The Toxicity of Diaminodiphenoxyalkanes

Abstract

Representative members of a series of schistosomicidal diaminodiphenoxyalkanes were examined for their toxic effects in laboratory animals. Primary amino-derivatives were, in general, more toxic than secondary methylamino-compounds; tertiary compounds were less toxic than either. Large doses given by mouth or by injection to mice or rabbits produced intravascular haemolysis; the haemoglobin and erythrocyte counts began to increase again about a week after the dose. Mice which had been given large doses of diaminodiphenoxyalkanes developed symmetrical bald patches 2 to 3 weeks after treatment. The exposed skin appeared normal and new fur grew to cover the hairless areas in about 6 weeks. Large doses of drug delayed water diuresis in mice.Many compounds of the series caused visual impairment when given to cats. In order to obtain a quantitative assessment of retinotoxic potency, a method was devised in which the ability of the retina of the frog to resynthesize rhodopsin was measured in treated and control animals. Compounds that produced blindness in cats also inhibited rhodopsin synthesis in frogs; the most toxic compounds were primary amines. Treatment with some tertiary amines caused retinal damage if the drugs were given for long periods. Diaminodiphenoxyalkanes may perhaps interfere in some way with the biological activity of vitamin A. However, toxic effects on the hair and retina were not prevented by supplements of synthetic or natural vitamin A.

THE SCHISTOSOMICIDAL AND TOXIC EFFECTS OF SOME αω‐DI(p‐AMINOPHENOXY)ALKANES AND RELATED MONOAMINES

“…Some of the compounds studied have been similarly examined by Goodwin, Richards, and Udall (1957). Our therapeutic results with these compounds agree very well with those of Standen, although there are minor differences which are discussed below.…”

“…Among the tertiary amines we found the hydroxyethyl derivatives of the pentane and octane member to be retinotoxic, although Goodwin et al (1957) found that the corresponding heptane did not possess this property.…”

THE SCHISTOSOMICIDAL AND TOXIC EFFECTS OF SOME N‐p‐AMINOPHENOXYALKYLAMIDES

“…(unpublished observation). We therefore conclude that the amides and imides discussed here are less retinotoxic in monkeys and cats than the compounds described by Goodwin et al (1957) and Collins et al (1958).…”

“…NH2 0/ [-[Ca-2]5-NH-C O (m As in the previous investigation (Collins et al, 1958) some of these compounds were examined for retinotoxicity in cats; this is known to be a potential hazard with substances of this type (Edge, Mason, Wien, and Ashton, 1956;Ashton, 1957;Goodwin, Richards, and Udall, 1957;Sorsby and Nakajima, 1958). Although some effect was found in a few of the cats given M&B2948A or M&B3002, it was much less common among the amides and imides than among the earlier compounds.…”

“…Isomers of M&B2948A in which the amino group was ortho or meta to the ether link were inactive, as was also an analogue which had no amino group. Substitution in the amino group of M&B2948A (Table V) (Table VI) Because of this and since at the time they were thought to be free from the ocular effects associated with some related compounds (Goodwin et al, 1957;Collins et al, 1958), further toxicity and therapeutic experiments were carried out to provide information for a clinical trial.…”