The main metabolic pathways of degradation of diazinon are: cleavage of the ester bond leading to the hydroxypyrimidine derivatives; transformation of P-S moiety to the P-O derivative; oxidation of isopropyl substituent leading to the corresponding tertiary and primary alcohol derivatives; oxidation of the methyl substituent leading to the corresponding alcohol; glutathione-mediated cleavage of the ester bond leading to a glutathione conjugate.
/STUDY OF METABOLISM IN RATS OF DIAZINON FOUND THAT/ THE METABOLITES 2-ISOPROPYL-4-METHYL-6-HYDROXYPYRIMIDINE ... /& TWO UNIDENTIFIED METABOLITES/ WHICH WERE EXCRETED IN THE URINE AND FECES, ACCOUNT FOR 70% OF THE DOSE. ... METB IN RATS OF DIAZINON ... LABELLED WITH (14)C, ... 3 METABOLITES WERE LOCATED ON GENERAL METABOLIC PATHWAY BY FOLLOWING THEIR METABOLIC FATE AFTER IV INJECTION. SINCE ACUTE ORAL TOXICITIES OF ALL 3 CMPD ARE LESS THAN 1/10 OF THAT OF DIAZINON, BIOTRANSFORMATION IS ASSOC WITH DETOXICATION.
DIAZINON ... APPEARS TO BE METABOLIZED INTO CORRESPONDING PHOSPHATE IN LACTATING COWS, AND INTO THE HYDROLYTIC PRODUCTS DIETHYL PHOSPHOROTHIOATE AND DIETHYL PHOSPHATE WITH LIBERATION OF 2-HYDROXY-6-ISOPROPYL-4-METHYLPYRIMIDINE /PLUS METABOLITE DIAZOXON/.
AFTER ADMIN OF DIAZINON BY STOMACH TUBE TO SHEEP, HYDROXYDIAZINON WAS FOUND IN TISSUES. DIAZINON, WHEN FED TO SHEEP, WAS METABOLIZED ALSO BY HYDROXYLATION OF C-4 METHYL GROUP. RESIDUES OF THIS & C-1' ISOPROPANOL ANALOG WERE FOUND ... .
来源:Hazardous Substances Data Bank (HSDB)
代谢
地亚农已知的人类代谢物包括地亚氧磷、二乙基硫代磷酸和嘧啶醇。
Diazinon has known human metabolites that include Diazoxon, Diethyl thiophosphate, and Pyrimidinol.
IDENTIFICATION: Diazinon is a clear colorless liquid with a faint ester-like odor. Diazinon is soluble in most organic solvents. It is stable in neutral media, but is slowly hydrolyzed in alkaline media and more rapidly in acid media. Diazinon is a contact organophosphorus insecticide with a wide range of insecticidal activity. It is also available in mixed formulations with other insecticides. Another major use is as a drug in veterinary medicine. HUMAN EXPOSURE: Environmental levels of diazinon are generally low. The routes of exposure for the general population are inhalational and dietary. Exposure through water is negligible. Occupational exposure is primarily dermal. Several cases of accidental or suicidal poisoning by diazinon hae been reported, some of which were fatal. In some of these the cholinergic syndrome may have been more severe than expected because of the presence of highly toxic impurities such as TEPP. In certain cases, acute reversible pancreatitis was associated with a severe cholinergic syndrome. Reported cases of poisoning after occupational exposure have always been associated with the presence of impurities. ANIMAL STUDIES: The acute oral, dermal and inhalational toxicity is low. Short-term and long-term studies in mice, rats, rabbits, dogs and monkeys have shown that the only effect of concern is dose-related inhibition of acetyl cholinesterase activity. Diazinon is slightly irritant to rabbit skin but not to the eye. Diazinon is not a dermal sensitizer. Reproductive and developmental studies have revealed no evidence of embryotoxic or teratogenic potential. There was no effect on reproductive performance at dose levels that were not toxic to the parent animals. Mutagenicity studies with various end-points in vivo and in vitro gave no evidence of a mutagenic potential. There is no evidence of carinogenicity in rats or mice. In the dog and guinea-pig, diazinon has been reported to cause acute pancreatitis; this is considered to be a species-specific effect. Diazinon may be absorbed from the gastrointestinal tract, through the intact skin and following inhalation. Diazinon is oxidized by microsomal enzymes to cholinesterase inhibiting metabolites such as diazoxon, hydroxydiazoxon and hydroxydiazinon.
Diazinon is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：不太可能对人类致癌
Cancer Classification: Not Likely to be Carcinogenic to Humans
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A4：不能归类为人类致癌物。
A4: Not classifiable as a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：地亚农
IARC Carcinogenic Agent:Diazinon
来源:International Agency for Research on Cancer (IARC)
Four laying Leghorn hens were treated with 2-14C-diazinon (specific activity 30.3 uCi/mg) in gelatin capsules for seven consecutive days at daily doses of 1.7 mg/kg body weight, corresponding to a dietary exposure of 25 mg/kg in feed. ... Elimination of most of the administered radioactivity occurred via the excreta, with 78.6% of the total dose being excreted during the study period. Approximately 0.1% of the radioactivity was found in tissues and blood, less than 0.01% appeared in the egg yolks and 0.07% was detected in the egg whites. The residual radioactivity in the tissues amounted to 0.148 mg/kg diazinon equivalents in the kidney, 0.137 mg/kg in blood, 0.11 mg/kg in the liver and 0.01-0.025 mg/kg in the other tissues examined. The residues in the egg yolks ranged from 0.006 mg/kg diazinon equivalents to 0.065 mg/kg while those in the egg whites ranged from 0.038 mg/kg to 0.066 mg/kg. On a whole egg basis, a plateau concentration of 0.047 mg/kg was reached on day 4 of treatment.
A lactating Hereford cow (body weight 268 kg) was orally treated with a gelatin capsule containing 20 mg/kg 32P-diazinon (specific activity 518 cpm/ug). ... Within 36 hr, approximately 74% of the administered radioactivity was excreted with the urine, 6.5% appeared in the feces and 0.08% was found in the milk. A peak concentration of 2.27 mg/kg diazinon equivalents was reached 18 hr after the administration.
Two lactating goats were orally treated with (pyrimidine-14C)-diazinon (specific activity 9.7 uCi/mg) in gelatin capsules for four consecutive days at a dose level of 4.5 mg/kg per day, corresponding to a dietary exposure of 100 mg/kg of feed. During the observation period, an average 64.1% of the administered radioactivity was excreted with urine, 10.4% with the feces and 0.31% with the milk. A plateau of radioactivity in the milk was reached after 3 days of dosing at a mean level of 0.46 mg/kg diazinon equivalent. At sacrifice, radioactivity in the blood accounted for 0.2% and the tissues examined accumulated 0.92% of the administered dose. The highest residual radioactivity was detected in the kidney (2.0 mg/kg) and the liver (1.2 mg/kg). The other tissues examined contained 0.23-0.3 mg/kg diazinon equivalents.
Two female Beagle dogs were intravenously dosed with 0.2 mg/kg (ethoxy-14C)-diazinon (specific activity 3.4 uCi/mg) in 0.7 mL ethanol. ... The half-life of elimination from blood for this second phase was calculated to be 363 min. Approximately 58% of the administered radioactivity was recovered in the urine within 24 hr after the administration. Another two female beagle dogs were orally dosed by capsule with 4.0 mg/kg (ethoxy-14C) diazinon in ethanol. Approximately 85% of the administered radioactivity was recovered within 24 hr after oral administration, with 53% of it occurring in urine.
8 g 2-异丙基-4-甲基-6-羟基嘧啶、0.63 g SMB、2.82 g 氢氧化钠、50 mL 丁酮混合，室温搅拌0.5小时后升温至55℃，加入9.5 g O, O-二乙基硫代磷酰氯并升温至70℃。搅拌0.5小时后再回流1小时，冷却后加入50 mL水溶解固体，用20% NaOH调节pH值至11，分层。
Diethyl phosphite production from phosphorothioate degradation with molybdenum peroxides and hydrogen peroxide in ethanol
摘要：
A polystyrene-supported molybdate-peroxide polymer (Mo-Y(s)) destroys phosphorothioate pesticides of the form (ArO)P( = S)(OEt)(2) in EtOH under mild oxidative (H2O2) conditions and produces a commodity organophosphate. This is the first report of a metal-based system that successfully degrades the "live" pesticides parathion, diazinon and coumaphos. In addition to the operational advantages of heterogeneous reaction chemistry, the Mo-Y(s) support degrades multiple equivalents of the pesticide in H2O2(aq). Of particular importance is the predominant production of diethyl phosphite, a commodity chemical, from diazinon degradation over Mo-Y(s) in EtOH; no toxic oxon is found. Coumaphos and parathion produce the corresponding oxon which have Delta H-double dagger (kcal/mol) of 15.4 (0.5) and 21.7 (0.8), respectively; these activation parameters are consistent with key observations found in the relative amount of coumoxon and paraoxon produced. Finally, a discrete molybdate-peroxide complex is presented as a possible solution model for this heterogeneous reaction.
[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.
The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof,
pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.
[EN] DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS<br/>[FR] PHARMACOPHORES DUALS, ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES ET INHIBITEURS DE L'ACTIVITÉ PDE4
申请人：GLAXO GROUP LTD
公开号：WO2009100169A1
公开（公告）日：2009-08-13
The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
