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.
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.
Grossi
Giancarlo
G
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy.
Di Braccio
Mario
M
Roma
Giorgio
G
Ballabeni
Vigilio
V
Tognolini
Massimiliano
M
Barocelli
Elisabetta
E
D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000188:drug therapy; D007035:Hypothermia / Q000139:chemically induced; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009287:Naphthyridines