Data regarding the metabolism of butabarbital in humans are not readily available. In dogs, butabarbital undergoes metabolism to a final glucuronide metabolite.
Butabarbital is metabolized in the liver by oxidation of the sec-butyl substituent at C5 to form 5-ethyl-5-(1-methyl-2-carboxyethyl) barbituric acid, an inactive metabolite, which is then excreted in the urine.
Barbiturates are transformed by 4 routes: 1. Oxidation of radical at C5. This is by far most important pathway ... Products are ... polar alcohols, ketones, phenols, or carboxylic acids ... /Barbiturates/
With the exception of the less lipid-soluble aprobarbital and phenobarbital, nearly complete metabolism and/or conjugation of barbiturates in the liver precedes their renal excretion. The oxidation of radicals at C5 is the most important biotransformation responsible for termination of biological activity. Oxidation results in the formation of alcohols, kentones, phenols, or carboxylic acids, which may appear in the urine as such or as glucuronic acid conjugates. In some instances (eg, phenobarbital), N-glucosylation is an important metabolic pathway. Other biotransformations include N-hydroxylation, desulfuration of thiobarbiturates to oxybarbiturates, opening of the barbituric acid ring, and N-dealkylation of N-alkylbarbiturates to active metabolites (eg, mephobarbital to phenobarbital).
Butabarbital binds at a distinct binding site associated with a Cl<sup>-</sup> ionopore at the GABA<sub>A</sub> receptor, increasing the duration of time for which the Cl<sup>-</sup> ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. All of these effects are associated with marked decreases in GABA-sensitive neuronal calcium conductance (gCa). The net result of barbiturate action is acute potentiation of inhibitory GABAergic tone. Barbiturates also act through potent (if less well characterized) and direct inhibition of excitatory AMPA-type glutamate receptors, resulting in a profound suppression of glutamatergic neurotransmission.
Barbiturates such as butabarbital are predominantly eliminated in the urine. In dogs, 3-5% of the dose is eliminated in the urine as the unchanged parent compound.
Butabarbital sodium tablets and butabarbital sodium oral solution, is the sodium salt of a weak acid. Barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver, and kidneys. Barbiturates are bound to plasma and tissue proteins. The rate of absorption is increased if it is ingested as a dilute solution or taken on an empty stomach.
Butabarbital sodium is absorbed from the GI tract. Peak plasma concentrations are achieved within 3-4 hours following oral administration of the drug. Plasma butabarbital concentrations of 2-3 ug/mL produce sedation, and plasma concentrations of 25 ug/mL produce sleep in most patients. Plasma butabarbital concentrations of greater than 30 ug/mL may produce coma, and those in excess of 50 ug/mL are potentially lethal.
Fluid & tissue specimens collected from 30 subjects at autopsy were assayed for amylobarbitone (amobarbital), butobarbitone (butethal), pentobarbitone (pentobarbital), quinalbarbitone (secobarbital) and the corresponding hydroxylated metabolites by gas liquid chromatography. Where one barbiturate was ingested, an inverse relationship between lipid solubility of the drug and the distribution in fluids and tissues was observed. In most cases the liver, and in the remainder the spleen, contained the highest concn of barbiturate. Bile concn were often in excess of those in the corresponding liver. The metabolites of the 4 sedative barbiturates were usually present in lower amounts than the parent drugs in the fluids and tissues of most subjects but urine often contained much higher concn of metabolites, sometimes exceeding that of the parent drug in the liver. Admin of 2 or more barbiturates together did not appear to affect the distribution and metabolism of the individual drugs.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
[EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
申请人：MERCK SHARP & DOHME
公开号：WO2011149801A1
公开（公告）日：2011-12-01
The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
