SYNTHESIS OF α,ω-BIS-(p-METHYLAMINOPHENOXY)PENTANE AND-HEPTANE-N,N'-DISUBSTITUTED DERIVATIVES

A series of α,ω-bis-(p-aminophenoxy)-alkanes was found to show high schi- stomicidal activity in experimental animals but have toxic effects on the eyes. This precluded the clinical use of these compounds on human beings. For this reason, we prepared a series of N, N'-disubstituted derivatives of α,ω-bis-(p-methylamino- phenoxy)-pentane (Ⅰ) and -heptane (Ⅱ) for the purpose to find the most active and least toxic compound, and at the same time, to study the relationship between their chemical constitution and schistomicidal activity. R=-CH₂SO·ONa, -CH₂SO₂·ONa, -CH₂COONa, -CH₂CONH₂, -CH₂CN, -CONH₂, -COCH₃, -COOC₂H₅, -CH₂CH₂OH The sodium salts of N, N'-di-methanesulfonic acid (R=-CH₂SO₂·ONa) and N, N'-di-methanesulfinic acid (R=-CH₂SO·ONa) derivatives were prepared by the condensation of sodium formaldehyde bisulfite and sodium formaldehyde sulfo- xylate with the corresponding amines in methanolic alkaline solution respectively. N, N'-di-methanesulfonate derivatives were treated with potassium cyanide to give the corresponding N, N'-di-acetonitril (R=-CH₂CN) derivatives, from which N, N'-di-sodium acetate (R=-CH₂COONa) derivatives were obtained by alkaline hydrolysis. The latter could also be resulted from the hydrolysis of N, N'-di-acet- amide (R =-CH₂CONH₂) derivatives by using the same reagent. Ⅱ was treated with ethyl chloroformate, to give the N, N'-di-ethyl formate (R=-COOC₂H_s) derivative. By the condensation of p-(N-Carbamylmethyl-N-methyl)-aminophenol, p-(N- carbamyl-N-methyl)-aminophenol and p-(N-β-hydroxyethyl-N-methyl)-aminophenol with α,ω-di-bromoalkanes, the corresponding N, N'-di-acetamide, N, N'-di-carbamide (R=-CONH₂) and N, N'-di-β-hydroxyethyl (R=-CH₂CH₂OH) derivatives were obtained respectively. N, N'-di-carbamide derivatives could also be obtained by direct reaction of Ⅰand Ⅱ with potassium cyanate. Tests of these compounds against Schistosonaes japonicum in experimentally infected animals are still in progress and will be reported elsewhere.