When chlorophenols are eaten, almost all of the compounds quickly enter the body. Chlorophenols also rapidly enter the body through the skin. Little is known about how much of the chlorophenols enter the body if one breathes air containing them... The other chlorophenols (dichlorophenol, trichlorophenols, tetrachlorophenols), which also leave through the urine as less harmful chemicals, can stay in the body for several days. /chlorophenols/
Human studies indicate that sulfation and glucuronidation are the main metabolic pathways of 2,4,6-TCP, which is excreted in the urine as conjugated metabolites. In general, 2,4,6-TCP undergoes biotic isomerization to other trichlorophenol isomers and conjugation with glucuronic acid. Glucuronic acid accounts for approximately 80% of the conjugates detected in urine. Metabolites generated following incubation of 2,4,6-TCP are 2,6-dichloro-1,4-hydroquinone and two isomers of hydroxypentachlorodiphenyl ether. The 2,6-dichloro-1,4-semiquinone free radical was also identified. (L159)
IDENTIFICATION AND USE: 2,4,6-Trichlorophenol (2,4,6 -TCP) is a colorless needle or yellow solid that has a strong phenolic odor. This germicidal agent was used as a fungicide, bactericide, wood preservative, biocide, and intermediate in production of higher chlorinated phenols. It is not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. HUMAN EXPOSURE AND TOXICITY: Trichlorophenols produce redness and edema on skin contact and on prolonged exposure mild to moderate chemical burns of skin of man. In eye they induce conjunctival irritation and sometimes corneal injury and iritis. Dusts are irritating to nose and pharynx and systemic effects presumably resemble phenol. Trichlorophenols can have an irritating effect on the lung, and it cannot be excluded that long-term exposure may produce pulmonary fibrosis. Children with low levels (<3.58 ug/g) and high levels (=3.58 ug/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection after adjusting for covariates. It was concluded that exposure to TCP may increase the risk of behavioral impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/contamination, especially in countries where organochlorine pesticides are still commonly used. 2,4,6-Trichlorophenol is reasonably anticipated to be a human carcinogen according to NTP. ANIMAL STUDIES: In rats lethal doses of chlorophenols produce restlessness, increased rate of respiration, rapidly developing motor weakness, tremors, clonic convulsions, dyspnea, and coma. 2,4,6-TCP produces these signs but decreased activity and motor weakness do not appear quite so promptly. 2,4,6-TCP was not hepatotoxic in rats as assessed by measurement of hepatic glucose-6-phosphatase and serum sorbitol dehydrogenase. Carcinogenesis bioassays were conducted by giving 2,4,6-TCP in feed to groups of male and female rats and male mice for two years. Adverse effects at two years were leukocytosis and monocytosis of peripheral blood and hyperplasia of bone marrow in both sexes of rats. In mice, liver toxicity, including individual liver cell abnormalities, focal areas of cellular alteration, and focal and nodular areas of hyperplasia were commonly present. TCP caused leukemias/lymphomas in male rats, and possibly in female rats and female mice as well, and induced liver tumors in male and female mice. 2,4,6-TCP, a non-mutagen to Salmonella, was negative in tests for chromosome breakage in vitro, but did produce numerical chromosome changes and micronuclei in V79 cells. 2,4,6-TCP induces structural chromosome aberrations in CHO cells and in V79 cells using a 3-hr treatment and 20-hr sampling time (17-hr recovery). Positive results were obtained when a recovery time of 4-12 hr was allowed after the 24-hr treatment with 2,4,6-TCP, and when 2,4,6-TCP was tested with S9. ECOTOXICITY STUDIES: 2,4,6-TCP was applied at single doses of into compartments of a natural experimental pond to study the effect on biota. Changes seen included a rapid decline of daphnia concentration to zero after phytoplankton, a continuous increase of contamination indicators like flagellates and microorganisms, and a significant decrease in O2 concentration as a secondary effect of the changed balance between autotrophic and heterotrophic populations.
2,4,6-Trichlorophenol 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.
CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on no human data and sufficient evidence in animals; namely, increased incidence of lymphomas or leukemia in male rats and hepatocellular adenomas or carcinomas in male and female mice. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Sufficient.
Evaluation: There is limited evidence in humans for the carcinogenicity of combined exposures to polychlorophenols or to their sodium salts. There is limited evidence in experimental animals for the carcinogenicity of 2,4,6-trichlorophenol. Overall evaluation: Combined exposures to polychlorophenols or to their sodium salts are possibly carcinogenic to humans (Group 2B). /Polychlorophenols/
The rate of excretion by rats of 2,4,6-trichlorophenol in urine and feces was studied. 6 Male wistar rats were dosed daily via stomach tube with a dose corresponding to 1 ppm of 2,4,6-trichlorophenol in the diet for 15 days. Storage of radioactivity reached a plateau after 3 days. At this level, excretion in the feces was 92.5% of the daily applied dose. Excretion decr after treatment stopped, reaching 4.3% in the urine and 1.9% in the feces after 3 days. 2,4,6-Trichlorophenol was conjugated and to a certain extent isomerized.
2,4,6-Trichlorophenol was investigated for its binding capacities to whole human serum and several human serum proteins in vitro. Percent binding to albumin and serum paralleled molecular wt, but no definite pattern was observed in ranking the percent binding to other proteins.
The concentration of 2,4,6-trichlorophenol was measured in the blood and various other tissues of the rat after ip administration of the compound at 25 mg/kg body weight. The highest concentration, 329 + or - 117 nmol per gram of tissue/, was found in the kidney. Half-times were between 1.4 and 1.8 hr in the blood, brain, fat, kidney, liver and muscle.
Urine from 230 Finnish sawmill workers exposed to a combination of 2,3,4,6-tetrachlorophenol (80%), 2,4,6-trichlorophenol (10-20%), and pentachlorophenol (5%), was analyzed for the sum of the three chemicals as chlorophenols. Samples were collected at the end of the work shift. Workers were divided into the following exposure groups according to work tasks: (I) primarily skin exposure (n= 112), (II) primarily respiratory tract exposure (n= 34), and (III) equal exposure by both routes (n= 84). Air concentrations at the workplace and amount of time spent with skin contact were not studied. There was no control group; values were compared to the nonexposed Finnish population level of <0.1 umol/L. Skin absorption was the most effective route of exposure as reflected by urinary chlorophenol concentrations. The median concentration in workers with skin absorption was 7.8 umol/L (range 0.1 to 210.9 umol/L) and was significantly different from that in workers with the respiratory tract as the main route of exposure (median concentration 0.9 umol/L; range 0.1 to 13.3 umol/L; p< 0.001) and from those with both routes of equal importance (1.4 umol/L; range 0.1 to 47.8 umol/L; p< 0.001).
/2,4,6-Trichlorophenol/ ... cleared rapidly from rats, most of it being excreted in the urine. 1 ug/g concentration of labeled phenol to the diet of rats /was added/ for a 3-day period. Eighty two percent of the dose was excreted in the urine and 22% in the feces. Radioactive trichlorophenol was not detected in liver, lung, or fat samples examined 5 days after the last dose was administered. ... 2,4,6-trichlorophenol is metabolized to 3,5-dichlorocatechol in the rabbit. Studies ... in the rabbit have shown that 2,4,6-trichlorophenol does not form a sulfate conjugate in vivo because of its low pK value.
1.周国泰，化学危险品安全技术全书，化学工业出版社，1997 2.国家环保局有毒化学品管理办公室、北京化工研究院合编，化学品毒性法规环境数据手册，中国环境科学出版社.1992 3.Canadian Centre for Occupational Health and Safety,CHEMINFO Database.1998 4.Canadian Centre for Occupational Health and Safety, RTECS Database, 1989
Mechanism of hydrolysis of phosphorylethanolamine diesters. Intramolecular nucleophilic amine participation
作者：Robert A. Lazarus、Patricia A. Benkovic、Stephen J. Benkovic
DOI：10.1039/p29800000373
日期：——
Intramolecular displacement reactions at phosphorus have been examined in a series of N-alkyl-O-arylphosphorylethanolamines in water at 35 °C. The examination of the pH–rate profiles and the direct observation by 31P n.m.r. of the reaction products implicate a nucleophilic role for the amine. A rate enhancement of 106–107 is observed. Structure–reactivity correlations derived by changing the pKa of
在35°C的水中，已在一系列N-烷基-O-芳基磷酰基乙醇胺中检测了磷下的分子内置换反应。pH速率曲线的检查以及31 P nmr对反应产物的直接观察表明该胺具有亲核作用。观察到速率提高了10 6 –10 7。通过改变P由来结构反应性的相关性ķ一个的胺和离去基团屈服值β NUC ≃0.7和β 1克1.25–1.25并支持非耦合的协调机制。讨论了涉及胺和氧阴离子与分子间和分子内磷酸二酯和三酯的亲核反应机理。
The reactions of unactivated aryl halides with sodium methoxide in HMPA
Sodiummethoxide reacts with dichlorobenzenes in HMPA to give the chloroanisoles as a result of a SNAr process. Excess MeONa then effects the demethylation of the ethers to give the chlorophenols via an SN2 reaction. With tri- and tetrachlorobenzenes the initially formed chloroanisoles can be dealkylated to chlorophenols or can suffer further substitution to give the chlorodimethoxybenzenes; these
由于S N Ar过程，甲醇钠与HMPA中的二氯苯反应生成氯茴香醚。然后过量的MeONa通过S N 2反应使醚脱甲基，得到氯酚。用三氯苯和四氯苯可以将最初形成的氯茴香醚脱烷基化为氯酚，或者可以进一步取代生成氯二甲氧基苯；它们与过量的MeONa反应，得到氯甲氧基苯酚。在取代基的电子效应的基础上，介绍并讨论了用二，三和四氯苯的各种异构体获得的结果。
[EN] AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRAZINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
申请人：NOVARTIS AG
公开号：WO2015162459A1
公开（公告）日：2015-10-29
The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.
The invention provides compounds of formula (I): Said compounds being inhibitors of Kv3 channels and of use in the prophylaxis or treatment of related disorders.
