The thiazide-type1 of sulfonamide diuretics offered the first useful departure from the mercurial agents. The clinical success as well as the shortcomings of the many drugs of this class has stimulated an intensive search for improved agents. This search has extended to new chemical classes of diuretics. More recent efforts in our laboratory have been directed toward compounds that are neither mercurials nor sulfonamides. One such class of compounds that exhibits a high order of activity in laboratory animals and in man is ,ßunsaturated ketone derivatives of aryloxyacetic acids of the general structure I.

A series of 2-(aminomethyl)phenols was synthesized and tested in rats and dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration. The most active compounds belong to a subseries of 4-alkyl-6-halo derivatives of which 2, 2-(aminomethyl)-4-(1,1-dimethylethyl)-6-iodophenol, is the most active. Compound 2 also possesses significant antihypertensive activity, an adjunctive pharmacological parameter which distinguishes 2 from the other compounds prepared in this series. In addition, 2 displays both topical saluretic and antiinflammatory activities.

A number of bicyclic ring-fused analogues of 2-(aminomethyl)phenol were synthesized and tested orally in rats and intravenously in dogs for saluretic and diuretic effects. Of the 15 alicylic, aromatic, and heterocyclic ring-fused compounds tested, only 2-(aminomethyl)-4-chloro-1-naphthalenol hydrochloride (2) and 7-(aminomethyl)-6-hydroxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene hydrochloride (6) displayed a high order of activity.

Vol. 69 temperature was maintained below 45°until the exothermic reaction stopped. Excess dimethyl sulfate was decomposed by heating to 90°for two hours. The upper layer of the reaction mixture was washed with water, dried, and fractionally distilled at reduced pressure to give a 60% yield of the ether. Calculated for CnHieO: C, 80.44; H, 9.82. Found: C, 80.37; H, 9.98. Cyclohexyl Methyl Ether.17-Anisóle (750 g., 7 moles) was hydrogenated in the presence of 75 g. of nickel-onkieselguhr catalyst at 180°to give 600 g. of ether, 76%.Cyclopropyl Methyl Ether.-Glycerol was brominated, in approximately 18 mole runs, to glycerol a,7-dibromohydrin, in 60% yields, following the procedure of Braun.18 The dibroinohydrin (10.8 moles, 2347.5 g.) was treated with 1449 g. (11.5 moles) of dimethyl sulfate according to Krantz and co-workers.19 A mixture of 212 g. (2 moles)

Vol. 70 duced pressure in an atmosphere of nitrogen. Unreacted acetophenone came over at 60-70°( 3 mm.) followed by a fraction, a heavy red oil, (4 g.) boiling at 210-225°( 1.5-2 mm.). A third fraction (4 g.) boiling at 225-250°( 1.5-2 mm.) was a heavy red tar. The second fraction was dissolved in alcohol and treated with a saturated alcoholic solution of picric acid. The red picrate was recrystallized from boiling dioxane, washed with benzene and decomposed with 50% potassium hydroxide solution. The alkaline solution was extracted with benzene and the extract, after drying yielded a semi-solid which was sublimed at 185-235°( 0.2 mm.). The sublimate was recrystallized from heptane and again converted to the picrate (0.1 g.).The picrate melted at 248-253°and did not depress the melting point of a known sample of the picrate of the imidazole, I.Condensation of n-Heptaldehyde with 6-Methoxy-8amino-l,2,3,4-tetrahydroquinoline.-A mixture of 18 g. of 6-methoxy-8-amino-l,2,3,4-tetrahydroquinoline and 23 g. of pure «-heptaldehyde was heated in an atmosphere of nitrogen at 150-250°for eight hours. The residue was distilled under reduced pressure, a main fraction (22 g.) boiling at 180-220°(0.3 mm.) being collected. After redistillation, the fraction boiling at 190-210°( 0.35 mm.) (19 g.) consisting of a viscous yellow oil was treated with a saturated absolute alcoholic solution of an equal weight of picric acid. The yellow needles of the imidazole picrate were recrystallized from alcohol yielding 20 g. of material melting at 127°.