Pregnancy and increased doses of theobromine were shown to modify theobromine metabolism. At a dose of 50 mg/kg bw, pregnant rabbits excreted more unchanged theobromine in the urine (51% versus 35%). Pregnant rats excreted a higher percentage of a 5 mg/kg dose as unchanged theobromine (53%) than non-pregnant rats (39%); this difference disappeared at the saturation dose (100 mg/kg), when unchanged theobromine corresponded to about 60% of the dose in the urine of both pregnant and non-pregnant animals. Rats given 100 mg/kg excreted more unchanged theobromine than those given 1 mg/kg (73% versus 51%), and showed a corresponding relative decrease in excretion of its uracil metabolite, 6-amino-5-(N-methylformylamino)-1-methyluracil (16% versus 28%).
The compounds identified in bile of phenobarbital-treated rats were 3,7-dimethyluric acid (64-76% of biliary radioactivity), dimethylallantoin (5-8%), 6-amino-5-(N-methylformylamino)- 1-methyluracil (10-17%) and theobromine (8-10%). In 3-methylcholanthrene-treated rats, urinary elimination of unchanged theobromine was reduced from 23-27% to only 2%, while excretion of 6-amino-5-(N-methylformylamino)-1- methyluracil was significantly increased. Only 3,7-dimethyluric acid was produced by liver microsomal incubation in control rats while phenobarbital and 3-methylcholanthrene pretreatment enhanced the biotransformation resulting in the production of all metabolites found in vivo as well as unknown polar compounds.
6-Amino-5-(N-methylformylamino)-1-methyluracil is quantitatively the most important theobromine metabolite in rats, accounting for 20-35% of urinary metabolites. The majority of theobromine-derived radioactivity in the feces of rats could be accounted for by 3,7-dimethyluric acid. The most extensive metabolism of theobromine was observed in rabbits and mice; male mice converted theobromine more extensively into this metabolite than did female mice. In contrast, oxidation of theobromine to 3,7-dimethyluric acid was significantly greater in female than in male rats. Rabbits and dogs metabolized theobromine primarily to 7-methylxanthine and 3-methylxanthine, respectively, and dogs excreted small quantities of an unidentified metabolite.
来源:Hazardous Substances Data Bank (HSDB)
代谢
作为咖啡因的代谢物，可可碱已在人类和不同动物物种的血浆和尿液中以不同量被检测到。
As a metabolite of caffeine, theobromine has been detected in variable amounts in plasma and urine of humans and different animal species.
来源:Hazardous Substances Data Bank (HSDB)
代谢
可可碱在人体内的已知代谢产物包括7-甲基黄嘌呤、3,7-二甲基尿酸和3-甲基黄嘌呤。
Theobromine has known human metabolites that include 7-Methylxanthine, 3,7-Dimethyluric acid, and 3-Methylxanthine.
IDENTIFICATION AND USE: Theobromine is a white powder. It is an alkaloid found in cocoa and chocolate products. Theobromine is used principally to make caffeine . Formerly, theobromine and its derivatives were used in diuretics, myocardial stimulants, vasodilators and smooth muscle relaxants. Theobromine salts (calcium salicylate, sodium salicylate and sodium acetate) were used previously to dilate coronary arteries at doses of 300 to 600 mg per day. There is no current therapeutic use of theobromine. HUMAN EXPOSURE AND TOXICITY: It has been stated that "in large doses" theobromine may cause nausea and anorexia and that daily intake of 50-100 g cocoa (0.8-1.5 g theobromine) by humans has been associated with sweating, trembling and severe headache. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In other studies, theobromine increased HDL-cholesterol concentrations by 0.16 mmol/L. Furthermore, there was a significant theobromine effect on increasing apolipoprotein A-I and decreasing apolipoprotein B and LDL-cholesterol concentrations. In human lymphocyte cultures, theobromine did not significantly increase the number of sister chromatid exchanges per cell, but, in another experiment using higher doses, the numbers of sister chromatid exchanges per cell were increased in the absence of an exogenous metabolic system. Theobromine induced breaks in human lymphocytes in culture, contrary to the results with rodent cells. ANIMAL STUDIES: High doses 250-300 mg/kg bw (mature animals) and 500 mg/kg bw (immature animals) have been shown to cause complete thymic atrophy in male and female rats. This effect was seen in hamsters only at a level of 850 mg/kg bw and in mice at levels of 1840-1880 mg/kg bw. Theobromine administration in rabbits resulted in marked changes in thymus and testes and the severity of lesions appeared to be related to the amounts of the ingested methylxanthine. Other experiments in rats also found the toxic effects of theobromine on the testis. In rats fed diets containing theobromine (daily doses, 53 or 99 mg/kg bw) on gestation days 6-19, no maternal toxicity was observed. Although no malformation occurred, slight decreases in fetal body weight were observed with the high dose, and a significant increase was seen in the frequency of skeletal variations. In rabbits, decreased fetal body weight and malformations were seen at doses of 125 or 200 mg/kg; the incidence of skeletal variations was increased with 75 mg/kg and over. Theobromine was mutagenic to Escherichia coli under conditions in which a constant growth rate and cell population density were maintained, but it was not mutagenic to Salmonella typhimurium. Theobromine induced mutations in a lower eukaryote, Euglena gracilis. Theobromine did not induce chromosomal aberrations in plants (Vicia faba). It was reported in an abstract that chromosomal aberrations were not observed in Drosophila melanogaster treated with 0.45% theobromine in feeding experiments. Chromosomal aberrations were not induced by theobromine in Chinese hamster cells.
Evaluation: There is inadequate evidence for the carcinogenicity in humans of theobromine. There are no data on the carcinogenicity of theobromine in experimental animaIs. Overall evaluation: Theobromine is not classifable as to ifs carcinogenicity to humans (Group 3).
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：可可碱
IARC Carcinogenic Agent:Theobromine
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：第3组：无法归类其对人类致癌性
IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构专著：第51卷（1991年）咖啡、茶、马黛茶、甲基黄嘌呤和甲基乙二醛
IARC Monographs:Volume 51: (1991) Coffee, Tea, Mate, Methylxanthines and Methylglyoxal
来源:International Agency for Research on Cancer (IARC)
The ratio of brain:blood theobromine concentrations decreased continuously from 0.96 at birth to 0.60 in 30-day-old rats. After 24 hr, no organ accumulation of theobromine or its metabolites could be seen in adult animals.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
可可碱在大鼠口服给药后能够被迅速吸收和分布，并且自由地在血浆和睾丸液之间达到平衡。
Theobromine is absorbed and distributed rapidly after oral administration to rats and equilibrates freely between plasma and testicular fluid.
Similar kinetic parameters were observed in male and female rabbits when theobromine was administered intravenously or orally at doses of 1 and 5 mg/kg bw, with complete gastrointestinal absorption. A reduction in the absorption rate constant was seen in rabbits when the dose was increased from 10 to 100 mg/kg bw. In spite of delayed gastrointestinal absorption at high doses, probably due to the low solubility of the compound, the absolute bioavailability of theobromine approached 100%. Labelled theobromine was almost completely absorbed after oral administration (1-6 mg/kg); the peak blood level tended to appear later with larger doses.
When theobromine was given as a single oral dose of 15-50 mg/kg bw to male dogs, peak plasma concentrations, with considerable individual variations, were observed within 3 hr. With a higher dose (150 mg/kg bw), the peak plasma concentrations were attained 14-16 hr later, showing delayed intestinal absorption. In rats, plasma protein binding was very low (8-17%) after oral administration of 1-100 mg/kg bw theobromine.
我们报告了一种远程官能化策略，该策略允许通过 Ni 催化的链从远处的烯烃位点步行来Z选择性合成（杂）芳族和脂肪族酮的甲硅烷基烯醇醚。位置选择性由链游走的方向性控制，并且与所得甲硅烷基烯醇醚的热力学偏好无关。我们的机理数据表明，在这些条件下形成Ni (I)二聚体，作为催化剂静止状态，并在与烷基溴反应后转化为 [Ni (II) -H] 作为活性链行走/功能化催化剂，最终生成稳定的 η 3 键合Ni (II) 烯醇作为关键的选择性控制中间体。
[EN] IMIDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS IMIDAZOLE UTILES COMME INHIBITEURS DE LA FAAH
申请人：MERCK & CO INC
公开号：WO2009152025A1
公开（公告）日：2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.
[EN] PYRAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS DE PYRAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人：MERCK & CO INC
公开号：WO2009151991A1
公开（公告）日：2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer disease, and Parkinson's disease
Compounds that have agonist activity at one or more of the SlP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.
[EN] OXAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS D'OXAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人：MERCK & CO INC
公开号：WO2010017079A1
公开（公告）日：2010-02-11
The present invention is directed to certain oxazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.
[EN] THIENOPYRIDONE DERIVATIVES AS AMP-ACTIVATED PROTEIN KINASE (AMPK) ACTIVATORS<br/>[FR] DÉRIVÉS DE THÉNOPYRIDONE COMME ACTIVATEURS DE LA PROTÉINE KINASE DÉPENDANTE DE L'AMP (AMPK)
申请人：MERCK PATENT GMBH
公开号：WO2009124636A1
公开（公告）日：2009-10-15
The present invention relates to compounds of formula (I) wherein R1, R2 and R3 are as defined in claim 1, including pharmaceutical compositions thereof and for their use in the treatment and/or prevention of diseases and disorders modulated by AMP agonists. The invention is also directed to intermediates and to a method of preparation of compounds of formula (I).
