The synthesis and antiallergic activity of a series of 2-hydroxy-N-1H-tetrazol-5-ylbenzamides and isomeric N-(2-hydroxyphenyl)-1H-tetrazole-5-carboxamides is described. A relationship between structure and intravenous antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test has been established using a Hansch/Free-Wilson model and used to direct studies toward potent derivatives. The contribution of physicochemical properties to activity is discussed. One member of this series, N-(3-acetyl-5-fluoro-2-hydroxyphenyl)-1H-tetrazole-5-carboxamide (3f), which was selected for further evaluation, has an ID50 value of 0.16 mg/kg po and is 130 times more potent than disodium cromoglycate (DSCG) on intravenous administration.

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The synthesis and antiallergic activity in the rat passive cutaneous anaphylactic reaction of a series of 2-phenyl-8-azapurin-6-ones are described. Early in the investigation, a linear free-energy equation was established in which the activity was related to the size and hydrogen bonding capacity of the ortho substituent in the phenyl ring. This relationship was used to provide guidance and limits for subsequent work leading to 2-o-propoxyphenyl-8-azapurin-6-one which is 40 times more potent than disodium cromoglycate. It is suggested that good antiallergic activity in this series is associated with coplanarity of the phenyl group with the azapurin-6-one which would be favored by a high degree of hydrogen bonding.

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