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CCK represents cholecystokinin, which is one of the members of the gastrin/cholecystokinin family of peptide hormones. CCK acts on CCK1 and CCK2 receptors. The CCK1 receptor is present in the gallbladder and pancreas and is involved in the regulation of enzyme secretion by the pancreas, secretion of gastric acid in the stomach, intestinal motility and signaling of satiety. The CCK2 receptor is expressed in the brain and the gastric fundus (Innis and Snyder, 1980). CCK occupies the CCK2 receptor present in the brain and mediates anxiety,panic,and pain which are correlated with the stimulation of gastric acid secretion via activation of cholecystokinin. It may produce rebound hyperacidity and gastroesophageal reflux via pentagastrin mediated CCK2 receptor stimulation in peripheral tissues. If this problem persists for a long time, it may cause gastrointestinal adenocarcinoma cancer and death of the patients (Wank 1995). Therefore, significant attempts have been made to develop small molecule CCK2 receptor antagonists having beneficial antisecretory actions as well as in therapy anxiety, pain and sleep disorders (Sandvik and Waldum, 1991; Walish, 1990; Jensen, 1996; Crespi, 1990). Potent CCK2 receptor antagonists include glutamic acid derivatives such as spiroglumide (CR2194), itriglumide and CR2622; 1,4 benzodiazepines analogues: L-365260, L-369466, L-736380, L-740093, YM-022 and YF476; dipeptoids: CI-988; benzobicyclooctane analogues: JB95008, JB93182; 1,5 benzodiazepine-2,4-dione analogues: GV191869X, GR199114X and GV 150013X; 1-benzazepine-2-one analogues:CP310713 and CP212454; ureidoacetamide analogues: RP73870 RP69758 and DA-3934; quinazoline-based analogues: LY-202769; pyrazolidinone and related heterocyclic analogues: LY288513; indol-2-one analogue: AG-041R, and tetronothiodin (Berna et al. 2007; McDonald 2001). But most of these compounds have poor bioavailability and the limitation of physicochemical data, including solubility and ligand selectivity towards receptor binding (McDonald, 2001).
1,3,4-benzotriazepines were developed from the core nucleus of 1,4-BDZ CCK2 receptor antagonists and were shown to produce a higher affinity towards CCK2 receptors than the parent compound. The 1,4-BDZ CCK2 receptor antagonists are chiral with lower affinity to bind the receptor and are difficult to synthesize whereas 1,3,4-benzotriazepine analogs are achiral with higher specificity towards the CCK2 target and are relatively easy to synthesize. Therefore, McDonald and colleagues synthesized a number of 1,3,4-benzotriazepine analogs and performed an in-vivo biological activity on CCK2 receptor antagonism by inhibiting pentagastrin stimulation in isolated, lumen-perfused immature rat stomachs (McDonald et al. 2007). Further, Spencer and co-workers prepared many 1H-1,3,5-benzotriazepine-2,4(3H,5H)-diones compounds which were achiral and produced higher biological activity than 1,4-BDZ CCK2 receptor antagonists (Spencer et al. 2008). Further, anthranilic sulfonamide based CCK-2R antagonists were reported with better CCK-2R selectivity with promising pharmacokinetics andin vivo activity in inhibiting pentagastrin-stimulated gastric acidsecretion in the rat (Pippel et al., 2009a, 2009b).