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.

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.

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.

SUMMARYBuspirone 1 is a novel, clinically effective anxiolytic agent which is devoid of the sedative, anticonvulsant or muscle relaxant properties normally associated with the benzodiazepines. Buspirone labelled with both radioactive (14C) and stable (15N) isotopes was required in order to investigate the metabolism of the compound. The synthesis of both labelled compounds beginning with either urea -14C or urea -15N2 is described.

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