RESUMEN
A plasma assay method for trazodone and a 2H4 analogue is described which uses gas chromatography--electron-impact selected-ion monitoring mass spectrometry. Etoperidone is used as an internal standard. The analytes are extracted from basic medium into n-butyl chloride, then back extracted into aqueous 0.1 M hydrochloric acid. The aqueous layer is made basic and re-extracted with n-butyl chloride. The solvent is reduced under nitrogen at 35 degrees C and the residue is redissolved in toluene for gas chromatographic--mass spectrometric analysis. The ions monitored are m/z 231, 235, and 225 for trazodone, [2H4] trazodone and etoperidone, respectively. Quantitation is in the range 40-1000 ng/ml with acceptable precision and accuracy. The method is suitable for biopharmaceutical studies.
Asunto(s)
Piperazinas/sangre , Trazodona/sangre , Disponibilidad Biológica , Cromatografía de Gases y Espectrometría de Masas , Humanos , Cinética , Masculino , Estándares de Referencia , Equivalencia Terapéutica , Trazodona/análogos & derivadosRESUMEN
A short series of the title compounds was prepared and evaluated for both antiallergic and bronchodilator activity. Members of the series exhibit good oral activity in the rat PCA test, the most potent being the parent compound, 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzothiazol-4-one, and its 8-chloro derivative. The latter two compounds are considerably more potent than either disodium chromoglycate or theophylline as antiallergic agents and also show significant bronchodilator activity.
Asunto(s)
Hipersensibilidad/tratamiento farmacológico , Tiazoles/síntesis química , Animales , Broncodilatadores/síntesis química , Fenómenos Químicos , Química , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Ratas , Tiazoles/farmacología , Difracción de Rayos XRESUMEN
The synthesis of a series of substituted 6,7-dihydroimidazo[1,2-a]purin-9(4H)-ones is described. Several members of the series exhibit enhanced antiallergic and bronchodilator activity and reduced side effects as compared to theophylline. Structure-activity relationships and metabolic considerations are discussed for the series. Analogues substituted with a 4-(4-chlorobenzyl) moiety, such as 33 and 40, shown an optimal balance of antiallergic and bronchodilator activity and are of particular interest. Compound 33 is significantly more potent than theophylline against both metacholine- and antigen-induced bronchospasms, does not affect spontaneous motor activity, and shows minimal cardiovascular effects in the rat.
Asunto(s)
Imidazoles/síntesis química , Purinonas/síntesis química , Animales , Espasmo Bronquial/inducido químicamente , Broncodilatadores/síntesis química , Fenómenos Químicos , Química , Femenino , Cobayas , Liberación de Histamina/efectos de los fármacos , Imidazoles/farmacología , Técnicas In Vitro , Pulmón/enzimología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Purinonas/farmacología , Ratas , Relación Estructura-Actividad , Tráquea/efectos de los fármacosRESUMEN
A series of novel 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid derivatives has been prepared and tested for antiallergenic activity. Members of the series, including both carboxylic acid salts and esters, have been found to exhibit oral activity in the rat passive cutaneous anaphylaxis (PCA) test. Activity is optimized by H or CH3 substitution at the 5 position and lower alkyl groups at the 6 position. Ethyl 6-ethyl-3,4-dihydro-4-oxothieno-[2,3-d]pyrimidine-2-carboxylate and 3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid dipotassium salt were the most potent of the esters and salts, respectively. Such compounds have been shown to have a duration of action of up to 4 h in the PCA test and to inhibit both histamine release from rat peritoneal mast cells in vitro and allergen-induced bronchospasm in the rat lung.