| A new approach to prostaglandin (PG) antagonist development is described. The rationale was based upon a retrospective analysis of the construction of cholinergic blocking agents and H-1 antihistamines. Synthesis and pharmacological activity of 2-alkyl-5-benzyloxy-1-oxo-2-indanpropionic acids and 2-alkyl-5-benzyloxy-1-hydroxy-2-indanpropionic acids were included.;5-Benzyloxy-1-indanone served as starting material for preparation of 5-benzyloxy-1-oxo-2,2-indandipropionic acid. Anion formation followed by Michael addition to methyl acrylate and alkaline hydrolysis afforded the dicarboxylic acid.;Sodium borohydride (NaBH(,4)) reduction of the ketoacids and one of the esters was included. Stereoselective reduction of the keto ester with NaBH(,4)/MeOH vs. reduction of the keto acids using NaBH(,4)/NaOH/H(,2)O is discussed.;A brief survey on nomenclature, biochemistry and selected pharmacological aspects of PGs are included. Moreover, compounds which selectively antagonize the effects of PGs are discussed. PG antagonists discussed are categorized as 7-oxo-compounds related to PGs, dibenzoxazepine hydrazides, polyphloretin phosphate and certain miscellaneous structures.;The synthetic outline was commenced by the preparation of 5-benzyloxy-1-indanone from 3-hydroxyphenylpropionic acid by cyclization (AlCl(,3)/NaCl/180-200(DEGREES)C) followed by benzylation. Condensation of 5-benzyloxy-1-indanone with dimethylcarbonate in the presence of NaH afforded the carbomethoxy intermediate. Alkylation of the carbomethoxy compound was carried out using NaH/n-alkyl bromide/THF/HMPA. Hydrolysis and subsequent decarboxylation (HCl/HOAc/H(,2)O) followed by Michael addition (t-BuOH, t-BuOK and methyl acrylate) yielded methyl esters which upon alkaline hydrolysis afforded the target keto acids.;Preliminary pharmacological acessment of selected keto and hydroxy acids was performed on the isolated mouse uterus stimulated with PGF(,2(alpha)). The 2-butyl-1-hydroxy analogue resulted in a 20% inhibition of the response to PGF(,2(alpha)) at 10('-4) M concentration. 2-Ethyl-, 2-n-propyl- and 2-n-butyl keto acids were found to produce 50% inhibition at about 10('-4) M. The results are discussed in perspective to data obtained in the more potent dibenzyloxy series. |
