sulfate after hydroxylation of the phenyl ring. In feces, up to 11 components were found in males and females, but there was a single large contributor that represented about 80% of the dose; this was unchanged fluopicolide.
In metabolic studies of fluopicolide in excreta of rats, up to 46 radioactive components were found in the urine and up to 14 radioactive components were found in the feces of males and females, taken together. Important reactions were hydroxylation of the phenyl ring in two positions, which could then be conjugated to form glucuronides or sulfates; and substitution of the chlorine atom on the phenyl ring by glutathione (catalyzed by glutathione S-transferase), followed by degradation to the cysteine conjugate. These conjugates could then be cleaved via beta-elimination by cysteine conjugate beta-lyases, leaving a resulting thiol that could serve as the methyl acceptor-a mechanism known as the thiomethyl shunt. The resulting S-methyl group could then be oxidized to provide sulfone and sulfoxide structures. In contrast to these multiple reactions of the phenyl moiety, the pyridyl structure appeared to be metabolically stable. Scission of fluopicolide resulted in the formation of M-01 and M-02. The former was further metabolized in a manner similar to the phenyl ring of intact fluopicolide, whereas the latter remained intact and appeared to undergo only conjugation reactions at the newly formed carboxylic group.
Five Sprague-Dawley rats/sex were dosed orally daily by gavage with a dose of 9.73 mg/kg/day of (Phenyl-U-(14)C) AEC638206 (/fluopicolide/, radiopurity: >98.3%, specific activity: 59.5 mCi/mmole) for 14 days. Unlabeled AE-C638206 (/fluopicolide, purity: 99.3%) was used to adjust the specific activity of the dosing preparations. Urine, feces and cage washing were collected daily during the dosing regimen and for 6 days post-final dose. At this time, the animals were euthanized and the tissues were assayed for the presence of radiolabel compound. ... Among the identified metabolites, hydroxylation of the phenyl ring alone or in conjunction with sulfation were the predominant alterations which were observed. The presence of methyl sulphide adducts alone or bound with glycine were noted on the phenyl ring as well. Glucuronide moieties associated with the hydroxylated phenyl ring were also isolated. The percentage of the administered dose which was recovered as the parent compound in the feces for the time period of sample collection constituted 43.4 and 54.9% for the males and females, respectively.
One or two Sprague Dawley rats/sex/group were dosed with 25 or 500 mg/kg of (14)C AE-C638206-benzene (/fluopicolide/, specific activity: 144uCi/mg, radiochemical purity: >99%) or 25 mg/kg of (14)C AE-C638206- pyridine (/fluopicolide/, specific activity: 159 uCi/mg, radiochemical purity: >99%) orally by gavage. ... Analysis of the metabolites in the urine and feces revealed cleavage of the amide linkage and the presence of glycine, sulfate, methylmercaptan and glucuronide conjugates.
IDENTIFICATION AND USE: Fluopicolide is a beige solid used as a fungicide. HUMAN STUDIES: In primary human lymphocyte culture treated with fluopicolide no treatment-related increase in chromosomal aberrations was evident with or without activation. ANIMAL STUDIES: Fluopicolide was slightly irritating to the rabbit eye. Fluopicolide was not irritating to rabbit skin. Fluopicolide was not a skin sensitizer in a guinea-pig Magnusson and Kligman test. Fluopicolide has moderate toxicity with no deaths noted in male or female rats at doses of > 2000 mg/kg when given orally, and > 4000 mg/kg dermally. Rats were exposed (nose only) for 4 hr to a dust aerosol of fluopicolide at a concentration of 5.16 mg/L. The rats were observed for 14 days after exposure, then killed and autopsied. There was no mortality during the exposure and observation period. Common observations noted both during and after exposure included wet fur, hunched posture, piloerection and increased respiratory rate. Weight gain was markedly decreased in male and female rats in a subchronic study at doses of 1668 mg/kg/day and 1673 mg/kg/day), respectively. Male and female rats also experienced reduced body weight gain in a subchronic neurotoxicity study at doses of 780.6 and 125.2 mg/kg/day, respectively. There was no effect on weight gain in dogs or mice in subchronic studies. Besides effects on body weight and body weight gain, no definitive cross-species target organ was identified in subchronic studies with fluopicolide. As in the subchronic studies, the main effect in the chronic studies was a decrease in body weight gain with no definitive cross-species target organ identified. No evidence for carcinogenicity was seen in rats administered fluopicolide in food for 24 months. No evidence of neurotoxicity was seen in acute or subchronic oral rat neurotoxicity studies with fluopicolide. In developmental studies in rats and rabbits, at the same dose affecting the dam, 700 mg/kg in rats and 60 mg/kg in rabbits, fetal growth was affected in both species and observed as decreases in body weight and crown-rump length. Also, at 700 mg/kg, delays in fetal ossification and increased incidence of skeletal malformations were observed in rat fetuses, with neither of these effects seen in rabbit fetuses. No external or visceral abnormalities were observed in either species. Reproductive performance was not affected in a two-generation reproduction toxicity study in which fluopicolide was administered to male and female rats. In Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA treated with fluopicolide there was no increase in the incidence of reverse mutations. ECOTOXICITY STUDIES: Fluopicolide is highly toxic to estuarine/marine fish and is highly toxic to moderately toxic to freshwater fish. Bobwhite quail and mallard duck chronic reproduction toxicity studies demonstrated significant reductions in multiple reproductive endpoints at the highest treatment level (1020 mg a.i./kg diet), including viable embryos (14%), live embryos (15%), number hatched (22%), the ratios of number hatched to eggs laid (20%) and to eggs set (18%), hatchling survival (21%), and the proportion of survivors to eggs set (18%).
/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 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/
/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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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 (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/GENOTOXICITY/ Primary human lymphocyte cultures, procured from the whole blood of male volunteers (stimulated with phytohemagglutinin for 48 hours), were treated with concentrations of AE C638206 (/fluopicolide; purity: 95.9%) ranging from 4.88 to 625 ug/mL for 3 hours, followed by a recovery period of 18 hours of incubation under conditions of both nonactivation and activation in Trial No. 1. In Trial No. 2, the cells were treated with concentrations of the test material ranging from 1.22 to 625 ug/mL for 21 hours (nonactivation) or with 4.88 to 625 ug/mL of the test material for 3 hours, followed by a recovery period of 18 hours prior to being harvested (activation). An Aroclor 1254-induced rat liver S9 fraction was used to metabolize the test material. No treatment-related increase in chromosomal aberrations was evident under conditions either conditions of nonactivation or activation. The positive controls were functional.
One or two Sprague Dawley rats/sex/group were dosed with 25 or 500 mg/kg of (14)C AE-C638206-benzene (/fluopicolide-benzene/ specific activity: 144uCi/mg, radiochemical purity: >99%) or 25 mg/kg of (14)C AE-C638206- pyridine (/fluopicolide-pyridine/, specific activity: 159 uCi/mg, radiochemical purity: >99%) orally by gavage. Unlabeled AE-C638206 (/fluopicolide/ batch no. CDB234167-2, purity: 99.5%) was used to adjust the specific activity of the dosing preparations. The position of radiolabeling on the molecule or the sex of the animal did not particularly affect the recovery profile of the radiolabel. The primary route of excretion of the radiolabeled material was in the feces (76 to 85% of the administered dose at 25 mg/kg, approximately 89% of the administered dose at 500 mg/kg). Eight to 12% of the radiolabel was recovered from the urine at 25 mg/kg and 5 to 6% in the 500 mg/kg treatment group. Radiolabeled carbon dioxide represented between 0.01 and 0.06% of the administered dose. Less than 0.4% of the administered dose was recovered from the tissues at 7 days postdose. The liver and kidneys had the highest concentrations of radiolabel. The pharmacokinetic parameters were calculated for the two 25 mg/kg treatment groups. The Tmax values ranged from 6 to 12 hours post-dose with the maximal blood concentrations ranging from 0.95 to 2.03 ug/g of blood. Clearance from the blood ranged from 9 to 11.5 g/min. Analysis of the metabolites in the urine and feces revealed cleavage of the amide linkage and the presence of glycine, sulfate, methylmercaptan and glucuronide conjugates. The percentage of each metabolite recovered was not quantified.
Five Sprague-Dawley rats/sex were dosed orally daily by gavage with a dose of 9.73 mg/kg/day of (Phenyl-U-(14)C) AEC638206 (/fluopicolide/, radiopurity: >98.3%, specific activity: 59.5 mCi/mmole) for 14 days. Unlabeled AE-C638206 (/fluopicolide/, purity: 99.3%) was used to adjust the specific activity of the dosing preparations. Urine, feces and cage washing were collected daily during the dosing regimen and for 6 days post-final dose. At this time, the animals were euthanized and the tissues were assayed for the presence of radiolabel compound. Urine and feces samples collected at various time points during the dosing regimen were pooled and metabolites of the parent compound were isolated and identified. The primary pathway of excretion was via the feces. For the males and females, 79 and 72%, respectively, of the administered dose was recovered in the feces. Another 15 and 21%, respectively, of the administered dose was recovered in the urine. At 6 days post-final dose, less than 0.5% of the total administered dose was recovered from the tissues. At that time, the liver, kidneys and cardiac blood had the highest concentrations of radiolabel. Among the identified metabolites, hydroxylation of the phenyl ring alone or in conjunction with sulfation were the predominant alterations which were observed. The presence of methyl sulphide adducts alone or bound with glycine were noted on the phenyl ring as well. Glucuronide moieties associated with the hydroxylated phenyl ring were also isolated. The percentage of the administered dose which was recovered as the parent compound in the feces for the time period of sample collection constituted 43.4 and 54.9% for the males and females, respectively.
Four Sprague-Dawley rats/sex/group were dosed orally by gavage with 9.61 or 76.5 mg/kg of Phenyl-U-(14)C AE-C638206 (/fluopicolide/, radiopurity: >98.3%, specific activity: 59.5 mCi/mmole). Unlabeled AE-C638206 (/fluopicolide/, purity: 99.3%) was used to adjust the specific activity of the dosing preparations. Urine and feces were collected up to 7 days post-dose. The residual radioactivity in the tissues was measured at the time the animals were euthanized. The feces were the primary path of excretion with 82 to 83% of the administered dose recovered in the feces at the lower dose and 87 to 88% at the higher dose. The recovery in the urine was 10 to 13% and 5 to 7% of the administered dose, respectively. At the lower dose, 85 and 94% of the administered dose was excreted within the first 48 hours postdose by the males and females, respectively. At the higher dose, 90 and 93% of the administered dose was excreted within the first 48 hours by the males and females, respectively. The adrenal, liver and kidneys were the three organs with the highest concentration of radiolabel.
Four Sprague-Dawley rats/sex/group were dosed orally by gavage with 10 or 100 mg/kg of (Phenyl-U-(14)C) AE-C638206 (/fluopicolide/, radiopurity: 99.1%, specific activity: 58.05 mCi/mmole). In the 10 mg/kg treatment group, 4 animals/sex were euthanized at 8 hours, 4 males at 24 hours, 4 females at 30 hours, 4 males at 36 hours, 4 females at 48 hours, 4 males at 72 hours, and 4 females at 120 hours. At the 100 mg/kg treatment level, 4 animals/sex were euthanized at 8 hours, 4 males at 24 hours, 4 females at 30 hours, 4 animals/sex at 48 hours, 4 males at 72 hours, and 4 females at 120 hours. Specified tissues and organs were recovered and the radioactivity in those tissues and organs was determined. Extracts of liver were analyzed by HPLC-mass spectroscopy in order to identify metabolites. Peak tissue levels were observed at 8 hours post-dose for both treatment levels. No sexual difference in the distribution of the radiolabel among the tissues was apparent. The adrenal, liver and kidneys were the three organs with the highest concentration of radiolabel over the course of the study. The concentration of radiolabel in fat was initially higher than these other tissues, but diminished more rapidly. The concentration of radiolabel in the intestinal tract demonstrated the progressive movement of the test material through the digestive tract. The percentage of administered dose absorbed into the tissues was proportionately less at the higher dose level. The concentration of radiolabel in the various tissues at 168 hours post-dose had decreased to less than 5% of the level observed at 8 hours post-dose. A total of 13 moieties were isolated from the liver extracts and represented between <0.01% and 0.20% of the administered dose. Hydroxylation and sulfation of the benzyl ring were identified as metabolic pathways.
[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.
[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.
