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

Abstract

An account is given of the results obtained with a number of p‐aminopbenoxyalkanes which were examined for activity against Schistosoma mansoni in mice and for the presence of retinotoxicity in cats. The first compound to be found active, 1: 5‐di(p‐aminophenoxy)‐pentane dihydrochloride (M & B 968A), was modified in a variety of ways in an attempt to increase its activity and to eliminate its ocular effects. It was found that a p‐aminophenoxyalkyl group was common to all the active compounds, but that the rest of the molecule could be any of several different groups, including alkoxy, phenoxy, and phenyl groups, without diminishing the activity. Although at least one p‐aminophenoxyalkyl group was essential for schistosomicidal activity, ocular toxicity was also shown by a p‐aminophenylalkyl derivative in which the ether linkage was absent.

The Antischistosomal and Retinotoxic Effects of Some Nuclear Substituted Aminophenoxyalkanes

“…No retinotoxic symptoms were observed. (Table 2) 2-Methoxy nuclear substitution to give M&B 4819 and 4717 decreased the toxicity of the inactive parent compounds (Collins et al, 1958, Table 7) and some activity became apparent. It had no effect on the activity or general toxicity of the pentane homologue, (1-p-aminophenoxy-5-phenylpentane) (Collins et al, 1958, Table 7).…”

“…Some of the compounds were administered to cats to see if they produced vomiting or the initial weakening of the light and blink reflexes which accompany visual impairment, as described by Collins et al (1958).…”

“…The methods used have been fully described by Hill (1956) andCollins et al (1958). Groups of 12 to 15 mice infected with adult S. mansoni were dosed by mouth once daily for four days.…”

“…Most of the nuclear unsubstituted parent compounds (R'= H) were therapeutically active in the last three series but not in the series of simple alkyl derivatives, where the methane, ethane, hexane and decane homologues were inactive (Collins et al, 1958, Table 7), although the octane member (III) has since been found to possess slight activity (acute oral LD50-1.2 g/kg; 90% curative at 0.4 g/kg/day, inactive at 0.1 g/kg/day). This is the simplest aminophenoxyalkane examined so far to exhibit antischistosomal properties.…”

“…The search was therefore continued for a compound completely devoid of retinal toxicity in cats and more active than M&B 2948A against S. mansoni in mice. Collins et al (1958) found that insertion of methoxy groups into 1,5-di-(p-aminophenoxy) pentane to give 1,5-di-(4-amino-2-methoxyphenoxy)pentane (described independently by Standen & Walls, 1956) eliminated, or at least reduced the incidence of, the ocular effects of the parent compound which were described by Edge, Mason, Wien & Ashton (1956); Ashton (1957) and Sorsby & Nakajima (1958). Although the antischistosomal activity was also greatly reduced this lead was pursued and many monoamines of the general formula (II) were prepared (Collins & Davis, 1961, 1966a.…”