Synthesis and properties of 2 S [2' (N,N dialkylamino)ethyl]thio 1,3,2 dioxaphosphorinone 2 oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents

Article abstract of DOI:10.1021/jm00228a600

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 x 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.