N-(4-Substituted-thiazolyl)oxamic acid derivatives, new series of potent, orally active antiallergy agents

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Abstract
A series of N-(4-substituted-thiazolyl)oxamic acid derivatives were synthesized and tested for antiallergy activity in the rat PCA [passive cutaneous anaphylaxis] model. These compounds were conveniently prepared by treatment of the appropriate acetophenone with thiourea and iodine or by reaction of the chloroacetylbenzene with thiourea to give the corresponding aminothiazoles; subsequent condensation with ethyloxalyl chloride gave the thiazolyloxamates. Many of the analogs showed a 50% inhibition at < 2 mg/kg p.o. [orally] or < 0.4 mg/kg i.v. and were significantly more potent than disodium cromoglycate, which in the rat PCA model is orally inactive and gives a 50% inhibition at 1.2 mg/kg i.v. Hydrolysis of the oxamates generally resulted in enhanced activities, while substitution of the phenyl ring with a variety of substituents (e.g., 4-F, 4-OEt and 4-NHCOCH3) did not significantly enhance the activity of the unsubstituted phenyl derivative. One of the ethanolamine salts, N-[4-(1,4-benzodioxan-6-yl)-2-thiazolyl]oxamic acid ethanolamine salt (61, PRH-836-EA), was selected for further pharmacological evaluation.