Synthesis and properties of novel alkoxy- and phenoxyalkyl ethers of secondary and tertiary ethynylpiperidin-4-ols possessing unusual analgesic,anti-bacterial,anti-spasmotic,and anti-allergic properties as well as low toxicity

Methodology was developed to obtain a series of unusual alkoxy- and phenoxyalkyl ethers of secondary and tertiary ethynylpiperidin-4-ols representative examples of which were evaluated for analgesic, anti-bacterial, anti-spasmotic, and anti-allergic activity. Twenty-two new compounds were prepared and identified by elemental and spectra analyses. Etherification of 4-hydroxypiperidin-4-ols was accomplished via Williamson ether-type syntheses in dry DMF. Side reactions of the bromides used appeared to involve complex processes with DMF under a variety of conditions employed which led to modest yields of products. Since all target molecules were oils at room temperature, conversions to β-cyclodextrins were accomplished and served as vehicles for pharmacological screening. Several ethynyl-substituted agents displayed deep analgesic activity in the “tail flick” model although some alkoxy- and phenoxy ethers from secondary alcohols were less effective as analgesics (Table 1). Interestingly, LD50 values for the agents exceeded that of a number of clinical agents including Dimedrole, Klemastine, Lidocaine, No-spa, Tramal, Streptomycin, and Euphilline. Three representative examples of the agents (Table 2) exhibited moderate anti-bacterial action against Escherichia coli, Salmonella chloerae suis, Salmonella typhimurium, and Staphylococcus aureus, but did not exceed that of Streptomycin. The absence of the ethynyl ether group resulted in no anti-bacterial activity in several ethers. A few agents possessed anti-spasmotic ability, especially the ethers of 1-(2-ethoxyethyl)-4-ethynyl-4-hydroxypiperidines in various preparations (Table 3), and included the systems of acetylcholine-induced spasms, the histamine-induced spasms, and the calcium chloride-induced spasms. Two examples void of the ethynyl group were not effective as anti-spasmotic compounds. A small survey of five agents for anti-allergic properties (Table 4) revealed that two with ethynyl groups were similar in activity with Dimedrole but less than that of Klemastine in screens using acetylcholine and histamine systems. Overall, these families of piperidines possess a wide variety of important biological properties which require further exploration.