Synthesis and psychotropic activity of triazoles and tetrazoles condensed with spyro(benzo[h]quinazoline-5,1′-cycloalkanes)

Abstract

Atypical anxiolytics (derivatives of triazolodiazepine and -quinazoline) recently came into use in medical practice, extending the class of tranquilizers. However, these drugs, like all benzodiazepine tranquilizers, exhibit certain side effects such as myorelaxation, negative action upon the cognitive function and memory, sleep perturbation, development of drug dependence, and teratogenic manifestations [I -6]. At the same time, anxiolytic doses of buspirone, which is an atypical tranquilizer of the nonbenzodiazepine series, lead to virtually no undesired side effects typical of benzodiazepines. However, this drug is toxic and insufficiently active as a tranquilizer [1, 2, 4]. The purpose of this work was to synthesize triazolo and tetrazolo derivatives of benzo[h]quinazoline, spyro-conjugated to carbocycles (cyclopentane or cyclohexane), and study their neurotropic properties using a new method developed for the assessment of tranquilizer activity. We have synthesized 2-substituted 4-hydrazino-5,6-dihydrospyro(benzo[h]quinazoline-5, l'-cycloalcanes) (Ila - Ill ) by condensation of the corresponding 4-chloro derivatives (la- If) with hydrazine hydrate. Note that the reaction could be performed only using a 99- 100% hydrazine hydrate, whereas a higher water content leads to hydrolysis of chlorine-containing compounds (la-If) with the formation of4-oxo derivatives of benzo[h]quinazoline. The IR spectra of compounds lla-IIf show absorption bands attributed to hydrazine groups in the region of 31503350 cm - i. The tH NMR spectra of these compounds contain signals due to protons of the hydrazine group, represented by broad lines with a 3H intensity in the region of 3.5 - 6.0 ppm. The condensation of hydrazines lla-llf with an orthoformic acid ether leads to the formation of 2-substituted 7,8dihydrospyro(benzo[h]triazolo[4, 3-c]quinazoline-7, l'-cycl oalkanes) (llla-lllf). Reactions of the same hydrazides t A. L Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Armenian Republic, Erevan, Armenia. with an aqueous solution of sodium nitrite under acidic conditions yields 2-substituted 7,8-dihydrospyro(benzo[h]tetrazolo[4, 5-c]quinazoline-7, l'-cycloalkanes) (IVa - IVf).