Benzotriazinones as virtual-ring mimics of o-methoxybenzamides: novel and potent 5-HT3 receptor antagonists

Abstract

the parent 17-ketones, and they also could be conjugated and excreted as water-soluble 17-conjugates. Covey et al.78 have already drawn attention to possible ways of circumventing this problem (cf. the use of D-secosteroids).

Synthesis and Structure−Activity Relationships of Potent and Orally Active 5-HT4 Receptor Antagonists: Indazole and Benzimidazolone Derivatives

“…The 1-naphthalenecarboxamide 14 and the dihydrobenzofuran derivative zatosetron ( 16 ) are two bicyclic aromatic amides which displayed only weak 5-HT 4 receptor antagonism in the concentrations tested. The tropane analogue of cisapride, 15 , has been previously characterized as a potent 5-HT 3 receptor antagonist, and we found that 15 was also a potent 5-HT 4 receptor antagonist.…”

“…While the less active indole and naphthalene systems have similar steric requirements as the indazole and benzimidazolone systems, they cannot form a similar rigidifying intramolecular hydrogen bond. The importance of analogous intramolecular hydrogen bonding interactions has been demonstrated with a series of dopamine D2 receptor antagonists and serotonin 5-HT 3 receptor antagonists. , While zatosetron can theoretically form an intramolecular hydrogen-bond, the gem -dimethyl substitution on the dihydrobenzofuran ring may provide sufficient steric bulk that the group can no longer participate in the required binding interactions with the 5-HT 4 receptor.…”

Serotonin 5-HT3 and 5-HT4 receptor antagonists

“…For some series, the 4-amino group is beneficial, though this can introduce 5-HT 4 activity. The intramolecular H-bonding "virtual ring" hypothesis was originally confirmed with a series of benzotriazinones, 86 and later extended to isoquinolone and isoquinoline-dione and quinazoline-dione derivatives (Table III). 53,87 This cyclization provided a conceptual link between the aromatics used in the ondansetronlike 5-HT 3 antagonists with the imidazole basic side chain and the esters/amides with the azacyclic side chains.…”

Synthesis and Anti‐inflammatory Activity of Some New 1,2,3‐Benzotriazine Derivatives Using 2‐(4‐Oxo‐6‐phenylbenzo[d][1,2,3]triazin‐3(4H)‐yl)acetohydrazide as a Starting Material

“…In connection with our program work on pyrimidine of expected anti‐inflammatory activity, we tried to synthesize new fused substituted benzotriazinones of expected biological activity. Numerous publications have appeared describing the synthesis of 1,2,3‐benzotriazines possessing a variety of pharmacological activities, such as anti‐inflammatory activity , cardiovascular activity , central nervous system activity , and antimicrobial activities . On the other hand, the prepared 1,2,3‐triazine compounds showed antitumor activity, partly by increasing free radicals production and partly by depletion of intracellular catalase, glutathione peroxidase, glutathione reductase, and reduced glutathione.…”