1,8-Naphthyridines V. Novel N-substituted 5-amino- N, N-diethyl-9-isopropyl [1,2,4]triazolo[4,3- a] [1,8]naphthyridine-6-carboxamides, as potent anti-inflammatory and/or analgesic agents completely devoid of acute gastrolesivity

• Published in: European journal of medicinal chemistry 2005-02, Vol.40 (2), p.155-165
• Main Authors: Grossi, Giancarlo, Di Braccio, Mario, Roma, Giorgio, Ballabeni, Vigilio, Tognolini, Massimiliano, Barocelli, Elisabetta
• Format: Article
• Language: English
• Subjects: [1,2,4]Triazolo[4,3- a] [1,8]naphthyridines; Analgesic; Analgesics; Analgesics - adverse effects; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Anti-inflammatory; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Dose-Response Relationship, Drug; Fever - drug therapy; Gastrolesivity; Hypothermia - chemically induced; Medical sciences; Motor Activity - drug effects; Naphthyridines - adverse effects; Naphthyridines - chemistry; Naphthyridines - therapeutic use; Neuropharmacology; Pharmacology. Drug treatments; Rats; Stomach Ulcer - chemically induced; Stomach Ulcer - prevention & control; Structure-Activity Relationship; Structure–activity relationships
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2004.09.022

Most N, N-disubstituted 5-amino- N, N-diethyl-9-isopropyl [1,2,4]triazolo[4,3- a] [1,8]naphthyridine-6-carboxamides 9 (compounds 9a, c– i) and the N-monosubstituted one 8c were obtained by treating with excess amine the corresponding 5-chloroderivative 7a, which was in turn prepared by cyclocondensation of the 2,4-dichloro- N, N-diethyl-1,8-naphthyridine-3-carboxamide ( 4a) with isobutyrohydrazide. Compounds 8a, b and 9b, j– m were obtained according with the methods shown in Scheme 1. The above now synthesized compounds, along with the previously described 8d and 8e, were tested for their anti-inflammatory, analgesic and antipyretic properties, and most compounds also for their effect on spontaneous mice locomotor activity and their acute gastrolesivity in rats. Several compounds showed potent anti-inflammatory and/or analgesic activities, and all the compounds tested proved to be completely lacking in acute gastrolesivity. In many cases compounds 8 and 9 produced hypothermic effect, usually at high doses. On the whole, the N-monosubstituted 5-aminoderivatives 8 appeared to be more potent anti-inflammatory agents than the corresponding N, N-disubstituted 9, whereas these latter compounds exhibited higher analgesic activity.