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

Eur J Med Chem. 2005 Feb;40(2):155-65. doi: 10.1016/j.ejmech.2004.09.022.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / adverse effects
  • Analgesics / chemistry
  • Analgesics / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Dose-Response Relationship, Drug
  • Fever / drug therapy
  • Hypothermia / chemically induced
  • Motor Activity / drug effects
  • Naphthyridines / adverse effects
  • Naphthyridines / chemistry
  • Naphthyridines / therapeutic use*
  • Rats
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / prevention & control*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Naphthyridines