1812-30-2

Quantitative study of an acid hydrolysis of bromazepam, which in acidic solution simultaneously undergoes reversible 4,5-azomethine bond cleavage and protolytic reactions, was performed (t = 25 °C). When an equilibrium is established, four species are sim

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.

The present invention relates to a benzodiazepine derivative of Formula I as a short-acting anesthetic, a pharmaceutical composition comprising the same, a kit comprising the same, a preparation method thereof, an method of anesthesia using the same and use thereof in the manufacture of an anesthetic medicament.

An improved synthesis of the anxiolytic, anticonvulsant, and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were synthesized in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of KRM-II-81, an alternative procedure was employed using the selective reducing reagent, potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA), to prepare the desired C(3)-aldehyde in the absence of N(5)-C(6) imine reduction in good yield on a 20 gram scale.

A new synthesis of 7-bromo-1,3-dihydro-3-hydroxy-5-(2'-pyridyl)-2H-1,4-benzoazepin-2-one (5) is described.Starting from bromazepam (3), C(3) acylation with lead tetraacetate/potassium iodide in acetic acid affords 4, while its mild hydrolysis according ou

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1,4-Benzodiazepin-2-ones are prepared via the reaction of a haloacetamidophenyl ketone with hexamethylenetetramine in the presence of ammonia. The 1,4-benzodiazepin-2-ones so prepared are known compounds useful as muscle relaxant and anti-convulsant agents.

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