STUDIES ON QUINAZOLINES .5. 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE DERIVATIVES - A NOVEL CLASS OF POTENT AND SELECTIVE ALPHA(1)-ADRENOCEPTOR ANTAGONISTS AND ANTIHYPERTENSIVE AGENTS

A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(subs tituted yl]-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones or-5(6H)-th iones, and 3-[(substituted -1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quin azoline derivatives were synthesized, as conformationally restricted a nalogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonis ts and antihypertensive agents. Most compounds containing a (substitut ed phenylpiperazinyl)methyl side chain displayed high binding affinity for alpha1-adrenoceptor with no significant activity at alpha2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-pos ition of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-posit ion. Structure-activity relationships for alpha1-adrenoceptor affinity are presented and indicate that compounds with substitution at the or tho position on the benzene ring of the phenylpiperazine side chain mo iety are more potent than those without substitution and/or substituti ons at the 3- and 4-positions. Computer-assisted superimposition of SG B-1534 and 20b showed little structural correspondence between the qui nazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and speci fic interactions of these molecular fragments with the receptor protei n appear unlikely. Antihypertensive activity was evaluated via intrave nous administration of each compound to spontaneously hypertensive rat s, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 Value for 16a against ph enylephedrine in rat aorta was much higher than that of prazosin. On t he basis of alpha1-adrenoceptor affinity/selectivity in vitro and dura tion of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.