More than 60% of oral doses of 14C-1,2,4-trichlorobenzene (ca. 21 mg/kg) administered to rats were excreted in bile as S-trichlorophenyl-mercapturic acid pathway metabolites. The biliary metabolites were ultimately excreted in urine mainly as the isomeric mercapturic acids. An acetylated glutathione conjugate was isolated as a major metabolite in bile (8% dose). The acetyl group was shown by mass spectrometry to be on the glutamyl moiety. A glutamylcysteine conjugate of trichlorobenzene was also isolated from bile as a major metabolite (8% dose). Trichlorothiophenols were deduced not to be intermediates or end-products of enzymic metabolism of trichlorobenzene in rats because 14C-2,4,5-trichlorothiophenol dosed ip to rats was excreted as the S-glucuronide (17% dose) and as S-(methylsulphonyl-dichlorophenyl)-mercapturic acid (36% dose).
Microsomal metabolism of 1,2,4-(14C)trichlorobenzene (1,2,4-TrCB) ... was studied with special emphasis on the conversion-dependent covalent binding to protein and DNA. 1,2,4-TrCB was metabolized to 2,3,6- and 2,4,5-trichlorophenol, and to a lesser extent to 2,4,6- and 2,3,5-trichlorophenol, and trichlorohydroquinone. About 10% of all metabolites became covalently bound to protein in a rather nonselective way. For 1,2,4-TrCB ... a strong correlation between secondary metabolism to hydroquinones and covalent binding was established. Protein binding was completely inhibited by the addition of ascorbic acid, indicating quinone metabolites as the sole reactive species formed. 1,2,4-TrCB ... alkylated DNA, although to a much lesser extent than protein (0.5% ... of all metabolites). Nonquinone intermediates, presumably epoxides, were responsible for a minor portion of the observed DNA binding, since complete inhibition by ascorbic acid was not reached. The differential role of cytochrome P450 both in primary and in secondary metabolism was demonstrated by the use of microsomes from rats pretreated with different inducers. Dexamethasone (DEX) microsomes (cytochrome P450IIIA1) showed the highest activity toward these chlorinated benzenes (14 nmol/mg/5 min for 1,2,4-TrCB ... both with regard to the formation of phenols and to the formation of protein-bound metabolites. In addition, DEX microsomes preferentially formed 2,3,6-trichlorophenol, whereas other microsomal suspensions formed 2,4,5-trichlorophenol as the major isomer. The present study clearly demonstrates the high alkylating potency of secondary quinone metabolites derived from chlorinated benzenes and poses a need for reevaluation of the role of epoxides in the observed toxicity of these compounds.
2,3,5- and 2,4,5-trichlorophenyl methyl sulfides, 2,3,5- and 2,4,5-trichlorophenyl methyl sulfoxides, and 2,3,5- and 2,4,5-trichlorophenyl methyl sulfones (TCPSO2Mes) were detected in the urine of rats dosed with 1,2,4-trichlorobenzene (TCB). After the administration of 1,2,4-TCB to rats, swift decreases in concentrations of 1,2,4-TCB in blood, liver, kidneys, and adipose tissue were observed. On the other hand, 2,3,5-TCPSO2Me appeared in blood, liver, kidneys, and adipose tissue and remained detectable in the blood and the three tissues until 120 hr. The increases in the activities of aminopyrine N-demethylase and aniline hydroxylase and the contents of cytochromes P450 and b5 in hepatic microsomes produced by 1,2,4-TCB occurred after increases in the hepatic concentration of 2,3,5-TCSO2Me. 2,3,5- and 2,4,5-TCPSO2Me increased the above four parameters in rat liver microsomes. The inducing intensity of 2,3,5-TCPSO2Me was much higher than that of 2,4,5-TCPSO2Me. 2,3,5-TCPSO2Me was considered to be a potent inducer and to play a principal role in the induction by 1,2,4-TCB. When 1,2,4-TCB was injected ip into bile duct-cannulated rats, little 2,3,5-TCPSO2Me was detected in blood, liver, kidneys, and adipose tissue. In the antibiotic-pretreated rats dosed with 1,2,4-TCB, 2,3,5-TCPSO2Me concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from 1,2,4-TCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of 1,2,4-TCB administration on the activities of aminopyrine- and aniline-metabolizing enzymes and the contents of cytochromes P450 and b5 in hepatic microsomes were not observed in the bile duct-cannulated rats. These findings provide evidence that the induction of drug-metabolizing enzymes by 1,2,4-TCB is not due to the action of 1,2,4-TCB itself but is due to its methylsulfonyl metabolite, 2,3,5-TCPSO2Me.
1,2,4-Trichlorobenzene was reductively converted into monochlorobenzene via dichlorobenzenes on incubation with intestinal contents of rats. The amounts of monochlorobenzene produced from o-dichlorobenzenes, m-dichlorobenzenes, or p-dichlorobenzenes, as substrates were compared, /and/ ... o-dichlorobenzenes /produced the least amount of monochlorobenzene/. This was consistent with the finding that o-dichlorobenzenes tended to accumulate more than the other isomers.
Trichlorobenzene may uncouple mitochondrial oxidative phosphorylation, inducing potassium ion release and inhibiting respiratory control. It's metabolites may covalently bind to cellular proteins and alkylate DNA. (A154, A155)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：D组 不可归类为人类致癌性
Cancer Classification: Group D Not Classifiable as to Human Carcinogenicity
CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: A dermal exposure study in mice was found inadequate for drawing conclusions as to carcinogenicity in humans. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
对人类无致癌性（未列入国际癌症研究机构IARC清单）。
No indication of carcinogenicity to humans (not listed by IARC).
More than 60% of oral doses of 14C-1,2,4-trichlorobenzene (ca. 21 mg/kg) administered to rats were excreted in bile as S-trichlorophenyl-mercapturic acid pathway metabolites. The biliary metabolites were ultimately excreted in urine mainly as the isomeric mercapturic acids. An acetylated glutathione conjugate was isolated as a major metabolite in bile (8% dose). The acetyl group was shown by mass spectrometry to be on the glutamyl moiety. A glutamylcysteine conjugate of trichlorobenzene was also isolated from bile as a major metabolite (8% dose). Trichlorothiophenols were deduced not to be intermediates or end-products of enzymic metabolism of trichlorobenzene in rats because 14C-2,4,5-trichlorothiophenol dosed ip to rats was excreted as the S-glucuronide (17% dose) and as S-(methylsulphonyl-dichlorophenyl)-mercapturic acid (36% dose).
1,2,4-Trichlorobenzene was fed to rats for 7 days at a dose of 1 mmol/kg per day. (14)C-Trichlorobenzene was admin and disposition of the radioactivity was determined. Tissue analysis showed highest levels in fat. Some was excreted in the urine, and fecal excretion was only 5-10% of the dose.
(14)C-labeled 1,2,4-trichlorobenzene was admin orally (10 mg/kg) and iv (10 mg/kg) to rats and rhesus monkeys. By 24 hr, the monkey had excreted 22% of the iv dose and roughly 40% of the oral dose in the urine. Less than 1% of the radioactivity was found in the feces. For the rat, 84% of the oral dose and 78% of the iv dose were collected in the urine by 24 hr; 11% and 7%, respectively, were the amounts collected in the feces.
Fingerling rainbow trout (Salmo gairdnerii) were exposed to (14)C-labeled 1,2,4-trichlorobenzene for 8 hr in a static exposure (0.018 mg/L) or for 35 days in a continuous-flow exposure (0.20 mg/L) followed by a subsequent elimination period. For 2 days after 8 hr exposure, half-time of elimination of (14)C from muscle & liver was 0.4 days, while after 35 day exposure an early rapid elimination of (14)C from these tissues (half-time= 0.4 days) was followed by slower elimination (half-time= 50 days) during days 4-36. Values for bile were much greater, reaching 240 after 8 hr exposure & 1400 during the 35 day exposure. When larger trout & carp were exposed to (0.2-0.4 mg/L), the bioconcentration factor for bile (14)C to water (14)C was less than 100. Pretreatment of trout with beta-naphthoflavone, an inducer of hepatic mixed-function oxidase, incr this bioconcentration factor for bile to several hundred. Solvent partitioning and thin layer chromatography indicated that about 60% of (14)C in bile from control trout or carp was present as highly polar biotransformation products, while for induced trout the value was more than 90%.
Novel processes for the preparation of adenosine compounds and intermediates thereto
申请人：——
公开号：US20030069423A1
公开（公告）日：2003-04-10
Novel processes for the preparation of adenosine compounds and intermediates thereto. The adenosine compounds prepared by the present processes may be useful as cardiovascular agents, more particularly as antihypertensive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as an antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. The present processes may offer improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability.
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。
Process facilitating the regeneration of a catalyst based on a zeolite used in an acylation reaction, catalyst and use
申请人：——
公开号：US20020120169A1
公开（公告）日：2002-08-29
The present invention relates to a process facilitating the regeneration of a catalyst based on a zeolite, employed in an acylation reaction.
Another subject of the invention is a process for acylation of an aromatic ether, comprising, in a preferred alternative form, an additional stage of regeneration of the catalyst.
The process of the invention, which makes it possible to regenerate more easily a catalyst based on a zeolite, employed in an acylation reaction, is characterized in that the zeolite is modified by addition of an effective quantity of at least one metallic element M chosen from the elements of group 8 of the Periodic Classification of the elements.
Condensed pyrazole derivatives, process for producing the same and use thereof
申请人：——
公开号：US20030187014A1
公开（公告）日：2003-10-02
Novel pharmaceutical compositions for inhibiting Th2-selective immune response and pharmaceutical compositions for inhibiting cyclooxygenase comprising condensed pyrazole derivatives represented by the general formula (I):
1
or salts thereof.
Bicyclic compounds and pharmaceutical composition containing tricyclic compound for treating or preventing sleep disorders
申请人：Takeda Chemical Industries, Ltd.
公开号：EP1199304A1
公开（公告）日：2002-04-24
A compound having the following general fomula:
wherein R1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R2 is H or an optionally substituted hydrocarbon group; R3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR4, NR4, O or S in which R4 is H or an optionally substituted hydrocarbon group; R5 is H, a halogen atom, C1-6 alkyl group, a C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group or an amino group wherein the C1-6 alkyl group, the C1-6 alkoxy group and the amino group may be substituted by 1 to 5 substituents, Y is C or N; ring B is an optionally substituted benzene ring; m = 1 to 4 and n = 0 to 2; L represents a leaving group such as a halogen atom, an alkylsulfonyl group, an alkylsulfonlyoxy group and arylsulfonyloxy group; or a salt thereof.
