AGENTS FOR THE TREATMENT OF OVERACTIVE DETRUSOR .6. SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF ACETAMIDE DERIVATIVES BEARING CYCLIC AMINESIN N-SUBSTITUENTS

With the aim of improving of the efficacy and decreasing the side effe cts of oxybutynin (1), N-[(tetrahydro-3- or 4-pyridyl)methyl]- N-(4-pi peridyl)-, and N-(3- or 4-piperidylalkyl)-2-hydroxyacetamides (3a-n, 4 a-g) and the related carboxamides (3o-r, 4h-k, 13', 17) were synthesiz ed and evaluated for inhibitory activity against urinary bladder rhyth mic contraction in rats and for mydriatic activity in rats. Some of th ese compounds were superior to oxybutynin in both inhibitory activity against bladder contraction and selectivity between inhibitory activit y against bladder contraction and mydriatic activity. Among them, N-[( 1,2,3,6-tetrahydro-4-pyridyl)methyl]- and -4-pyridyl)methyl]-2-hydroxy -2,2-diphenylacetamide (3e, 3f) exhibited the most potent inhibitory a ctivity against bladder contraction (ED(30)=0.005 and 0.003mg/kg i.v., respectively). Judging from the effect of 3e on detrusor contraction in vitro in guinea-pigs, it appeared that the inhibitory activity of 3 e against bladder contraction in vivo was related mainly to its inhibi tory activity against detrusor contraction in vitro induced with carba col (antimuscarine-like activity). The selectivity (20-fold) of 3e bet ween inhibitory activity against bladder contraction and mydriatic act ivity was greatly superior to that (0.48-fold) of oxybutynin. Compound 3e was synthesized by debenzylation (method E or F) of the correspond ing [[1-(4-methoxybenzyl)-tetrahydro-4-pyridyl]methyl] derivative (3k) , which was prepared by acylation (method B) of the corresponding (tet rahydro-4-pyridyl)methylamine (7k) or by reduction (method D) of the c orresponding pyridinium chloride (14k)with NaBH4.