Antiallergic compounds, structures

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

In the metabolism study (29, 30, 31) the following seven metabolites, 6-(1-hydroxyethyl)-3-(Ijl-tetrazol-5-yl)-chromone (1 ), 6-acetyl-3-(lH-tetrazol-5-yl)chromone (I7)j 6-(2-hydroxyethyl)-3-(lH-tetrazol-5-yl)chromone (l ), (l,2-dihydroxyethyl)-3-( Ifl-tet razo 1 -5-y 1) chromone (1 ), glucuronide (20) (the structural elucidation is described below), 5 ethylsalicylic acid ( ) and 3-carboxy-4-hydroxy-phenylacetic acid ( ), were identified in the urine of rats, guinea pigs, rabbits, dogs and monkeys. These seven compounds were synthesized and used as reference compounds to unequivocally establish the structures of the urinary metabolites, and to allow evaluation of their antiallergic activity (32). The synthetic routes are shown below (Figure 4). 

There are other compounds in the literature which seem to have a potentially useful blend of bronchodilator and antiallergy action. Compound IX, having a cromolyn-type structure, is effective in the passive cutaneous anaphylaxis test in rats as well as in the histamine aerosol test in guinea pigs (22). It has less cardiovascular effects than theophylline but causes some CNS stimulation. Compound X is a recent compound which in animals appears to be more potent than theophylline in its bronchodilator/antiallergic actions and also appears to have greater broncho-selectivity (23, 24). 

UP—106 ( ), also was active in various animal tests in which most anti-depressives are effective and it demonstrated clinical activity. The structurally similar U-17,660 ( ) was the most potent antiallergic and antianaphylactic compound in a series of 5- and 10-aminoallcylated dibenzodiazepines. ... 

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