The synthesis of some 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acids and esters with potent oral and intravenous antiallergic activity against passive cutaneous anaphylaxis in the rat is described. Requirements for high activity include a free NH group in the pyrimidinone nucleus and a small to medium size ortho alkoxy or alkenyloxy group on the phenyl ring. It is suggested that in the case of the highly active compounds hydrogen bonding occurs between a nitrogen of the pyrimidine ring and the ethereal oxygen. The nature of this bonding and its possible contribution to an optimum configuration for the molecules is discussed.
Some 2-(2-alkoxyphenyl)-and 2-[2-(alkenyloxy)phenyl]-5-(l/f-tetrazol-5-yl)pyrimidin-4(3fí)-ones were prepared and found to be about 5-10 times more potent than the corresponding pyrimidine-5-carboxylic acids when tested orally against passive cutaneous anaphylaxis in the rat. Structure-activity relationships within the two series are similar. 2-(2-n-Propoxyphenyl)-5-(lH-tetrazol-5-yl)pyrimidin-4(3H)-one is in clinical trial for the prophylactic treatment of asthma.
A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).
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