Journal of Medicinal and Pharmaceutical Chemistry VOL. 2, No. 2 (1Ri3O)
Central Nervous System Depressants-I. 4-Alkoxy-3,5-dipropylbenzoicAcids and Derivatives.* ROBERTBRUCEMOFFETT, PATRICK H. SEAY and WILLIAM BRADLEY REID, Research Laboratories of The Upjohn Company, Kalanmoo, Michigan I n the course of testing a wide variety of compounds for possible use in mental disease it was found that 4-allyloxy-3,5-dipropylbenzoic acid (I; R = allyl) and a number of its derivatives greatly increased the sleeping time of mice given small doses of hexobarbital. These compounds also had a depressant effect on the motor activity of mice. Consequently a considerable number of derivatives and analogues were prepared. Those in which other ether substituents replace the allyloxy group, and esters, amide or nitrile functions replace the carboxyl group are included in this paper. These compounds are listed in Table I together with a few compounds (obtained from the same intermediates) in which one or both propyl groups are replaced by allyl groups (footnotes d and e ) . Table I gives the toxicities of these compounds and their pharmacological activities in the two tests mentioned above. More detailed discussion on the pharmacology is given below. Ethyl 3,5-diallyl-4-hydroxybenzoate(11) was obtained by repeated allylation and rearrangement from ethyl 4-hydroxybenzoate, as described by Claisen and Eis1eb.l This was hydrogenated to the 3,5-dipropyl ester (111)which was the starting material for most of these compounds as shown on the next page. When R=allyl, a satisfactory yield of the allyloxy ester (IV) could be obtained by refluxing a mixture of the phenolic ester and allyl bromide in acetone in the presence of solid potassium carbonate. Allyl chloride was not satisfactory. With some less
* Presented in part before the Division of Medicinal Chemistry, American Chemical Society, September 1959, abstracts p. 11-0. 179
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R. B. MOFFETT, P. H. SEAY AND W. B. REID
reactive alkyl halides better yields could be obtained by using an excess of sodium ethoxide in ethanol and a slightly larger excess
k 0
6
6
