A NEW SERIES OF 6-CHLORO-2,3-DIHYDRO-4(1H)-QUINAZOLINONE DERIVATIVES AS ANTIEMETIC AND GASTROINTESTINAL MOTILITY ENHANCING AGENTS

New 6-chloro-2,3-dihydro-4(1H)-quinazolinones (24-27) have been synthe sized and evaluated for gastrointestinal prokinetic and antiemetic act ivities in comparison with structurally related benzamides (21-22) and 6-chloro-2,3-dihydro-(1H)-1,3-benzoxazolin-4-ones (28). Their key pha rmacophoric element has been defined as a 6-membered ring replacing th e ''virtual ring'' arising from the hydrogen bond between amidic nitro gen and methoxy group in metoclopramide (1) and structurally related b enzamides (2-10). Variations of heterocycle linking groups have pointe d out that a lipophilic aromatic group in position 1 plays an importan t role for pharmacological properties, while the steric restriction an d the modification of the side-chain nucleophilicity are uneffective b oth for the in vitro and in vivo activity. Some of these compounds ver y effectively enhance gut peristaltic activity in vitro (rabbit jejunu m), increase gastric emptying of a semisolid meal (in rats), and inhib it cisplatin-induced emesis (in pigeons), favourably comparing with ci sapride.