Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers

Series of alkyl esters of 6-(diethylamino)-, 6-(pyrrolidin-1-yl)-, 6-(pi- peridin-1-yl) and 6-(morpholin-4-yl)hexanoic acids and alkylamides of 6-(di- methylamino)-, 6-(piperidin-1-yl) and 6-(morpholin-4-yl)hexanoic acids, con- taining 8-12 carbon atoms in the alkyl chain, were prepared by methods of classical organic synthesis. The appropriate secondary amine was alkylated with ethyl 6-bromohexanoate to give ester of ω-substituted hexanoic acid, ex- cept of ethyl 6-(dimethylamino)hexanoate (1), which was prepared by Esch- weiler-Clarke methylation of 6-aminohexanoic acid followed by direct este- rification with ethanol. The resulted esters of ω-substituted hexanoic acids underwent direct transesterification with long chain alkanols to yield the de- sired amino esters, or they were treated with long-chain alkylamines to prepare secondary amides of the appropriate heterocyclic hexanoic acids. These pro- ducts were in vitro tested on their activity as transdermal permeation enhancers on the strips of the excised human skin with theophylline as the model per- meant. The activity was evaluated using parameter enhancement ratio (ER), defined as the ratio between the overall amount of the permeant passing through the skin with the tested enhancer and that without tested substance. Decyl 6-(pyrrolidin-1-yl)hexanoate (9) with ER = 30 showed the highest ac- tivity. The enhancing effects of the esters were generally better than those of the amides.