Synthesis and Properties of 2-S-[2′-(N,N-Dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-Oxide and of the Corresponding Quaternary Derivatives as Potential Nontoxic Antiglaucoma Agents

A new series of cyclic organophosphorus esters, 2-S-[2′ -(N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. These compounds inhibit acetylcholinesterase (E.C. 3.1.1.7) at a bimolecular rate constant (k_i) in the range of 10³-10⁴ M^-1 min^-1. Values of the affinity {K) and phosphorylation (k) rate constants for this enzyme indicate that k is responsible for the relatively low values of k_i as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10⁶ M^-1 min^-1). The mammalian toxicity of the new compounds in terms of acute LD₅₀ values in mice is 1-3×10³ less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C₂H₅) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.