2-Bromohydroquinone was identified as a metabolite of both bromobenzene and o-bromophenol in the rat in vivo and in vitro. Identification was based on high-pressure liquid chromatography and gas chromatography-mass spectrometry. Formation of 2-bromohydroquinone by rat liver microsomes from both bromobenzene and o-bromophenol was increased by treatment of rats with either phenobarbital or 3-methylcholanthrene. Covalent binding of o-bromophenol to rat liver microsomes was inhibited by glutathione and ascorbate but not by superoxide dismutase or catalase. Liver microsomes converted o-bromophenol to 2-bromohydroquinone and covalently bound material, whereas kidney and lung microsomes metabolized o-bromophenol less rapidly.
p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates.
Incubation of either o-bromophenol or 2-bromohydroquinone with rat liver microsomes and 0.25 mM 35S-glutathione (GSH) gave rise to several isomeric 35S-GSH conjugates. A mixture of these isomeric GSH conjugates was prepared chemically and two were purified by HPLC; 1H-NMR spectroscopy revealed that one was 2-bromo-3-(glutathion-S-yl)hydroquinone and the other was a disubstituted GSH conjugate which could be either 2-bromo-3,5-(diglutathion-S-yl)hydroquinone or 2-bromo-3,6-(diglutathion-S-yl)hydroquinone. Injection of the disubstituted GSH conjugate intravenously to rats caused substantial elevations in blood urea nitrogen levels. Treatment of rats with AT-125 (Acivicin; NSC 163501; 10 mg/kg ip) caused a substantial inhibition of kidney gamma-glutamyl transpeptidase activity and decreased 2-bromohydroquinone-mediated elevations in blood urea nitrogen. These findings are consistent with the view that the kidney necrosis observed after administration of either bromobenzene (1), o-bromophenol (2), or 2-bromohydroquinone (3) might be due in part to 2-bromohydroquinone GSH conjugates formed in the liver and subsequently transported to the kidney and converted to ultimate nephrotoxic metabolite(s).
4-Bromocatechol and the /o-, m- and p-/ bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (iv).
2-bromophenol (2-(BP)), 3-BP, and 4-BP can all be formed during the metabolism of bromobenzene in both rats and guinea-pigs. 2-BP is formed predominantly by spontaneous isomerization of the 2,3-oxide. 3-BP is formed via the sulfur-series pathway to phenols, which involves the enterohepatic circulation, with the key intermediate being S-(2-hydroxy-4-bromocyclohexa-3,5-dienyl)-L-cysteine, derived from the 4-S-glutathione conjugate of the 3,4-oxide. 4-BP is formed by the sulfur-series route from the S-(2-hydroxy-5-bromocyclohexa-3,5-dienyl)-L-cysteine. Additional suggested in vivo routes to 3- and 4-BP involve dehydration/aromatization of the 3,4-dihydro-3,4-diol, possibly by way of conjugates.
IDENTIFICATION AND USE: 2-Bromophenol is used as a precursor to resorcinol. It is a yellow to red oily liquid with an unpleasant odor. It is slightly soluble in chloroform; soluble in ethanol, ether, alkali, and water. HUMAN EXPOSURE AND TOXICITY: It is harmful if swallowed.2-Bromophenol causes skin irritation. It may be harmful if absorbed through the skin. Causes eye irritation and is irritating to mucous membranes and the upper respiratory tract. Occupational exposure to this chemical may occur through inhalation, and dermal contact with these compounds at workplaces where these chemicals are produced or used. Monitoring data indicate that the general population may be exposed to bromophenols by inhalation, ingestion of food, and drinking water, and dermal contact. In an in vitro assay based on H295R human adrenocortical carcinoma cell line, which possesses most key genes or enzymes involved in steroidogenesis, of five bromophenols. Among the genes tested, 3betaHSD2 was the most markedly upregulated, with a range of magnitude from 1.6-20.0 fold. The results demonstrate that bromophenol bromobiphenyls and bromodibenzo-p-dioxin/furan are able to modulate steroidgenenic gene expression, which may lead to endocrine disruption. ANIMAL STUDIES: 2-Bromophenol administered ip caused a decrease in renal glutathione levels. In contrast, hepatic glutathione levels remained close to control values after chemical administration. Renal glutathione was far more susceptible to the initial rapid depleting effects of 2-bromophenol than was hepatic glutathione, the dose response curve for hepatic glutathione depletion being shifted to the right. 2-Bromophenol was found to be hepatotoxic in English sole, as indicated by the presence of hepatocellular coagulation necrosis and fatty change in the liver, altered glutathione and ascorbic acid levels in liver tissue, elevated serum aspartate aminotransferase and alkaline phosphatase activity and increased serum glucose and triglyceride levels. No evidence of nephrotoxicity was found in English sole exposed to either toxicant
/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/
/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/
/SIGNS AND SYMPTOMS/ Causes skin irritation. May be harmful if absorbed through the skin. Causes eye irritation. Inhalation: May be harmful if inhaled. Material is irritating to mucous membranes and upper respiratory tract. Harmful if swallowed. TARGET ORGAN(S) OR SYSTEM(S) Eyes. Depending on the intensity and duration of exposure, effects may vary from mild irritation to severe destruction of tissue.
Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
申请人：Abbott Laboratories
公开号：US20040116518A1
公开（公告）日：2004-06-17
The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immune diseases and cerebral vasospasm, to pharmaceutical compositions containing these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
[EN] CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF<br/>[FR] MODULATEURS DE CALPAÏNE ET LEURS UTILISATIONS THÉRAPEUTIQUES
申请人：BLADE THERAPEUTICS INC
公开号：WO2019190885A1
公开（公告）日：2019-10-03
Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.
Compounds are provided having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R2, X1, X2, Y1, and Y2 are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.
[EN] PYRROLOTRIAZINES AS ALK AND JAK2 INHIBITORS<br/>[FR] PYRROLOTRIAZINES EN TANT QU'INHIBITEURS D'ALK ET DE JAK2
申请人：CEPHALON INC
公开号：WO2010071885A1
公开（公告）日：2010-06-24
The present invention provides a compound of formula (I) or a salt form thereof, wherein Q1, Q2, Q3, and Q4 are as defined herein. The compound of formula (I) has ALK and/or JAK2 inhibitory activity, and may be used to treat proliferative disorders.
Synthesis of chiral sulfonylmethyl isocyanides, and comparison of their propensities in asymmetric induction reactions with acetophenones1
作者：Frans J.A. Hundscheid、Vishnu K. Tandon、Pieten H.F.M. Rouwette、Albert M. van Leusen
DOI：10.1016/s0040-4020(01)87684-5
日期：1987.1
Seven chiral analogues of tosylmethyl isocyanide (TosMIC) were synthesized in order to investigate and compare their ability to achieve asymmetricinduction in base mediated reactions with acetophenone and trifluoroacetophenone. Acid hydrolysis of the intermediate 2-oxazolines (10 and 11) gave optically active α-hydroxy aldehydes (12 and 13).
